Osteoporos Int (2002) Suppl 1:S1–160 ß 2002 International Osteoporosis Foundation and National Osteoporosis Foundation

Osteoporosis International

PLENARY LECTURE ABSTRACTS PL1. WHY IS OSTEOPOROSIS COMPLICATED BY FRACTURES? Ego Seeman, Austin and Repatriation Medical Centre, University of Melbourne, Melbourne, Australia The bone is a lever needed for movement and speed, with properties that meet the contradictory needs of strength yet lightness, and stiffness yet flexibility by stiffening the rope-like triple helical fibres of type 1 collagen with mineral crystals. Stiffness confers resistance to bending for propulsion. Excessive stiffness produces glass-like brittleness; cracks occur with slight deformation. The collagen weave confers flexibility. If energy is imparted to bone by impact loading or muscle contraction and no movement occurs, flexibility allows the energy to be stored in reversible (elastic) deformation. When exceeded, bone can store more energy but at the price of microfracture and irreversible (plastic) deformation. If the imparted energy exceeds the elastic and plastic limits of deformation, fracture occurs. Bone material is fashioned into long bones with a medullary canal and cortical mass placed distant from the central long axis conferring greater resistance to bending. In the axial skeleton, the vertebral bodies have a thin cortical shell and a trabecular spongiosa or cancellous network of plates and sheets that absorb energy during compressive loading like a spring and then returning to their original height. These features are fully expressed at the completion of linear growth. Bones break because advancing age is accompanied by degradation of the material and structural properties responsible for resistance to structural failure. Two cellular mechanisms available to construct and reconstruct the skeleton, bone modelling and remodelling, fail to maintain and structural properties, in a host increasingly predisposed to falls. Remodelling replaces old with new bone and repairs material fatigue and micro-fractures. During ageing less bone is formed than removed in the basic multicellular units (BMUs) producing a negative bone balance. Whether this is an ‘appropriate’ response to reduced loading, or an ‘abnormality’ produced by reduced osteoblast lifespan, increased osteoclast lifespan, or abnormal osteocyte mechanical signalling, is uncertain, but the effect is the same – bone loss and structural damage. Trabecular thinning removes horizontal trabeculae, increases loading of the remaining vertical trabeculae causing failure in buckling and vertebral collapse in compression. Endocortical resorption thins long bone cortices and increases cortical porosity predisposing to buckling. The increased remodeling due to hypogonadism and secondary hyperparathyroidism produces more BMUs, each with a more negative bone balance. More bone is removed more rapidly from a bone already diminished in mass and disrupted in architecture. Mineral distribution of the remaining bone becomes uneven; older, more mineralized interstitial bone distant from remodeling may become susceptible to micro-damage and less repairable. Bone modelling effectively changes bone size and shape in response to loading during growth, but may be impaired during

ageing. Periosteal apposition is an adaptive response to increased strains caused by relatively increased loads at this surface produced by endosteal bone loss and trabecular disruption. Periosteal apposition maintains apparent volumetric density, reduces compressive stress by distributing loads on a larger area, and increases bone’s bending strength. Periosteal apposition during ageing may be reduced due to abnormalities in periosteal osteoblast function, osteocyte signaling or deficiency. Women sustain fractures more often than men because of less periosteal apposition, greater disruption of trabecular architecture and thinner more porous cortices (due to higher remodelling intensity, and perhaps a more negative BMU imbalance), more micro-damage, and perhaps more osteocytic apoptosis. Women and men who sustain fractures may differ from women and men who do not for similar reasons. Fractures in Caucasians and Asians may be more common than in African Americans for similar reasons. There is progress. We have identified and quantified, in vitro, and in animal studies, the material properties of bone, the structural properties of the bone, the three major cell types participating in the construction, maintanence and reconstruction of these materials and structures, and many local and systemic regulators that determine the number, lifespan and activity of these cells. Advances are needed to (i) link these causally to bone fragility in vivo, (ii) develop non-invasive methods to identify individuals with these, and (iii) develop specific treatments to correct the morphological abnormality. Densitometry has met some of the needs but 50% of fractures occur in persons without ‘osteoporosis’ and many women with osteoporosis do not sustain a fracture. Whether in vivo measurements of the material and structure determinants of bone strength can improve the sensitivity and specificity of available risk assessments remains to be seen.

PL2. CONTRIBUTION OF BONE BIOLOGY TO THE DEVELOPMENT OF NEW THERAPIES IN OSTEOPOROSIS Roland Baron, Yale University School of Medicine, New Haven, CT, USA and Aventis Pharmaceuticals, Romainville, France Many of the most important recent advances in the biology of bone cells and in the understanding of their role in the regulation of bone remodeling have lead to innovative approaches to the treatment of osteoporosis and other skeletal disorders, giving us an opportunity to get a glimpse at what the drugs of the future maybe for skeletal diseases. These drug discovery approaches can be classified in three categories: 1) Pathophysiological approaches, attempting to correct the mechanisms that lead to altered bone remodeling, 2) Anti-resorptives, and 3) Anabolics. The pathophysiology of osteoporosis being centrally related to sex hormones (estrogen in women and possibly androgens in elderly men), three major findings in this field have been the discovery of a second receptor for estradiol (ER beta, in addition to the known ER alpha), the reports that some of the actions of the ERs may affect bone cell

S2 apoptosis through non-genomic mechanisms and finally the validation of the concept of selective modulators of the estrogen receptor(s), affecting differentially the various target organs of estradiol (SERMs), raising the possibility to selectively target bone and to develop similar compounds for the androgen receptor. In the field of antiresorptives and beyond the currently available compounds (bisphosphonates, calcitonin), several major findings in bone biology have lead to programs in drug discovery. The main targets currently used in these programs are : the vitronectin receptor (osteoclast adhesion), cathepsin K, an extracellular enzyme involved in the degradation of collagen, cSrc, an intracellular tyrosine kinase, the vacuolar proton pump, involved in acidification, and most importantly the pathway of RANK Ligand and its receptor RANK in osteoclast differentiation. In addition, the mevalonate pathway has been demonstrated to be the target for bisphosphonate action, leading to a new drug discovery approach. But the therapies of the future will certainly also involve a new class of compounds, bone anabolics. In this very active area of research, both in academia and in industry, several breakthroughs have recently been made. First and foremost, the anabolic potential of PTH when given intermittently has now been firmly established in human studies, validating the concept that anabolism is possible in osteoporosis treatment. An alternative to the use of PTH being the regulation of the endogenous synthesis and secretion of this hormone, one approach is targeting the calcium receptors in the parathyroid gland, antagonising the binding of Ca and thereby increasing PTH levels (calcilytics). Other major findings in this area are the identification of Cbfa-1, a transcription factor necessary for osteoblast differentiation, of the potential role of central hypothalamic regulation by leptin of bone formation, and the recent identification of LRP5, a receptor involved in bone mass regulation in humans. Finally, most companies are currently engaged in genetic, genomic and gene expression profiling studies to identify novel genes involved in bone formation. Thus bone biology contributes significantly to the development of new therapies for osteoporosis and new and more efficient drugs should be forthcoming in the next decade.

PL3. QUALITY OF LIFE IN WOMEN WITH OSTEOPOROSIS Elizabeth Barrett-Connor and Susan Brenneman, UCSD, La Jolla Ca, 92093-0607; Merck & Co., Inc, West Point, PA 19486-0004, USA Osteoporotic fractures can cause site-specific declines in physical capabilities, poor body image, poor perceived health, depression, and fear of falling. Vertebral fractures with or without pain can impair physical activity, pulmonary function, and selfimage. Functional capacity and independence are most dramatically changed after hip fracture, which results in loss of independence or death in more than half of affected women. The preponderance of quality of life studies have been conducted in elderly women where comorbidity confounds the consequences of fracture. Unpublished data from the NORA study of 95,489 community-dwelling postmenopausal women, mean age 64, will be used to evaluate quality of life in younger women who have little co-morbidity. Approximately one in 10 of these NORA women reported a prior fracture of the hip, spine, rib, or distal forearm that had occurred after age 45. Quality of life, assessed by the SF-12 Health Surveys (Medical Outcomes Trust & the Health Assessment Lab) will be compared in women with and without osteoporosis (as defined by the WHO diagnostic criteria of T-score 4–2.5) and with and without a fracture history, stratified by age (565: 65+). Scores will be compared before and after adjusting for confounders. None of the NORA women had been told they had osteoporosis, so quality of life will not have been influenced by knowledge of the diagnosis.

Abstracts PL4. TRANSGENIC MODELS TO UNDERSTAND OSTEOPOROSIS Gerard Karsenty, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA Mouse genetics, defined here as a group of techniques aimed at altering gene expression and/or function in vivo, has invaded every field of biology, including bone biology. In doing so it has revolutionized thinking in each field it has entered. There are several reasons that fully justify such prominence. The first reason to explain the popularity of mouse genetics comes from the versatility of the technology. Indeed, it is now possible to delete a gene, decrease or increase its expression, or express it ectopically. The fact that these different manipulations can be done in vivo, during development or after birth, and in the cell type of choice, allows two equally important questions regarding any gene product to be addressed: what it normally does and what it can do. This latter aspect may be of greater interest from a therapeutic perspective. Moreover, the ability to delete several contiguous genes or an entire cell population expands considerably the scope of the information that can be obtained and analyzed. The second reason stems from the issues that are at stake in bone biology. Little is known about the mechanisms controlling skeleton during development. Mouse genetics has shown that it is, along with chick embryology, the most powerful and elegant approach to address these questions. However, what is specific to bone and only very few other mechanisms controlling the function of its constituent cells: the osteoblasts and, to a lesser degree, the osteoclasts. That such questions of physiology and pathophysiology can be addressed successfully by mouse genetics has become increasingly evident over time. Although there are physiologic differences between mice and humans, the similarities for every organ far outnumber these differences. This has now been amply demonstrated for most organ physiology including bone. A final reason explaining the importance of mouse genetics as a tool comes from its track record. The functions of most cloned genes have now been studied in mice. In a few instances these studies have generated such clear-cut and unexpected results that they have substantially altered the way we think. Recent developments that illustrate the fundamental changes in conception that mouse genetics has brought to bone biology include the discovery of osteoprotegerin (OPG) and its ligand (RANKL, receptor activator of NF-kB ligand/ODF, osteoclast differentiation factor), the phenotype of vitamin D receptor (VDR)-deficient mice, the dual functions of Cbfa1 during development and postnatally, the independence of bone resorption from bone formation during bone remodeling, and the regulation of osteoblast function by the hypothalamus.

PL5. GENETICS OF COMPLEX DISEASES: THE BAD AND THE GOOD GENES Stuart H Ralston. Bone Research Group, Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, UK Osteoporosis is a common disease with a strong genetic component. Twin and family studies have shown that genetic factors play an important role in regulating bone mineral density, ultrasound properties of bone, skeletal geometry, and bone turnover and well as contributing to the pathogenesis of osteoporotic fracture itself. Bone mineral density and other osteoporosis-related phenotypes are usually determined by the effects of several genes, but occasionally, osteoporosis or unusually high bone mass may occur as the result of mutations in a single gene. Examples are the osteoporosis-pseudoglioma syndrome, known to be due to inactivating mutations in the LRP5 gene and a high bone mass syndrome, caused by activating mutations in LRP-5. In keeping with the hypothesis that polygenic influences determine BMD in the general population, linkage studies in man have so far defined several loci on chromosomes

Abstracts 1p36, 1q21, 5q33-35, and 6p11-12 that show definite or probable linkage to bone mineral density. So far, the causative genes that influence BMD in these loci remain to be defined. Linkage studies in experimental animals have also identified several loci, which regulate BMD and bone structure, and a future challenge will be to investigate the relevance of these in humans. Most work in the field of osteoporosis genetics has focused on candidate gene studies in populations, and case-control studies. Amongst the most widely studied candidate genes are the vitamin D receptor (VDR), the Collagen type I alpha 1 gene (COLIA1) and the oestrogen receptor gene (ER). Polymorphisms of VDR have been associated with bone mass in several studies and there is evidence to suggest that these effects may be modified by dietary calcium and vitamin D intake. An Sp1 binding site polymorphism has also been identified in the COLIA1 gene, which predicts osteoporotic fractures independently of bone mass, and there is functional evidence to suggest that this polymorphism influences collagen gene regulation and bone quality. Polymorphisms of the ER gene have been associated with BMD in several studies, although the effects of ER on fracture have been less widely investigated. An important defect in most candidate gene studies is small sample size and this has led to conflicting results in different populations. Some researchers are exploring the use of meta-analysis as a means of overcoming this problem and trying to gain an estimate of effect size for different polymorphisms in relation to relevant endpoints such as BMD and fracture. From a clinical standpoint, advances in knowledge about the genetic basis of osteoporosis are important since they offer the prospect of developing new markers for assessment of fracture risk and the identification of novel molecular targets for the design of new treatments that might be used to prevent osteoporosis.

S3 rate decreased and chronic pain disappeared, resulting in improved quality of life. No adverse effects on growth, bone modeling or fracture repair have been observed. At the tissue level, the impact of the treatment is most evident in cortical bone which thickens considerably, with lesser gain in cancellous bone. The cortical effect results from decreased endocortical resorption in the face of maintained periosteal apposition. The rate of the latter being age dependent, the younger the patient, the more striking the effect. Pamidronate can be safely administered to two-week old babies with definite gain in terms of pain control, mobility and fracture incidence. Whether similar results can be obtained with daily/weekly oral alendronate administration is currently under evaluation. Overall reduction of bone turnover may have, on the long term, a significant impact on bone remodeling. This may lead to alteration in bone tissue quality that will require careful evaluation. Other potential therapeutic avenues include the use of anabolic agents like growth hormone, bone marrow transplantation leading to engraftment of mesenchymal cells giving rise to competent osteoblasts, and various approaches of somatic cell therapy (in animal models). At this point none of these attempts have matched the results obtained with bisphosphonate therapy. The encouraging results obtained in OI make it reasonable now to consider extending the indication to other osteoporotic conditions in children, such as long-term use of steroids, prolonged immobilization, endocrine disorders, etc. In all these instances, the use of bisphosphonates, although not a cure, will likely improve the patients’ clinical condition to an extent unforeseen only a few years ago.

PL7. DECISION MAKING PROCESS IN THE MANAGEMENT OF OSTEOPOROSIS: CAN THE SAME TOOLS BE USED WORLDWIDE PL6. BONE FRAGILITY IN CHILDREN: OPPORTUNITIES OF THERAPY Francis H. Glorieux, Shriners Hospital for Children and McGill University, Montreal, Quebec, Canada With senescence, bone will lose mass and resistance often resulting in fractures, decreased mobility and chronic pain. Such a picture may, at times, develop in a neonate or a growing child. It will then severely compromise growth and development, and restrict ambulation, further aggravating bone loss. The paradigm for such a severe osteoporosis in children is represented by Osteogenesis Imperfecta (OI) or brittle bone disease. It is a syndrome with a wide spectrum of clinical expression (from lethal to minor forms), in most cases associated with mutations in the genes encoding type I collagen, the major component of bone matrix. There is no evident correlation between mutations and severity of phenotype, and collagen mutations are not found in about 25% of the severe cases. Thus other factors (genes) are at play that have yet to be identified. In OI, osteoblasts produce an abnormal matrix that does not respond to mechanical loads. In reaction, the osteoblast population is increased, and osteoclast activity is raised leading to the characteristic high turnover rate. Until recently, treatment had focused on fracture management, surgical corrections of deformities, and supportive rehabilitation programs. All medical therapies, other than those aiming at symptomatic pain relief have been ineffective in altering the course of the disease. They include fluoride, magnesium oxide, calcitonin and anabolic steroids. Compromised bone acquisition in young OI patients is further compounded by secondary bone loss induced by immobilization. In adults, bisphosphonates decrease turnover and reduce bone loss. Such a therapy (intermittent intravenous pamidronate) has been recently extended to children with severe OI, with remarkable results. Bone mineral density and physical activity greatly increased, fracture

L. Joseph Melton III, Mayo Clinic, Rochester, MN USA Huge increases in the elderly population worldwide will cause a dramatic rise in osteoporotic fractures, with hip fractures alone increasing from 1.7 to 6.3 million annually between 1990 and 2050. However, similar increases will be seen for other agerelated diseases (e.g., cancer cases increasing from 10.1 to 23.8 million), and these will be superimposed on other major public health problems (e.g., malaria, alcoholism). Thus, osteoporosis prophylaxis will have to compete for medical resources, and other urgent health care needs will have priority in some regions. Other societies will focus control efforts on broad public health measures. Public health interventions are culture-sensitive and vary with the target population but do not involve individual risk assessment. Clinical decision-making will be limited to treating patients with fractures (who fail public health measures) or, in some wealthy countries, patients with low bone mass identified by targeted case-finding. The approach to casefinding will vary with the resources available, although unselective (mass) screening by densitometry is largely unaffordable anywhere. Key to clinical decision-making for individual patients will be an assessment of near-term (5-10 years) absolute fracture risk, and prediction tools are now being developed. These incorporate bone density, which predicts fractures equally in white women and men, and risk estimates may be refined by including other factors (e.g., risk of falling). Inclusion of these other factors may allow extension of fracture risk prediction to nonwhite populations, but this must be validated. Even with a universal risk prediction tool, cost-effective treatment thresholds will vary by country based on population fracture risk and available resources, and this will also affect clinical decision-making. Because of the competition for resources, accelerated efforts are needed to improve the effectiveness and lower the cost of osteoporosis interventions, as well as provide hard evidence that they result in the improved health outcomes promised.

S4 PL8. NEW PERSPECTIVES IN OSTEOPOROSIS TREATMENT Gregory R. Mundy, CTRC Institute for Drug Development, University of Texas Health Science Center San Antonio, USA Osteoporosis treatment in the next decade will likely be dominated by the search for anabolic agents. The forerunner will be parathyroid hormone, which has shown that substantial increases in bone mass and improvements in fracture rates are possible. However, an ideal agent will be one that is safe and efficacious, but also orally available. Agents such as strontium ranealate will be thoroughly evaluated for their potential, but the likely candidates will come from agents identified by their capacity to affect specific molecular targets controlling bone formation. Key transcription factors such as CBFA-1 will provide such targets, and important enzymes in the mevalonate pathway that regulate BMP 2 transcription will also be likely sources. There is also a place for new resorption inhibitors, since the current drugs, albeit effective, are not ideal pharmaceutical agents. A major limitation to drug discovery and development in our field is the cost of bringing a drug to market, and this will continue to provide a barrier until we provide faster and more efficient ways to satisfy regulatory requirements necessary for drug approval.

ORAL ABSTRACTS

Abstracts O2. DETERMINANTS OF MATERNAL AND FETAL CIRCULATING LEPTIN CONCENTRATION AND INTRAUTERINE BONE MINERAL ACCRUAL Javaid MK1, Shore SR1, Taylor P2, Robinson S1, Godfrey KM1, Cooper C1; 1MRC Environmental Epidemiology Unit, University of Southampton, UK, 2Department of Medical Physics & Bioengineering, Southampton General Hospital, UK Size and growth during early life have been shown to be predictors of both peak bone mass and fragility fractures in later life. Observational studies have identified different maternal factors such as diet, smoking and exercise which influence neonatal bone size; however the molecular mechanisms underlying such associations are at present unknown. Leptin is strongly related to body size both at birth and during adulthood, furthermore it may control the differentiation of mesenchymal stem cells into those of the osteoblast lineage. We therefore investigated the relationships between circulating maternal and fetal leptin with neonatal bone mass. 109 Caucasian pregnant women completed a lifestyle and dietary questionnaire and had their height, weight, skinfold thickness and serum leptin and IGF1 measured during early (median 14.6 weeks) at late (median 28.1 weeks) pregnancy. Following delivery, anthropometry and DXA (total body and lumber spine) were performed on the neonate. Cord leptin and IGF1 were also measured. Cord leptin was associated with fat and bone mass (p50.0001) to a greater extent than with lean mass (p = 0.02). Maternal leptin strongly reflected maternal fat mass, while neonatal leptin strongly reflected neonatal fat mass, but there was a poor correlation of maternal leptin with neonatal leptin, fat mass and bone mass [see table]. Cord IGF1 was significantly (p = 0.0003) correlated with cord leptin but cord leptin and IGF1 were independent determinants of neonatal fat mass.

O1. POSSIBLE ROLE OF SEXUAL STEROIDS IN THE REGULATION OF BONE FORMATION AND RESORPTION IN MEN. THE MINOS STUDY

Spearman r(p)

Early maternal Late maternal Cord leptin leptin leptin

Szulc P1, Beck TJ2, Delmas PD1; 1INSERM 403 Unit, Lyon, France; 2 The Johns Hopkins Outpatient Center, Baltimore, USA

Neonatal lean mass Neonatal fat mass Neonatal BMC Cord Leptin

0.07 (0.48)

0.12 (0.24)

0.23 (0.02)

0.08 (0.42)

0.18 (0.07)

0.64 (50.0001)

0.12 (0.21) 0.07 (0.50)

0.20 (0.04) 0.18 (0.06)

0.42 (50.0001)

In men, bone mineral density (BMD) is determined by periosteal apposition and bone loss which are regulated by sexual steroids. In a cohort of 934 men aged 19 to 85 years, we evaluated correlation of circulating testosterone and estradiol with: 1. external diameter of tubular bones (femoral neck, radius, ulna) and projected area of total hip and trochanter, which reflect periosteal apposition, 2. estimated endosteal diameter, estimated cortical thickness, bone mineral apparent density (BMAD) and volumetric BMD (vBMD) determined mainly by bone loss. Between 25 and 80 years, external diameter and estimated endosteal diameter increased by 10–12% and 13–16%, respectively, whereas estimated cortical thickness decreased by about 16%. BMAD (third lumbar vertebra, trochanter, total hip) and vBMD (femoral neck, radius, ulna) were highest in young men (20 to 30 years) and decreased by about 17 to 24% until 80 years. Body weight, body mass index (BMI) and body height were significant positive determinants of bone dimensions (p = 0.0001). Body weight was a determinant of BMAD and of vBMD in weightbearing sites (spine, hip) but not in the distal forearm. Correlation of BMI and body height with BMAD and vBMD was weak or nonsignificant. In multiple regression models including age, body height and BMI as independent variables, total testosterone level contributed positively to the explanation of variability of external diameter of tubular bones and of projected areas of hip (partial T = 2.4, p50.02). In similar models, total estradiol level contributed significantly to the explanation of parameters of bone loss (p50.05–0.0001): BMAD, vBMD, estimated cortical thickness, and estimated endocortical diameter (negative determinant). In conclusion, our data suggest that, in men, estradiol acts mainly as an inhibitor of bone resorption and testosterone acts mainly as a weak stimulator of bone formation.

BMC = total bone mineral content

O3. SEX STEROIDS AND GROWTH FACTORS DURING ADOLESCENCE AND YOUNG ADULTHOOD: RELEVANCE TO BONE TURNOVER Henry YM, Fatayerji D, Eastell R; University of Sheffield, UK Men have greater and prolonged increases in bone turnover markers (BTMs) in early adult life compared to women, reflecting greater modelling and remodelling and hence greater increases in bone size. However, the relative contribution of growth factors and sex hormones to these changes in BTMs is only partially understood. Therefore, the aim of the study was to identify which hormones may play a role in the greater bone size in males as reflected by higher concentrations of BTMs. 132 healthy Caucasian children (63 boys and 69 girls, ages 11 to 19 years) and 134 healthy Caucasian adults (66 men and 68 premenopausal women, ages 20 to 50 years) were studied. IGF-1, total testosterone, dehyroepiandrosterone and oestradiol were measured. Free androgen index and free oestrogen index were calculated. OC, bone ALP and PINP were measured as bone formation markers and i-free DPD and NTX as bone resorption markers. During adolescence, IGF-1 was not significantly correlated with BTMs. However, in adults IGF-1 was positively correlated with all BTMs in men (OC, r = 0.53, P50.001; bone ALP

Abstracts r = 0.28, P50.01; PINP, r = 0.44, P50.001; i-free DPD, r = 0.35, P50.01; NTX, r = 0.37, P50.001) and bone ALP (r = 0.32, P50.01) in women. During adolescence, there were strong negative correlations between sex hormones and BTMs. In contrast, sex hormones generally did not correlate with BTMs in adults. In men OC, PINP and NTX were associated with both IGF-1 and sex hormones. When investigated further, only IGF-1 remained significantly related to BTMs (OC, R2 = 29.8, P50.0001; PINP, R2 = 22.2, P50.01; NTX, R2 = 14.5, P50.01). To conclude, sex hormones are important determinants of bone turnover during adolescence but IGF-I may be a stronger determinant during young adulthood. Thus, in boys sex steroids may be responsible for their greater bone size compared to girls but in adult men IGF-1 may be the key hormone driving periosteal apposition.

O4. VITAMIN D AND ATTAINMENT OF PEAK BONE MASS AMONG PERIPUBERTAL FINNISH GIRLS: A 3-YEAR PROSPECTIVE STUDY Lehtonen-Veromaa M1, Mo¨tto¨nen T2, Nuotio I2, Irjala K3, Leino A3, Viikari J2; 1Paavo Nurmi Centre, Turku, Finland, 2Department of Medicine, Turku University Central Hospital, Turku, Finland, 3 Central Laboratory, Turku University Central Hospital, Turku, Finland Aims: To examine whether the vitamin D status is associated with accrual of bone mineral density (BMD) at the lumbar spine and femoral neck. Methods: 3-year prospective study to examine the association between the change of BMD and serum 25-hydroxyvitamin D (S25(OH)D) in 171 healthy Finnish girls aged 9–15 years. BMD of the lumbar spine and femoral neck were measured by dual X-ray absorptiometry. Dietary intakes of vitamin D and calcium were estimated by food frequency questionnaires. The statistical models were adjusted for reproductive age at baseline, increase of height and weight, mean amount of physical activity, mean intake of calcium, and baseline BMD. Results: Baseline mean S-25(OH)D among the whole study group was 34.0 nmol/l (SD 13.2). These values correlated significantly with the adjusted 3-year change of BMD at the lumbar spine r = 0.35 and at the femoral neck r = 0.32. The difference between those who had severe hypovitaminosis D (S25(OH)D 520 nmol/l) and those who had a normal vitamin D status (S-25(OH)D 437.5nmol/l) regarding the adjusted 3-year BMD accumulation from baseline was 4% (12.7% vs 16.7%, p = 0.022) at the lumbar spine among the girls with advanced sexual maturation at baseline (n = 129). The adjusted 3-year change of BMD of the lumbar spine was 27% (p = 0.024) greater in the highest vitamin D intake tertile than in the lowest one in the girls with advanced sexual maturation. Conclusion: Pubertal girls with hypovitamionosis D seem to be at risk of not reaching the maximum peak bone mass, particularly at the lumbar spine. Dietary enrichment or supplementation with vitamin D should be seriously considered to assure an adequate vitamin D status.

O5. PROTEIN UNDERNUTRITION-INDUCED BONE RESORPTION IS DEPENDENT ON TUMOR NECROSIS FACTOR ALFA (TNF) Ammann P1, Garcia I2, Bonjour JP1, Rizzoli R1; 1Div. of Bone Diseases, Dpt. of Internal Medicine, Geneva, Switzerland, 2Dpt of Pathology,Geneva, Switzerland The mechanisms underlying bone loss encountered in protein undernutrition comprise an uncoupling in bone turnover with increased bone resorption and decreased formation. TNF, which participates to numerous catabolic processes, could be involved in this higher bone resorption. We studied the effects of isocaloric

S5 low (2.5%) or normal (15%) protein diet in 6-month old female transgenic mice (TgMice) expressing high levels of soluble tumor necrosis factor receptor-1 fusion protein, which blocks the actions of TNF. Negative littermates (NegLit) were used as controls. We measured bone strength (integrating all the modifications of bone structures) at skeletal site containing cortical and trabecular bone (proximal tibia) or cortical mainly (midshaft tibia), and bone mineral density (BMD) before and after 16 weeks of low/normal protein intake. Similar decreases in IGF-I (–47vs–47%) and osteocalcin (–37vs–47%) were observed in NegLit and TgMice fed an isocaloric low protein diet. Proximal tibia bone strength was significantly decreased in NegLit (13.1±1.8* vs 23.3±2.8N) but not in TgMice (19.0±3.0 vs 22.2±1.3). Similar trend was observed at the midshaft tibia with a decreased bone strength observed in NegLit (8.5±0.6* vs 11.2±0.8N) but not in TgMice (9.2±1.1 vs 10.9±0.3). The BMD decrease (in % of pretreatment values) was less pronounced in TgMice (–6.4±3.1*8 vs +7.9±5.4) than in NegLit (719.6±2.6* vs +7.0±3.6%) (*p50.05 vs 15%; 8 vs 2.5% NegLit by ANOVA, x±SEM). The midshaft diameter in protein-undernourished groups was lower in both NegLit (1.12±0.02* vs 1.25±0.01mm) and TgMice (1.18±0.01* vs 1.25±0.02) suggesting a reduced periosteal apposition. Thus, blocking TNF attenuated the increased bone loss and decreased bone strength induced by protein undernutrition. Decrease IGF-I and osteocalcin, and possible depressed periosteal apposition were observed in both NegLit and TgMice. This suggests that TNF might play a role in increased bone resorption but not in the depressed bone formation caused by an isocaloric low protein diet.

O6. TRABECULAR BONE MICROARCHITECTURE IS RELATED TO CLINICAL RISK FACTORS IN OSTEOPOROSIS IN MEN Legrand ER1, Chappard D2, Insalaco P1, Simon V1, Basle MF2, Audran M1; 1Service de rhumatologie, CHU, angers, France, 2 Laboratoire d’histologie-embryologie, CHU, Angers, France We have shown that trabecular bone connectivity is a major determinant of vertebral fracture in men with osteoporosis (1). To examine the relationships between risk factors for osteoporosis and trabecular bone microarchitecture (evaluated on transilliac bone biopsy) we included 152 men with low BMD (lumbar T-score 5–2.5) in a prospective study. The risk factors were checked: age, BMI (522 kg/m2), smoking, alcohol abuse (480 gr/day), use of corticosteroids, hypogonadism, chronic disease associated with bone loss. The histomorphometric analysis was done on a Leica quantimet image processor and the followings measures were performed : trabecular bone volume (BV/TV), trabecular thickness (Tb Th) and number (Tb N), Interconnectivity Index (ICI), Star Volume of the bone marrow, Characterization of the trabecular network (node and free-end count). Results: the patients with at least 3 clinical risk factors (n = 36) had a lower trabecular bone connectivity with a significant decrease in trabecular number and node count and a significant increase in star volume of the marrow spaces, interconnectivity index of the marrow spaces and free-end count. Furthermore, to evaluate the role of the different risk factors, logistic regression analysis was performed. Age, alcohol abuse and steroid were not associated with disorganisation of the bone microarchitecture. In contrast, smoking (OR 2.4, p50.05), low BMI (OR 1.6, p50.05), hypogonadism (OR 11.9 p50.05) and chronic disease (OR 1.4 p50.05) were significantly associated with a low trabecular bone connectivity. These results strongly suggest that, in men with low BMD, higher the number of clinical risk factors, lower the connectivity of the trabecular network and probably higher the fracture’ risk.

Reference 1. E Legrand et al. Trabecular bone microarchitecture, bone mineral density and vertebral fractures in male osteoporosis. J Bone Miner Res 2000;15:13–19.

S6 O7. STRUCTURAL AND BIOMECHANICAL BASIS FOR FEMORAL NECK BONE FRAGILITY IN MEN AND WOMEN Duan YB1, Beck TJ2, Wang XF1, Seeman E1; 1Austin & Repatriation Medical Centre, Melbourne, Australia, 2The Johns Hopkins University, Maryland, USA The aim of this study is to gain insight into the structural and biomechanical basis of the pathogenesis of bone fragility by comparing the gender differences in the age-related changes on the periosteal and endocortical surfaces, cortical thickness and bone strength at the femoral neck. We studied 395 healthy men and 801 women, and 127 men and 180 women with hip fractures. We measured femoral neck (FN) width, and estimated endocortical width, cortical thickness, CSMI and buckling ratio by using the DXA structural analysis program. In young women but not in men, larger FN width was associated with a thinner cortical thickness. During ageing, FN width increased by 0.91 SD and 0.25 SD, endocortical width increased by 1.11 SD and 0.52 SD, so net cortical thickness decreased by 1.03 SD and 1.40 SD in men and women, respectively. Thus, CSMI increased by 0.34 SD in elderly men but decreased by 0.35 SD in elderly women, while buckling ratio increased similar in elderly men and women (1.49 vs 1.58 SD). Compared to age-matched controls, men with hip fractures had reduced FN width (70.45 SD), normal endocortical width (70.17 SD), and reduced cortical thickness (71.52 SD). Women with hip fracture had increased FN width (0.77 SD), increased endocortical width (0.90 SD), and reduced cortical thickness (70.75 SD). The buckling ratio was similar in men and women with hip fractures (13.88 vs 13.44) and both were higher than the age-matched controls (1.69 vs 1.45 SD). In summary and conclusions: (i) Men and women with hip fracture have similar fracture threshold (buckling ratio). (ii) Attainment of a larger femoral neck in women during growth is accompanied by a lower peak cortical thickness which confers a structural disadvantage as age-related bone loss erodes the already thin cortex increasing the fracture risk. (iii) Smaller FN width in men with hip fractures suggests that reduced periosteal apposition during growth or aging may contribute to the pathogenesis of femoral neck fragility in men.

O8. LONGITUDINAL EFFECTS OF SEX HORMONES ON BONE MASS AND BONE TURNOVER IN ELDERLY MEN Gennari L, Merlotti D, Gonnelli S, Mangeri M, Montagnani A, Franci MB, Campagna S, Lucani B, Gennari C; Institute of Internal Medicine, University of Siena, Italy Sex steroid hormones play an important role in regulating bone turnover and bone mass in males, as well as in females. However, the exact mechanism of bone loss in men remains unknown. In this study 200 elderly men (age range 55–82 yrs) were recruited and followed for two years to evaluate the relationships between hormone levels, bone turnover, bone mineral density (BMD), and bone loss. Femoral and lumbar BMD (DEXA), bone ultrasound parameters at the os calcis, serum dehydroepiandrosterone (DHEA), serum testosterone (T), serum estradiol (E2), sex hormone binding globulin (SHBG), and bone turnover markers (urinary CTX and bone alkaline phosphatase, BALP) were evaluated at the enrollment and two years after. The free androgen index (FAI) and free estrogen index (FEI) were calculated as the ratios between total hormone levels and SHBG. In the total population, T, DHEA, FAI and FEI but not E2 decreased significantly with age while SHBG increased significantly. Subjects with FEI or E2 below the median (45.5% and 24.9 pg/ml respectively) showed higher rates of bone loss at the femoral neck and Ward’s triangle as well as higher SOS decrease at the calcaneous with respect to men with FEI or E2 above the median. Serum basal BALP was significantly higher and increased significantly after two years in men with FEI or E2 below the median than in men with FEI and E2 above the median. No statistically significant differences were observed between

Abstracts subjects with T or FAI below and above the median. Finally, the ratio between T and E2, an indirect measure for aromatase activity, increased significantly with age and was higher in normal vs. osteoporotic subjects. In conclusion, results from the present study indicate a dominant role of the aromatization process of T into E2 in the regulation of bone metabolism in elderly men.

O9. HIGH PREVALENCE OF OSTEOPOROSIS INDEPENDENTLY OF TREATMENT IN HIV-INFECTED PATIENTS Amiel C2, Ostertag A1, Slama L2, Lajeunie E3, NGuyen T2, CohenSolal ME1, Baudoin C1, Rozenbaum W2, de Vernejoul MC1; 1 INSERM U349, Paris, France, 2Department of infectious disease, Paris, France, 3Lab. Endoc Biology, Paris, France Osteoporosis has been reported in HIV-infected patients and has been related to treatment with protease inhibitors (PI) In order to assess the prevalence and mechanism of osteoporosis in HIVinfected patients, we studied bone mineral density (BMD) of 119 male patients HIV-infected, mean ± SD age, 40 ± 8, and compared them to 147 HIV-negative male controls aged 41± 9 years.Compared to controls BMD was significantly decreased in HIVinfected patients at the hip (FN) (0.91±0.13 vs 1.05±0.1 g /cm2, p50.001) and lumbar spine (LS) (1.07±0.14 vs 1.31±0.16 g /cm2, p50.001 ). Prevalence of osteoporosis/osteopenia at the LS was 56% in HIV-infected patients vs 13% in controls (p50.01). There was no difference in BMD in patients without any treatment (n = 25), patients treated with PI (n = 47) or without PI (n = 47). Main determinant of BMD was the BMI at the time of the study (r2 = 0.91) and the nadir of the weight (r2 = 0.18).Fat mass (r = 0.40) as well as lean mass (r = 0.48) were correlated with total body BMD. Treatment, duration of the diasese and the presence of lipodystrophy were not predictors of BMD. Biochemical markers were measured in all the HIV-infected patients (n = 119) and in 38 age-matched controls. Mean Leptin, IGF1, 25(OH)D and PTH plasma levels were not different from controls and among HIV infected subgroups. Cortisol was higher in HIV-infected patients than in the controls (11±4 vs 15±5 p50.01 ) and was no different among HIV-infected patients according to the presence or the type of treatment. There was a significant increase in urinary crosslaps (3±2 vs 2±1, p50.01) and decrease in bone alkaline phosphatase (9±4 vs 12±4, p50.01) compared to controls. There was no difference among the HIV-infected patients according to the treatments. In conclusion, these data show that there is a high prevalence of osteoporosis/osteopenia in male HIV- infected patients independently of treatment. BMD is mainly dependent on nutritional status. Low bone formation and high bone resorption could be related to hypercorticism.

O10. THE PREVALENCE OF SECONDARY HYPERPARATHYROIDISM IN PERSONS WITH PAKISTANI AND NORWEGIAN BACKGROUND LIVING IN OSLO, NORWAY Meyer HE1,3, Søgaard AJ1, Falch JA2, Pedersen JI3, Haug E2; 1 National Health Screening Service, Oslo, Norway, 2Hormone Laboratory, Aker University Hospital, Oslo, Norway, 3Institute for Nutrition Research, University of Oslo, Norway Aims: To study the prevalence of secondary hyperparathyroidism (2.HPT) and its effects on bone mineral density (BMD) in the Pakistani immigrant population and the population of Oslo with Norwegian background. Methods: As part of the Oslo Health Study, a population-based multipurpose study, we measured s-iPTH, s-Ca2+ and s-25(OH)D in random samples of the population of Oslo. In the present analyses we have concentrated on persons born in Norway (mean age 62 years (range 45-75), n = 852) and persons born in Pakistan (mean age 43 years (range 30-76), n = 173). BMD was measured at the forearm site with SXA.

Abstracts

S7 2+

Results: 2.HPT defined as s-iPTH 4= 8.5 pmol/l, s-Ca 41.35 mmol/l and s-25(OH)D 550 nmol/l was found in 6.4% (women) and 3.5% (men) in persons with Norwegian background and in 23.9% (women) and 16.7% (men) in the Pakistanis. Even in the youngest age groups (30-40 years), the prevalence in Pakistanis was as high as 21.3% in women and 12.7% in men. Only 10% of the women and 8% of the men with Pakistani background had s25(OH)D 4= 50 nmol/l compared to 85% of men and women with Norwegian background. In separate strata of sex and ethnicity, those with 2.HPT had significantly lower age-adjusted BMD compared to those with normal vitamin D status in women with Norwegian background (p = 0.001), and tended to be lower in men with Pakistani background (p = 0.08), whereas there were no differences in men with Norwegian background or women with Pakistani background. Conclusion: In this study the prevalence of secondary hyperparathyroidism was 4-5 times higher in persons with Pakistani background compared to persons with Norwegian background living in Oslo. A high prevalence was also found in younger Pakistani women and men.

O11. THYROXIN TREATMENT DOES NOT INCREASE FUTURE FRACTURE RISK OR BONE LOSS IN A PROSPECTIVE STUDY AMONG 6083 WOMEN Stenstro¨m M1, Johnell O2, Olsson J1, Oden A3, Mellstro¨m D1; 1 Dept of Geriatric Medicine, Gothenburg University, Sweden, 2 Dept of Orthopedics, University of Malmo¨, Sweden, 3Dept of Statistics, Chalmers University of Technology, Sweden Aim: The purpose of this study was to investigate the risk of fractures and bone loss among women with thyroxin treatment. We have earlier reported that current thyroxin treatment was not associated with any significant difference in bone mineral density (708 women with thyroxin treatment and 9584 controls, WCO Chicago 2000). Methods: 10,364 women aged 49–69 participated in a simultaneous screening of breast cancer and osteoporosis in the cities Go¨teborg and Varberg in Sweden. Bone mineral density was measured in the non-dominant forearm with DXA technique (Osteometer 2000). The investigation was repeated three years later. Fracture data from 6083 women in the city of Go¨teborg was collected from hospital files and X-ray archives. Health questionnaires were obtained. Results: 444 women was on thyroxin treatment (7,3%). During three years 378 women sustained one or more fractures among the 6083 included. 28 women among the thyroxin treated and 350 in the control group. The age adjusted risk for all fractures was among thyroxin treated, RR 0,90 (0,60–1,34) and forearms fractures RR 0,82 (0,41–1,62). There was a non-significant tendency towards an increase of BMD in the thyroxin group. In the control group there was a significant decrease of BMD (p50.001). Conclusion: Treatment with thyroxin among postmenopausal women was in this longitudinal study not afflicting skeletal integrity, nor in terms of BMD or in future fracture risk compared with others in a period of three years.

O12. OSTEOPOROSIS IN MEN AND WOMEN: A STORY ABOUT HIP FRACTURE THRESHOLDS De Laet CE1,2, Van der klift M1,2,3, Hofman A3, Pols HAP2,3; 1 Institute for Medical Technology Assessment, Erasmus University Medical Center Rotterdam, The Netherlands, 2 Department of Internal Medicine, Erasmus University Medical Center Rotterdam, The Netherlands, 3Department of Epidemiology and Biostatistics, Erasmus University Medical Center Rotterdam, The Netherlands In women the T-score is a well-accepted diagnostic criterion for osteoporosis. It is unclear whether in men similar thresholds

should be used. Different hypotheses have been proposed for the relation of BMD with hip fracture risk in men. In this study we tested those hypotheses in a mathematical model and compared the results with observed prospective data from the Rotterdam Study. For men, we tested the following hypotheses: either the relation of BMD with hip fracture risk is similar in men and women (scenario 1), or the relative risk (RR) per standard deviation (SD) decrease of BMD is either larger or smaller in men than in women (scenario 2a and 2b), or at a similar fracture risk, men have a higher BMD (scenario 3). In the prospective data men with a hip fracture had an average BMD that was 0.070 g/cm2 higher than women. The calculated results from the first scenario were consistent with those data and were consistent with the observed hip fracture incidence and the female to male (F/M) risk ratio (1.7). When the RR for each SD decrease of BMD would either be larger or smaller in men than in women (second scenario) the average BMD difference in men and women became respectively smaller or larger than observed. When men would have a higher fracture risk at similar BMD levels (third scenario), the number of hip fractures would increase and even exceed that in women, with a F/M risk ratio of 0.94 in our example. In women a larger proportion of hip fractures occurs with a T-score at or below –2.5 than in men using the same absolute BMD threshold, but using a male specific T-score largely solves this diagnostic problem. The average hip fracture risk, however, is much lower in men than in women and they appear to have a similar fracture risk at the same absolute BMD. Therefore, we propose the use of the same absolute BMD thresholds for decisions about interventions.

O13. NULLIPAROUS WOMEN AND WEAKER HIP BONE STRUCTURE: POTENTIAL MECHANISM FOR INCREASED POSTMENOPAUSAL HIP FRACTURE RISK INDEPENDENT OF BONE MINERAL DENSITY Hillier TA1, Beck TJ2, Oreskovic TL2, Rizzo JH1, Pedula KL1, Stone KL3, Cauley JA4, Bauer DC3, Cummings SR3; 1Center for Health Research Kaiser Permanente Northwest/Hawaii, Portland, OR, USA, 2Department of Radiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA, 3Department of Medicine, University of California San Francisco, San Francisco, CA, USA, 4Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA We recently reported that nulliparous women have a marked increased risk of hip fracture (Hazard ratio = 1.45) independent of measured bone mineral density (BMD) (Hillier et al, ASBMR 2001). The current study seeks to determine if there are structural differences in the hip between nulliparous and parous women that BMD does not measure. We employed our hip structural analysis program on hip scans measured in 4,458 postmenopausal women participating in the Study of Osteoporotic Fractures (Beck TJ et al, JBMR 16(6), 2001). Parity status was ascertained by self-report. Measurements of areal BMD and geometric properties, including cross-sectional area (CSA), subperiosteal width(W), section modulus (SM), and estimated cortical thickness (CRT), were calculated at the femoral neck. Multiple linear regression was used to determine structural differences in the hip between nulliparous and parous women. A parameter estimate was calculated to assess the trend of the relationship with each additional birth. Although nulliparous women had no difference in BMD, structural analysis would predict their hips are weaker at the femoral neck (Table). There was also a strong relationship with each additional birth to improve hip structure. Nulliparous women have structural differences in the hip that may increase their fracture risk but are not apparent in BMD due to underlying dimensional differences. Parity status may be an important variable to assess in addition to BMD in counseling women about osteoporosis risk and recommendations for preventive therapy. More research is needed to assess the utility of measuring bone structural measurements in predicting fracture risk.

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Abstracts

Multivariate Adjusted* Models at Femoral Neck

Nulliparous (mean) Parous (mean) p-value Parameter Estimate (each birth, range 0-14) p-value

BMD (gm/cm2)

CSA (cm2)

W (cm)

SM (cm3)

CRT (cm)

.696 .700 .41 .0014

2.12 2.14 .03 .0075

3.21 3.23 .02 .0048

1.12 1.15 .009 .0066

.132 .133 .45 .0003

.007

.045

.0002

.18

.20

* Adjusted for 14 potential confounders, including age, weight, knee height

O14. NATIONAL VARIATION IN HIP FRACTURE RATE IN SWEDEN DEPENDS ON LATITUDE AND SEASON – A COHORT STUDY OF 26 MILLION OBSERVATION YEARS Johnell J1, Ode´n A2, Rosengren B1, Mellstro¨m D3, Kanis J4; 1Dept of Orthopaedics, Malmo¨ University Hospital, Malmo¨, Sweden, 2 Consulting Statistician, Gothenburg, Sweden, 3Dept of Geriatrics, Vasa Hospital, Gothenburg, Sweden, 4WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, Sheffield, UK Several studies have shown a two-fold range of hip fracture rates within countries. The aim of this study was to examine whether hip fracture rates within Sweden varied according to likely vitamin D status. We studied the entire Swedish population aged 50 years or more between 1987 and 1996. In men 36,800 hip fractures occurred in 12 million years of observation and in women 98,000 hip fractures arose in 14 million observation years. We studied the effect of age, secular trend, population density (urban-rural), seasonal variation and latitude using a Poisson model that also takes account of mortality. The effect of latitude was highly significant and a 10-degree increase in latitude (more northern) was associated with a 46% (95% CI = 39–52%) increased risk for men and a 27% (23–30%) risk in women. There was also a marked seasonal variation. The increase in risk between 15th July to 15th December was +34% (29–38%) for men and +25% (22–27%) for women. The pathophysiology of the effect of season and latitude is unknown, but may be related to differences in vitamin D status. This study also shows a large variation within a standardised population.

O15. CLINICAL RISK FACTORS FOR PREDICTION OF HIP OSTEOPOROSIS IN ELDERLY WOMEN Kayan K1, Bal S1, Kohler B1, Jalava T2, Ball A1, Cliff J1, Charlesworth D1, Bostock J1, Kanis JA1, Mccloskey EV1; 1Who Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, Sheffield, UK, 2Leiras Oy, Helsinki, Finland The efficacy of anti-resorptive therapies to prevent hip fracture appears to be greatest in those with low bone mineral density (BMD) at the hip. We wished to determine whether simple clinical assessments in elderly women could predict hip osteoporosis (DXA measured T score BMD 5–2.5). 4347 community dwelling women aged 75 years or above were studied at enrolment to a randomized placebo-controlled bisphosphonate study. At entry, each woman had a detailed assessment of her current and past general health, quality of life and disability. The gradient of risk for the presence of osteoporosis for each of a large number of risk factors was computed from univariate logistic regression analysis. All significant factors affecting 5% or more of the population were entered to a multivariate forward conditional regression to determine independent factors associated with hip osteoporosis. 19.1% of the women had osteoporosis at the hip. In univariate analysis, the odds-ratio for hip osteoporosis ranged from 4.9 (95% CI 4.2–5.8) for low body weight (lowest quartile; 556.8 kg) to 1.2 (95%CI 1.0–1.5) for hospital admission in the

previous 12 months. In the multivariate model, older age (highest quartile; 482.3y), low body weight, difficulty in rising from a chair, self-reported wrist fracture, lack of current exercise and non-use of vitamin D remained significant independent variables associated with hip osteoporosis. Using combinations of these risk factors, the positive predictive values for hip osteoporosis ranged from 6% for lack of current exercise as a sole risk factor (prevalence 3.6%, population RR 0.32) to 77% for women with all 6 risk factors (prevalence 0.3%, population RR 4.0). Simple clinical assessments are able to predict low BMD but the positive predictive values may not be sufficient to exclude the need for BMD assessments. Clinical risk factors remain useful tools for targeting assessments with DXA.

O16. COLLES’ FRACTURE AND SUBSEQUENT HIP-FRACTURE RISK IN MEN: A META-ANALYSIS Boonen S1, Autier P2, Collins J3, Vanderschueren D1, Haentjens P4; 1Katholieke Universiteit Leuven, Leuven, Belgium, 2 Luxembourg Health Institute, Luxemburg, Luxemburg, 3 McMaster University, Hamilton, Canada, 4Vrije Universiteit Brussel, Brussels, Belgium Aims: To compare the relative risk of hip fracture after sustaining a wrist (distal radius) or spine (vertebral body) fracture between men and women. Methods: Studies published from January 1982 through August 2000 in English, French, or German were identified from the PubMed database and reference lists of retrieved articles. We included cohort studies that reported low-trauma (radiologically confirmed) wrist or spine fracture as a risk factor for subsequent hip fracture among (white) women and men aged 50 years or older. Results: Ten cohort studies contributed to this meta-analysis. After demonstrating homogeneity of association across studies, a fixed effects meta-analysis was used to calculate a pooled relative risk (RR) with 95% confidence interval (95% CI). Among postmenopausal women, RRs for future hip fracture after wrist and spine fracture were 1.53 (95% CI 1.34–1.74, P50.001) and 2.22 (95% CI 1.95–2.52, P50.001), respectively. In older men, these RRs were 3.26 (95% CI, 2.08 to 5.11, P50.001) and 3.54 (95% CI, 2.01 to 6.23, P50.001), respectively. The risk of sustaining a hip fracture was significantly higher in women with a previous spine fracture than in those with a history of a Colles’ fracture (P = 0.001). In men, however, spine and wrist fractures appeared to be equally predictive of a subsequent hip fracture (P = 0.82). In line with these observations, fractures of the distal radius increased the relative risk of hip fracture significantly more in men than in women (P = 0.002). The impact of a spine fracture, on the other hand, was similar in both genders (P = 0.12). Conclusions: Prevalent vertebral fractures have an equally important impact on the risk of sustaining a subsequent hip fracture in both genders. The prospective association between Colles’ fracture and subsequent hip fracture, however, is significantly stronger in men than among postmenopausal women. Men with a Colles’ fracture are high-risk individuals for future hip fracture and should be evaluated as candidates for intervention.

O17. THIAZIDES AND THE RISK OF HIP FRACTURES Schoofs MWCJ1,2, van As C1, van der Klift M3,2,1, de Laet CEDH3,2, Hofman A1, Pols HAP2,1, Stricker BHC1; 1Dept of Epidemiology & Biostatistics, Erasmus Medical Centre, Rotterdam, The Netherlands, 2Dept of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands, 3Institute for Medical Technology Assessment, Erasmus Medical Centre, Rotterdam, The Netherlands Aims: To examine the features of the association between thiazide diuretics and the risk of hip fracture in men and women.

Abstracts Methods: We used data from the Rotterdam Study, a prospective population-based cohort study in 7983 men and women aged 55 years and over. Information on potential risk factors was gathered during a baseline interview and clinical examination. Information on all (non-) fatal events was reported by the general practitioners and verified by trained research assistants. In contrast with other studies, data on all drugs dispensed to the participants were available on a day to day base. To study the effect of duration of therapy, cumulative use of thiazides was divided into 4 mutually exclusive time intervals: past use, current use for 0–42 days; current use for 43–365 days; and current use for more than 365 days. To determine the hazard ratio of use of thiazides and risk of incident hip fracture a Cox proportional hazards model was used. Results: During an average follow-up time of 7.3 years, 257 subjects suffered a hip fracture. Results were adjusted for age, gender, previous fractures, and lower limb disability. Both current long-term use(4365 days)of thiazides (HR 0.41 [95% CI: 0.43– 0.98]) and current use irrespective of duration (HR 0.65 [95% CI: 0.43–0.98]) were significantly associated with a reduced risk of hip fracture as compared to never use. After cessation of longterm use, a non-significant risk reduction up to 150 days was observed (HR 0.4 [95% CI: 0.1–2.8], 0.5 [95% CI: 0.2–2.2], 0.9 [95% CI: 0.3–2.4] at days 50, 100 and 150 respectively). Restriction to female gender gave approximately the same protective hazard ratios. Conclusion: These prospective data suggest a beneficial effect of thiazide diuretics on the risk of hip fracture. A protective effect can be observed up to 150 days after cessation of long-term thiazide use.

O18. IDENTIFYING COMMUNITY-DWELLING ELDERLY AT HIGH RISK FOR RECURRENT FALLING: RESULTS OF A THREE YEAR PROSPECTIVE STUDY Pluijm SMF1, Smit JH2, Tromp AM1, Stel VS1, Deeg DJH1,3, Bouter LM1, Lips P1,4; 1Institute for Research in Extramural Medicine (EMGO Institute), Vrije Universiteit Medical Centre (VUMC), Amsterdam, The Netherlands, 2Dept of Sociology and Social Gerontology, Vrije Universiteit, Amsterdam, The Netherlands, 3 Dept of Psychiatry, Vrije Universiteit, Amsterdam, The Netherlands, 4Dept of Endocrinology, Vrije Universiteit Medical Centre (VUMC), Amsterdam, The Netherlands Aims: The aim of this prospective study was to develop a risk profile that can be used to identify community-dwelling elderly at high risk of recurrent falling. Methods: The study was conducted among 1365 communitydwelling subjects (667 men and 698 women) of 65 years and older (mean age ± SD: 75.3 ± 6.4 years) who were all participants of the Longitudinal Aging Study Amsterdam (LASA). Information on potential predictors, including physical, cognitive, emotional and social aspects of functioning, was assessed by means of physical tests and a structured interview at home. Falls were prospectively recorded during three years by means of a ‘fall calendar’. A ‘recurrent faller’ was defined as a subject who fell at least two times in six months during the three year fall follow-up. Results: Using backward logistic regression analysis, a high education level, dizziness, the presence of functional limitations, low body weight, weak grip strength, two or more falls in the year preceding the interview, fear of falling, drinking at least 15 alcohol units per week, the presence of dogs or cats in the household, and two interaction terms (high education – the use of at least 15 alcohol consumptions per week and fear of falling – falls in the year preceding the interview) were included in the risk profile model for recurrent falling. The probability of recurrent falling ranged from 10% when none of these predictors was present to 97% when all predictors were present. Conclusions: We constructed a risk profile of recurrent falling that included nine predictors. Since this risk profile has a high

S9 predictive value and is easily to assess, it seems a useful tool for the identification of community-dwelling elderly with a high risk of recurrent falling.

O19. CORRELATION OF FEMORAL FAILURE LOADS IN SIDE IMPACT AND VERTICAL LOADING WITH IN SITU DXA, PERIPHERAL QCT, QCT, AND QUANTITATIVE ULTRASOUND Lochmu¨ller EM1, Kuhn V1,2, Mu¨ller R3, Eckstein F2; 1Universita¨tsauenklinik, Mu¨nchen, Germany, 2Institute of Anatomy, Mu¨nchen, Germany, 3Orthopaedic Biomechanics Lab, Boston, USA Aim: Femoral fractures have the most striking personal and socioeconomic impact in osteoporosis. Bone densitometry is used to predict mechanical strength, but it is unclear which technique is best suited for this purpose. In this study we experimentally determine failure loads of the proximal femur and their correlation with in situ DXA, QCT, pQCT, and quantitative ultrasound. Methods: 120 specimens were investigated, aged 80 ± 10 years. In situ DXA was performed in the left femur, lumbar spine, and left radius (DPX-L, Lunar), and pQCT at the distal radius, tibia, and femur (XCT 2000 and 3000, Stratec) also with natural soft tissues. QCT of the spine (Somatom+, Siemens) and quantitative ultrasound of the calcaneus (Achilles+, Lunar) were performed ex situ in degassed specimens. Pairs of femora were tested to failure (Zwick 1445), one in side impact and one in vertical loading (parallel to the shaft). Results: For the side impact, the highest correlation was with cervical BMD (r = 0.73), and lower values were found for DXA of the spine (0.64) and radius (0.61). pQCT of the radius displayed lower coefficients (0.48 to 0.58), with measurements at the tibia and femur being in the same range. QCT and ultrasound displayed significantly (p50.05) lower correlations (0.44 and 0.45) than cervical BMD. For the vertical loading configuration, the highest correlation was with cervical BMC (r = 0.72). Ultrasound did not provide significant additive information to femoral DXA in multiple regression models for both testing configurations. Conclusions: Femoral DXA is able to predict approx. 50% of the variability in femoral failure loads under in situ conditions. Despite theoretical advantages, other techniques show lower predictive ability, and calcaneal ultrasound does not contribute relevant information to estimating femoral strength. Clinical diagnosis of femoral fracture risk should thus rely on site specific DXA of the femur.

O20. COMPARISON OF 3 BONE ULTRASOUNDS FOR DETERMINING HIP FRACTURE RISK IN 7494 ELDERLY WOMEN: THE SEMOF STUDY Cornuz J, Krieg MA, Burckhardt P; University Hospital, Lausanne, and the SEMOF study group, Switzerland The SEMOF study group: Bu¨che D, Dambacher MA, Hartl F, Ha¨uselmann HJ, Kraenzlin M, Lippuner K, Neff M, Pancaldi P, Rizzoli R, Tanzi F, Theiler R, Tyndall A, Wimpfheimer K. Aims: The Swiss Evaluation of the Methods of Measurement of Osteoporotic Fracture Risk (SEMOF) study is a prospective multicenter study which compares 3 bone ultrasounds (QUS), Achilles+ (GE-Lunar), Sahara (Hologic), and DBM sonic 1200 (IGEA) for the assessment of hip fracture risk in elderly women. Methods: 7494 women aged 75±3 years (mean±SD) were assessed with the following parameters: SI for Achilles+, QUI for Sahara, and AD-SOS (and UBPI for 80% of the measurements)

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Abstracts

for DBM sonic 1200. During a mean 2.5-year follow-up, 62 hip fractures (HF) were reported. Age-adjusted relative risks (RR and 95% confidence intervals) were calculated for QUS parameters and expressed per decease of 1 SD of the respective parameter. To compare the different devices, areas under the ROC curve (AUC) were calculated. Results: The RR are presented in the table. No significant difference was found between the AUCs of Achilles+ and Sahara. However, AUC of AD-SOS and UBPI were both lower (p50.0001) than AUCs of Achilles+ and Sahara. Conclusions: These preliminary results of the SEMOF study showed that QUS of the heel (Achilles+ and Sahara) were both good predictors of hip fracture risk in elderly women. The usefulness of the phalanges’ measurements with DBM sonic for determining hip fracture risk could not be demonstrated in this cohort of elderly women. Device

QUS parameter

Achilles+ SI Sahara QUI DBM sonic 1200 AD-SOS UBPI (n = 6022, 52 HF)

Age-adjusted RR

AUC

(95% CI)

(SE)

2.0 2.4 0.9 0.9

0.69 0.72 0.50 0.50

(1.5–2.7) (1.7–3.3) (0.7–1.2) (0.7–1.2)

(0.04) (0.03) (0.04) (0.04)

O21. LOW BMD IS LESS PREDICTIVE THAN RISK OF FALLING FOR FUTURE LIMB FRACTURES IN WOMEN ACROSS EUROPE

O22. PREVIOUS FRACTURE COMBINED WITH FOREARM BMD MEASUREMENT AS A PREDICTOR OF NEW FRACTURES Olsson J1, Johnell O2, Kanis J3, Mattson L4, 0den A5, Stenstro¨m M1, Waern E1, Mellstro¨m D1; 1Dept of Geriatric Medicine, University of Go¨teborg, Sweden, 2Dept of Orthopedics, University of Malmo¨, Sweden, 3Dept of Human Metabolism, University of Sheffield, UK, 4 Dept of Gynecology, University of Go¨teborg, Sweden, 5Dept of Statistics, Chalmers University of Technology, Sweden Aim: Scandinavian women have a very high risk for osteoporotic fractures. The question is how valid a former fracture is as a predictor for new fractures in early postmenopausal age. Methods: 7070 women from Go¨teborg, Sweden (mean age 55) participated in a prospective study of simultaneous screening of breast cancer and osteoporosis. Bone mineral density was measured in the non-dominant forearm with DXA technique (Osteometer 2000). Fracture data from 7070 women was collected from hospital files and x-ray archives. Health questionnaires were obtained. We investigated the importance of previous fracture as a predictor of new fractures, any fracture, hip fracture and forearm fracture. BMD forearm was included together with age and time period since start of measurement in a Poisson regression model. Previous fracture was a zero-one variable attending the value 1 if there was a fracture not ankle fracture after the age 45 and 0 otherwise. Results: There was a significant contribution of previous fracture as a predictor for any fracture and forearm fractur (p50.001) but not for hip (p = 0.11). The risk ratio between those with and without previous fracture was 2.1 for hip fracture and 2.0 for forearm when we adjusted for age and BMD. The mentioned risk ratios corresponded to a difference of BMD of 2.0 SD (any fracture), 2.5 SD (hip fracture) and 2.0 SD (forearm), respectively. Conclusion.In this study of early postmenopausal women previous fracture was a strong independent predictor for any new fracture (risk ratio 2.1).

Kaptoge SK1, Roy DK2, Lunt M2, Pye SR2, Cockerill WC2, Silman AJ2, O’Neill TW2, Reeve J1, The EPOS Study Group EPOS1; 1 University of Cambridge, UK, 2University of Manchester, UK Our objective was to investigate effects of BMD alongside personal fracture history (PFH), parental hip fracture history (PARHIP), fall rates and age on the risk of non-spine fractures in the European Prospective Osteoporosis Study (EPOS). History of fracture was assessed in 2,510 men and 3,034 women aged 50-80 from 22 EPOS centres using standardized questionnaires (mean follow up = 3yrs). Validation was done by reference to medical records when possible. Femoral neck and trochanter BMD were measured in 4,136 subjects and cross calibration of DXA machines was by means of the European Spine Phantom. We previously showed that centre and sex specific fall rates (CSSFR) explained 33% of between centre variation in upper limb fractures in women; these were estimated using Poisson regression. Coxregression was used to model the risk of incident fracture associated with these variables. In women the risk of any incident limb fracture (n = 199) was significantly determined by CSSFR, age, PFH and PARHIP (all P50.020) but not BMD. Lower limb fracture (n = 57) was determined by trochanteric BMD and PFH (P 5 0.051). Upper limb fractures (n = 98) were determined by CSSFR, age, time spent walking/cycling and PARHIP (P50.034). Risk of forearm fracture (n = 69) was determined by CSSFR, walking/cycling and PARHIP (P50.014). In men, risk of any limb fracture (n = 66) was determined by trochanteric BMD (P = 0.027) and in Cox modeling of risk stratified by sex, the significant determinants were the same as for women except that trochanteric BMD substituted for age. We conclude that across diverse populations in Europe the effects of BMD in women on risks of upper limb fractures are less impressive than the effects of fall risk and of personal/parental fracture history. The causes of high fall rates in Scandinavia and central Europe may hold an important key to reducing limb fractures.

O23. PERIPHERAL BONE MASS MEASUREMENT IS A BETTER PREDICTOR OF CENTRAL BONE MASS THAN OSTEOPOROSIS RISK QUESTIONNAIRES Picard D1, Couturier M1, Rosenthall L2, Brown JP3, Le´vesque J3, Dumont M3, Ste-Marie LG1, Tenenhouse A2, Dodin S3; 1St-Luc Hospital, Montreal, Canada, 2Montreal General Hospital, Montreal, Canada, 3Centre Hospitalier Universitaire de Que´bec, Que´bec, Canada Clinical risk questionnaires or peripheral measurement of bone mass could be an alternative approach where central DXA which is the preferred method of diagnosis of osteoporosis, is not readily accessible. The Osteoporosis Risk Assessment Instrument (ORAI) and the Simple Calculated Osteoporosis Risk Estimation (SCORE) as well as peripheral BMD in 835 women aged 20 to 85 years were compared to the BMD measured by DXA in the spine (s) and femoral neck (fn) (1 Hologic, 3 Lunar), phalanx (p) with Schick AccuDXA, as well as proximal (pfa) and distal forearm (dfa) with Norland pDXA. The sBMD and fnBMD were converted to a Hologic base and t-score derived using data from Canadian Multicentre Osteoporosis Study (CaMos). In the regression models the peripheral measurements explained between 63% and 75% of the central BMD and risk indexes between 2% and 5%, p40.0001. The areas under the ROC curves (where a positive case was defined as a t-score 4–2.5 either on s or fn) were not significantly different between sites or risk indexes and were between 0.848 and 0.893.This table presents the sensitivity and specificity at optimal point of absolute BMD cutoff values for each peripheral apparatus as well as at the optimal score of risk indexes. Combining peripheral measurement with risk indexes increases sensitivity but decreases specificity. Hence, peripheral bone mass measurements present more interesting sensitivities and specificities and thus are a better tool for the diagnosis of osteoporosis in areas where central DXA is not available.

Abstracts

S11

Absolute Optimal BMD cutoff score values

With Optimal ORAI score

With Optimal SCORE score

Sensitivity Specificity Sensitivity Specificity Sensitivity Specificity p pfa dfa pfa+dfa combined values ORAI SCORE

0.436 0.703 0.280 0.641 and 0.252 13 11

79% 84% 90% 83%

83% 79% 75% 84%

77% 72%

81% 83%

91% 90% 97% 91%

71% 67% 65% 72%

91% 88% 95% 89%

73% 69% 68% 75%

O24. CHROMOSOMAL MAPPING OF QUANTITATIVE TRAIT LOCI FOR BONE MINERAL DENSITY: THE FRAMINGHAM STUDY Karasik D1, Hannan MT1, Cupples LA2, Myers RH3, Kiel DP1; 1 Hebrew Rehab Ctr for Aged & Harvard Med Sch, Boston, MA, USA, 2Dept of Epidemiology/Biostat, Boston University Sch of Public Health, Boston, MA, USA, 3Neurogenetics Dept, Boston University Sch of Medicine, Boston, MA, USA Aims: To estimate age- and sex- related heterogeneity of quantitative trait loci (QTLs) linked to BMD in pedigree members from a population-based sample. Methods: A genome-wide scan was performed in the Framingham Osteoporosis Study participants (1557 members of 330 Caucasian pedigrees), with 401 microsatellite markers spaced on average at 10 cM. BMDs measured at femoral neck (FN), trochanter (TR), Ward’s area (WR), and lumbar spine (LS) with DEXA, were adjusted for age, anthropometry, nutrition, physical activity, and estrogen use in females. The sample was stratified by sex [males (n = 674, age range 35–96 yrs old), females (872, 29– 91)] and by age [’60 or younger’ (706, 29–60), and ‘older than 60’, (822, 61–96)]. Results: Heritability estimates of BMD ranged from 0.466 to 0.693. Two-point and multipoint variance component linkage analyses of BMD in subsamples supported findings of suggestive linkage (LOD 41.9) in whole sample on 6pter, 8q24, 12q23, and 21qter. However, age- and sex-specific maxima were also found. Thus, in males, 4q34 showed suggestive linkage with FN, TR, and LS BMD (LOD scores 41.8), while in females, 12q23 provided suggestive linkage with FN and TR BMD (LODs 41.9). At 9q219q31, a long supportive interval (~20 cM, LODs 41.8) was in suggestive linkage with FN, TR, and LS BMD in ‘younger’, ‘older’, and female subsamples. Region 11q14 was linked with FN BMD in females and ‘younger’ group (two-point LODs 2.68 and 2.05, respectively). Conclusions. This study shows that although putative QTLs were linked linked to BMD at 4 skeletal sites, some heterogeneity of QTL effect was shown in pedigree members stratified by sex and by age; in some instances new loci were identified in subgroups. This may suggest that effects of genes on the determination of BMD differ between men and women and between younger and older adults.

O25. THE AROMATASE REPEAT POLYMORPHISM AND BIOAVAILABLE ESTRADIOL ARE ASSOCIATED WITH BONE LOSS IN COMMUNITY-DWELLING ELDERLY MEN Goemaere S, Van Pottelbergh I, Demuynck R, Myny H, Kaufman JM; Unit for Osteoporosis and Metabolic Bone Diseases, Ghent University Hospital, Belgium Aging in men is accompanied by a variable decline in bioavailable (Bio) testosterone (T) and estradiol (E2). The contribution of hormonal changes in senile bone loss is not unequivocal. Moreover, to which extent the potential effects of androgens on bone are mediated through their aromatisation product, estro-

gens, is currently unknown. In a population of 273 communitydwelling men aged 71–86 years, we assessed whether baseline BioT and BioE2 measurements are associated with bone loss and whether the tetranucleotide (TTTA)-repeat polymorphism of the aromatase gene modulates serum estrogens or hormonal actions on bone directly. Fasting blood was analysed for T, E2 and sex hormone binding globulin (SHBG). BioT and BioE2 were calculated using a validated equation. Bone mineral density (BMD) was measured at yearly interval over a period of 4 years (DXA;QDR1000+, HologicInc). Mean annual BMD changes were 70.42±1.29% and –0.39±0.60%, at the hip and at the distal forearm, respectively. BioE2, but not BioT, was significantly associated with bone loss at both the forearm and the femoral neck subregion, (r = 0.16 and 0.14, respectively, P50.05), with the highest bone loss observed in subjects with the lowest BioE2. For the remaining subregions of the hip, similar trends for association between BioE2 and bone loss were observed. The (TTTA)- repeat length (determined by fragment-analysis, GeneScan, PEAppliedBiosystems) was not associated with either baseline (Bio)E2, (Bio)T, SHBG nor with the T:E2 ratio. A consistent trend was observed between the (TTTA)repeat polymorphism and bone loss: the highest loss was observed in the subjects homozygotic for the shortest observed allele length (297 bp) at practically all measured sites (P = 0.01 and P = 0.02 at the distal forearm and at the radius midsubregion, respectively). In conclusion, the present study suggests that both BioE2, the aromatisation product of T, and the aromatase gene (TTTA)repeat polymorphism are associated with bone loss in community-dwelling elderly men.

O26. TESTOSTERONE MODULATES THE EFFECT OF ANDROGEN RECEPTOR GENE CAG REPEAT POLYMORPHISM ON BONE IN ELDERLY MEN Gennari L1, Becherini L2, Merlotti D1, Lucani B1, Gonnelli S1, Masi L2, Falchetti A2, Bargagli G1, Gennari C1, Brandi ML2; 1Institute of Internal Medicine, University of Siena, Italy, 2Department of Internal Medicine, University of Florence, Italy Testosterone has long been assumed to be critical for skeletal maintenance in men, even though the extent to which its effects on bone may be attributed to a direct action via the androgen receptor (AR) rather than to its aromatization into estradiol is not established. The human AR contains a CAG repeat polymorphism in exon 1, encoding for a poliglutamine sequence of variable length, which has been associated to differences in the androgenic activity. In this longitudinal study we analyzed the role of the AR trinucleotide (CAG)n repeat polymorphism in 300 elderly males (age range 55–85 years), recruited by direct mailing. Femoral and lumbar BMD (DEXA), bone ultrasound parameters (calcaneous and phalanx), estradiol, testosterone, sex hormone binding globulin, and bone turnover markers (urinary CTX and serum bone specific alkaline phosphatase) were evaluated for each man. The number of CAG repeats varied from 10 to 31, with a mean (plus/minus SD) repeat length of 21.28±3.2. There was no overall statistically significant association between the CAG repeats length and BMD, ultrasound parameters or bone markers. After classification of subjects into three major CAG groups (A417, 175B526, and C526 repeats), subjects in group C (526 repeats) had higher rates of bone loss at the femoral neck and lower phalangeal thickness than those in the lowest CAG group (group A417). These differences increased significantly when subjects in the low testosterone quartile were considered, while disappeared in men in the high testosterone quartile. Moreover a higher number of CAG repeats was observed in osteoporotic vs. non osteoporotic men in the low testosterone quartile (24.8±1.5 vs. 21.1±2.1; p50.05) but not in those in the high testosterone quartile (21.5±2.1 vs. 22.1±1.9; ns). Taken all together, these results suggest that the effect of AR poliglutamine repeat polymorphism on bone in elderly males is modulated by circulating androgens.

S12 O27. INTERACTION BETWEEN THE VITAMIN D RECEPTOR (VDR) GENE AND ESTROGEN RECEPTOR (ER) a GENE IN SUSCEPTIBILITY TO VERTEBRAL FRACTURE Colin EM, Uitterlinden AG, Meurs JBJ, van de Klift M, Fang Y, Arp PP, van Duyn CM, Hofman A, Pols HAP, van Leeuwen JPTM; Erasmus University Medical Center, Rotterdam, The Netherlands Aims: Polymorphisms in the VDR and ERa have been associated with BMD and vertebral fracture risk. In view of suggested interactions between vitamin D and estrogens the combined influence of polymorphisms in the ERa gene and VDR gene in susceptibility to osteoporotic fractures in postmenopausal women was analyzed. Methods: 1062 women of 55 years and older derived from the Rotterdam Study were studied. Haplotypes of the BsmI, ApaI, and TaqI RFLPs at the 3’ end of the VDR gene and haplotypes of the PvuII- and XbaI RFLPs in the first intron of the ERa gene were determined. Three VDR haplotypes (1, 2 and 3) and three ERa haplotypes (1, 2 and 3) were identified. Results: ERa haplotype 1 showed a dose-dependent negative association with lumbar spine BMD, corresponding with a 0.1 SD decline of BMD per copy of ERa haplotype 1. ERa analyzed according to carrier status for VDR haplotype showed only in women homozygous for VDR haplotype 1 a significant allele dose effect of ERa haplotype 1 (p = 0.09 for the interaction term). From a subgroup of 634 women complete fracture data were available. In this subgroup ERa haplotype 1 was dose-dependently associated with increased vertebral fracture risk (p50.001), corresponding with an odds ratio of 1.9 (95% CI, 0.9–4.1) per copy of the risk allele. This was independent of BMD, and not found for nonvertebral fractures. Fracture risk was not ERa genotype dependent in non-carriers and heterozygous carriers of VDR haplotype 1. In VDR haplotype 1 homozygotes the risk of fracture was 2.5 (95% CI, 0.6–9.9) for heterozygous and 10.3 (95% CI, 2.7– 39.6) for homozygous carriers of ERa haplotype 1 (p = 0.005 for the interaction term). Conclusion: Interactions between ERa and VDR gene polymorphisms lead to strongly increased risk of osteoporotic vertebral fractures in women, independent of BMD.

O28. SERUM OSTEOPROTEGERIN-LEVEL AS A NOVEL INDEPENDENT PREDICTOR OF BMD CHANGES AFTER INITIATION OF BISPHOSPHONATE TREATMENT IN OSTEOPOROTIC PATIENTS Fahrleitner A1, Hofbauer LC2, Viereck V3, Obermayer-Pietsch B1, Leb G1, Dobnig H1; 1Div. of Endocrinology, Karl Franzens University, Graz, Austria, 2Div. of Gastroenterology and Endocrinology, Philipps-University, Marburg, Germany, 3 Department of Obstetrics and Gynecology, Georg August University, Goettingen, Germany Aims: Since the endogenous anti-resorptive cytokine osteoprotegerin (OPG) is produced by osteoblasts and these cells undergo significant changes during antiresorptive treatment we hypothesized that treatment with bisphosphonates (BIS) would be accompanied by changes in serum OPG levels. Methods: Oral BIS (alendronate/risedronate) and calcium/ vitamin D treatment was started in 42 previously untreated, otherwise healthy postmenopausal women with established osteoporosis. Follow-up (at months 2, 6 and 12) was completed for 37 patients. Standardized spinal X-rays and DEXA measurements of the hip were performed at baseline and year 1. Serum OPG levels were measured by a polyclonal antibody-based ELISA system (Biomedica GmbH, Austria). Results: After 1 year there was a mean increase in neck and trochanteric BMD of 3.3 and 4.6%, respectively (both p50.0001). Serum CTX and osteocalcin decreased by 42 and 27% (6mos) and 50 and 27% (12mos). Initiation of BIS-treatment was paralleled by both decreases in sCTX and OPG. At 2 months, these changes were highly correlated to each other (0.78, p50.0001). Despite further decreases in sCTX and osteocalcin,

Abstracts mean OPG levels increased by 5% (6 mos, p = 0.01) and 7% (12 mos, p = 0.001). Multiple regression analysis revealed that after adjusting for sCTX the change in serum OPG after 12 months was positively correlated to the change in trochanteric BMD (r = +0.77, p50.0001). In contrast, the change in sCTX was an independent negative predictor (r = –0.50, p50.0001) of bone mass changes. Together, OPG and sCTX explained 71% of the variance in BMD changes. Results for the femoral neck were also statistically significant. Conclusions: Changes of OPG serum levels following BIS treatment could reflect altered OPG production in response to decreased bone resorption or direct effects of BIS on osteoblastic OPG production (as was recently demonstrated in vitro). Consideration of OPG changes add substantial information as to the predicted increase in BMD with BIS treatment.

O29. THE EFFECTS OF STATINS ON BONE MINERAL DENSITY AND QUANTITATIVE BONE HISTOMORPHOMETRY IN RODENTS Maritz FJ1,3, Conradie MM2, Hulley PA3, Hough FS2,3; 1Dept Medicine, Karl Bremer Hospital, Cape Town, 2Endocrinology and Metabolism Unit, Tygerberg Hospital and University of Stellenbosch, 3Dept Internal Medicine, University of Stellenbosch Aims: To investigate the effect of different doses of simvastatin, atorvastatin and pravastatin on femoral bone mineral density (BMD) and quantitative bone histomorphometry (QBH). Methods: Forty 3-month-old Sprague Dawley (SD) rats were randomised to 4 groups:- 20 were ovariectomised and 20 received a sham operation. Half in each group received simvastatin 20mg/Kg/dy orally and the rest placebo for 8 weeks. A further 70 intact SD rats were randomised to 7 groups and treated for 12 weeks: Simvastatin 20mg/Kg/dy, 10mg/Kg/dy, 5 mg/Kg/dy and 1mg/Kg/dy, and atorvastatin 2,5mg/Kg/dy, pravastatin 10mg/Kg/dy and a placebo group. Tibias and femurs were harvested for QBH and femurs for BMD. Results: BMD was decreased by simvastatin 1mg/Kg/day (p = 0.042), atorvastatin (p = 0.0002) and pravastatin (p = 0.002). The effect on QBH parameters differed with different doses of simvastatin (ANOVA; p = 0.00012). QBH parameters of both bone formation and resorption were equivalently and markedly increased by simvastatin 20mg/Kg/day in two groups of rats, and reflected by a relatively unchanged BMD. At lower doses, simvastatin 1mg/Kg/day decreased bone formation while increasing bone resorption as reflected by a marked decrease in BMD. Ovariectomised animals receiving simvastatin 20mg/Kg/ day showed no change in BMD relative to untreated ovariectomised controls, their increase in bone formation was smaller than in sham-operated rats receiving simvastatin and there was no change in bone resorption. Dose response curves of simvastatin for bone formation and resorption differed. Conclusions: These studies indicate that: a) statins decrease BMD in rodents; b) high-dose simvastatin increases bone formation and resorption; c) low dose simvastatin decreases bone formation and increases bone resorption; d) effects of simvastatin on QBH differ at different dosages; e) effects of simvastatin seen in intact rats are not observed in ovariectomised rats; f) simvastatin is unable to prevent the bone loss caused by ovariectomy.

O30. CATABOLIC EFFECTS OF GROWTH HORMONE ON BONE UNDER LOW PROTEIN INTAKE Ammann P1, Aubert ML2, Meyer JM3, Rizzoli R1; 1Div of Bone Diseases, Dpt of Internal Medicine, University Hospital, Geneva, Switzerland, 2Div of Pediatric Endocrinology and Diabetology, Dept of Pediatrics, University Hospital, Geneva, Switzerland, 3 School of Dentistry, University Hospital, Geneva, Switzerland Isocaloric protein undernutrition is associated with bone loss and decreased bone strength, which seem to be related to a decrease

Abstracts

S13

in Growth Hormone (GH) and/or IGF-I secretion and/or action. Whether GH administration can reverse the protein undernutritioninduced alterations in bone turnover, bone mineral mass and bone strength under a low protein diet is not known. Six-month old female rats were fed isocaloric diets containing 2.5% (LowProteinLP) or 15% (NormalProtein-NP) casein for 2 weeks. At this time, plasma IGF-I is markedly decreased in LP rats. Then, GH (0.5 or 2.5mg/kgBW) or its solvent were given subcutaneously to rats on either diet twice daily for 4 weeks. Proximal tibia (PT) and spine bone mineral density (BMD) and ultimate strength, together with urinary deoxypyridinolin excretion (Dpyr), osteocalcin and IGF-I were measured. GH caused a dose–dependent increase in IGF-I under both NP and LP diets (585±17, 709±20 for 0.5 and 2.5mg GH vs 476±22ng/ml in controls, p50.05, and 450±30, 556±29 vs 304±19, p50.05), respectively. GH increased bone turnover in rats on both NP and LP diets as indicated by change in osteocalcin and Dpyr. At this time, when BMD decrease under LP is not yet detectable, GH dose-dependently decreased BMD and bone strength in rats fed the LP diet. Similar trends were observed for midshaft tibia and spine. Thus, a stimulation of bone turnover results in a negative bone balance, when the protein intake is low. These results emphasize the major importance of dietary protein intake in the bone response to GH administration.

2

PT BMD (mg/cm ) PT Strength (N) Osteocalcin (ng/ml) Dpyr (nmol/day)

NP

NP

NP

LP

LP

LP

Control

GH 0.5

GH 2.5

Control

GH 0.5

GH 2.5

253.1±4.9 208.0±11.9 16.2±1.6 2275±164

254.4±5.0 209.9±5.4 17.5±1.1 3295±326*

263.0±4.5 262.7±3.5 191.1±14.9 225.7±9.4 25.7±2.5* 10.9±0.9 4223±628* 1832±221

248.8±5.4 199.7±12.2 13.5±0.7 1893±217

234.0±4.7* 139.9±13.9* 18.7±1.6* 2591±113*

Values are means±SEM, * p50.05 as compared to controls by ANOVA

O31. OVARIECTOMY CAUSES AN INCREASED BONE REMODELING LEADING TO AN ACCELERATED GROWTH OF MYELOMA CELLS Libouban H1, Moreau MF1, Bataille R2, Basle´ MF1, Chappard D1; 1 LHEA-GEROM, Faculty of Medicine, Angers, France, 2INSERM, Nantes, France We hypothesized that an increased bone remodeling due to ovariectomy (OVX) could influence the development of myeloma cells. OVX is well known to stimulate bone remodeling and to increase IL-6 levels in the bone marrow. C57BL/KaLwRij mice were OVX 7 days before injection of the malignant plasma cells (5T2MM). Three groups of mice were injected with 26106 5T2MM cells: control, OVX and OVX+pamidronate. The development of the disease was monitored from 6 weeks after cells injection by serum electrophoresis. Paraproteinemia was detected 6 weeks post injection in the OVX and OVX-pamidronate groups and 9 weeks post injection in the control group. At 9 weeks, the concentration of the paraprotein was 5 fold higher in the OVX group than in the control group. All OVX mice developed a hindlimb paralysis after 9–10 weeks and were euthanazied. In contrast, control mice were euthanazied 16 weeks post injection. Osteolytic lesions were quantified by numeric radiography, scanning electron microscopy and X-ray microtomography. At the time of euthanasia, we observed the presence of numerous bone lacunae in the long bones of the OVX mice. The lesions were localized in the metaphysis of the femur and tibia with a preferential localization in the tibial crest. In control animals, the development of bone lesions was followed by X-ray performed under anesthesia, at 10 weeks post injection and at the day of sacrifice. No lesions were observed at 10 weeks post injection; at 16 weeks, numerous lesions were observed in both femur and tibia. An accelerated bone remodeling (due to OVX) dramatically

increased the growth of malignant plasma cells. This is, in turn, associated with an earlier bone destruction confirming the close relationships between bone and MM cells. Pamidronate decreased bone remodeling due to OVX and prevented trabecular osteolysis.

O32. TESTOSTERONE, ESTRADIOL AND RISK FACTORS FOR PREDICTION OF ER+ AND ER– BREAST CANCER IN OLDER WOMEN Cummings SR1, Lee J1, Lui L1, Cauley JA2; 1University of California, San Francisco, 2University of Pittsburgh, USA Aims: Breast cancer is often regarded as a single condition, however estrogen-receptor-positive (ER+) and negative (ER–) cancer differ and SERMs prevent ER+ but not ER– cancer. Identifying women at risk of ER+ cancer may help target treatment with SERMs. Methods: To compare risk factors for ER+ and negative cancer, we assessed risk factors, BMD, estradiol (E2) and testosterone (T) in 8708 women age 65. We validated 328 new cases of invasive breast cancer (249 ER+ and 37 ER–) during 10.7 years of 99% complete follow-up. Results: Risk of ER+ breast cancer increased with weight (1.2 per 10 kg), radius BMD (1.3 per S.D.; 1.1, 1.8) and 16 years education (1.6; 1.1, 2.2) but not with any conventional risk factors. Family history of breast cancer indicated a 4.6-fold (2.4, 8.8) risk of ER– cancer but no significantly increased risk of ER+ cancer (1.3; 0.9, 1.8). Current estrogen use increased risk of ER– (2.7; 1.3, 5.5; adjusted for family history) but not ER+ cancer (1.2; 0.9,1.8). T levels in the highest vs. lowest quintile indicated a 5.5-fold (2.7, 11.4) increased risk of ER+ but not ER– cancer. E2 levels in the highest vs. lowest quintile increased risk of ER+ (2.8; 1.4, 5.3) but not ER– cancer (1.3; 0.3, 5.0). In multivariate models, T level, but not risk factors or E2, remained a strong predictor of ER+ breast cancer (RR = 4.2 {1.9, 9.4} for highest vs. lowest quintile). Conclusion: Risk factors for ER+ and ER– breast cancer differ. Conventional risk factors have little value for predicting ER+ breast cancer in older women. Testosterone level was the strongest risk factor for ER+ breast cancer and measuring T might identify women most likely to benefit from SERMs.

O33. VERTEBRAL OSTEOPOROSIS IN A COHORT OF BONE MARROW TRANSPLANT RECIPIENTS: PREVALENCE AND ASSOCIATED RISK FACTORS Rousie`re M1, Bergot C3, Mary JY4, Socie´ G2, Orcel P1; 1Fe´de´ration de Rhumatologie, Hoˆpital Lariboisie`re, 2rue Ambroise Pare´, 75010 Paris, France, 2Service d’He´matologie Greffe de Moelle, Hoˆpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France, 3 Service de Radiologie, Hoˆpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France, 4Centre de Bioinformatique, INSERM Unite´ 444, Universite´ Paris VII, France Aims: Osteoporosis commonly occurs after organ transplantation but little is known about its incidence after bone marrow transplantation (BMT). The purpose of this study was to examinate the lumbar bone density and to identify risk factors for osteoporosis after BMT. Patients and Methods: Lumbar spine bone mineral density was measured by dual-energy X-ray absorptiometry and gonadal hormonal measurements were performed in 105 adult allogenic BMT-recipients (55 women and 50 men, median age : 32 years), surviving free of haematological disease. Screening examination took place at a median time of 15 months post-transplantation (minimum 10 months). Clinical (bed rest duration, anthropometric characteristics) and therapeutic (cumulative prednisone-equivalent dose) variables were analysed using univariate and multivariate logistic regression to identify independent prognostic factors for osteoporosis.

S14

Abstracts

Results: The mean lumbar spine bone mineral density (BMD) was 0.959 g/cm2 (plus/minus 0.132), with no significant difference between males and females. T score was below –1 SD for 46.7% of the patients. According to the WHO definition (ie T-score 572.5), 32.6% of the patients were osteopenic, and 14.1% were osteoporotic. When considering a cut-off value of –1.5 for the definition of osteoporosis in glucocorticoid-treated patients, 32.6% of the patients had vertebral osteoporosis. Low BMD values at lumbar spine were correlated with immmobilization, as assessed by the length of hospital stay following transplantation, and with the cumulative prednisone dose. Using multivariate analysis, low BMD was associated with chronic graft-versus-host disease (GVHD) (OR: 3.9; p = 0.001). Conclusion: Our findings emphasize that low vertebral bone mineral density is common after BMT. Risk factors for osteoporosis in these patients include long-lasting prednisone therapy, and associated morbidities (bed rest and chronic GVHD). Early recognition, prevention and treatment of osteoporosis should be integrated components of the follow-up to improve life quality of this graft recipients.

O34. ORAL CORTICOSTEROIDS INCREASE FRACTURE RISK INDEPENDENTLY OF BMD Johnell O, De Laet C, Johansson H, Melton LJ, Eisman J, Reeve J, Tenenhouse A, McCloskey EV, Kanis JA; University of Sheffield, UK The adverse effects of corticosteroids on skeletal metabolism are well established, but it is unknown whether fracture risk is mediated solely by their adverse effects on BMD. The aims of this study were to examine whether BMD-independent effects contributed to fracture risk. We studied 5704 men and 12253 women aged 21-103 (mean = 52.1 years) from 5 prospective studies in which corticosteroid use and BMD was assessed at baseline. The studies comprised the Dubbo cohort (n = 2071; BMD measured at the femoral neck), the European Prospective Osteoporosis Study (EPOS; n = 4438; trochanteric BMD), Rochester cohort (n = 1000; lumbar BMD) Canadian Multicentre Osteoporosis Study (CAMOS; n = 8306; femoral neck BMD) and the Sheffield HIPS study (n = 2142; total hip BMD). Individuals were followed for a total of 65745 person years. Another cohort, the Rotterdam study, was used to estimate the prevalence of corticosteroids use in a population sample from a western European municipality (calculated by a logistic regression model). Poisson regression was used to examine the effects of steroid use (ever use), BMD and age on all fracture risk in each cohort. The results of the different studies were merged by calculating weighted means of b coefficients. Ever use of corticosteroids was associated with a significant increase in fracture risk, independently of BMD at all ages (see Table). Thus, corticosteroid use confers a risk of fracture of substantial importance beyond that explained by BMD. Moreover, a history of corticosteroid use augments the ability of BMD to characterise fracture risk in case finding strategies. Age (years)

Risk ratio

95% confidence interval

Prevalence (%)

Population RR

50 55 60 65 70 75 80 85

2.09 1.93 1.74 1.62 1.62 1.63 1.59 1.64

1.34–32.6 1.35–2.76 1.31–2.31 1.29–2.03 1.33–1.97 1.35–1.96 1.28–1.97 1.24–2.17

2.4 2.3 2.2 2.1 2.0 2.0 1.9 1.8

2.04 1.89 1.71 1.60 1.60 1.61 1.57 1.63

O35. A CALCIUM-VITAMIN D3 COMBINED SUPPLEMENTATION IS COST-SAVING FOR PREVENTING HIP FRACTURES IN INSTITUTIONALISED ELDERLY WOMEN : AN ECONOMIC EVALUATION FROM THE PERSPECTIVE OF SEVEN EUROPEAN COUNTRIES (BELGIUM, FRANCE, GERMANY, THE NETHERLANDS, SPAIN, SWEDEN, UNITED KINGDOM) Meunier PJ1, Pamphile R2, Chapuy MC1, Schulten J2, Arlot M3, Lilliu H4; 1Edouard Herriot Hospital, Lyon, France, 2Merck KGaA, Darmstadt, Germany, 3INSERM U. 403, Lyon, France, 4CLP Sante´, Paris, France Aims: To evaluate the cost-effectiveness of calcium and vitamin D3 combined supplementation for preventing hip fractures (HF) in institutionalised women, taking into account the medical costs in seven European countries. Methods: Our economic evaluation is based on the results of the 3-year placebo-controlled study Decalyos, in which 3,270 elderly women were randomised to two groups. One group received elemental calcium (1,200 mg) together with vitamin D3 (800 IU) daily, the other placebo. After 36 months of follow-up, the intention-to-treat analysis revealed 25% fewer HF in the active group versus the placebo group. Unit costs of supplementation with calcium and vitamin D3 and of HF were based on the specific published data from the aforementioned countries.This evaluation consists in computing an incremental cost-effectiveness ratio (ICER), which is defined as the ratio of the additional cost to the number of avoided HF with calcium and vitamin D3 supplementation compared to placebo. Results: This preventive strategy results in a significant net financial benefit ranging from E79,000 to E711,000 per 1,000 treated women depending on the country. The sensitivity analysis showed that the combined supplementation remains costeffective for all countries in the worse case hypothesis (+20% HF in the active group) and becomes highly cost-saving for all countries in the best case hypothesis (–20% HF in the active group). The target price analysis showed that the highest daily price that can be attained for the preventive treatment, such that overall costs to the healthcare system reach a break-even, ranged from E0.52 to E1.45 depending on the country (current treatment costs actually range from E0.29 to -E0.54). Conclusion: Our economic analysis strongly suggests that calcium and vitamin D3 combined supplementation for preventing HF in institutionalised elderly women could be both effective and cost-saving in several European countries.

O36. THREE-MONTHLY 2MG INTRAVENOUS IBANDRONATE BOLUS INJECTIONS SIGNIFICANTLY INCREASE BONE MINERAL DENSITY IN WOMEN WITH POSTMENOPAUSAL OSTEOPOROSIS Adami S, Delmas P, Felsenberg D, Christiansen C, Robinson J, Coutant K, Meinert R, Schimmer R, von Stein T; for the Ibandronate Intravenous Study Group Aim: Oral bisphosphonates (BPs) provide significant efficacy in the treatment of postmenopausal osteoporosis (PMO). However, due to inconvenient dosing requirements and low gastrointestinal (GI) absorption, intravenous (i.v.) formulations are being investigated. I.v. injections could be a convenient way to overcome GI safety concerns and ensure compliance. However, potential renal side effects mean that current i.v. BPs must be administered by slow infusions. Ibandronate is a potent, nitrogen-containing BP that can be administered intermittently as a bolus injection. This phase III study compared the efficacy and safety of 2 mg versus 1 mg ibandronate given as a 3-monthly i.v. bolus injection. Methods: In this multicentre, double-blind, placebo-controlled study, 520 women (aged 55–75 years, at least 5 years since menopause onset) with a mean bone mineral density (BMD) Tscore below –2.5 SD at the lumbar spine (L1-L4) were randomised to receive placebo (n = 128), i.v. ibandronate 1 mg

Abstracts (n = 131) or 2 mg (n = 261) as a 3-monthly bolus injection. All women received daily calcium (500mg) and vitamin D (400IU). The primary endpoint was relative change in BMD of the lumbar spine. Results: At 12 months, ibandronate 2 mg increased lumbar spine BMD by 5% compared to 3% with ibandronate 1mg (p50.0001) and 0.3% with placebo. Greater BMD gains were also observed at the femoral neck and trochanter. Ibandronate produced significant suppression of bone markers. The BMD increases and bone marker suppression achieved with 2 mg i.v. ibandronate were similar to those achieved with oral ibandronate (that has demonstrated a significant and substantial fracture reduction in a pivotal phase III study). I.v. bolus injections were well tolerated with a similar incidence of adverse events to placebo. No differences were found in laboratory parameters, including renal function. Conclusions: Quarterly 2 mg i.v. ibandronate bolus injections are well tolerated and more effective than 1mg. The BMD increases with 2 mg are consistent with those observed in an oral study that demonstrated significant fracture benefit. I.v. administration offers a promising, convenient alternative to current oral BP therapy in the treatment of women with PMO.

O37. ORAL IBANDRONATE SIGNIFICANTLY REDUCES FRACTURE RISK IN POSTMENOPAUSAL OSTEOPOROSIS WHEN ADMINISTERED DAILY OR WITH A UNIQUE DRUG-FREE INTERVAL: RESULTS FROM A PIVOTAL PHASE III STUDY Delmas P, Recker R, Stakkestad JA, Chestnut III C, Hoiseth A, Weichselberger A, Huss H, von Stein T, Schimmer R; for the Oral Ibandronate Fracture Study Group Aim: Despite oral bisphosphonates (BPs) being widely recognised as an important treatment for postmenopausal osteoporosis (PMO), they are associated with stringent dosing recommendations due to their poor gastrointestinal (GI) absorption. Ibandronate, a highly potent nitrogen-containing BP, is being investigated as a convenient alternative to current BP treatment. This study was designed to investigate the fracture efficacy and safety of oral ibandronate administered either daily or with a novel extended drug-free interval of 42 months, in PMO. Methods: 2,946 women (aged 55–80 years, at least 5 years since onset of menopause) with a bone mineral density (BMD) Tscore below –2.0 SD at the lumbar spine in at least one vertebra (L1-L4) and 1–4 vertebral fractures were enrolled in this multinational, double-blind, placebo-controlled, pivotal phase III study. Patients were randomised to receive placebo (n = 982) or oral ibandronate given daily (2.5 mg; n = 982) or on alternate days for 12 doses every 3 months (20 mg; n = 982). Both ibandronate treatment arms received similar total doses. All patients received daily oral calcium (500 mg) and vitamin D (400IU). The primary endpoint was new vertebral fracture (VF) incidence after 3 years (ITT). Results: Daily and intermittent oral ibandronate significantly reduced the risk of radiologically confirmed VF by 62% and 50%, respectively compared with placebo. Significant clinical VF reduction was also shown in both groups. Both regimens significantly and consistently suppressed markers of bone turnover (urinary CTX, osteocalcin). A significant non-vertebral fracture reduction was observed in patients with a femoral neck BMD T-score below –3.0 SD. Oral ibandronate was well tolerated with no differences in upper GI tolerability between ibandronate and placebo. Conclusions: This pivotal study demonstrates that oral ibandronate is highly efficacious in reducing fractures associated with PMO. This is the first report of a fracture benefit with a Ncontaining bisphosphonate given with a drug-free interval of 42 months. Ibandronate holds promise as a convenient alternative to current BP therapy as it is effective, well tolerated and can be administered with an extended drug-free interval.

S15 O38. LONG-TERM PREVENTIVE EFFECT OF ALENDRONATE ON OSTEOPOROSIS: WHAT HAPPENED AFTER WITHDRAWAL OF TREATMENT? Bagger YB, Tanko´ LB, Alexandersen P, Christiansen C; Center for Clinical and Basic Research A/S Aim: Since their introduction bisphosphonates have revolutionized the prevention and treatment of osteoporosis. The aim of the present study was to investigate the long-term effect of alendronate following withdrawal of treatment. Methods: Study participants were 172 postmenopausal women aged 45–59 years who received therapy with alendronate (5–20 mg/day) for 2, 4 or 6 years in two placebo-controlled clinical trials. Overall follow-up time was 9 years. Bone mineral density (BMD) of the lumbar spine was measured using DEXA on a yearly basis during the studies and was revisited in 2001. Bone turnover markers (osteocalcin and CTx) were assessed at baseline and at the end of the follow-up period. Results: Women who received 5 mg alendronate for 2 years showed 3.1% higher BMD at the lumbar spine compared to those receiving placebo when reassessed 7 years after withdrawal. This residual effect on BMD was proportionally larger in those receiving treatment for 4 or 6-years. However, the largest residual effects on BMD assessed at the end of 7 years follow-up were found in the group receiving 20 mg alendronate for 2 years (9.6% compared to the placebo). CTx reversed after withdrawal of alendronate, but remained below values in the placebo group. Conclusion: These results indicate that 1) the efficacy of alendronate in preventing bone loss was proportional to the duration of the therapy, 2) after withdrawal of alendronate, the rate of bone loss corresponded to normal postmenopausal rate, 3) the residual effect of alendronate on spine BMD maintained after withdrawal of treatment.

Fig. 1. Mean percentage changes in spine BMD with alendronate treatment following withdrawal. * placebo; ^ 2 yrs alendronate; ~ 4 yrs alendronate; & 6 yrs alendronate; * 2 yrs 20 mg alendronate; Error Bars show Mean ± 1.0 SE O39. EFFECTS OF BASELINE VERTEBRAL BMD, AGE, PREVIOUS VERTEBRAL FRACTURE, FREE TESTOSTERONE, ESTRADIOL, SMOKING AND ALCOHOL ON THE RESPONSE TO TERIPARATIDE INJECTION (RHPTH [1–34] IN MEN WITH OSTEOPOROSIS Orwoll E1, Scheele WH2, Clancy A2, Adami S3, Syversen U4, DiezPerez A5, Gaich GA2; 1Oregon Health and Sciences University, Portland, OR, USA, 2Eli Lilly and Company, Indianapolis, IN, USA, 3 University of Verona, Valeggio sul Minicio (VR), Italy, 4University Hospital, Trondheim, Norway, 5Hospital del Mar, Barcelona, Spain Aim: To analyze effects of baseline covariates on vertebral BMD (vBMD) response to teriparatide.

S16

Abstracts of BMD data in the entire population including also the patient treated only for 12 months: Age group

n.

SPINE

n.

TOTAL HIP

0-6 0-12 0-18 0-24

46 46 31 31

3.0 3.6 4.6 6.9

29 29 19 19

1.2 3.5 5.5 7.6

± ± ± ±

6.4* 5.4* 6.0* 3.5*

± ± ± ±

3.5 3.9* 5.1* 6.3*

* p5 0.02 from baseline IV bisphosphonates has been shown to be of great benefit in children with severe OI. In this study we have shown for the first time that clinically significant BMD changes are obtained also in adult with type I OI. A trend for clinical fracture reduction (3/year vs 0.5/year) was also observed. The real benefit of this treatment in term of fracture events and for long term preservation of bone mass in older ages remains to be ascertained.

POSTER PRESENTATIONS Methods: In a double-blind clinical trial, 437 men with spine or hip BMD greater than 2 SD below young adult male mean were randomized to once-daily self-injection of placebo, teriparatide 20 microg or 40 microg plus supplemental Ca (1000 mg) and Vit D (400-1200 IU). The effects of baseline vBMD, age, previous nonvertebral fracture, free testosterone (fT), estradiol, smoking and alcohol intake were analyzed to determine whether they influenced response to teriparatide. Results: At baseline, 49% had low age-specific fT; 59% had previous fracture. Mean baseline vBMD was 0.87±0.14 g/cm2. After a median 11 months of exposure, vBMD increased by 5.9% and 9.0%, respectively, in the 20microg and 40microg groups (P50.001). Baseline vBMD stratified by tertiles influenced % change in vBMD (P = 0.030), but the absolute change did not differ between tertiles, indicating that the differences in BMD change were due to lower baseline vBMD, not a greater absolute BMD response. Age, previous fracture, fT, estradiol, smoking and alcohol intake had no influence on vBMD response. Smokers had lower baseline vBMD (P = 0.015), but the response to therapy was similar to nonsmokers. In a stepwise regression, therapy was the most important predictor of response. Conclusion: Teriparatide increased vertebral BMD in men regardless of age, previous fracture, sex steroid levels, smoking or alcohol intake.

O40. EFFECTS OF CYCLIC ADMINISTRATION OF INTRAVENOUS NERIDRONATE ON BONE DENSITY IN ADULT PATIENTS WITH OSTEOGENESIS IMPERFECTA Colapietro F, Gatti D, Braga V, Bakri J, Rossini M, Corallo F, Adami S; Rheumatological Rehabilitation, University of Verona In an ongoing randomised clinical trial neridronate (2 mg per kg body weight up to a maximum of 100 mg) were given intravenously every three months to patients affected by Osteogenesis Imperfecta (OI). The study group includes 46 subjects (23 males and 23 premenopausal women) aged 34.9±7.9 (range: 21–50 y.o.) with OI type1 (n.38), type III (n. 2) and type 4 (n.6). The study population was randomized in 2 groups: the first started therapy at visit 1, the second one only after 12 months of follow up. In the control group during first 12 months no significant changes at lumbar spine BMD (70.84%±4.27), and at total hip BMD (–0.55%±4,3) were observed. In the neridronate treated patients BMD rose progressively up to 5.83%±3.48 and 6.89%±3.48 at hip and spine respectively at year 2. In the table are reported the changes (%)

P41SA. ONCE-A-WEEK (35 MG) RISEDRONATE IS AS EFFECTIVE AS DAILY (5 MG) Lindsay R1, Adachi JD2, Emkey RD3, Li Z4, Balske A4, Brown J5; 1 Helen Hayes Hospital, West Haverstraw, USA, 2McMaster University, Hamilton, Canada, 3Emkey Arthritis & Osteoporosis Clinic, Wyomissing, USA, 4Procter & Gamble Pharmaceuticals, Mason, USA, 5Le Centre Hospitalier Universitarie de Quebec, Quebec, Canada Risedronate (RIS) 5 mg daily reduces the risk of fractures, including hip fractures, and increases bone mineral density (BMD) in postmenopausal, osteoporotic women. The aim of our study was to determine an effective once-a-week (OaW) dose. This randomized, double-blind study enrolled women 50 years or older, 45 years postmenopausal with a lumbar spine (LS) BMD T-score 5–2.5 or 5–2 with at least one prevalent vertebral fracture. A rigorous, non-inferiority test was used to compare the daily and once-a-week doses. A total of 1456 women (RIS 5 mg daily, 480; RIS 35 mg OaW, 485; RIS 50 mg OaW, 491) took at least one dose of study medication. Significant increases in LS BMD were observed from baseline at 12 months in all treatment groups (4.00%, 3.94%, and 4.25% in the 5 mg daily, 35 mg OaW, and 50 mg OaW groups, respectively). The upper boundaries of the 95% CI for the difference between groups were 0.47% and 0.15% for the 35mg and 50mg groups, respectively. Total hip, femoral neck, and trochanteric BMD increased significantly from baseline in all treatment groups and differences between the daily and OaW treatments were 50.5%. At 12 months, reductions from baseline in NTx/creatinine were 60%, 61%, and 65% for the 5mg daily, 35mg OaW, and 50 mg OaW groups, respectively; the reductions in BAP were 42%, 41%, and 46%. Adverse event profiles were similar in all 3 groups. The 50 mg OaW dose provided no benefits over the 35 mg dose. RIS 35 mg OaW provides an effective, well-tolerated alternate dosing option to daily risedronate.

P42SU. WEEKLY DOSING OF ORAL IBANDRONATE IS EFFECTIVE IN THE PREVENTION OF POSTMENOPAUSAL OSTEOPOROSIS Felsenberg D, Christiansen C, Cerwinski E, Burdeska A, Jonkanski I, Meinert R; for the Oral Ibandronate Study Group Aim: Oral bisphosphonates (BPs) are becoming increasingly important in the prevention of postmenopausal osteoporosis

Abstracts (PMO). Weekly dosing of BPs may offer advantages over daily dosing in terms of patient preference, convenience and compliance. Ibandronate is a potent nitrogen-containing BP that can be administered intermittently. Oral ibandronate provides highly significant fracture reduction when administered with a drug-free interval of 9–10 weeks, in PMO. This phase II/III study investigated the efficacy, safety and optimal dose of oral weekly ibandronate in the prevention of PMO. Methods: In this multicentre, double-blind, placebo-controlled study, 630 postmenopausal women were randomised to one of four strata based on time since menopause (TSM) and baseline lumbar spine (L1–L4) bone mineral density (BMD): stratum A, normal BMD, TSM up to 3 years; stratum B, osteopenic, TSM up to 3 years; stratum C, normal BMD, TSM 43 years; and stratum D, osteopenic, TSM 43 years. Patients received calcium supplementation (500mg daily) plus oral weekly ibandronate 5mg (n = 159), 10mg (n = 154) or 20mg (n = 159) or placebo (n = 158) for 2 years. The primary endpoint was relative change from baseline in lumbar spine BMD (L1-L4). Results: After 2 years, oral weekly ibandronate produced a dose-related and consistent increase in BMD at the lumbar spine and hip (total hip, femoral neck, trochanter, Ward’s triangle), relative to baseline. Consistent results were seen across strata; greatest increases in lumbar spine BMD were seen with 20 mg in osteopenic women with TSM 43 years (stratum D: relative BMD increase from baseline 3.6% vs 2.9% across all strata vs –1.1% with placebo). The 10 mg dose maintained bone mass. BMD increases correlated with dose-dependent and sustained reductions in bone turnover markers. Oral weekly ibandronate was well tolerated and no safety concerns were identified. Conclusions: Oral weekly ibandronate provides dose-dependent increases in BMD at the lumbar spine and total hip. The most significant and substantial BMD gains are with 20 mg. Weekly oral ibandronate holds promise as an effective, well-tolerated and convenient alternative to oral daily BPs for the prevention of PMO.

P43MO. THREE-MONTHLY INTRAVENOUS IBANDRONATE BOLUS INJECTIONS: A NOVEL TREATMENT REGIMEN TO PREVENT POSTMENOPAUSAL BONE LOSS Stakkestad JA, Skag A, Nordby A, Burdeska A, Jonkanski I, Meinert R; for the Ibandronate Intravenous Study Group Aim: Oral bisphosphonates (BPs) are important for women unsuitable for HRT in the prevention of postmenopausal osteoporosis (PMO). However, conventional oral BPs have relatively stringent dosing guidelines that may reduce dosing convenience and compliance. Ibandronate, a potent nitrogencontaining BP, can be given as 3-monthly intravenous (i.v.) bolus injections that may overcome the limitations of oral administration. This phase II/III study investigated the efficacy, safety and optimal dose of ibandronate given as 3-monthly i.v. bolus injections in the prevention PMO. Methods: A total of 627 postmenopausal women were enrolled in this multicentre, double-blind, placebo-controlled dose-finding study (2-year design but prematurely terminated at 1 year). Patients were randomised to one of four strata according to BMD T-score at the lumbar spine (L1-L4) and time since menopause (TSM): stratum A, normal BMD, TSM up to 3 years; stratum B, osteopenic, TSM up to 3 years; stratum C, normal BMD, TSM 43 years; and stratum D, osteopenic, TSM 43 years. Patients received daily calcium supplementation (500 mg) plus either ibandronate 0.5 mg (n = 157), 1mg (n = 156) or 2 mg (n = 158) given as an i.v. bolus injection every 3 months or placebo (n = 156) for 1 year. The primary endpoint was relative change from baseline in lumbar spine BMD (L1-L4). Results: After 1 year, ibandronate produced significant and dose-dependent increases in lumbar spine and hip BMD, relative to baseline. Consistent results were seen across strata; greatest increases in lumbar spine BMD were seen with 2 mg i.v.

S17 ibandronate in osteopenic women with TSM 43 years (stratum D: 2.88% vs 2.50% across all strata vs –0.37% with placebo). BMD increases correlated with dose-dependent and sustained reductions in bone turnover. Therapy was well tolerated, in agreement with other studies. Conclusions: Three-monthly i.v. ibandronate bolus injections produce significant and dose-dependent increases in lumbar spine and hip BMD, and sustained suppression of bone turnover. Ibandronate 2 mg was the most efficacious dose. This is the first study demonstrating efficacy and tolerability of a BP given as 3monthly i.v. bolus injections in the prevention of PMO.

P44SA. EFFECTS OF RISEDRONATE ON RISK OF FEMORAL NECK AND INTERTROCHANTERIC FRACTURES Geusens P1, Adami S2, Bensen WG3, Miller PD4, Meunier P5; 1 Biomedical Research Institute-LUC, Diepenbeek, Belgium, 2 Centro Ospedaliero Clinicizzato di Valeggio, Valeggio, Italy, 3 McMaster University, Hamilton, Canada, 4Colorado Center for Bone Research, Denver, USA, 5Hopital Edouard Herriot, Lyon, France The Hip Intervention Program was the largest, randomized, placebo-controlled trial (N = 9331) designed to investigate the effects of risedronate (RIS) on hip fracture risk. The study enrolled 2 groups of women: those aged 70 to 79 years who had low femoral neck BMD, and women aged 80 years and older who had risk factors for hip fracture. Overall, RIS significantly reduced hip fracture risk by 30% over 3 years. In women age 70–79 with confirmed osteoporosis, RIS reduced the risk of hip fractures by 40% over 3 years; a reduction of 60% was observed in these women who also had a prevalent vertebral fracture. Although there is evidence that femoral neck (FN) and intertrochanteric (IT) fractures differ in their pathophysiology, little is known about the effects of treatment on these 2 types of fracture. Because of its size, the HIP study database provides a unique opportunity to investigate the effects of treatment on the incidence of each type of fracture. In the younger, osteoporotic women, RIS reduced the risk of IT fractures by 46% (0.5% vs. 1.0%; p = 0.089) and of FN fractures by 39% (1.2% vs. 1.9%; p = 0.048). In the older women with clinical risk factors, RIS reduced the risk of IT fractures by 40% (1.4% vs. 2.2%; p = 0.07), but did not change the risk of FN fractures (2.7% vs. 2.7%; p = 0.77). These findings are consistent with previous research indicating that there is a stronger relationship between low BMD and IT fractures in women over 80, while nonskeletal factors (such as propensity to fall) contribute proportionally more to FN fractures in older patients. Among older women (480 years), FN and IT fractures appear to respond differently to treatment, which supports the hypothesis that these fractures differ in pathophysiology.

P45SU. EFFICACY OF ONCE-A-WEEK RISEDRONATE IN REDUCING VERTEBRAL FRACTURE RISK Watts NB1, Li Z2, Hoseyni MS2, Seeman E3, Lindsay R4; 1 University of Cincinnati, Cincinnati, USA, 2Procter & Gamble Pharmaceuticals, Mason, USA, 3University of Melbourne, Melbourne, Australia, 4Helen Hayes Hospital, West Haverstraw, USA Risedronate (35 mg) once-a-week (OaW) and 5 mg daily increase BMD and reduce bone remodeling comparably. Antifracture efficacy could not be evaluated due to lack of a placebo group in the OaW trial. To estimate the efficacy of OaW

S18

Abstracts

risedronate in reducing the risk of new vertebral fractures at one year, placebo and 5 mg daily risedronate groups were constructed by matching patients from the risedronate Phase III vertebral fracture studies to patients in the OaW trial using OaW’s enrollment criteria. Comparison of important baseline characteristics indicated high degree of similarity between the constructed placebo and 5 mg groups, and the 35 mg once-aweek and 5 mg daily groups from the OaW study (mean lumbar spine T-score: –3.17 to –3.03; mean age: 67.6 to 68.1; % w/ prevalent fractures: 34.8% to 35.7%). The incidence of vertebral fractures and relative risks at one year are provided in the table below. Group

Incidence

RR (95% CI)

p-value

5 mg daily (Phase III) 5 mg daily (OaW study) Placebo (Phase III) 35 mg OaW (OaW study)

1.7% 1.5% 5.0% 1.2%

– 0.88 (0.16,9.0) 1.00 – 0.23 (0.05, 0.91) 0.018

No statistically significant difference was observed in fracture incidence for the 5 mg groups from the phase III (1.7%) and OaW (1.5%) studies. Compared to matched placebo, OaW treatment reduced the risk of new vertebral fractures by 77% within one year. This is consistent with previously reported one-year fracture efficacy of daily risedronate.

P46MO. RISEDRONATE SIGNIFICANTLY REDUCES OSTEOPOROSIS-RELATED NONVERTEBRAL FRACTURE RISK IN JUST ONE YEAR Bensen WG1, Ribot C2, Bolognese M3, Currie A4, Geusens P5; 1 McMaster University, Hamilton, Canada, 2Hopital Rangueli, Toulouse, France, 3Bone Health Center, Bethesda, USA, 4Procter & Gamble Pharmaceuticals, Staines, UK, 5Biomedical Research Institute-LUC, Diepenbeek, Belgium Four clinical studies conducted in Europe and North America were analyzed (n = 4845) to evaluate the one-year treatment effect of risedronate on reducing osteoporosis (OP)-related nonvertebral fractures (clavicle, humerus, wrist, hip, pelvis, leg). Women less than or equal to 80 years old were enrolled in 2 of these studies (BMD-NA and BMD-MN), based on low lumbar spine BMD (T-score 5–2.0). In the other two (VERT-NA and VERT-MN), women less than or equal to 85 years old and at least 5 years postmenopausal were enrolled based on low lumbar spine BMD (T-score 5–2) and one prevalent vertebral fracture (VERT-NA) or two or more prevalent vertebral fractures (VERT-NA and VERTMN). All patients received either placebo or risedronate 5 mg daily. Patients also received a calcium supplement (1 g/d). Vitamin D supplements were provided (500 IU) if baseline serum 25-OH Vitamin D levels were low. Two types of populations were investigated: all patients from the ITT population and subjects from ITT with a lumbar spine Tscore 5–2.5. Nonvertebral fractures were collected as adverse events and confirmed radiographically. Kaplan-Meier estimates were used to derive the percent of patients who had an incident nonvertebral fracture. Across all trials, in the ITT population, there was an overall statistically significant 40% reduction in OPrelated nonvertebral fractures in 1-year. In ITT women with low baseline lumbar spine BMD (T-score 5–2.5), risedronate was associated with significant 74% (p = 0.001) nonvertebral fracture risk reduction in 1-year. The fracture risk reduction at 1-year in this population in the BMD studies was 88% (p = 0.015) and was 66% in the VERT studies (p = 0.027). In conclusion, in postmenopausal women, risedronate significantly reduced OP-related nonvertebral fracture risk in just 1 year.

P47SA. ONCE WEEKLY ALENDRONATE PRODUCES A GREATER DECREASE IN BONE RESORPTION THAN DAILY RISEDRONATE. Hosking D1, Adami S2, Felsenberg D3, Reginster JY4, Cannata J5, Valimaki M6, Santora A7, Suryawanshi S7; 1Nottingham City Hospital, Nottingham, UK, 2Ospedale Valessio, Verona, Italy, 3 University Hospital, Berlin, Germany, 4Chu De Liege, Liege, Belgium, 5Hospital Central De Asturias, Asturias, Spain, 6Helsinki University Central Hospital, Helsinki, Finland, 7Merck Research Labs, Rahway, NJ We report the results of the first head-to-head trial designed to compare the efficacy of alendronate and risedronate for the treatment of osteoporosis. The 3-month, randomized, doubleblind, multicenter international study enrolled 550 postmenopausal women, 60-90 year old (mean, 69), with osteoporosis defined by low BMD T-score (either lumbar spine or total hip/femoral neck 4–2.5, or 4–2.0 at both sites). The primary endpoint was 3-month change in urinary N-telopeptides of type 1 collagen / creatinine (NTx), a marker of bone resorption. Patients maintained a calcium intake of at least 1000 mg daily through food and/or calcium supplements. Patients were randomized into three treatment groups: alendronate 70mg once weekly using standard am. dosing; risedronate 5mg daily dosed 2 hours after a meal and at least 2 hr before the next; or matching placebo for each. Results are based on an intention-to-treat analysis of urinary NTx for the initial 351 patients completing Month 3. In this study, alendronate produced a 50% greater reduction in bone resorption than did risedronate. This difference may be due to the superior anti-resorptive efficacy of alendronate 70 mg once weekly, reduced bioavailability of risedronate resulting from postmeal dosing, or both. Percent change in bone resorption from baseline at month 3 Placebo N=69

Urine Urinary NTx

Alendronate N=129

Risedronate N=139

Mean

Mean ±SE

Mean

Mean ±SE

Mean

Mean ±SE

–10.5

(–15.5, –5.2)

–55.1***

(–57.2, –52.9)

–36.0***

(–38.7, –33.1)

***:p<=0.001: Within-treatment test of mean=0 Tests for between treatment comparison of Alendronate Vs Risedronate, Alendronate Vs Placebo, and Risedronate Vs Placebo had p-values <0.001.

P48SU. BMD AND FRACTURE EFFECTS OF MONOFLUOROPHOSPHATE (MFP) COMBINED WITH RALOXIFENE (RLX) AS COMPARED TO MFP ALONE IN POSTMENOPAUSAL WOMEN WITH LOW BONE MASS Reginster JY1, Felsenberg D2, Gluer CC3, Stepan J4, Schmitt H5, Quail D5, Pavo I5, Nickelsen T5; 1Bone and Cartilage Metabolism Unit, University of Liege, Belgium, 2Center of Muscle and Bone Research, Free University Berlin, Germany, 3Department of Radiology, University Hospital Kiel, Germany, 4Department of Internal Medicine 3, Charles University Prague, Czech Republic, 5 Lilly Research Laboratories, Indianapolis, USA The aim was to determine whether combining raloxifene with fluoride treatment influences the BMD response and fracture risk associated with fluoride treatment alone.Postmenopausal women with low bone mass (average age of 61.9 and baseline femoral neck T-score of –2.87, 25% of patients had preexisting vertebral fractures) were randomized to 20 mg/day fluoride (as MFP) and 60 mg/day RLX (MFP+RLX arm, N = 300) or 20 mg/day fluoride and placebo (MFP arm, N = 296) for 18 months. All patients received calcium (1000 mg/day) and vitamin D (500 IU/day) supplements.

Abstracts BMD (primary endpoint: femoral neck), clinical nonvertebral and radiologic osteoporotic vertebral fractures were assessed at baseline and after 18 months. BMD increases at endpoint were significantly greater at all measurement sites in the MFP+RLX group than in the MFP group. In the MFP group, treatment was associated with no significant change in BMD at the femoral neck (+0.33%; p = 0.558) and a decrease at the total hip (–0.42%; p = 0.023). In contrast, the MFP+RLX group had mean BMD increases of 1.37% (p50.001) at the femoral neck and of 0.89% (p = 0.001) at the total hip. The BMD changes at the lumbar spine were 5.47% and 8.80% (p50.001 for each), respectively. In the MFP group, 22 patients sustained 33 incident osteoporotic fractures (vertebral and nonvertebral combined), as compared with 16 fractures in 15 patients in the combination group (p = 0.056); the numbers of patients with multiple fractures were 8 and 1 (p = 0.020) for the MFP and MFP/ RLX groups, respectively. Separate analyses of vertebral and non-vertebral osteoporotic fractures showed fewer patients with fractures in the MFP+RLX group but the differences were not statistically significant. We conclude that adding RLX 60 mg/day to fluoride therapy for 18 months in postmenopausal women with low bone mass results in a favourable effect on BMD and tends to decrease the risk of osteoporotic fractures.

P49MO. THE PRESERVATION OF BONE ARCHITECTURE AND STRENGTH BY RISEDRONATE (RIS) – INVESTIGATION BY 3D MICROCT Dufresne TE, Borah B, Chmielewski PA, Gross GJ, Prenger MC, Phipps RJ, Manhart MD; Procter & Gamble Pharmaceuticals, Mason, USA RIS reduces the risk of new vertebral fractures by up to 70% within the first year of treatment. While the mechanism of antifracture benefit is not fully understood, changes in bone architecture may play a role. Our aim was to evaluate the effects of RIS on trabecular architecture and bone strength in minipigs and humans. In one study, 18-month-old Sinclair minipigs were ovariectomized (OVX) and treated daily with RIS for 18 months. Vertebral bone samples were analyzed by 3dimenisional microcomputed tomography (3D microCT) and subjected to biomechanical testing. In a second study, we used 3D microCT to analyze architectural changes in paired iliac crest biopsy samples (baseline & 3 year) from postmenopausal osteoporotic (PMO) women treated with 5 mg RIS or placebo for 3 years. In the minipigs, RIS (2.5 mg/kg) preserved trabecular architecture as evidenced by significantly higher bone volume, trabecular thickness, trabecular number, and connectivity in comparison with the OVX controls. Treatment also resulted in a significant preservation of cross-struts (trabeculae orthogonal to the spinal axis). Biomechanical analysis showed that the changes in architectural parameters contributed significantly to bone strength. In the PMO women, after consideration of baseline bone turnover, we observed a deterioration of trabecular architecture in the placebo group (n = 8 pairs), including decreases in bone volume (p = 0.016) and trabecular thickness (p = 0.024), and increases in structural model index (p = 0.014) and Bone Surface/Bone Volume (p = 0.008). In the RIS group (n = 11 pairs), the bone volume and the architectural parameters did not change. 3D microCT indicates that RIS preserves trabecular architecture in PMO women, which is tightly coupled to bone strength as shown in a relevant large animal model. Pre-clinical and clinical data support our hypothesis that preservation of trabecular bone architecture contributes to risedronate’s antifracture benefits.

S19 P50SA. LONG-TERM ALENDRONATE THERAPY FOR THE PREVENTION OF POSTMENOPAUSAL OSTEOPOROSIS: SIXYEAR RESULTS FROM THE EPIC STUDY Wasnich R1, McClung M2, Workman P2, Christiansen C3, Ravn P3, Hosking D4, Wu M5, Kaur A5, Mantz AM5, Snodgrass S5, A. Santora5 for the EPIC Study Group; 1Radiant Research, Honolulu, Hawaii, 2Oregon Osteoporosis Center, Portland, Oregon, USA, 3 CCBR, Ballerup, Denmark, 4City Hospital, Nottingham, UK, 5 Merck Research Laboratories, Rahway, NJ, USA Alendronate (ALN) is an established treatment for the prevention of osteoporosis. We now report the long-term effects of continuous treatment with alendronate versus placebo for 6 years in the Early Post-menopausal Interventional Cohort (EPIC) study. Results through four years were previously reported (Hosking et al. NEJM 338:485-92, 1998; Ravn P, et al. Ann Intern Med 131:935-42, 2000). 1609 healthy early postmenopausal women, aged 45–59 years, were randomized to placebo (PBO), ALN 2.5 or 5 mg daily, or estrogen/progestin (E/P). After 4 years, active treatment with ALN was switched to placebo in a proportion of patients, and all E/P patients were off therapy. Bone mineral density (BMD) was evaluated at the lumbar spine, hip, forearm and total body at baseline, and then annually. Adverse experiences (AEs), including upper gastrointestinal events (GI) and fractures, were recorded throughout the study. Patients who continued to receive alendronate 5 mg for 6 years experienced significant gains in mean lumbar spine, hip femoral neck, hip trochanter and total hip BMD, that were maintained through 6 years (Table). In contrast, BMD steadily decreased in the placebo group. The tolerability of both alendronate 5 mg and 2.5 mg daily continued to be good through Year 6, with AE incidences (including upper GI) similar to placebo. Fractures occurred in 11.5, 10.3, and 8.9% of patients in the PBO, ALN 2.5 mg and 5 mg, groups, respectively. Over the entire six-years of treatment, patients who continued to receive alendronate experienced significant gains in mean lumbar spine, hip femoral neck, hip trochanter and total hip BMD, that were maintained through 6 years. Mean Change in BMD from Baseline at Month 72 Lumbar Spine{

Total Hip

Femoral Neck

Trochanter

Total Body

Treatment

n

%

n

%

n

%

n

%

n

%

PBO ALN 2.5 mg ALN 5 mg

230 150 149

–3.2 1.5 3.4

230 150 149

–2.3 1.5 2.6

230 150 149

–3.5 0.5 1.0

230 150 149

–2.1 2.9 4.4

226 149 146

–3.7 –1.3 –0.4

{

Primary endpoint; all differences between ALN and PBO p<0.001

P51SU. A NOVEL PTHRP ANALOG WITH DECREASED CALCIUM-MOBILIZATION POTENTIAL, BUT WITH ENHANCED BONE BUILDING ACTIVITY Culler MD1, Dong JZ1, Taylor JE1, Carlile L1, Sullivan T1, Bonin P1, Fisch C2, Be´cret A2, Legrand JJ3, Woon CW1; 1Biomeasure, Inc., Milford, MA, USA, 2CIT, Evreux, France, 3Beaufour-Ipsen, Paris, France While hPTH1-34 is well recognized to effectively restore bone mineral density (BMD) in osteopenic individuals, concomitant stimulation of bone resorption, especially in cortical regions, and induction of transient hypercalcemia, remain areas of concern. We have recently identified a novel analog of hPTHrP1-34, BIM44058, with greater potency than hPTH1-34, yet with lower calcium mobilizing potential. In adult rats made osteopenic by ovariectomy, both hPTH1-34 and BIM-44058 induce dose-related increases in BMD when administered as once daily, subcutaneous injections for 4 weeks; however, BIM-44058 is 2x more potent than hPTH1-34 (ED50 BIM-44058 = 0.87 mg/kg versus ED50 hPTH1-34 = 1.75 mg/kg). Full restoration of BMD is attained

S20 with 2.5 mg/kg BIM-44058. Histological analysis of the femurs revealed high-quality, mature bone growth in response to BIM44058. The enhanced potency of BIM-44058 in restoring BMD may be due to it’s activity at the hPTH-1 receptor. In HEK293 cells transfected with the hPTH-1 receptor, BIM-44058 stimulates cAMP production with an ED50 2.4x lower (ED50 = 0.17 ± 0.06 nM) than hPTH1-34 (ED50 = 0.40 ± 0.16 nM)) and 2.8x lower than it’s parent compound, hPTHrP1-34 (ED50 = 0.48 ± 0.13 nM). Despite having greater potency than hPTH1-34, BIM-44058 is less active than hPTH1-34 in mobilizing calcium at higher doses. In young male rats maintained on a calcium-free diet for 4 days prior to being parathyroidectomized, both hPTH1-34 and BIM-44058 stimulate dose-related increases in plasma calcium levels; however, at higher doses, the calcium mobilizing activity of BIM-44058 sharply plateaus while hPTH1-34 continues to increase plasma calcium. The observed lower calcium mobilizing potential of BIM-44058, as compared with hPTH1-34, coupled with the ability of BIM-44058 to achieve comparable BMD restoration at lower doses, suggests that BIM-44058 may have a wider safety margin than PTH1-34. These qualities make BIM44058 an attractive candidate for non-parenteral delivery options.

P52MO. SUSTAINED SUPPRESSION BY 50% BELOW PREMENOPAUSAL LEVELS OF THE MARKER OF BONE FORMATION (PINP) IN POSTMENOPAUSAL WOMEN TREATED WITH ALENDRONATE Stepan JJ, Michalska´ D, Vokrouhlicka´ J; Charles University Faculty of Medicine, Prague, Czech Republic Aim: Alendronate increases bone strength and decreases fracture rate during the first 4 yr of use. Surprisingly, during yr 6 and 7, 3.3%/yr of women taking alendronate had a clinical vertebral fracture (JCEM 2000;85:3109). In the women taking alendronate for 3 yr, the mineralisation of bone was 11% higher and the activation frequency was 91% lower than in patients with placebo (Bone 2000;27:687). The aim of this study was to compare markers of bone remodeling after long-term alendronate treatment with those in premenopausal women. Methods: The study involved 85 healthy premenopausal women and 80 women with postmenopausal osteoporosis treated with alendronate (10 mg/day) for 3.6 ± 0.6 yr, who were responders (Osteoporos Int 2000;11:2). Serum aminoterminal propeptide of type I collagen (PINP) was measured by a radioimmunoassay (Orion Diagnostica). Serum type 1 collagen cross-linked C-telopeptide (S-betaCTX) was measured using the Elecsys (Roche). Results: The increase in the spine and femur BMD, and decrease in serum CTX and PINP concentrations (p50.01) in patients treated with alendronate was similar to that observed elsewhere (Clin Chim Acta 1999;288:121). In the treated patients, serum CTX (mean 136 ng/l, 1 SD range 76-245 ng/l) was 58% below the mean premenopausal values (mean 322 ng/l, 1 SD range 254-408 ng/l) (p50.01) and serum PINP (mean 18.3 ug/l, 1 SD range, 12–27 ug/l) was 47% below the mean premenopausal values (mean 35.1 ug/l, 1 SD range, 24–52 ug/l) (p50.01). Conclusion: Evaluation of consequences on bone quality of the long-term profound suppression of bone formation rate in postmenopausal women treated with alendronate is needed.

P53SA. BIM-44058, A NOVEL PTHRP ANALOG, RESTORES BMD BY SELECTIVELY INCREASING BONE FORMATION IN OLD OVARIECTOMIZED OSTEOPENIC CYNOMOLGUS MONKEYS Legrand JJ1,4, Fisch C2, Guillaumat PO2, Be´cret A2, Dong JZ3, Woon CW3, Forster R2, Claude JR4, Culler MD3; 1Beaufour-Ipsen, Paris, France, 2CIT, Evreux, France, 3Biomeasure Inc, Milford MA, USA, 4Faculty of Pharmacy, Paris, France BIM-44058, a novel analog of human PTH-related protein (1-34) (hPTHrP1-34), was evaluated for bone anabolic activity in elderly,

Abstracts ovariectomized, osteopenic cynomolgus monkeys. Old female monkeys were either ovariectomized (OVX) or sham-operated (SHAM), and were maintained for 10 months before treatment to allow development of osteopenia in the OVX animals. The OVX, osteopenic animals were treated daily by subcutaneous bolus injection with either vehicle (saline) (n = 7) or BIM-44058 at the doses of 1 mg/kg/day (n = 10) or 10 mg/kg/day (n = 8) for 10 months. SHAM animals (n = 13) remained untreated. Bone mineral density was almost completely restored within 3 months of treatment with 10 mg BIM-44058/kg/day, and within 6 months of treatment with 1 mg BIM-44058/kg/day. This bone anabolic effect was achieved by a selective stimulation of bone formation, as reflected by early increases in serum alkaline phosphatase activity and osteocalcin levels and by higher values of histomorphometric formation and mineralization markers (ObS/ BS, OS/BS and MS/BS) in treated animals as compared with SHAM and OVX control animals. Connectivity density was also higher in the vertebrae of treated animals than in control SHAM and OVX vehicle-treated animals. In contrast, biochemical and histomorphometric resorption markers only moderately increased in treated animals at the end of the 10-month treatment period. No deleterious effects were observed at cortical sites and cortical porosity in treated animals remained close to or lower than the values measured in OVX control animals. These results demonstrate that treatment with BIM-44058 at the doses of 1 and 10 mg/ kg/day has a strong anabolic effect on trabecular bone without deleterious effect at cortical sites in a recognized model of human osteoporosis in a bone-remodeling species.

P54SU. VERTEBRAL FRACTURE INCIDENCE IN POSTMENOPAUSAL OSTEOPOROTIC WOMEN TREATED WITH RISEDRONATE: THE ROLE OF PRE-TREATMENT BONE TURNOVER Seibel MJ1, Barton I2, Grauer A2; 1University of Sydney, Sydney, Australia, 2Procter & Gamble Pharmaceuticals, Geneva, Switzerland Previous evidence suggests that patients with vertebral osteoporosis and accelerated pre-treatment bone resorption (PBR) have greater gains in bone mass during anti-resorptive treatment than patients with lower PBR. To investigate whether these observations are also relevant with regard to fracture incidence (FI), we studied the effect of PBR on vertebral FI in the Risedronate (RIS) phase III clinical trials, including 1196 postmenopausal osteoporotic women from both the VERT and HIP programs. Bone resorption rate was assessed by urinary Deoxypyridinoline (uDPD; normative median (NM) = 15.4nM/ mM creat). FI was evaluated by vertebral radiographs taken at baseline, 1 and 3 years. Patients received 5 mg RIS or placebo, 1000 mg calcium and, if needed, 500 IU Vitamin D per day. As expected, the cumulative new vertebral FI in patients receiving placebo was significantly higher in those with PBR 4 NM compared to subjects with PBR 5 NM. In the pooled data set, RIS reduced the risk of new vertebral fractures after year 1 of treatment irrespective of PBR (RR5NM DPD 0.28, p = 0.032 vs. RR4NM DPD 0.33, p = 0.0001. In the osteoporotic patients from the HIP trial (T5 –2.5SD), there was a trend towards a higher vertebral fracture reduction in those with higher rate of bone resorption (treatment by low/high level interaction p = 0.11), which interestingly was not present in the subgoup with prevalent fractures (p = 0.99).We conclude that 5mg RIS reduces the risk of new vertebral fractures in postmenopausal osteoporosis irrespective of PBR. However, in certain subgroups there is a trend towards even higher efficacy in patients with accelerated PBR.

Abstracts

S21

P55MO. DEHYDROEPIANDROSTERONE REPLACEMENT THERAPY PREVENTS MALE SENILE BONE LOSS Gaudio A, Morabito N, Lasco A, Fazio P, Reitano N, Di Pietro C, Atteritano M, Basile G, Nicita-Mauro V, Frisina N; Department of Internal Medicine – University of Messina, Messina, Italy The aim of our study is to evaluate the effect of DHEA replacement therapy, on bone turnover, BMD, plasma levels of Testosterone, 17 beta-estradiol in a group of male patients with senile osteoporosis. Forty normal-weight, no smokers men (mean age 70 plus/minus 10 years) with senile osteoporosis (T-score 5–2.5 S.D.) and serum DHEAS levels 5 0.8 microg/ml were randomly assigned to receive for 1 year oral micronized DHEA (n = 20, 50 mg/die) at 8 a.m. every morning or an identical placebo tablet (n = 20) in a double blind fashion. Before inclusion, secondary osteoporosis and neoplastic prostatic disease were excluded. Plasma levels of DHEAS (microg/ml), testosterone [T] (ng/ml), 17-beta estradiol [E2] (pg/ml), osteocalcin [BGP] (ng/ml), urinary levels of hydroxyproline [HOP] (mg/g creat) and collagen crosslinks [PYR and D-PYR] (pmol/micromol creat) were measured at 0 and 12 months. At the same time bone mineral density (g/cm2) was evaluated by DXA at lumbar and femoral level. Biochemical parameters of patients treated with DHEA are presented in Table 1. In placebo-controlled patients there were not significant variations of these parameters. DHEA replacement therapy increased lumbar BMD by 3% (p50.05) and femoral BMD by 2% (p50.05) respect to placebo, but not respect to basal values. These results show that our group of senile patients had, at baseline, an unbalanced bone turnover with a low neoformation phase, that could be correlated with reduced levels of DHEAS, E2 and Testosterone, which are known for their anabolic activity on bone. In fact DHEA replacement therapy, able to improve the above-mentioned hormonal parameters, restored in these patients a physiologic bone turnover and prevented senile bone loss. Table 1

DHEAS T E2 HOP PYR D-PYR BGP

Baseline

12 months

0.58 ± 0.1 2.7 ± 0.5 20.9 ± 1.1 26.1 ± 8.3 102.7 ± 18.3 21.0 ± 2.8 10.4 ± 3.1

1.2 ± 0.2* 3.5 ± 0.6* 32.5 ± 11.8* 19.9 ± 4.5* 70.8 ± 11.3* 15.6 ± 2.9* 12.3 ± 2.7*

Data are expressed as mean plus/minus SD.* p50.05

P56SA. EFOPS – 2 YEAR RESULTS OF A 3 YEAR HIGH IMPACT EXERCISE STUDY FOR EARLY POSTMENOPAUSAL WOMEN Engelke K1, Kemmler W1, Weineck J2, Hensen J3, Kalender W1; 1 Inst. Med. Physics, Univ. Erlangen, Germany, 2Inst. Sport Sci., Univ. Erlangen, Germany, 3Klinikum Hannover Nordstadt, Germany Several recent exercise studies conducted in pre- and postmenopausal women demonstrated beneficial effects on bone mineral density (BMD). Exercise effects during early menopause, a period of large changes within the endo-crine system, are less well known. Here we report two-year results of EFOPS (Erlangen Fitness Osteoporosis Prevention Study), a three-year controlled exercise trial in 137 early (1-8 years) postmenopausal osteopenic women (–4DXA-T-Score4–2.5 at L1-L4 or total hip) undergoing a vigorous, combined high impact, strength, and endurance training. 86 women started in the train-ing group composed of 2 jointly held training sessions and 2 individual home sessions. 51 age-, BMD-, and BMI-matched subjects served as control. Both

groups were individually supplemented with Ca and Vit D according to a nu-tritional analysis. After 2 years 50 women exercising more than two sessions per week com-pleted the training group, 33 remained in the control group. Amongst others isometric strength parameters and bone mineral density (DXA: LS, total hip), were measured, and a detailed questionnaire was conducted at baseline, year one, and year two. BMD measured by QCT (LS) and DXA (forearm) were determined at baseline and year two. The table shows percentage changes between baseline and year two for a se-lection of relevant measured parameters. The fourth column denotes inter-group differences. Our results show that even in early postmenopausal women a dedicated exer-cise program can offset bone loss. Muscle strength and quality of life parame-ters were significantly improved in the exercise group and remained stable in the control group.

Variable (%-changes)

Exercise (n=50)

Control (n=33)

p

L1-L4: BMD (DXA) Total hip: BMD (DXA) L2-L4: trabecular BMD (QCT)* L2L4: cortical BMD (QCT) Trunc flexors: isometric force Trunc extensors: isometric force VO2max LS: pain-frequency index

+0.7 ± 2.9 –0.4 ± 2.5 +0.4 ± 3.7 +2.8 ± 4.1*** +40 ± 19*** +35 ± 21*** +14 ± 12*** –40 ± 24***

–2.3 –1.7 –6.5 –1.7 +2.0 –0.8 –0.4 +23

*** * *** ** *** *** *** ***

± ± ± ± ± ± ± ±

2.4*** 2.9** 6.1*** 4.4 13 12 11 22***

*n = 45 (exercise group), n = 33 (control group). The last column lists the significance (p-value) of differences between the exercise and the control group.

P57SU. SEVEN-DAY TRANSDERMAL MATRIX PATCH OF 17 BETA ESTRADIOL FOR PREVENTING POSTEMENOPAUSAL BONE LOSS: THE OSPREY STUDY Delmas PD1, Pamphile R2, Schlichting M2; 1Hopital Edouard Herriot, Lyon, France, 2Merck KGaA, Darmstadt, Germany Aim: To assess the efficacy on postmenopausal bone loss of three doses (25, 50 and 75 microg/day) of a seven-day matrix patch of transdermal 17beta estradiol (Fem7, Merck KGaA, Darmstadt, Germany) combined with sequential oral medroxyprogesterone acetate (5 mg/day for 12 days per 28-day cycle), versus placebo. Methods: A multinational, randomised, double-blind, parallelgroup, 2-year placebo-controlled study. Efficacy was assessed by bone mineral density (BMD) at lumbar spine (L2-L4) and hip, measured with dual-energy X-ray absorptiometry and bone markers (osteocalcin, bone-specific alkaline phosphatase, serum and urine pyridinium cross links). Results: 370 postmenopausal women were randomised. The intention-to-treat analysis of the annualised mean rate of change in BMD at lumbar spine showed a statistically significant doseresponse effect (p = 0.0001). The estimated mean differences to placebo per year and associated 95% confidence intervals were: at lumbar spine, 1.32% [0.12%, 2.53%], 3.57% [2.33%, 4.80%], 4.22% [2.94%, 5.51%], 2) at total hip: 0.42% [-0.82%, 1.65%], 2.40% [1.12%, 3.66%], 2.46% [1.11%, 3.73%], with estradiol 25, 50 and 75 microg/day, respectively. Corresponding response rates (BMD increase over baseline) were 1) at lumbar spine: 64.6%, 88.1%, 96.2% compared to 35.5% for placebo, 2) at total hip: 60.9%, 75.9%, 86.5% compared to 30% for placebo. In the estradiol groups, bone markers decreased significantly versus baseline and placebo. The matrix patch was well tolerated during the study period. Conclusion: At dosages between 25–75 microg/day, the sevenday matrix patch of estradiol is effective in preventing postmenopausal bone loss and is well tolerated. The 25-microg/day dose is an interesting option for older women who cannot tolerate higher doses.

S22

Abstracts

P58MO. ABSTRACT WITHDRAWN

P59SA. NON-RESPONDERS TO HRT IN EARLY POSTMENOPAUSAL YEARS:A 3-YEARS CLINICAL TRIAL Bruschi F, Rossi M, Daguati R, Fiore V, Di Pace R, Dal Pino D, Crosignani PG; I Obstetric Gynecologic Dept. University of Milan, Italy We performed a 3-y prospective clinical trial to evaluate the effect of HRT on bone loss in the first 3-y of menopause and the occurence of no-bone response to HRT. Two-hundred and ninety healthy postmenopausal women were enrolled. Each subject underwent at baseline and then yearly to lumbar (L2-L4) and left proximal femoral BMD measure by a dualenergy X-ray absorptiometry. A densitometric non-responder to HRT was defined as a woman with a 3-y BMD change equal or worse than the mean BMD change of the control group.80 women,who did not want any HRT were the control group, and 210 women were randomized to: group 1 (n.134) = CEE 0.625 mg/ d+ MPA 10 mg/d for 12 days, every 3mo.; group 2 (76) = transdermal 17B-E2 50 ug/d+MPA 10 mg/d for 12 days, every 3mo. 259 women completed the study. Our data show a median 5.3% BMD decline in the control group, after 3 years;whereas oral and transdermal HRT were equally effective(+3.3 and +4.1%, respectively)in preventing bone loss. Therefore oral and transdermal HRT were considered a whole group. We identified 13 women (7%) in the HRT group, who lost more than 5.3%in BMD after 3-y of therapy. In table 1 shows the main characterists of the women according to the bone sparing response. In conclusion, this prospective study shows that HRT is effective in preserving bone mass but 7% of early postmenopausal women do not have a favorable densitometric response to HRT. Smoking seems to be the major factor influencing the positive response of bone to HRT. Characteristics of the women according to the bone-sparing response Non-responders

Responders

Controls

n.

13

182

64

Age y(SD) YSM y(SD) BMI (SD) BMI522(%) Smoking (%) L1-L4(t0) %change 3y

51(3) 1.1(0.3) 23.9 (2.6) 31 38% 0.940 (0.149) –8.4 (2)

51(4) 1.6 (0.8) 24 (3.6) 39 12% 0.885 (0.139) 4 (5)

52 (3.4) 1.5 (0.7) 24.5 (3.9) 42 18% 0983 (0.159) –4.6 (5)

P60SU. REDUCTIONS IN NON-VERTEBRAL FRACUTRE WITH ALENDRONATE DEPEND ON BASELINE BMD: THE FOSIT STUDY. Black D1, Palermo L1, Pols H2; 1University of California, San Francisco, San Francisco, USA, 2Erasmus University, Rotterdam, The Netherlands Results from Fracture Intervention Trial (FIT) Clinical Fracture arm suggested that alendronate significantly reduced hip fractures and other non-vertebral fractures among women with lower hip BMD T-score. Those with higher hip BMD (T4–2.0) did not have reductions in non-vertebral fractures. However, there were significant reductions in vertebral fractures in all women with low bone mass (T 5–1.6). The HIP trial of risedronate did not show significant reductions in hip fracture in those over 80. Only about 25% of these women had BMD T-scores below –2.5.

To further examine whether risk reductions in non-vertebral fractures with bisphosphonates are more pronounced among women with lower BMD, we analyzed data from the Fosamax(TM) International Study (FOSIT). FOSIT was a 1 year randomized trial of 1908 women from 153 centers in 34 countries. Women had lumbar spine BMD T-scores 5–2. They were randomized to 10 mg. of alendronate or placebo. Baseline BMD was assessed on Hologic or Lunar densitometers. In this analysis, fracture reductions were compared across baseline BMD categories. Results are shown in the table below: Baseline hip BMD T

N

RR*

95% CI

4–2 –2 to –2.5 5–2.5 Overall

955 279 674 1908

1.2 0.32 0.26 0.53

(0.5, 2.9) (0.07, 1.5) (0.1, 0.7) (0.3, 0.9)

*Relative risk for non-vertebral fractures in alendronate vs. placebo

The risk reductions were larger among those with lower baseline BMD. The differences between the relative risks among the 3 categories were statistically significant (p = 0.04). This was mainly due to a lack of effect in women with hip BMD T4–2. Similar results were seen when women were classified according to other BMD sites. These results support the view bisphosphonates more strongly reduce risk of non-vertebral fractures among women with lower BMD.

P61MO. GENISTEIN PREVENTS BONE LOSS IN EARLY POSTMENOPAUSAL WOMEN Morabito N1, Gaudio A1, Crisafulli A1, Vergara C1, Lasco A1, D’Anna R2, Corrado F2, Pizzoleo MA1, Squadrito F3, Frisina N1; 1 Department of Internal Medicine, 2Department of Obstetrical and Gynecological Sciences, 3Department of Clinical and Experimental Medicine and Pharmacology – University of Messina, Messina, Italy The aim of the study is to evaluate and compare with hormone replacement therapy (HRT) the effect of the phytoestrogen genistein on bone metabolism and bone mineral density in postmenopausal women. We enrolled 90 healthy, ambulatory women who were 52 to 60 years of age, with a BMD ranged –1 to –2.5 SD T-score. Participants to the study were randomly assigned to receive for 1 year continuous HRT (n = 30; 1 mg 17 beta estradiol combined with 0.5 mg norethisterone acetate), the phytoestrogen genistein (n = 30; 54 mg/day) or placebo (n = 30). Urinary levels of the pyridinium cross-links and serum alkaline phosphatase were measured at baseline and 12 months following treatment, whereas bone mineral density of the antero-posterior lumbar spine and femoral neck (studied by dual-energy x-ray absorptiometry) was performed at baseline and after 12 months. No measured parameters were significantly modified by placebo administration at 12 months. Genistein treatment significantly reduced the excretion of pyridinium cross-links (PYR = –42% ± 12%; DPYR = –44% ± 16%; p50.001) and increased serum ALP (29% ± 10%; p50.05) at 12 months. Group of women treated with HRT had a similar decrease in excretion of pyridinium cross-links, but in contrast, decreased serum ALP levels either at 12 months (–22% ± 8%; p50.001). At the end of experimental period, genistein and HRT significantly increased bone mineral density (BMD) in femur (femoral neck: genistein = 3.6% ± 3%; HRT = 2.4% ± 2%; placebo = –0.65% ± 0.1%; p50.001) and in the lumbar spine (genistein = 3% ± 2%; HRT = 3.8% ± 2.7%; placebo = –1.6% ± 0.3%; p50.001). No significant modifications between HRT and genistein groups.

Abstracts The present study confirms the genistein positive effects on bone loss already observed in the experimental models of osteoporosis and indicates that the phytoestrogen reduces bone resorption and increases bone formation in postmenopausal women.

P62SA. PTH INHIBITS ADIPOCYTES AND INCREASES RED MARROW CONTENT IN THE PROXIMAL FEMUR OF NONHUMAN PRIMATES Ma L1, Zeng Q1, Turner CH2, Westmore M1, Jerome CP3, Sato M1; 1 Lilly Research Labs, Indianapolis, USA, 2Indiana University Medical Center, Indianapolis, USA, 3Skeletech, Bothell, USA PTH effects on cellular composition of the proximal femur were evaluated for ovariectomized cynomologus monkeys that were treated with 1 or 5 ug/kg/day sc PTH for 18 months or for 12 months followed by 6 months of withdrawal. PTH increased the strength of the proximal femur after 18 months of PTH treatment, with much of the enhanced strength retained after 6 months of withdrawal. Histomorphometry showed that PTH increased the number and activity of osteoblasts, with little to no effect on osteoclastic activity. PTH increased cancellous bone volume, trabecular number, trabecular connectivity, bone formation rate, and mineral apposition rate, with no effect on trabecular thickness. Interestingly, thickened trabeculae were associated with increased intratrabecular remodeling (tunneling), which may be a process by which PTH increased trabecular number and connectivity. Bone turnover decreased following withdrawal of treatment; however, improvements in trabecular bone volume, number, and connectivity were largely retained. Quantification of the cellular composition of the marrow showed a 100% increase in adipocytes in the femoral neck with ovariectomy (Ovx) compared to Sham controls. Both PTH groups had significantly fewer adipocytes compared to Ovx, with increased osteoblast number after 18 months. Adipocyte number was also reduced in both PTH withdrawal groups, indicating that even transient PTH treatment retards conversion of red to fatty marrow. Cortical bone analyses showed increased cortical thickness and area that was retained after 6 months of withdrawal. However, cortical bone porosity was increased by ovariectomy and further increased with PTH, although porosity declined with withdrawal of treatment. These data show that PTH effects on the proximal femur and femoral neck are not limited to bone but include inhibition of ovariectomy stimulated adiposity of the marrow. PTH preservation of red marrow may help to explain the rapidity of skeletal efficacy in monkey femoral necks, and suggest additional physiological benefits beyond the treatment phase.

P63SU. RALOXIFENE DECREASES BIOCHEMICAL MARKERS OF BONE TURNOVER IN MIDDLE AGED HEALTHY MEN WITH LOW BASELINE SERUM ESTRADIOL VALUES Uebelhart B1, Herrmann F2, Pavo I3, Rizzoli R1; 1Division of Bone Diseases, Department of Internal Medicine, Geneva, 2Department of Geriatrics, Geneva, 3Lilly Area Medical Center Vienna, Austria Raloxifene (RLX) is a Selective Estrogen Receptor Modulator which acts as an estrogen-agonist in bone of postmenopausal women. To investigate the effects of estrogen on bone remodeling in men without the risk of its feminizing action, we conducted a randomized RLX vs placebo (PBO) two-sequence crossover study in 43 healthy eugonadal men (mean age:56 years, range 49-70). Subjects were randomly assigned to receive either RLX 120 mg/day or PBO for 6 weeks followed by a 2-month washout period, before crossing over. RLX increased total testosterone (16.9±5.0 vs 14.9±4.2nmol/l, x±SD, +13%, p50.01), bioavailable testosterone (3.5±1.4 vs 3.2±1.1nmol/l, +9%, p = 0.02) and

S23 total estradiol (E2, 109.9±4.1 vs 99.2±3.8pmol/l, +11%, p50.002,). RLX decreased serum osteocalcin (OC) (17.8±5.9 vs 19.8±6.1 mg/l, –10%, p50.0003) and total alkaline phosphatase (Alk.Ph.) (58.4±17.2 vs 62.1±15.3U/l, -6%, p50.005) without significantly affecting urinary total deoxypyridinoline/creatinine (d-Pyr) (10.6±0.5 vs 10.8±0.4nmol/mmol, p = 0.46). To test the hypothesis whether serum E2 levels could influence the bone response to RLX, we used a logistic regression model to predict the decrease of d-Pyr in relation to baseline E2 as the independent variable. We thus determined a threshold of E2 of 101.8pmol/l which maximized both sensitivity and specificity of the predictive model. The 43 subjects were separated into 2 groups according to this E2 threshold. RLX 120 mg/day for 6 weeks decreased biochemical markers of bone turnover in middle-aged healthy men with baseline estradiol values below 101.8pmol/l, without any significant change in subjects with values above this threshold. These results could be related to an estrogen-agonist action of RLX in bone detectable in healthy men with lower estradiol levels. Baseline E2 (pmol/l) 5101.8 (N = 23)

Alk.Ph. OC D-Pyr

4101.8 (N = 20)

RLX 120

PBO

p-value

RLX 120

PBO

p-value

55.1±14.7 17.8±5.8 9.4±2.3

59.4±12.7 20.5±5.4 10.5±2.9

0.01 0.001 0.002

62.9±19.5 17.8±6.0 11.9±3.6

65.4±17.7 19.0±6.9 10.9±2.9

0.21 0.12 0.07

Results are expressed as means ± SD

P64MO. INFLUENCE OF ALENDRONATE ON BONE ALKALINE PHOSPHATASE AND BONE MINERAL DENSITY IN POSTMENOPAUSAL OSTEOPOROTIC WOMEN Korzh OM, Bondarenko TI; Ukrainian Research Institute of Therapy, Kharkov, Ukraine We have investigated changes resulting from alendronate therapy with an enzyme immunoassay for bone alkaline phosphatase (BAP) and compared it with bone mineral density (BMD) of the lumbar spine, hip, and total body. Methods: Subjects were drawn from a multicenter randomized, placebo-controlled trial of alendronate in postmenopausal women with osteoporosis. BAP level was measured at baseline and following 3, 6 and 12 months of therapy with either placebo (n = 112) or alendronate 10 mg/day (n = 107). All subjects also received 500 mg/day supplemental calcium. BMD was measured at baseline and following 3, 6, 12, 18, 24 and 36 months of therapy. To compare BAP and BMD at each site for identifying women that experienced a skeletal effect of alendronate, we calculated least significant change (LSC) values from the longterm intraindividual variability in each placebo-treated woman. Results: Median levels of BAP decreased by 34%, 44% and 43% at 3, 6 and 12 months, respectively, in alendronate-treated women (p50.0001 compared with baseline and with placebo). Following 6 months of alendronate therapy, 90% of the women had experienced a decrease in BAP exceeding the LSC. The greatest number of women similarly identified with BMD at any site (i.e. a gain in BMD exceeding the LSC) was 81% for spinal BMD at 36 months. All other sites were less than 70% at 36 months. Short-term changes in BAP were modestly associated with subsequent changes in BMD at all sites (Spearman’s rho 70.29 to –0.57, p50.05). Conclusions: Compared with BMD, BAP testing rapidly and sensitively identified skeletal effects of alendronate thus enabling appropriate drug monitoring of osteoporotic women. Though BAP changes were modestly predictive of BMD changes, the value of the bone marker tests is their ability to detect rapidly a skeletal effect of therapy.

S24 P65SA. CALCIUM-VITAMIN D SUPPLEMENTATION IN CLINICAL TRIALS OF OSTEOPOROSIS SHOULD BE TITRATED ON THE BASIS OF PRE-STUDY ASSESSMENTS Reginster JY1,2, Diez-Perez A3, Ortolani S4, Pors-Nielsen S5, Meunier PJ6; 1Bone and Cartilage Metabolism Unit, University of Lie`ge, Lie`ge, Belgium, 2WHO Collaborating Center for Public Health Aspects of Osteoarticular Disorders – Dept of Epidemiology and Public Health, University of Lie`ge, Lie`ge, B, 3 Hospital del Mar, Departamento de Medicina Interna, Barcelona, Spain, 4Centro Auxologica Italiano, Divisione di Endocrinologia, Milano, Italy Rheumatology and Bone Diseases, Edouard Herriot Hospital, Lyon, France Dose-finding studies have reported that 2g/day of Strontium Ranelate (SR) was the first treatment ever able to simultaneously decrease bone resorption and increase bone formation. After two years, this resulted in a significant increase in spinal and femoral BMD, while reduction in new vertebral fracture was observed during the second year. SR also revealed an outstanding safety profile. This new paradigm in the treatment of postmenopausal osteoporosis justified an extensive phase III program assessing the efficacy/safety of SR, with particular focus on its anti-fracture effects on the axial and appendicular skeleton (SOTI and TROPOS studies respectively). Regulatory agencies recommend that post-menopausal women (PMW) included in such trials, be adequately supplemented with calcium (Ca) and vitamin D (VitD). In order to correct any potential deficit in these parameters, a short-term (mean duration 101 days) run-in phase (FIRST study) was designed before inclusion in SOTI or TROPOS. A total of 9196 PMW from 12 countries were included in FIRST. Mean daily calcium intake was 754(± SD)334mg (range 57– 3606mg/day). 22.8% of the women had dietary intake below 500mg/day, 57.5% having 500-1000mg/day and 19.7% above 1000mg/day. Significant geographical variations were observed, ranging from a mean dietary Ca of 985mg/day in United Kingdom to 503mg/day in Hungary. A similar pattern was observed for circulating 25OHvitD levels with an overall mean of 40.9 (± SD) 29.3nmol/l (range 12–542) with 41.3% of women below 30nmol/l, 23.6% between 30 and 45nmol/l, 27.8% between 45 and 75nmol/l and only 7.3% over 75nmol/l. As for calcium intake, the distribution of 25OHvitD serum levels varied between countries, highest values being observed in Spain (51.8nmol/l) and lowest in Switzerland (30.3nmol/l). These data do not intend to constitute an epidemiological survey of Ca-vitD values in European countries and Australia. However, they reemphasize the differences observed in Ca-vitD in PMW depending upon their country of origin. We therefore suggest that, in order to obtain the most homogeneous study populations in clinical trials, Ca and vitD supplementations should be titrated on the basis of pre-study assessments.

P66SU. LONG-TERM EXPOSURE TO STRONTIUM RANELATE DOSE-DEPENDENTLY INCREASES BONE STRENGTH IN INTACT MALE AND FEMALE RATS Ammann P1, Shen V2, Robin B3, Bonjour JP1, Meyer JM4, Tsouderos Y3, Rizzoli R1; 1Div. of Bone Diseases, Dept of Internal Medicine, Geneva, Switzerland, 2SkeleTech Inc., Bothell, USA, 3 Inst. Recherches Internationales Servier, Courbevoie, France, 4 School of Dentistry, Geneva, Switzerland Earlier studies in rats have suggested that strontium ranelate (SR) stimulates bone formation and inhibits bone resorption. We have investigated the long-term effects of SR on bone strength and its determinants like bone mineral density (BMD; mg/cm2), microarchitecture and outer bone dimensions.Seven-week old intact female (30 animals/groups) and male rats (20 animals/ group) were fed respectively ad libitum a diet containing SR at a dose of 0-225-450-900 mg/kg/day and 0-625 mg/kg/day for 104 weeks. Ultimate strength (US;N) and stiffness were measured using a compression test for vertebral body and a bending test of

Abstracts the femur. Histomorphometry was evaluated in the secondary spongiosa of the proximal tibia (BV/TV: trabecular bone volume; Tb.Th: trabecular thickness; Tb.N: trabecular number; Tb.Sp: trabecular separation; OV/TV : osteoid volume).In females, the dose-dependent increase in bone strength was associated with a change of its two major determinants, i.e. BMD and microarchitecture (histomorphometry) (see table below) together with an increase of vertebral volume. No alteration of bone mineralization was observed as assessed by histomorphometry (no increase in OV/TV) and bone stiffness. Similar modifications of bone strength, BMD and dimensions were observed in the midshaft femur of females and in vertebrae and midshaft femur of males. In these males similar histomorphometric modifications were shown in the tibia and an increment of bone formation markers as well as of plasma IGF-I was observed.These results indicate that SR, even at high doses, does not impair mineralization but increases dose-dependently bone mass and bone strength in male and female rats. Dose of SR

Control

Vertebra US (N) 271±10 Vertebra BMD§ 187±2 Vertebra volume (microL) 69.8±1.2 BV/TV (%) 27.0±2.4 Tb.Th (microm) 74.4±5.3 Tb.N 3.5±0.1 Tb.Sp (microm) 216±13 OV/TV (%) 0.005±0.003

225 mg/kg/d

450 mg/kg/d

900 mg/kg/d

274±18 216±3* 70.6±6.1 34.2±2.7* 89.8±6.1* 3.8±0.1 180±9* 0.003±0.001

308±17 238±3* 70.6±1.1 35.0±2.0* 82.5±3.8* 4.2±0.1* 159±8* 0.002±0.001

327±17* 294±4* 74.3±1.4* 38.2±1.7* 83.5±4.5* 4.6±0.1* 135±5* 0.005±0.001

Values are means ± SEM; *indicates p50.05 vs control by ANOVA. §BMD was not adjusted for the amount of strontium incorporated into bone.

P67MO. EFFECTS OF RALOXIFENE 60 MG/DAY ON BONE MINERAL DENSITY AND BONE TURNOVER MARKERS IN HEALTHY POSTMENOPAUSAL ASIAN WOMEN Thiebaud D1, Crans G1, Kung A2, Limpaphayom K3, Gonzaga F4; 1 Lilly Research Laboratories, Indianapolis, Indiana, USA, 2 University of Hong Kong, Hong Kong, 3Chulalongkorn Hospital, Bangkok, Thailand, 4Philippine General Hospital, Manila, Philippines Aims: To determine the effects of raloxifene 60 mg/d (RLX), a selective estrogen receptor modulator (SERM), on lumbar spine bone mineral density (BMD) and serum biochemical markers of bone metabolism in healthy postmenopausal Asian women. Methods: This randomized, double-blind, placebo-controlled study enrolled 968 Asian women (mean age 57 years) from 10 countries. BMD was measured in 309 women from India, Indonesia, Malaysia and Thailand at baseline and 1 year. The bone turnover markers, serum osteocalcin and urinary Ntelopeptide normalized to creatinine, were assessed at baseline and 6 months in all women. Treatment-by-country interactions were determined by ANOVA, at a P = 0.10 significance level. Results: Overall, compared with placebo, RLX increased BMD by 1.85% at 1 year (P = 0.0003) and decreased osteocalcin and Ntelopeptide by 15.9% and 14.6% respectively (both P50.0001) at 6 months. The Table shows the percentage changes between placebo and RLX for each country, with asterisks (*) indicating significant differences (P50.05) between treatments. Women in Singapore had significant median decreases in osteocalcin (14.17%) and N-telopeptide (8.94%) from baseline. Women in Taiwan had a significant median decrease in N-telopeptide (9.52% from baseline), but the 10.16% decrease in osteocalcin was not significant from baseline. The treatment-by-country interactions were not statistically significant for BMD (P = 0.61), osteocalcin (P = 0.66) or N-telopeptide (P = 0.98), indicating that RLX had similar effects on these endpoints in each country. Conclusion: Raloxifene 60 mg/d has beneficial effects on BMD and bone turnover in postmenopausal Asian women.

Abstracts

S25

Country

BMD (mean % change)

Osteocalcin (median % change}

N-telopeptide (median % change)

Australia Hong Kong India Indonesia Malaysia Pakistan Philippines Thailand

not done not done 2.77* 0.92 1.76 not done not done 2.24*

–13.08* –14.97* –15.72* –7.86 –20.95* –9.89 –20.93* –19.16*

–11.24 –19.87* –21.20* –19.13* –19.67* –16.53 –13.01* –19.48*

P68SA. COMBINED CALCIUM AND VITAMIN D3 SUPPLEMENTATION TO PREVENT HIP FRACTURE IN ELDERLY WOMEN. A CONFIRMATORY STUDY: DECALYOS II. Chapuy MC1, Pamphile R2, Paris E3, Kempf C4, Schlichting M2, Arnaud S1, Garnero P1,3, Meunier PJ1; 1Edouard Herriot Hospital, Lyon, France, 2Merck KGaA, Darmstadt, Germany, 3Synarc, Lyon, France, 4Integrated Clinical Data, Ottrott, France Aims: To confirm the effects of a daily combined supplementation with calcium (1,200 mg) and vitamin D3 (800 IU) on hip fracture (HF) risk, femoral neck bone mineral density (BMD) and bone biochemical parameters in elderly women. Methods: A multicentre, prospective, randomised, doubleblind, parallel-group, 2-year placebo-controlled study. Efficacy was assessed by estimation of HF risk ratio and from BMD at femoral neck and distal radius, measured with dual/single-energy X-ray-absorptiometry, respectively. Serum intact parathyroid hormone (iPTH), 25 hydroxyvitamin D [25(OH)D], bone alkaline phosphatase, calcium and phosphate were also measured. Results: The intention-to-treat population [583 ambulatory institutionalised women (mean age 85.2 years, SD = 7.1)] was randomised to three arms: calcium plus vitamin D3 fixed combination group (199); calcium plus vitamin D3 separate combination group (190) and placebo group (194). The relative risk (RR) of HF in the placebo group compared to the active treatment group was 1.69 (95% CI = [0.96, 3.0]), which is similar to that found in Decalyos I (RR = 1.7; 95% CI = [1.0, 2.8]). The cumulative probability curve for HF started to deviate about 9 months after initiation of the trial. In a subgroup (114 patients), femoral neck BMD decreased in the placebo group (mean = 72.36% per year, SD = 4.92), while remaining unchanged in women receiving active treatment (mean = 0.29% per year, SD = 8.63). The difference between the two groups was 2.65% (95% CI = [–0.44, 5.75%]) with a trend in favour of the active treatment group. Both active regimens had similar biochemical effects with increased serum 25(OH)D and decreased serum iPTH. Conclusion: These data are in agreement with those of Decalyos I: calcium and vitamin D3 combined supplementation can 1) reverse senile secondary hyperparathyroidism, 2) reduce hip bone loss and the risk of HF in elderly institutionalised women.

P69SU. RISEDRONATE (RIS) PRESERVES TRABECULAR ARCHITECTURE IN EARLY POSTMENOPAUSAL WOMEN IN JUST 1 YEAR: A PAIRED BIOPSY STUDY USING 3D MICROCT Borah B, Dufresne TE, Chmielewski PA, Prenger MC, Manhart MD; Procter & Gamble Pharmaceuticals, Mason, USA RIS increases BMD at the spine and reduces morphometric vertebral fracture risk by up to 65% within the first year. Increases in bone mineral density (BMD) explain only about one third of the fracture reduction, suggesting that other factors such as the preservation of architecture contribute to bone strength and, consequently, to reduced fracture risk. We analyzed paired (baseline and 1 year) iliac crest bone biopsy specimens from early postmenopausal women, using three-dimensional micro-

computed tomography (3D microCT) to examine the effects of RIS on trabecular architecture. Biopsy samples were obtained from women (6–60 months postmenopausal) who were enrolled in a double-blind, placebo-controlled study evaluating the effects of RIS (5 mg/daily) on lumbar spine (LS) BMD. After 1 year, mean percent change from baseline in LS BMD was –2.9% in the placebo group and +1.4% in the RIS group. In comparison to the RIS group, the placebo group ( n = 12 pairs) showed decreases in bone volume (BV/TV) (p = 0.032), trabecular thickness (p = 0.061), and trabecular number (p = 0.025), and increases in trabecular separation (p = 0.014) and bone surface/bone volume (p = 0.051). These changes indicate a deterioration of trabecular architecture in the placebo group. In the risedronate group (n = 14 pairs), the bone volume and the architectural parameters did not change significantly from baseline. In summary, the data demonstrate that RIS preserves trabecular architecture in postmenopausal women within 1 year, which may contribute to the rapid antifracture benefit observed with this therapy.

P70MO. ACTIVATION OF THE RAT AND MOUSE CATIONSENSING RECEPTOR BY STRONTIUM RANELATE AND ITS MODULATION BY EXTRACELLULAR CALCIUM Coulombe J1, Faure H1, Robin B2, Tsouderos Y2, Ruat M1; 1CNRS, Laboratoire de Neurobiologie Cellulaire et Mole´culaire, CNRS, Gif/ Yvette, France, 2Institut de Recherches Internationales Servier, Courbevoie, France The extracellular cation-sensing receptor (CaSR) is involved in calcium homeostasis and is tightly regulated by local extracellular calcium. This study was aimed to delineate the action of strontium ranelate, a therapeutic agent against osteoporosis, toward the rat and mouse CaSR. The cloned rat CaSR, transfected in Chinese hamster ovary (CHO) cells, and the mouse CaSR constitutively expressed in AtT20 cells, have been studied. The Sr2+ concentrations ranged from 0.1 to 15mM of Sr2+ in the presence of 0.3 or 2mM of Ca2+, or in the presence of 2mM Ca2+ in the culture medium. The activation of the CaSR was evaluated by the production of tritiated inositol phosphate (3H-IP). Results were obtained from 3 separate experiments performed in triplicate, and are expressed as mean ± SD. Strontium ranelate stimulated the 3H-IP response both in CHO(CaSR) and AtT20 cells and the activation was more pronounced in the presence of 2mM Ca2+. In AtT20 cells and in the presence of 2mM Ca2+, the effects of strontium ranelate began at 0.4mM Sr2+), and strontium ranelate induced a 15-fold increase in the 3H-IP response at 5.4mM Sr2+. In CHO(CaSR) and in the presence of 0.3mM Ca2+, Sr2+ stimulated the 3H-IP response with an EC50 of 5.3 ± 0.8 mM (as compared to an EC50 of 4.2 ± 0.3 mM for Ca2+ alone) and with a maximal effect representing 80 to 100% of the maximal effect of calcium chloride. The effects of Sr2+ were more modest at 0.3mM Ca2+. These data indicate that activation of the CaSR by Sr2+ depend on the local concentration of Ca2+. Strontium ranelate, which has been shown to increase proliferation of preosteoblastic cells and to decrease osteoclasts activity, is an agonist of the rat and mouse CaSR with a lower affinity than Ca2+.

P71SA. SECONDARY OSTEOPOROSIS IN RHEUMATOID ARTHRITIS: EARLY ONSET AND EFFECTIVE INHIBITION OF BONE RESORPTION AFTER A SINGLE INFUSION OF THE TNF-a ANTIBODY INFLIXIMAB Dimai HP1, Mueller T2, Fahrleitner A1, Hermann J2; 1University Clinic of Graz, Endocrinology, Graz, Austria, 2University Clinic of Graz, Rheumatology, Graz, Austria Aims and background: Patients with rheumatoid arthritis (RA) are at increased risk of developing generalised osteoporosis. Among potentially underlying causes, the pro-inflammatory cytokine

S26 tumor necrosis factor-alpha (TNF-a) appears to play a key role, by (a) driving the production of other pro-inflammatory cytokines, (b) promoting differentiation of osteoclast-progenitors into mature osteoclasts, and (c) activating mature osteoclasts to resorb bone. The TNF-a antibody infliximab has been shown to be highly effective in relieving signs and symptoms of active inflammation in RA. We therefore hypothesised that infliximab could also act to prevent increased bone loss in these patients. Methods and Subjects: Twelve RA-patients irresponsive to methotrexate therapy received a single infusion of 10 mg/kg body-weight intraveniously. Blood samples were obtained twice before (i.e. visit –2 and visit –1), and 24 hours after (i.e visit +1) and 14 days (i.e. visit +2) after the infusion, respectively. The following parameters were determined: Disease activity score (DAS), c-reactive protein (CRP), serum b-CrossLaps, and osteocalcin. b-CrossLaps and osteocalcin were determined using an electrochemiluminiscence immunoassay (ECLIA)and measured on the ELECSYS 2010 immunoassay analyzer (Roche Diagnostics GmbH, Mannheim, Germany). Results: b-CrossLaps showed a 41% decrease at 24 hours after the infusion. At day 14, levels were still lower compared to pretreatment levels, albeit not significant. No effect was seen on serum levels of osteocalcin. As expected, DAS and CRP were significantly lower at 24 hours and 14 days after the treatment. No difference was seen between visit –2 and visit –1 in any of the measured parameters. Conclusion: We conclude that infliximab treatment of RA may be sufficient to inhibit bone resorption, probably without affecting bone formation. Furthermore, our findings raise the intriguing question as to whether infliximab could be sufficient to prevent or even treat secondary osteoporosis in RA patients, particularely if given repeatedly.

P72SU. A 104-WEEK TREATMENT WITH STRONTIUM RANELATE INCREASES VERTEBRAL BONE MASS WITHOUT DELETERIOUS EFFECT IN MICE Delannoy P1, Bazot D2, Robin B3, Tupinon-Mathieu I3, Marie PJ1; 1 Inserm U349 affiliated CNRS, Lariboisiere Hospital, Paris, France, 2Biologie Servier, Gidy, France, 3Institut de Recherches Internationales Servier, Courbevoie, France The aim of this study was to determine the long-term effects of strontium ranelate (SR) on vertebral bone metabolism in adult mice. SR (0, 200, 600, or 1800 mg/kg/d) was given in the diet to normal 6-week-old B6C3F1 male and female mice over 104 weeks. Strontium plasma levels were monitored throughout the study and the caudal vertebrae were removed at sacrifice in 20 male and 20 female per group, defleshed, fixed, embedded without decalcification and sectioned. The histomorphometric analysis was performed in the endosteal vertebral bone on 5microm-thick toluidine blue-stained sections while structural parameters were measured on unstained sections. SR dose-dependently increased plasma strontium concentration (0.015 to 0.181, and 0.023 to 0.266 mmol/L for treated males and females, respectively) as well as exposure to the drug, as reflected by the AUC0-24h (0.37 to 4.39, and 0.55 to 6.55 mmol.h/L for treated males and females, respectively). SR significantly increased bone mass as evidenced by a 25% and 59% increase in trabecular bone volume in females treated with 600 and 1800 mg/ kg/d, respectively. This was associated with a 27% and 62% significant increase in mineralized bone volume. Bone mass was also significantly increased by 17% and 38% in male mice treated with 200 and 1800 mg/kg/d, respectively. In parallel, SR significantly increased osteoblastic surface by 131% in males. In addition to this stimulatory effect on bone formation, a 52% decrease in osteoclast surface, and a dose-dependent decrease in osteoclast number (30% to 47%) was observed in female mice. Finally, SR even at the highest dose tested had no deleterious

Abstracts effects on bone mineralization (unchanged osteoid thickness in treated male and female groups compared with control animals). These results show that SR simultaneously increases bone formation and decreases bone resorption in male and female mice, which results in increased vertebral bone mass without deleterious effects on bone mineralization.

P73MO. CHF 4227.01 A NOVEL BENZOPYRAN DERIVATIVE WITH IMPROVED SERM PROFILE IN VIVO Civelli M1, Galbiati E1, Caruso P1, Amari G2, Armani E2, Ghirardi S2, Delcanale M2; 1Pharmacology Dept., Chiesi Farmaceutici S.p.A, Parma, Italy, 2Chemistry Dept., Chiesi Farmaceutici S.p.A., Parma, Italy CHF 4227.01 is a new benzopyran derivative that binds with high affinity to the human estrogen receptors ER-a and ER-b(Ki were 0.017 and 0.099 nM, respectively). The aim of the present study was to test whether treatment with CHF 4227.01 can protect against ovariectomy-induced bone loss in 9-10-month-old virgin female rats. We also investigated the effect on serum cholesterol levels and uterine tissue. CHF 4227.01 was given daily by oral gavage, commencing on day one of postsurgery. Lumbar spine L1-4 bone mineral density (BMD) was measured before ovariectomy and 4 weeks after surgery by dual energy x-ray absorptiometry. Cholesterol was assayed using a colorimetric assay, whereas osteocalcin was determined by RIA. At sacrifice, uteri were removed in order to perform histological evaluation and eosinophil peroxidase activity. A significant reduction in BMD (7.23%) in ovariectomized rats compared with sham rats was observed. CHF 4227.01 completely inhibited ovariectomy effects on BMD with ED50 of about 0.003 mg/kg.day (100% protection against ovariectomy-induced bone loss at 0.1–1 mg/kg.day). This effect was comparable with that achieved with 17a-ethynylestradiol (EE2), whereas raloxifene was less efficacious (maximal protection: 60% at 1–10 mg/kg.day) and about 100 times less potent. Ovariectomy-induced serum osteocalcin gain was prevented by treatment with CHF 4227.01 or EE2. CHF 4227.01 reduced serum cholesterol by 76% compared to ovariectomized rats (ED50 was 0.007 mg/kg.day) and had little to no stimulatory effects on uterine weight, uterine peroxidase activity, endometrium ephitelial thickness and myometrial thickness. In conclusion, CHF 4227.01 is a new SERM that compares favourably in potency and efficacy with raloxifene and is at least equally as effective as EE2 in preventing bone loss. This profile along with the minimal uterine stimulation suggests a potential therapeutic advantage of CHF 4227.01 over EE2 or raloxifene for the treatment of postmenopausal osteoporosis.

P74SA. HORMONE REPLACEMENT THERAPY AND SOFT TISSUE COMPOSITION INTERACTIVELY INFLUENCE BONE MINERAL DENSITY IN FEMALE TWINS Margerison C1, Paton LM1, Nowson C2, Lan L1, Kantor S1, kaymakci B1, Wark JD1; 1University of Melbourne, Melbourne, Australia, 2Deakin University, Melbourne, Australia Hormone replacement therapy (HRT) increases bone mineral density (BMD) significantly, though variably, in postmenopausal women. In studies of female twins, within-pair differences in BMD were associated with fat mass (FM) and lean mass (LM). Moreover, soft tissue composition may influence the response to HRT. Therefore, we sought the potential interactive effects of HRT use and soft tissue composition as determinants of BMD. Lumbar spine (LS) and femoral neck (FN) BMD, and total and regional FM and LM were measured by dual-energy Xray

Abstracts

S27

absorptiometry in 127 pairs of healthy female twins aged 30-65 years (Group 1) and in 39 pairs with discordance for HRT use (Group 2). Total and regional FM and LM were associated significantly with LS and FN BMD in both groups. For most soft tissue measures, the strength of the association with BMD approximately doubled in HRT-discordant pairs compared with Group 1 pairs, indicating a significant interaction between HRT use and soft tissue composition. The strongest interaction was with total abdominal fat mass: for the FN, the within-pair difference (SE) in BMD increased from 4.7(1.9)%, P = 0.01, per kg abdominal fat in Group 1 to 14.1(3.1)%, P50.001, per kg abdominal fat associated with HRT discordance in Group 2. Similarly, for the LS the within-pair BMD difference increased from 6.2(1.6)%, P50.001, per kg in Group 1 to 11.6(3.2)%, P = 0.001, per kg abdominal fat in Group 2 twins. There was no within-pair difference in FM or LM in Group 2. These finding demonstrate that the association between soft tissue composition and BMD is enhanced in HRT-discordant twin pairs. Abdominal fat mass was identified as a powerful determinant of FN and LS BMD associated with HRT use. These interactions have important implications concerning the effects of HRT on bone mass.

P75SU. ALENDRONATE REDUCES RISK OF VERTEBRAL FRACTURE IN WOMEN WITH BMD T-SCORES ABOVE –2.5: RESULTS FROM THE FRACTURE INTERVENTION TRIAL (FIT) Black D1, Thompson D2, Quandt S3, Palermo L1, Ensrud K4, Johnell O5; 1University of California, San Francisco, CA, 2Merck Research Laboratories, Rahway, NJ, 3Wake Forest University, Winston-Salem, NC, 4University of Minnesota, Minneapolis, MN, USA, 5Malmo¨ General Hospital, Malmo¨, Sweden Alendronate has been shown to be effective in reducing risk of non-vertebral, hip and vertebral fractures among women with BMD T-scores below –2.5. However, several studies have suggested that bisphosphonates are less effective in reducing risk of non-vertebral and hip fractures among women with BMD above –2.5. The question of whether reductions in vertebral fractures depend on initial BMD has not been fully explored. We performed an analysis of data from FIT in order to examine whether reductions in vertebral fractures were larger in those with lower BMD. FIT was a randomized trial of 6459 women with femoral neck T-scores below –1.6 of whom 2027 had existing vertebral fractures. In this analysis, we combined data from women with and without existing vertebral fracture. Women were assigned to alendronate (5 mg for first two years, then 10 mg) or placebo and followed for an average of 3.8 years. We stratified the population according to initial femoral neck T-score into those with T-scores at or below –2.5 and those with T-scores above 72.5. We analyzed the effect of alendronate on incidence of morphometric and clinical vertebral fractures within those strata (see table below).We found no significant differences between the two groups in reductions of morphometric vertebral fractures or clinical vertebral fractures. We conclude that alendronate is effective in reducing the risk of both morphometric and clinical vertebral fracture in women with BMD T-scores above –2.5. There is no evidence that the effect of alendronate on vertebral fractures is different in those with lower BMD.

Type of fracture

FN BMD T4–2.5 (n = 2715)

FN BMD T 4–2.5 (n = 3741)

N

RR (aln vs. pbo)

N

RR (aln vs. pbo)

0.50 (0.37, 0.67) 0.62 (0.39, 0.98)

130 41

0.57 (0.39, 0.82) 0.41 (0.21, 0.80)

Morph. vertebral 214 Clinical vertebral 78

P76MO. EVALUATION OF A RISK INDEX FOR CLINICAL SPINE AND NONSPINE FRACTURES IN POSTMENOPAUSAL WOMEN: DATA FROM THE FRACTURE INTERVENTION TRIAL (FIT) Hochberg MC1, Feldstein A2, Schneider D3, Thompson DE4, Ross PD4; 1University of Maryland, Baltimore, MD, 2Kaiser Permanente, Portland, OR, 3University of California, San Diego, CA, 4Merck Research Laboratories, Rahway, NJ, USA We reported a risk index for clinical fracture (CFx) based on 7 variables (age, height, number of prevalent vertebral fractures (VFx), tertile of femoral neck BMD, height loss, falls in the prior year, and prior nonspine fracture (NSFx)) that were independently associated with risk of incident CFx (Bone 2001;28(Suppl):S191) in the Fracture Intervention Trial (FIT). The ability of these same risk factors to predict separately the risk of clinical VFx and NSFx was tested using data from 3223 postmenopausal female participants who were randomized to the placebo group in FIT. Mean (SD) age was 69.6 (7.6) years at entry and all had femoral neck bone mineral density (BMD) 40.68 g/cm2; 1005 women had one or more prevalent VFx. A total of 68 (2.1%) women sustained 4 = 1 new clinical VFx and 367 (11.4%) women had 4 = 1 new NSFx during 3 years of follow-up. Separate risk indices for new VFx and NSFx were calculated by assigning scores based on the regression coefficient of each variable derived from separate regression models. The 3-year incidence of each Fx increased progressively by index quartile (Q). The gradient was greater for VFx than NSFx; the incidence of new VFx in Q4 was 13 times that in Q1 (6.7 vs 0.5%), whereas the incidence of NSFx in Q4 was only 2.5-times that in Q1 (18.5 vs 7.0%). A revised index without BMD and number of prior VFx performed similarly to that of the full index for NSFx, but the full index yielded better discrimination for VFx. These data suggest that it may be possible to stratify postmenopausal women by clinically relevant differences in fracture risk using a small number of risk factors obtained by self-report.

P77SA. ALENDRONATE* 70 MG ONCE WEEKLY VS. PLACEBO: TOLERABILITY STUDY IN PATIENTS WITH OSTEOPOROSIS Palmisano J1, Melton M1, Greenspan SL2, Field-Munves EM3, Tonino RP4, Dinh AC1, Smith ME1, Wang L1, Keene W1; 1Merck & Co., Inc., West Point, USA, 2Osteoporosis Prevention & Treatment Center, Pittsburgh, USA, 3Springhouse Professional Center, Allentown, USA, 4Good Health P.C., Burlington, USA Objectives: Primary: to examine the percentage of patients reporting any upper gastrointestinal (UGI) adverse experience (AE) while on alendronate (ALN) 70 mg once weekly as compared to placebo (PBO). Secondary: to examine the percentage of patients who discontinue due to a drug-related UGI AE; to assess change from baseline in bone turnover as measured by urinary Ntelopeptide; and to assess overall safety and tolerability. Design: This double-blind, randomized, PBO-controlled study was conducted at 48 centers in the U.S. Four hundred and fifty men and postmenopausal women with osteoporosis were randomized to receive either ALN 70 mg once weekly or PBO once weekly (1:1 ratio) for 12 weeks. Results: The treatment groups were considered equivalent based on the primary endpoint UGI AEs for ALN and PBO of 11.2% and 13.4%, respectively. Conclusions: Alendronate 70 mg administered once weekly to patients with osteoporosis has an upper gastrointestinal tolerability profile comparable to that of placebo. *Trademark: Fosamax1, Merck & Co., Inc., West Point, PA

S28 P78SU. ASSESSMENT OF NEW NON-VERTEBRAL OSTEOPOROTIC FRACTURES DURING A SHORT-TERM RUNIN PHASE CONTRIBUTES TO THE INTERNAL VALIDATION OF PATIENT SAMPLE SIZE CALCULATIONS Reginster JY1,2, Meunier PJ3; 1Bone and Cartilage Metabolism Unit, University of Lie`ge, Lie`ge, Belgium, 2WHO Collaborating Center for Public Health Aspects of Osteoarticular Disorders – Dept of Epidemiology and Public Health, University of Lie`ge, Lie`ge, Belgium, 3Department of Rheumatology and Bone Diseases, Edouard Herriot Hospital, Lyon, France Regulatory agencies request new chemical entities (NCE) developed for the treatment of osteoporosis to demonstrate a reduction in the number of patients experiencing new vertebral and/or femoral fractures, compared to either a placebo or an active comparator, before being granted marketing authorisation. A major issue for companies developing such NCE relates to the number of patients to be included in fracture trials and the subsequent costs. Power calculations defining the appropriate size of the requested patient sample are of prime importance to ensure both a reliable evaluation of the tested drug and to avoid any unnecessary burden that would be generated by an excessive study size. Currently available data of non-vertebral fractures incidence in control populations are scarce, leading study sponsors to base their patient sample on weak assumptions. The phase III program of Strontium ranelate, a new paradigm in the treatment of postmenopausal osteoporosis, includes a large multicenter placebo-controlled study, assessing the efficacy of this NCE on non-vertebral fractures in elderly patients (TROPOS). Prior to the randomisation of the patients, a short run-in study (FIRST) was performed to both correct any prevalent deficit in calcium/vitamin D and to optimise the quality of the data collected in TROPOS by excluding protocol violators and patients likely to prematurely withdraw.During FIRST, a careful assessment of new peripheral fractures was performed allowing to internally validate the assumptions having lead to the study sample size calculation. Thus 9196 patients were included in FIRST and were followed for a mean duration of 101 (± SD) 52 days. During this period, 108 patients experienced a total of 134 new osteoporotic non-vertebral fractures. This represents an observed incidence at 265 days of 3.71% (95%CI [1.42;6.00]) and corresponds to an extrapolated annual incidence of 5.07%. The most frequently affected sites were the hip (n = 29), wrist (n = 19), ribs (n = 17) and shoulder (n = 17). These short-term data could be of significant help in modelling the subsequent fracture risk of the study population, hence testing the robustness of sample-size calculations.

P79MO. CANDOO: A LONGITUDINAL CANADIAN MULTICENTER TERTIARY-CARE NETWORK FOR OBSERVATIONAL RESEARCH IN OSTEOPOROSIS (OP) AND OSTEOPENIA USING STANDARDIZED CLINICAL PRACTICE DATA: 11 YEARS OF FOLLOW-UP Adachi JD1, Sebaldt RJ1, Olszynski WP2, Brown JP3, Hanley DA4, Josse RG5, Murray T5, Petrie A1, Ioannidis G1, Goldsmith CH1; 1 McMaster University, Hamilton, ON, Canada, 2University of Saskatchewan, Saskatoon, SK, Canada, 3University de Laval, Laval, QC, Canada, 4University of Calgary, Calgary, AB, Canada, 5 University of Toronto, Toronto, ON, Canada The CANDOO Project (Canadian Database of Osteoporosis (OP) and Osteopenia) is a collaboration of OP specialists from across Canada for generating new knowledge about long-term outcomes of OP and its treatments and for validating clinical trial results in clinical practice. A comprehensive standardized clinical dataset appropriate to OP subspecialty practice was iteratively evolved by consensus. It has been collected by the CANDOO collaborators as integral part of the clinical care of new and follow-up

Abstracts patients since as early as March 1990. Dataset updates accommodate new diagnostic and therapeutic options, and a self-administered OP-related quality of life questionnaire (miniOQLQ) was added in 1995. Data are aggregated anonymously into a central database using standard operating procedures. The 7 collaborators, a biostatistician and a sponsor representative form the steering committee to monitor progress and plan data analyses and publications. By June 1, 2001, 9,855 patients were recorded (86% women (86% postmenopausal)), having at baseline: mean age 59 years, mean t-score at lumbar spine = –2.0, mean number of fractures = 1.3. 38,826 visits (assessments) were recorded, 74% of which were follow-up visits, with a median total patient follow-up of 3.0 years. 80% of patients were last seen within the past 2 years. Over the past 7 years, CANDOO data analyses and publications have confirmed the effectiveness of: (i) etidronate for treatment of corticosteroid-induced OP, (ii) etidronate and alendronate for treatment of male OP, (iii) addition of etidronate or alendronate to stable hormone replacement therapy for treatment of postmenopausal OP, (iv) mini-OQLQ for the demonstration of effect of vertebral and non-vertebral fractures on quality of life. We conclude that aggregate standardized longitudinal clinical practice data can provide valuable information about OP and treatment outcomes under clinical practice conditions.

P80SA. CONSUMPTION OF A HIGH CALCIUM MINERAL WATER LOWERS BIOCHEMICAL INDICES OF BONE REMODELING IN POSTMENOPAUSAL WOMEN WITH LOW CALCIUM INTAKE Jenvrin C1, Munoz F2, de la Gueronnie`re V3, Garnero P4, Meunier PJ1; 1Dept of Rheum & Bone Diseases, Lyon, France, 2INSERM Unit 403, Lyon, France, 3Centre Evian pour l’Eau, Paris, France, 4 Synarc, Lyon, France A 6 month randomized double blind placebo controlled trial was designed to assess the effects of a calcium (Ca) supplementation from a high Ca sulphated mineral water (HCMW, containing 596 mg Ca/l), on serum parathyroid hormone level (PTH) and serum and urinary biochemical markers of bone remodeling [serum and urinary CTX, serum osteocalcin (OC) and bone alkaline phosphatase (bone ALP)] in postmenopausal women with a low dietary Ca intake (5700 mg/day). The additive effect of a vitamin D supplementation to the effects of this HCMW were also evaluated. The placebo group drunk a mineral water having a low Ca content (9 mg Ca/l). 181 healthy postmenopausal women (mean age 70.1 ± 4.0 years) were recruited and 155 completed the trial. Fasting blood samples and morning urine collection were obtained at baseline and after 3 and 6 months of drinking 1 liter of water/day. The changes from baseline of biochemical indices consisted in a significant decrease of sPTH and all bone markers in the HCMW group compared to placebo one (per cent changes from baseline) (on Table). In women receiving 400 IU vitamin D/day in addition to HCMW, the decrease of bone indices was not significantly greater than in women drinking the HCMW alone.In conclusion, a daily supplementation of 596 mg of Ca through the consumption of a liter of a HCMW is capable to lower sPTH and to reduce bone turnover in elderly women with a low Ca intake. This could contribute to reduce age-related bone loss rate in this population.

HCMW placebo HCMW vs pl.

sPTH

sCTX

uCTX

sOC

boneALP

–14.2 +1.9 p:0.01

–16.3 +29.6 0.0003

–13.0 +22.3 0.0005

–8.6 +15.5 0.0001

–11.5 +5.1 0.0002

Abstracts P81SU. PHARMACOLOGICAL CHARACTERIZATION OF ANTAGONISTS ACTING AT THE EXTRACELLULAR CALCIUM SENSING RECEPTOR Faure H1, Ruat M1, Kessler A2, Dauban P2, Dodd RH2; 1 Laboratoire de Neurobiologie Cellulaire et Mole´culaire, CNRS, Gif sur Yvette, 2Institut de Chimie des Substances Naturelles, CNRS, France, Gif sur Yvette The calcium sensing receptor (CaSR), a member of the G-protein coupled receptor family, regulates the secretion of parathyroid hormone (PTH). Molecules aimed at inhibiting the CaSR should result in increased PTH secretion. Recently, the use of PTH or PTH fragments have been evaluated as a novel anabolic therapy for osteoporosis (Seeman and Delmas, 2001). An alternative approach, based on inhibiting the parathyroid CaSR by small, orally available molecules (calcilytics), thereby transiently elevating serum PTH levels, has been investigated (Gowen et al, 1999). However, selective and potent calcilytics with an adequate pharmacokinetic profile are still lacking. We have now synthesized and characterized novel molecules which inhibit the activity of the CaSR induced by extracellular calcium. PHD263 and its derivatives were tested as antagonists of cloned rat CaSR expressed in Chinese hamster ovary cells (CHO(CaSR)) or the mouse CaSR constitutively expressed in AtT20 cells. PHD263 and its derivatives dose-dependently inhibited 60 to 100% of calcium- induced (4–9 mM) formation of tritiated inositol phosphate (IP). PHD263 up to 10 microM did not show calcimimetic activity in CHO(CaSR) cells, nor did it potentiate the IP response induced by ATP acting on G-protein coupled purinergic receptors expressed in CHO cells. These data suggest that PHD263 and its derivatives possess antagonist activity at the rat and mouse CaSR. Further characterization of the chemical, pharmacological and biological properties of this novel class of calcilytics should allow further delineation of the biological roles of the CaSR in tissues where it is expressed, and to develop molecules therapeutically useful for the treatment of osteoporosis.

P82MO. A LONG-TERM STRONTIUM RANELATE ADMINISTRATION IN MONKEYS HAS NO EFFECT ON MINERAL CRYSTALS AND DEGREE OF MINERALIZATION OF BONE. Boivin G1, Farlay D1, Panczer G2, Dupin-Roger I3, Simi C1, Buffet A1, Tupinon-Mathieu I3, Meunier PJ1; 1Laboratoire d’Histodynamique Osseuse, Faculte´ de Me´decine R. Laennec, Lyon, France, 2LPCML CNRS UMR 5620, Universite´ C. Bernard, Villeurbanne, France, 3Institut de Recherches Internationales Servier, Courbevoie, France As Strontium Ranelate (Protos1) prevents bone loss and increases bone mass and strength in normal and ovariectomized rats by a dual effect on bone remodeling, increasing bone formation and decreasing bone resorption, it was interesting to evaluate in monkeys the interactions of Strontium Ranelate (SR) with bone mineral.Iliac bones were obtained from untreated monkeys, monkeys sacrificed at the end of a 13-week SR treatment (100-275-750 mg/kg/day PO) and of a 52-week SR treatment (200-500-1250 mg/kg/day PO) followed or not by a 6week and 10-week recovery period, respectively. Strontium uptake and distribution in these samples were quantified by Xray microanalysis. Changes at the crystal level were evaluated by X-ray diffraction or Raman spectrometry. After the 52-week treatment, the degree of mineralization of bone (DMB) was measured by quantitative microradiography. In monkeys sacrificed after the two exposure periods, strontium was uptaken in a dose-dependent manner into compact and cancellous bone, with higher contents in new than in old bone (3-4 and 1.7-2 times after 13-week and 52-week treatments). At the end of the recovery periods, strontium contents were generally strongly decreased (2 times) in new bone. No significant changes in crystal characteristics were shown even if strontium was slightly linked to crystals

S29 through ionic substitutions (less than 1.2 calcium ion replaced by 1.2 strontium ion in each unit cell at the highest doses tested). The great part of incorporated strontium was adsorbed at crystal surface. DMB was not modified in the different groups of monkeys. In conclusion, strontium was heterogeneously distributed between new and old bone but in a dose-dependent manner without alteration of crystal characteristics and DMB, even after the long-term administration of high doses of SR. This confirms the potential interest, as anti-osteoporotic treatment, of Strontium Ranelate which is safe at the bone mineral level.

P83SA. ONCE-WEEKLY ALENDRONATE 70 MG: SUSTAINED SUPPRESSION OF BONE RESORPTION Bone H1, Schnitzer T2, Reid I3, Adami S4, Miller P5, Kaur A6, Snodgrass S6, Santora A6, Orloff J6; 1Michigan Bone Clinic, Detroit Michigan, 2Northwestern University, Chicago, IL, USA, 3 University of Auckland, Auckland, NZ, 4University of Verona, Valeggio sul Mincio (VR), IT, 5CCBR, Lakewood, CO, 6Merck & Co., Inc, Rahway, NJ, USA Most currently available oral bisphosphonates provide continuous suppression of bone resorption, which is thought to be an important element contributing to their anti-fracture efficacy. It has been suggested that reactivation of bone resorption between intermittent IV doses of some bisphosphonates may reduce the effect on fracture risk. Recently, alendronate 70 mg once-weekly was shown to be therapeutically equivalent to alendronate 10 mg daily (Schnitzer et al., Aging 2000). We analyzed results from this study to determine if alendronate 70mg once-weekly provided continuous suppression of bone resorption, similar to daily dosing, throughout the dosing interval. We examined the relationship of urinary N-telopeptides of type 1 collagen/creatinine (NTx) and serum bone-alkaline phosphatase (BAP) levels in the alendronate 70mg once-weekly group (n = 519) as a function of time (in days) since the administration of the last active dose. The mean percent change from baseline to Month 12 in NTx and BAP levels was analyzed. Since patient visits at Month 12 occurred randomly with respect to when a tablet was taken, measurements were obtained on groups of patients whose last weekly dose ranged from 0-6 days prior to the visit. There was no significant variation (p40.10) in the antiresorptive effect of once-weekly alendronate as measured by NTx within the seven-day interval between doses, and the change in NTx was comparable to that seen with daily dosing. BAP results were similar. Treatment with alendronate 70 mg once weekly provides a sustained reduction of bone turnover throughout the dosing interval, similar to the effect achieved with daily dosing.

S30 P84SU. ONCE-WEEKLY ALENDRONATE: TWO-YEAR SUBGROUP EFFICACY ANALYSES IN POSTMENOPAUSAL WOMEN WITH OSTEOPOROSIS Bone H1, Felsenberg D2, Greenwald M3, Schnitzer T4, Kaur A5, Peverly C5, Cudny M5, Orloff J5, Santora A5; 1Michigan Bone and Mineral Clinic PC, Detroit, MI, USA, 2Freie Universitat Berlin Klinikum, Berlin, Germany, 3Desert Medical Advances, Palm Desert, CA, 4Northwestern Univ., Chicago, IL, 5Merck Research Laboratories, Rahway, NJ, USA In a multicenter study of 1258 postmenopausal women with osteoporosis, treatment with alendronate (ALN; manufactured by Merck & Co., Inc.) 70 mg once weekly (OW) was shown to be therapeutically equivalent to treatment with ALN 10 mg once daily (D) (Schnitzer et al, Aging 2000;12:1-12). We further examined the efficacy of treatment with ALN 70 mg OW (n = 519), ALN 35 mg twice weekly (TW) (n = 369), and ALN 10 mg D (n = 370) by way of a subgroup analysis of two-year spine and hip BMD including a oneyear study extension. The following prespecified patient subgroups were analyzed for percent change from baseline in lumbar spine (LS) and total hip BMD at month 24: baseline age greater or less than 65 or 75 years; vertebral fracture (VF); LS BMD greater or less than median; and years since menopause greater or less than 10 years. The treatment response was consistent across subgroups for LS BMD. In all ALN treatment groups, patients without baseline VF had a slightly but not statistically significantly greater response to treatment than those with VF, as did those with lower vs. higher baseline LS BMD. Additional analyses showed consistent treatment responses across subgroups for total hip BMD (data not shown). In summary, for all ALN treatment groups (once weekly, twice weekly and once daily), percent change in LS and hip BMD was consistent across all examined baseline demographic characteristics (see Figure below).

P85MO. A SHORT-TERM RUN-IN STUDY CAN SIGNIFICANTLY CONTRIBUTE TO INCREASING THE QUALITY OF LONG-TERM OSTEOPOROSIS TRIALS. THE STRONTIUM RANELATE PHASE 3 PROGRAM Reginster JY1,2, Spector T3, Badurski J4, Ortolani S5, Martin TJ6, Diez-Perez A7, Lemmel E8, Balogh A9, Pors-Nielsen S10, Phenekos C11, Meunier PJ12; 1Bone and Cartilage Metabolism Unit, University of Lie`ge, Lie`ge, Belgium, 2WHO Collaborating Center for Public Health Aspects of Osteoarticular Disorders – Dept of Epidemiology and Public Health, University of Lie`ge, Lie`ge, B, 3 Saint Thomas’ Hospital, Department of Rhumatology, London, UK, 4Polish Foundation of Osteoporosis, Center for Osteoporosis and Osteo-Articular Diseases, Dept of Medicine and Rheumatology, Bialystok, Poland, 5Centro Auxologica Italiano, Divisione di Endocrinologia, Milano, ITALY, 6St Vincent’s Institute of Medical Research, Melbourne, Australia, 7Hospital del Mar, Departamento de Medicina Interna, Barcelona, Spain, 8Max Grundig Klinik, Innere Medizin / Rheumatology, Bu¨hl, Germany, 9 University of Debrecen Medical and Health Sciences Center, Department of Obstetrics and Gynecology, Debrecen, HUNGARY,

P84SU Fig. 1.

Abstracts 10

Hillerød Hospital, Dept of Clinical Physiology, Hillerød, Denmark,11Red Cross Hospital, Dept of Endocrinoly, Athens, Greece, 12 Department of Rheumatology and Bone Diseases, Edouard Herriot Hospital, Lyon, France Strontium Ranelate (Protos1 SR) was consistently shown, in preclinical and animal studies, to be the first compound to simultaneously increase bone formation and decrease bone resorption, hence being a putative new paradigm in the treatment of postmenopausal osteoporosis. Following the positive results obtained on BMD and vertebral fracture in a phase II study (STRATOS), an extensive study plan was designed to confirm the efficacy of SR in reducing the incidence of patients with new fractures both at vertebral (SOTI) and non-vertebral (TROPOS) levels. Previous studies have suggested that early randomisation, at the investigators’ site, may result in a high rate of false inclusions or early drop-outs. Therefore, in the SR phase III program, a run-in phase (FIRST) was designed with two distinct objectives: normalizing calcium vitamin D status and excluding non-eligible patients or those most likely to prematurely discontinue the trial, prior to randomization. Thus 9196 patients in 12 countries were included in FIRST, based on the investigators opinion on the suitability of the patients as potential candidates for SOTI or TROPOS. Out of this population, 1591 patients were subsequently assessed as noneligible for the main studies, mainly due to their failure to meet inclusion/exclusion criteria (1173) or because some concomitant medical conditions precluded their participation (338). Furthermore, despite the short duration (mean duration : 101 days), 215 patients had to be withdrawn following the occurrence of at least one adverse event. Additional 56 patients were lost to follow up and 594 were withdrawn for non medical reasons. These prebaseline exclusions left a total of 6740 eligible patients for inclusion in SOTI (1649) or TROPOS (5091). This procedure is instrumental in minimizing major violations of the protocol for further therapeutic studies.We conclude that performing a shortterm run-in trial before initiating long-term studies in osteoporosis can significantly increase the quality of such studies by optimizing the adherence to the inclusion/exclusion criteria, and by avoiding the inclusion of patients likely to prematurely withdraw either for low compliance or adverse reactions.

P86SA. PAIN REDUCTION IN PATIENTS WITH OSTEOPOROSIS BY SPORT REHABILITATION: A RANDOMIZED CONTROLLED PROSPECTIVE STUDY Franck H; Center of Rheumatology, Oberammergau, Germany Aims: Patients with osteoporosis have lower back pain of different clinical severity. Similar is true for patients with lower back pain. In patients with osteoporosis mainly fractures are the cause of it. The aim of the study was to examine, whether patients with lower back pain have different pain intensities and activities of daily living (ADL) than patients with osteoporosis. Can patients with osteoporosis overcome the problems by specific physiotherapy.

Abstracts Methods: 130 patients with osteoporosis (WHO-definition) and 90 patients with lumbar spine syndrome were randomized in a prospective study investigating pain perception (Owestry-Score). Group I had classic physiotherapy, group II received additionally lower back strength training, group III sport therapy, group IV sport therapy plus lower back strength therapy. Results: There was no difference concerning the Owestryquestionnaire between patients with osteoporosis and patients with lower back pain. After therapy patients with osteoporosis had reduction of pain intensity of 1.28 ± 1.44 to 0.85 ± 1.1 (p50.01). The Owestry-score decreased significantly (p50.01 from 19.9 ± 10 to 17.3 ± 10,0). Similiar results were obtained in the group of patients with lower back pain. The greatest reduction of pain was gained in group IV (1.42 ± 5 to 0.2 ± 1.4). Consequently, the Owestry-score improved significantly in this group (20.9 ± 9.7 to 4.4 ± 10.6). Conclusion: Patients with osteoporosis don’t have different pain perceptions than patients with lower back pain concerning visual analog scale and Owestry-score. Physiotherapy especially sport therapy including lower extensor strength training improve effectively pain in patients with osteoporosis.

P87SU. LARGER INCREASES IN BONE MINERAL DENSITY (BMD) DURING THE FIRST YEAR OF TREATMENT ARE ASSOCIATED WITH GREATER REDUCTIONS IN NONVERTEBRAL FRACTURE INCIDENCE DURING ANTIRESORPTIVE THERAPY Hochberg MC1, Greenspan S2, Miller PD3, Wasnich RD4, Ross PD5, Thompson DE5; 1Univ of Maryland, Baltimore, MD, USA, 2 Univ of Pittsburgh, Pittsburgh, PA, USA, 3CCBR, Lakewood, CO, USA, 4Radiant Research, Honolulu, HI, USA, 5Merck Research Labs, Rahway, NJ, USA Our previous meta-analysis indicated that larger BMD increases were associated with larger reductions in risk of nonvertebral fracture (NVFx). In the current analysis, we examined whether the antifracture efficacy could be predicted from BMD changes during the 1st year of treatment. We performed a meta-analysis of all randomized, placebo-controlled trials of antiresorptive agents (alendronate, calcitonin, etidronate, estrogen, raloxifene, risedronate, tiludronate) conducted in postmenopausal women with osteoporosis with available relevant data. 16 trials were identified including a total of 1872 women with incident NVFxs over 55,870 person-years of follow-up. Poisson regression was used to estimate the association between increases in BMD (active treatment vs placebo) during the 1st year and the relative risk reduction in the incidence of NVFx across all trials; separate models were constructed for spine and hip BMD. Both models found a significant relationship between the magnitude of BMD increases and reductions in NVFx risk. For each 1% increase in spine BMD during the 1st year (vs placebo), there was an 8% decrease in risk of NVFx (P = 0.02); for each 1% increase in hip BMD, there was a 23% decrease in risk (P = 0.006). In neither model was there a significant decrease in risk of NVFxs in the absence of increase in BMD. These models indicate that an agent that increases spine BMD by 6% (vs placebo) in the first year of treatment (upper limit of the observed range) reduces NVFx risk by 39%, and an agent that increases hip BMD by 3% in the first year of treatment reduces NVFx risk by 46%. These data confirm that larger increases in BMD during the first year are associated with greater reductions in risk of NVFxs. Accordingly, only antiresorptive agents which produce large increases in BMD would be expected to (and have been reported to) decrease the risk of NVFxs.

S31 P88MO. A COMPARISON OF THE EFFECT OF RISEDRONATE AND ETIDRONATE ON LUMBER BONE MINERAL DENSITY IN JAPANESE PATIENTS WITH INVOLUTIONAL OSTEOPOROSIS: A RANDOMIZED CONTROLLED TRIAL Fukunaga M1,2, Kushida K2, Kishimoto H2, Shiraki M2, Taketani Y2, Minaguchi H2, Inoue T2, Morita R, Yamamoto K2, Morii H2, Orimo H2; 1Department of Nuclear Medicine, Kawasaki Medical School, Okayama, JAPAN, 2Risedronate Research Group, Japan To demonstrate the clinical benefit of risedronate in the treatment of involutional osteoporosis, the effect of risedronate on bone mineral density (BMD) at the lumbar spine was compared with that of etidronate selected as a representative of the already marketed bisphosphonates. In this multicenter, randomized, double-blind, active (etidronate) controlled comparative study, a total of 235 Japanese patients with involutional osteoporosis were randomized to receive either 2.5 mg/day of risedronate for 48 weeks or intermittent treatment with etidronate (4 cycles of 2-week treatment with 200 mg/day followed by 10-week medication-free periods). All patients were supplemented with 1.54 g/day of calcium lactate. L2-4 BMD was determined at 12, 24, 36 and 48 weeks by DEXA. The primary endpoint was the percent change in L2-4 BMD from baseline to the time of final evaluation. Changes in biochemical markers of bone turnover and safety profiles were also compared. A significant increase in L2-4 BMD was observed at 12 weeks after initiation of therapy in both the risedronate (2.8%) and etidronate (1.8%) groups. The increase in L2-4 BMD at the time of final evaluation in the risedronate group (4.9%) was significantly greater (p = 0.002) than that in the etidronate group (3.1%). The changes in bone resorption markers (free urinary deoxypyridinoline and NTx) from baseline to 48 weeks were –37.6% and –41.3% for risedronate and –22.5% and –26.6% for etidronate, respectively. New vertebral fractures or deterioration of existing fractures were observed in 2.8% (3/106) of the patients in the etidronate group, while no such cases (0/101) were observed in the risedronate group. No significant difference in the incidence of adverse events was found between two treatments.Daily oral risedronate (2.5 mg) exhibited efficacy superior to that of intermittent cyclical etidronate (200 mg) in increasing L2-4 BMD, and was well tolerated by Japanese patients with involutional osteoporosis.

P89SA. TREATMENT WITH ALFACALCIDOL* SIGNIFICANTLY DECREASES IPTH SERUM LEVELS IN COMMUNITYDWELLING ELDERLY USING DIURETICS Dukas L1, Bischoff HA2, Schacht E3, Staehelin HB1; 1Geriatric University Clinic, Basel, Switzerland, 2Brigham and Women’s Hospital, Boston, USA, 3Orthopa¨dische Universita¨tsklinik Balgrist, Zurich, Switzerland Aims: We previously reported a significant association between increased iPTH serum levels and the use of non-thiazide diuretics in elderly community-dwelling men and women. In this study we analyzed the effect of a treatment with Alfacalcidol compared with placebo on iPTH serum levels (iPTH-SL) in this population. Methods: We included 75 healthy Swiss community dwelling and diuretics using elderly (37 women and 38 men) from the AIMS-Study. Measurements of iPTH-SL were performed at baseline (September 2000/wk 0) and after 12 (wk 12) and 24 weeks (wk 24). In these ITT analyses the p values for the reported results are two sided. Results: From the 75 diuretics users 40 were treated with Alfacalcidol and 35 with placebo. The difference of iPTH-SL between groups at baseline was N.S.. In the Alfacalcidol treatment group we observed over 24 weeks a significant decrease in the mean iPTH-SL of 48% from baseline (wk 0: 40.9 pg/ml wk 12: 20.9 pg/ml wk 24: 21.2 pg/ml, p50.0001). In the placebo treatment group we observed over 24 weeks a slight increase in mean iPTH-SL (wk 0: 35.9 pg/ml wk 12: 39.0 pg/ml wk 24: 37.4 pg/ml, p40.05). Compared to treatment with placebo

S32 treatment with Alfacalcidol after 24 weeks in diuretic users was associated with a 77% lower mean iPTH-SL (p40.001). In the subgroup of non-thiazide diuretic users treated with Alfacalcidol (n = 11) we observed from baseline over 24 weeks an even more impressive 65% decrease in the mean iPTH-SL (wk 0: 58.7 pg/ml wk 12: 23.0 pg/ml wk 24: 20.7 pg/ml, p50.01). Conclusions: In this study elderly using diuretics and treated with Alfacalcidol showed a significant decrease in iPTH serum levels compared to those treated with placebo. This association was particularly impressive in user of non-thiazide diuretics. Since increased iPTH serum levels are associated with increased bone resorption, our results suggests that elderly requiring treatment with diuretics, in particular with non-thiazide diuretics, could benefit from Alfacalcidol as a preventive or causal treatment of osteoporosis. Results from the Aims-Study *Alpha-D3 by Teva

P90SU. DETERMINANTS OF COMPLIANCE WITH HIP PROTECTORS: THE AMSTERDAM HIP PROTECTOR STUDY van Schoor NM1, Smit JH1,2, Bouter LM1, Lips P1,3; 1EMGO Insitute, VU University Medical Center, Amsterdam, The Netherlands, 2Department of Sociology and Social Gerontology, VU University, Amsterdam, The Netherlands, 3Department of Endocrinology, VU University Medical Center, Amsterdam, The Netherlands Aims: In Amsterdam and surroundings, a randomised clinical trial is performed to investigate whether external hip protectors can reduce the incidence of hip fractures in elderly persons at high risk of fracturing their hip (n = 561). The compliance results of this randomised clinical trial will be presented. Methods: The elderly who are included are all residents of apartment houses for the elderly, homes for the elderly and nursing homes. All persons should have a high risk for falls and a low bone mineral density. High-risk groups: (1) broadband ultrasound attenuation (BUA) 440 or (2) 40 5 BUA 460 and at least 2 risk factors for falls or (3) 60 5 BUA 470 and at least 3 risk factors for falls. The following risk factors for falls were used: one or more falls during the previous half year, dizziness while standing up, stroke, urinary incontinence, low physical activity, impaired mobility and cognitive impairment. The compliance is measured by unexpected visits at 1, 6 and 12 months after inclusion in the trial. During these visits, it is checked whether a participant wears the hip protector. Furthermore, the determinants of compliance are assessed using a questionnaire. Results: Preliminary analyses show that the compliance after 1 month was 61%. Of these, 87% was wearing the hip protector correctly. The compliance was higher in nursing homes and in psychogeriatric patients. No statistical significant relationship was found for age and sex. Other determinants of compliance were ‘wearing the hip protector as underwear’, ‘using incontinence material’ and ‘being comfortable’. ‘Difficulty in handling the hip protector’ was a determinant for non-compliance. Other determinants of compliance will be statistically examined and the long-term compliance will be calculated. Conclusions: The short-term compliance of wearing hip protectors was reasonable. However, not everyone was wearing the hip protector correctly.

P91MO. EFFECT OF VARIOUS DOSES OF PAMIDRONATE WITH CONSTANT YEARLY DOSE IN WOMEN WITH OSTEOPOROSIS : A 2-YEAR PILOT STUDY Lamy O, Pache I, Fatio S, Sandini L, Krieg MA, Burckhardt P; Department of internal medicine, University Hospital of Lausanne, Switzerland Aims: Tolerance and compliance to oral bisphosphonate treatment is often poor. Pamidronate (APD) administered iv is well

Abstracts tolerated. However the best regimen is not known. We tested various doses of pamidronate with constant yearly dose in postmenopausal women with osteoporosis. Methods: 45 women (age 63 ± 12) received 120 mg/year iv APD in 4x30mg (n = 25), 3x40mg (n = 13) or 2x60mg (n = 7) for two years. All got calcium and vitamin D. The three groups didn’t differ (age, BMI, baseline BMD). Osteocalcine (OC), urinary C-telopeptides (UCTX) and DEXA were measured at months 0 and 24. Results: The BMD change (% ± SEM) were respectively for group 30, 40 and 60mg: lumbar spine 8.6% ± 2.3%*, 6.0% ± 0.9%* and 8.2% ± 2.6%***; trochanter 2.9% ± 0.8%**, 4.4% ± 1.0%** and 2.9% ± 1.6%; femoral neck 1.0% ± 1.1%, 1.0% ± 0.9% and 4.2% ± 2.0%. The median BMD change was: lumbar spine 5.8–6.1%; trochanter 3.1-3.8%; femoral neck 1.5-1.8%. UCTX (microg/mmol ± SEM) decrease respectively for group 30, 40 and 60mg from: 299 ± 42 to 100 ± 16*, 296 ± 54 to 90 ± 17* and 183 ± 56 to 142 ± 62; and OC (microg/l ± SEM) from 21.7 ± 3.0 to 12.2 ± 1.1**, 19.7 ± 2.1 to 11.6 ± 1.0** and 29.4 ± 8.8 to 16.6 ± 3.0. (*P50.001 **P50.02 ***P50.05 student T-test). Conclusions: The increase of BMD was of same magnitude for the three groups. The decrease of bone remodelling parameters was more pronounced when iv ADP was administered in 4x30 mg or 3x40 mg every year. These results are of particular interest considering the possibility to treat osteoporosis with only three perfusions yearly. More study should be done on the possibility to treat osteoporosis with only two perfusions every year.

P92SA. PATIENT PREFERENCE OF ONCE WEEKLY OR DAILY ADMINISTRATION OF ALENDRONATE (FOSAMAX) FOR OSTEOPOROSIS: A RANDOMIZED CROSS-OVER STUDY Kendler DL1, Diez-Perez A2, Gaines KA3, Verbruggen N3, Melton ME3; 1St. Vincent’s Hospital, Vancouver, British Columbia, Canada, 2Hospital del Mar, Barcelona, Spain, 3Merck & Co., Inc., Whitehouse Station, NJ, USA It is well accepted that patients prefer once daily dosing to dosing two or more times a day. Whether patients would prefer even less frequent dosing, such as once weekly dosing, is unknown. Alendronate given once weekly has now been shown to have equivalent efficacy to once daily dosing. We designed this study to examine patient preference for a once weekly or a once daily alendronate dosing regimen. 406 postmenopausal women with osteoporosis were recruited at 45 study sites in 19 countries representative of Europe, the Americas, and the Asia Pacific region. The patients were randomly assigned to one of 2 groups: alendronate 70 mg once weekly followed by alendronate 10 mg daily, or alendronate 10 mg daily followed by alendronate 70 mg once weekly. Each treatment was given open label for 4 weeks using standard a.m. dosing. After experiencing both regimens, a questionnaire was administered which addressed preference, convenience, and willingness to take the regimens long term. The mean age of the patients was 63 years. 65% were Caucasian, 22% Asian, and 8% Hispanic. 92% of the patients expressed a preference for dosing regimen. Of those, 84% of the patients preferred the once weekly regimen. In addition, 87% found that the once weekly regimen was more convenient and 84% chose the once weekly regimen as the one that they would be more willing to take long term. These results were statistically significant (P50.001 for each item) and consistent across subgroups (including country, age, number of concomitant medications and medical conditions). In conclusion, this study demonstrates that the once weekly dosing regimen for alendronate is preferred by a large majority of patients, that it is more convenient, and that it is the regimen that patients are more willing to take long term.

Abstracts P93SU. A DOUBLE-BLIND DOSE-RANGING STUDY OF RISEDRONATE IN JAPANESE PATIENTS WITH INVOLUTIONAL OSTEOPOROSIS Shiraki M1,2, Fukunaga M2, Kushida K2, Kishimoto H2, Taketani Y2, Minaguchi H, Inoue T2, Morita R2, Morii H, Yamamoto K2, Ohashi Y2, Orimo H2; 1Research Institute and Practice for Involutional Diseases, Nagano, 2The Risedronate Late Phase II Research Group, Japan To determine an optimal dosage regimen of risedronate for the treatment of involutional osteoporosis in Japanese patients, dose-response relationships for the efficacy and safety of this drug were investigated using a multi-center, randomized, doubleblind, parallel group comparative design with 4 dose levels of risedronate (placebo, 1 mg, 2.5 mg and 5 mg per day). A total of 211 patients diagnosed with involutional osteoporosis were randomized, and received one of the 4 doses once daily for 36 weeks. All patients were supplemented with 1.54 g/day (200mg of elemental calcium) of calcium lactate. The primary efficacy endpoint was the percent change in bone mineral density of the lumbar spine (L2-4BMD) determined by DXA from baseline to the time of final evaluation. Changes in biochemical markers of bone turnover and safety profiles were also compared. Percent changes in L2-4BMD at final evaluation in the placebo, and 1 mg, 2.5 mg and 5 mg risedronate groups were 0.79%, 2.71%, 5.29% and 5.15%, respectively. A linear dose-response relationship was obtained up to a dose of 2.5 mg, while no further increase in BMD was observed at 5 mg. The decrease in bone metabolic markers including N-terminal osteocalcin and urinary deoxypyridinoline also showed a linear dose-response relationship up to a dose of 2.5 mg. Alkaline phosphatase level decreased linearly up to a dose of 5 mg. Neither the overall incidence of adverse events nor the percentage of patients without problem in overall safety assessment differed significantly among the dose groups including the placebo group, indicating no dose-response relationship concerning the safety of risedronate. Based on these results, a once-daily dose of 2.5 mg of risedronate, which is half that used in Caucasians, will be recommended for the treatment of involutional osteoporosis in Japanese patients.

P94MO. ACUTE EFFECTS ON PARATHYROID FUNCTION OF THE REPEATED INGESTION OF A HIGH-CALCIUM MINERAL WATER AS COMPARED TO A PHARMACEUTICAL PREPARATION Guillemant J1, Accarie C2, de la Gue´ronnie`re V3, Guillemant S1,2; 1 Faculte´ de Me´decine Pitie´-Salpeˆtrie`re, Paris, France, 2EPHE Nutrition Hydromine´rale, Paris, France, 3Poˆle Expertise Eau, Bourg-la-Reine, France The present study was designed to compare the effects on calcium metabolism and parathyroid function of the repeated ingestion of a high-calcium mineral water (596 mg/L) along the day with those of a single oral intake of a calcium salt bringing the same total dose (600 mg) of calcium. Fifteen healthy young men (mean ± SD age : 23.3 ± 1.2) participated in the study and performed 3 successive assays in a random order. During each assay they ingested 330 ml of mineral water at 08.00, 11.00 and 14.00, a) high-calcium water, b) low-calcium water (510 mg/L) as a control assay, c) one bag of tricalcium phosphate powder (calcium 600 mg) dissolved in 330 ml of low-calcium water at 08.00 and followed by the ingestion of low-calcium water at 11.00 and 14.00. Blood samples were drawn before 08.00 and every hour from 09.00 to 17.00. After oral intake of both high-calcium water and tricalcium phosphate than in control assay, serum ionized calcium (iCa) concentrations were significantly (P50.0001) higher and serum intact parathyroid hormone (iPTH) concentrations were significantly (P50.01) lower. After either the first ingestion of high-calcium water or the tricalcium phosphate intake, the time courses of iCa and iPTH changes were similar for

S33 3h but differed later. A statistically significant difference (P50.05) using Bonferroni t test between the effects of either ingestion of high-calcium mineral water or tricalcium phosphate intake was observed from 15.00 to 17.00 for iCa ; and from 13.00 to 17.00 for iPTH. The same total amount of calcium (# 600 mg) as 1 liter of a high-calcium mineral water, divided into three intakes, resulted in a significantly more prolonged suppression of iPTH than the single ingestion of a pharmaceutical calcium salt. Drinking highcalcium mineral water can therefore offer an interesting alternative.

P95SA. LARGER REDUCTIONS IN BIOCHEMICAL MARKERS OF BONE TURNOVER ARE ASSOCIATED WITH GREATER REDUCTIONS IN NONVERTEBRAL FRACTURE INCIDENCE DURING ANTIRESORPTIVE THERAPY Hochberg MC1, Greenspan S2, Miller PD3, Wasnich RD4, Ross PD5, Thompson DE5; 1Univ of Maryland, Baltimore, MD, USA, 2 Univ of Pittsburgh, Pittsburgh, PA, USA, 3CCBR, Lakewood, CO, USA, 4Radiant Research, Honolulu, HI, USA, 5Merck Research Labs, Rahway, NJ, USA Both lower bone mineral density (BMD) and higher levels of biochemical markers (BCM) of bone turnover have been reported to be independent risk factors for osteoporotic fractures. A previous meta-analysis found that larger BMD increases were associated with larger risk reductions in nonvertebral fractures (NVFxs). In the current analysis, we examined the extent to which decreases in BCM during antiresorptive therapy are associated with reductions in risk of NVFxs. We performed a meta-analysis of all randomized, placebo-controlled trials of antiresorptive agents (alendronate, calcitonin, etidronate, estrogen, raloxifene, risedronate, tiludronate) conducted in postmenopausal women with osteoporosis with available relevant data. 14 trials were identified including a total of 1794 women with incident NVFxs over 54,615 person-years of follow-up. Poisson regression was used to estimate the association between decrease in BCM (treatment vs placebo) and decrease in risk of NVFxs across all trials; separate models were constructed for resorption and formation markers. Both models found a significant relationship between reductions in BCM of bone turnover and reductions in NVFx risk. For each 10% decrease in bone resorption marker, there was a 6% decrease in risk of NVFx (P = 0.047); for each 10% decrease in bone formation marker, there was a 13% decrease in risk (P = 0.009). In neither model was there significant decrease in risk of NVFxs in the absence of decrease in BCM. Thus, an agent that decreases a bone resorption BCM by 70% reduces NVFx risk by about 40%; an agent that decreases a bone formation BCM by 45% also reduces risk by about 40%. These data demonstrate that agents that produce larger decreases in both formation and resorption BCM are associated with greater reductions in risk of NVFxs. Accordingly, only antiresorptive agents that produce large decreases in BCM would be expected to (and have been reported to) decrease the risk of NVFxs.

P96SU. TWO-YEAR CLINICAL FRACTURE EXPERIENCE WITH ALENDRONATE 70 MG ONCE WEEKLY Miller P1, Recker R2, Rosen C3, Adami S4, Meng L5, Kaur A5, Santora A5, Orloff J5; 1Colorado Center for Bone Research, Lakewood, CO, USA, 2Creighton University, Omaha, NE, USA, 3 Maine Center for Osteoporosis Research, Bangor, ME, USA, 4 Ospedale Valeggio, Verona, Italy, 5Merck Research Laboratories, Rahway, NJ, USA The therapeutic equivalence of alendronate (ALN) 70 mg once weekly (OW) and ALN 10 mg daily (provided by Merck and Co., Inc., Whitehouse Station, NJ, USA) in the treatment of postmenopausal osteoporosis for one year has been shown in a double-blind, multicenter study (Equivalence Study; Schnitzer et

S34

Abstracts

al, Aging 2000). A one-year extension demonstrated comparable changes in BMD and bone turnover over 2 years, confirming the therapeutic equivalence of ALN 70 mg OW and ALN 10 mg daily (Rizzoli et al, Bone 2001). Clinical fractures for this study were captured as adverse experiences and were confirmed by radiologic reports. Clinical vertebral fractures were adjudicated centrally using semiquantitative criteria. The incidence of clinical fractures over 2 years of treatment with ALN 70 mg OW was similar to that with ALN 10 mg daily, and comparable to the incidence rates over the same period in alendronate-treated patients in the osteoporotic cohort of the Fracture Intervention Trial (FIT; Black et al, JCEM 2000). There were no apparent differences between the weekly and dailydosing groups in the distribution of fracture adverse events by location. Height loss, measured by Harpenden stadiometry, was similar for ALN 70 mg OW and ALN 10 mg daily (mean changes from baseline at Month 24 were –0.92 and –0.96 mm, respectively). While the current study was not designed as a fractureendpoint equivalence trial, the clinical fracture data for ALN 70 mg OW and ALN 10 mg daily were similar and consistent with those from prior fracture studies.

All Clinical Fractures (%) Clinical Vertebral Fractures (%) Non-Vertebral Fractures (%)

Equivalence Study

FIT

ALN OW (N = 519)

ALN daily (N = 370)

ALN daily (N = 1841)

Placebo (N = 1817)

7.3

7.0

8.1

11.7

0.8

1.6

0.8

2.4

6.6

5.4

7.5

9.9

P97MO. MONITORING RISEDRONATE THERAPY FOR OSTEOPOROSIS: EFFECT OF DUPLICATE URINE COLLECTIONS ON RESPONSE RATE IN THE IMPACT STUDY Eastell R1, Hannon RA1, Garnero P2, Delmas PD3; 1University of Sheffield, Sheffield UK, 2Synarc, Lyon, France, 3University Claude Bernard, Lyon, France Risedronate therapy results in a decrease in bone resorption markers that is maximal at about 3 months. These bone resorption markers could be used to monitor the effect of treatment in the individual using the approach of least significant change (LSC). The aim of this analysis was to compare the percentage of women taking risedronate in the IMPACT study, who exceed the LSC based on duplicate measurements as compared to single measurements of urinary N-telopeptide of type I collagen. The IMPACT study included 2386 women that had osteoporosis, i.e. a T score 5 or equal to –2.5 at the spine and/or hip or a T score between –2.5 and –1 with a peripheral fragility fracture. The present preliminary report is based on 1030 women who had urinary NTX measurements at baseline, 3 and 6 months using the Ortho Clinical Vitros analyzer. At each time point, two samples were taken one day apart (second morning void). The LSC for double measurements was set at 30% and this is equivalent to a P-value of 0.1 (as the CV based on the double baseline measurements was 23%). With double measurements, the response rates at 3 and 6 months were 70 and 72%. With single measurements, the LSC was 42% (30*1.414) and the response rates at 3 and 6 months were 55 and 61%, respectively. These response rates are conservative as the subjects were treated with calcium supplements (1000mg Ca/400 IU Vitamin D) two to 4 weeks prior to obtaining the baseline urine samples, and do not take into consideration the blinded compliance and persistence data of the subjects while on treatment. We conclude that the reduction in the variability achieved by taking the mean of two measurements results in a substantial improvement in the ability to detect responders to risedronate therapy.

P98SA. EUROPEAN BONE AND JOINT HEALTH STRATEGIES PROJECT Woolf AD1, Akesson K2, Thorngren KG3, van Riel P4, Compston J5, Magyar G3, Watt A1, and the European Bone and Joint Health Strategies Group A1; 1Royal Cornwall Hospital, Truro, UK, 2Malmo University Hospital, Malmo, Sweden, 3Lund University Hospital, Lund, Sweden, 4University Hospital Nijmegen, Nijmegen, The Netherlands, 5Addenbrooke’s Hospital, Cambridge, UK WHO Health21 has emphasised the importance of integrated care and rehabilitation for people with chronic disease but European public health policy recommendations are lacking for most common musculoskeletal conditions. This project addresses this by developing a common public policy from existing knowledge that can be implemented across the European Community for people at risk of or with musculoskeletal conditions focusing on osteoporosis, joint diseases, back pain and musculoskeletal trauma. Recommendations will be common for the health problems they cause of pain and disability but specific for interventions to treat the conditions themselves. This is a collaboration between the Bone and Joint Decade, IOF, EULAR and EFORT with the support of the European Commission. Key areas are being identified 1) the burden of musculoskeletal conditions in Europe to establish priorities; 2) risk factors for and determinants of outcome to establish targets for intervention; 3) effective interventions for primary, secondary and tertiary prevention to develop strategies; 4) barriers to care that affect implementation. Additional work focuses on dissemination and implementation of any identified policy. A resource document will be developed which considers incidence and prevalence, priority areas and targets for intervention and gives a range of evidence-based intervention options. Evidence will be drawn from existing systematic reviews, guidelines and recommendations. Then practical and appropriate policy recommendations will be developed that can be implemented at the regional and district level throughout the European Community. These will link where possible into existing health promotion activities. The goals of the project are being achieved by a project management group and inter-related multi-professional expert task groups that includes all stakeholders – patients, public, health care providers, health policy and promotion. The evidencebased recommendations will be widely disseminated and will be evaluated.

P99SU. THE HOSPITAL COST OF VERTEBRAL FRACTURES IN THE EUOPEAN UNION (EU) Finnern HW1,2, Sykes DP1; 1Eli Lilly European Health Outcomes Research, Erl Wood Manor, Windlesham, UK, 2The London School of Economics and Political Science, London, UK The aim of this study was to assess the hospital cost of vertebral fractures in the EU and compare these costs to those associated with hip fractures. All EU Ministries of Health were asked for the number of patients discharged with vertebral fractures without neurological deficit (ICD 9 805) and with neurological deficit (ICD 9 806), the average length of stay and average cost per day for patients aged 50 and over with these diagnoses. The hospital cost data was inflated to 2001 using the OECD inflation index for the retail price of individual countries while the data was adjusted to account only for vertebral fractures caused by low trauma. A marked difference in the length of stay has been found for the treatment of vertebral fractures in the EU ranging from 5 days in Greece to 48.2 days in the UK, while differences in the length of stay between men and women were found to range from 0.32 days in Austria to 20.2 days in Spain. The total cost of vertebral fractures caused by low trauma is estimated at EURO 329 million, while the hospital cost of a vertebral fracture was on average 76% that of a hip fracture in the EU.

Abstracts Large variations in the length of stay of patients with vertebral fractures have been found across the EU. Further research is needed to explain these differences in the length of stay especially between men and women, in order to improve the quality of care in the EU.

P100MO. ANALYSIS OF BONE MASS AND MICROSTRUCTURE IN GH TRANSGENIC MICE SHOWS THAT SKELETAL CHANGES ARE SPECIFIC TO BONE COMPARTMENT AND GENDER Eckstein F1, Lochmu¨ller EM2, Weusten A1,2, Wolf E3; 1Institute of Anatomy, Mu¨nchen, Germany, 2Universita¨tsfrauenklinik, Mu¨nchen, Germany, 3Gene Center, Mu¨nchen, Germany Aim: Growth hormone (GH) is one of few agents that has an anabolic effect on bone by increasing bone formation. Previous studies in rats indicate that GH acts on cortical, but not on trabecular bone. In this study we use a transgenic model to investigate effects of supraphysiologic GH levels on bone mass, density and microstructure in mice. Methods: 28 mice, aged 12 weeks, were examined (14 male, 14 female). Half of the animals displayed systemic overexpression of GH, with serum levels 4100ng/ml vs. 10 ng/ml baseline in controls. Bone mass (BMC) of the total skeleton and the femur were measured with DXA (Sabre, Stratec), and femoral volume by Archimedes principle. Mikro-CT scans (Scanco mCT 20) were acquired at the shaft and distal femur with 9 mm voxel size. Results: Total skeletal and femoral BMC, and femoral volume were increased by 450% in GH-transgenic mice (p50.01). The ratio of BMC/body weight was, however, not significantly different, and the apparent femoral density was only slightly elevated in transgenic females (p50.05). The cortical and total cross sectional area of the femoral diaphysis were significantly elevated in transgenic animals (p 5 0.05), but not the ratio cortical/total area. Female mice displayed a 130% increase (p50.01) in trabecular bone volume fraction (BV/TV 38% vs. 16%), with thicker trabeculae and decreased trabecular spacing. Male transgenics showed microstructural changes (thinner trabeculae, decreased spacing), but no effective increase in BV/ TV. At the tissue level, mineralized matrix density was reduced (p50.05) in both male and female transgenic mice. Conclusions: The study shows that female GH has anabolic effects on trabecular bone in female, but not in male transgenic mice, whereas tissue matrix properties are impaired. Effects of GH excess are thus specific to bone compartment and gender.

P101SA. RANDOMIZED DOUBLE BLIND TWELVE MONTHS STUDY OF 1 *G/DAY OF ALPHACALCIDIOL VS PLACEBO IN A HIGH BONE TURNOVER POSTMENOPAUSAL WOMEN Riera-Espinoza G, Naressi M, Vela´squez G, Ramos J, Herrera B; UNILIME, Universidad de Carabobo, Hospital Universitario Angel Larralde, IVSS, Valencia, Venezuela Vitamin D metabolites have been used for osteoporosis treatment. Main actions on bone are: mineralization, stimulation of osteoblast and diminished resorption, however available information about action on resorption markers in a prospective double-blind, placebo control trial are started. 85 postmenopausal patients with low BMD (T-score between –1 and –3 at L2L4 or femoral neck) and high turnover (N-telopeptide-NTx-, Tartrate Resistant Acid Phosphatase -TRAP- or Alkaline Phosphatase -AP- 1SD or more above the premenopausal mean) were randomized in a double-blind, placebo control, 12 month trial of 1 mg/day of aD3 vs placebo, according to the principles of the Helsinski Declaration. Exclusion criteria were: secondary osteoporosis, fracture 6 months prior to the study, medication such as TRH, insulin, steroids, diuretics, biphosphonates, calcitonin,

S35 raloxifene, antituberculosis drugs and thyroid hormones, allergy to vitamin D. Group A: alphacalcidiol 1mg/day + calcium citrate 500mg/day, Group B: placebo + calcium citrate 500mg/day. Mean age was 61.58 ± 6.69 and 62.4 ± 6.30. Age of menopause was 45.6 ± 5.14 and 46.4 ± 5.5, there were no differences on risk factors between groups. Modest hypercalciuria occurs in 48% (Group A) and 18% (Group B), Calcium supplement was stopped to control this side effect. We did not have hypercalcemia. Drop out rate was 3.5% in the placebo group and 2.4% in the alphacalcidiol group. BMD remained stable in both groupsIn conclusion the use of alphacalcidiol 1 mg/day during 12 months in postmenopausal women with low BMD and high turnover was very well tolerated and decreased NTx by 27.7%, TRAP by 23.6% and AP by 16%. Placebo Marker

Initial

Alphacalcidiol 3 mo

6 mo

12 mo

Initial

3 mo

6 mo

12 mo

AP (UI/L) 47±14 43.2±15 43.3±12.6 43.2±12 48.6±15.3 43.1±14.7 39.2±10.1** 40.8±10.4** TRAP (UI/L) 10.2±3.3 9±2.3 8.4±1.9*** 8.1±2.2*** 9.9±2.9 8.67±12.6 7.4±1.8*** 7.5±2.3*** 133.5±58.3 103.6±64* 118.5±67.5 114.5±85.1* 128.7±67.2 115.2±28* 102±6 92.9±55.7* NTx nMolBCE mMolCreat * = p50.05, ** = p50.01, *** = p50.001 vs Initial

P102SU. EFFECT OF CYCLICAL PAMIDRONATE TREATMENT IN PEDIATRIC PATIENTS WITH SEVERE AND MILD FORMS OF OSTEOGENESIS IMPERFECTA Marowska J1, Jelonek E2, Olszaniecka M2, Kobylinska M1, Matusik H1, Lebiedowski M2, Lorenc RS1; 1Department of Biochemistry and Experimental Medicine, 2Department of Rehabilitation, Children’s Memorial Health Institute, Warsaw, Poland Osteogenesis Imperfecta (OI) is an autosomal dominant disorder of connective tissue, affecting mainly bone. The clinical symptoms include low bone mass, fractures after minimal trauma, skeletal deformity, bone pain, growth retardation and restricted ambulation. No causal treatment is available at present, but administration of pamidronate to children with OI has been recently reported to improve bone mass and reduce fracture rate without significant adverse effects. The aim of our observational study was to evaluate changes in clinical status of children with OI treated for 12–24 months with cyclical intravenous pamidronate given according to two regiments. Six patients with OI (type I: N = 2; III: N = 3; IV: N = 1), aged 5–15 years, with low L2–L4 BMD by DEXA and high bone resorption measured by urinary excretion of pyridinoline and deoxypyridinoline (HPLC), entered the study. Pamidronate was administered iv in cycles of 3 consecutive days with 4 month intervals at a dose of 1 mg/kg/d (5 patients), or once a month (first year) and once every two months (second year) at a dose of 30 mg/m2 body surface (1 patient with OI type I). The treatment period varied from 12 to 24 months. We evaluated short- and long-term changes in bone resorption, annual changes in bone mineral content and density, as well as clinical performance of patients under treatment. Pamidronate treatment of pediatric patients with OI resulted in marked relief of bone pain, improved mobility and reduced fracture rate. In most patients, the therapy substantially decreased deviation of BMD from normal and did not result in long-term suppression of bone resorption below the reference range. No delay in fracture healing was observed. It is concluded that pamidronate treatment of pediatric patients with OI improves their clinical status and does not result in excessive inhibition of bone resorption, which could be harmful for the growing skeleton.

S36

Abstracts

P103MO. PREFERENCE STUDY OF ALENDRONATE* 70 MG ONCE WEEKLY AND ALENDRONATE 10 MG ONCE DAILY IN POSTMENOPAUSAL WOMEN WITH OSTEOPOROSIS

P105SU. ALENDRONATE TREATMENT DECREASES URINARY CALCIUM EXCRETION IN WOMEN WITH POSTMENOPAUSAL OSTEOPOROSIS

Palmisano J1, Melton M1, Lewiecki EM2, Rosen R3, Bockman RS4, Dinh AC1, Smith ME1, Wang L1, Keene W1; 1Merck & Co., Inc., West Point, USA, 2New Mexico Clinical Research & Osteoporosis Center, Albuquerque, USA, 3Maine Center for Osteoporosis, Bangor, USA, 4Hospital for Special Surgery, New York, USA

Ochodnicky´ M1, Ochodnicky´ B1, Ochodnicka´ E, Galajda P1, Vlada´r L1, Moka´n M1; 1Jessenius Faculty of Medicine, Dept. Internal Medicine I, Comenius University, Martin, Slovakia, 2 Jessenius Faculty of Medicine, Institute Histology & Embryology, Comenius University, Martin, Slovakia

Objectives: Primary: to examine preference for once weekly (OW) 70 mg alendronate (ALN) or once daily (OD) 10 mg ALN. Secondary: to examine which treatment, OW ALN or OD ALN is considered more convenient and would provide better overall compliance. Design: This open-label, crossover study was conducted at 38 U.S. sites with 288 women. Patients were randomized (1:1) to receive either ALN 70 mg OW or ALN 10 mg OD for 4 weeks and then crossover to the opposite treatment for 4 weeks after a 1 week off therapy period. Preference, convenience, and compliance were assessed by Questionnaire. Results: Alendronate 70 mg OW was preferred by 86.4%**, thought to be more convenient by 89.0%**, and found easier to comply with by 87.5%** of patients when compared to ALN 10 mg OD. Conclusions: Patients preferred ALN 70 mg OW to ALN 10 mg OD, as measured by Questionnaire, and felt it was more convenient and provided better overall compliance.*Trademark: Fosamax1, Merck & Co., Inc., West Point, PA**p50.001 relative to alendronate 10 mg daily.

Alendronate sodium is an aminobisphosphonate, whose efficacy in the treatment of postmenopausal osteoporosis is well documented. Much less attention has been devoted to changes in calcium metabolism during alendronate treatment. Aims: To further evaluate the effect of alendronate treatment on urinary calcium excretion in women with postmenopausal osteoporosis. Methods: A group of postmenopausal women (aged 50-70 years, at least 5 years postmenopausal with BMD [DTX-200, Osteometer] T-score greater than 2.5 SD below the mean) was enrolled in this study. During the treatment period 10 mg of alendronate sodium was administered orally. All patients received 1250–1500 mg of elemental calcium and 800 I.U. of cholecalciferol daily. We measured the fasting serum calcium and intact parathyroid hormone, and urinary calcium and creatinine both after an overnight fast and in a 24-h collection. Fasting and 24-h urinary calcium were assessed at baseline and after one-year treatment with alendronate sodium. Results: No significant changes in serum calcium and immunoreactive PTH were noted during the treatment. There were statistically significant (P50.001) decreases in urinary calcium/creatinine ratio and calcium excretion/GFR after oneyear treatment with alendronate as compared with pre-treatment values. Statistically significant (P50.001) decrease in 24-h urinary calcium excretion was noted after one-year alendronate treatment. This significant decrease in urinary calcium excretion occurred in women with postmenopausal osteoporosis despite the supplementation of calcium and cholecalciferol. Conclusions: The fasting urinary calcium excretion is useful, inexpensive and easily accessible marker of bone resorption. Alendronate treatment significantly decreases 24-h urinary calcium excretion in women with postmenopausal osteoporosis.

P104SA. THE ORTHOPAEDIC SURGEON’S ROLE IN DIAGNOSING AND TREATING OSTEOPOROSIS: STANDING DISCHARGE ORDERS MAY BE THE SOLUTION FOR TIMELY MEDICAL CARE Skedros JG, Milleson NM, Henderson GL; Utah Bone and Joint Center, 2490 South State Street, Suite 100, Salt Lake City, Utah USA 84115 Patients with osteoporotic fractures typically do not receive subsequent medical treatment for osteoporosis. We hypothesized that even if patients with osteoporotic fractures were specifically referred to their primary care providers (PCPs), the majority would not be treated within 84 days (12 weeks) of fracture. We evaluated the effectiveness of 13 orthopaedic surgeons in facilitating a timely PCP visit for their patients with apparent osteoporotic fractures. Surgeons received remuneration for each study participant. None of the surgeons routinely treated osteoporosis. Patients who qualified were 450 years old, had an apparent osteoporotic (low-energy) fracture, and had no prior treatment for osteoporosis. Two letters requesting a PCP appointment were sent: the first within 10 days of fracture, and the second within 3-10 weeks after fracture. Patients were also instructed to make a PCP appointment for evaluation, and possible medical management for presumed osteoporosis. The orthopaedic surgeon told the patient that medical treatment, if needed, would be the responsibility of their PCP. Results showed that of 42 patients (39 females, 3 males: avg. age 73, range 53-90) 16 (38%) were not seen by a PCP within 84 days. 26 (62%) patients saw a PCP within 84 days, but in 4 patients osteoporosis was not addressed (avg. days to PCP, 37: range 7-71 days). Of patients seen within 84 days, pharmacologic treatment (e.g., estrogen, bisphosphonate, etc.) was started in 14 patients (54%), but typically not within 36 days after fracture. Of the 13 surgeons, five were non-compliant and six were inconsistent in their participation, forgetting to send the letters and to inform their patients to make a PCP appointment. We suggest that standing discharge hospital orders (for medications, PCP follow up, etc.) may be more effective in achieving timely medical treatment for patients with osteoporotic fractures.

P106MO. ACTNOW, A PATIENT INFORMATION AND SUPPORT SERVICE, LEADS TO A HIGH ADHERENCE RATE IN OSTEOPOROTIC PATIENTS RECEIVING RISEDRONATE Blair SC1, Ebeling PR2; 1Aventis Pharma, 27 Sirius Road, Lane Cove NSW 2066, Australia, 2The Royal Melbourne Hospital, Parkville Vic 3050, Australia Aim: To address the perceived inconvenience of oral daily bisphosphonate therapy and the poor adherence rates associated with osteoporosis treatments, the ActNow patient information and support service was developed for osteoporotic patients receiving risedronate. Methods: The service was commenced on Feb 1st 2001. Upon enrolment in ActNow, patients receive printed materials providing information on osteoporosis and practical advice on diet, exercise and the different treatments available. Also, patients receive monthly newsletters and counselling from trained nurses via the telephone at 0, 2, 4, 8, 12, 24 and 52 weeks after commencing risedronate. During these calls, data on treatment adherence are collected. Patients enrolled in ActNow for 1 month or more (n = 1196) received a questionnaire and were asked to rate the various components of ActNow and provide feedback on the convenience of taking risedronate daily. Results: Of the1196 patients who were sent the questionnaire, 599 provided a response. When asked to rate the ActNow on a scale of 1 to 5, with 5 being extremely useful, 77% of patients

Abstracts rated it as a 4 or a 5. In response to the question ‘Can you tell us about how you found taking your daily dose of risedronate?’ 85% of patients reported taking their risedronate daily to be of no inconvenience, 13% some inconvenience and 2% a major inconvenience or almost impossible. As the ActNow service commenced only recently, only 257 patients have been enrolled for 6 months or longer. 92% of these patients reported that they were still taking their risedronate. Conclusions: The majority of patients enrolled in ActNow for 1 month or more rated the service highly and found taking risedronate daily to be of no inconvenience. This, along with the counselling and information provided to patients, may explain the high self-reported treatment adherence rates observed in patients enrolled in ActNow for 6 months or longer.

P107SA. LOWER EXTENSOR STRENGTH IN PATIENTS WITH OSTEOPOROSISA COMPARISON OF DIFFERENT THERAPY STRATEGIES Franck H; Center of Rheumatology, Oberammergau, Germany Aims: Patients with osteoporosis have lower back pain of different clinical severity. Similar is true for patients with lower back pain. In patients with osteoporosis mainly fractures are the cause of it. On the other hand lower back pain can lead to muscular dysfunction. The aim of the study was to examine if patients with osteoporosis have a lower extensor strength than patients with lower back pain. Methods:130 patients with osteoporosis (WHO-definition) with mean age (51.6 ± 15 years) and 90 patients with lumbar spine syndrome (mean age 50.8 ± 16) were included in the study. The lower extensor strength was measured in different angels (128, 248, 368, 488, 608, 708) by MedX. Both groups were randomized in different therapy groups (group I classic physiotherapy, group II received additionally lower back strength training, group III sport therapy, group IV sport therapy plus lower back strength therapy). Results: Patients with osteoporosis had a significantly lower extensor strength than patients with lower back pain for the angels 248 to 728 (248: 92.6 ± 33 versus 105 ± 48, 368: 106 ± 37 versus 125.7 ± 54.6, 488: 115.2 ± 37 versus 137.6 ± 59, 608: 126.6 ± 37.2 versus 153.3 ± 65.8, 728: 125.5 ± 55 versus 154.4 ± 83, p50.05). All groups gained extensor strength but only group IV of patients with osteoporosis, which performed both sport therapy and lower extensor strength training has significantly higher increment of strength than group III. Conclusion: All results shows that patients with osteoporosis have significantly lower extensor strength than patients with lower back pain. These deficit can by compensated by specific physiotherapy especially lower extensor strength training.

P108SU. ALENDRONATE IN POSTMENOPAUSAL OSTEOPOROSIS: A 5 YEAR FOLLOW–UP

S37 and repeated every year after treatment with ALN for 5 years. All women started out therapy with a T score of at least –1.5 SD. Patients treated with ALN showed progressive increases in BMD at all measured sites. Mean BMD had increased significantly (p50.001) from baseline at the lumbar spine (4.5%), femoral neck (2.1%), trochanter (3.1%), and total hip (2.8%). Biochemical markers of bone turnover were significantly reduced by 45–65%. No major adverse effects were seen. 5 vertebral, 1 humerus and 2 pelvic fractures were occurred during 5 year period. Humerus and pelvic fractures were due to traffic accidents. The incidence of fractures was decreased on ALN treatment (8/300, 2.7%). In conclusion, ALN is an effective and well tolerated treatment for the prevention and treatment of postmenopausal osteoporosis.

P109MO. FOUR HEALTH RELATED QUALITY OF LIFE ASPECTS AND THEIR ASSOCIATION TO FRACTURE STATUS IN WOMEN WITH POSTMENOPAUSAL OSTEOPOROSIS Glueer MG1, Minne H2, Lazarescu D2, Begerow B2, Pollaehne W2; 1 Bundesanstalt fuer Milchforschung Kiel, Germany, 2Insitut fuer Kinische Osteologie, Bad Pyrmont, Germany Vertebral osteoporotic fractures affect patients‘ Health Related Quality of Life (HRQoL). Frequently patients suffering from these impairments nevertheless report an excellent HRQoL while some patients with very few impairments report a poorer HRQoL. Aiming to differentiate various aspects of HRQoL, we investigated 283 women with postmenopausal osteoporosis (age 63.47 ± 7.92) with regard to various HRQoL aspects, e.g. well-being (BBS Hobi 1985), pain (Hoppe 1990, Miltner 1988), limitations in daily living (Leidig 1991), load of disease (Badura 1987), and life satisfaction (Bullinger 1990). Moreover we investigated the fracture status by SDI (Minne 1991). 47% (n = 132) of the patients had an of average 3.8 fractures (SD: 2.9). Using factor analysis (direct oblimin) on a dataset of 99 HRQoL questions, each variable could be distinctly assigned to one of four main factors: 1. ‘objective’ aspects like pain and limitations (17% variance explained); 2. ‘subjective’ aspects like satisfaction with health, quality of life, social support (10% var.expl.); 3. subjective aspects of well-being (8% var. expl.); 4. disease specific HRQoL like load of disease (11% var. expl.). The associations with fracture status differed substantially for the four factors. No associations were observed for well-being and life satisfaction. The ‘pain and limitations’ factor showed a trend to higher levels in the fracture group (p50.8). The load of disease however was significantly increased in the group with fractures (p50.2). Current attempts to improve patients’ HRQoL mainly focus on the improvement of the more objective HRQoL aspects like pain and functional limitations. Our data also suggest that the load of disease is very important to be included in these attempts and HRQoL could be improved by preventing fractures. The missing associations to the more subjective quality of life aspects indicate that more than fracture prevention is needed to improve these aspects of HRQoL in patients with osteoporosis.

Dilsen Dilseng, Issever Isseverh; Istanbul Medical School/Turkey Alendronate (ALN) has been shown to inhibit bone resorption, to increase bone mineral density (BMD), and prevent fractures in postmenopausal osteoporotic women. 300 osteoporotic postmenopausal women were treated with ALN and followed up for 5 years with an oral dose of 10 mg per day. All patients also received 500 mg elemental calcium once daily. The patients ages ranged between 40 and 79 years with a mean age of 62.5 years. BMD measurements were analyzed and assays for biochemical markers were performed every year. Bone mass was measured in the lumbar spine and femoral neck before beginning treatment

P110SA. LOW REBOUND AFTER INDUCTION OF OSTEOPOROSIS IN SHEEP WITH A COMBINATION PROTOCOL Goldhahn J1, Jenet A1, Eckhardt C1, Lill CA2, Schneider E1; 1AO Research Institute, Davos, Switzerland, 2Orthopa¨dische Universita¨tsklinik, Heidelberg, Germany Aims: New solutions for treatment of fractures in osteoporosis need to be tested in an appropriate animal model. In a former sheep study the BMD in cancellous bone could be reduced by

S38 30% using a combination protocol of steriods. The goal of this study was to investigate the magnitude of the rebound effect subsequent to the end of steroid treatment to determine the suitable time window. Methods: 10 female white alpine sheep (age 6.8 ± 0.8 years) underwent ovarectomy, were kept in single box husbandry, received vitamin D3 and Calcium restricted diet and 4 injections at 500 mg Methylprednisolone within 3 months. 8 healthy sheep served as a control. BMD of the cancellous bone was measured initially, after 3,4,5,6, and 9 months by pQCT in the distal radius. Structural parameters were determined finally in iliac crest and lumbar vertebra biopsies using microCT 20. Additionally the level of basal cortisone in the blood was measured using RIA every 3 weeks. 2-tailed t-tests (a = 0.05) were carried out to test any difference between healthy and osteoporotic sheep. Results: Whereas the linear rate of bone loss was –5.9% per month until maximal decrease of –29.2 ±6.5%. The Rebound of BMD started at month 5 with a linear coefficient of +0.9% per month. The final BMD value was still less than –2.5 SD (–24,9%) below the origin. Structural changes in the iliac crest revealed significant differences between healthy and osteoporotic sheep 5 months after induction (Tb.N –21%, Tb.Sp. +36%. After start of steroid treatment endogenous level of all sheep dropped below the detection limit of 2 mg/dl but reached physiological values after 4,5 month. Conclusions: The findings suggest that the model offers reproducible conditions for testing in an appropriate animal model in an adequate window of about 4 month.

P111SU. EFFECTS OF LONG-TERM TREATMENT WITH MINODRONATE ON BONE LOSS AND MECHANICAL STRENGTH IN OVARIECTOMIZED RATS Mori H, Tanaka M, Ochi Y, Kawada N, Yamada H, Masuda T, Kawabata K, Obata T; Ono Pharmaceutical Co., Ltd., Osaka, Japan Present study examined the effects of 12-month treatment with an aminobisphosphonate, minodronate (YM529/ONO-5920) on bone loss and mechanical strength in ovariectomized (OVX) rats. Seventy-five Fischer F344 rats, 14 weeks of age, were assigned into five groups (one sham group and four OVX groups) each consiting of 15 animals. In OVX groups, rats were orally administered either a vehicle or three doses of minodronate (6, 30 or 150 microg/kg) once a day for 12 months beginning the day after ovariectomy. Bone mineral density (BMD) of lumbar vertebrae was measured by dual X-ray absorptiometry every three months under anesthesia. Twelve months after ovariectomy, rats were sacrificed and their BMD (lumber vertebrae, femur and tibia) and mechanical strength (lumber vertebral body, femoral shaft and femoral neck) were measured. In the vehicle group, lumbar vertebrae BMD at 3, 6, 9 and 12 month postovariectomy was significantly reduced (9.2, 11.5, 14.8 and 19.7%, respectively) as compared with the sham group. Minodronate treatment significantly ameliorated the reduction in lumbar vertebrae BMD at all the time points in a dose dependent manner. Particularly, at 12 months post-ovariectomy, the increase in lumber vertebrae BMD was 15.1, 23.3 and 30.8%, at 6, 30 and 150 microg/kg, respectively as compared with the vehicle group. Moreover, the treatment dose-dependently increased BMD of femur and tibia with a potency order of tibia5femur5lumber vertebrae. In mechanical strength studies, minodronate significantly increased both the ultimate compressive load of the fifth lumbar vertebral body and the ultimate bending load of femoral shaft, although its effects on the ultimate bending load of the femoral neck were not clear. Both urinary deoxypyridinoline and serum osteocalcin levels in minodronate treated group were significantly decreased compared with the vehicle group. We conclude that oral minodronate treatment prevents loss of BMD and mechanical strength in OVX rats.

Abstracts P112MO. EFFECT OF EIGHTEEN MONTHS TREATMENT WITH 1.0 MICROG ALFACALCIDOL PLUS CALCIUM SUPPLEMENTATION IN POSTMENOPAUSAL WOMEN WITH OSTEOPOROSIS Daniluk S, Badurski JE, Dobrenko A, Nowak NA; Centre of Osteoporosis & Osteo-Articular Diseases, Bialystok, Poland Introduction: Application of alfacalcidol (AC) in the treatment of postmenopausal osteoporosis was several times described with no clear conclusions. Also AC has never been checked in comparable conditions in polish women population with osteoporosis. The aim of the study was to asses the efficacy of two years treatment with 1.0 microg/day of AC in the dose of 1.0 microg per day in polish women with postmenopausal osteoporosis without vertebral fractures. We present interim analysis after eighteenth months of the treatment. Material and Methods: 70 postmenopausal osteoporotic women, without vertebral fractures were included. All these women received 1.0 microg of AC and 500 mg of calcium per day. Mean dietary calcium intake was 700 mg/d. Bone mineral density (BMD) of the neck and lumbar spine L1-L4 was measured after 6, 12 and 18 months by use of DXA- HOLOGIC QDR4500SL machine. Quantitative ultrasound (QUS)- speed of sound (SOS) and broadband ultrasound attenuation (BUA) of the heel was performed after 12 and 18 months by the use UBIS 3000. Results: Mean value of BMD and QUS are placed in table.BMD after 6 months increased 2.0% in hip neck(p50.05) and 1.2% in the spine L1-L4 (p50.05). After 12 months- 1,1% (p50.05) and 0.9% (p50.05) respectively. After 18 months 1.4% (p50.05) in hip neck and 0.9% in lumbar spin L1-L4 (p = 0.08). In QUS only SOS increased after 12 and 18 months (p50.05). Conclusions: 1.0 microg alfacalcidol daily prevents bone loss after 12 and 18 months of the treatment. Months

Neck BMD

L1-L4 BMD

SOS

BUA

0 6 12 18

0.655 0.668 0.662 0,664

0,747 0.756 0.754 0.754

1480.8 NA 1486.5 1485.3

56.85 NA 56.22 55.86

P113SA. BAZEDOXIFENE ACETATE, A NEW TISSUE SELECTIVE ESTROGEN, PRESERVES SKELETAL MASS AND VERTEBRAL COMPRESSIVE STRENGTH IN THE OVARIECTOMIZED RAT MODEL (OVX) OF OSTEOPENIA WITHOUT UTERINE LIABILITY Komm B, Kharode Y, Bex F; Wyeth-Ayerst Research, Collegeville, USA Aim: To demonstrate bazedoxifene acetate (BZA, a third generation, tissue selective estrogen has an improved pharmacologic profile when compared to raloxifene (RAL) and lasofoxifene (LAS). Methods: These compounds are not equivalent in their ability to prevent ovx-induced bone loss as revealed by DEXA and pQCT bone mineral density (BMD) measurements and by histomorphometric and bone compressive strength testing. Results: While BZA, RAL and LAS all have bone sparing activity in the ovx rat, there are differences in their potency and efficacy. In terms of total body and lumbar vertebral BMD these compounds are fairly comparable, but histology of the proximal tibia shows that BZA is consistently superior to RAL in maintaining cancellous bone mineral area (B.Ar.). The fact that BZA maintains compressive strength of lumbar vertebral bone unlike RAL, which is much less effective and often no different from the ovariectomized control animals, might reflect BZA’s superiority in maintaining cancellous structure. While LAS is quite potent in its bone sparing activity, this activity is associated with

Abstracts uterine effects. Unlike BZA, which at its optimal bone sparing dose in the ovx model (0.3mg/kg/day) does not significantly affect uterine wet weight or endometrial C3 gene expression (a specific estrogen regulated epithelial marker in the rodent uterus), LAS stimulates the uterus and produces a robust stimulation of C3 gene expression. Conclusion: Thus, BZA offers greater cancellous bone protective activity in the ovx model than RAL without introducing any uterine activity, whereas LAS has potent bone sparing activity, but this activity is associated with evidence of uterine stimulation.

P114SU. MANDIBULAR BONE LOSS IS PREVENTED BY RISEDRONATE IN THE ORCHIDECTOMIZED RAT Lerouxel E1, Libouban H1, Moreau MF1, Horlait S2, Basle´ MF1, Chappard D1; 1LHEA-GEROM, Faculty of Medicine, Angers, France, 2Procter & Gamble Pharmaceuticals, Paris, France The aim of the present study was to assess the effects of orchidectomy (ORX) and the preventive activity of an antiresorptive compound (risedronate) on the mandible bone loss in the ORX rat using X-ray microtomography. We have studied 3 groups of rats (6 animals per group): shamoperated control rats (SHAM), ORX rats, ORX treated with risedronate 10 mg/kg/day (RISE10). Risedronate was injected subcutaneously 5 days per week. Rats were sacrified at 16 weeks post-ORX. The mandible of each rat was dissected. X-ray microtomography was performed on each mandible with a Skyscan microCT. Two vertical sections (one on the incisor, one on the molars) were realized from the 3D reconstruction model. They were transferred to an image analyzor to measure BV/TV (Trabecular Bone Volume) and porosity of the alveolar bone on the molar section. Surface, thickness and fractal dimension of the periodontal ligament of the incisor were studied on the incisor section. In the molar section, a significant decrease of BV/TV and a significant increase of porosity were observed in the ORX vs SHAM group. Risedronate maintained BV/TV and porosity in the RISE10 group; the results were not different from the SHAM group. In the incisor section, surface, thickness and fractal dimension of the periodontal ligament were increased in the ORX vs the SHAM group, but the difference did not reached significance. The mandible, that does not grow by an endochondral process, represents a most suitable region for the study of bone loss due to sex hormon deprivation. This study confirms that in the male rat, orchidectomy is associated with alveolar bone loss. Risedronate appears to be a preventive treatment for orchidectomy-induced bone loss in the mandible.

P115MO. COMPARISON OF SINGLE VERSUS REPEATED DAILY ADMINISTRATION OF ORAL CALCIUM TO SUPPRESS BONE RESORPTION IN POSTMENOPAUSAL WOMEN Ortolani S1, Scotti A2, Cherubini R1; 1Istituto Auxologico Italiano, Milan Italy, 2Italfarmaco, Cinisello Balsamo (Milan), Italy Calcium administration acutely suppresses PTH secretion and bone resorption, leading to long term prevention of postmenopausal bone loss. Nevertheless, recent data indicate that 1 g of calcium at evening in healthy postmenopausal women suppresses bone resorption during the following night but not the following day, raising the question about the most appropriate timing and dosing schedule for calcium therapy. In a three-way,

S39 within subjects, randomised study in 12 postmenopausal women, we compared no treatment and two different dosing schedules, (one dose of 1200 mg of calcium at evening, or two doses of 600 mg at 12-hour interval; Natecal D3, Italfarmaco, Italy) to test if these dosing schedules induce similar acute metabolic effects and if two separate doses of calcium lead to more steady suppression of bone resorption. In each study day serum ionised calcium and intact PTH were measured at multiple time points for 24 hours. Urine was collected every 6 hours during 24 hours for the determination of type I collagen C-terminal telopeptide (CTX). Serum calcium was significantly increased and serum PTH reduced by calcium administration, with either dosing schedule, as compared to control study-day (p50.01), without significant differences between active treatments. Twenty-four hours urine excretion of CTX was significantly reduced by calcium administration given by single or repeated dosing (–31% and –26%; p50.01 for both vs. no treatment). This effect only lasted 12 hours after the single administration of 1200 mg of calcium, whereas a significant second inhibition of CTX excretion was evident after the second administration of 600 mg of calcium during the treatment with two daily doses. We conclude that overall suppression of PTH and bone resorption obtained with two daily doses of 600mg of calcium is similar to that of a single dose of 1200mg. Repeated doses provide a more steady suppression of bone resorption.

P116SA. SHORT-TERM METABOLIC EFFECTS OF CALCITRIOL IN POSTMENOPAUSAL OSTEOPOROSIS Nuti R, Martini G, Valenti R, Giovani S, Franci B, Campagna S, Silvestri GM, Picchi A, Salvadori S, Galli B; Metabolic Disease Unit, Siena, Italy This study in postmenopausal women aged 55-75 years was designed in order to investigate some of the aspects regarding bone metabolism changes that are induced by calcitriol and, particularly, to evaluate the effects of different dosages of the drug compared to treatment with calcium. The study is a double blind, comparative, randomised, threearms parallel clinical study and calcitriol was administered at dosages 0.25 mcg (C25) and 0.50 mcg (C50) twice daily for 3 months in 11 and 9 patients respectively, while calcium was given at a dose of 1000 mg (CA) once daily for 3 months in 8 women. At basal time and after 1, 2, 3 months of treatment were evaluated: serum and urinary calcium; serum osteocalcin, serum procollagen and serum skeletal alkaline phosphatase as marker of osteoblast activity; urine deoxypiridinoline, urine N-telopeptide and urine pyridinoline cross-links as markers of osteoclast activity. In basal condition and at the end of therapy, intestinal calcium absorption was determined using stable strontium (Sr) test and expressed as fraction of absorbed dose (fx). Calcitriol administration promoted a significant increase of intestinal Sr absorption: in C25 e C50 groups mean increase of fx resulted of 42% and 47% respectively compared to 5% of CA group. A parallel increase of urinary calcium excretion was observed ranging from 99% (C25) to 154% (C50) while in CA group the increase was 46%. No significant differences were appreciated among groups as it concerns markers of bone formation and resorption. The safety of treatment with calcitriol was satisfactory and the main events occurring were gastrointestinal symptoms, never leading to interruption of the study. In conclusion the study confirmed a positive effect of calcitriol in the improvement of calcium malabsorption in osteoporotic women; on the other hand it failed to clearly demonstrate an effect of calcitriol in increasing markers of bone formation and decreasing those of bone resorption, probably due to low number of patients studied.

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Abstracts

P117SU. SALMON CALCITONIN NASAL SPRAY (SCNS) IS EFFECTIVE AND SAFE IN REDUCING VERTEBRAL FRACTURES IN ELDERLY POSTMENOPAUSAL WOMEN Silverman SL1, Chesnut C2, Andriano K3, Gimona A4, Mindeholm L4; 1Cedars Sinai and GLA VAHS, Los Angeles, CA, USA, 2 University of Washington, Seattle, WA, USA, 3Novartis Pharma, East Hanover, NJ, USA, 4Novartis Pharma, Basel, Switzerland. A randomized, double-blind study (PROOF) demonstrated the efficacy and safety of salmon calcitonin nasal spray (SCNS) in preventing recurrence of vertebral fractures in postmenopausal women with osteoporosis. From this data it was hypothesised that SCNS would be particularly safe and effective in prevention of vertebral fractures in the elderly after 5-years. A post-hoc stratification was utilized to test this hypothesis. In 1255 postmenopausal women with established osteoporosis, randomized to placebo or SCNS 100, 200, 400 IU/day plus 1g calcium and vitamin D 400 IU, a 33% [95% CI: 0.03–0.53, p = 0.032] reduction in the relative risk of new vertebral fractures was found in patients taking the 200 IU as compared to placebo. Also, a 36% [95% CI: 0.045-0.571, p = 0.029] reduction in the relative risk of new fracture was observed in patients that had 1-5 prevalent (i.e., baseline) fracture. Using the post-hoc stratification analysis, women over 70-years (n = 238) showed a reduced risk of 53% in new vertebral fractures (p = 0.012, 95% CI: 0.15–0.74), increasing to 62% in women over 75-years (n = 105), as compared to placebo (p = 0.03, 95% CI = 0.1 to 0.84) over 5-years. SCNS is a very well tolerated therapy within this age group. There were no unexpected adverse events observed within the group treated with 200 IU SCNS. The only adverse event more frequently observed in the active group (37.5%) compared to placebo (17.3%, p = 0.02), was rhinitis. There were no reports of headaches in the SCNS 200 IU group compared with 5.8% in the placebo group (p = 0.052). In conclusion, SNCS 200 IU significantly reduces the risk of new vertebral fractures in the elderly population (over 70 and 75years). SCNS was extremely well tolerated within this population, which is an important consideration for the elderly, where polypharmacy and the ability to tolerate chronic medicines for osteoporosis are of concern.

P118MO. EARLY PREVENTION BY RISEDRONATE OF AN ACUTE AND MASSIVE BONE LOSS INDUCED BY ORCHIDECTOMY AND DISUSE IN THE RAT: A DXA STUDY Moreau MF1, Libouban H1, Alsayed N2, Basle´ MF1, Audran M3, Chappard D1; 1LHEA-GEROM, Faculty of Medicine, Angers, France, 2Procter & Gamble Pharmaceuticals, Petit Lancy, Switzerland, 3Rhumatologie, CHU, Angers, France Numerous risk factors for osteoporosis include deficiency of sexual steroids and disuse. The orchidectomized (ORX) rat is a suitable model for hypogonadic osteoporosis. An IM injection of botulinum (BTX) neurotoxin in the quadriceps produces a paralysis and induces a localized bone loss of the tibia and femur. ORX and BTX models were combined and to see if their effects were cumulative and if bone loss could be prevented by risedronate or testosterone.48 aged male rats were randomized into 4 groups. Animals were either SHAM operated; bilaterally orchidectomized +paralyzed with BTX; orchidectomized +paralyzed +testosterone (30 mg/kg/day); orchidectomized +paralyzed +risedronate (5 mg/kg/d). ORX and BTX injection were done the same day under general anaesthesia. Testosterone or risedronate therapy began on the day of surgery. Animals were euthanazied after one month. DXA was used to measure lean and fat mass and total BMC. These measurements were also obtained on ROI overimposed on the left and right hindlimbs. BMC was also measured on isolated right vs left tibia and femur.

Lean mass was decreased after ORX and testosterone (but not risedronate) partially avoided this effect. Whole body BMC was decreased after ORX and this was abolished by risedronate but not by testosterone. Effects of ORX and BTX on bone loss were cumulative: a –30% BMC was observed in the isolated tibia of ORX+BTX animals on the paralyzed side. Risedronate appears to have an early effect and to avoid the massive and acute bone loss induced by this combination of factors in the rat.

P119SA. ACUTE SUPPRESSION OF PTH AND BONE RESORPTION BY ORAL CALCIUM IN HEALTHY MEN Ortolani S1, Scotti A2, Cherubini R1; 1Istituto Auxologico Italiano, Milan Italy, 2Italfarmaco, Cinisello Balsamo (Milan), Italy Acute effects of oral calcium supplementation has been studied mainly in pre- and post-menopausal women, whereas very few data are available in men. We investigated in 18 healthy young men the effects of 1.2 g. of oral calcium administered for 4 days. The day before the first calcium dosing (day –1) and the day of the last calcium dosing (day 4) total and ionised serum calcium and intact parathyroid hormone (PTH) were measured at multiple time-points up to 24 hours; calcium, C-terminal telopeptide (CTX), pyridinoline (PYD) and deoxypyridinoline (DPD) were measured in urine collected every six hours for 24 hours. In day 4, total and ionised serum calcium increased during the 6 hours after oral calcium: the maximum increase over baseline was 5.04% and 7.4% respectively, occurring after 2.9±1.9 hours (mean±SD) and 2.6±0.9 hours. The AUC was significantly higher in day 4 than in day –1 for both total serum calcium (+4.6%, p50.02) and ionised serum calcium (+9.2%, p50.0001). Twentyfour hour urinary excretion of total calcium increased significantly in day 4 (+15.1%, p50.02), mainly as a consequence of increased excretion during the first 6 hours. Serum PTH was suppressed by oral calcium, with a significant reduction of AUC in day 4 (715.1%, P5 0.05). Serum concentrations of intact PTH dropped from 26.4±9.8 pg/ml at time zero to a minimum mean value of 14.9±7.6 pg/ml at time +2h. Bone resorption markers significantly decreased in day 4 (CTX –33.2%, p50.001; PYD –28.5%, p50.05; DPD –35.8%, p50.02). Most of the effect was seen in the first 6 hours after oral calcium load. These data support the concept that acute suppression of PTH and bone resorption induced by calcium administration is not gender specific, providing the rationale basis for using oral calcium in the prevention and treatment of osteoporosis also in men.

Abstracts

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P120SU. TWO YEARS CALCIUM AND VITAMIN D SUPPLEMENTATION MAINTAINS LUMBAR BMD WITH SLIGHT DECREASE IN THE HIP IN POSTMENOPAUSAL OSTEOPENIC WOMEN Nowak NA, Badurski JE, Dobrenko A, Daniluk S; Centre of Osteoporosis & Osteo-Articular Diseases, Bialystok, Poland Background: Supplementation of calcium and vitamin D in elderly institutionalised women is documented to increase bone mass and decrease new fractures (1). However, whether such therapy in postmenopausal ambulatory women with osteopenia is sufficient for prevention of bone loss is still a matter of discussion (2). Subjects and Methods: To observe the effect of 3 years supplementation of calcium and vitamin D on bone density and bone markers, 121 postmenopausal women with WHO criteria of low bone mass (T-score between –1.0 and –2.5 m intake was calculated from diary questionnaire. Mean value was 620 mg/d. Preparation of 500 mg of Calcium and 500 I.U of vit.D (Calcium 500D by Polfa £o´deˆ) were added to each individual diet. We measured lumbar and neck bone density by DXA – HOLOGIC QDR 4500SL as well as broadbound ultrasound attenuation (BUA) and speed of sound by QUS – UBIS3000 at baseline and after 12 and 24 months. Conclusions. Supplementation with calcium and vit. D in postmenopausal osteopenic women maintains bone mass in lumbar spine with 0,8% decrease in the hip after 24 months of the treatment.

References 1. Chapuy M.C, et al.: Eect of calcium and cholekalcyferol treatment for three years on hip fractures in elderly men and women. BMJ, 1994, 308, 1081. 2. Dawson-Hughes B. et al.: A controlled trial of the eect of calcium supplementation on bone density in postmenopausal women. N Engl J Med 1990;323(13):878.

Neck L1–L4 BUA

Baseline

12-months 24-months % after % after p (12 12 months 24 months months)

p (24 months)

0.762 0.921 66.97

0.763 0.918 66.97

0.03 NS NS

0.755 0.916 66.10

+0.23 –0.5 0.0

–0,8 –0,5 –1,6

NS NS NS

P121MO. EFFECT OF ORAL MAGNESIUM SUPPLEMENTATION ON BIOCHEMICAL MARKERS OF BONE TURNOVER IN POSTMENOPAUSAL OSTEOPOROTIC WOMEN Aydin H1, Yavuz D2, Deyneli O2, Gozu H2, Mutlu N3, Kaygusuz I1, Akalin S2; 1Marmara Medical School, Department of Internal Medicine,Istanbul, Turkey, 2Marmara Medical School, Department of Endocrinology and Metabolism, Istanbul, Turkey, 3 Marmara Medical School, Department of Biochemistry, Istanbul, Turkey Magnesium has been shown to increase bone mineral density in postmenopausal osteoporosis. The aim of this study was to evaluate the effects of oral magnesium supplementation on biochemical markers of bone turnover in postmenopausal women. Material and methods: Twenty postmenopausal women were included in the study after exclusion of other systemic illnesses. Ten patients were given magnesium citrate p.o. for 30 days and 10 subjects were taken as controls. Four tablets of magnesium (16 mmol/day, Magnesium Diasporal Pastille-Med Ilac¸ San, Tu¨rkiye) were given 2 hours after breakfast. Fasting blood and first void urine samples were collected on days 0, 1, 5, 10, 20 and 30 days, respectively. Total magnesium, calcium, phosphorus,

iPTH and osteocalcin were determined in blood samples and deoxypyridinoline (DPD) levels were measured in urine samples by electrochemiluminescence. In conclusion, magnesium supplementation in postmenopausal osteoporotic patients leads to reductions in serum iPTH and biochemical markers of bone turnover. This indicates that oral magnesium supplementation may reduce bone turnover in postmenopausal osteoporotic women. Because increased bone turnover has been implicated in the pathogenesis of postmenopausal osteoporosis, oral magnesium supplementation may have beneficial effects in the treatment. Results

Magnesium treated group Before treatment

Serum Mg (mg/dl) 2.17 Serum iPTH(pg/ml) 49.29 Serum Osteocalcin(ng/ml) 3.19 Urine DPD(nM DPD/nM creatinine) 8.48

Control group

After treatment 2.43 41.35* 4.73** 5.21***

2.51 52.7 4.02 7.62

*p50.001, **p50.001, ***p50.001, compared with before treatment and control group

P122SA. COMPARISON OF THE EFFECTS OF TWO DIFFERENT TYPES OF CALCIUM SUPPLEMENTATION ON MARKERS OF BONE METABOLISM IN A POSTMENOPAUSAL OSTEOPENIC POPULATION WITH LOW CALCIUM INTAKE: A DOUBLE BLIND PLACEBO CONTROLLED TRIAL Albertazzi P1, Steel SA1, Purdie DA1, Howarth E2; 1Centre for Metabolic Bone Disease, University of Hull, Hull,UK, 2Applied Statistics Centre, University of Hull, Hull,UK Aim: To assess the effects on bone loss of two types of calcium preparations (500 mg/day) derived from a porcine bone powder versus placebo on postmenopausal osteopenic women. One compound contained ossein-hydroxyapatite (OHC), the second consisted only of tri-calcium phosphate (TCP) having had the organic matrix destroyed by ashing. Method: In total 153 postmenopausal osteopenic women (mean age 68 years) were randomised across the 3 treatment groups. Markers of bone turnover were performed at baseline, 3 months and 6 months. The markers of bone formation (osteocalcin, aminoterminal propeptide of type I collagen (PINP) and bone specific alkaline phosphatase) were performed on fasting serum while markers of bone resorption (N-telopeptide (NTX) and urinary deoxypyridinoline (DPD) were performed on second voided morning urine samples. Bone densitometry at hip and spine were performed at baseline and 6 months. Results: Ossein-hydroxyapatite significantly decreased markers of bone formation at 6 months compared to baseline. Serum osteocalcin decreased by 12% (baseline = 7.8 ± 3.6; 6 months = 6.9 ± 3.7), serum PINP decreased by 8.1% (baseline = 44.5 ± 18.9; 6 months = 40.3 ± 17.4) and bone specific alkaline phosphates decreased by 6.8% (baseline = 17.0 ± 7.3; 6 months = 15.8 ± 7.5). The mean percentage change compared to placebo was also statistically significant for all 3 bone formation markers (95% CI (difference): serum osteocalcin = 738.7% to 77.7%; serum PINP = –23.2% to –6.0%; bone specific alkaline phosphates = –20.9% to –3.7%). Tri-calcium phosphate also significantly reduced bone formation markers, but the effect was not as marked as that obtained with OHC. Spine BMD increased by 0.5% with OHC and decreased with both placebo (0.8%) and tri-calcium phosphate (0.7%). BMD at the hip decreased in all three treatments (TCP = 0.2%; OHC = 0.4%; placebo = 0.5%). Conclusion: Dietary supplementation with ossein-hydroxyapatite arrested bone loss in the lumbar spine and significantly reduced bone turnover markers. The effects of ossein-hydroxyapatite were superior to that of tri-calcium phosphate.

S42 P123SU. ASSESSMENT OF UPPER GI TOLERABILITY OF ALENDRONATE (FOSAMAX) 70 MG ONCE WEEKLY VS. PLACEBO Eisman J1, Rizzoli R2, Gaines KA3, Verbruggen N3, Melton ME3; 1 St. Vincent’s Hospital, Sydney, Australia, 2University Hospital Geneva, Geneva, Switzerland, 3Merck & Co., Inc., Whitehouse Station, NJ, USA This study was designed to examine the upper gastrointestinal (GI) tolerability profile of alendronate 70 mg once weekly. Previous studies have compared alendronate once weekly to alendronate daily. This is one of the first studies to compare the tolerability profile of alendronate given once weekly to placebo.Patients with osteoporosis (men and women) were recruited for this multicenter multinational study from Europe, the Americas and Asia-Pacific. Patients were randomized to either alendronate 70 mg or placebo once weekly for 12 weeks. Over 400 patients have been enrolled. The analysis of this study is currently in progress and the results will be available for presentation. Analyses include the percentage of patients reporting any upper GI adverse event and the percent of patients who discontinue due to a drug-related upper GI event. Overall safety and tolerability will also be examined.This study will be one of the first to provide data on the upper GI tolerability profile of alendronate 70 mg once weekly as compared to placebo. This data will lead to a better understanding of the tolerability profile of alendronate when dosed using the once weekly regimen.

P124MO. OPERATIVE TREATMENT OF SEVERE OSTEOPOROTIC FRACTURES* Jaksche H, Bierschneider M, Robert B, Boszczyk B; BGUnfallklinik Murnau, Dept. of Neurosurgery Introduction: Percutaneous transpedicular vertebroplasty with polymethylmethacrylate (PMMA) has become an established method for the treatment of aggressive vertebral haemangiomas, osteoporotic fractures and selected osteolytic lesions. However, decompression of neural structures cannot be undertaken and epidural PMMA leakage with the risk of neurological compromise in severe fractures with disruption of the posterior wall is difficult to control. A microsurgical, unilateral interlaminary approach is described, which allows the decompression of the spinal canal and safe augmentation of the adjacent vertebrae of the affected motion segment even in severe cases. Materials and methods: Under general anaesthesia the patient is placed in the prone position. After microsurgical unilateral laminotomy and spinal decompression, a trochar or kyphoplasty balloon is introduced into the affected vertebral body directly through the posterior wall while gently retracting the dural sac. Augmentation is performed with PMMA under fluoroscopic control after visualisation of the venous drainage with contrast medium. This method has been applied in severe osteoporotic fractures with spinal encroachment and pathologic fractures with neoplastic epidural infiltration. Results: Homogenous vertebral filling is achieved through central positioning of the trochartip or balloon. The spinal canal is well controlled using a surgical microscope. There was no neurological complication and good pain relief was afforded in all cases. Conclusion: Interlaminary vertebroplasty causes minimal unilateral muscle trauma, allows spinal decompression and augmentation of two adjacent vertebrae while increasing safety through control of neural structures. We believe this surgical technique to be of use in severe osteoporotic fractures which are not treatable percutaneously and in select cases of pathological vertebral fractures with encroachment of the spinal canal and neurological compromise. *Presented in part at Eurospine 2001 and Brussels international Spine Symposium 2001.

Abstracts P125SA. BONE MINERAL DENSITY IN PATIENTS WITH TURNER’S SYNDROME AND IT’S CORRECTION BY HRT Povoroznjuk VV1, Bondarenko LI2, Bondarenko EV1; 1Institute of Gerontology, Kiev, Ukraine, 2Ukrainian Center of osteoporosis, Kiev, Ukraine Aim research is to study prevalence of osteoporosis and osteopenic syndrome among women with Turner’s syndrome (TS), peculiarities of anthropometric women indexes and their tie with BMD, and also to clear up influence of hormone replacement therapy (HRT) on BMD in patients with TS. Inspected 32 women with TS in age 16-39 years old. Osteoporosis was found in 31%, osteopenic syndrome – in 50%, and normal BMD – in 19% patients. Height and body mass were reliable low, and body mass index was not differ from these indexes in women of proper age of Ukrainian population. BMD does not depend on women age with TS; with more high closeness indexes of BMD are connected more high body mass, height and body mass index, more early beginning and more duration of taking HRT. Women with TS was distributed on two group: 1 group, which didn’t receive HRT on extent of last 6 years; 2 group, which took HRT on research moment. The Groups do not differ between oneself on age and to anthropometric descriptions. Osteopporosis was found in 83% cases among women 2 of group, osteopenic syndrome – in 17%. In 1 group normal indexes BMD marked in 23%, osteopenic syndrome – in 58%, osteoporosis – in 19% cases. Under our supervision were 15 women, which for 1 year got HRT (Cycli-Proginova). Reliable changes BMD, was not exposed. However attached to distribution of women in dependence on BMD on two group appeared that in patients group with osteoporosos marked augmentation of BMD, in the main, for account of elasticity of bones, and in women group with osteopenic syndrome of BMD was not exposed. Like so, HRT prevents a loss of BMD in women with osteopenic syndrome and promote an increase in BMD in women with osteoporosis.

P126SU. IMPACT OF AN EDUCATIONAL PROGRAM ON OSTEOPOROSIS AWARENESS AND KNOWLEDGE OF PATIENTS WITH A RECENT LOW-TRAUMA FRACTURE Chevalley T1,2, Hoffmeyer P3, Bonjour JP1, Rizzoli R1; 1Division of Bone Diseases, WHO Collaborating Center for Osteoporosis and Bone Diseases, Department of Internal Medicine, 2Unit of Geriatric Evaluation, Department of Geriatrics, 3Orthopedic Clinic, Department of Surgery, University Hospitals Geneva, Switzerland Patients with a fracture have an at least two-fold risk of subsequent fracture and deserve thus a particular attention for osteoporosis diagnostic and prevention procedures. Were enrolled in an osteoporosis clinical pathway (OCP) for the medical management of low trauma fracture, patients with a recent osteoporotic fracture and evaluated the impact of a multidisciplinary and interactive educational slide presentation, proposed 8 to 12 weeks after the fracture, on osteoporosis awareness and knowledge, assessed at baseline and at 6-month. During a 42-month period, 434 patients (356 women and 78 men, mean age±SD : 72.6±12.8 years, hip fracture 46%, ankle/ tibia 22%, proximal humerus 8.5%, distal forearm 5.5%, spine 5%, pelvis 4% and other sites 17%) without cognitive impairment were included in the OCP. Dual X-ray absorptiometry, performed in 66% of patients, showed that 88% had low bone mass or osteoporosis. An osteoporosis awareness questionnaire administered within 10 days of fracture revealed that 15% only had a previous DXA. Whereas 80% have already heard of osteoporosis, the majority (72%) believed that their fracture was not related to bone fragility. A survey performed in 207 patients six months later, indicated that knowledge about osteoporosis significantly improved among the 77 patients having attended the educational program compared with 130 patients who did not participate (69% vs 44%, p50.001). On the other hand, the majority of

Abstracts patients still thought that their fracture was not related to bone fragility (69% vs 75%, NS) but to a traumatic event. Assuming that increased awareness and knowledge of osteoporosis would lead to positive behavioral changes in the perspective of fracture prevention, we conclude that our interactive educational program should better emphasize the link between bone fragility and occurrence of fracture among this high-risk population of patients with a recent low-trauma fracture.

P127MO. MONOFLUOROPHOSPHATE COMBINED WITH CALCIUM AND HORMONE REPLACEMENT THERAPY REDUCES RISK OF VERTEBRAL FRACTURES IN ESTABLISHED POSTMENOPAUSAL OSTEOPOROSIS Ringe JD1, Setnikar I2; 1Klinikum Leverkusen, Leverkusen, Germany, 2Rotta Research Lab., Monza, Italy Aims: To investigate the efficacy of monofluorophosphate (MFP) combined with calcium and HRT in established postmenopausal osteoporosis (EPO). Methods: In an open label safety and efficacy trial sixty women with EPO (T-score 5–2.5 and at least 1 vertebral fracture) were treated for 3 years with MFP+Ca+HRT, i.e. with daily oral MFP (15 mg F eq) intermittently (3 months on – 1 month off), combined with continuous HRT and daily calcium supplement. Results: Bone mineral density (BMD) after 3 years increased by 15.5% in the lumbar spine and by 2.3% in the femur neck. During the 3 years, 5 patients (8.3%) suffered 6 new vertebral fractures (NVF) and 6 patients (10%) had 6 non-vertebral fractures. Back pain score at the end of the 3rd treatment year was decreased by 84%. Tolerability was good. No treatment-related dropouts occurred. The results were compared with those of a previous study conducted in the same center with a similar protocol on 134 patients suffering from EPO and treated for 3 years with MFP, either continuously (MFPcont) or intermittently (MFPint), combined with calcium, but without HRT, or with a calcium supplement only (Calcium). The rate of patients with NVF in 3 years was 18% in the MFPint group, 27% in the MFPcont group and 67% in the Calcium group. Conclusions: The 3-year treatment with MFP+Ca+HRT reduced the risk of NVF to 12% of that in the Calcium control group.

P128SA. SALMON CALCITONIN NASAL SPRAY (SCNS): EFFECT ON HIP FRACTURES IN POSTMENOPAUSAL WOMEN Chesnut C1, Richardson P2, Mindeholm L3; 1University of Washington, Seattle, WA, USA, 2Novartis Pharma, East Hanover, NJ, USA, 3Novartis Pharma, Basel, Switzerland. The PROOF (Prevent Recurrence of Osteoporotic Fractures) study, a double-blind, randomized trial of 5-years duration compared three doses of SCNS (100, 200 and 400 IU daily) to placebo in postmenopausal women with between 1 to 5 vertebral fractures at study entry. The primary end point was vertebral fracture relative risk reduction. Overall, there was a low incidence of hip fractures in the study, results showing a non-significant trend of 48% reduction of hip fracture with the 200 IU daily dose. However, a post-hoc analysis demonstrated that over 3-years there was a 72% reduction [95% CI: 0.13–0.91, p = 0.046] in hip fracture vs placebo for the marketed doses of 100 and 200 IU combined. This reduction was sustained with a relative risk reduction of 68% [95% CI: 0.14–0.88, p = 0.047] vs placebo at 5years. These data from a post-hoc analysis demonstrate a significant (p = 0.046 or p = 0.047) reduction in the risk of hip fracture at marketed doses of SCNS spray. Further studies are needed to confirm this potential beneficial effect in postmenopausal women.

S43 Therefore, the Skeletal Protection in Elderly at Risk (SPEAR) study is being initiated. This is a 3-year multicenter, double-blind, randomized, placebo-controlled study using SCNS, 200 IU daily, in 6000 women greater than/equal to 70-years of age. The patient population will mainly live in a nursing home or assisted-living facility and have at least one prevalent osteoporotic fragility fracture. The primary objective of SPEAR is to demonstrate the efficacy of SCNS 200 IU in reducing the frequency of radiographically confirmed appendicular fractures. The secondary objective is to demonstrate the reduction of multiple new clinical fractures and to evaluate the effect on psychological well-being, quality of life, sensory-motor function assessment and muscle strength in a subset of patients. The design and protocol for the study will be discussed.

P129SU. USE AND SIDE EFFECT PROFILE OF THREE DIFFERENT NON-HRT TREATMENTS USED IN OSTEOPOROTIC WOMEN Akarirmak U, Tuzun F, Eskiyurt N, Eryavuz M, Alper S, Arpacioglu O, Atalay F, Goncu K, Kavuncu V, Kokino S, Kuru O, Nas K, Ozerbil O, Savas S, Sindel D, Sendur OF, Yilmaz H, Akyuz G, Polat N; Turkish Osteoporosis Society, Istanbul, Turkey Objective: The aim of this study was to assess compliance and side effects of three different treatments used in osteoporosis (alendronate, calcitonin, vitamin D and metabolites) and to compare results. Material and Methods: A total of 2170 patients with 759 receiving Alendronate (35%), 727 Calcitonin (33.5%), 684 Vitamin D and active metabolites (31.5%) for a minimum of 6 months duration were included. Results: There was no significance difference of demographic data between the three groups. All patients were recieving additional calcium supplementation. 94% of patients used alendronate on empty stomach, without chewing or sucking. 91% of patients used alendronate with water. Adverse effects were reported in 230 patients (30%). 90% of adverse effects did not require discontinuation or additional medication. 529 (91%) patients in Calcitonin group were using nasal spray form, mostly 200 IU/daily. Main adverse effects were hot flashes. Discontinuation due to adverse effects was necessary in 31 (4%) patients. Side effects in Vitamin D and metabolites group were reported by 103 patients (15%). Medication had to be stopped in 35 patients (5%). Conclusion: Side effect rates were comparable in all three treatment groups.

P130MO. EFFICACY OF ALENDRONATE IN THE TREATMENT OSTEOPOROSIS IN ANKYLOSING SPONDYLITIS: ONE YEAR PRELIMINARY RESULTS Capaci K, Hepguler S; Ege University Medical Faculty Physical Therapy and Rehabilitation Dept, Izmir, Turkey Objective: To investigate the efficacy of alendronate in the treatment of osteoporosis in Ankylosing Spondylitis (AS). Materials and Methods: Criteria for admission were decreased bone mineral density, osteopenia or osteoporosis according to WHO, and being mild AS on the basis of radiographic findings. Twenty-two patients fulfilling the modified New York criteria for definite AS were studied. Thirteen were men, and nine were women. The mean age was 36.09 years (SD 6.96 years), the mean disease duration was 8.91 years (SD 6.15 years). All patients were given 10 mg of alendronate, 1000 mg of elemental calcium, and 400 IU of vitamin D for a day. Bone mineral density (BMD) measurements with dual-energy X-ray absorptiometry (DEXA) was performed baseline and one year after.

S44

Abstracts

Results: There were significant increases in lomber spine and femoral (except femur neck and Ward’s triangle) BMD values, and t scores. Percentage changes from baseline for lumbar spine (L14 vertebrae) BMD was 5.69 (SD 6.18), and 3.62 (SD 4.48) for total femoral BMD. Conclusion. The preliminary results of this one year study suggest that alendronate can be an efficient drug in the treatment of osteoporosis in AS.

P131SA. THE ORTHOSIS SPINOMED IMPROVES POSTURE, LUNG FUNCTION, TRUNK MUSCLE STRENGTH, AND QUALITY OF LIFE IN POSTMENOPAUSAL WOMEN WITH SPINAL OSTEOPOROSIS: RESULTS OF A PROSPECTIVE, RANDOMIZED, CONTROLLED, CROSS-OVER STUDY Pfeifer M, Begerow B, Minne HW; Medwiss Bad Pyrmont, Germany Thoracolumbar braces are widely used in the care of patients with vertebral fractures due to osteoporosis. Their usefulness, however, has never been tested under standardized conditions. To our knowledge, this is the first randomized, controlled, prospective, cross-over study to determine the efficacy of an orthosis in the treatment of spinal osteoporosis. In this cross-over study, patients had been randomized into two groups: group A started with an intervention period of six months, while group B served as controls. After six months the groups changed. Measurements include trunk muscle strength, body sway, angle of kyphosis, pain, and limitations of everyday life and were performed at base-line and every three months thereafter. At base-line, we did not observe any differences between both groups concerning age (p = 0.77), height (p = 0.90), weight (p = 0.84), loss of height (p = 0.35), and number of vertebral fractures (p = 0.87). Results after six months are presented in Table 1. The orthosis spinomed improves posture, trunk muscle strength, lung function, body sway, and quality of life in postmenopausal women with osteoporosis and may therefore play an integral part in the rehabilitation process of osteoporotic patients. The efficacy of thoracolumbar braces needs to be further investigated in prospective, randomized and controlled trials. Table 1. Presents initial values and changes at 6 months in 61 study subjects Initial value Angle of kyphosis (8) Group A 74.2 ± 9.8 Group B 69.8 ± 9.9 Back extensor strength (N) Group A 264 ± 131 Group B 262 ± 119 Abdominal flexor strength (N) Group A 165 ± 71 Group B 155 ± 64 Body Sway (mm) Group A 84 ± 70 Group B 78 ± 37 Vital capacity (%) Group A 83 ± 21 Group B 93 ± 16 Pain (Score) Group A 4.0 ± 1.1 Group B 3.9 ± 1.0 Limitations of daily living (Score) Group A 4.8 ± 1.9 Group B 4.1 ± 1.7

Change

P-Value

P132SU. RECALLED MAXIMAL HEIGHT IN OSTEOPOROTICS CORRELATES WITH CURRENT MEASURED ARM SPAN Walsh SEW1, Iqbal SJ2, Jones PRM1, Davies T2; 1Loughborough University, Loughborough, UK, 2Leicester Royal Infirmary, Leicester, UK Height loss in women has been used as a clinical index of suspicion for osteoporosis and progressive height loss has been utilised in some of the recent major treatment trials. Arm Span (AS) should equate with maximal attained height. In order to see whether recalled maximal height was accurate, we compared recalled peak height with AS. 49 osteoporotic patients 43 females and 6 males, mean age 65 years ± 12.9 years age range 26-85 were studied. Heights were measured using a portable stadiometre which was re-calibrated between each measurement and heights recorded. AS was measured with all subjects facing the wall, arms abducted at 90 degrees at full stretch. The AS was measured from middle finger tip to finger tip, marks were made on the wall and an anthropmetre was used to measure the distance. Maximal recalled height MH by each subject was recorded. Percentage height loss was derived by using Current height, MH (Method 1) and AS (Method 2). 13 subjects were unable to recall MH. In 36 osteoporotics; AS = 2.91 + 1.02 MH (cm) r; 0.78, p50.05. Percent height loss regression between using MH and AS was Method 2 = 0.59 (Method 1) + 0.77; r; 0.41 p50.05. When available either recalled MH or AS could also be used in estimating height loss as a simple clinical index of osteoporosis.

P133MO. THE INFLUENCE OF DEHYDROEPIANDROSTERONE (DHEA) INTAKE ON FEMUR BONE MINERAL DENSITY (BMD) AND BONE FORMATION MARKERS IN AGING FEMALE AND MALE Jedrzejuk D, Milewicz A, Bohdanowicz-Pawlak A, Medras M; Medical University of Wroclaw, Department of Endocrinology and Diabetology, Wroclaw, Poland The influence of endogenous DHEA-S levels on BMD in men and women is not clear. Also it has been shown that supplemetation of DHEA could increase BMD in aging people. The aim of the study was to compare the BMD and serum osteocalcin before and after orally DHEAS treatment in aging people. 26 healthy, non-smoking persons were studied: 14 postmenopausal – without any HRT – women (aged 56.363.59 yrs, BMI – 26.764.21kg/m2) and 12 men (aged 594.9 yrs, BMI – 25.882.54 kg/m2). We have measured femur BMD using DEXA method and serum osteocalcin using RIA kit, alkaline phosphatase using EIA method before and after 3 months of taking 2 x 25 mg daily orally DHEA tablets vs placebo. We have not found any statistically significantly differences in all measured parameters, but the differences betweeen the levels of DHEAS and estradiol levels before and after treament were statistically significant (DHEAS – p = 0.0001 in both sexes, estradiol – p = 0.02 in men, p = 0.0001 in women). We suggest that the lack of the influence of DHEA on bone metabolism and BMD is caused by not sufficient daily dose, what needs further study.

–2.2 ± 4.1 1.4 ± 4.3

0.007

122 ± 107 18 ± 55

<0.001

66 ± 61 25 ± 41

0.005

–14 ± 45 10 ± 43

0.045

0.5 ± 13 –8.2 ± 13

P134SA. DESIGN OF THE RECORD TRIAL: AN EVALUATION OF CALCIUM AND/OR VITAMIN D IN THE SECONDARY PREVENTION OF OSTEOPOROTIC FRACTURES

0.020

–0.9 ± 1.0 0.1 ± 0.9

<0.001

Grant A1, Cooper C2, for the RECORD trial group MRC1; 1Health Services Research Unit, University of Aberdeen, Aberdeen, UK., 2 MRC Environmental Epidemiology Unit, University of Southampton, Southampton, UK.

–1.3 ± 1.4 0.2 ± 0.8

0.007

Aims: The Medical Research Council-sponsored RECORD trial is a placebo-controlled, multicentre UK-based Randomised Evalua-

Abstracts tion of Calcium and/or vitamin D, which aims to evaluate treatment for the secondary prevention of osteoporotic fractures. Methods: Participants aged 70 years and over, from fracture clinics or hospital wards, within five years of a previous osteoporotic fracture, are randomised to 1g calcium/d, 800IU (20mcg) vitamin D3/day, both, or placebo. Results will be available in 2004. The principal outcome is new fracture, and the study has 80% power (2P 50.05) to detect an absolute reduction in fractures from 15% to 12%. Secondary outcomes are all cause mortality, hospital admissions, change of residence, falls and adverse events (hypercalcaemia, renal calculi and renal failure, gastrointestinal symptoms). Participants are also followed up for cancer registration, cardiovascular and cerebrovascular mortality, and development of non-insulin dependent diabetes mellitus. Planned sub-group analyses will examine the effect of age, type of osteoporotic fracture at recruitment, latitude of recruitment centre, dietary calcium intake, vitamin D intake and sunlight exposure, body weight, and compliance with tablet taking. An economic evaluation will examine cost per quality adjusted life year, utilising data from the SF-12 and EuroQol-5D. Results: Recruitment began in 1999, 4940 participants out of a target of 5250 have been recruited. Reasons for ineligibility for the study include low mental test score (43%), prescription of boneactive medication (29%), and consumption of calcium and/or vitamin D supplements (5%). Fractures leading to recruitment include proximal femur (17%), distal forearm (35%), other types of arm fractures (26%), and other leg and pelvic fractures (22%). Conclusions: The RECORD trial will provide important information about the value.

P135SU. THE EFFECTS OF EXERCISE IN BONE MINERAL DENSITY AND LIFE QUALITY AT POSTMENOPAUSAL WOMAN WITH OSTEOPOROSIS* ¨ , Aky´ S, O ¨ ncel A; Istanbul Medical School. Eskiyurt N, Erkan O Department of Physical Therapy and Rehabilitation, Istanbul, Turkey We carried out a study with 30 cases by putting them randomly into 3 groups in order to evaluate effects of exercise on bone density, bone production-destruction markers, pain and life quality in postmenopausal women with osteoporosis. We strengthened hip fleksors in one group and back extansors in another group. Patients took daily total 1500mg. calcium and in addition to this 400IU¨ D vit was given to both exersice and control groups who haven’t had any hormon replasman treatment and other medical treatment. Cases in exercise group were observed weekly during first 3 months, later monthly during another 3 months. Pain of cases was evaluated by visual analogue scala and life quality was evaluated by Modified Mc Master Health Index. BMD of cases were evaluated by DEXA metod before and after treatment, and by quantitative ultrasound measurements every 3 months. Also in order to learn bone turn-over rate, bone production (BALP, Prokollajen) and destruction (Piridinolin, Deoxipiridinolin, N-telopeptid) markers were evaluated before treatment,in 3 rd month of treatment and after treatment. As result of our study, statistically significant increase in BMD of exercise groups was observed when compared with pretreatment or control group. In all groups life quality increasing was detected by Modified Mc Master Health Index. Biochemical markers decreased as in first group piridinolin was 6.1%, deoxipiridinolin was 2.9%, N-telopeptid was 8.2%, in second group piridinolin was 2.7%, deoxipiridinolin was 1.8%, Ntelopeptid was 7.7%. But as this wasn’t statistically significant, it may be connected with short following period. As result, progressive resistive exercises when supported with calcium and D vit shows its prominent effect on bone density and may increase patients’ life qualities. *This study was supported by Research Foundation of Istanbul University.

S45 P136MO. TREATMENT OF IDIOPATHIC OSTEOPOROSIS IN MEN Cokolic M1, Hren R2; 1Teaching Hospital Maribor, Maribor, Slovenia, 2University of Ljubljana, Ljubljana, Slovenia It is now well established that osteoporosis in men is often caused by secondary factors. However, in those patients with no obvious cause (‘idiopathic’), the treatment choice remains to be clearly established. The aim of this study was to assess the effectiveness of alendronate therapy in treatment of male patients with idiopathic osteoporosis. Ten men with idiopathic osteoporosis (T-score at lumbar spine or hip 5–2.5, serum concentrations of free testosterone, Ca, P, Mg, and ALP within normal limits) were enrolled in a prospective study between March 1997 and September 2000. Patients were 48 to 65 years old (mean: 59 years). They were treated with alendronate sodium (10 mg/d) in combination with 500-mg elemental calcium. The BMD of the lumbar spine (L2-L4) and left hip was measured in all patients using dual energy X-ray densitometry (Hologic QDR2000+) at the start of the treatment and at 12 to 48 months after initiation of the treatment. The serum levels of Hgb, Hct, WBC, Plt, testosterone, Ca, P, Mg, Na, K, Cl, ALP, AST, ALT, BUN, and creatinine were measured every 12 months. Average baseline BMD was 0.762 g/cm2 (n = 10, range 0.686 to 0.816 g/cm2) at the lumbar spine and 0.721 g/cm2 (n = 10, range 0.697 to 0.742 g/cm2) at the hip. After treating patients on average for 28 months, the average BMD was 0.808 g/cm2 (n = 10, range 0.729 to 0.888 g/cm2) at the lumbar spine and 0.775 g/cm2 (n = 10, range 0.751 to 0.795 g/cm2) at the hip. BMD thus increased on average by 6% at the lumbar spine and 7.5% at the hip. Serum levels remained within normal limits throughout the treatment, with no adverse events observed during the study. Results of our on-going study suggest that alendronate sodium can provide clinically relevant benefits in male patients with idiopathic osteoporosis.

P137SA. EVALUATION OF RISEDRONATE IN AN OSTEOPOROSIS CLINIC Hannan FM1, Kyd P1, Thomas E2, Fairney A1; 1Department of Endocrinology and Metabolic Medicine, Imperial College Faculty of Medicine (St Mary’s), 2Department of Clinical Physics, St Mary’s NHS Trust, Praed Street, London W2 1NY, UK The pyridinyl bisphosphonate risedronate has been available in the UK as an anti-bone resorptive agent since August 2000. It is approved for treatment of post menopausal or corticosteroid induced osteoporosis. Randomised controlled trials show risedronate reduces vertebral and non-vertebral fracture risk. Risedronate has also been shown to increase lumbar spine bone density and preserve bone density at the femoral neck. Endoscopic studies show use of risedronate to have a significantly reduced incidence of gastric ulcers as compared to alendronate. Risedronate has been prescribed to 55 patients attending our osteoporosis clinic for prevention or treatment of osteoporosis and for patients unable to tolerate alendronate. Mean baseline bone mineral density measured by LUNAR DXA was 0.854 g/cm2 (T – 2.88) at the lumbar spine and 0.722 g/cm2 (T-2.15) at the femoral neck. Bone turnover was assessed in 18 patients at 0, 3 and 6 months using the urine resorption marker N-telopeptide (NTX) measured by an ELISA, Osteomark1. There was a 22.2% mean reduction in NTX at 6 months (52.3 BCE/mmol creatinine at 0 months compared with 40.7 BCE/mmol creatinine at 6 months, NS). 10 patients (18%) developed adverse effects, the majority of which were mild and transient. These consisted of either gastrointestinal disturbance or musculoskeletal pain. However 3 patients (5.5%) ceased therapy due to intolerable adverse effects. Risedronate has been previously shown to be an effective treatment for osteoporosis. However early measurement of NTX

S46 showed no significant reduction in bone resorption. Our study found a greater incidence of adverse effects than previously suggested and these were usually mild and transient.

Abstracts P140SA. CONCURRENT THERAPY OF OSTEOPOROSIS USING ETIDRONATE AND VALUE CHANGE OF BONE CHEMICAL MARKERS Nakajima IN; Yamanashi Medical University, Yamanashi, Japan

P138SU. EFFECT OF CONTINUOUS AND INTERMITTENT NASAL CALCITONIN ON BONE TURNOVER MARKERS IN POSTMENOPAUSAL OSTEOPOROSIS Karadag A, Sermez Y, Yu¨ksel D, Kaptanoglu B; Pamukkale University Hospital, Denizli-Turkey The effect of nasal salmon calcitonin(SCT)treatment on bone has been examined by biochemical markers of bone turnover in 50 postmenopausal women (mean age: 55.5±8.4 years) with osteoporosis. 25 patients received continuous nasal SCT (200 IU/day), the others received intermittent nasal SCT (15 days per month, 200 IU/day) for 3 months. Biochemical markers reflecting bone turnover including serum alkaline phosphatases, osteocalcin and urinary deoxypyridinoline were assessed before and after SCT treatment. In the patients taken continuous treatment alkaline phosphatases (p50.01) and urinary deoxypyridinoline (p50.05) decreased and osteocalcin (p50.01) increased significantly. In patients with intermittent treatment serum alkaline phosphatase and deoxypyridinoline did not change while osteocalcin increased significantly (p50.001). Urinary calcium decreased in both groups, but not statistically significant. The present study indicates that continuous nasal SCT treatment is more effective than intermittent SCT treatment on bone turnover in short-term period.

P139MO. ALENDRONATE FOR THE PREVENTION OF CORTICOID INDUCED OSTEOPOROSIS IN POSTMENOPAUSAL WOMEN WITH POLYMYALGIA RHEUMATICA Sfoudouris C, Trifonidis P, Chilas G, Fragkakis N, Stamatiadou A, Lappa B, Karamitsiou V, Xatzhgiannhs I, Boudouris K, Georgiadis AE; Osteoporosis Center, LHTO Gynecol. Hospital, Athens, Greece Secondary Osteoporosis is a common complication of steroid therapy. The situation became more serious if the steroid treated patients are old postmenopausal women (PMW) suffer from a generalized inflammatory condition as Polymyalgia Rheumatica (PR). Studies concern the prevention and/or treatment of osteopenia in these patients are very rare. It is well known that Alendronate (ALN) is a very potent bisphosphonate that increases the bone mineral density (BMD) in PMW with osteoporosis. In order to evaluate the potential action of this agent on PWM suffer from PR and treated with corticosteroids we carried out an on year open clinical trial. 51 PMW (MA = 71,4+5,32yrs) suffer from recent PR ( mean duration of disease 2,35 +1,3 months) were measured by Lunar DPX-L or Hologic 1000QDR DEXA machines at Lumbar Spine (LS) and/or Hip(Neck). At base line 7 were osteopenic and the rest osteoporotic according to WHO criteria. All patients were treated for 1 year with ALN 10mg/day plus Calcium 500mg/day plus Alfacalcidol 0,25 microg/EOD and prednisone 7,5 to 15 mg/day( mean dose 11,2 +4,35 mg/day) according to the needs of each patient. The patients were seen at 6 months and at the end of the study with a new DEXA measurement with the same DEXA machine. Our primary end point was to evaluate the difference in the mean percent change in LS and Hip BMD from base line.Our results, at 12 months, show that with this treatment schedule the mean BMD increased by 3,11 +1,85 percent at LS and by 2,7 +1,92 percent at Hip. According to these results it seems that Alendronate prevents the secondary osteopenia from corticosteroids in postmenopausal women suffer from Polymyalgia Rheumatica.

Aims: Several pharmaceutical agents exist that have more or less proven positive effects on osteoporosis. Among these drugs, alphacalcidol (D3) and menatetrenon (K2) are commonly used in Japan. However, the windows of efficacy for these two drugs are quite narrow. Therefore we investigate the efficacy of concurrent treatments using etidronate in increasing bone mineral density (BMD) and preventing development offragility fracture. And there has been little available data regarding bone chemical marker (especially, urinary N-telopeptide of type I collagen(NTX), urinary deoxypyridinoline (DPD)) associate with concurrent therapy using etidronate. Methods: To evaluate the chemical marker changes and the effects on the BMD of concurrent treatment, following four groups were assigned to 400 female patients: A) established osteoporosis who is no history of treatment start D3 (l microgram/day) continuing 6 months and three months after starting, etidronate (200 mg/day for 2 weeks) was given, B) also no history of treatment start K2 (45 mg/day) continuing 6 months and three months after starting, etidronate (200 rag/day for 2 weeks) was given, C) already continuing D3 with etidronate (200 mg/day for 2 weeks followed by 10 weeks intermission) was given two cycles, D) already continuing K2 with etidronate (200 mg/day for 2 weeks followed by 10 weeks intermission) was given two cycles. Thoracic and lumber spine radiographs and biochemical bone markers were taken at the time of beginning and every three months interval. Results: After using etidronate, lumber BMD is getting higher ranging 2–4 percents. But after administration of etidronate, NTX and DPD significantly decreased through three months demonstrated highly gain in BMD. And there were no significant differences the suppression of bone absorption between two agents comparing NTx and DPD. There were no significant differences in the rate of development of new vertebral fractures among four groups, also. Conclusions: Concurrent therapy of osteoporosis using etidronate is safe.

P141SU. THE EFFECTS OF ALENDRONATE TREATMENT ON VERTEBRAL MINERAL DENSITY AND BONE TURNOVER IN 16 WOMEN WITH GLUCOCORTICOID INDUCED OSTEOPOROSIS Dumitrache C1, Grigorie D1, Barbu C1, Neacsu E1, Dumitrache M1, Grigorie M2; 1C.I. Parhon Institute of Endocrinology, Bucharest, Romania, 2A. Aslan Institute of Geriatrics, Bucharest, Romania Sixteen women with mean age of 57.8 yrs. (range 42–61yrs.), with previously untreated glucocorticoid induced osteoporosis (mean T score = –3.6 SD) were treated with 10 mg alendronate daily for 10 month; all patients received 500 mg Ca++ and 400 UI vitamin D supplements. We measured serum intact osteocalcin (IRMA), urinary free deoxypyridinoline (ELISA), 25 hydroxivitamin D3 plasma level (RIA) and serum intact parathyroid hormone (IRMA). Bone mineral density measurements were obtained at the lumbar spine (L2-L4) by dual X-ray absorbtiometry and data are expressed as T and Z scores. Alendronate was generally well tolerated and no serious adverse events were attributed to its use. Mean percent changes in vertebral mineral density (VMD), was 1.9% (NS) after a mean period of 10 months of treatment with alendronate. Urinary excretion of free deoxypyridinoline (DPyr, mean value = 5.6 nmol/mmol ur creat) slightly decreased (15%) after 10 month of treatment (NS). Mean serum level of osteocalcin (5.1 ng/ml) decreased by 10% after treatment (not significant). All patients reported improvement in bone pain and disability as early as 3 months after treatment. In conclusion, alendronate

Abstracts administration preserved the lumbar bone mineral density in women with glucocorticoid induced osteoporosis. We were not able to find any significant change in biochemical markers of the bone turnover; the wide range of the individual values in a small study group could be an explanation. Taking into account that some of our patients experienced a high rate of lumbar bone loss in a previous period of follow-up and the relative short term of this study, 10 mg of alendronate seems to be a valuable therapy for glucocorticoids induced osteoporosis.

P142MO. THE COMPARISON OF THE EFFECTS OF VITAMIN D3 AND ALPHACALCIDIOL WITH DEXA IN OSTEOPOROSIS Hepguler S, Goksel A, Capaci K, Aksit R; Ege University Medical Faculty Physical Therapy and Rehabilitation Dept, Izmir, Turkey Objective: Aim of this study was to determine and to compare the effects of 300000 IU vitamin D3 ampul for a month and 0.25 mcg twice for a day Alphacalcidol on bone mineral density (BMD), addition to 10 mg of alendronate for a day, and 1000 mg of elemental calcium for a day treatment in osteoporosis. Material and Methods: 60 patients with ages between 53-82 years were included in the study. A questionnaire about patients’ specialities was given. According to DEXA, routine blood, urine, liver functional tests, alkalene phosphotase, urea, creatinine, serum calcium and phosphorus, urine calcium, were investigated for all patients with the diagnosis of osteoporosis. In addition to 10 mg of alendronate for a day, and 1000 mg of elemental calcium to 30 patients, 300000 IU peroral vitamin D3 ampul for a month, and to 30 patients 0.25 mcg twice for a day alphacalcidiol were given. Results: In both of the groups significant density increase was obtained in lumbar 1-4 vertebrae, total femoral regions in DEXA tests at 12th month (p50.05), but there was no statistically significant difference between groups (p40.05). Percentage changes from baseline for lumbar spine (L1-4 vertebrae) BMD was 2.77 (SD 3.89), and 3.20 (SD 4.15) for total femoral BMD in vitamin D3 group, and 1.98 (SD 3.43) for lumbar spine BMD, and 1.43 (SD 1.73) for total femoral BMD in alpha calcidiol group. Although the percentage changes were higher in vitamin D3 group, there was no significant difference between groups (p40.05). Conclusion: There was no difference on increase of BMD between groups, so that we suggest treatment with vitamin D3 because of being inexpensive.

P143SA. RARER SECONDARY CAUSES OF OSTEOPOROSIS Iqbal SJ1, Muehlbayer S1, Howlett T2; 1Department of Chemical Pathology, Leicester Royal Infirmary, Leicester, 2Department of Endocrinology, Leicester Royal Infirmary, Leicester Commoner secondary causes of osteoporosis such as steroid therapy and alcohol excess are well-documented. We describe some cases with rarer secondary causes of osteoporosis. These patients all presented with features of osteoporosis. In osteoporosis, unusual clinical features should be carefully investigated so that rarer secondary causes are correctly diagnosed and appropriate therapy instituted. T Z = BMD Scores

S47 Clinical Features

Main Diagnosis

Treatment

1. 51 yr female. Ht 1.44 m Colles’ fracture Under developed secondary female characteristics Primary Amenorrhoea 2 Cell lines: 55%, 45 X 0 45% x chrm arms (q) trisomy (p) monosomy

Turner’s Syndrome (Mosaic)

HRT Etidronate Calcium & Vitamin D

2. 56 yr female. Acute Progressive Vertebal Collapse T 7, 8, 9, 10, L3, 4 Slight Immuno Suppression No BJP No Paraprotein bana lg’s A, I.0, G 7.5, M 0.6 gm/l

Nonsecretory Myeloma Bone Marrow 60% Plasma Cells No BMD

Chemotherapy Radiotherapy Bisphosphonate Calcium & Vitamin D

3. 50 yr female. Infertility Secondary Amenorrhoea Prolactin :1303 miu/l

Pituitary Microadenoma Prolactinoma

Bromocriptine HRT

4. 48 yr male. Back Pain X-ray Osteopenia Ur free Cortisol 550 nmol/24hr? :ACTH 90 ng/l

Cushing’s Disease Pituitary Adenoma

5. 65 yr male. Mild Wedge L2 Collaps T12 LH 1.5 FSH 0.7 iu/l Testosterone 2.8 nmol/l Synacthen Subnormal

Functionless Pituitary Tumour Secondary Hypogondalism Adrenalism

BMD T Z L2–L4 –4.57 –2.76 FN –3.40 –1.81

BMD T Z L2–L4 –2.34 –1.64 Neck –2.05 –1.28

BMD T Z L2–L4 –2.53 –2.12 FN –2.20 –1.04

Hypophysectomy Hydrocortisone Metyarapone Atenolol

Hypophysectomy Hydrocortisone Testosterone Calcium & Vitamin D

BMD T Z LH-4 –1.73 –1.61 FN –1.88 –0.77

P144SU. LIVIAL IN TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS: EXPERIMENTAL AND CLINICAL DATA Povoroznjuk VV1,2, Grygoryeva NV1,2, Fedosenko OV2, Zhurochka EA2, Luzin. VI2; 1Institute of Gerontology, Kiev, Ukraine, 2 Ukrainian centre of osteoporosis, Kiev, Ukraine Tibolon (Livial1) was proved to prevent bone loss in postmenopausal women and relieve climacteric symptoms as effectively as estrogen without stimulating endometrium and breast. The aim of research was to study biomechanic, biochemical and osteometric bone data of rats belonging to two age groups (six months- and eighteen months-old) after surgical bilateral oophorectomy and Livial therapy. We studied structural-functional state of bone mass, climacteric symptoms of postmenopausal women with and without Livial therapy. Experiments showed bilateral oophorectomy to reduce biomechanic characteristics of bone (bone destruction and bone strength indices) and osteometric indices, as well as to change biochemical bone properties. Six-week tibolon (Livial1) therapy improves biomechanic, biochemical and osteometric bone data of rats in both groups. Clinical research revealed structural-functional state of bone and climacteric symptoms of women after natural menopause (duration of postmenopausal period made up 3-5 years) after Livial1 therapy. Structural-functional state of bone was determined by ultrasound densitometer ‘Achilles+’ (Lunar Corp., Madison, WI). Speed of ultrasound spreading (SOS, m/s), broadband ultrasound attenuation (BUA, dB/MHz) and Stiffness index of bone tissue (SI, %) were calculated, and acuteness of climacteric symptoms was determined by Kupperman scale. It was established that one-year Livial1 therapy of postmenopausal women removed climacteric

S48 symptoms, improved structural-functional state of bone mass (increased the Stiffness index (p50.05)). This research hasn’t shown any side effect attached to tibolon application. Therapy by Livial1 is effective in correction of structural-functional disturbances and treatment of postmenopausal osteoporosis and its complications.

P145MO. CALCANEAL QUANTITATIVE ULTRASOUND IN ANKYLOSING SPONDYLITIS Capaci K, Hepguler S, Eyigor S, Ozturk C; Ege University Medical Faculty Physical Therapy and Rehabilitation Dept – Izmir – Turkey Objective: To investigate the harmony of calcaneal quantitative ultrasound (QUS) with dual-energy X-Ray absorptimometry (DEXA) and its usage as a hatch-test in the diagnosis of osteoporosis in patients with Ankylosing Spondilitis (AS). Method: 50 patients (33 men,17 women) with the diagnosis of Ankylosing Spondilitis, whose mean age were 36.90b 8.65 (18-60) years were included in the study. All the patients were selected from the patients who did not have syndesmophytes, ligament calcifications, ankylosis of faset joints at lumbar region or who were in the beginning level and in the mild radiological stage so as not to be mislead with the results of DEXA of lumbar region. In all the patients bone mineral density measurements were done with DEXA (Hologic1) from the lumbar vertabraes and femoral regions and with calcaneal QUS (Sahara1) from calcaneus; Broadband ultrasound attenuation (BUA) values and t scores were determined. The ones whose t scores were less than V1 SD, were evaluated as ‘osteopenia, osteoporosis’. Pearson correlation analysis, regression analysis, cross-table and Kappa harmony measurement analysis were used for statistical analysis. Results: Between calcaneal QUS-BUA and DEXA-BMD values and between calcanealQUS-tscore and DEXA-tscore there were significant positive correlations (r = 0.280-0.583). By using these, the regression equalities were established which would help to estimate the DEXA-BMD and t score values from calcaneal QUS BUA and t score values.In the analysis which were evaluating the diagnostic harmony of calcaneal QUS and DEXA values according to t score, there were found to be a harmony in between (Kappa 0.206-0.477). In the cases which were told to have osteopenia/osteoporosis with calcaneal QUS, same results were obtained at the rate of aproximately 95.8% with DEXA. Conclusion: Calcaneal QUS, which is an easy, quick and cheap method, has a high diagnostic harmony with DEXA and can be used as a hatch-test for the diagnosis of osteoporosis in the patients with AS.

P146SA. THE IMPACT OF A STANDARD PHYSICAL TRAINING PROGRAM UPON HORMONE STATUS, SKELETAL MUSCLE STRENGTH AND BONE MASS DENSITY IN ELDERLY WOMEN Revnic CR1, Teleki N2, Revnic F3; 1U.M.F.‘Carol Davila’, Bucharest, Romania, 2University Clinique Hospital, Bucharest, Romania, 3I.N.G.G. ‘Ana Aslan’, Bucharest, Romania Physical activity is an essential factor in bone mass health.Aging is associated with a decrease in growth hormone resistance which is ‘the locomotive that pulls all the hormones in the aging process with a negative impact upon locomotor system function. The lack of physical activity also play an important role in body composition and the metabolic status could be related with GHRH-GHIGF axis. The aim of this was related with the evaluation of moderate levels of physical exercise (N. teleki, F. Revnic, Geriatria VIII,5,1996) upon hGH secretion, upon muscle strength as well as upon BMD in postmenopausal women with/without physical activity.

Abstracts Our study has been done on 32 female patients aged between 35–78 years old admited in the Rehabilitaion Clinique for osteoarticular or postraumatic pathologies able to perform a standard physical exercise of moderate intensity. 16 patients (group A) with physical activity (Controls) and the other 16 patients without physical activity due to postraumatic or osteodegenerative pathology represent (group B). hGH has been estimated before and after training with DELFIA 1234 Research Spectrofluorimeter using hGH Eu+labelled Pharmacia LKB kit, also alcaline and acid phosphatases the markers of bone disruption and bone formation have been estimated with the standard biochemical methods. EMG of biceps and triceps muscle have been also performed with a Schwartzer–Picker EMG 2000. BMD has been estimated using osteodensitometry tecnique. Our data have pointed out an increase in hGH secretion in elderly women after training program and an increase in muscle strength. An increase in acid phosphatase activity following training is a proof of physical training efficiency with an positive impact upone bone mass density. Conclusion: Our data have pointed out the benefit of moderate levels of physical exercises in elderly patients, upon hGH secretion with a positive effect upon muscle strength which also yield to a bone-building effect as BMD measurements have pointed out.

P147SU. GASTRIC ANTRAL VASCULAR ECTASIA IN TWO OSTEOPOROTIC POSTMENOPAUSAL WOMEN TREATED WITH BISPHOSPHONATES Sikorski T1, Marcinowska-Suchowierska E1, Wejman J2; 1 Postgraduate Medical Education Center, Warsaw, Poland, 2Prof. W. Orlowski Hospital, Warsaw, Poland Background: Bisphosphonates, powerful inhibitors of osteoclast bone resorption, are highly effective in the treatment of postmenopausal and steroid-induced osteoporosis. However, gastrointestinal toxicities may reduce their widespread use. Two cases of gastric antral vascular ectasia (GAVE), a vascular anomaly of antral mucosa, thus far not observed in patients treated with bisphosphonates, are presented. Aims: To present the details of 2 cases of GAVE diagnosed during bisphosphonates treatment and to reveal possible pathogenetic relations between GAVE and bisphosphonates. Methods: For diagnosing osteoporosis the WHO criteria were used. GAVE was diagnosed if a typical picture of red streaks in the antrum (watermelon stomach) was seen endoscopically and if dilated capillaries and fibromuscular hyperplasia in lamina propria were found histologically. A review of medical literature using Medline system was done with keywords referring to bisphophonates and stomach. Results: Case 1: A 78-yr old, postmenopausal woman, with established osteoporosis treated with ibandronate from one week presented in early 1997 as iron deficiency anemia. In gastroscopy there were features of GAVE confirmed by biopsy. During 4 years of follow-up endoscopic picture of GAVE did not change despite a withdrawal of bisphosphonate after 3 years. Case 2: A 67-yr old, postmenopausal woman, with osteoporosis treated with alendronate from 2 years presented in early 2000 as dyspepsia. In gastroscopy there were features of GAVE confirmed by biopsy. In one year follow-up after a withdrawal of bisphosphonate red streaks in the antrum are poorly visible on endoscopy, but dilated vessels are easily identifiable on histology. Conclusions: Although a review of the medical literature did not reveal convincing data about pathogenetic relations between GAVE and bisphosphonates, a long-term monitoring of potentially harmful, gastric effects of bisphosphonates, is indicated.

Abstracts P148MO. EFFECTS OF BLACK COHOSH ON BONE MARROW CYTOLOGY AND EPIPHYSEAL BONE ARCHITECTURE

S49 Our study has pointed out the importance of association between drug therapy and kinetotherapy in osteoporosis management.

Nisslein T, Freudenstein J; Schaper & Bruemmer GmbH & Co KG, Salzgitter, Germany A standardized isopropanolic extract of rhizoma cimicifugae racemosae (iCR) is traditionally used for alleviating gynecological disorders which are mostly associated with postmenopausal estrogen deficiency. In spite of its proven estrogen receptorbinding capacity, none of many preclinical laboratory or animal experimental settings have, however, demonstrated any estrogen agonistic effects for iCR so far. Neither uterine nor mammary tissues exhibited an increased proliferation rate as a consequence of iCR treatment in animal or cell culture models. Only in an ovariectomized (ovx) rat model of human osteoporosis, iCR exhibited characteristics (increased bone density, levelled urinary crosslink excretion) that might propose bone as a target organ for its estrogen agonistic properties. Besides maintaining the equilibrium of bone formation and resorption, other features of bone are estrogen-regulated as well. It has recently been shown that the number of bone marrow megakaryocytes expressing estrogen receptor beta as well as transforming growth factor (TGF) beta and TGF beta-receptor increase in postmenopausal women under estradiol therapy. We therefore examined epiphyseal bone architecture and bone marrow cytology in 3 groups of ovx female Sprague Dawley rats. The first of these groups received iCR, the animals of the second group were treated intragastrically with ethinyl-estradiol, whereas those of the third group remained untreated. The results that will be presented clearly demonstrate that iCR, besides its inhibitory potential on estrogen deficiency-caused net bone loss possesses other bone specific estrogen-agonistic properties. Absence of estrogen-like activities in critical neoplasia-prone target organs in combination with beneficial agonistic activities in other systems suggests iCR as a candidate-SERM and recommends it as a safe alternative for hormone replacement therapy.

P149SA. EVALUATION OF CLINICAL FUNCTIONAL, AND BIOLOGICAL PARAMETERS OF ELDERLY MALE WITH OSTEOPOROSIS DURING REHABILITATION PROGRAM Nica AS1, Revnic F2; 1University Hospital, Bucharest, Romania, 2 I.N.G.G. ‘Ana Aslan’, Bucharest, Romania The complex process of osteoporosis develops progresively over the whole life span but, more rapidly in the elderly. Osteoporosis in male patients has particular characteristics being associated with andropause, lack of physical activity and tobacco and alcohol abuse. This study impose a better understanding of mechanisms implicated in the development of osteoporosis as an important factor implicated both in the quality of life as well as of complications related to osteoporosis. The aim of this study was related with the analysis of osteoporosis forms (concerning clinical, functional and biological aspects in elderly men and the response after a complex therapeutic program including also a three weeks kintetotherapy. Materials and Methods: 42 patients aged between 55-70 years old with postraumatic and osteoarticular degenerative pathologies with different degrees of physical activity have been investigated biologicaly and radiologicaly for osteoporosis. 21 patients (group A) control,with postraumatic pathologies and 21 with osteorticular degenerative pathologies without physical activity (group B) has recived specific treatment for osteoporosis (Fosamax, Alfa D3, Calcitonin) associated with 3 weeks kinetotherapy programm with intermediary and then final clinico-functional testing. Our data deal with the importance of a complex therapeutic program (dietary, beside the specific adapted drug therapy, as well as physical training for treatment and prevention of osteoporosis as well as for the recovery of somatic support.

P150SU. THE ROLE OF PHYSICAL EXERCISE IN POSTMENOPAUSAL OSTEOPOROSIS Mologhianu G, Nica AS, Scarlet R; International Association for the Study of Pain, Seattle, USA, AMR: Romanian Medical Association, Bucharest, Romania, International Society of Physical and Rehabilitation Medicine, Assenede, Belgium Aims: Proving the effects physical exercise has on bone mass in postmenopausal women. Materials and Methods: The research has been done on two groups of patients in the Rehabilitation Center of the University Hospital in Bucharest. The groups were composed of 18 women aged around 62 (the study group) and 16 women aged around 65 (the control group), both groups with osteoporosis, with BMD under –2,5 SD score T at hip and spine levels measured through DXA. The patients in the study group have been subjected to a physical exercise program, three times a week for 50 minutes, consisting of aerobic and muscular strengh groth exercises, for the lower limbs muscles and the spinal extensors. The patients were also told to walk at an alert pace, at least 30 minutes a day and to do heel-drops, 50 times a day at home. The patients in the control group were only administered calcium and vitamin D (the same as the other group) but have not undergone a supervised exercise program. The patients were monitored for a year and the BMD was determined through DXA twice, at 0 and 12 month. Results: A moderate increase in BMD was registered in the study group, while in the control group there was no change. Other factors registered were vertebral statics disorders, stability and gait, psychical condition. All of these have significantly improved in patients from the study group as compared to the ones in the control group. Conclusions: It is necessary to apply a standardised physical exercise program to any postmenopausal woman with BMD decrease; -The exercise must be within the limits of certain parameters regarding intensity, duration and frequency; -Even though BMD increases were not significant, no loss was registered, and some improvement of the parameters stated above was observed. This provement prevents bone fractures, pain and disfunction.

P151MO. ARE THE PHARMACEUTICAL INDUSTRY SERVICES TO THE CONSUMERS USEFUL Anti SMAA, Echeverria C, Tosi FC, Correa WBP, Heringer R; Laborato´rios Biosinte´tica Ltda The ‘Biosintetica Assistance’ is a consumer attending service of Biosintetica Labs (Brazilian pharmaceutical industry) formed by a multidisciplinar paramedical team. Since 1998, ‘Biosintetica Assistance’ registers by phone, patients who orientated by their doctors express spontaneous desire to be part of an orientation program of osteoporosis independently of medicine use. These patients receive information about registry, benefits and limitations and only after their authorisation they are registered. The main aim of this service is to promote to the patients some knowledge about their illness through information by phone in the moment of the registration; as well as information papers and magazine for the secular public. Aim: To check if the information offered by ‘Biosintetica Assistance’, provoked any changes in the habits of patients lives, and to check the patient’s satisfaction with the offered service. Methods: Two hundred registered patients were randomly chosen from different regions of Brazil, from 4018 patients who took part in the program. All should answer by phone if they

S50 remembered the information and the received material. It was also asked if after receiving information some living habit had changed, and the degree of satisfaction with the service. Results: 94% of the interviewees, independently of the school degree, remembered receiving the informative material, and 78% remembered their context. 72% of the patients reported some changes in their living habits, in which the most important ones were in the diet that became richer dairy products (47%), regular practice of physical exercises (25%) and solar exposition (20%). There was not any change concerning smoking habit. The service was classified as good or very good for 99% of interviewees. Conclusion: The results suggest that together with the medical counselling, any orientation service similar to the ‘Biosintetica Assistance’, can be useful to a better comprehension of the illness, as well as in the change of living habits.

P152SA. OSTEOPOROSIS CLASS – EXPERIENCE OF THE PORTUGUESE INSTITUTE OF RHEUMATOLOGY TWO YEARS EVALUATION Miguel R, Simo˜es E, Micaelo M, Marques C, Vilar A; Portuguese Institute of Rheumatology Introduction: Osteoporosis is an important problem of public health. Fracture is the most dramatic consequence; that depends much on bone mineral density (BMD) but also on falls. Increasing deformity of spine causes limitations of daily activities. In our institution, we make a multidisciplinary approach of osteoporotic patients, who can benefit from a specific exercise program, that we call osteoporosis class. Class endpoints: evaluate changes in spine flexibility, deformity, and performance of daily living activities (DLA), occurrence of falls and fractures. As secondary endpoint, changes in BMD. Methods: Female patients with osteopenia or osteoporosis referred to our metabolic bone unit, were evaluated for: posture, spine flexibility, DLA, equilibrium and propensity to falls. Also was noted risk factor for osteoporosis, pharmacological therapy, presence of fractures and BMD. The exercise program, consists on posture correction, spine flexibilization, muscular strengthening and equilibrium training. Each session had 45 minutes long and each patient did, at least 15 sessions. Results: 35 female patients were enrolled in this program. The youngest patient was 46 years old and the oldest 77 (medium 64,7 years). 16 patients (45,7%) had already fractures at baseline. All were medicated with anti-resorptive drugs and calcium supplement. As far as flexibility is concerned, 36% had no change, and 64% were better, especially in the patients that did the program three times a year. With the deformity parameter, 43% were stabilized and 52% were better, mainly in the group who did three times a year. 17% of the patients had no changes of DLA and 83% were better. 21 women completed follow-up of 24 months and were evaluated for changes of BMD. 17 (80.9%) had improved significantly and 4 (19.1%) had worsened or stabilized. No falls reported and 34 patients had no new fractures. Conclusions: Specific exercise program may be a valuable measure that can complete the approach to osteoporotic patient.

P153SU. EFFECTS OF PHYSICAL THERAPY AND EXERCISE ON BONE MINERAL DENSITY IN POSTMENOPAUSAL WOMEN Brankovic S, Pilipovic N; Institute of Rheumatology, Belgrade, Yugoslavia The purpose of study was to assess the efficacy of a physical therapy and exercise program in the treatment of low mineral density.We developed exercise program in Institute of Rheumatology, Belgrade, and the patients with low bone mineral density (BMD) exercised 3 times a week (for 4 weeks). After that period patients continued regularly with exercise at home. Fifty-seven postmenopausal women, with Calcium/vitamin D supplementa-

Abstracts tion, aged 44–68 years, were divided into two groups: Group A: 24 cases who only exercised and Group B: 33 cases who take some physical therapy (analgesic electrotherapy, TENS, Interferential current or pulsed electromagnetic field – PEMF) and exercised. Bone mineral density of lumbar spine was measured using the Lunar DPX-L device. Results: Group A, mean age 57,38 yrs, mean BMD 0,915 gr/cm2 with average T score –2,40 SD. After 1 year period BMD was increased to mean 0,925 gr/cm2 (1,50%) and T score to –2,28 SD. (NS) Group B, mean age 55,90 yrs, mean BMD 0,906 gr/cm2 and T score –2,44 SD at study entrance, was show significant increase after 1 year period: BMD = 0,926 gr/cm2 (2,16%) and T score – 2,28 SD (p50,001). In 13 patients of Group B, who were treated by PEMF, BMD increased from 0,914 gr/cm2 to 0,939 gr/cm2 (2,70%, p50,001). Sixteen patients from Group A and 18 patients from Group B did not continue with exercising and after average 11,7 months BMD was decreased in Group A to 0,904 gr/cm2 (2,10%); (t = –2,21; p50,05) and in Group B to 0,918 gr/cm2 (2,71%); (t = –5,40; p50,001). Our results indicate that exercise and physical therapy (especially PEMF) could improve BMD even in patients not taking any medication for osteoporosis. It is necessary that exercise program is continued at home because patients who stooped exercising, had decreased BMD compared to baseline.

P154MO. THREE MINERALS AND THREE VITAMINS – FACTORS IN OSTEOPOROSIS PREVENTION AND TREATMENT Ribarova F, Shishkov S, Rizov N; National Center of Hygiene, Medical Ecology and Nutrition, Sofia, Bulgaria Nutrition a principal preventive factor against osteoporosis initiation and development. Its effective application depends on the knowledge of food composition. This gives the authors the background for the elaboration of tables presenting data about the content of the nutrients, essential for bone metabolism: the minerals Ca, Mg, P and vitamins D, C, B6. The tables cover the traditional and most popular foods, consumed by the Bulgarian population, distributed in 7 groups (cereals, oils and fats, milk and dairy products, meat and meat products, eggs and poultry, fish and fish products, fruits and vegetables). A brief information about the biological role of each nutrient is presented together with respective referent values for the different age and risk population groups according to physiological demands. The presented data can be used by professionals (physicians, dietologists, nutritionists, and technologists) and by the public, who requires more and more information on osteoporosis hazard. Diet and nutrition regimes design on the basis of necessary minerals and vitamins content on one hand and their conformity with physiological demands on the other will provide effective osteoporosis prevention and will support the treatment.

P155SA. EFFECT OF ACTIVE ABSORBABLE ALGAL CALCIUM WITH COLLAGEN ON OSTEOPOROSIS AND OSTEOARTHRITIS Fujita T1,2, Fujii Y2, Miyauchi A3, Takada Y3; 1Katsuragi Hospital, Osaka, Japan, 2Calcium Research Institute, Osaka, Japan, 3 National Sanatorium Hyogo Chuo Hospital, Hyogo, Japan The effect of active abosorbable algal calcium (AAA Ca or Adva Cal) on aging-associated skin changes and backache and joint pain due to osteoporosis and osteoarthritis was evaluated in a case-controlled study on age-matched 40 test and 40 control subjects with a mean age of 65, complaining of backache and joint pain due to osteoporosis and/or degenerative joint disease such as spondylosis deformans and osteoarthritis of the knee. Supplementation with 900 mg calcium as AAA Ca and 3.5 gram collagen and polysaccaride-hexosamine daily for 4 months resulted in a marked alleviation of subjective pain and fall of skin impedance measured by elestroalgography m in response to

Abstracts

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exercise load such as standing up, bending, squatting, walking and climbing up and down stairs. The basal skin impeadance which increases with age was significantly reduced in responce to Ca-Collagen supplementation, suggesting a change of skin properties towards rejuvenation, along with subjective smoothening and moistening of the skin. In addition to suppression of parathyroid hormone secretion by calcium supplementation, preventing calcium release from bone and entrance into cartilage inhabiting degeneration, collagen acting on intestinal lymphocyre system may prevent anti-collagen antibody and collagenase production, preserving bone and skin callagen.

animals fed with the experimental diet for 4 weeks was significantly higher (by 33–38%) compared with the control rats. Four experimental groups had slightly different composition. However, all experimental groups demonstrated a slowdown in bone resorption. There was observed a better bone mineralization in two groups where the calcium to phosphorus ratio was (2.7–3) : 1. The most pronounced beneficial effect of the product was in the group enriched with silicon, inulin but no vitamin D. The results of this work lead to the development of dairy-based phyto products, namely ‘850’, ‘Rusj’, and ‘Doctor-D’. Clinical studies with humans are currently under way.

P156SU. POST-TRAUMATIC ALGO-DISTROPHIC SYNDROME OF THE LOWER LIMB

P158SA. FIVE YEARS FOLLOW-UP STUDY OF NONAGENARIAN PATIENTS WITH HIP FRACTURES

Donelli F; Centro Di Ortopedia Geriatrico, Milano, Italia

Nieto E, Natale A, Useche R; University Hospital of Los Andes, Orthopedic Dept., Merida, Venezuela

Algo-neurodistrophia defines a district, poly-tissure syndrome, marked by pain, hyperalgia, vasomotorial disorders, subsequent bone atrophy. A traumatic event, apart from its severity as a trauma, concerning the skeleton structures, is most likely the predisposing factor in about 50%–60% of cases. In general, the spongy bone tissue shows thinner trabeculae with fewer anastomosis and some clear signs of necrosis both of the bone cellular and medullar population. Aside from some aspects of an osteoplastic activation, the most frequent histologic examination shows smaller number of these cells.Instrumental tests: alteration of hormonal bio-chemical parametres of the phosphor-calcium metabolism. X-ray and scintillography, CAT and magnetic resonance, total-body bone densitometric test. Post-traumatic algodistrophy of the lower limb: the elective sites are: foot, ankle, 1/3 leg distal, to a minor extent the knee, and rarely the hip. The transient osteoporosis of the hip, which is almost constant, with spontaneous recovery in between 4–24 months, holds a series of particular clinical aspects which deserves a separate treatment. A pharmacological treatment is obtainable by systemic inhibition of the sympathetic nervous system – sympathetic blocks –: this method includes drugs given at various levels to inhibit the activity of the sympathetic nervous system through epidural infusion of anaesthetics, as well as ganglion and venous infusione of sympathetico-lytic agents. Treatment by clodronate phleboclysis shuold also be of choice. A physical rehabilitating treatment should also be associated with the above therapy, at each stage of the disease, to be completed with hydro-kinesitherapy. To prevent wear and overload pathology phenomenons a computer controlled baropodometric test is useful, to evaluate the dynamics of walking. In conclusion, the state of the art and vision of myo-articular mechanics acknowledge the importance of postural alterations, as a post-traumatic exitus of foot algodistrophy of upper systems reaching as far as the upper limb.

P157MO. DAIRY-BASED PHYTOPRODUCTS THAT AID IN PROPHYLAXIS OF OSTEOPOROSIS Donskaya GA, Skobeleva NV, Charitonov VD; All-Russian Scientific Research Institute of Dairy Industry Osteoporosis is a multifactorial disorder in which nutrition, and dairy foods in particular, plays a great role. The objective of this study was to develop a dairy-based product that would stimulate osteotropic processes in the body. A number of natural biologically active substances of plant and animal origin were estimated and thoroughly studied. The composition of dairy based product was developed to maximize calcium absorption from the product. As a result of a 5-year (1996–2001) research, there were created a number of quark-based products enriched with the natural plant supplements, osteotropic elements, inulin and vitamins which enhance calcium absorption. Bone morphology, including the femur size and mass ratio of calcium and phosphorus was determined in rats. The bone mass of femur in

Twenty-five nonagenarian (Age 93.0 ±3.5M±SD) patients with hip fractures were followed-up between 1992–1997, at the University of Los Andes Hospital in Merida Venezuela. There were 19 female and 6 males. All patients lived at home. 72% were active and independent. 60% had mainly cardiovascular diseases and diabetes mellitus. 32% had no cardiac or metabolic illnesses. The fracture was located in the trochanteric area in 64%. Hospital stay was 12.7±5.02 days. Surgical correction was performed within 8.4±4.0 days. 62% (8/13) of patients with trochanteric fractures received the 958 angulated blade plate. 38% had telescoping screw devices implanted. Those with femoral neck fracture received the Thompson prosthesis (67%) and the remainder the canulated screw. In 42% the surgical time was longer than 120 minutes. Spinal anesthesia was performed in 21% and general anesthesia in 79%. Those unoperated patients remained bedridden and died between 6 and 12 months post fractures. Five operated (26%) patient died during the same period of time. Mortality at 1 to 3 years was 47%. Survival at 3 years was 26%. By the year 2000 (8 year of follow up) only 2 patients were still alive. The most common postoperative complications were pain (75%), limb shortening (70%) and inability to walk in 64%. Sixtyseven percent of these complications were related to the angulated blade plates, where as only 25% patients with Thompson prosthesis had complications. Conclusions: 1. – Nonagenarian patients with hip fractures should be offered surgical correction; 2. – Post op complications are mainly related to the selected device and absence of an appropriated post op rehabilitation plan; 3. – This particular group of nonagenarian patients should be assessed and treated by a special Geriatric Assessment Team (GAT).

P159SA. COMPARATIVE MINERAL BINDING AFFINITIES OF SELECTED BISPHOSPHONATES Nancollas GH1, Mangood AH1, Gaafar EM1, Wu W1, Ebetino FH2, White DJ2, Phipps RJ2, Russell RGG3; 1SUNY Buffalo, Buffalo, USA, 2Procter & Gamble Pharmaceuticals, Mason, USA, 3Oxford University, Oxford, UK Aims: Clinical and experimental data suggest that individual bisphosphonates (BPs) may have different interactions with bone, that result in subtle but distinctive differences in their pharmacological behaviour. This current study extends our earlier work on the potential important contribution of mineral binding to the potency and duration of action of different BPs. Methods: The effects of alendronate, risedronate and etidronate on hydroxyapatite (HAP) and octa calcium phosphate (OCP) crystal growth and dissolution were investigated with the Constant Composition method at ionic strength 0.15 M and 37 deg C. Adsorption affinity constants (KL) were calculated from the kinetic results.

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Abstracts

Results: There were significant differences (P50.001) in KL among the three BPs for HAP growth (pH 7.4) and OCP growth (pH 6.5), with alendronate 4 risedronate 4 etidronate. These conditions probably simulate the rate and extent of BP binding onto bone. Binding affinities were lower for crystal dissolution under conditions likely to prevail during osteoclastic resorption (HAP at pH 4.5 and OCP at pH 6.0), but the rank order alendronate 4 risedronate 4 etidronate was the same. Preliminary results from other BPs suggest that ibandronate and zoledronate have higher KL than alendronate and risedronate, at least for HAP dissolution. Conclusions: Risedronate has lower kinetic binding affinity than alendronate for the mineral substrates HAP and OCP. This difference may contribute to the apparent shorter terminal (bone) half-life of risedronate, and to a faster clinical on-response (fracture reduction) and off-response (recovery of bone turnover after cessation of dosing) seen with risedronate compared to alendronate. BP

K(subL) HAP Growth (L/mole) pH 7.4

K(subL) OCP Growth (L/mole) pH 6.5

K(subL) HAP Dissolution (L/mole) pH 4.5

Alendronate Risedronate Etidronate

11.67 x 106 4.46 x 106 1.17 x 106

8.0 x 106 5.3 x 106 4.0 x 106

1.97 x 105 1.39 x 105 0.97 x 105

P160SU. HIGH AND LOW BONE TURNOVER CLASSIFICATION OF POSTMENOPAUSAL WOMEN BY BIOCHEMICAL MARKERS: INFLUENCE OF THE DAY-TO-DAY VARIABILITY: THE IMPACT STUDY Garnero P1, Eastell R2, Delmas PD3; 1Inserm Unit 403, Synarc, Lyon, France, 2University of Sheffield, Sheffield, United Kingdom, 3 Inserm Unit 403, Lyon, France High bone resorption is a risk factor for fragility fracture in postmenopausal women. However the day-to-day variability of bone markers has raised concern about their clinical utility in individual patients. In this study we investigated the re-test reliability of urinary NTX, a marker of bone resorption, in a large prospective trial, the IMPACT study. The primary aim of the IMPACT study is to assess the effect of using bone turnover marker monitoring of risedronate treatment on patient’s compliance and persistence. 2386 women (65 to 80 yr) with osteoporosis were recruited in 172 centers in Europe, North and Latin America. At baseline, two second-morning void urine samples (one day apart) were collected for centralized measurements of NTX by automated analyzer. We report preliminary baseline data, prior to initiation of risedronate therapy, from the 1921 patients who have had both baseline samples analyzed so far. Women were categorized in tertiles (T1, T2, T3, from lowest to highest) of NTX values for measurements performed one day apart. The agreement of classification between the two measurements was moderate [kappa: 0.60 (95% CI: 0.57–0.63)] with 67% of women remaining in the same tertile. Only 3% of patients in T3 (high turnover) at the first measurement were in T1 (low turnover) one day after. Conversely, 3% of patients in T1 were found in T3 at the second measurement. Among women in T2 (intermediate bone turnover), 53% remained in the same tertile one day after. We conclude that less than 6% of women in T3 or T1 at one occasion were classified in the opposite group the day after, suggesting that a single measurement of NTX accurately classifies women with a definitively high or low turnover. For those women with intermediate NTX levels (T2), an accurate classification may require a second measurement.

P161MO. OSTEOPROTEGERIN SERUM LEVELS IN WOMEN: INFLUENCE OF AGE, BONE MASS, BONE TURNOVER AND FRACTURE STATUS Fahrleitner A, Dobnig H, Leb G, Dimai HP, Piswanger-So¨lkner C, Bonelli CM, Obermayer-Pietsch B; Department of Internal Medicine, Division of Endocrinology, Karl-franzens University School of Medicine, Graz, Austria Aims: Preclinical data have shown that osteoprotegerin (OPG) inhibits osteoclast function and therefore plays an important role in bone remodelling. This study was aimed to evaluate whether higher OPG serum levels in human also reflect decreased bone resorption and eventually higher bone mass. Methods: Serum OPG levels were measured by a polyclonal antibody-based ELISA system (Biomedica GmbH, Austria) in 177 healthy women (aged 17–85 years) as well as in 48 untreated women (mean age 71 ± 5) with established osteoporosis and set in relationship to age, bone mass, bone turnover markers and in case of osteoporotic patients to prevalent vertebral fractures. Results: In healthy women a positive correlation with age (r = 0.25; p 5 0.001) but none to bone mass or bone turnover markers was found. In osteoporotic women, however, there was a strong relationship between serum OPG and bone turnover markers (serum c-terminal crosslinked telopeptides of type I collagen (sCTX): r = 0.82; p 5 0.0001; osteocalcin: r = 0.69, p 5 0.0001) with patients having higher bone turnover markers demonstrating higher serum levels of OPG. After adjustment for bone mass and bone markers patients with prevalent vertebral fractures had significantly lower serum OPG levels when compared to non-fractured individuals (57+ 8 vs. 97 + 10 pg/ml, [mean + SE], p 5 0.01). Conclusions: The increase of OPG as antiresorptive factor with ageing may reflect an insufficient paracrine mechanism by bone cells in order to compensate for bone loss. In osteoporotic patients, however, OPG correlated strongly with turnover markers which may point towards a higher level of RANKL/OPG expression in these patients. Since low OPG serum levels seem to be predictive of vertebral fractures we hypothesise that less OPG for a given degree of bone turnover may be indicative for higher fracture risk in osteoporotic patients.

P162SA. ALTERNATIVE INSULIN SIGNALLING PATHWAYS IN OSTEOBLAST CELL LINES Langeveldt CR, Engelbrecht Y, Hough FS, Hulley PA; Faculty of Health Sciences, University of Stellenbosch, Cape Town, South Africa There is an urgent need for the development of bone anabolic agents for the treatment of steroid osteoporosis, which is characterised by bone loss and decreased osteoblast numbers. Severe osteopenia is also seen in the IRS-1 -/- mouse, and in rats and humans with inadequate insulin levels. Insulin may therefore be an important anabolic agent for bone in both development and adulthood, and yet insulin signalling in Obs is poorly described. We therefore investigated the mitogenic effects of insulin on immature mouse MBA-15.4 and human MG-63, and more mature mouse MBA-15.6 and rat Rob-C26, Ob cell lines. Compared to the relatively differentiated Rob-C26 cells, the other 3 cell lines were more insulin-sensitive and showed a marked increase in proliferation over control levels. Insulin can activate proliferation through both the classical mitotic Raf-MEK-ERK pathway, or through the initial steps of the metabolic pathway comprising insulin receptor, IRS-1 and PI3-kinase. U0126, a noncompetitive MEK inhibitor, and wortmannin, a PI3-kinase inhibitor, were used to determine whether signalling was MEK – or PI3-K dependent. Wortmannin had no effect on proliferation of MBA-15.4 and -15.6 Obs, but inhibited phosphorylation of PKB, the metabolic downstream target of PI3-kinase. Surprisingly, in both MBA15.4 and -15.6 Obs, blocking the MEK-ERK pathway with U0126, followed by insulin treatment, did not inhibit proliferation and in

Abstracts fact frequently stimulated it. However, this inhibitor completely abrogated ERK activation induced by insulin and blocked both FCS-induced proliferation and ERK activation. In contrast, insulininduced proliferation of human MG-63 Obs was partially inhibited by Wortmannin and totally inhibited by U0126, indicating involvement of both PI3K and MEK-ERK, with PI3K signals converging on ERK. These data suggest that a novel pathway may be involved in insulin-induced proliferation in mouse Obs, and highlight a potential species difference in the insulin response pathways of mouse and human bone.

P163SU. SERUM TARTRATE-RESISTANT ACID PHOSPHATASE 5B IS AN INDEPENDENT PREDICTOR OF BONE MINERAL DENSITY IN WOMEN BUT NOT IN MEN Franzson L, Indridason OS, Sigurdsson G; University Hospital, Reykjavik, Iceland Aims: Serum tartrate-resistant acid phosphatase 5b (TRAP5b) isoform is formed in active osteoclasts and serum concentration is directly related to osteoclastic activity and thereby bone resorption affecting bone mineral density (BMD). The aim of our study was to evaluate the association between TRAP5b and BMD controlling for other factors. Methods: We have measured TRAP5b (ELISA, Suomen Bioanalyttika, Finland) and several other bone markers in fasting blood samples in 40-85 year old in an ongoing population-based cohort study. BMD was measured by DEXA in lumbar spine (BMDLS) and total hip (BMDH). For this preliminary analyses we excluded subjects receiving bisphosphonates, HRT, thiazides or glucocorticoids. We used Spearman’s correlation to assess bivariate correlation and multivariable linear regression to examine independent association between BMDH or BMDLS and TRAP5b after controlling for variables of interest. Analysis was performed separately for women and men. Results: Data for 52 women, age 57±14.0, and 49 men, age 61±12.0, were analyzed. Amongst women TRAP correlated positively (p50.01) with osteocalcin r = 0.75, alkaline phosphatase r = 0.302, Crosslaps r = 0.706, serum calcium 0.33, age 0.260 and negatively with oestradiol r = –0.315, BMDLS r = –0.615, and BMDH r = –0.415, (p50.01). Amongst men TRAP correlated positively with osteocalcin r = 0.558 and Crosslaps r = 0.628, p50.01, but not to BMD or to other markers measured. Upon multivariable regression amongst women TRAP showed an independent negative association with BMD, p50.01, stronger in lumbar spine than in the hip, the strength similar as between age and BMD. Together TRAP and age explained 40-50% of the variability in BMD amongst women. No such association was found between TRAP and BMD in men. Conclusions: TRAP is a strong predictor of bone mineral density in women but not men after the age of forty, as strong as the age. This might suggest a gender difference in the significance of osteoclastic bone resorption in determining BMD.

P164MO. LONG-TERM VARIABILITY OF MARKERS OF BONE TURNOVER IN POSTMENOPAUSAL WOMEN AND IMPLICATIONS FOR THEIR CLINICAL UTILITY. THE OFELY STUDY Garnero P1, Mulmann D2, Munoz F2, Sornay-Rendu E2, Delmas PD2; 1Inserm Unit 403, Synarc, Lyon, France, 2Inserm Unit 403, Lyon, France High levels of bone turnover markers is a risk factor for fragility fracture in postmenopausal women, but the variability of their measurement has raised concern about their clinical utility. In this study we investigated the long-term variability of markers in 268 healthy untreated postmenopausal women (1 to 39 yr post

S53 menopausal) in the OFELY cohort. A fasting blood sample was collected every yr for 4 yr (5 samples) to measure serum osteocalcin (OC) for formation and serum CTX (S-CTX) by automated analyzer for bone resorption. Bone turnover remained stable over 4 years (OC, +1.3%/yr, p = 0.003; S-CTX; –0.13%/yr, p = 0.7). Women were categorized in tertile (T1, T2 and T3, from lowest to highest) of bone marker levels. Agreement of classification between baseline and 4 yr measurements was moderate (kappa: 0.51 and 0.52, for OC and S-CTX, respectively) with 60% of women remaining in the same group for both markers. However, only 4% and 5% of patients in T3 (high turnover) for OC and S-CTX respectively at baseline were found in T1 (low turnover) after 4 years. Conversely, 10% and 4% of women in T1 for OC and S-CTX respectively were found in T3 after 4 years. Among women in T2 (intermediate bone turnover), 51% and 43% for OC and S-CTX respectively, remained in the same tertile at the second measurement. When the 2 markers were combined, only 2% of women at high turnover at baseline – defined as OC and/or S-CTX in T3 – were classified at low turnover 4 years later. We conclude that serum bone turnover markers are stable over 4 years in postmenopausal women. A single measurement of one or two markers accurately classifies most women with a definitively high or low turnover. For those women with intermediate levels (T2), classification may be improved by a second measurement.

P165SA. SHORT-TERM MONITORING OF RISEDRONATE THERAPY IN POSTMENOPAUSAL WOMEN WITH MARKERS OF BONE TURNOVER: CONSISTENCY IN THE RESPONSE Garnero P1, Eastell R2, Watts NB3, Van De Langerijt L4, Cahall D5, Delmas PD6; 1Inserm UNIT 403, Synarc, Lyon, France, 2University of Sheffield, Sheffield, United Kingdom, 3Emory University, Atlanta, GA, USA, 4Aventis Pharma, Hoevelaken, The Netherlands, 5Aventis Pharma, Bridgewater, NJ, USA, 6Inserm UNIT 403, Lyon, France Bone marker changes have been proposed for monitoring response to anti-resorptive therapy. We assessed the consistency of changes in urinary NTX after 3 and 6 months of risedronate treatment, 5mg/daily. The primary aim of the IMPACT study is to assess the effect of using bone marker monitoring of risedronate treatment on patient’s compliance and persistence. We report data from 1864 subjects out of 2386 women with osteoporosis enrolled in the study. Two secondmorning void urine samples (one day apart) were collected for NTX measurements at baseline, 3 and 6 months. NTX decreased by a median 39% and 44% at 3 and 6 months, respectively (p50.0001). The least significant change (LSC) based on the CV of double baseline measurements was 30%. In 65% of the patients, NTX decreased by 30% or more at 3 months; 83% of them also had a decrease of at least 30% at 6 months and only 0.8% of this group had an increase above the LSC (+30%). Conversely, among the few women with an increase of NTX above the LSC at 3 months (52%), only 8% had a decrease that exceeded the LSC at 6 months. Among the 34% of women with an intermediate change (between –30 and +30%) at 3 months, 49% had an intermediate response at 6 months whereas 45% who were intermediate at 3 months demonstrated a decrease that exceeded the LSC at 6 months. These preliminary results, in the absence of compliance and persistence data, suggest that most women with a significant change in urinary NTX (increase or decrease, based on LSC) after 3 months of treatment with risedronate will have a similar response at 6 months. Among women with a change of NTX that is inconclusive at 3 months, it is recommended to repeat the measurement a few months later.

S54 P166SU. THE EFFECT ON BONE TURNOVER OF MONOFLUOROPHOSPHATE (MFP) COMBINED WITH RALOXIFENE (RLX) AS COMPARED TO MFP ALONE IN POSTMENOPAUSAL WOMEN WITH LOW BONE MASS Stepan J1, Payer J2, Resch H3, Reginster JY4, Muehlenbacher D5, Quail D5, Nickelsen T5, Pavo I5; 1Department of Internal Medicine 3, Charles University Prague, Czech Republic, 2First Clinic of Internal Medicine, Comenius University Bratislava, Slovakia, 3 Department of Internal Medicine, St. Vincent Hospital Vienna, Austria, 4Bone and Cartilage Metabolism Unit, University of Liege, Belgium, 5Lilly Research Laboratories, Indianapolis, USA Fluoride administration considerably increases bone turnover and BMD. Data on fracture prevention with fluoride treatment are conflicting. The aim was to determine whether adding the antiresorptive raloxifene to fluoride treatment influences the bone turnover changes characteristic of fluoride. Postmenopausal women with low bone mass (average age of 61.9 and femoral neck T-score of –2.87 SD, 25% of patients had preexisting vertebral fractures) were randomized to 20 mg/day fluoride (as MFP) and 60 mg/day RLX (MFP+RLX arm, N = 300) or 20 mg/day fluoride and placebo (MFP arm, N = 296) for 18 months. All patients received calcium (1000 mg/day) and vitamin D (500 IU/day) supplements. Biochemical markers of bone turnover (bone specific alkaline phosphatase BSAP and urinary type I collagen fragment/creatinine ratio [uCTX/Cr]) were determined in a subset (N = 451) at baseline and after 2, 6 and 18 months and IGF-1 and IGFBP-3 at baseline and 18 months.In the MFP group both bone formation markers BSAP, mean increase from 13.9 to 18.8 microg/L, p50.001) and bone resorption markers (uCTX/Cr, mean increase from 289 to 398 mg/mol, p50.001) increased at study endpoint. In the MFP+RLX group, the BSAP increase was blunted (mean increase 14.2 to 16.2 microg/L, (p50.001)) and no significant change in bone resorption was observed (uCTX/Cr decrease from 305 to 295 mg/mol, n.s.). Differences in change from baseline between the groups were significant for both markers (p50.001). IGF-1 was increased in the MFP group (from 14.2 to 15.7 nmol/L (p50.001)) but was unchanged in the MFP-RLX study arm (from 14.4 to 13.6 nmol/L, n.s.). The circulating level of IGFBP-3 did not change significantly in either of the groups. We conclude that adding RLX 60 mg/day to fluoride therapy in postmenopausal women with low bone mass favourably influences the balance of bone formation and resorption as assessed by markers of bone turnover.

P167MO. MOLECULAR MODELING OF THE BISPHOSPHONATES IN FARNESYL DIPHOSPHATE SYNTHASE. POTENTIAL NEW DETAILS OF THE PRECISE BIOCHEMICAL MECHANISM OF ACTION OF POTENT NITROGEN CONTAINING BISPHOSPHONATES Ebetino FH1, Rogers MJ2, Dunford J1, Liu X1, Phipps RJ1, Russell RGG3, Barnett B1, Correa P1, Mieling G1; 1Procter & Gamble Pharmaceuticals, Mason, USA, 2University of Aberdeen Medical School, Aberdeen, UK, 3Oxford University, Oxford, UK Bisphosphonates (BP’s) have been used in the treatment of metabolic bone disorders for a number of years. However, it is only recently that the mechanism of action of these agents was elucidated. The more potent of these drugs have been shown to inhibit enzymes in the mevalonate pathway, where farnesyl diphosphate (FPP) synthase appears to be the major target involved in this antiresorptive mechanism of BP action within the osteoclast. This confirmed the suggestion of a stereochemical recognition event, hypothesized from structure-activity relationships, under evaluation in our laboratories for many years. Inhibitory activity at this enzyme (zoledronate 4 risedronate 4 alendronate 4 pamidronate) correlates with known in vivo potencies. These potential interactions in the enzyme can be visualized via molecular modeling techniques allowing research-

Abstracts ers to hypothesize the inhibitory interactions that may be taking place within this enzyme and to better understand the potent and specific effects of BPs. For example, Martin et al recently hypothesized the inhibition of Geranyl pyrophosphate (GPP) within the FPP synthase enzyme. On close analysis of active and inactive structurally related pairs of bisphosphonates, we have developed an alternative hypothesis for a potentially more specific inhibition / competitive binding using the IPP binding site in this enzyme. Docking active nitrogen containing bisphosphonates in the IPP binding site enables the nitrogen to form a salt bridge with the pyrophosphate of GPP. Thus, in the putative IPP binding site, a conformationally restricted – antiresorptive potent nitrogen containing BP, appears to bind similarly to the counterpart clinically active BP’s, whereas an inactive conformationally restricted nitrogen containing bisphosphonate is unable to form a salt bridge in this region of the enzyme. Work continues to further validate these hypotheses, utilizing enzyme purification and crystallography.

P168SA. CALCITONIN LOADING TEST TO ASSESS THE SUSTAINED EFFICACY OF SALMON CALCITONIN Stepan JJ, Zika´n V; Charles University Faculty of Medicine, Prague, Czech Republic Aim: Intranasal administration of salmon calcitonin (sCT) decreases bone resorption, which is dependent on hormone binding with its receptors in the osteoclasts. An eventual resistance to intranasal sCT may develop with continued use, which may be due to an escape phenomenon, to the effect of the neutralizing antibodies, or impaired absorption due to rhinitis and atrophic changes of the nasal mucosa. The aim of the study was to assess biological response in postmenopausal osteoporotic women on long-term treatment with CT. Methods: The time course and extent of suppression of plasma type 1 collagen cross-linked C-telopeptide (CTX) after administration of different doses of s.c. and intranasal sCT were determined in healthy volunteers The CTX concentrations showed a dose dependent decrease over a dosage range of 2, 10 and 50 IU s.c. administered sCT (p50.05). Measurement of CTX before and 90 minutes after intranasal administration of 400 IU sCT (calcitonin loading test, CLT) was conducted in 100 postmenopausal osteoporotic women treated with Miacalcic Nasal spray (Novartis) for 1 to 4 years. Results: The CV of the CLT was 15%, the least significant change (95% CI) was 23%. A significant decrease (63% ± 11%) in plasma CTX after CLT was observed in 75/100 patients. Only a quarter of the remaining patients did not respond to the subcutaneous administration of sCT (10 IU) by a significant decrease in plasma CTX. Conclusion: The resistance to intranasal sCT, that affects a substantial proportion of patients with continued use, is mainly due to impaired absorption of sCT from the nasal mucosa. The CLT can be used to assess efficacy of nasal sCT in individual patients.

P169SU. OSTEOPROTEGERIN IN RELATION TO OTHER MARKERS OF BONE METABOLISM AND BONE MINERAL DENSITY IN A POPULATION-BASED STUDY Indridason OS, Franzson L, Sigurdsson G; University Hospital, Reykjavik, Iceland Aims: Ostoeprotegerin (OP) seems to be involved in the regulation of bone resorption by preventing RANKL-induced osteoclast differentiation/activation and may be protective in the development or progression of osteoporosis. The aim of our study was to evaluate the association between OP and bone mineral density (BMD) controlling for other factors.

Abstracts Methods: We have measured BMD [DEXA, Hologic 4500A], OP (Sandwich Immunoassay, Biomedica) and several other bone markers in 40-85 year old subjects in an ongoing populationbased cohort study. For this preliminary analysis we excluded subjects receiving bisphosphonates, HRT, thiazides or glucocorticoids and those with diseases affecting bone. We used Spearman’s correlation to assess bivariate correlation and multivariable linear regression to examine independent association between BMD at the hip (BMDH) or lumbar spine (BMDLS) and OP after controlling for variables of interest. Analysis was performed separately for women and men. Results: Data for 57 women, age 57±14.0, and 57 men, age 61±12.7, were analyzed. In women there was a significant (p = 50.05) negative correlation between OP and BMDLS (r = – 0.383) and oestradiol (–0.440), and positive correlation with cystatin-C (r = 0.512), sex hormone binding globulin (r = 0.318), creatinine (r = 0.270) and age (r = 0.426). In men, OP was positively correlated with cystatin-C (r = 0.471), sex hormone binding globulin (r = 0.270) and age (r = 0.694). Significant correlation was not found with other markers, including serum calcium and phosphorus, 25(OH)- and 1.25(OH)2 vitamin D, PTH, alkaline phosphatase, osteocalcin and Crosslaps. Upon multivariable regression, OP did not show an independent association with BMD in women, however, it had a borderline significant positive association with BMDLS (p = 0.08, beta = 0.216) in men. Conclusions: The increases in OP with age may be related to decreasing renal function or in response to increased prevalence of osteoporosis. Results from multivariable analysis suggest that OP may have an independent protective effect on BMD in men. Larger studies are needed.

P170MO. EVOLUTION OF BONE MARKERS IN WOMEN WITH LOW DIETARY CALCIUM INTAKES AFTER DRINKING A CALCIUM-RICH MINERAL WATER: A RANDOMIZED CONTROLLED TRIAL Constant F1, Aeschlimann JM2, Weryha G3, Detalance N3, Renaud D3, Arnaud MJ1; 1Perrier Vittel Water Institute, Vittel, France, 2 Nestle Research Center, Lausanne, Switzerland, 3University and Hospital Center, Nancy, France Aim: A randomized controlled study has been set up to assess the effect of calcium from natural mineral water on bone markers in women with spontaneous low calcium intakes. Methods: A total of 39 subjects (mean ± SD: aged 21 ± 1 years, BMI 19 ± 1, calcium intakes 604 ± 105 mg/day) were randomly allocated to two groups in a cross over design. Each group drank for one week either 1.5l per day of calcium-rich natural mineral water (202 mg/l Ca) or spring water with low calcium content (15 mg/l Ca). After a three-week washout period, each group changed the water. Blood and urine samples were collected in the morning after an overnight fast at 8.00 am on Day 0 and Day 7, and on Day 28 after the washout period. A kinetics study was performed on Day 1 at 8.30, 9.00, 10.00, 11.00, 12.00, and in the afternoon at 2.00 and 4.00 pm on subjects fed a standardized calcium diet. Serum and urinary CrossLaps, PTH and osteocalcin were measured. Groups were compared using adapted Student’s t tests. Results: All the serum and urinary variables measured at 8.00 am in fasting subjects showed no significant change in relation to the water drunk after a day or a week of consumption. On day 1, subjects who drank calcium-rich mineral water exhibited a significant decrease in serum CrossLaps especially at 11.00 am (p = 0,012), 12.00 am (p = 0,012) and 4.00 pm (p = 0,009). A significant decrease in PTH was also observed at every time of the kinetic study (p50,05). Osteocalcin decreased until 12.00 am but with a significant difference at 11.00 when subjects drank mineral water. Conclusion: This study shows a rapid and significant effect of a daily ingestion of 300 mg from a calcium-rich mineral water on bone metabolism in healthy young women.

S55 P171SA. EFFECT OF CALCIUM SULFATE-RICH WATER AND MINERAL WATERS ON BONE RESORPTION IN THE RAT Mu¨hlbauer RC1, Lozano A1, Arnaud MJ2; 1Group for Bone Biology, Department for Clinical Research, University of Bern, Bern, Switzerland, 2Perrier Vittel Water Institute, Vittel, France Aim: The efficiency of natural calcium (Ca) sulfate sources as calcium supplement has not been thoroughly investigated. As Ca in natural mineral waters is mainly present as Ca sulfate, a doseeffect study with different mineral waters on bone resorption was performed. Methods: Male Wistar rats were prelabeled from the first week of their life for 6 weeks with [3H]-Tetracycline (TC). During this period the rats were fed a standard laboratory chow. After discontinuation of labeling the animals were transferred to individual metabolic cages and were switched to a semi-purified diet [0.2g Ca; 0.2g P per 100g dry diet]. After 10 days of adaptation, daily bone resorption was assessed by the urinary excretion of TC released from bone. Basal bone resorption was analyzed during 10 days and the effect of five different waters were studied for another 10 day period. Demineralized water, the mineral waters Vittel (202mg Ca/l), Contrex (486mg Ca/l), He´par (555mg Ca/l) and a Ca sulfate solution (1000 mg/l) were provided in a blinded fashion to drink and to prepare wet food. Effects are expressed as % of control (demineralized water)± SEM. The results were compared using the Student’s t test. Results: There was a continuous effect of the waters throughout the 10 days of observation. Vittel inhibited the 10 day cumulative bone resorption by 8 ± 4%, Contrex by 18 ± 3% (p50.01), He´par by 24 ± 2% (p50.001) and the Ca sulfate solution by 29 ± 3% (p50.001). Thus, a significant Ca-dose-dependent inhibition of bone resorption by Ca sulfate containing waters was observed. Conclusion: This study shows with a very sensitive experimental model that calcium sulfate in water or mineral waters inhibits bone resorption. This opens the possibility for natural mineral waters to be used as a calcium supplement.

P172SU. CLINICAL EVALUATION OF A NOVEL ACTIVITYBASED IMMUNOASSAY FOR TARTRATE RESISTANT ACID PHOSPHATASE (TRACP) ISOFORM 5B Hannon RA, Eagleton AC, Clowes JA, Machado ABC, Eastell R, Blumsohn A; University of Sheffield, Sheffield,UK Most serum TRACP isoform 5b is likely to be derived from osteoclasts and therefore it may be a useful indicator of osteoclastic activity in vivo. Serum markers of bone turnover tend to be more robust than urinary markers. However previously reported TRACP 5b immunoassays have not shown clinical utility in independent studies. The aim of this study was to evaluate the clinical performance of a new microtitre immunofixed-enzyme activity assay for TRACP 5b in 5 clinical models. Serum TRACP 5b was measured with the Bone TRAP assay (Suomen Bioanalytiikka Oy, Oulu, Finland). All samples were stored at –80deg C. The response of TRACP 5b to alendronate therapy (10mg with Ca 500mg/day) in postmenopausal women with osteoporosis was –39%±4 (SEM) at 25 weeks (n = 16). Following calcium supplementation in postmenopausal women with osteoporosis (500 mg/day) TRACP 5b decreased by 12%±3 (SEM) at 25 weeks (n = 7). Within subject variability (CVi) was 6.6% (20 healthy premenopausal women sampled on 5 alternate days). In contrast to other markers of bone resorption, TRACP 5b did not show a marked decrease in response to feeding (difference between levels 1 hour after breakfast and levels after overnight fast – 2.4%±0.8, P50.05). In contrast to other markers of bone resorption TRACP 5b did not show a marked diurnal rhythm – peak to trough difference 8%; ANOVA for time of day effect P 5 0001. We conclude that this novel assay for TRACP 5b activity may have clinical utility. Although TRACP 5b shows a much smaller

S56 response to antiresorptive therapy than other resorption markers within subject variability, response to feeding and diurnal rhythm are also smaller when compared to other markers of bone turnover. It remains to be determined whether the smaller response to therapy will be offset by the lower measurement noise shown by this analyte.

P173MO. RATLAPS ELISA: FURTHER VALIDATION OF A NEW BIOCHEMICAL TEST OF RODENT BONE RESORPTION Qvist P, Delaisse JM, Jespersen MK, Heegaard AM; Nordic Bioscience, Herlev, Denmark It has previously been demonstrated that two new biochemical markers for application on rodent serum samples, i.e. the RatLaps ELISA for detection of C-telopeptides of type I collagen (CTX-I) released during bone resorption and the Rat-Mid ELISA for detection of osteocalcin generated by the osteoblasts, both are increased significantly one and two weeks after ovariectomy of the rat. In the present study it was investigated if (1) the increase in bone resorption induced by a low calcium diet was reflected in RatLaps ELISA, and (2) RatLaps ELISA reflected the acute suppression induced by calcitonin. Five weeks old male Wistar rats were fed on regular (Altromin C1000, n = 8) or low Ca diet (Altromin C1031, n = 16) for five days, and then serum calcium and RatLaps were assessed. In another study, five weeks old male Wistar rats were kept on low Ca diet for five days, and then allocated to one of three groups: Vehicle (n = 7), Calcitonin (Miacalcic) 5 IE/kg by intra peritoneal injection (i.p.) (n = 8), and calcitonin 10 IE/kg (i.p., n = 9). Blood samples were obtained before injection and 0.5, 1.0 and 6.0 hrs post injection, and serum calcium and RatLaps were assessed. To reduce the acute effect of food intake on bone metabolism all blood samples were collected in the morning after an overnight fast. Serum calcium was maintained during five days of low calcium intake in the rat (data not shown). Simultaneously, RatLaps was increased by 25% (p50.05) compared to control diet. In the second experiment it was observed that 30 and 60 min. following i.p. injection of 5 or 10 IE/kg of calcitonin in rats kept on low calcium diet a significant reduction in both serum calcium and RatLaps ELISA compared to vehicle. Six hours post injection the serum calcium and RatLaps levels were similar to vehicle.

P174SA. LOW-DOSE CERIVASTATIN DECREASES BONE RESORPTION MARKER IN POSTMENOPAUSAL WOMEN WITH HYPERCHOLESTEROLEMIA Shibata M, Oooka H, Hayashi T, Tanaka H, Sakamoto Y, Mokuda O, Okazaki R; Teikyo University, Ichihara, Japan HMG-CoA reductase inhibitors (Statins), antihypercholesterolemic agents, have been shown to inhibit bone resorption in vitro and enhance bone formation in vivo when locally injected into rat calvaria. These results suggest that statins have beneficial effects on bone when an appropriate concentration is achieved in bone. Indeed, cross-sectional studies have indicated that statin users have higher bone mineral density (BMD) and lower fracture risk. However, it remains unclear how statins affect bone metabolism, when orally administered into humans. A few short-term prospective studies have given contradictory results. Among statins, cerivastatin distributes to bone most efficiently in animal studies. Thus, we studied its effects on bone turnover markers in postmenopausal Japanese women. Cerivastatin (0.15 mg/day) was given to 15 postmenopausal women (age: 57.8 ± 2.2; mean ± SEM) with hypercholesterolemia (serum total cholesterol level: 260.3 ± 7.2 mg/dl) who had never taken statins or medications that affect bone metabolism. Blood and urine samples were collected in the morning after over-night fasting at baseline, 1, 3 and 6 months after treatment.

Abstracts At 1 month, serum total cholesterol level exhibited a significant decrease of 21.9 ± 3.0% from the baseline, which remained unchanged thereafter. Urinary type I collagen N-telopeptide level tended to decrease after 3 months, but did not reach significance until 6 months, when a decrease of 11.4 ± 7.2% (p50.04) was observed. Serum bone-specific alkaline phosphatase level did not change during the 6 months period. There was no change in the lumber spine or hip BMD. These findings indicate that cerivastatin, even at a low dose efficacious for treating mild hypercholesterolemia, may inhibit bone resorption in postmenopausal women. However, its effects on bone appear to be delayed compared to its effects on lipid. Our results suggest that low-dose cerivastatin has long-term benefits on bone in postmenopausal women.

P175SU. CAN SYSTEMATIC DAILY SUPPLEMENTATION OF 1 G ELEMENTAL CALCIUM AND 880 IU VITAMIN D IN ANY AMBULATORY POSTMENOPAUSAL WOMEN BE SAFELY ADMINISTERED? Devogelaer JP, Depresseux G; Rheumatology Unit, St-Luc University Hospital, B-1200 Brussels, Belgium Calcium and vitamin D deficiencies are relatively common and may be detrimental for bone. Systematic vitamin D and calcium supplementations are therefore recommended. However, blind supplementation could be toxic. We have, therefore, administered elemental calcium (1 g) and vitamin D (880 IU) daily for 2 months to 30 ambulatory postmenopausal women with lumbar spine osteopenia [Tscore = – 1.5 (1.2)], aged 67.7 (6.4 SD), whose 25OHD level was lower than 30 ng/ml. Following therapy, 25OHD increased from 14.7 (7.0) to 29.2 (7.0) ng/ml, 50% of patients reaching levels higher than 30 ng/ml. Serum calcium and creatinine clearance did not change significantly. iPTH decreased significantly from 34.1 (14.8) to 25.5 (8.7) pg/ml (p 5 0.01). 24-H urinary calcium excretion increased from 173 (83) to 223 (93) mg and from 2.7 (1.2) to 3.5 (1.6) mg/kg, respectively (p 5 0.01). 24-H urinary N-telopeptide (NTx)/creatinine and NTx/whole body BMC decreased non significantly. 13.3% of patients increased their total serum calcium and 24-H urinary calcium/body weight over 10.4 mg/dl (up to 10.9 mg/dl) and 5 mg/kg (up to 6.6 mg/kg), respectively, and 20% developed 24-H urinary calcium excretion superior to 300 mg (up to 444 mg). If we divided the patients in tertiles, according to the initial serum levels of 25OHD (3.7–10.0, 10.1– 17.5, 17.6–30.0 ng/ml), significant decreases in iPTH were confined to the lower tertiles, and significant increases in 24-H urinary calcium restricted to the higher tertiles. In conclusion, calcium and vitamin D supplementations in elderly patients are able to induce a significant decrease in serum iPTH and a non-significant decrease in urinary NTx excretion, potentially favorable for bone strength. However, 24-H urinary calcium excretion should ideally be checked after 2 months in order to detect frank hypercalciuria which can occur in up to 20% of patients. This could be of clinical significance in a minority of patients, particularly in those in which the positive metabolic effect on bone expected from vitamin D supplementation will be poor.

P176MO. DECREASED PHYSICAL ACTIVITY INDUCE DECREASED BONE FORMATION AND INCREASED BONE RESORPTION Karlsson KM1, Karlsson C1, Ljunghall S2, Obrant KJ1; 1 Department of Orthopaedics, University Hospital MAS, SE 205 02 Malmo, Sweden, 2Department of Medicine, Uppsala, Sweden Aims: Evaluate relationship between bone formation, resorption and bone mineral density (BMD) in male soccer players and controls. Follow bone turnover with changed activity level.

Abstracts

S57

Methods: Bone formation was assessed by serum osteocalcin (OC) and carboxy-terminal propeptide of type I collagen (PICP). Bone resorption by carboxyterminal cross-linked telopeptide of type I collagen (ICTP). BMD (g/cm2) total body, lumbar spine, hip by Dual X-ray Absorptiometry (DXA). 12 male soccer players aged 23, exercising 12 hours/week during season and 3 hours/week during off-season were measured at the end of one season, followed weekly through four weeks rest into renewal of full activity in the new season. Twenty-seven age- and gender matched volunteers served as controls for the biochemical and 24 for the BMD measurements. Data is presented as mean (SEM). Results: Male soccer players had 22 (12) % higher OC (p50.05), 13 (9) % higher PICP (NS) and 34 (17) % higher ICTP (p50.05) compared to controls at the end of the season. Soccer players had higher BMD than controls; 7 (1) % total body BMD, 15 (3) % lumbar spine BMD, 14 (2) % femoral neck BMD (all p5 0.001). PICP decreased by 21 (7) % (p50.05) and ICTP increased by 8 (10) % (p5 0.05) with 2–4 weeks rest. Bone PICP increased by 23 (5) % (p5 0.01) and ICTP decreased by 4 (4) % (p50.05) after 10 days recommencing of seasonal activity compared to the end of resting period. Conclusions: Decreased activity level may be followed by increased BMD loss compared to controls due to increased bone resorption and decreased bone formation.

P178SU. DEVELOPMENT OF A SENSITIVE, AUTOMATED, NONEXTRACTED, DIRECT LIAISON* ASSAY FOR 25 OH VITAMIN D Ersfeld DL, Sackrison JL, Miller AB, Olson GT, MacFarlane GD; DiaSorin, Inc., Stillwater, MN, USA The measurement of 25 OH Vitamin D is becoming increasingly important in the management of calcium disorders associated with rickets, neonatal hypocalcemia, nutritional and renal osteodystrophy, hypoparathyroidism, and post-menopausal osteoporosis. We have developed an automated direct Liaison1 assay for the measurement of 25 OH Vitamin D in plasma or serum which does not require pre-extraction of the sample. Serum or plasma (20 mL) is incubated with polyclonal anti-Vitamin D coated microparticles and ABEI-conjugated Vitamin D. After a 30 minute 378 incubation, the particles are washed and counted. Performance characteristics of the assay are determined from standard protocols. Sensitivity is determined as 1.5 nanogram/ milliliter. Intra- and inter-assay precision average 5 8%. The assay range is from 0 to 200 nanogram/milliliter. Crossreactivities for other hydroxylated Vitamin D metabolites are 5 0.1%. Cross-reactivity to D2 and D3 forms of Vitamin D is 100%. Method correlation by linear regression to the DiaSorin 25 OH Vitamin D RIA results in a slope of 0.9 and an r = 0.97. Similar analysis vs. HPLC results in a slope of 0.9 and r = 0.87. Matched plasma and serum samples results in equivalent values. The time to first result is 40 minutes, with a throughput of 4 90 samples per hour. We conclude that the DiaSorin 25 OH Vitamin D assay presented offers a simple and direct assay for the determination of Vitamin D sufficiency in a minimal amount of time.

P177SA. COMPARATIVE STUDY OF THE SENSITIVITY OF BIOCHEMICAL MARKERS OF BONE FORMATION IN PATIENTS WITH OSTEOPENIA OR OSTEOPOROSIS C. Toth I3, Dumon JC1, DiRomana S3, Kheddoumi N1, Cheblal H2, Body JJ1,3,4; 1Laboratory of Endocrinology and Bone Diseases, 2 Laboratory of Clinical Chemistry, 3Supportive Care Clinic, 4Inst. J. Bordet, Univ. Libre de Bruxelles, Brussels, Belgium We have measured in 162 postmenopausal women (median age 57 years, range 40-82) total Alk Phos, its bone isoenzyme (BAP, Hybritech) and intact osteocalcin (BGP, Biosource). Of these 162 patients, 89 were osteopenic and 73 osteoporotic. None of them took HRT nor was treated for osteoporosis. There was a significant correlation between BAP and BGP levels in osteopenic (rs = 0.36; P = 0.002) and in osteoporotic women (rs = 0.31; P = 0.01). Normal values were determined in 109 healthy premenopausal (PreMP). The means ± SEM values are tabulated below. Parameter

PreMP

Osteopenia

Osteoporosis

Alk Phos, mU/ml BAP, mg/l BGP, ng/ml

61 ± 2 6.7 ± 0.4 8.3 ± 0.4

79 ± 3 10.5 ± 0.5 12.6 ± 0.8

81 ± 3 12.4 ± 0.6 16.4 ± 1.3

Values were significantly (P50.0001) different in the three groups for all markers, but only BAP and BGP levels were higher in osteoporotic than in osteopenic women (P50.01). The upper limit of normal ( = 97.5th percentile in PreMP women) was 104 mU/ml for Alk Phos, 14 mg/l for BAP, and 15 ng/ml for BGP. In osteopenic women, Alk Phos levels were elevated in 23% of the cases, BAP in 21% and BGP in 34% (NS). In osteoporotic women, Alk Phos levels were elevated in 17%, BAP in 34% and BGP in 47% (P50.001). Along the same line, in osteopenic women, T scores were not significantly different, but in osteoporotic women, T scores were higher for BGP (2.4 ± 0.4) than for BAP (1.7 ± 0.2) and Alk Phos (1.0 ± 0.2). In summary, we have shown in osteoporotic patients that BGP was more sensitive than BAP and Alk Phos, whether in terms of percentages of increased values or T scores.

P179MO. DEVELOPMENT OF A SENSITIVE AUTOMATED LIAISON1 ASSAY FOR PARATHYROID HORMONE Fenske JS, Sackrison JL, Van Patten CM, Olson GT, Twumasi DY, MacFarlane GD; DiaSorin, Inc., Stillwater, MN, USA The accurate diagnosis of primary hyperthyroidism (PHPT) has been facilitated by recent development of increasingly sensitive and specific assays for PTH. We have developed an automated Liaison1 assay for the measurement of human Parathyroid Hormone (PTH) in plasma or serum. Serum or plasma (200 mL) is incubated with ABEI conjugated anti-PTH Antibody (N-terminal) and anti-PTH antibody (C-terminal) coated microparticles. After a 30 minute 378 incubation, the particles are washed and counted. Performance characteristics of the assay are determined from standard protocols. Sensitivity is determined as 1 picogram/ milliliter. Intra- and inter-assay precision average 5 8% and 5 10% respectively. The assay range is from 0 to 2000 picogram/ milliliter. Hook effects are not observed below 0.5 microgram/ milliliter. Cross-reactivities for C-terminal fragments is less than 0.1% when assayed at 200,000 picograms/milliliter. Dilution linearity, assessed by regression of Expected vs. Observed values, result in a linear equation with slope = 0.9 and r = 0.99. Recovery is determined to be 100 ± 28% for all dilutions. Calibrators are stable through four freeze/thaw cycles. Method correlation by linear regression to the DiaSorin PTH SP IRMA results in a slope of 1.2 and an r = 1.00. Matched plasma and serum samples resulted in equivalent values. The time to first result is 35 minutes, with a throughput of 180 samples per hour. We conclude that the PTH assay presented offers significant diagnostic sensitivity in a minimal amount of time. In conjunction with calcium levels this quantitation should distinguish between hyperparathyroidism, hypoparathyroidism or hypercalcemia of malignancy.

S58 P180SA. BONE TURNOVER MARKERS CAN BE USED FOR MONITORING SODIUM FLUORIDE TREATMENT EFFICACY IN POSTMENOPAUSAL WOMEN WITH GLUCOCORTICOIDINDUCED OSTEOPOROSIS (GIO) Dreval AV1, Martchenkova LA1, Poliakova EU1, Ernakova IP2, Milov NM1, Buzulina VP2; 1Moscow Regional Research Clinical Institute, Moscow, Russia, 2Research Institute of Transplantology and Artificial Organs, Moscow, Russia The aim of this study was to investigate usefulness of bone turnover biochemical markers for assessment of response to sodium fluoride treatment in postmenopausal women with GIO.20 postmenopausal women with GIO received 80 mg/day of sodium fluoride for 6 months. Control group consisted of 10 postmenopausal women with GIO did not receive any treatment. BMD was measured by DEXA at baseline and after 6 months. Serum osteocalcin (OC), total alkaline phosphatase (AP), C-terminal telopeptide of type I collagen, parathyroid hormone, calcium and inorganic phosphorus (iP), and renal tubular maximum reabsorption of phosphate relative to glomerular filtration rate (TmP/GFR) were measured at baseline and after 4 months. In treated patients we found an increase in OC from 27.3±15 (M±s) to 47.1±37 ng/ml (p = 0.04 vs baseline and p = 0.03 vs controls) and AP from 134±24 to 170±71 IU/l (p = 0.007 vs controls), and a decrease in TmP/GFR from 1.19±0.28 to 0.86±0.24 (p = 0.006 vs baseline) and iP from 1.18±0.16 to 1.02±0.23 mmol/l (p = 0.02 vs baseline). No significant mean BMD changes were found both in treated and control groups at all skeletal sites, but spinal BMD increased in 70% of treated women vs 30% of controls. In responders to sodium fluoride treatment by spinal BMD (n = 14) there were an increase in OC from 27.9±17 to 57.9±47 ng/ml (p = 0.04 vs baseline) and AP from 123±43 to 172±67 IU/l (p = 0.03 vs baseline), and a decrease in TmP/GFR from 1.14±0.31 to 0.74±0.18 mmol/l (p = 0.0009 vs baseline, p = 0.001 vs non-responders) and iP from 1.16±0.20 to 0.97±0.21 mmol/l (p = 0.04 vs baseline). There were no significant changes in biochemical picture in non-responders. These results demonstrate that sodium fluoride increases bone formation, and influences phosphate metabolism by means of suppress the TmP. OC, AP and iP are sensitive biochemical markers for monitoring sodium fluoride efficacy in postmenopausal women with GIO.

P181SU. BIOCHEMICAL AND DENSITOMETRIC EVALUATION OF POST-MENOPAUSIC OSTEOPOROTIC PATIENTS SUBMITTED TO ANTI-REABSORPTIVE TREATMENT DURING ONE YEAR Rodrigues A, Ferreira P, Lourenc¸o P, Garrett V, Moura E; Bone Metabolism Department, Medical School – University of Coimbra, Portugal Introduction: Osteoporosis is an important public health problem, especially among post-menopausic females due to its morbidity and mortality. Therapy has to be maintained over a prolonged period of time and its result can be verified only by radiologic densitometry after one or two years. Biochemical markers permit the evaluation of bone metabolism and may therefore be useful in early monitoring of treatment in order to adjust doses and to promote compliance. Methods: One hundred and twenty-one post-menopausic women referred from their GP, were randomly assigned to one of three therapeutic groups: 1 – calcium and vitamin D; 2 – calcium and calcitonin; 3 – calcium and alendronate. Levels of bone alkaline phosphatase (BAP), osteocalcin (OC), deoxypyridinoline (Dpd) and cross-linked N-telopeptide (NTx) were determined at baseline and after three, six and twelve months of treatment. One year after starting therapy, the lumbar spine, proximal femur and distal forearm were evaluated by DEXA (Hologic QDR 4500 E´lite).

Abstracts Results: The patients treated with alendronate had a significant increase of bone mineral density (BMD) in the lumbar spine. After three months there was a statistically significant decrease of BAP and NTx levels in the group treated with alendronate. In this group there was also a statistically significant decrease in the level of all markers determined after twelve months. Conclusions: The group treated with alendronate was the only one to show significant increase on BMD after one year of treatment. In this very group the determination of BAP and NTx levels after three months showed a biochemical profile consistent with a response to anti-reabsorptive treatment.

P182MO. INFLUENCE OF POWDER HYDROXYLAPATITE CERAMICS ON REPARATIVE REGENERATION OF BONE TISSUE IN RATS IN EXPERIMENT Luzin VI, Golovchenko VV; State Medical University, Lugansk, Ukraine Aims: Study of influence of hydroxylapatite of ceramics as powder with the size of particles less 63 microns on reparative regeneration of bone at plastics of bone defects. Materials: Investigations were made on 60 white rats with primary mass 130–150 gr. Animals of first group were formed defects in proximal metaphysis of tibial bones, in the second group defect was filled by hydroxylapatite (HAP) ceramics as a powder with size of particles less 63 microns. On sections, painted by hematoxylin-eosine, were carried out morphometric analysis of biodegradation of particles of hydroxylapatite, and also counted an index of osteointegration. Results: It was established that formation of bone tissue around implants take place from peripheria to centre. Particles of ceramics in soft tissues, even in the near with periosteum, didn’t influence on ectopic osteogenesis. Biodegradation of hydroxylapatite took place most intensively during first 2 months. Then the speed of a biodestruction mostly reduced, and in 6 months in zone of implantation remained only 12,50, 8% of ceramics. During investigation were proved osteoconductive properties of a HAP material. So index of osteointegration on 15th day observation was 0,150,001 s.u., on 30 – 0,540,013 s.u., on 60 – 0,750,007 s.u., on 90 – 0,840,008 s.u., and on 180 days – 0,910,006 s.u. Conclusions: Powder hydroxylapatite ceramics with size of particles less 63 microns has expressive osteoconductive qualities and improves optimization reparative osteogenesis at implantation in bone defect. Formation of bone tissue takes in a centric direction. The particles of HAP-ceramics in soft tissues, even in the near with periosteum, doesn’t cause formation of bone tissue. Between particles of ceramics and newly formed bone of formation connective tissue capsule does not take place, and is formed bone-ceramic complex with gradual decrease of size of hydroxylapatite particles and formation of bone tissue on its place.

P183SA. HIGH REMODELING TURNOVER IN VENEZUELAN OSTEOPOROTIC PATIENTS Riera-Espinoza G, Cordero Y, Ramos J, Marcano L; UNILIME, Universidad de Carabobo, Hospital Universitario Dr. Angel Larralde, Valencia, Venezuela Bone mass is the result of a lifelong balance between bone formation and resorption, and in fact, most metabolic bone diseases including osteoporosis, are consequent to an unbalanced bone turnover. Osteoporotic syndromes are characterized by wide spectrum of bone turnover, ranging from accelerate to

Abstracts reduced remodeling rates. Higher rates of bone remodeling are in general associated to higher rate of bone loss and predict fractures. Biochemical Markers of Bone turnover were measured in 283 women. N-telopeptide: NTx, Osteomark, Ostex, Seattle, USA, Tartrate Resistant Acid Phosphatase: Hydrolysis of paranitrophenyl phosphate at 4.8 pH, Alkaline Phosphatase: Labtest. Roy Modified. Mean age was 57,93 ± 9.6 (30–85). BMD (T-score) at lumbar spine L2-L4 was –2,36 and –1,6 at femoral neck. Previous fractures were present in 4,5%. Family history of osteoporosis was present in 8%, hypertension in 27.6% diabetes in 7.8%. Surgical menopause in 36.4% and HRT was taken by 35%. Mean values of bone markers were NTx 113.5 ± 69 nMolBCE/ mMolCreat, Tartrate Resistant Acid Phosphatase 9.79 ± 3.2 and Alkaline Phosphatase 47.7 ± 21. (Control premenopausal values in our lab are: NTx 40 ± 15 nMolBCE/mMolCreat, TRAP 8.37 ± 2.2 UI/l and AP 35 ± 8.6 UI/l). Cut-off point for 2 and 3 SD above control mean were for NTX 70 and 85, for TRAP 12.77 and 14.9, and for AP 52.2 and 60.8. 62.2% or 55.8% of patient were classified as High Turnover, if the cut-off point is set at 2 or 3 SD above premenopausal mean of NTx. With TRAP values were 16.9% and 7.4% and with AP we found 31.8% and 18.0% Conclusion: High Turnover osteoporosis (2 SD above the control mean) was present in 62.2% of our Venezuelan osteoporotic patients and 86.5% had resorption over the premenopausal mean according to N-telopeptide determination (NTx), this marker was able to identify more patients with high remodeling state than TRAP or Alkaline Phosphatase.

S59 P185MO. BONE METABOLISM (MARKERS) AND HIGH DOSE CORTICOSTEROID PULSE TREATMENT Branda˜o F, Vaz C, Bernardes M, Bernardo A, Valente P, Mariz E, Maia C, Ramos J, Lopes Vaz A; S. Joa˜o Hospital, Porto, Portugal Objective: To examine the effect of high dose corticosteroid pulse treatment on the markers of bone metabolism in patients with chronic rheumatic diseases. Patients and Methods: Twenty patients were submitted to high dose corticosteroid pulse treatment. The markers of bone remodeling were evaluated before the corticosteroid and one, three and fifteen days after the treatment. We have also evaluated calcium, vitamine D and PTH. The disease activity was measured by C reactive protein. Results: Osteocalcin and bone alkaline phosphatase decreased in three cases on the first and third days after the pulse, but returned to normal by the fifteenth day. The markers of bone resorption presented heterogeneous variations, in relation to normal limits, but in the majority they returned back to baseline by the fifteenth day. In all patients C reactive protein decreased by the fifteenth day. Conclusions: The disease activity improved in all patients who had the treatment.The variation in bone markers was very mild, notably by the first and third days, returning to baseline by the fifteenth day. In conclusion, we can suggest that the effect of high dose corticosteroid pulse treatment may not be significant on bone metabolism markers.

P186SA. BONE REMODELLING IN OSTEOARTHROSIC SUBJECTS UNDERGOING A PHYSICAL EXERCISE PROGRAM P184SU. THE QUEST STUDY: BONE QUALITY AND FRACTURE REDUCTION Chesnut C1, Shields A1, Kriegman A2, Mindeholm L3; 1University of Washington, Seattle, WA, USA, 2Novartis Pharma, East Hanover, NJ, USA, 3Novartis Pharma, Basel, Switzerland. Salmon calcitonin nasal spray (SCNS) may have an effect on bone quality (i.e., trabecular microarchitecture and strength) that is independent of, or potentially in combination with, modest effects on BMD and bone resorption and this may further explain the significant fracture reduction demonstrated with SCNS (in the PROOF study). The Qaalitative Effects of Salmon-Calcitonin Therapy (QUEST) study was initiated to evaluate the effects of SCNS 200 IU daily on bone quality, bone quantity and bone turnover, and also to more fully delineate the actions of SCNS in reducing fracture. Ninety one postmenopausal women (mean age 67.4 ± 8.05, at least five years past last menses) were evaluated in a 2 year double-blind calcium-controlled study. Bone quantity (BQUANT) was measured at spine, hip and wrist by DXA and at os calcis by DXA and ultrasound. Bone quality (BQUALT) was also measured by iliac crest bone biopsy (histomorphometry and microCT [mCT]). Bone quality was also measured with high-resolution non-invasive magnetic resonance imaging techniques in terms of trabecular microarchitecture, at os calcis, radius, and hip. Bone remodelling was measured using biochemical markers of bone formation and resorption. Baseline analyses of the data have shown that whilst ultrasound analysis at the calcaneus provides little additional information over DXA with respect to measuring BQUAL, trabecular microarchitecture can be assessed using non-invasive MRI at the radius (as compared to bone biopsy with mCT). For the first time, results will be shown during the scientific programme on the assessment of the interrelationships of the parameters BQUAL, BQUANT and bone turnover. These will provide further elucidation of the hypothesized effects of SCNS on bone quality to explain the observed fracture reduction in PROOF.

Bellometti S1,3, Richelmi P2, Gregotti C3, Berte` F3; 1P.d’Abano Research Centre, Abano T. (PD) Italy, 2Insubria University, Varese, italy, 3Pavia University, Pavia, Italy Aim: To evaluate the general response of bone cells and connective tissue to physical exercise and thermal treatment examining specific biomarkers of bone metabolism in osteoarthrosic patients. Methods: 40 OA patients were randomised in group A and B. Both the groups underwent a 4 months physical activity program. Group A patients underwent a cycle of mud pack treatment during the 3rd month.Blood samples were collected before and after the treatments to assay BGP, ALP, BSAP, PTH, hydroxyproline. Results: All the results are shown in table 1. Conclusions: in this study it is evident an increase of bone formation markers as a reduction of bone resorption parametrs, above all in group A. It is possible that a combination of physical activity and mud pack therapy (MPT is able to emphasize each other). Moreover it is well known that MPT provokes a decrease in PGE 2 serum levels (a potent agonist increasing number and activity of osteoclasts). In conclusion physical activity is important to mainatain skeletal and bone health. Yet, in those subjects with important functional limitations and joint pain, often taking NSAIDs, would be useful combine physical activity and MPT, because its influence on pain and on the main proinflammatory cytokines. This could ensure less NSAIDs consumption and a direct beneficial influence on bone metabolism. group A before BGP (ng/mL) ALP(mU/ml) BSAP(U/L) PTH(pg/mL) Hydroxypt.(mg/L)

group B after

p-value

6.01 16.29 50.01 117.73 126.93 p50.05 51.5 59.27 p40.05 42.21 27.63 p50.01 2.57 2.19 p40.05

before

after

p-value

8.12 9.79 p40.05 124.13 126.67 p40.05 61.60 53.80 p40.05 27.16 28.78 p40.05 2.58 2.84 p40.05

Serum levels of BGP, ALP, BSAP, PTH, hydroxyproline before and after the treatments, in group A and in Group B

S60 P187SU. BIOCHEMICAL MARKERS OF BONE TURNOVER AND BONE LOSS AMONG MEN AND WOMEN IN A RURAL COMMUNITY IN JAPAN, 1993–2000 : THE TAIJI STUDY Yoshimura N1, Nakatsuka K2, Nishizawa Y2, Sakata K1, Hashimoto T1, Cooper C3; 1Department of Public Health, Wakayama Medical University School of Medicine, Japan, 2Department of Metabolism, Endocrinology & Molecular Medicine, Osaka City University Graduate School of Medicine, Japan, 3MRC Environmental Epidemiology Unit, Southampton General Hospital, UK This study aimed to ascertain whether biochemical markers of bone turnover predict bone loss. The survey was carried out in the town of Taiji, Wakayama Prefecture, Japan. From a list of inhabitants aged 40 to 79 years, 400 participants-50 men and 50 women in each of four age groups-were selected randomly. At the initial survey in 1993 and the follow up study in 2000, bone mineral density (BMD) was measured, and blood and urine samples of all participants were examined to obtain values for following biochemical markers: Bone alkaline phosphatase (BAP), amino-terminal propeptide of type I procollagen (PINP), serum type I collagen cross-linked N-telopeptide(NTx), and urinary excretion of pyridinoline (Pyr), and deoxypyridinoline (DPD). Each marker was assessed the association with the rate of bone change in lumbar spine and femoral neck BMD over a seven-year period. The values of BAP, PINP, NTx, Pyr and DPD of the initial survey were significantly related to the change of BMD at femoral neck in men (p50.05) after adjustment of age. Those of BAP,NTx, Pyr and DPD were found to be significant associated with the change of spine BMD in women (p50.05) after adjustment for the change of menstrual status. Also, serum levels of BAP and PINP were significantly correlated with bone loss at the femoral neck. However, the coefficient of determination at the femoral neck was between 8% and 10% in men. That of lumbar spine was less than 7%, at the femoral neck only 8% in women. We therefore conclude that these bone metabolic markers measured only once might not be sufficiently helpful to predict the change of BMD in middle-aged or elderly Japanese men and women over a seven-year period. Second measurement and the change of biochemical marker levels should be considered in a clinical diagnosis.

P188SA. SITE- AND SEX-SPECIFIC FAMILIAL EFFECT IN THE DETERMINATION OF BONE MINERAL DENSITY IN OSTEOPOROTIC MEN AND THEIR RELATIVES Van Pottelbergh I, Goemaere S, Toye K, Daems M, Kaufman JM; Unit for Osteoporosis and Metabolic Bone Diseases, Ghent University Hospital, Belgium The pathophysiology of idiopathic osteoporosis (IO) in men remains poorly understood. To address the question whether familial/genetic factors contribute in male IO, we evaluated bone mineral density (BMD) of 62 male IO probands, 197 relatives and 173 age-matched controls. BMD (DXA;QDR2000,HologicInc) was measured at the lumbar spine (LS), the hip and at the distal forearm; vertebral volumetric BMD (vBMD) was calculated by standard formulae. In men with IO mean BMD-values were 0.742 ± 0.075 g/cm2, 0.803 ± 0.114 g/cm2 and 0.568 ± 0.058 g/cm2 at the LS, the hip and at the forearm, respectively. In the group of 62 probands, BMD-values were significantly lower as compared to their agematched controls at all sites (P50.001). In the latter group LS BMD was more affected as compared to hip and forearm BMD (P50.001); however, BMD at the hip was also substantially reduced (P50.001 as compared to forearm BMD). Moreover, for

Abstracts all subgroups of relatives, BMD-values at all sites were lower as compared to their age-matched controls with values being significantly reduced at both the LS and the hip, except for the subgroup of daughters. Furthermore, LS vBMD, accounting for bone size, was lower in all subgroups (P50.05, except for the daughters). At all sites, the reduction in BMD seemed more pronounced in male relatives as compared to females.In conclusion, the present study suggests that familial/genetic factors contribute to male IO in a sex-specific way. Furthermore, skeletal sites consisting, at least in part, of trabecular bone appear to be more markedly affected in male IO. Group

N

Probands Sons Brothers Fathers Daughters Sisters Mothers

62 20 29 12 31 32 11

Age (Years) LS

Total Hip Distal Forearm

LS vBMD

78.5*** 86.5*** 88.1** 88.6** 100.0 93.7* 90.1*

75.1*** 81.9*** 84.7*** 89.1* 98.0 93.5* 85.1***

Mean ± SD 48 30 49 63 29 46 60

± ± ± ± ± ± ±

12 5 12 12 7 12 8

72.5*** 80.6*** 85.3*** 89.9* 97.2 92.5** 83.2**

90.5*** 92.9** 97.8 94.6 99.4 96.3 94.4

Table 1. Mean BMD expressed as % of age-matched controls. *P50.05, **P50.01, ***P50.001; according to independent samples T-testing. LS = lumbar spine; vBMD = volumetric BMD

P189SU. POLYMORPHISMS OF THE GROWTH HORMONE GENE ARE ASSOCIATED WITH ADULT BONE MASS AND INFANT GROWTH Dennison EM1, Day I2, Voropanov A2, Syddall H1, Cooper C1; 1 MRC Environmental Epidemiology Unit, Southampton, UK, 2 Wessex Human Genetics Institute, Southampton, UK Recent studies suggest that programming of the GH/IGF-1 axis may explain, in part, the association between intrauterine environment and adult bone mass. We report a study designed to investigate the relationship between infant growth, bone mass and polymorphism in the GH and IGF-1 genes. One hundred ninety six men and 124 women aged 63-73 at baseline who had been born in Hertfordshire and who still lived there were recruited. Their birthweight and weight at one year had been recorded; bone mass at the lumbar spine and femoral neck were measured at baseline and follow-up 4 years later. Whole blood samples were taken and DNA obtained using standard extraction techniques. Two single nucleotide variants in the GH gene (coded GHV001 and GHV002) and 1 variant in the IGF-1 gene were analysed. The distribution frequencies of each allele were as follows, and did not differ by sex; GHV001: 11 31.9%, 12 44.4%, 22 23.8% GHV002: 11 0.2%, 12 9.4%, 22 90.4% IGF-1: 11 85%, 12 13.5%, 22 1.5%. Among men, the GHV001 2 allele was associated with greater bone spine loss rate (p = 0.03) and tended to be associated with lower weight at one year. Similarly, men in the GHV002 22 genotype group were, on average, 20oz lighter at one year than their counterparts in the 11/12 group (p = 0.04). In women, the GHV001 2 allele was significantly associated with lower bone mineral content at all sites, and with lower femoral neck bone density and accelerated femoral bone loss rate. There was no association between bone mass, intrauterine environment and the IGF-1 gene in either sex. We conclude that single nucleotide variants in the GH gene are associated with infant growth and adult bone mass in healthy elderly UK men and women.

Abstracts

S61

P190MO. POLYMORPHISMS IN THE PROMOTOR REGION OF OSTEOPROTEGERIN AND BONE SIALO PROTEIN GENES ARE ASSOCIATED WITH LOW BONE MASS IN POSTMENOPAUSAL WOMEN Qvist P1, Kusk P1, Bagger Y2, Christiansen C2; 1Nordic Bioscience, Herlev, Denmark, 2CCBR, Ballerup, Denmark There is a strong genetic control of bone mineral density (BMD) and this control is polygenic in nature. Recently, novel single nucleotide polymorphisms (SNPs) in osteoprotegerin (OPG) and bone sialo protein (BSP) were reported (PCT/EP00/00319), i.e. OPG-A163G, BSP-A1496G and BSP-G1869A all of which are found in the promotor regions. The present study was initiated to evaluate the association of these SNPs with measurements of bone mineral content (BMC) and density (BMD) in a Danish cohort of postmenopausal women. In 1977, 315 women aged 45-55 living in the Copenhagen region were recruited from a questionnaire survey and a medical screening procedure for a two year follow up study on the prevention of postmenopausal bone loss. In 1979, 1989 and 1995 the women who were alive and living in the area were asked to participate in the follow up. In 1995 a total of 149 women agreed, but 13 were excluded for various reasons. DNA from 133 women were available for the present study of genetic polymorphisms. The wild type (WT) A allele of BSP-A1496G and the non-WT A alleles BSP-G1869A, respectively, were weakly associated with low BMC/BMD at all four visits, but reached statistical significance for forearm measurements only (data not shown). However, the non-WT G allele of OPG-A163G was significantly linked to low BMC/BMD at any skeletal site at all visits as shown in the table. OPG-A163G Polymorphism & Bone Mass TOTAL HIP Year 1977 1979 1989 1995

DIFF.1 (%)

10,6 9,0

ARM

SPINE

T-Test (p value)

DIFF. (%)

T-Test (p value)

DIFF. (%)

T-Test (p value)

0,0003 0,004

6,4 8,2 7,3 7,6

0,020 0,009 0,026 0,039

8,2 7,5

0,013 0,025

1 Difference (in %) in mean of the parameter for WT compared to non-WT, i.e. (XWT – XNONWT)/XWT.

P191SA. CONGENITAL HIP DYSPLASIA AND DISTURBANCES OF BONE AND CONNECTIVE TISSUE IN ADULT FEMALE PATIENTS Bonelli CM1, Walter D1, Fahrleitner A1, Piswanger-So¨lkner CJ1, Dobnig H1, Linhart W2, Reitinger T2, Windhager R3, Leb G1, Obermayer-Pietsch BM1; 1Department of Internal Medicine, Div. Endocrinology/Nuclear Medicine, Karl-Franzens University Graz, Austria, 2Department of Pedriatic Surgery, Karl-Franzens University Graz, Austria, 3Department of Orthopaedics, KarlFranzens University, Graz, Austria. Aims: Congenital hip dysplasia (CHD) affects about 5 to 10% of the female European population and is one of the most frequent congenital malformations of the skeleton. It is known that in girls with CHD hernias occur five times more frequently than in healthy girls. Recently, we reported on decreased bone mineral density (BMD) at the hip in adult CHD patients (JBMR 15, 2000). The aim of this study was to investigate BMD, parameters of connective tissue, bone and collagen metabolism and joint laxity in adult female CHD patients. Methods: 150 premenopausal women with a history of conservatively treated CHD were studied by clinical examination regarding connective tissue and joint laxity parameters, past

medical history, DEXA measurements of spine and hips (Hologic 4000 plus) and bone ultrasound measurements at several sites (Sunlight, Lunar) and compared to 249 matched controls. Biochemical characteristics included osteocalcin (OC), crosslaps (CTX), 25(OH)vitamin D, calcium, phosphate, alkaline phosphatase, propeptide of type III procollagen (PIIINP), propeptide of type I procollagen (PICP) and telopeptide of type I collagen (ICTP). Secondary causes of osteoporosis were excluded. Results: Adult CHD patients showed significantly decreased BMD at the hip (neck, ward) as compared to respective values in controls (p = 0.01, p = 0.04, respectively), but lumbar BMD was comparable. Parameters of bone and collagen metabolism were significantly increased in CHD patients (OC p = 0.0001; CTX p = 0.03; PINP p = 0.03) as compared to controls. Furthermore, the incidence of hernias, joint laxity and peripheral bone fractures was significantly increased (p = 0.0009; p = 0.02; p = 0.03, respectively). Discussion: Congenital hip dysplasia is not only an infant’s problem. It seems to be a more general disorder of connective tissue, bone and collagen metabolism during lifetime affecting a large part of the (female) population. Since BMD at the hip differs significantly from the general population, a careful follow-up for the prevention of early bone fractures is suggested in CHD patients.

P192SU. OPTIMIZATION OF PHARMACOLOGICAL TREATMENT OF OSTEOPOROSIS USING GENOME INFORMATION Hosoi T1, Shiraki M2, Horiuchi T1, Baba T3, Kusaba N3, Inoue S4, Orimo H1; 1Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan, 2 Research Institute and Practice for Invokutional Disease, Nagano, Japan, 3R & D laboratory Nipro Corporation, Shiga, Japan, 4Dept. of Geriatric Medicine, Tokyo University, Tokyo, Japan The drugs for osteoporosis are evaluated with the ability to prevent fragile fractures. Bone mineral density (BMD) is the most important measure to estimate fracture risk and the effectiveness of the treatment. However, the fracture prevention efficacy is not correlated completely with the increment of BMD. This phenomenon may reflect the heterogeneous pathophysiology of osteoporosis and also variation of therapy response among individuals. These situations made us to try optimizing the pharmacological treatment of osteoporosis using genome information. In this study, we compared the effects of medical treatments on BMD among the genotypes of bone-metabolism-related genes. Postmenopausal women who gave informed consent to join the study were treated with calcium alone (n = 89), 1a-hydroxy vitamin D 3(n = 114), vitamin K2 (n = 36), or estrogen combined with progesterone (n = 47). BMD of lumbar spine was measured and followed up by dual energy-X ray absoroptiometry (DXA). Polymorphisms of estrogen receptor alpha (ERa), apolipoprotein E (ApoE), vitamin D receptor (VDR) were determined using a newly developed reverse hybridizaion system with fixed DNA probes to detect each genotype. Three DNA fragments including the polymorphic sites of each gene were amplified by PCR using specific biotin-labeled primers at the same time. The PCR products were hybridized with the fixed DNA probe and the reaction was visualized with enzyme reaction to know each genotype. As a result, ERa genotype corresponding to Xba I restriction fragment length polymorphism was correlated with the response to estrogen replacement therapy. In addition, ApoE genotype was associated with the baseline BMD and the BMD change by the treatment with vitamin K2. Our results suggest the usefulness of genome analysis to estimate future bone loss and to optimize the pharmacological treatment of osteoporosis. Similar approach will be valuable to predict the outcome of bisphosphonates or SERM treatment.

S62 P193MO. CHANGES IN BONE QUALITY WITH AGE IN SCA-1 KNOCK-OUT MICE Grynpas MD1,2, Liu D1, Stanford WL1,2, Beamer WG3; 1Samuel Lunenfeld Research Institute, Toronto, 2University of Toronto, Canada, 3Jackson Laboratory, Bar Harbor, Me, USA Sca-1 is a murine antigen expressed on most peripheral lymphocytes, thymocytes as well as osteoblasts from bone marrow. It is involved in the homeostasis between osteoclasts and osteoblasts. Sca-1 null mice (N), which were healthy and had a normal body weight compared to wild type (WT) mice, were produced by gene targeting methods. Groups of female mice ranging in age from 2 to 19 months were analyzed for bone mineral density (BMD) using DEXA and pQCT, bone remodeling using histomorphometry, bone architecture using image analysis. Bone mechanical properties of cortical bone in the femur using 3point bending, and trabecular bone in the vertebrae using compression, were also determined. The BMD was similar in young N and WT mice but lower in old N versus WT mice. As well, the mechanical properties of the femur and vertebrea were similar in the young mice but lower in the old N versus the old WT mice. The pQCT results showed that the cortical bone area and cortical thickness of the old null mice were significantly lower than the WT mice, while in young mice the cortical bone geometry were similar in the N and WT groups. Histomorphometry showed that N mice had lower bone formation than WT mice and that old N mice had much less trabecular bone than the WT mice. We conclude that in the young mice the BMD, the geometrical, structural and material properties of the bone were similar between the WT and the N mice, while there were no changes with age in N mice versus normal aging changes found in the WT mice.

P194SA. HEIGHT IN ELDERLY WOMEN IS INFLUENCED BY VITAMIN D RECEPTOR AND ESTROGEN RECEPTOR GENE POLYMORPHISMS Schuit SCE1,2, Bergink AP1,2, Meurs JBJ2, van der Klift M1,2,3, Fang Y2, Arp P2, van Leeuwen JPTM2, Pols HAP1,2, Uitterlinden AG1,2; 1Department of Epidemiology & Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands, 2Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands, 3Institute for Medical Technology Assessment, Erasmus Medical Center, Rotterdam, The Netherlands Aims: Aspects of frame size have been implicated in risk of diseases, including osteoporotic fractures. To examine the association between polymorphisms in the vitamin D (VDR) and estrogen receptor (ER) genes and adult height we genotyped women aged 55 to 80 from The Rotterdam Study, a prospective population-based cohort study. Methods: At baseline standing height data was obtained and blood samples were drawn. We analysed a random set of 672 women from The Rotterdam Study. Direct haplotypes for three clustered anonymous RFLP’s at the 3’end of the VDR gene (BsmI, ApaI and TaqI) and 2 RFLP’s in intron 1 of the ER gene and (XbaI and PvuII) were determined by PCR. In a subset of 523 subjects the FokI RFLP in exon 2 of the VDR gene was genotyped. The number of TA-repeats in the microsatelite polymorphism 1kb 5’ upstream of exon 1 was determined in a subset of 223 individuals. Results: We observed an allele dose effect for the VDR haplotype on height, whereby extreme genotypes differed 3 cm (ANOVA p = 0.09). A recessive effect was seen for the VDR FokI TT genotype (p = 0.02). We also observed an allele dose effect for the ER haplotype 1 (p = 0.04). The ER gene TA-repeat polymorphism, showed a stronger association to height (p = 0.01); the difference between extreme genotypes was 3 cm. These results remained unchanged and significant after adjustment for age, lumbar spine BMD and prevalent vertebral fractures. Our results suggest that the microsatelite TA-repeat, rather than the ER haplotype, may be either a functional

Abstracts polymorphism or in close linkage to a functional polymorphism within the ER gene. Conclusions: In women, both VDR and ER genotypes were associated with height, independent of the presence of vertebral fractures.

P195SU. TGF-b1 GENE POLYMORPHISM AFFECTS BONE TURNOVER CHANGES AFTER ALENDRONATE WITHDRAWAL IN POSTMENOPAUSAL OSTEOPOROSIS Bertoldo F1, Franchina G1, Fracalossi A1, Zenari S1, D’Agruma L2, Zelante S2, Gasparini P2, Lo Cascio V1; 1Dipartimento di Scienze Biomediche e Chirurgiche Universita` di Verona, Verona, Italy, 2 OCCS S. Giovanni Rotondo, Foggia, Italy The presence of the polymorphic allele 713-8delC(t) of the TGF-b1 gene is supposed to be a determinant of high bone turnover and low bone mass in postmenopausal women. The aim of the study was to assess if the polymorphic allele of TGF-b1 gene could influence the trend of bone turnover after Alendronate withdrawal. We compared bone turnover and BMD changes after withdrawal (10 mg/daily for 1 year) in 21 women with postmenopausal osteoporosis (age 61-SD 4 years) carrying the ‘t’ allele. As controls, we selected 40 women with the TT genotype with a similar bone turnover and a similar bone mass (spine DXA BMD), after one year of treatment. The two groups were not different in age and in menopausal age. NTX, ALP and CaE were dosed at 3, 6, and 12 months after withdrawal and spine BMD was assessed at 0 and 12 months. In the subjects carrying the TT genotype, NTX values increased by 27% at month 3, by 68% at month 6 and by 102% at month 12, the last value being 66.3% of the pretreatment value (NTX 79.4-SD25 molBCE/molCr). In the Tt group, NTX increased by 34% at month 3, by 141% at month 6 and by 159% at month 12, reaching 87.8% of the baseline value (NTX 96.9-SD11 molBCE/molCr). During the follow up period, the mean percent NTX changes were significantly different between the two groups at 6 and 12 months (p = 0.001). The tALP levels raised more gradually than NTX values, reaching a statistically significant difference between the two groups only at month 12 (TT +7.3-SD6.8% vs Tt +11.1-SD7.2%; p = 0.043). After one year of withdrawal, lumbar spine BMD value in the TT group lowered by 0.67-SD 0.9%, while in the Tt group the BMD reduction reached the 1.3-SD1.4% (p = 0.048, TT vs Tt). The presence of the allele(t)of TGF-b1 gene is associated with a faster and more substantial increase in bone turnover after Alendronate withdrawal.

P196MO. LACK OF ASSOCIATION BETWEEN THE PPARGAMMA PRO12ALA POLYMORPHISM, BONE MASS, BONE TURNOVER OR FRACTURE IN ELDERLY WOMEN A˚kesson K1, Gerdhem P1, Johnell O1, Isaksson A2, Obrant K1, Groop L3; 1Department of Orthopedics, Malmo¨, Sweden, 2 Department of Biochemistry, Lund, Sweden, 3Department of Endocrinology, Malmo¨, Sweden The nuclear receptor and transcription factor, peroxisome proliferator-activator receptor-gamma (PPARgamma) is involved in the regulation of adipogenic differentiation and possibly associated with a decreased risk of diabetes type 2, as shown in large population studies. Recent data also suggest that PPARgamma may have a modulatory effect both on osteoclastogenesis and on osteoblast maturation in tissue culture. Aim: To evaluate a hypothesized association between a common variation in the PPARgamma gene (Pro12Ala), bone mass, bone markers and fracture incidence in 75-year old women. Methods: 1044 women, all aged 75, were recruited within the Malmo¨ Prospective Osteoporosis Risk Assessment study (OPRA). The phenotype in this study was bone mass assessed by DXA and genotyping for PPARgamma using standard PCR

Abstracts technique was done in the highest and lowest quartiles according to femoral neck BMD (n = 425). In addition, body composition, calcaneal ultrasound and fracture were assessed. Serum osteocalcin and Crosslaps were determined. Results: The PPARgamma genotype frequencies were Pro/Pro 77%, Pro/Ala 21%, Ala/Ala 2%. No association between BMD measured at any site of the hip, spine, total body or calcaneus was identified, nor with previous fracture. Neither did we find any association between the Pro12Ala polymorphism and variations in lean or fat mass, body weight or height. No association between bone turnover, as measured by osteocalcin and Crosslaps, and PPARgamma was found. Conclusion: In this population-based and well characterized cohort of elderly Swedish women, we found no association between the Pro12Ala polymorphism in the PPARgamma gene and variations in bone mass, bone turnover or a linkage to fracture.

P197SA. VITAMIN D RECEPTOR POLYMORPHISM (FOKI) DETERMINES BONE MASS AND SERUM PARATHYROID HORMONE IN POSTMENOPAUSAL WOMEN Zajı´ckova K, Zˇofkova´ I, Hill M; Institute of Endocrinology, Prague, Czech Republic The role of gene for vitamin D receptor (VDR) has been previously studied in pathogenesis of primary and/or secondary hyperparathyroidism. The objective of the present study was to analyze a relationship between VDR genotypes and serum parathyroid hormone (PTH) in healthy postmenopausal women. We studied 114 women, age 62.5±8.9 years, who underwent measurement of hip and spine bone mineral density (BMD) and were genotyped for VDR FokI, BsmI, ApaI and TaqI polymorphic sites. Intact serum PTH was determined by IRMA (Nichols Institute, USA). After adjustment for years since menopause and ionized calcium ANCOVA showed that serum PTH (within the reference range) differed significantly in the FokI genotypes (p50.03). Women with ff genotype had serum PTH levels significantly higher than women carrying FF genotype (p50.05, the least significant difference test). In addition, BMD at the hip ( adjusted for age and body mass index) was significantly lower in ff genotype than in Ff genotype (p50.05, Tukey’s test). The importance of remaining investigated VDR polymorphisms were not found. To conclude, these data suggest that women with ff genotype are at substantially increased risk of postmenopausal osteoporosis due to a relative hyperparathyroid status.

P198SU. ASSOCIATIONS OF THE VITAMIN D RECEPTOR GENE POLYMORPHISMS WITH BONE DENSITY IN REPRESENTATIVE SAMPLES OF THE JAPANESE FEMALE POPULATION: JPOS COHORT STUDY Morita A1, Iki M1, Dohi Y2, Ikeda Y1, Kagamimori S3, Kagawa Y4, Matsuzaki T5, Yoneshima H6, Marumo F7; 1Kinki Univ School Med, Osaka-Sayama, Japan, 2Nara Med Univ, Kashihara, Japan, 3 Toyama Med Pharm Univ, Toyama, Japan, 4Kagawa Nutr Univ, Tokyo, Japan, 5Inst Comprehens Com Care, Tokyo, Japan, 6 Kasukabe Shuuwa Hosp, Kasukabe, Japan, 7Tokyo Med Dent Univ, Tokyo, Japan Aims: To evaluate the associations previous reported four vitamin D receptor (VDR) gene polymorphisms and bone mineral density (BMD) with consistent results in a large-scale representative study for the Japanese female population. Methods: Fifty women were randomly selected from each 5year age stratified populations (15-79 years) in each of 3 municipalities as a part of Japanese population-based osteoporosis (JPOS) baseline study in 1996. BMD at the lumbar spine, hip and distal forearm were measured using DXA. Genotypes were determined in the VDR gene locus identified by the

S63 restriction endonucleases ApaI, TaqI, and FokI using PCR-RFLP method, and in the Cdx-2 binding site of the promoter region of the VDR gene by an allelic discrimination method with fluorogenic probes. Changes in BMD was determined 3 years after the baseline. Results: After exclusion of women who had medical and menstrual history affecting BMD, 1434 women were analyzed. The ApaI, TaqI and Cdx genotypes weakly associated with baseline BMD at the several skeletal sites in pre- or postmenopausal women. These associations, however, were inconsistent over the different skeletal sites. The decrease in BMD at the lumbar spine of the subjects with genotype tt was significantly greater than that of the subjects with Tt or TT, although such an association was not observed at other skeletal sites. Conclusions: None of the individual VDR gene polymorphisms showed consistent association with BMD at baseline or change in BMD in the present representative study of Japanese female population. The effect of the VDR genotype on bone mass may not be substantial in Japanese women.

P199MO. RELATIONSHIP BETWEEN VITAMIN D RECEPTOR GENE POLYMORPHISM AND BONE MINERAL DENSITY IN POSTMENOPAUSAL KOREAN WOMEN Kim JG, Kwon JH, Kim SH, Choi YM, Moon SY, Lee JY; Seoul National University Hospital, Seoul, Korea Aim: To investigate whether vitamin D receptor (VDR) gene polymorphisms are associated with bone mineral density (BMD) in 276 postmenopausal Korean women. Methods: The BsmI, TaqI, ApaI, and FokI polymorphisms were analyzed by restriction fragment length polymorphism (RFLP) and poly (A) polymorphism by GeneScan and direct DNA sequencing. Serum bone alkaline phosphatase (BAP), CrossLaps (CTX), osteocalcin and vitamin D3 levels were measured by immmunoassay and BMD at the lumbar spine and proximal femur by dual energy X-ray absorptiometry. Results: The distributions of VDR BsmI, ApaI, TaqI, and FokI RFLP were as follows; bb 63.4%, Bb 35.9%, BB 0.7%, aa 55.1%, Aa 40.2%, AA 4.7%, tt 0.7%, Tt 11.2%, TT 88.0%, ff 16.7%, Ff 44.6%, and FF 38.8% respectively (uppercase letters signifying the absence and lowercase letters the presence of the restriction site). When alleles of poly (A) microsatellite were classified into two groups, long (L: A18-22) and short (S: A12-17), based upon the length of the repeat, the prevalence of SS was 3.6%, LS 8.4%, and LL 88.0%. The combined genotype of VDR BsmI, ApaI, TaqI RFLP and poly (A) polymorphisms was associated with BMD at the lumbar spine and proximal femur. The BbAaTtLS genotype had significantly lower BMD at any skeletal site than the bbaaTTLL genotype. The BbAaTtLS genotype was more prevalent in osteoporotic women than in normal BMD women, while bbaaTTLL genotype was more prevalent in normal BMD women than in women with low BMD. No significant association between adjusted BMD at any skeletal site and the FokI genotype was observed. There were no significant differences in the adjusted levels of bone turnover markers and vitamin D3 among genotypes. Conclusion: The VDR BsmI, ApaI, TaqI and poly (A) polymorphisms are genetic factors which may affect BMD at the lumbar spine and proximal femur in Korean women.

P200SA. APOLIPOPROTEIN E GENOTYPES AND BONE MINERAL DENSITY IN POSTMENOPAUSAL WOMEN Zajı´ckova´ K, Zˇofkova´ I, Hill M; Institute of Endocrinology, Prague, Czech Republic Association analysis between apolipoprotein E (Apo E) alleles and bone mineral density (BMD), carried out in different populations, has not brought unambiguous results. The objective of this study

S64 was to examine a relationship between the most common Apo E genotypes (Apo E 3/2, E 3/3 and E 4/3) and BMD at the lumbar spine and at the hip in a cohort of 113 postmenopausal women of Caucasian origin. Apo E genotypes were assessed by PCR amplification followed by digestion with CfoI (an isoschizomer of HhaI). The Apo E genotype frequencies in our population were as follows: 15% for E3/2, 71.7% for E3/3, 1.8% for 4/2, 10.6% for E4/ 3 and 0.89% for E4/4. BMD was measured by dual-energy X-ray absorptiometry (DXA, g/cm2). After adjustment for body mass index and years since menopause, the BMD values differed significantly in the most frequent Apo E genotypes (E2/3, E3/3, E4/3) both at the lumbar spine and at the hip (p50,0002 and p50.03, respectively, ANCOVA). In 4/3 genotype BMD at the lumbar spine reached significantly lower levels as compared to 3/ 3 (p50.05) and to 3/2 (p50.05, the least significant difference test) allele combinations. BMD at the hip was significantly lower in 2/3 than in 3/3 genotype (p50.05, the least significant difference test). In conclusion, these data suggest that BMD at the lumbar spine and at the hip in postmenopausal women are related to different ApoE allele combinations.

P201SU. GENES FOR VITAMIN D RECEPTOR (FOKI) AND ESTROGEN RECEPTOR (XBAI AND PVUII) REGULATE SEX-STEROID PRODUCTION IN POSTMENOPAUSAL WOMEN

Abstracts disturbances and lack of vitamin D. We wondered, if genetic factors like polymorphisms of the vitamin D receptor (VDR) or the collagen I alpha 1 gene (COLIA) may prospectively contribute to osteoporotic fractures in this high-risk setting. Methods: We investigated 1254 elderly Caucasian persons (age range 70+) living in Austrian nursing homes. Bone ultrasound (at the radius, proximal phalanx and calcaneus), neurophysiological parameters (e.g. bio-impedance, muscle strength) and serum parameters (vitamin D, crosslaps, PTH, osteocalcin, routine lab) were measured in all of them. DNA was prepared from peripheral leucocytes and genotyped for the VDR BsmI and FokI and the COLIA Sp1 polymorphisms. Results: The frequency of VDR genotypes as defined by BsmI and FokI was 11.4% for the genotype BB and 7.7% for FF carriers. The frequency for the COLIA genotype ss was lower than 4% in correspondence to the literature and prior studies in Austria. Bone fractures were prospectively collected and compared to past bone fractures. We correlated also parameters of bone metabolism and neuro-muscular influences to genotypes and patients with bone fractures. Conclusions: The increasing age in our population faces us with higher socio-economic burdens in the case of bone fractures and decreased individual quality of life in elderly persons. It is highly important to diagnose patients at high risk for bone fractures in order to start financially feasible and convenient measures of prevention. The analysis of genetic polymorphisms may help to define persons at high risk for disturbed bone metabolism in a complex context of prevention and therapy.

Zˇofkova´ I, Zajı´e`kova´ K, Hill M; Institute of Endocrinology, Prague, Czech Republic The positive action of sexual hormones including androgens on the female skeleton is well known. In addition, the regulating role of vitamin D receptor (VDR) gene and estrogen receptor (ER) gene in the development of bone mass have been demonstrated in a number of studies. The aim of this investigation was to determine the relationship between VDR or ER genes and serum levels of the precursors of sex-steroids – dehydroepiandrosterone sulphate (DHEAS) and androstendione (AD) in postmenopausal women. Circulating hormones and bone mass (DXA) were estimated in 114 women. Genotyping was performed by PCR, using specific primers and restrictases. After adjustment to body mass and years since menopause, higher DHEAS values were found in the Ff genotype than in ff or FF genotypes of FokI polymorphism (p50.001 and p50.05, respectively, ANCOVA). A similar association was documented between ER gene and AD levels, the highest values being found in the xx (XbaI) and pp (PvuII) genotypes as compared to XX or PP (for both polymorphisms p50.05, ANCOVA). The Ff genotype also contributed to the highest bone mass at the hip (p50.01) and at the spine (p50.05, ANCOVA). Women with the Ff genotype had a higher bone density than those with ff (p50.01, ANCOVA). To conclude, the results suggest the modulated functions of VDR gene and ER gene, both of which may control bone metabolism through the sex-steroid synthesis.

P202MO. POLYMORPHISMS OF THE VITAMIN D RECEPTOR AND THE COLLAGEN I ALPHA 1 GENES AS GENETIC RISK FACTORS FOR BONE FRACTURES IN A HIGH RISK POPULATION IN AUSTRIAN NURSING HOMES Obermayer-Pietsch BM, Li W, Fahrleitner A, Piswanger-So¨lkner CJ, Bonelli CM, Leb G, Dobnig H; Dept. Internal Medicine, Div. Endocrinology/Nuclear Medicine, Karl-Franzens University Graz, Austria Aims: Bone fractures are determined by genetic and environmental factors. In elderly people in nursing homes fracture risk may further be increased by disability, neurophysiological

P203SA. BONE DENSITY AND BONE TURNOVER IN HUNTINGTON’S DISEASE Bonelli CM1, Bonelli RM2, Eichinger M1, Suppan K1, Reisecker F2, Leb G1, Obermayer-Pietsch BM1; 1Department of Internal Medicine, Div. Endocrinology/Nuclear Medicine, Karl-Franzens University Graz, Austria, 2Department of Neurology and Psychiatry, Hospital BHB Eggenberg, Graz, Austria Aims: Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disorder due to an increase of CAG repeats in chromosome 4p16.3. It is characterised by movement disorders like chorea or gait disability, psychiatric symptoms (depression or psychosis) and dementia. HD patients have an increased risk for falling and perhaps for bone fractures due to their movement impairment. Methods: 12 HD patients (31-73 years) and 100 controls underwent BMD measurements at the lumbar spine and femoral neck by dual-energy X-ray absorptiometry (DXA, Hologic 4000 plus). Biochemical markers of bone metabolism (osteocalcin (OC), c-terminal linked telopeptides of type I collagen (CTX), 25(OH)-vitamin D), prolactin (PRL) and routine laboratory parameters were assessed. Results: Patients and controls were comparable for anthropometric data and lifestyle factors. Past medical history was evaluated using patient’s neuropsychiatric documentation. HD patients had a significantly decreased BMD at the spine as compared to controls (p = 0.03). Furthermore, OC and CTX were significantly elevated in HD patients (p = 0.0001 and p = 0.02, respectively). PRL levels had no statistical effect on BMD so far. Conclusions: HD patients had a significantly decreased lumbar BMD and significantly increased bone turnover. This is the first time to describe disturbed bone metabolism and BMD in these patients. Possible causes for these findings may be either an influence of molecular changes due to HD on bone metabolism or the effect of neuroleptic medication in these patients. Our findings indicate that investigation of BMD and bone metabolism is relevant in HD patients due to their high risk for falling.

Abstracts P204SU. TOTAL BODY BONE MINERAL DENSITY IN MULTIETHNIC PREMENOPAUSAL WOMEN: A POPULATION BASED STUDY IN SOUTHERN BRAZIL Guimara˜es SVM1, Fuchs SC2, Sisson de Castro JA1; 1 Endocrinology Division, UFRGS, 2Public Health Department, UFRGS, Porto Alegre, Brazil Aims: To verity differences of bone mass according to ethnicity and contributing factors among premenopausal women. Methods: In a cross-sectional study we sampled for evaluation 158 women representative of Porto Alegre, RS, Brazil residents. They completed an interview at home as well as anthropometric and bone densitometric measurements in our University hospital (HCPA). Race was determined by observation of the skin color by trained interviewers and by self-reported number of black ancestors(BA). Total body bone mineral density (TBBMD) and content (TBBMC) were measured by one qualified technician in a Hologic 4500A DXA scan. Results: 105 women who did not have BA were classified as white, 13 women as mixed (1–2 BA) and 40 as black (3–6 BA). White women had TBBMD 1.088 0.091 mg/cm2 and TBBMC 2057.4 286.4 mg. Black women had TBBMD 1.131 0. 095 mg/cm2 and TBBMC 2196.6 324.9 mg. There were significant associations of TBBMD and TBBMC with race (p = 0.013). These associations were independent of age, height, weight, calcium intake, alcohol ingestion and cigarette smoking. The women with 1–2 BA had intermediate values of TBBMD, not significantly different from the other two groups. Height, number of BA and calcium intake explained most of the differences of TBBMD and height and number of BA the differences of TBBMC for the entire group. Conclusions: Self-reported number of BA and height are important contributors to TBBMD and TBBMC and should be taken into account when reference values are established for populations with variable ethnicity and race admixture,such as seen in Brazil.

P205MO. OSTEOPOROSIS IN SYSTEMIC LUPUS ERYTHEMATOSUS – NEW GENETIC FACTORS? Masaryk P, Bosak V, Letkovska A, Lukac J, Rovensky J; Institute of Rheumatic Diseases, Piestany, Slovakia Systemic lupus erythematosus (SLE) is an inflammatory rheumatic multisystemic disease of unknown etiology. The incidence of osteoporosis in SLE is dependent on several factors. Genetic factors play an important role in the development of SLE. The issue of genetic factors in the development of osteoporosis in SLE however has not yet been paid attention to in the world literature! A group of 188 female patients with SLE was analyzed in our study; the average age of our patients was 42.6 (13–78) years, and the duration of the disease was 11.1 (1–31) years, 100 patients were in post-menopausal age. Bone mineral density of the lumbar spine and femoral neck was measured in these patients using HOLOGIC QDR 4500A device. Osteoporosis was defined based on WHO criteria. BMD values and frequencies of osteoporosis were correlated with selected patient’s history data and HLA antigens. Osteoporosis could be found in at least one localisation in 64 (34%) of the patients. Osteoporotic fracture of femoral neck in the mother could be identified in the history of 6 out of 188 women. Compared with the remaining patients, bone mineral density values in these women were as follows: spine, 0.892 vs. 0.912 (p = 0.34); femur, 0.663 vs. 0.739 g/cm2 (p = 0.10). Only negligible differences in bone mineral density could be found upon immunogenetic analysis of a subgroup of 27 patients between carriers of the DR3 and B8 alleles. However, B8+ patients showed femoral neck bone mineral density values of 0.651g/cm2 compared to 0.737 g/cm2 for B8- patients (p = 0.07). Conclusion: The results of this pilot study suggest a possible participation of genetic factors in the development of osteoporo-

S65 sis in also female patients with SLE. However, an immunogenetic analysis of a larger population would be required.

P206SA. GENETIC STUDIES IN HEALTHY AND OSTEOPOROTIC POSTMENOPAUSAL WOMEN FROM THE CITY OF CORDOBA, ARGENTINA Tolosa de Talamoni NG1, Perez AV1, Ulla MR2, Binci ME1, Rivoira MA2, Garcia BA1, Costero BP1; 1Laboratorio de Metabolismo Fosfocalcico ‘Dr. Canas’, Facultad de Ciencias Medicas, UNC, Cordoba, Argentina, 2Centro de Endocrinologia, Osteologia y Metabolismo, Cordoba, Argentina The aim of this study was to investigate if there is an association between vitamin D receptor (VDR) and estrogen receptor (ER) genotypes and bone mineral density (BMD) and between those genotypes with bone markers in healthy (H) and osteoporotic (O) and postmenopausal women from the city of Cordoba, Argentina. Subjects and Methods: One hundred ten postmenopausal women were studied. Half of them were osteoporotic women without medication. BMD from lumbar spine was measured by DEXA (Norland XR 36,QS). Procollagen type I N and C terminals propeptides (PINP, PICP), and osteocalcin were measured in serum by RIA, while deoxypyridinolin was determined in urine by RIA. DNA was isolated from blood and VDR genotypes were determined by using Bsm I as a restriction enzyme and ER genotypes by using PvuII and Xba I as restriction enzymes. Results: The distribution of VDR genotypes in the studied entire population was BB 30%, Bb 50% and bb 20%. There was no association between BMD values and the Bsm I polymorphic site for VDR or the ER genotypes. However, in the O group, those women with bb genotype presented higher BMD values. PINP was the only bone marker that showed significant differences between both groups when women were older than 60 years old (H: 37.63 ul/L ± 4.92 and O: 52.67 ul/L ± 5.97*, *P5 0.05 vs H), being this difference larger with aging. O women with BB genotype (for VDR) or xx or pp (for ER) genotypes presented PINP values much higher than women with other genotypes. Conclusions: There is no association between BMD and VDR and ER genotypes. However, in osteoporotic women the prognosis seems to be worse when they have BB genotype for VDR and xx or pp for ER because they exhibit the lowest BMD and the largest values of PINP.

P207SA. PREDICTION OF VERTEBRAL FRACTURE BY BONE MINERAL DENSITY AMONG JAPANESE MEN AND WOMEN Fujiwara S1, Masunari N1, Kasagi F1, Suzuki G1, Fukunaga M2; 1 Radiation Effects Research Foundation, Hiroshima, Japan, 2 Kawasaki Medical School, Kurashiki, Japan Low bone mineral density (BMD) is one of the most important predictors of a future fracture at any skeletal site. This has been demonstrated in numerous prospective studies in the US and Europe. However, there have been no reports among Japanese. We examined the relationship between BMD and subsequent vertebral fracture (VF) among men and women in a populationbased study (Adult Heath Study (AHS)) in Japan. The AHS recruited a cohort of about 20,000 people in Hiroshima and Nagasaki based on the 1950 Japanese national census; this cohort has received biennial health examinations since 1958. The subjects of the present analysis are 763 men and 1,593 women aged 47 years and older (average age 65 years) who received both spine and femoral neck BMD measurements and spine X-ray examinations at least twice during 1994–2000. An average followup period was four years. After adjusting for age and prevalent VF, the incidence of VF increased 1.5 times for men and 1.8 times for women for every standard deviation (SD) decrease in BMD. The relative risk for VF for a 1SD decrease in BMD decreased with increasing age among women. The relative risk was 1.8 among

S66

Abstracts

women in their forties and 1.2 in their eighties. Using a prospective cohort study, we found that BMD could predict occurrence of future VF in Japanese men and women. The predictive ability of BMD measurements was similar for men and women. An old age BMD could predict VF, but the predictive ability of BMD decreased with age among women.

P208SU. CURRENTLY USED DXA REFERENCE DATA MAY NOT BE APPROPRIATE FOR WESTERN EUROPE: RESULTS FROM THE OPUS STUDY Glueer CC1, Barkmann R1, Eastell R2, Reid DM3, Felsenberg D4, Roux C5; 1University Hospital, Kiel, Germany, 2University of Sheffield, Sheffield, UK, 3University of Aberdeen, Aberdeen, UK, 4 Free University, Berlin, Germany, 5Rene´ Descartes University, Paris, France The use of adequate dual X-ray absorptiometry (DXA) reference data is important for accurate diagnosis of osteoporosis. Most centres in Europe currently use reference data largely sampled in the United States. We investigated whether these DXA reference data are appropriate for use in Europe. In the Osteoporosis & Ultrasound (OPUS) study, we recruited a population-based sample of 2910 women (473 of ages 20–40, 2437 of ages 55 to 80 years) in 5 European cities. All subjects had DXA of the lumbar spine and the proximal femur on Hologic QDR4500 or Lunar Expert devices. Thorough quality assurance and standardisation measures were implemented. Outliers likely due to degenerative changes were excluded. OPUS results (mean ± SD) for spine (SP) or total femur (TF) expressed in standardised units (mg/cm2) were higher by .1 to .6 SD compared to age-matched standardised Lunar (Mazess CTI 1999) or Hologic (Looker OI 1998, Hologic info) reference data (table). For classification based on OPUS reference ranges compared to those from Lunar or Hologic, the percentage of OPUS subjects of ages 55–80 with T-scores below –2.5 differed by –18% to +43%; the fraction of subjects with Z-scores below –1 was higher by up to 179% for postmenopausal women (table). Our results demonstrate that European postmenopausal but not premenopausal women have substantially higher DXA results than expected. Discrepancies in classification up to 179% indicate that current reference data may not appropriate for Western Europe. Reference data

OPUS

Lunar

SP, age 20–40 (mg/cm ) TF, age 20–40 (mg/cm2) SP, age 55–80 (mg/cm2) TF, age 55–80 (mg/cm2)

1163±134 983±129 1025±163 866±136

1145±133 954+129 975±147 819±129

1160±118 950±127 931±118 795±135

Below T= –2.5 SP Below T= –2.5 TF Below T= –2.5 SP or TF

11.8% 7.7% 15.8%

10.0% 5.4% 12.7%

17.4% 5.4% 19.3%

Below Z= –1 SP Below Z= –1 TF Below Z= –1 SP or TF

16.1% 14.8% 23.3%

12.0% 8.9% 16.6%

10.2% 5.3% 13.0%

2

Hologic

P209MO. CHANGES IN BONE MINERAL DENSITY DURING A DECADE IN URBAN AND RURAL WOMEN AGED 40-80 YEARS Ahlborg HG, Gardsell P, Sernbo I, Johnell O, Karlsson KM; Department of Orthopaedics, Malmo University Hospital, Malmo, Sweden This prospective, population-based, cohort study evaluated changes in bone mineral density (BMD, mg/cm2) during a decade in one urban and one rural group of Swedish caucasian women aged 40 to 80 years.

Baseline measurements were undertaken in 1988–89 on 328 urban women and 231 aged-matched rural women. Follow-up measurements were undertaken in 1998–99 and included 178 of the urban women (69%) and 121 of the rural women (75%). Additionally, 21 urban and 33 rural women aged 40 years at follow-up were added in 1998 in order to study any possible cohort effects. BMD in the dominant forearm was measured by single-photon absorptiometry (SPA). Urban women have today lower BMD than rural women (p50.05), a difference that did not exist a decade ago. This discrepancy is probably at least partly derived from a lower peak bone mass in the urban women and is not exclusively due to a higher bone loss, as urban women aged 40 years today had lower BMD than a decade ago (p50.05) and no difference was found in bone loss in comparison between urban and rural women during the study period. The longitudinally evaluated rate of bone loss differed compared with the expected rate of bone loss evaluated by cross-sectional data at baseline. We conclude that the discrepancies in fracture rate, previous found in the comparison between urban and rural women, may in future grow even larger.

P210SA. VERTEBRAL DEFORMITIES IN URBAN CHINESE MEN: THE BEIJING OSTEOARTHRITIS STUDY. Nevitt M1, Bent S1, Lui L1, Zhang Y2, Yu W3, Cummings S1, Xu L3; 1 University of California, San Francisco, USA, 2Boston University, Boston, USA, 3Peking Union Medical College Hospital, Beijing, China Prior studies indicate similarities in the prevalence of deformity between Caucasian women and men. The prevalence vertebral deformity among men in mainland China has not been studied, and it is uncertain if prevalence is similar in Chinese men and women. We conducted a population-based study of the prevalence of deformity in men age 560 in Beijing, and examined the association of deformity with risk factors and outcomes. 588 men (82% of contacted) completed the study. Radiographic methods and definitions of deformity (reductions in samplespecific height ratios 43SD of normal) were identical to those used in our previous studies of older women in Beijing (Xu, et al. JBMR 2000;15: 2019). The prevalence of deformity in men increased with age and was nearly identical to the prevalence in Beijing women (table), with an age standardized prevalence ratio for men vs. women = 0.9, 95% CI 0.8 to 1.2. Vertebral deformity in men was associated with low total hip BMD (age-adjusted OR per –1 SD: 2.0; 95% CI 1.4 to 2.4) and history of nonspine fracture OR 2.0 (1.1, 3.7) in MV models, but not with quadriceps strength, BMI, smoking, alcohol use, or heavy manual labor. Deformity was associated with increased physical disability and back pain. We conclude that the prevalence of vertebral deformity in older Beijing men is no different than in Beijing women, and similar to that reported in studies of Chinese men living in Hong Kong and Taiwan and Caucasian men in Europe. The association of deformity with low hip BMD suggests that osteoporosis is an important contributing factor. Osteoporosis in men is likely to become an increasingly important health problem in China as the population ages Age (n of men)

Beijing Men (95% CI)

Beijing Women (95% CI)

60–69 (363) 70–79 (184) 80+ (41)

9.9% (6.8, 13.0) 16.3% (11.0, 21.6) 24.4% (11.2, 37.5)

10.5% (4.6, 16.3) 15.0% (8.0, 22.0) 31.2% (21.8, 40.6)

Abstracts P211SU. HIP STRUCTURAL ANALYSIS IN WOMEN WITH CERVICAL AND INTERTROCHANTERIC FRACTURES Wehren LE1, Beck TJ2, Oreskovic TL2, Magaziner J1; 1University of Maryland School of Medicine, Baltimore, USA, 2Johns Hopkins University School of Medicine, Baltimore, USA Aims: To describe structural parameters of the proximal femur in women hospitalized for acute hip fracture and to evaluate changes in structure of femoral neck, intertrochanteric region, and femoral shaft during the year after fracture, comparing cervical and intertrochanteric fracture types. Methods: Using DXA scans for 158 women entering two Baltimore, MD hospitals, Hip Structural Analysis of the nonfractured hip was performed at 3–10 days and 2, 6, and 12 months after fracture to calculate cortical bone equivalent surface area (CSA), subperiosteal width (W), section modulus (Z), mean cortical thickness (CT), and buckling ratio (BR) of the femoral neck, intertrochanteric region, and proximal femoral shaft. Results: Femoral neck and shaft structures were similar at baseline; at the intertrochanteric region women with intertrochanteric fractures had lower BMD, smaller CSA, smaller Z, and higher BR. Women with intertrochanteric fractures underwent greater changes toward skeletal fragility at all 3 sites during the first 6 months; changes were greatest at the intertrochanteric region. At baseline, women with cervical fractures had higher total body bone mineral content (TBBMC), but similar lean body mass (LBM). During the year after fracture TBBMC declined in women with intertrochanteric fractures, but was unchanged in women with cervical fractures. LBM declined more in women with intertrochanteric fractures. Conclusions: Important differences in hip structure, apart from BMD, characterized women with cervical and intertrochanteric hip fractures. The intertrochanteric region was significantly more fragile at the time of fracture and fragility increased to the greatest extent at this site during the year after fracture. Decrements occurred at all 3 sites and were greatest at the intertrochanteric region. Structure appears to confer risk of specific fracture type, and adaptations after fracture produce markedly increased fragility, especially at the intertrochanteric site, underscoring the need for prompt interventions targeting bone quality after hip fracture.

P212MO. A CLASSIFICATION TREE FOR PREDICTING RECURRENT FALLS IN COMMUNITY-DWELLING ELDERLY Stel VS1, Pluijm SMF1, Deeg DJH1, Smit JH1,2, Bouter LM1, Lips P1,3; 1EMGO Institute, VU University Medical Center, Amsterdam, The Netherlands, 2Department of Sociology and Social Gerontology, VU University, Amsterdam, The Netherlands, 3 Department of Endocrinology, VU University Medical Center, Amsterdam, The Netherlands Aims: The aim was to develop a risk profile for classifying community-dwelling elderly with respect to their risk of recurrent falling (at least two falls within six months) using tree-structured survival analysis (TSSA). Methods: This prospective study was performed in a sample of 1365 community-dwelling elderly (667 men and 698 women) aged 65 years and older of the Longitudinal Aging Study Amsterdam (LASA). During a visit at home, physical, cognitive, emotional and social aspects of functioning were assessed. After the visit, a prospective fall follow-up of three years was conducted. TSSA was used to develop a classification tree. Results: TSSA identified eleven groups differing in risk of recurrent falls, on the basis of a minimum of two and a maximum of six predictors. The first major split in the tree involved ‘two or more falls’ versus ‘less than two falls’ in the year preceding the interview. Three groups were identified for respondents who reported two or more falls in the year preceding the interview (n = 193). Of these, respondents with at least two functional limitations (n = 98) had 75% risk of becoming a recurrent faller,

S67 while respondents with less than two functional limitations were further divided into a group who reported regular dizziness (n = 11, risk of 68%) and respondents who did not report regular dizziness (n = 84, risk of 30%). The risk of becoming a recurrent faller in the groups with less than two falls in the year preceding the interview varied between 9 to 70%. Conclusions: This classification tree, developed by TSSA, included eleven subgroups differing in the risk of recurrent falling on the basis of specific combinations of a maximum of six easily measurable predictors. Identification of risk groups can be used for preventive measures in public health strategies.

P213SA. RISK FACTORS FOR INCIDENT VERTEBRAL FRACTURES IN MEN AND WOMEN: THE ROTTERDAM STUDY van der Klift M1,2,3, de Laet CEDH1,2, McCloskey EV4, Johnell O5, Kanis JA4, Hofman A3, Pols HAP2,3; 1Institute for Medical Technology Assessment, Erasmus Medical Center, Rotterdam, the Netherlands, 2Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands, 3Department of Epidemiology & Biostatistics, Erasmus Medical Center, Rotterdam, the Netherlands, 4WHO Collaborating Center for Metabolis Bone Diseases, University of Sheffield Medical School, United Kingdom, 5Department of Orthopaedics, Malmo General Hospital, Sweden Aims: To study potential risk factors for incident vertebral fractures in 3001 men and women aged 55 or over. Methods: We used data from the Rotterdam Study, a prospective population-based cohort study. Spinal radiographs were obtained at baseline and again after a mean follow-up of 6.3 years. These follow-up radiographs were scored for vertebral fractures using the McCloskey-Kanis assessment method. Whenever a vertebral fracture was detected the radiograph was compared with the baseline radiograph. If this fracture was not already present at baseline, it was considered incident. At baseline, information on various potential risk factors was obtained. For men and women separately, all potential risk factors were tested univariately, and when significant, tested for independence from age, BMD, and additionally the presence of baseline prevalent vertebral fractures. Finally all risk factors that were still significant, were entered into a multivariate model. Results: Subjects with prevalent vertebral fractures were at increased risk of incident vertebral fractures (OR 2.8 [1.3–5.8] and 4.1 [2.5–6.7], for men and women, respectively). Also, the risk of an incident vertebral fracture doubled per SD decrease in lumbar spine BMD (OR 2.3 [1.6–3.4] and 2.0 [1.6–2.6], for men and women respectively). For women age, early menopause (at or below age 45), current smoking and use of a walking aid were additional independent risk factors. For men, only a five-year history of nonvertebral fractures was a significant independent risk factor besides a low BMD and prevalent vertebral fractures. For current smoking, a similar but non-significant trend was observed as in women. Conclusions: This study shows that for both genders a low BMD and the existence of prevalent vertebral fractures are strong independent risk factors for incident vertebral fractures. Furthermore, also other factors, such as smoking and early menopause are associated with an increased vertebral fracture risk.

P214SU. HIP FRACTURES IN YOUNG PATIENTS – A POPULATION BASED STUDY Lofthus CM1, Osnes EK2, Kristiansen IS2, Meyer HE2, Nordsletten L2, Falch JA1; 1Department of Medicine, Aker University Hospital, Oslo, Norway, 2HIPOS-group, Oslo, Norway Aims: Hip fractures in young patients are rare and the present study was aimed to clarify whether the fractures in this patient group are attributable mainly to high-energy trauma or if there might be other significant risk factors.

S68 Methods: Using electronic diagnosis registers and lists of the operating theatres for the hospitals in Oslo, patients with a new hip fracture during a two years period were identified. All patients aged 550 years at the time of fracture were included (n = 50), and a detailed medical history was recorded. Thirty-three of these patients volunteered to be examined. BMD was measured in all the 33 patients using Lunar DPX-l while SOS and BUA were measured in 20 patients using Lunar Achilles. One sample t-test was applied. Results: Of the study population, 31 patients were men (62%) and 19 women. The median age was 40 years (range 15–49). In 32 patients (64%) the fracture occurred after fall at the same level, 9 (18%) after fall from a higher level, and 9 (18%) in traffic accidents. Ten patients (20%) had a history of alcohol or drug abuse, 19 (38%) neuromuscular diseases, and 6 (12%) endocrine diseases. In the 33 patients examined (22 men and 11 women), the median age was 40 years (range 15–49). The BMD expressed as Z-score for L2-4 was –1.0 ± 0.9 (mean ± SD), femoral neck –1.5 ± 1.0, and total body –1.3 ± 1.1. In the 20 patients examined by ultrasound, Z-score for SOS was –1.9 ± 0.8 and BUA –1.1 ± 1.0. All values were significantly different from zero (p50.001). Conclusions: There is a male predominance in young patients with hip fracture. The majority of the patients had a history of lowenergy trauma and a clinical condition predisposing for falls or decreased bone strength. The bone mass estimated by DXA and ultrasound was significantly lower than expected.

P215MO. MORTALITY ASSOCIATED WITH PRIMARY HYPERPARATHYROIDISM Clifton-Bligh P1,2, Nery L1, Reeve T3, Delbridge L3, Stiel J4, McElduff A2,4, Wilmshurst E4, Robinson B2,5, Fulcher G4, Posen S2; 1Northern Metabolic Bone Centre, Royal North Shore Hospital, St. Leonards NSW Australia, 2Department of Medicine, University of Sydney, Sydney NSW Australia, 3Department of Surgery, Royal North Shore Hospital & University of Sydney, Sydney NSW Australia, 4Department of Endocrinology, Royal North Shore Hospital, St. Leonards NSW Australia, 5Kolling Institute of Medical Research, Royal North Shore Hospital, St. Leonards NSW Australia Aim: To evaluate survival in all patients with primary hyperparathyroidism seen at the Royal North Shore Hospital and Sydney Hospital between 1961 and 1994. Methods: 561 patients were retrospectively studied: 448 had surgery (SX) and 113 did not have surgery and remained hypercalcaemic (NSX). 124 patients died during the 33-year period of observation. The death rate of the hyperparathyroid (HPT) group was compared with that of the state population (CTRL) of the appropriate time period. The HPT and CTRL populations were matched for age, sex, year observation was begun, and duration of observation1. Results: (See table) The death rate of the HPT population was significantly greater than CTRL (p50.00001). The relative risk of death for the SX group, adjusted for age, sex and period of diagnosis, was 0.67 (95% C.I. 0.38–1.18), not significantly different from the NSX group. In the total HPT group, there was no significant difference in the death rate between those with Ca 43.00mmol/L compared with Ca 53.00mmol/L. In the SX group, risk factors significantly associated with death were diabetes (p = 0.001), kidney stones (p = 0.001), CCF (p = 0.02), CAD (p = 0.03), and hypertension (p = 0.044). In the NSX group, death was significantly associated with high PTH (p = 0.001), CAD (p = 0.004) and kidney stones (p = 0.035). Conclusion: This study does not support the concept that surgery for primary hyperparathyroidism confers a survival benefit even though the severity of the disease, as judged by the Ca and PTH, was greater in the SX group. 1 Using Relsurv, a program for relative survival developed by G Hedelin, Laboratory for Epidemiology and Public Health, Faculty of Medicine, University of Strasbourg, France.

Abstracts

Age Serum Ca (mmol/L) Serum PTH (ng/ml)

SX (n = 448)

NSX (n = 113)

p value

52.9±14.7 3.04±0.35 1.34±1.12

55.5±15.9 2.80±0.18 0.90±0.74

NS p50.001 p50.001

P216SA. THE EFFECT OF VITAMIN D LEVELS ON PTH AND BONE MINERAL DENSITY IN HEALTHY POSTMENOPAUSAL WOMEN Barrett-Connor E, Von Muhlen D, Wan L; University of California San Diego Aims: To examine the cross-sectional association between vitamin D and parathyroid hormone (PTH) levels with bone mineral density (BMD) by postmenopausal estrogen therapy (ET) in older women. Methods: 654 healthy community-dwelling women aged 50–97 had hip BMD measured by DEXA and validated medication use. Serum for 25(OH)D was measured by HPLC and intact PTH was measured by chemiluminescence. Results: 414 women were using ET and 240 were not. Estrogen users were younger and had a higher intake of milk and calcium supplement, but did not differ by body mass index, exercise, smoking, or vitamin D supplements. 25(OH)D and BMD levels decreased with age, and PTH levels increased. Age-adjusted BMD levels increased by each successive quintile of 25(OH)D (p = 0.01) in women using or not using ET, but women using ET had better BMD levels at every level of 25(OH)D compared to nonusers. PTH levels were inversely associated with 25OHD levels only in women not using ET (p = 0.01. Mean PTH levels were 60 pg/ml in women whose 25(OH)D levels were in the lowest quintile (531 ng/ml), and significantly lower for each of the other four quintiles. The prevalence of PTH levels 465 pg/ml exceeded 50% in non-ET using women whose 25(OH)D levels were in the lowest quintile, suggesting secondary hyperparathyroidism. The prevalence of PTH levels 465 pg/ml was less than 30% in all other women. These results were independent of all other variables associated with ET. Conclusion: BMD levels were lower in women in the lowest quintile of 25(OH)D, which was also associated with higher PTH levels, but only in women not taking ET. Even in sunny California, vitamin D supplements may prevent secondary hyperparathyroidism and preserved bone in older women not using ET.

P217SU. IS CHOLESTEROL OR BMD A BETTER PREDICTOR OF LATER CARDIOVASCULAR DISEASE IN WOMEN? La´szlo´ B. Tanko´ LBT, Yu Z. Bagger YZB, Henrik B. Hansen HBH, Claus Christiansen CC; Center for Clinical and Basic research Aim: To compare serum cholesterol and bone mineral density as independent predictors of cardiovascular disease in postmenopausal women. Methods: 945 healthy postmenopausal women (mean age 62 years) who participated in previous clinical trials at our center have been revisited during 2001. Follow-up time varied between 6–9 years. Of these women 64 reported documented cardiovascular disease (angina pectoris, AMI, claudicatio intermittens, or stroke). None of the participants has taken any medication known to influence bone mass (HRT, SERM, bisphosphonate) during the follow-up period. BMD in the distal arm, total hip and the lumbar spine (L1–L4) were estimated at baseline using the DEXA technique. Serum samples were analyzed for total serum cholesterol using an automatized colorimetric assay. Results: At baseline, no differences in age, BMI and serum glucose were seen between those found healthy (n = 881) and those reporting documented cardiovascular disease (CVD, n = 64) at the follow-up visit. However, BMD in the lumbar spine

Abstracts

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(0.860±0.02 vs. 0.940±0.004; p50.001), the distal forearm (0.380±0.01 vs. 0.410, p50.05), and the hip (0.820±0.02 vs. 0.850±0.005, p = 0.166) were lower in patients with CVD compared to healthy participants. Serum total cholesterol at baseline showed no differences between CVD patients (6.84±0.16) and healthy participants (6.75±0.04). Conclusion: These results indicate that in postmenopausal women low BMD has a stronger value in predicting the incidence of cardiovascular disease at later age compared to serum cholesterol, which is known to have a strong predictive value in men.

and between first trimester and 1 year postpartum: BMD (0,56 vs 0,52 and 0,56 vs 0,55, p50,001), QUI (99,2 vs 95,1 and 106,3 vs 98,4, p50,0001), BUA (83,3 vs 73,8 and 86,1 vs 74,3, p50,0001), respectively. The chemical biomarkers of bone turnover were statistically increased: osteocalcin (4,3 vs 10,7 p50,0001and 2,5 vs 3,3, p = NS), NTx (51,5 vs 67,8, p50,0001 and 47,6 vs 38,4, p50,05). The mean levels of urine calcium decrease significantly (13,5 vs 6,0, p50,0001 and 14,0 vs 11,7 p = NS). Only between the first trimester and 1 year pospartum were statistically increased for phosphorus (35,4 vs 67,6, p50,0001) and creatinine (88,2 vs 129,1, p50,0001). Conclusions: The decreased of bone mass during pregnancy and lactation is associated with a increased of bone turnover and a significantly decrease of the mean levels of urine calcium.

P218MO. COMPARISON OF POINT PREVALENCE METHODS FOR THE DETECTION OF NEW OSTEOPOROTIC VERTEBRAL DEFORMATIONS Blenk T, Armbrecht G, Felsenberg D; Free University Berlin, Berlin, Germany The aim was to assess the quality of point prevalence methods for the detection of new osteoporotic vertebral deformations. Therefore, the point prevalence methods with the algorithms of Eastell, Melton and McCloskey were compared with a longitudinal method of 20% ratio (a/p, m/p, p/pu or p/pl) reduction and a qualitative evaluation. Spinal radiographs of a vertebral fracture population (1733 cases) with four follow up visits over four years were analyzed. A qualitative evaluation including a differential diagnosis of new osteoporotic deformations and morphometric measurements were performed. The incidence rate of each method and sensitivity, specificity, and kappa score compared to the qualitative method were calculated.See table for results. In the table ‘rr’ means ratio reduction and ‘pp’ means point prevalence. Regarding the results of this comparison the point prevalence methods can not be recommended for the detection of new osteoporotic vertebral deformations. Method

Incidence

Sensitivity

Specificity

Kappa score

qualitative 20% rr eastell pp melton pp mccloskey pp

189 196 828 548 782

0.96 0.99 0.98 1.00

0.99 0.58 0.77 0.62

0.93 0.23 0.41 0.26

(10.91) (11.31) (47.78) (31.62) (45.12)

P219SA. PREGNANCY, LACTATION, BONE METABOLISM AND BONE MASS: A LONGITUDINAL STUDY Peixoto Cardoso MJ, Pereira S, Barros H; Department of Hygiene and Epidemiology of University Medical School, Porto, Portugal Background: Pregnancy and lactation characterized by intense physiologic changes in hormones involved in calcium homeostasis, can lead to calcium losses and reduced maternal bone mass. This studies of bone characteristics were possible because a new quantitative ultrasound technique fully radiation-free is avalable. Objective: The aim of this study was to measure the impact of pregnancy and lactation in maternal bone mass by means of longitudinal ultrasonographic parameters and biochemical markers of bone turnover. Participants and Methods: 55 women were evaluated at the first trimester of pregnancy and at the immediatly postpartum. 40 women were evaluated at the one year postpartum. Ultrasound parameters and bone mineral density were estimated at the calcaneus (Sahara aˆHologic) and biochemical markers of bone turnover were measured (osteocalcin, NTx-telopeptides, calcium and phosphorus). Results: We observed a statistically significant reduction in all ultrasonographic parameters between first trimester and delivery

P220SU. POPULATION SCREENING FOR OSTEOPOROSIS RISK IN THE ELDERLY – EFFECTS ON FALL AND FRACTURE RATES Barr RJ1, Stewart A1, Stewart AD1, Seymour DG2, Torgerson DJ3, Reid DM1; 1Osteoporosis Research Unit, University of Aberdeen, UK, 2Department of Medicine for the Elderly, University of Aberdeen, UK, 3Centre for Health Economics, University of York, UK Aim: To determine how to target calcium and vitamin D therapy to reduce hip and non-spine fractures in elderly women (70+) by a population based screening programme. Method: 5,306 women were randomly selected from their General Practice (GP) age-sex registers and sent a simple osteoporosis risk factor questionnaire. Of the 3590 responders (67.7%), 2516 (47.4%) were willing to participate in a second phase. These subjects were randomly allocated (1/3) to active (A) or control (C) (2/3) groups. The A group were invited to attend for broadband ultrasound (BUA) measurement, and falls risk advice. The GPs of those with 2 or more clinical risk factors or BUA in the lowest 1/3 of the normal range were advised to be prescribe calcium & vitamin D therapy. Results: A fall and fracture questionnaire was sent to A and C groups 1–2 years later (response rate A:86%, C = 78%).The number of fallers in the A group remained unchanged from baseline to follow-up (25.7 c.f. 25.3%), while it increased in the C group (28.0 to 29.6%, P = 0.032). There was no difference in the use of calcium, vitamin D and other osteoporosis medications at baseline in the A & C groups. At follow up the use of osteoporosis drug had increased dramatically from 7.7 to 43.5% of the A group advised to receive treatment, with no change in the rest of the A (7.3%) or the C groups (7.5%, P50.001). Validated fracture rates were significantly lower in the entire A compared to C group (RR 0.53, 0.31-0.91). Conclusions: Screening for osteoporosis in the elderly seems to increase awareness of falls, increases the uptake of osteoporosis treatments and is associated with a reduction in fracture rates. Acknowledgements: Supported by funding from Research into Ageing and Strakan Pharmaceuticals

P221MO. PREDICTIVE VALUE OF BIOCHEMICAL MARKERS OF BONE TURNOVER FOR SUBSEQUENT BONE LOSS AND FAST BONE LOSERS Iki M1, Akiba T2, Nishino H2, Matsumoto T2, Kagamimori S2, Kagawa Y2, Matsuzaki T2, Yoneshima H2, Marumo F3; 1Kinki University School of Medcine, Osaka-Sayama, Japan, 2JPOS Study Group, 3Graduate School of Tokyo Medical & Dental University, Tokyo, Japan Aims: To assess predictive values of biochemical markers of bone turnover at baseline in estimating amount of subsequent bone loss and incidence of fast bone losers (FBL).

S70 Methods: For 1,650 women aged 15 to 79 at baseline selected randomly from 3 municipalities in Japan, we measured bone mineral density (BMD) by DXA at the spine (LS), femoral neck (FN) and distal 1/3 site of the radius (DR), and serum osteocalcin (OC) and bone alkaline phosphatase (BAP), and type I collagen Cterminal telopeptide (CTx) and free (fDPD) and total deoxypyridinoline (tDPD) in fasting urine. Change in BMD was determined 3 years after the baseline. 1,153 women without any disease or medication affecting bone metabolism were analyzed. Results: [Markers and change in BMD] No significant association between the marker level at baseline and subsequent change in BMD was observed in the subjects aged 60 years and older. In subjects aged 45-59, however, we found that the subjects with the higher level of markers showed the greater bone loss. This tendency was observed evidently in OC and CTx among the markers and so at DR among the skeletal sites. [Markers and fast bone losers] We defined FBL as those who had lost BMD by 3% annually or more. The incidence of FBL during the follow-up period was about 10% at every skeletal site in the subjects aged 45–59. In this group, significant increased risk of FBL at FN was observed for the groups with the elevated levels of OC, CTx or tDPD and at DR the increased risk was observed in all the markers. Conclusions: Biochemical markers of bone turnover at baseline may predict the extent of subsequent bone loss and the risk of FBL although their predictive value varied with the markers and the skeletal sites.

P222SA. SEQUENTIAL CHANGES IN QUALITY OF LIFE AFTER OSTEOPOROTIC FRACTURES Johnell O1, Kanis J2, deLaet C3, Jo¨nsson B4, Zethraeus N4, Ode´n A5; 1Dept of Orthopaedics, Malmo¨ University Hospital, Malmo¨, Sweden, 2WHO Collaborating Centre for Metabolic Bone Diseases, Univeristy of Sheffield, Sheffield, UK, 3Institute for Medical Technology Assessment, Rotterdam, The Netherlands, 4 Dept of Economics, Sockholm School of Economics, Stockholm, Sweden, 5Consulting Statistician, Gothenburg, Sweden There are few empirical data for health state utility values after osteoporotic fracture using the same instrument for different fractures, none that examine changes with time after fracture. We assessed quality of life by using the EQ-5D EuroQol questionnaire and SF-36 prospectively in 206 men and women within 2 weeks of the fracture (99 wrist, 50 hip, 25 clinical vertebral and 32 shoulder fractures). The values from EuroQol were converted to a utility tariff with values 0–1. The patients were reassessed after 6, 9 and 12 months. Results: Quality of life was reduced 2 weeks after the fracture with the lowest value for spine fractures (0.20) then shoulder (0.38), hip (0.41) and the highest for wrist fractures (0.53). After 6 months the corresponding values were between 0.49, 0.70, 0.62, 0.75, after 9 months 0.52, 0.66, 0.57, 0.79 and after 12 months 0.54, 0.66, 0.54, 0.81. Interestingly in this prospective study the patients with clinical spine fractures have a slightly worse outcome than hip fracture patients. Both regained part of the lost quality of life after 6 months but after that there was a stable reduction of quality of life. For wrist fracture patients it was mainly during the first month that the patient had a reduced quality of life. The values for domains in SF-36 followed a similar pattern. Conclusions: Quality of life has rarely been determined by the patients. This study shows that there was a marked reduction of quality of life, especially after hip and spine fracture which lasted for the entire year. For wrist and shoulder fractures the main reduction of quality of life occurred in the first month after the fracture. These data will have a marked effect on health economic calculations, since fractures have a lower utility value than previously calculated, especially spine fractures.

Abstracts P223SU. SEASONAL VARIATION IN BONE MINERAL DENSITY OF THE CALCANEUS IN A COHORT OF 2805 YOUNG MEN Nyman C1, Pettersson U2, Lorentzon R2, Landin-Wilhelmsson K1, Hulthe´n L1, Johnell O3, Kullenberg R4, Norjavaara E5, Samuelsson L5, Mellstrom D1; 1Dept. of Geriatric and Internal Medicine, Goteborg, Sweden, 2Sports Medicine Unit, Umea, Sweden, 3Dept. of Orthopaedics, Malmo, Sweden, 4Dept. of Radiophysics, Goteborg, Sweden, 5The National Service Administration, Goteborg, Sweden Aims: The aim of this study was to evaluate any seasonal difference in bone mineral density (BMD) in the calcaneus in young men. The present study is part of an ongoing study investigating relationships between anthropometric parameters, muscle strength, lifestyle factors including physical activity, genetic analysis and BMD in 12000 male military recruits. Methods: Since November 1998 until June 2000, 2805 men (mean age 18.3±0.3 years) have been recruited from the compulsory military service in Gothenburg, Sweden. BMD (g/ cm2) and bone thickness (cm) in calcaneus were measured with DEXA, Calscan. Measurements were done throughout the whole year, except for July-August, and divided into measurements done in the autumn (Sept-Dec) or spring (Jan-June). Lifestyle factors including smoking, training habits and calcium intake were evaluated by a questionnaire. Results: When all measurements during 1998-2000 were pooled into two groups (autmun vs. spring), BMD was significantly higher in subjects measured in the autumn (0.64 ± 0.09 vs. 0.59 ± 0.08, p50.0001) with an absolute difference of 0.05 ± 0.01 g/cm2 or +8.5%. This difference was also evident when investigating the two years separately. Hence a difference of 8.5% (p50.0001) was found between autumn and spring measurements during both the first and second year. No differences were found in bone thickness, physical activity, weight, age or calcium intake. Conclusions: This study reports a significantly seasonal variation of BMD in calcaneus in young men with higher values of measurements performed in the autumn. We believe that this difference is secondary to a variation in serum 25-hydroxy vitamin D levels during the year. The difference in BMD is of the same magnitude that can be expected during prospective studies, i.e. studies evaluating the effect on BMD of different preventive measures (e.g. nutritional factors, physical activity) or different treatments for osteoporosis and could therefore influence the results in those types of studies.

P224MO. SURGICAL MENOPAUSE AS A RISK FACTOR FOR OSTEOPOROSIS (OP) AND RELATED FRACTURES (FX) Varenna M, Binelli L, Zucchi F, Casari S, Sinigaglia L; Department of Rheumatology, University of Milan, Milan, Italy Early menopause both spontaneous and surgically induced by ovariectomy (OVX) is a well-recognized risk factor for OP and related Fx. The lost of postmenopausal ovarian hormonal production due to OVX could be a further variable able to increase OP risk. Aim of this study was to verify the effective pathogenetic role of OVX versus spontaneous menopause on OP and related Fx. A sample of 531 women with surgical menopause (mean age 55.8 ± 5.0 yrs; mean age at menopause 45.5 ± 4.4 yrs) was recruited and underwent lumbar DXA measurement (L2–L4). Patients with previous OP treatments or oophorectomized for malignancy were excluded. The prevalence of OP was 38.2%, and 9.4% of these women reported postmenopausal fractures due to minimal trauma. As control group, 1593 healthy postmenopausal women never treated for OP were selected matching for age (±1 year) and with spontaneous physiological menopause (49.9 ± 1.3). Comparisons between the groups showed a significantly higher prevalence of OP and Fx in OVX subjects (p = 0.001). To investigate the independent role of each considered variable, multiple logistic analyses were performed. The variables able to influence the risk for OP and Fx were age, BMI, calcium intake and OVX, but the last

Abstracts

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one was not longer significantly predictive when the number of years of estrogen exposure was entered in the models. When OVX group was then compared with a sample of 1593 women matched for age and age at spontaneous menopause, no differences in OP prevalence and postmenopausal Fx was found. According to the previous models, multivariate analyses showed that age, BMI, calcium intake and estrogen exposure but not ovariectomy significantly influenced the risk for OP and Fx. Our data confirmed that OVX is a strong risk factor for postmenopausal OP and Fx but without any additional effect in comparison with spontaneous menopause.

P225SA. THE ACCURACY OF HEIGHT LOSS DURING PROSPECTIVE MONITORING FOR DETECTION OF INCIDENT VERTEBRAL FRACTURES Hanley DA1, Siminoski K2, Adachi JD3, Cline G4; 1University of Calgary, Calgary, Canada, 2Endocrine Centre of Edmonton, Edmonton, Canada, 3McMaster University, Hamilton, Canada, 4 Procter & Gamble Pharmaceuticals, Mason, USA We have evaluated the accuracy of using height loss during prospective monitoring to detect the development of new vertebral fractures. Subjects were women in the placebo arms of the VERT MN/NA risedronate studies (average age 69 yrs; range: 38–85 years) who had post-baseline data for both variables. Height loss was determined as the difference between the baseline measurement and the subsequent measurement (using a stadiometer). Lateral vertebral radiographs were performed at the same times and were analyzed by digital morphometry from T4 to L4. Vertebral fractures were determined using both quantitative and semiquantitative methods. New fractures occurred in 18.1% of the 985 subjects over 3 years of observation. Accuracy results are shown in the table for use of height loss to detect new vertebral fractures. The findings demonstrate that the greater the amount of height loss, the higher the probability of a new fracture. There was no cut-off that produced high positive predictive values. A cut-off at 2 cm produced high specificity (93%) and a high negative predictive value (87%). The area under the receiver operating characteristic curve was 0.75 (95% CI: 0.70–0.79; P 5 0.001) The following applications can be made from this data. Height loss 5 2 cm during monitoring rules out the development of a new fracture with moderate to high accuracy. Height Loss 42 cm over 3 years of monitoring suggests, but does not confirm, a new fracture. Individuals with height loss 42 cm should have vertebral radiographs to look for a new fracture. Height Loss (cm)

OR

Sensitivity

Specificity

PPV

NPV

None 40 41 42 43 44

1 2 5 13 23 25

100 89 62 38 23 13

0 35 78 93 97 98

18 23 38 56 63 64

INF 93 90 87 85 84

OR = odds ratio, PPV = positive predictive value, NPV = negative predictive value, INF = infinity

P226SU. DOES HRT PREVENT WEIGHT LOSS INDUCED BONE LOSS? Sirola J1,2, Kro¨ger H2, Honkanen R1, Jurvelin J3, Saarikoski S4; 1 Univ. of Kuopio, Kuopio, Finland, 2Kuopio Univ. Hospital, Dpt. of Surgery, Kuopio, Finland, 3Kuopio Univ. Hospital, Dpt. of Clinical Physiology & Nuclear Medicine, Kuopio, Finland, 4Kuopio Univ. Hospital, Dpt. of Obstetrics and Gynaecology, Kuopio, Finland Aims: Evaluation of the effects of HRT and weight change on periand postmenopausal bone loss (Part 1) and the effect of HRT in weight loss induced bone loss (Part 2).

Methods: 602 healthy peri- and postmenopausal women were selected from a random sample (n = 2025) of the OSTPRE-study cohort (n = 13 100) in Kuopio, Finland. BMD at lumbar spine (LS) and femoral neck (FN) was measured with DXA absorptiometry at baseline in 1989-91 and at five years in 1994–97. Results: Part 1: In multiple regression model for 602 peri- and postmenopausal women long term HRT, long duration of menopause and weight increase were found to significantly predict lower bone loss at both lumbar spine and femoral neck. Part 2: Of the 602 women 106 lost weight during follow-up which of 70 were HRT never users (no HRT during or before follow-up) and 36 HRT ever users (HRT use during follow-up). See Table for results (linear regression model, adjusted for age, baseline weight, mean calcium intake and duration of menopause). Conclusions: Menopausal transition, HRT and weight change are the most important determinants of longitudinal bone loss at both lumbar and femoral bone. Furthermore, HRT seems to be effective in prevention of weight loss induced bone loss at both lumbar spine and femoral neck.

HRT use

Equations predicting mean annual BMD change (%) according to weight change (%) (WC)

p-value

Never (n = 70) Ever (n = 36)

–4.24+0.097*WC (LS) / –2.86+0.060*WC (FN)

0.001 (LS) / 0.022 (FN) 0.634 (LS) / 0.730 (FN)

–0.49+0.030*WC (LS) / –0.45+0.017*WC (FN)

P227MO. ASSOCIATION BETWEEN LIPID PROFILE AND BONE MASS IN HEALTHY POPULATION Braga V1, Gatti D1, Bakri J1, Malerba G2, Rossini M1, Adami S1; 1 Rheumatology Unit, University of Verona, 2Institute of Biology and Genetics, University of Verona It has been recently reported that statins increase new bone formation in vitro. In case-control studies an association between statin use and lower risk of osteoporotic fractures was found. However, the results of prospective studies were far more controversial. This might raise the suspicion that some positive results were driven by biases in the study population. From the data-set of healthy subjects aged 20 to 70 years of our Health District, we re-examined the relationship between lipid profile and bone mineral density (BMD) [QDR 4500, Hologic, USA] at the spine, femoral neck and total hip. The individuals with conditions or on treatment with drugs known to interfere with bone metabolism and those on statins or other lipid lowering agents were excluded. Overall the study population included both healthy males (n. 427, mean age 57.61) and females (n. 260, mean age 56.29). The subjects were divided in three groups according to tertiles for values of LDL cholesterol, HDL cholesterol and LDL/HDL ratio respectively. The subjects with the highest HDL levels had consistently the lowest bone mass values expressed in terms of z-score (table). HDL levels were related to all skeletal sites (r range = –0.20 to –0.30, p50.05). The level of significance in bone mass did not change after ‘adjusting’ for body weight, bmi, age, smoking habit, dietary calcium intake. Our results indicate that the lower incidence of osteoporotic fracture among statin users might be explained more by their prevailing higher bone mass rather than by a pharmacological effect of statins on bone metabolism.

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Abstracts

BMD zscore (mean±SD)

HDL TERTILES

MALES

LOWEST

MEDIUM

HIGHEST

Lumbar spine Femoral neck Total hip

–0.17 ± 2.12 0.28 ± 1.40 0.12 ± 1.07

–0.71 ± 1.84* 0.12 ± 1.28 –0.03 ± 1.08

–0.70 ± 1.49* –0.09 ± 1.18** –0.21 ± 1.02**

FEMALES Lumbar spine Femoral neck Total hip

LOWEST –0.72 ± 1.45 –0.80 ± 1.12 –0.82 ± 0.94

MEDIUM –1.08 ± 1.17 –0.92 ± 0.95 –0.88 ± 0.88

HIGHEST –1.69 ± 1.13*** –1.32 ± 1.02** –1.19 ± 0.86*

* p50.05; ** p50.01; ***p50.001

P228SA. SEASONAL VARIATION IN FOREARM BONE MINERAL DENSITY IN 10,364 WOMEN AGED 49–69 Mellstrom D1, Olsson J1, Waern E1, Johnell O2, Oden´ A3, Kanis J4; 1 Dept of Geriatric Medicine, Gothenburg University, Go¨teborg, Sweden, 2Dept of Orthopedics, Malmo¨ University, Malmo¨, Sweden, 3Dept of Mathematics, Chalmers University of Technology, Go˜teborg, Sweden, 4Dept of Human Metabolism, University of Sheffield, UK. Aim: The purpose of this study was to examine if there is an existing seasonal variation in forearm bone density in 10,364 postmenopausal women. Earlier studies have indicated seasonal variation in vitamin D, PTH and biochemical bone markers. The question is if there is a corresponding seasonal variation in bone mass? Methods: We have performed a simultaneous screening of osteporosis and breast cancer in 10,364 women aged 49–69, mean age 58, in Go¨teborg and Varberg, Sweden between year 1994–2000. Swedish women aged 49–69 are offered breast cancer screening with mammography each 18 month. Bone density was in this study measured in nondominant forearm with DTX 200 (Osteometer) two times with an interval of 36 months. A health inquiry consisted of variables concerning osteoporosis.Prospective fractures, breast cancer and survival are collected. Results: The variation in BMD with daily phantom measurements from October 1998 to October 1999 was 0.41%. We found a seasonal variation in BMD with an annual amplitude of 1.4% (P50.001). Peak BMD was in December and the lowest value was in June. The seasonal variation was similar each year during the period year 1994 to 2000. The seasonal amplitude, in BMD is similar to a difference in age with about one year. Conclusion: We found a seasonal variation in forearm BMD with an amplitude of 1.4% with peak BMD in December and the lowest BMD in June. Seasonal variation of vitamin D and bone turnover might explain our findings. Seasonal variation of BMD could influence prospective studies if the second measurement is after 18 months.

P229SU. NORMAL 25(OH) VITAMIN D SERUM LEVELS DO NOT EXCLUDE D-HORMONE DEFICIENCY IN COMMUNITYDWELLING ELDERLY Dukas L1, Bischoff HA2, Schacht E3, Staehelin HB1; 1Geriatric Universuty Clinic, Basel, Sitzwerland, 2Brigham and Women’s Hospital, Boston, USA, 3Orthopa¨dische Universita¨tsklinik Balgrist, Zurich, Switzerland Aims: Normal 25(OH)D serum levels may not exclude D-Hormone (1,25(OH)2D) deficiency. This implies that till now a large number of D-Hormone deficient patients remain undiagnosed, untreated or insufficiently treated by plain vitamin D. In this study we

investigated the frequency of D-Hormone deficiency in community-dwelling elderly with normal 25(OH)D serum levels. Methods: We included the healthy elderly women (N = 192) and men (N = 187) from the AIMS-Study. Serum 25(OH)D, D-Hormone, and iPTH concentration were measured by radioimmunoassay (Nichols1). The p values for the reported results are two sided. According to international definition serum levels of 25(OH)D above 12ng/ml were defined as normal and 1,25(OH)2D less than 30pg/ml were defined as D-Hormone deficiency. Results: The prevalence of 25(OH) D deficiency was 1.6% in women and 3.7% in men and 15.1% of women and 29.3% of men were diagnosed as D-Hormone deficient. 96.6% of women and 89% of men with D-Hormone deficiency had normal 25(OH)D serum levels. On the other hand 6 out of 7 men and 2 out of 3 women with 25(OH)D deficiency had D-Hormone serum levels in the normal range. Conclusions: In this study group the large majority of women and men with D-Hormone deficiency had normal 25(OH)D serum levels. This could be explained by decreasing activation of 25(OH)D to D-Hormone with aging (1-alpha-Hydroxylase deficiency). Furthermore most of men and women with 25(OH)D deficiency had normal D-Hormone serum levels. This means that had we performed only 25(OH)D serum measurements, most of participants would not have been diagnosed D-Hormone deficient and most participants with 25(OH) deficiency would have been false positively diagnosed as D-Hormone deficient. This findings raise the question if measuring 25(OH)D alone is efficient enough to diagnose vitamin D deficiency and if vitamin D deficiency should not be better diagnosed by measuring DHormone first.

P230MO. POSTPONEMENT OF FRACTURES – A NOVEL WAY OF EXPLAINING THE BENEFIT OF OSTEOPOROSIS THERAPY Kristiansen IS1, Christensen PM1, Brosen K1, Brixen K2; 1Institute of Public Health, University of Southern Denmark, Odense, Denmark, 2Department of Endocrinology, University Hospital, Odense, Denmark Aim: To estimate benefits from osteoporosis therapy in terms of postponement of hip fractures. Methods: We developed a Markov model using Nordic data on mortality and hip fracture incidence. A cohort of women were followed for up to 50 years to estimate fracture free survival benefits from therapy. The model allowed for adjusting risk of hip fracture, effect of therapy and length of therapy. Results: A hypothetical 3-years therapy that halves the fracture risk in 50 years old women with z-score of –2.5 would postpone hip fractures on average by 19 days. A similar therapy would postpone hip fractures by 36, 87, 141 and 92 days if it were started at age 60, 70, 80 or 90, respectively. The benefits, however, are much greater (3,544, 2,283, 1,210, 596 and 224 days, respectively) when apportioned only to the fraction of patients who actually sustain a fracture without therapy. Depending on the duration of intervention (1 year to lifelong), risk of hip fracture in the intervention group (z-score –1.0 to –3.5), age at start of therapy (between 50 and 90 years), and effect of therapy (25%– 75% risk reduction), the average delay of a hip fracture may vary from 1 day to 860 days. Conclusion: The benefit from treating osteoporosis varies considerably according to patient group, age and effectiveness of therapy. The likelihood of having benefit is smallest among the youngest patients, but the benefit is greatest among the relatively few who benefit at young ages. Effect of osteoporosis therapy may be better understood by informing patients about the risk of sustaining a fracture and the postponement among those who benefit, rather than informing about risk reductions such as number-needed-to-treat.

Abstracts P231SA. VALIDATION OF SELF-REPORTED ESTROGEN REPLACEMENT THERAPY (ERT), A RETROSPECTIVE POPULATION-BASED ANALYSIS IN 11377 WOMEN OF THE KUOPIO OSTEOPOROSIS RISK FACTORS AND PREVENTION STUDY (OSTPRE) Sandini L1, Tuppurainen M2, Kro¨ger H3, Honkanen R1; 1Public Health Research Institute, University of Kuopio, Finland, 2 Department of Gynecology and Obstetrics, Kuopio University Hospital, Kuopio, Finland, 3Department of Orthopedics and Traumatology, Kuopio University Hospital, Kuopio, Finland Aims: The evaluation of the effects of ERT in a population necessitates self-reported use. We validated self-reported ERT use over a period of 41 months in 1996–99 using the Finnish Social Security (KELA) records of prescriptions, where all medical prescriptions delivered to the population are recorded. Methods: A questionnaire was sent to 12562 57–66 year-old women of the OSTPRE cohort, and 11377 answers were eligible for analysis. We asked: ‘Have you been taking estrogen-based hormone replacement therapy for example for the treatment of climacteric symptoms or osteoporosis (vaginal creams, tablets and ovules not included)? If yes, specify the brand and duration for each year from 1994 to 1999’. We retained as ERT the preparations having systemic estrogenic properties, applied as a gel, plaster or tablet. Results: Overall, 3105 women reported the use of an estrogenbased preparation in 1996–99. From those, 97.2% were confirmed by KELA as having been prescribed ERT during that time. Mean duration of use was 28 ± 11 months. According to KELA, 1738 women had been prescribed ERT, but they did not report ERT use. Of those, 54% had been prescribed ERT for 6 months or less.Examined year by year, the proportion of self-reported ERT users varies between 22.2% (1996) and 23.9% (1998). Of those, 91% (1996) to 97.1% (1998) are confirmed as being ERT users in the KELA records.The self-reported duration of use of ERT was compared to the duration of availability of ERT in the KELA records. A difference in the duration of use of 0–3 months was regarded as a good agreement, and was observed in 63.4% (1996) to 77.0% (1998) of cases. Conclusion: Self-reported ERT use and its duration are in accordance with the Finnish Social Security records. A minority of cases of short-term ERT users fail to report ERT use.

P232SU. A POPULATION BASED STUDY OF THE CONSEQUENCES OF HIP FRACTURE ON ACTIVITIES OF DAILY LIFE AND RESIDENTIAL NEED Osnes EK1,2, Lofthus CM1,3, Meyer HE1, Nordsletten L1,2, Cappelen I1, Falch JA1,3, Kristiansen IS1,4; 1HIPOS-group, Oslo, Norway, 2Ulleva˚l University Hospital, Oslo, Norway, 3Aker University Hospital, Oslo, Norway, 4University of Odense, Odense, Denmark Aims: To estimate the consequences of hip fracture with respect to changes in residential need and the ability to perform activities of daily life. Methods: Using electronic diagnosis registers and medical records all patients with hip fracture in Oslo during the period from May 1996 through April 1997 were identified (n = 1300). In November 1997 a questionnaire was sent to those still alive (n = 772), and after reminders 617 questionnaires were returned. Chi-square test was applied. Results: While 73% lived at home before fracture, 60% lived at home after fracture (p50.001). The percentage of patients living in nursing homes was doubled from 14% before, to 30% after sustaining hip fracture (p50.001). Of the patients living in their homes both before and after fracture (n = 341), 15% were dependant on help more than once a week from either relatives or home help/community nurse before fracture, and 28% after fracture (p50.001). The percentage of patients able to walk without any support was reduced from 76% before fracture to

S73 35% after fracture (p50.001). Also the ability to move outdoors independently and to prepare own food was significantly reduced after sustaining hip fracture. Conclusions: Hip fracture has profound impact on the way of living for the patient. Fewer patients are able to live at home, and many patients require additional assistance in the activities of daily life. Hip fracture represents a great threat for patients’ quality of life.

P233MO. SURVIVAL AND POTENTIAL YEARS OF LIFE LOST AFTER HIP FRACTURE IN MEN AND AGE-MATCHED WOMEN Trombetti A1, Herrmann F2, Hoffmeyer P3, Schurch MA1, Bonjour JP1, Rizzoli R1; 1Division of Bone Diseases, Department of Internal Medicine, University Hospital of Geneva, Geneva, Switzerland, 2Department of Geriatrics, University Hospital of Geneva, Geneva, Switzerland, 3Orthopedic Clinic, Department of Surgery, University Hospital of Geneva, Geneva, Switzerland Background: Hip fracture is associated with a higher mortality rate in men than in women. However, mean age of men and women with hip fracture markedly differs. To avoid the influence of age on gender-specific outcome, we analyzed prefracture conditions and hip fracture outcome in a cohort of men and of age-matched women. Method: We prospectively assessed 106 men (mean age ± SD, 80.3 ± 9.3 years) and 264 age-matched women (mean age 81.4 ± 8.0) with hip fracture. Living conditions, risk factors for low bone mass or falls, fracture outcome, including mortality rate, survival, years of potential life lost and modifications of housing conditions were compared prior to hip fracture and up to 7 years thereafter. Results: Men with hip fracture differed from age-matched hipfractured women by a higher alcohol and tobacco consumption, a greater frequency of living in couple, and by less prevalent fractures. Mortality rate after hip fracture was significantly higher in men (RR = 1.74, 95% CI 1.34–2.24). Since mortality is higher in the general male population, we compared reduction in life expectancy taking into account the gender-specific mortality rate. Reduction in life expectancy due to hip fracture was similar in both genders (7.1 ± 4.3 and 7.2 ± 4.6 years, in men and women respectively, NS), but the proportion of the years of life lost was higher in men (70 ± 33, and 59 ± 42%, in men and women respectively, p 5 0.01). Conclusion: For the same age, mortality rate after hip fracture was higher in men than in women. The proportion of the years of life lost was higher in men, suggesting a worse impact of hip fracture on survival in men, even after consideration of the higher mortality rate in the general male population.

P234SA. COMPARISON OF QUANTITATIVE ULTRASOUND AT THE HEEL WITH A CLINICAL RISK FACTOR SCORE FOR THE ASSESSMENT OF POSTMENOPAUSAL OSTEOPOROSIS Goemaere SJAG1, Zmierczak H1, Lauwerier D2, Hoet H2, Roman E2, De Boever E2, Reginster JY3, Kaufman JM1; 1Unit for Osteoporosis, Ghent University Hospital, Ghent, Belgium, 2 Medisch Centrum, Oudenaarde, Belgium, 3Bone & Cartilage Metabolism Unit UlG, Lie`ge, Belgium Targeting the intervention to a high fracture risk population, identified by DXA, seems a reasonable strategy for the management postmenopausal osteoporosis. However, high cost and low availability of DXA stimulate research on less costly alternatives: e.g. clinical risk factors and quantitative ultrasound. We assessed 2597 postmenopausal women (median age 61y; range: 34–95y) by heel quantitative ultrasound measurement (QUS) on SaharaR Clinical Bone Sonometer (Hologic Inc, Bedford, USA) and by a self-administrative questionnaire for osteoporosis

S74 risk profile (SCORE). Assessment of bone mineral density (BMD) by DXA (Hologic QDR-1000 & 2000) was performed in a subgroup of 575 women (22%). The prevalence of osteoporosis (T-score 5–2.5) at the spine or hip was 23.8%. The best diagnostic cutoff (as assessed by ROC analysis) for SaharaR T-score was –1.7 with a sensitivity and specificity for assessing osteoporosis of 72% and 75%, respectively. For SCORE the best cutoff was 10, with sensitivity and specificity of 48% and 70%. Prediction of osteoporosis was significantly better for the SaharaR T-score compared to the SCORE (AUC : 0.786 vs 0.683, p5 0.001). This difference was mainly due the a better performance of QUS in the older subpopulation (age *65y). When for screening purposes one considers a cutoff, which does not miss more than 10% of osteoporotic women, the positive predictive value (PPV) of having osteoporosis was 42% with QUS (cutoff T-score: –1.0) and 32% with the risk score (cutoff SCORE : 7) and the NPV was 92% and 94%, respectively. Implementing the SaharaR measurement did increase the performance of SCORE in the overall study group, as well as in the elderly (465y). It can be concluded that in postmenopausal women, especially in those 4 65y, QUS at the heel (SAHARA1) performed better than a clinical risk score (SCORE) in prediciting osteoporosis as diagnosed by DXA.

P235SU. PHYSICAL ACTIVITY AND THE RISK OF FALLS IN OLDER MEN AND WOMEN Pluijm SMF1, Stel VS1, Visser M1, Deeg DJH1,2, Smit JH3, Lips P1,4; 1 Institute for Research in Extramural Medicine (EMGO Institute), Vrije Universiteit Medical Centre (VUMC), Amsterdam, The Netherlands, 2Department of Psychiatry, Vrije Universiteit, Amsterdam, The Netherlands, 3Department of Sociology and Social Gerontology, Vrije Universiteit, Amsterdam, The Netherlands, 4Department of Endocrinology, Vrije Universiteit Medical Centre (VUMC), Amsterdam, The Netherlands Aims: The role of physical activity in the prevention of falling remains controversial. In this prospective study, we examined the relationship between daily physical activity and falls in older men and women. Methods: The study population consisted of 1383 participants (705 women and 678 men) of the Longitudinal Aging Study Amsterdam (LASA) who were 65 to 88 years old as of the first of January, 1996. The level of physical activity in the previous two weeks was estimated by means of a detailed, intervieweradministered questionnaire regarding walking, cycling, sports and household activities. During three years of follow-up, fall events were recorded with a ‘fall calendar’. Data were analysed using Generalized Estimating Equation (GEE), adjusted for age, sex, chronic disease, urinary incontinence and cognition. Results: Physical activity was non-linearly, inversely related to the risk of falls. As compared with people in the lowest quintile, people in the highest quintile of energy expenditure (expressed in kcal/d) had an adjusted relative risk for multiple falls of 0.76 (95% CI 0.59–0.97). Walking outside was also inversely associated with falls; people in the highest quintile, who walked at least 40 minutes per day, had a relative risk of 0.79 (95% CI: 0.61–1.00) as compared with women who never walked. Performing sports activities (yes/no) was not associated with multiple falls. However, when we distinguished between inside and outside falls, performing sports activities (yes/no) appeared to be protective against inside falls (RR: 0.69; 95% CI: 0.55–0.87), but modestly increased the risk of outside falls (RR: 1.19; 95% CI: 1.00–1.41). Conclusions: These prospective data indicate that a high level of total physical activity and walking activity protect against falls among older men and women.

Abstracts P236MO. USE OF DIURETICS IS ASSOCIATED WITH LOWER DHORMONE SERUM LEVELS BUT NOT WITH SERUM 25HYDROXYVITAMIN D IN COMMUNITY-DWELLING ELDERLY MEN AND WOMEN RESULTS FROM THE BASELINE CROSSSECTIONAL ANALYSES OF THE AIMS-STUDY Dukas L1, Bischoff HA2, Schacht E3, Staehelin HB1; 1Geriatric University Clinic, Basel, Switzerland, 2Brigham and Women’s Hospital, Boston, USA, 3Orthopa¨dische Universita¨tsklinik Balgrist, Zurich, Switzerland Aims: The objective of this cross-sectional study was to investigate the effect of diuretics on the metabolism of calcitropic hormones in community-dwelling elderly. Methods: The AIMS study, its population and methods of measurements were described previously. The p values for the reported results are two sided. Use of diuretics was analysed as dichotomous variable (user/nonuser) as well as categorical variable according the type of diuretic. Serum levels of 1,25(OH)2D less than 30pg/ml was defined as D-Hormone deficiency. Results: Significantly more participants who used diuretics (N = 75) were D-Hormone deficient compared to non-users (32.9% vs. 19.0%; p50.01). For 25(OH)D deficiency there was no significant difference between groups. D-Hormone serum concentrations were significantly lower in users of diuretics compared to non-users (34.2 ± 8.6 pg/ml versus 40.9 ± 11.6 pg/ ml, p = 5 0.0001). For 25(OH)D serum concentrations we found no significant difference between groups. The analyses for 25(OH)D and D-Hormone serum levels showed similar results when stratified by gender and when performed for thiazides, furosemides or spironolactones separately. We found significant differences (P 5 0.001) in iPTH serum levels for users of nonthiazide diuretics compared to thiazide diuretic users and nonusers of diuretics (mean serum levels iPTH 52.8 pg/ml, 34.7 pg/ml and 37.0 pg/ml respectively). Conclusions: In this study group the use of diuretics, independent of the type of diuretic, was associated with lower D-Hormone but not with lower 25(OH)D serum concentrations. One possible explanation for this findings is that diuretics may suppress the activity of the renal enzyme 1-alpha-Hydroxylase, which is responsible for the conversion of 25(OH)D to 1,25 (OH)2D. Furthermore, iPTH serum levels were the lowest in users of thiazides, explained by thiazide induced increased renal reabsorption of calcium. The use of non-thiazide diuretics showed significant higher serum level of iPTH compared to non-users of diuretics.

P237SA. CONTRIBUTION OF AGE AND CLINICAL RISK FACTORS TO DXA-BASED HIP FRACTURE RISK STRATIFICATION USING A MULTIDIMENSIONAL MODEL Leslie WD1, Metge C2, Ward L3, Caetano P2; 1Department of Medicine, University of Manitoba, Winnipeg, Canada, 2Faculty of Pharmacy, University of Manitoba, Winnipeg, Canada, 3 Department of Nuclear Medicine, St. Boniface General Hospital, Winnipeg, Canada Aims: Hip fractures are independently associated with advancing age, specific clinical risk factors (CRF), and low BMD. The use of T-scores for reporting BMD ignores the contribution of age and CRFs. We previously developed a multidimensional model of hip fracture risk that incorporates patient age, bone mineral density (BMD), and the results of 11 specific CRFs: poor general health, inactivity, immobility, current smoking, greater height, height loss, low body weight, hyperthyroidsim, fractures after age 50, falls, and family history of osteoporotic fracture (JBMR 2000;15:S416). The purpose of this study was to compare the contribution of the multidimensional mode (M-DM) with a unidimensional model (1MD) based on BMD alone. Methods: We selected 213 consecutive postmenopausal females (mean age 65.3, range 50-87.9) with CRF data referred

Abstracts for BMD assessment of fracture risk. Absolute hip fracture risk (over the next 5 years and remaining lifetime) was estimated using both the M-DM and 1-DM (latter assumes constant patient age of 65 and three common CRFs – family history of osteoporosis, fall in last 12 months and ambulatory less than 4 hours/day). The ratio of absolute hip fracture risks (1-DM/M-DM) was derived for each patient and displayed in a modified Bland-Altman plot (geometric mean vs ratio with upper and lower 95% CI). Results: The fracture risk ratio was 0.8+2.2 for hip fracture in the next 5 years and 1.1+1.9 for remaining lifetime, with respective 95% CIs of 0.16–4.0 and 0.3–3.9. This indicates a large contribution of M-DM over 1-DM in fracture risk stratification. The ratio was not constant across the risk range (P50.05), with M-DM less than 1-DM at lower levels of risk (ratio41) while M-DM exceeded 1-DM at higher levels of risk (ratio51). Conclusions: A multidimensional approach to hip fracture risk stratification is feasible and greatly modifies risk stratification based on BMD alone.

P238SU. HOSPITAL CARE COSTS OF OSTEOPOROTIC HIP FRACTURES – COMPARATIVE STUDY WITH OTHER PREVALENT DISEASES Mateus MM, Cruz CM, Alves de Matos AC, Branco JC; Unidade de Reumatologia, Hospital de Egas Moniz, Lisboa, Portugal Aims: Osteoporotic hip fractures are a relevant public health problem, due to its high morbility and mortality. This study aims at performing a comparative retrospective assessment of the demographic, epidemiologic and economic characteristics of an hospital admitted population with the following diagnostics: osteoporotic hip fracture (OHF), miocardial infarction (MI), chronic obstructive pulmonary disease (COPD) and chronic liver disease (CLD). Methods: It is a four-year retrospective study from 1997 to 2000, comprising 52568 admissions in a Lisbon central hospital. The population studied was selected from the discharge diagnosis, following the ICD.9.CM system, corresponding to OHF, COPD, MI and alcoholic CLD. In the case of OHF group, the following cases were excluded: cancer, pathologic fracture, women below 50 years old, men below 65 years old. The economic parameters were evaluated using the national data tables for DRGs. The data analysis was performed in MS-Excel 97. Results: The final sample was composed by 460 OHF, 542 COPD, 424 MI and 647 alcoholic CLD patients. From the OHF patients, 92.6% had surgical treatment, 2.4% conservative and 5% were not specified. The average inward duration was 21.7 days for OHF patients. The average hospital care cost is EUR6037.8 for each OHF patient, EUR3479.6 for COPD, EUR3518.7 for MI and EUR2236.7 for alcoholic CLD patients, which accounts respectively for 36,7%, 24,8%, 19,7% and 18,8% of the total expense. Conclusions: It was shown that the average hospital care cost of OHF patient is EUR6037.8, nearly twice that of any of the other disease groups. It was also shown that OHF patients are relevant in what concerns bed occupation duration, because their inward average time is also approximately twice that of the others. These conclusions highlight the relevance of osteoporosis preventive programs and early treatment in reducing hospital care cost due to OHF.

P239MO. EFFECTS OF LIFESTYLE FACTORS ON BONE MINERAL DENSITY IN JAPANESE BOYS AND GIRLS Naka H1, Iki M2, Morita A2, Aihara H2, Ikeda Y2; 1Kyoto University of Education, Kyoto, Japan, 2Kinki University School of Medicine, Osaka-Sayama, JAPAN Aim: Adolescence is a critical time for skeletal growth and mineralization. The achievement of a higher peak bone mass is

S75 considered to be one of the best preventive strategies against osteoprosis fractures. Lifestyle factors are believed to modify bone health. However, there have been few reports on this topic in Japanese children and adolescents. The purpose of present study was to clarify associations between lifestyle factors such as past and present diet and exercise habits, and bone mineral density (BMD) at the lumbar spine and hip in Japanese boys and girls. Methods: We examined 412 first grade students (133 boys and 279 girls) of 3 junior high schools in Kyoto, Japan. BMD at the lumbar spine, femoral neck and total hip were measured by DXA (QDR4500A, Hologic). Past and present history of illness, lifestyle factors such as diet and exercise habits, and information on maturity were obtained from detailed interviews. Results: More mature students had higher BMD at every skeletal site in both sexes. Height, weight and grip strength were highly correlated with BMD at every skeletal site in both sexes regardless of the onset of the maturity. Therefore BMD was adjusted for height, weight and grip strength by the analysis of covariance (ANCOVA). In ANCOVA, the boys with greater intake of milk in the lower grades at elementary school and those with greater intake of milk or yoghurt at present tended to have greater BMD. The girls with greater intake of milk or yoghurt in elementary school and those with more active lifestyle at present showed greater BMD. Conclusion: These findings suggest that the intake of milk in elementary school influences bone development in adolescents.

P240SA. DIETARY CALCIUM INTAKE ASSESSMENT IN 5990 WOMEN IN TUSCANY, ITALY Mazzantini M1, Delle Sedie A1, Bernini L2, Bencivelli W1, Di Munno O1; 1Rheumatology Unit, Department of Internal Medicine, University of Pisa, 2Geriatric Unit S. Miniato Hospital, Empoli Calcium represents one of the main factors in the bone metabolism regulation and it is well documented that low calcium intake (CaI) plays a role in postmenopausal and senile osteoporosis. Aim of the present study was the assessment of dietary CaI in a population of 5990 women (mean age 57.5 years, range 20–80), referred consecutively to the Center for Bone Densitometry of the S. Miniato Hospital (Pisa, Tuscany) from January 1993 to July 2000. Women were asked by a questionnaire about the habitual consumption of cheese, milk, yogurt, type of water and vegetables in the last 3 months. Body mass index (BMI), age and duration of the menopause, number of deliveries, and BMD of the distal third of the forearm by single photon absorptiometry (Osteometer DT 100) were also evaluated. Mean daily CaI was 703 ± 335 mg. In women over 65 yrs the value was 665 ± 317 mg, significantly lower (p50.005) than that found in women between 56–65 yrs (695 ± 327), 46-55 yrs (722 ± 335) and 20-45 yrs (751 ± 424). Furthermore in 4064 women (67,8%) mean daily CaI was 5800 mg. The Table shows other variables divided according to different ranges of daily CaI. Radial BMD showed a significant negative correlation with age (r = 0.545, p50.0001) and duration of menopause (r = 0.474, p50.0001); and a significant positive correlation with BMI (r = 0.089, p50.0001) and CaI (r = 0.055, p50.0001). In conclusion these data show that in 5990 women living in Tuscany, Italy, the mean daily CaI is 703 mg which is below the recommended dietary allowance. The lower daily CaI was found among the older women (465 yrs) who are at higher risk for osteoporosis. CaI (mg/day)

No. (%)

Age (m±SD)

BMI (m±SD)

8 OP (%)

5500 501–800 801–1000 41000

1774 (29.6) 2290 (38.2) 986 (16.5) 940 (17.7)

58.2 57.6 57.4 56.3

27.1 27.1 26.9 26.9

33.9 38.9 14.2 13.0

(± (± (± (±

9.1) 8.8) 8.5) 8.3)

8 OP = osteoporosis defined as T-score 5–2.5.

(± (± (± (±

6.8) 7.3) 6.7) 6.7)

S76 P241SU. EVALUATION OF BONE MINERAL DENSITY IN YOUNG ADULTS WITH CYSTIC FIBROSIS Pache I1, Udry E2, Sauty A2, Lamy O1; 1Department of Osteology, University Hospital, Lausanne, Switzerland, 2Department of Pulmonology, University Hospital, Lausanne, Switzerland Aims: To determine the bone mineral density (BMD) and the relation with body mass index (BMI), 25-OH-vitamin D (25-OH-D) level and calcium and vitamin D supplementation in young adults with cystic fibrosis (CF). Methods: 25 patients with a stable disease or on a waiting list for lung transplantation. Results: The mean age at which the first densitometry was done in adult patients with CF was 26.4 ± 5.8 years. Twelve (48%) patients had osteoporosis on one or more site, 8 (32%) had osteopenia on one or more site and 5 (20%) had a normal BMD. The site where we most frequently found a low BMD were the lumbar spine (90%) and the femoral neck (85%). Seven out of eight patients waiting for lung transplantation had osteoporosis and one had osteopenia. Patients with a low BMI had a significantly lower BMD (p = 0.04). Calcemia, phosphatemia and alkaline phosphatase values were similar in all patients. 25-OH-D values were also similar with 78.6% of the patients having a level under 25 mmol/l. Only 50% of the patients with a low BMD received calcium and vitamin D supplementation before the bone evaluation. 25-OH-D values were not higher in patients under 800 UI oral vitamin D supplementation. Conclusions: Low BMD is a frequent problem in young adults with CF. In our population, the first bone evaluation in patients over 18 years occurred rather lately and only half of the patients received a calcium and vitamin D supplementation before densitometry assessment. In order to prevent complications related to osteoporosis or graft-induced osteoporosis, such as vertebral fractures, more attention should be given to the bone status of these patients. Earlier bone evaluation would lead to a better prevention of osteoporosis. More studies should be done on a possible malabsorption of oral vitamin D supplementation in patients with CF.

P242MO. PREVALENCE OF OSTEOPOROSIS AND FRACTURE IN DIFFERENT ETHNIC SUBGROUPS IN MILAN AND NEIGHBOURHOOD

Abstracts age at menopause, BMI, HRT, and calcium intake significantly influenced the risk of OP and fracture as well as belonging to the Southern subgroup, despite of protective anthropometric measures. Besides lifestyle variables and then modifiable risk factors, interaction between genetic background and geographic setting can modify the prevalence of OP and related fracture.

P243SA. BONE MINERAL DENSITY IN DIFFERENT REGIONS OF NORWAY. THE NOREPOS STUDY Meyer HE1,5, and in alphabetic order: Berntsen GKR2, Forsmo S3, Fønnebø V2, Langhammer A3, Schei B3, Søgaard AJ1, Tell G4; 1 National Health Screening Service, 2University of Tromsø, 3 Norwegian University of Science and Technology, 4University of Bergen, 5University of Oslo Aims: Norway has a very high incidence of osteoporotic fractures, and a higher incidence of fractures has been reported in urban as compared to rural areas. The purpose of the present study was to evaluate whether there are regional differences in bone mineral density (BMD) within Norway. Methods: We used data collected in 4 large population based health surveys performed in the cities of Oslo and Bergen in South Norway, the city of Tromsø in Northern Norway and the rural county of Nord-Trøndelag in Middle Norway. In all studies, distal forearm BMD was measured by DTX-100 (SXA) in subsamples following the same protocol, and cross-calibration was done using the European Forearm Phantom. Whereas two of the studies included random samples of all adults, the Oslo study only included ages 30, 40, 45, 60 and 75, and Bergen ages 49–50 and 73–75. In the present analysis we have therefore concentrated on ages 40–50 and 70–75 (n = 3,522). The Tromsø data was used as reference population, and comparison was made by twosample t-test and analysis of covariance (age adjustment). Results: As a general pattern, distal BMD was similar in the three cities of Oslo, Bergen and Tromsø. On the other hand, BMD was approximately ½ standard deviation higher in the rural county of Nord-Trøndelag. This was evident in middle-aged men (p50.001) and women (p50.001) and in older men (p = 0.002), but not in older women (p = 0.5). Conclusion: We found differences in BMD between urban and rural areas in Norway, which might help explain differences in fracture incidence.

Varenna M, Binelli L, Zucchi F, Rossi V, Sinigaglia L; Department of Rheumatology, University of Milan, Milan, Italy Ethnic differences as well as racial differences have been shown to affect bone mass and fracture incidence. Ethnic differences can be referred both to environmental variables and behavioral variables such as diet, parity, physical activity, and hormon replacement therapy (HRT). Aim of this study was to ascertain if a different prevalence of OP and fracture could be detected in different Italian ethnic subgroups under the influence of the same environmental factors. In the last five years, 1764 women (mean age 55.7 ± 5.1 yrs) at their first lumbar densitometric evaluation (DXA, L2–L4) were recruited. These women were born in the Southern regions of Italy, but were living in the Northern regions (Milan and neighbourhood) for more than 20 years. As control group a sample of 4019 subjects born and living in Milan and neighbourhood was selected. No differences in age, age at menarche and menopause were found between the two groups. Parity and body mass index (BMI) were higher in women born in Southern Italy. Calcium intake, prevalence of subjects in HRT and women regularly doing physical activity were greater in the control group, while job-related physical activity did not show difference between the groups. Prevalence of OP (30.5% vs 25.0%; p50.001) and the number of postmenopausal fractures, excluding fractures following major trauma, (4.8% vs 3.6%; p = 0.01) were significantly higher in women born in Southern Italy. To investigate the independent role of each considered risk factor, stepwise multiple logistic analyses were performed. Age,

P244SU. PREVALENCE OF OSTEOPOROTIC VERTEBRAL FRACTURES Armbrecht G1, Blenk T1, Eastell R2, Glueer CC3, Reid DM4, Roux C5, Felsenberg D1; 1Centre of Muscle and Bone Research, Free University Berlin, Germany, 2Clinical Sciences Centre, University of Sheffield, UK, 3Dept. of Diagnostic Radiology, University Hospital CAU, Kiel Germany, 4Dept. of Medicine &Therapeutics, University of Aberdeen, UK, 5CEMO, Hopital Cochin, Paris, France In the framework of the Osteoporosis and Ultrasound Study (OPUS) the prevalence, shape and spatial distribution of vertebral osteoporotic fractures were determined. In this population-based study lateral radiographs of the t-spine and l-spine of 2435 females aged 55 to 80 years were taken according to a standardized protocol. 5 centres in 3 European countries (UK, France, Germany) participated, all X-rays were evaluated centrally. The vertebrae T4 to L4 were evaluated quantitatively including the morphometric measurement of three vertebral heights and the calculation of ratios from these heights for determination of deformed vertebrae. If one or more of the ratios (a/p, m/p, p/pup, p/plow) were below the threshold of 0,8 the vertebra was defined

Abstracts as deformed. For each quantitative deformed vertebra additionally a qualitative evaluation including a differential diagnosis was performed and for each osteoporotic deformed vertebrae (according to quantitative and qualitative evaluation) the shape of the deformation (wedge, concave, biconcave, crush) was described. The prevalence of vertebral deformation was 19,96%, for osteoporotic fractures a prevalence of 16,18% was found. A total of 859 vertebral bodies were deformed: 728 (84,26%) osteoporotic, 116 (13,43%) degenerative and 20 (2,31%) due to other reasons. No significant difference in the prevalence of vertebral osteoporotic fractures was found between the different countries but, as expected, there was an increase in prevalence with age. Of all osteoporotic deformed vertebrae, 30,35% were wedge shaped, 57,69% concave, 9,2% biconcave and only 2,74% crushed (according to the prominent appearence). The spatial distribution showed a peak for wedge shaped deformities in the mid t-spine and the thoracic-lumbar junction, for the concave fractures a peak in the thoracic-lumbar junction and the l-spine. No peaks were found for biconcave and crushed fractures.

P245MO. POSITIVE ASSOCIATIONS BETWEEN FRUIT & VEGETABLE CONSUMPTION AND BONE MASS IN LATE POSTMENOPAUSAL AND ELDERLY WOMEN New SA1, Smith R2, Brown JC1, Reid DM2; 1University of Surrey, Guildford, England, UK, 2University of Aberdeen, Aberdeen, Scotland, UK There is support for the importance of the skeleton in acid-base homeostasis. The findings of the DASH II intervention trial showing a significant reduction in bone turnover in the fruit & vegetable group are noteworthy (Lin et al 2001). The aim of this study was to determine the influence of fruit & vegetable consumption on bone mineral density (BMD) in late postmenopausal and elderly women, for whom we have previously shown positive associations between potassium intake and bone health (New et al 1998). Women (n 159) were aged 55–87 years and were recruited at random through medical practices as part of a European osteoporosis study (COMAC). BMD scan of the spine [LS] and hip (femoral neck [FN], femoral trochanter [FT] and femoral Wards [FW]) was measured using DXA and dietary intake of fruit & vegetables (calculated as both frequency of consumption and amounts per week) was assessed using our validated FFQ. Information was also collected on weight, height, smoking history, use of medication etc. The mean frequency of fruit & vegetable consumption was 13.7 times/wk and 19.0 times/wk respectively. Significant correlations were found between fruit intake and both LS BMD (P50.02) and FT BMD (P50.01) with similar trends seen at the FN and FW BMD sites. Total fruit & vegetable intake was also found to be significantly correlated to the BMD sites measured (LS BMD, r = 0.2, P50.05; FT BMD r = 0.24, P50.005). Associations remained significant after adjustment for the confounding factors. These data confirm previous findings in the elderly population (Tucker et al 1999) and although limited by the cross-sectional study design, provide further evidence of a positive link between alkali-forming foods and skeletal health.

References Lin et al (2001). J Bone Miner Res 16(S1):S511 New et al (1998). Proc Nutr Soc 57:37A Tucker et al (1999). Am J Clin Nutr 69:727-736

S77 P246SA. HYPERCHOLESTEROLEMIA AND ELEVATED LIPOPROTEIN (A) ARE ASSOCIATED WITH HIGHER PREVALENCE OF LOW BONE MASS IN POSTMENOPAUSAL WOMEN Orozco P; ABS Gotic, Barcelona, Spain Aims: To compare the bone mineral density (BMD) in early postmenopausal women with normal and atherogenic lipid profile. Methods: Fifty-two postmenopausal women with overweight (body mass index 25–30 kg/m2) and physiological menopause after 45y (1–7 y), and without any current or past pathology or treatment that altered bone or lipid metabolism (as estrogens, diabetes or hypertension, etc), no heavy smoker (510 pack/y), regular exercise, no alcohol abuse. Lumbar and femoral BMD was assessed by DXA. Lipidic profile included cholesterol, HDLc, LDLc, triglycerides, lipoprotein (a), Apo-A1, Apo-B. Hypercholesterolemia (5240 mg/dl), elevated LDLc (5160 mg/dl), elevated Lp(a) (525 mg/dl), and low BMD (t-score 5–1 SD). Results: Hypercholesterolemic group (n = 23) had higher prevalence of low BMD than those with normal cholesterol (lumbar spine: 82.6% vs. 55.2%, p = 0.04, OR: 3.8 [95%CI: 1.04–14.2]; femoral neck: 65.2% vs. 37.9%, p = 0.05, OR: 3.1 [95%CI: 0.98–9.6]). Elevated LDLc group (n = 16) had higher prevalence of low BMD at femoral neck (75% vs 39%, p = 0.01, OR: 4.7 [95%IC: 1.26–17.5]). Elevated Lp(a) group(n = 23) had higher prevalence of low BMD at lumbar spine (87% vs. 51.7%, p = 0.007; OR: 6.2 [95%CI: 1.5–25.6]). Those with any lipidic parameter elevated had higher prevalence of low BMD than those with normal levels (lumbar spine: 81.8% vs 42.1%, p = 0.003, OR: 8.6 [95%CI: 1.7–22.0]; femoral neck: 60.6% vs 31.6%, p = 0.04, OR: 3.3 [95%CI: 1.01–11.0]). Curiously intercorrelations between lumbar and femoral BMD were always not significant in all any elevated lipids. Hypercholesterolemia and elevated Lp(a) were independent predictors of lumbar BMD and modified negatively the effect of neck BMD in the prediction of lumbar BMD (R2 = 0.60). Calcium intake, time since menopause, age, age at menopause and BMI did not show interaction or confusion. Conclusions: Hypercholesterolemia and elevated Lp(a) are associated with low BMD and their effect seem to be more important in lumbar spine.

P247SU. IMPACT OF DIFFERENT MORPHOMETRIC CRITERIA FOR EVALUATION OF INCIDENT VERTEBRAL DEFORMITIES Hoseyni MS1, Ritter-Hrncirik C1, Li Z1, Eastell R2, Miller PD3; 1 Procter & Gamble Pharmaceuticals, Mason, USA, 2University of Sheffield, Sheffield, UK, 3Colorado Center for Bone Research, Denver, USA To evaluate the impact of different Quantitative Morphometric (QM) criteria (15%/4mm vs. 20%/4mm) on the determination of incident vertebral deformities, a random sample of 300 osteoporotic women with paired (baseline and one year follow-up) radiographs and digitized measurements was analyzed. The estimated one-year incidence was 27% for the 15%/4mm criterion and 16% for 20%/4mm vs. the radiologically assessed and verified incidence of 8%. The 15%/4 mm and 20%/4 mm criteria resulted in 76% and 87% specificity, 65% and 52% sensitivity, and 81% and 73% false positive incident deformities, respectively, when compared to Semi-Quantitative assessments with verification (using the Genant scoring method). Therefore, while both criteria were deemed useful for initial screening (based on acceptable specificity), the 15%/4mm criterion with adjudication was specified and used in the risedronate VERT clinical trials to attain both maximum sensitivity, and to remove the false positives. The impact of the 20%/4 mm height reduction criterion (QM) was further compared to the criterion that was specified and used

S78 (15%/4 mm reduction) for determination of incident vertebral deformities in the risedronate VERT clinical trials. The results indicated that while the 15%/4 mm criterion produced more false positive deformities vs. the 20%/4 mm criterion, the pre-specified adjudication process eliminated almost all (99%) of the additional deformities resulting from the 15%/4 criterion (vs. 20%/4mm criterion). In the VERT trials, only 4/2442 patients would have been re-classified as not fractured using the 20% criterion (2 placebo, 2 risedronate). In conclusion, when used within an adjudication process, a 15%/4 mm criterion vs. 20%/4 mm does not have any meaningful impact on the estimated incidence of deformities as adjudication eliminates almost 100% of discrepancies.

P248MO. PEAK BONE MASS AND RISK FACTORS IN HEALTHY YOUNG MEN Kyriazopoulos P, Trovas G, Lyritis PG, Galanos A, Lyritis GP; Laboratory Research of Musculoskeletal System The aim of the study was to evaluate the effects of dietary factors (calcium, proteins, alcohol, coffee and tea intake), exercise level, sun exposure and period of immobilization on bone mineral content (BMC) and bone mineral density (BMD) in healthy young men. Methods: we examined a group of 100 healthy men, aged 19– 22. Mean weight was 77kg + 11,66 and height 179,15cm + 6,06. Distal BMC, distal BMD and ultradistal BMD at the radius were measured by single X-ray absorptiometry (Osteometer DTX 100). The data concerning these factors were obtained through a questionnaire. The correlation between BMD, BMC and these factors was evaluated using a one-way analysis of variance ANOVA model. The 100 men were divided in four groups of calcium intake (5400 mg/d, 400–800 mg/d, 800–1200 mg/d, 4200mg/d) and in two groups by the duration of immobilization (51 month, 4 1 month). Results: Calcium intake and the duration of immobilization were statistically significant correlated with BMD and BMC at distal radius. The subjects that had low calcium intake (5400 mg/d) were found to have significant lower BMD than those consuming higher amounts of this element (the three other groups) (p5 0,014). As it concerns the duration of immobilization those who were immobilized for more than one month had lower BMC at distal radius than those of the other group (5 1 month) (p5 0,043). There was no significant correlations between the other factors (alcohol, coffee, tea, proteins intake and sun exposure) and BMD or BMC. Conclusions: Low calcium intake (5400mg/d) and periods of immobilization for more than 1 month have significant negative effect on peak bone mass of young men.

P249SA. PHYSICAL ACTIVITY, QUANTITATIVE BONE ULTRASOUND AND BONE MINERAL DENSITY IN A RANDOM SAMPLE OF URBAN PORTUGUESE ADULTS Araujo D1, Costa L1, Santos AC2, Pereira S2, Barros H2; 1Dpt. Reumatology, H de Ponte de Lima, Ponte de Lima, Portugal, 2Dpt. Epidemiology, University of Porto Medical School, Porto, Portugal Aims: Physical activity has been related to enhanced bone mass. There is evidence supporting a role for physical activity in minimizing bone loss and contributing to bone mineral gain. However, conflicting results were reported after both crosssectional and prospective studies namely when the effect is related to age strata. Thus we aimed to evaluate the association between physical activity and bone characteristics in a random sample of non-institutionalized adults.

Abstracts Methods: Bone mineral density (BMD) was measured at the femur and lumbar spine using DXA (Hologic QDR 1500) in 538 randomly selected healthy women. Osteoporosis was defined according to WHO. Additionally bone ultrasound parameters were measured at the calcaneus (Sahara-Hologic) in 498 women and in 124 men (age range 20–90 years). Information on demographic, social, anthropometric and behavioral characteristics was obtained using a structured questionnaire. Physical activity was measured as MET through a detailed validated daily activities questionnaire pertaining to the previous year. Participants were categorized according to tertiles of physical activity. Results: In women, evaluated using DXA, osteoporosis prevalence and BMD significantly increased at the femur and the lumbar spine (1st tertile –0.895 vs. 3rd 0.942 g/cm2, p50.001) with increasing tertiles of physical activity. This increase remained statistically significant after adjusting for body mass index, but age modified the effect – older women (460 years) presented a reverse effect. Similar results were found for the bone ultrasound parameters, with BUA increasing from 68.4 to 79.0 dB/MHz, p50.001. In male participants, every quantitative bone ultrasound parameter significantly increased with increasing physical activity, even after adjusting for confounders. Conclusions: Bone mineral density at all evaluated sites and regardless of measurement technique was positively and significantly associated with physical activity. However, older women showed a decrease in BMD with increasing physical activity.

P250SU. AGE-RELATED TRENDS IN HIP FRACTURE IN GREECE FROM 1977 TO 1997 Kataxaki EV, Koundis G, Galanos A, Koulouris I, Lykomitros V, Paspati I, Lyritis G; Laboratory For The Research Of The Musculoskeletal System (LRMS), University of Athens, KAT Hospital, Kifissia 145 61, Greece We investigated hip fracture incidence occurred in Greece in years 1977, 1982, 1987, 1992 and 1997 with the purpose to investigate the trends in hip fracture incidence within these 20 years. Data collection was achieved with the cooperation of public and private orthopaedic departments all over Greece. Greek population details were taken from the National Census Department. The absolute number of hip fractures were in 1977: 5100, 1982: 6900, 1987: 9250, 1992: 10953, and 1997: 12106. Ageadjusted incidence increased 96.05% during the period 19771997, more than expected due to population aging. The most affected age-group was that of 80 and over. Approximately 51% of the patients with hip fracture in 1997 were 80 and over, while this age-group was only 22.49% of patients in 1977. The rate of increase of hip fracture incidence appears to slow down (from annual increase of 9.05 fractures/100.000 inhabitants in 1977– 1982 period and 11.01 in 1982–1987 to 8.04 in 1987–1992 and 5.23 in last study period). Looking to the secular trends of hip fracture incidence in different age-groups, it was found that people aged 50–69 did not present any change in hip fracture incidence during the 20 years of observation. People aged 70–79 showed a significance increase of the rate of hip fracture incidence during the decade 1977-1987, but during the next decade 1987–1997 the rate of increase appears to slow-down dramatically. The group of patients aged above 80 demonstrates a continuous increase of hip fracture incidence during study period. These findings sugggest the existence of heterogeneity in the etiology and epidemiology of hip fractures in Greece. It seems that although hip fracture incidence rate tends to slow down hip fracture incidence in the very elderly increases continuously suggesting that other factors than osteoporosis play role in the pathogenesis of hip fracture.

Abstracts P251MO. ILIOCOSTAL DISTANCE (ILCD) IS ASSOCIATED WITH PREVALENT VERTEBRAL (VERT) AND NON-VERTEBRAL (NV) FRACTURES IN PATIENTS REGISTERED IN THE CANADIAN DATABASE OF OSTEOPOROSIS AND OSTEOPENIA (CANDOO) Adachi JD1, Olszynski WP2, Sebaldt RJ1, Ioannidis G1, Hanley DA3, Brown JP4, Josse RG5, Murray T5, Petrie A1, Goldsmith CH1; 1 McMaster University, Hamilton, ON, Canada, 2University of Saskatchewan, Saskatoon, SK, Canada, 3University of Calgary, Calgary, AB, Canada, 4University de Laval, Laval, QC, Canada, 5 University of Toronto, Toronto, ON, Canada To optimize the treatment of osteoporosis, it is essential to diagnose, as early as possible, patients at risk for fracture. Thus, the objective of this observational study was to assess the relationship between ILCD and the number of VERT and NV fractures. CANDOO is a prospective, observational database designed to capture clinical data in patients with osteoporosis. CANDOO was searched for patients with at least one ILCD measurement. ILCD was defined as the vertical distance between the iliac crest and the tenth rib (cm). A total of 549 individuals were enrolled in the study. We performed multivariable regression analyses modeled for the number of VERT and NV fractures. Potential covariates included anthropometric, medications, illnesses, dietary calcium intake, family history of fracture, lifestyle factors and bone mineral density. Regression models were selected based on Mallows C(P) statistic. Regression Coefficient parameter estimates and 95% confidence intervals (CI) were calculated. The number of VERT and NV fractures per patient varied from 0 to 9 and 0 to 7 respectively. Adjusted results indicated that ILCD was negatively associated with the number of prevalent VERT (–0.21; 95% CI: –0.029, –0.13) and the number of prevalent NV fractures (–0.10; 95% CI: –0.15, –0.04). ILCD measurements may help physicians identify patients at risk for osteoporotic fractures.

P252SA. POSTMENOPAUSAL WOMEN WITH FOREARM FRACTURE SHOULD BE DIAGNOSED FOR OSTEOPOROSIS Jutberger H1, Sinclair H2, Malmqvist B3, Obrant K4; 1Sahlgrenska ¨ stra, Gothenburg, Sweden, 2Alingsa˚s University Hospital, O Hospital, Sweden, 3Ga¨vle Hospital, Sweden, 4Univerity Hospital, Malmo¨, Sweden Aim: Should postmenopausal women with forearm fracture be diagnosed for osteoporosis? Method: In a case-control study at two country hospitals in Sweden, 110 consecutive postmenopausal women (age 50–75) with distal radius fracture were examined with the DEXAtechnique (Hologic 4500), on the uninjured radius, lumbar spine and the right hip within three weeks after the fracture occurrence. Data was compared with 55 age-matched controls from the Swedish Population Register. Results: There were no disparities in measurements in the two hospitals. The mean age of each group was 64 and BMI 26. The incidence of osteoporosis according to the WHO’s definition (Tscore 5–2.5)at any measurement site was higher in the fracture group, 44 percent compared with 27 percent in the control group (p = 0.029).The fracture group had 12 percent lower bone mineral density in the distal radius compared with the control group (p = 0.001), and 5 percent lower bone mineral density in the lumbar spine and hip compared with that of the control group (NS). Normal bone mineral density was found in 13 percent of those in the fracture group compared with 31 percent in the control group, (p = 0.009). A higher rate of previous fractures was noted in the fracture group: 37 percent compared with 16 percent in the control group (p = 0.006). Conclusion: The study reflects the situation in general health care, where osteoporosis is common in postmenopausal women

S79 with distal radius fracture. This patient group can easily be identified and is suitable to be diagnosed for osteoporosis using bone density measurement prior to a decision being reached with regard to any treatment. According to the guideline for medical treatment (T-score 5–2.0 and fragile-fracture) as outlined by the Swedish Osteoporosis Society, 75 percent of postmenopausal patients with forearm facture should be considered for such treatment.

P253SU. BURDEN OF SPECIFIC ILLNESSES IN RELATION TO OUTCOMES OF HIP FRACTURE Wehren LE, Magaziner J; University of Maryland School of Medicine, Baltimore, USA Aims: To evaluate the magnitude of effect of individual comorbid illnesses on multiple outcomes after hip fracture in elderly men and women. Methods: Community-dwelling elderly men and women (n = 804) who sustained hip fractures in 1990 and 1991 who were admitted to one of 8 hospitals in the metropolitan Baltimore, MD, USA area were invited to participate in a longitudinal study of sequelae of hip fracture. Information about health conditions and functional ability was collected during the hospitalization and at 2, 6, 12, and 24 months later. Nursing home residence and survival were also ascertained. Eight specific index medical illnesses (arthritis, chronic obstructive pulmonary disease [COPD], congestive heart failure [CHF], diabetes mellitus [DM], hypertension [HBP], myocardial infarction [MI], stroke, and transient ischemic attacks [TIA]) that were common and/or serious were chosen from a list of more than 20 conditions, comparing status at the time of fracture and subsequent functional ability, nursing home residence, and survival. Results: Participants with a history of COPD, DM, or stroke were somewhat younger than participants reporting other illnesses. Multiple comorbid illnesses were common; on average, participants reported at least 3 conditions in addition to the index illness. Functional limitations at time of fracture were greatest in participants with a history of CHF or stroke. CHF, COPD, and MI were associated with significantly longer hospital stays postfracture. Participants with a history of TIA were more likely to be in nursing homes; participants with MI, COPD, DM, and HBP were less likely to survive one or two years. Functional limitations after fracture were more common in participants with CHF, MI, stroke, and TIA. Conclusions: The consequences of co-existing illness at the time of hip fracture vary according to the condition. Estimates of quality of life and impact of fracture must consider this variation.

P254MO. THE PREVALENCE OF VERTEBRAL FRACTURE IN THE POPULATION AGED 50 YEARS AND OVER ACCORDING TO DIFFERENT MORPHOMETRIC ALGORITHM Yevsigneeva LP1, Lesnyak OM1,2, Piven’ AI3; 1Ural’s State Medical Academy, Yekaterinburg, Russia, 2Ural’s State Medical Academy, Yekaterinburg, Russia, 3Regional Hospital no1, Yekaterinburg, Russia Assessment of prevalence of vertebral fractures depends on using morphometric algorithms. The aim of this study was to determine the prevalence of vertebral fracture using different morphometric algorithms and to examine the agreement between them. Methods: The sample of 495 subjects (236 male and 259 female) aged 50 years and over was randomly selected from the population of Yekaterinburg, Russia. The vertebral deformities

S80 were evaluated by lateral thoracic and lumber spine radiographs. Vertebral deformity was defined morphometrically using 25% level by Felsenberg and Eastell algorithm. According to Eastell algorithm deformities were graded 1 if the deformity 4 3 SD, but 5 4 SD, and grade 2 if 4 4 SD. A visual assessment of radiographs allowed exclude nonosteoporotic deformities. Results: Using 3 SD as a limit of normality, the male prevalence of osteoporotic vertebral fractures of 10,2% was similar to the female prevalence of 8,5%. Using 25% level by Felsenberg this reduced to 7.6% in male and 6.9% in female (p40.05) and using 4 SD this was 6.4% and 6.6% respectively (p40.05).The agreement (per subject) between Eastell (5 3 SD) and Eastell (5 4 SD) was 97,2% (kappa = 0.81), the agreement (per subject) between Eastell (5 3 SD) and Felsenberg (25% level) was 98.0% (kappa = 0.88) and one between Eastell (5 4 SD) and Felsenberg (25% level) was 97,6% (kappa = 0.81). Almost one third of persons with vertebral deformities had nonosteoporotic ones. Although prevalence of vertebral fracture was similar among sex, the severe deformities (2 grade) prevailed in female group (86.2%) then male one (62.5%), p50.05. Conclusion: There is good agreement between morphometric algorithms for assessing prevalent vertebral fractures. The prevalence of vertebral fracture is similar among men and women, but the female group may be presented with more severe deformities then the male group.

P255SA. BONE MINERAL DENSITY OF PORTUGUESE POPULATION: NORMATIVE DATA AND PRELIMINARY REPORT Vilar A, Simoes E, Micaelo M, Vaz Patto J; Portuguese Institute of Rheumatology, Lisbon, Portugal To determine bone mass in general Portuguese population, a randomly nationwide survey was held through 14 locations representing an appropriate selection of cities. The inclusion criteria were Caucasians randomly selected, between 20 and 80 years old from both sexes without previous hip fracture, non pregnant, or without menopause before 45 years. Height, weight, body mass index, spine and hip DEXA with a QDR Hologic was taken. A questionnaire regarding demographic data, nutritional habits, diseases and medications known to affect bone mineral metabolism, maternal history, estrogen status or fragility fractures was recorded. We analyzed results of 813 man and women divided by decennial agegroups from 20 to 80 years. For each agegroup and region we calculated the Mean and its 95% Confidence Interval. A short-term precision test (Glu¨er et al.) was conducted in 31 individuals to determine precision error (0,008g/cm2) and coefficient of variation (0,78%). Results of spine BMD in Table 1 show in woman a steady state between 20 and 39 and a progressive decrease of the mean thereafter with age until last decennial; the descending slope beginning at age group 50. Peak BMD occurred at 30 year-old woman. The mean annual loss of BMD was 0.0028 g/ cm2 on the lowest side of published international studies. In man Table 2 show a similar age peak BMD with higher absolute values through all agegroups and a mean annual loss of 0,0017g/cm2. Proximal hip values showed a peak BMD in the 20-year-old group in both sexes. Results shown in Table 3 and 4 reveal a steady slope decreasing in last decennial agegroups with a mean annual loss for man and woman of 0,0025 and 0,003g/cm2 respectively. There were no significant differences of the mean BMD between inland and seaside cities. When compared with similar studies these BMD results are in absolute values lower. Further stratification will clarify this first attempt to assess were our BMD stand among European and Mediterranean countries.

Abstracts P256SU. INCREASED PREVALENCE AND RISK OF OSTEOPOROSIS IN RHEUMATOID FACTOR-POSITIVE RHEUMATOID ARTHRITIS (RF POS RA) AS COMPARED TO RHEUMATOID FACTOR\NEGATIVE RHEUMATOID ARTHRITIS Dreher R1, Lingg G1,2, Listing J1,2, Zink A1,2; 1Hospital of Rheumatic Disease Bad Kreuznach, 2Epidemiology Department Berlin Aims: To compare different rheumatological diseases as risk factors for osteoporosis. To define patients functional capacity, the severity of the disease, the disease duration and inflammatory activity as risk factors for osteoporosis. Methods: Women 4 50 years with various underlying rheumatological diseases were evaluted. Osteoporosis was defined as values for bone mineral density 2.5 SD. or more below the young mean in DXA L2–L4 or DXA Neck (LUNAR) or below 122 mg HAE (Hydroxyapatite Equivalent) in lumbar QCT. Results: Prevalence of osteoporosis: RF pos. RA (329/953, 34.5%), RF neg. RA (142/595, 23.9%) Polymyalgia Rheumatica (54/173, 31.2%), Connective Tissue Diseases (17/103, 16.5%), Ankylosing Spondylitis (12/35, 34.3%), Osteoarthritis (141/1158, 12.2%), Low Back Pain Syndrome (76/408, 18.6%), Risk factors for osteoporosis calculated as odds ratios (OR) in logistic regression analysis models adjusted for age and underlying rheumatological diseases (OR for osteoporosis compared with osteoarthritis), RF pos. RA OR = 3.45 RF neg. RA OR = 2.56 Polymyalgia Rheumatica OR = 2.65 Connective Tissue Diseases OR = 1.85 Ankylosing Spondylitis OR = 5.13.Risk factors for osteoporosis in inflammatory rheumatic diseases compared with osteoarthrosis calculated as adds ratio (OR) adjusted for age, disease duration, functional capacity, severity of the disease and steroid treatment: RF pos. RA OR = 1.74 RF neg. RA OR = 1.72 Polymyalgia Rheumatica OR = 2.53 Connective Tissue diseases OR = 1.00 Ankylosing Spondylitis OR = 4.27. Conclusion: The increased risk of osteoporosis in RA is not dependent on the seropositive or seronegative disease entity but on to the severity, functional capacity and duration of the disease.

P257MO. PREVALENT AND INCIDENT OSTEOPOROTIC VERTEBRAL FRACTURES AS RISK FACTOR FOR SUBSEQUENT OSTEOPOROTIC FRACTURE AND MORTALITY Naves M, Dı´az Lo´pez JB, Go´mez C, Rodrı´guez Rebollar A, Rodrı´guez Garcı´a M, Cannata JB; Bone and Mineral Research Unit, Instituto Reina Sofı´a de Investigacio´n, Hospital Central de Asturias, Oviedo, Asturias. Spain There are few data concerning the morbidity, mortality and epidemiology of vertebral fracture. The aim of this study was to evaluate the effect of prevalent and incident vertebral fractures as risk factors for further osteoporotic fractures and mortality. The study was performed in a cohort of 316 women and 308 men older than 50 years belonging to the EVOS study, randomly selected from our city register. At the beginning of the study and fours years later, dorsal and lumbar x-rays were performed. In addition, evaluation of the incidence of osteoporotic non vertebral fractures was performed throughout 8 years. Overall, the incidence of vertebral fracture, Colles fracture and hip fracture was 985, 428 and 306 fractures/100,000 person-years respectively. The incidence of all osteoporotic fracture was higher in women than in men (twice in the vertebral fracture and 5 times in Colles and hip fractures). Vertebral fracture (adjusted by age and sex) was a strong risk factor for a new vertebral fracture [RR = 4.7 (1.8–11.9)], hip fracture [RR = 6.7 (2.0–22.7)] and Colles fracture [RR = 3.0 (1.1– 7.8)]. The presence of both, prevalent and incident vertebral fracture was associated with a higher risk of having a hip fracture [RR = 10.0 (2.0–50.2)] and Colles fracture [RR = 5.5 (1.3–23.4)]. In addition, in women, the vertebral fracture was associated with a higher mortality using the most restrictive radiological

Abstracts criteria to define vertebral fracture (Genant grade II and McCloskey-Kanis). By contrast, no association was found in men. These results demonstrate the association between a previous vertebral fracture with increments in the incidence of new osteoporotic fractures of any type. In addition, we found a significant higher mortality rate in women having vertebral fractures. These findings support the necessity to prevent the occurrence of vertebral fractures in order to limit their strong negative impact on morbidity and mortality.

P258SA. BONE MINERAL DENSITY MEASURED BY DUALENERGY X-RAY ABSORPTIOMETRY IN THE NORMAL TURKISH POPULATION Dilsen Dilseng, Ertungealp Ertungealpe, Goksoy Goksoyt, Barden Bardenh, Selim Selimn, Issever Isseverh; Istanbul Medical School/Turkey, Van Medical School/Turkey, GE-Lunar/Madison USA, Ge-Lunar/Turkey, Istanbul Medical School/Turkey We aimed to establish normal reference values for vertebral, proximal femur, distal radius and total body bone density (BMD in g/cm2) of healthy Turkish population; to examine the effect of age and body mass index on BMD; to compare our results with the reference values of USA/European and Middle East countries. The investigation was conducted at 22 centers in 13 cities, and included 515 women and 288 men aged 20–80 years. BMD measurements were performed at lumbar spine (L2–L4), femur (four regions), distal radius and total body using a DEXA system (Model DPX-IQ, GE-Lunar, Madison, WI, USA). BMDs were analyzed as the mean values for all measurement sites. Comparisons between age groups were made by Student’s ttest and Mann Whitney U test. The affect of age, weight and height on BMD were determined using linear regression and multiple regression analysis. The mean weight and height of the women was 66±10.7 kg and 157.8±5.9cm. The mean weight and height of the men was 73.8±10.8 kg and 170.9±6.2cm. BMD values of Turkish were generally lower than USA/European values. Women spine BMD was about 4% lower than USA/European values, 5.5% higher than Lebanese women. Femoral neck BMD values for Turkish women were 3% lower in all ages compared with USA/European and 5% higher than Lebanese women. The spine BMD of Turkish men was 11% lower than USA/European values throughout the age range (20–80), and only 3% higher than Lebanese spine values. Femoral neck BMD for men were 2.8% lower compared to USA/European and 4.8% higher than Lebanese men. Measurement of the distal radius in both sex were 51% lower than USA/ European and 48% lower than Lebanese references in all age ranges. Our study is the first in Turkey aimed at creating reference values for BMD using the DEXA method in a large sample as 803 normal Turkish subjects. The mean BMD of Turkish subjects at spine, femoral neck and radial shaft were lower than USA/ European reference data. These differences ranged from 2–11% depending on measurement sites. Weight was a significant predictor of BMD at weightbearing sites. If we use USA/European reference values, based on WHO criteria, we potentially over diagnose the prevalence of osteoporosis in Turkish subjects.

P259SU. PROPOSAL OF RATIONAL SCREENING FOR OSTEOPOROSIS IN THE PRIMARY CARE SETTING Hren R1, Salobir B2, Breznik M1, Kocijancic A2; 1University of Ljubljana, Ljubljana, Slovenia, 2Clincial Center, Ljubljana, Slovenia Objective of our study is to assess simple decision rules that could enhance identifying patients with high risk of fracture while concurrently minimizing number of unnecessary measurements. In the study, 357 primary care physicians (GPs and gynecologists) referred their patients to BMD measurements based on

S81 the following decision rules: women should be postmenopausal for at least 5 years, should have body mass index (BMI) less than 26 kg/m2, and should have never been diagnosed with osteoporosis. BMD of lumbar spine and/or hip was measured by DEXA at 5 centers. Results of BMD measurements were expressed in terms of the T-score and were forwarded to the primary care physicians. 2323 women were enrolled in the study; by the end of the study, 331 physicians (93%) reported results on 2189 women (94%). 1331 women of 2189 (61%) were identified as osteoporotic and 631 (29%) as osteopenic. Approximately 27% of patients with osteoporosis suffered from previous low-trauma fracture. Average age of patients with osteoporosis was 67 years (range 31 through 92 years), with 8% younger than 55 years and 17% older than 75 years. Among patients with osteoporosis, 81% had BMI from 21 to 27 kg/m2, and 4% had BMI less than 19 kg/m2. Results of our study suggest that three simple decision rules provide efficient guidance for BMD measurement referrals. Moreover, these decision rules proved to work well in the primary care setting. Since a vast majority of women enrolled in the program (90%) had either osteopenia or osteoporosis, it can be expected that the decision rules primarily apply to identification of patients who are at relatively high risk of fracture. These rules should be thus recognized as the initial judicious tool for identifying patients with osteoporosis, which should be later supplemented by other broader criteria.

P260MO. APPLICATION OF D.M. BLACK ET AL. ‘FRACTURE INDEX’ IS POSSIBLE ALSO WITH THE USE OF FOREARM BMD MEASUREMENT AND QUESTIONNAIRE SCORING Dobrenko A, Badurski JE, Nowak NA, Daniluk S, Jeziernicka EZ; Centre of Osteoporosis & Osteo-Articular Diseases, Polish Foundation of Osteoporosis, Bialystok, Poland Recently Black et al. (1) have elaborated simple scoring system called ‘fracture index’ scoring gradually increase risk of fracture as a result of combination of seven clinical risk factors with and without total hip BMD measurement. Also recently (2) we have conducted similar study of prevalence of osteoporosis in 6615 women at a mean age of 55,7 years in Northern-East region of Poland with the use of questionnaire containing the same as in the case of SOF study seven questions but with forearm BMD. The objective of this work is to evaluate if ‘fracture index’ can be applicative also for other than hip localization of BMD measurement, in this case in forearm and for retrospective analysis. The ‘fracture index’ has been calculated by the summarizing of ‘points’ from the questionnaire: Current age 0–5 pts, fractures due to low trauma after 40 years of age 0–1 pts, mother’s hip fracture 0–1 pts, weight below 58 kg 0–1 pts, current smoker 0–1 pts, neuro-muscular weakness and susceptibility to falls 0–2 pts and forearm BMD 0–4 pts. The number of low trauma fractures and their percentage in all examined population of women is showed in table 1. Conclusion: Number of patients with past history of fractures increases proportionally with increase of points calculated from questionnaire. It supports the use of DM Black et al. ‘fracture index’ also in forearm BMD measurement. Points

Number of patients

Fractures

No fractures

% of fractures

0–2 3–4 5 6–7 8–13

3392 1528 560 648 487

121 218 122 204 241

3271 1310 438 444 246

3,57 14,27 21,79 31,48 49,49

References 1. Black DM et al., Osteoporos Int 2001;12(7):519-528. 2. Dobrenko A et al., Osteoporos Int 2001;12(Suppl 1):86

S82 P261SA. QUANTITATIVE BONE ULTRASOUND MEASUREMENTS IN PATIENTS WITH CROHN’S DISEASE Machado Pereira SP, Barros JH, Veloso T; Department Hygiene and Epidemiology, Porto, Portugal, Department Higyene and Epidemiology, Porto, Portugal, Department of Gastroenterology, Porto, Portugal Background: The extent and the determinants of bone density reduction in patients with Crohn’s disease is remains controversy. Objective: The aim of this study was to examine bone mineral density (BMD) and factors associated with reduced BMD in a population of patients with Crohn’s disease. Methods: Bone ultrasonographic parameters were measured at the calcaneus using a ultrasound bone densitometer (Sahara1Hologic) in 83 Crohn’s disease patients (51 females and 32 males), and in 166 randomly selected age and sex-frequency matched healthy community controls. A structured questionnaire comprising information on demographic, social, familial, anthropometric and behavioral characteristics was used. Diet was evaluated with a previously validated semi-quantitative food frequency questionnaire. Results: Compared to controls, Crohn’s disease patients had lower values for estimated bone mineral density (0,530±0,152 vs 0,546±0,118). Calcaneal SOS, BUA and QUI-stiffness evaluated presented lower values when compared with sex- and agematched controls, although this reduction was not statistically significant. In Crohn’s disease patients, only the duration of corticoid use was significantly associated with lower bone mineral density. The longer the use of corticoids the larger the reduction in all parameters evaluated, statistically significant only for BUA (77,0±20,8 vs 74,0±20,8, p50,05). Conclusions: Crohn’s disease patients presented lower values of bone mineral density, although there was not statistically significant. Corticoids were associated with lower bone mineral density values.

P262SU. PREVALENCE OF OSTEOPOROSIS IN AMERICAN INDIANS ATTENDING ARTHRITIS CLINIC Lisse JR, Power DJ, Yocum DE, Villanueva I, Botzong B, Lampert KJ; University of Arizona, Arizona Arthritis Center, Tucson, USA Aims: Osteoporosis has been stated to be uncommon in the American Indians. This information is based on small studies, comprising less than 150 subjects, that rarely studied older patients with high disease prevalence. Few have used dual X-ray absorptiometry (DEXA), and none quantitative heel ultrasonography (QUS). Methods: American Indian patients attending arthritis referral clinics for musculoskeletal complaints were screened for osteoporosis as part of their clinical care using either DEXA or QUS. Patients were on a variety of medications, including many on prednisone. Using the World Health Organization Definitions, patients with T-scores of 5–1.0 were considered osteopenic, and T-scores 5–2.5 osteoporotic. Results: A total of 235 people were studied from 3 distinct American Indian nations. 35 (14.9%) were male, 200 female (85.1%). The mean age of the population was 49.03 years (range 17–91) but 51 (21%) were greater than age 60 years and 102 (43%) were greater than age 50. QUS was performed on 228 poeple. 60.1% of these were osteopenic, and 18.4% osteoporotic using this device (total percentage with low bone density 68.5%). DEXA was performed on 162 people. At the hip, 30.2% were osteopenic, 6.2% osteoporotic (total 36.4%). At the spine, 50.0% were osteopenic, 14.2% osteoporotic (64.2% total). Conclusions: In American Indian subjects attending an arthritis clinic, osteoporosis is not unusual. Although our population examined only ill people, osteoporosis is often overlooked. Earlier studies examined mainly younger people, where osteoporosis is not often found in any population. More information on normal

Abstracts bone mass and fracture rates in American Indians is essential to help diagnose and treat this problem.

P263MO. LOW INCIDENCE OF HIP FRACTURES IN AN EQUATORIAL AREA Rocha FAC, Ribeiro AR; Universidade Federal do Ceara´, Brazil Hip fractures in patients older than 60 years of age represent a serious morbidity linked to osteoporosis that contributes to its mortality rates. Both genetic and environmental influences have been reported as important factors related to the epidemiology of osteoporosis. Sobral, a city located in the northeast (equatorial zone) of Brazil (3 deg 41 min 10 sec South / 40 deg 20 min 59 sec East) has 138565 inhabitants, which are mostly white Portuguese and native Brazilian descendants. We evaluated the occurrence of hip fractures in Sobral between July/1996 and June/2000. This was a retrospective cohort-based study. Data were obtained from the medical records of the Santa Casa de Sobral that is the reference hospital in this area. All chart records of patients aged more than 20 years with a diagnosis of femoral or hip fracture were revised. A total of 79 fractures were identified. 10 (12.6%) cases that occurred in patients less than 50 years of age were excluded from further analysis. 69 cases (87.3%) occurred in patients aged more than 50 years comprising 19 (27.5%) men and 50 (72.4%) women giving an age-adjusted annual incidence rate of 5.59/10000/year in men and 12.4/10000/year in women, respectively for people in this age range. Two patients, aged 79 and 82, died 9 and 6 days after hospital admission, respectively. The average time of hospitalization was 7.5 days (range 4–19 days). As expected, there is a significant rise in hip fractures in people older than 50 years. Interestingly, the hip fracture rate in this population is considerably lower (around 4 times less) than the reported rates in white Caucasians.

P264SA. COST-EFFECTIVENESS OF BISPHOSPHONATE THERAPY IN HIGH-RISK OSTEOPOROTIC WOMEN Grima D1, Burge RT2, Becker D1, Tosteson ANA3; 1Innovus Research, Inc., Burlington, Canada, 2Procter & Gamble Pharmaceuticals, Mason, USA, 3Dartmouth College, Lebanon, USA Aim: To evaluate the cost-effectiveness and budget impact of Actonel and Fosamax therapy when treating US osteoporosis patients at high risk of fracture. Methods: Outcomes for patients treated with Actonel or Fosamax were estimated using a Markov model of osteoporosis. Health states included hip and vertebral, fractures; healthy, and death. The base case analysis used women aged 65 years with low bone mineral density (BMD) and prevalent vertebral fracture, with 3 years of treatment and observation. General population fracture rates were adjusted to reflect the 6-fold increased risk of hip fracture and 5-fold increased risk of vertebral fracture in the target population. Therapy inputs included published daily therapy prices (Actonel $1.95, Fosamax $2.21), and relative risk reductions for hip and vertebral fractures. A 3% discount rate was applied to costs and outcomes. Sensitivity analyses were conducted on efficacy rates, fracture rates, unit costs, discontinuation rates, follow-up duration, and patient age. Results: Actonel therapy resulted in fewer fractures versus Fosamax per 1,000 patients (all fractures: 134 vs. 144; hip fractures: 23.1 vs. 28.3) and similar QALYs (2,247 vs. 2,245). Total cost per patient was lower for Actonel ($3,184) compared to Fosamax ($3,617) due to better efficacy and lower acquisition costs. Actonel versus no therapy revealed incremental cost per hip fracture avoided and cost per QALY gained of $13,376 and $17,886, respectively. The budget impact analysis showed estimated cost savings of $488 per patient (discounted) with Actonel vs. Fosamax. The sensitivity analyses suggest possible

Abstracts cost-savings with Actonel compared to no therapy when using a lifetime follow-up, or the upper confidence limit for hip fracture efficacy. Conclusions: Actonel is cost saving relative to Fosamax due to lower costs and better efficacy. Compared to no therapy, Actonel therapy for high-risk women is highly cost-effective producing a cost per QALY ratio favoring therapy adoption.

P265SU. EPIDEMIOLOGY OF WRIST AND HIP FRACTURE IN RUSSIA Lesnyak OM1, Kuznetsova EV1, Kuzmina LI2; 1Ural State Medical Academy, Yekaterinburg, Russia, 2Hospital of Veterans Affairs, Yekaterinburg, Russia In USA and Western Europe the number of hip and wrist fractures in people over 50 usually is equal or hip fracture prevail (Riggs,1995; Cooper 1993). The aim of this study was to examine the ratio of hip and wrist fractures in Russian population over 50. Methods: This was a population-based retrospective survey in Yekaterinburg, the Middle Urals. Medical records of all city hospitals and files from outpatient emergency units during 1992– 1997 years were analysed. Only low trauma fractures were included. All cases were confirmed with X-rays. Results: The overall incidence of wrist fracture during the period analysed was 758.5/100 000 population. This was 5.7 times higher than that of hip fracture – 132.3/100 000 population. The average age was 63.9±7.8 years in wrist fracture group and 74.8±10.3 years in hip fracture group (p50.05). There was a 2.6-fold increase in incidence of wrist fracture during October to March associated to season of glassy ice on the ground. This tendency repeated every year. On the contrary, the incidence of hip fracture did not vary during different seasons. Conclusions: The variations in incidence of different types of osteoporotic fractures in different populations among other factors also depend on climate. Thus, one of the ways of prevention of wrist fractures is prevention of falls through cleaning of pavements. The incidence of hip fracture in Russia is lower than that in Western countries. This fact might related to significantly smaller size of population of 85 and over.

P266MO. QUANTITATIVE ULTRASOUND IN HEALTHY JAPANESE ADOLESCENTS: ITS RELATION TO AGE, HEIGHT, WEIGHT AND PUBERTAL STAGE Ikeda Y1, Iki M1, Aihara H1, Morita A1, Kagamimori S2, Kagawa Y3, Matsuzaki T4, Yoneshima H5, Marumo F6; 1Kinki University School of Medcine, Osaka-Sayama, Japan, 2Toyama Medical & Pharmaceutical University, Toyama, Japan, 3Kagawa Nutrition University, Tokyo, Japan, 4Institute of Comprehensive Community Care, Tokyo, Japan, 5Kasukabe Shuuwa Hospital, Kasukabe, Japan, 6Graduate School of Tokyo Medical and Dental University, Tokyo, Japan Aims: To establish age-specific reference values for quantitative ultrasound (QUS) indices at the calcaneus in healthy Japanese adolescents, and to clarify the influence of height, weight and pubertal stage on the QUS indices which may show a different response to these factors from that previously reported for bone mineral density (BMD). Methods: QUS indices were obtained in 599 healthy Japanese adolescents (297 girls and 302 boys) aged 12 to 17 years using an ultrasonic bone densitometer (SAHARA, Hologic). BMD at the forearm was measured by DXA (pDXA, Norland/Stratec) concurrently. Pubertal stage was determined according to the time of pubarche or menarche through interviews.

S83 Results: We obtained age-specific reference values from the subjects. The overall means of BUA in girls were 95.2% and SOS were 100.3% of the Japanese young adult female reference. Agerelated increase was seen only in BUA of boys even though BMD clearly increased with advancing age in both gender. Weightrelated increase in BMD and BUA was clearly seen but not in SOS both boys and girls. The correlation coefficients between weight and BUA were significant (r = 0.291 (p50.01) in boys and r = 0.138 (p50.05) in girls) but turned out to be insignificant in girls when adjusted for the effect of age (r = 0.133 (p50.05) in boys and r = 0.105 (p40.05) in girls). BMD showed a significant difference between before and after puberty onset in both gender. Significant differences in SOS and BUA between the same groups observed in girls but not in boys. Conclusions: The effects of age and pubertal and physical development on the QUS indices were different from those on BMD. The QUS indices may provide different information on the skeletal development from that represented by BMD.

P267SA. CORRELATION BETWEEN A QUESTIONNAIRE ABOUT RISK FACTORS AND THE DIAGNOSIS OF OSTEOPOROSIS IN WOMEN Messina OD, Pate D, Peralta A, Khoury M, Riopedre AM, Villa NG; Argerich Hospital, Buenos Aires, Argentina We performed a study correlating several risk factors for osteoporosis and bone mineral density in lumbar spine and femoral neck (DEXA) in 785 women. Asked factors were age, body weight, height, BMI, postmenopausal state, late menarche, early onset menopause, low calcium intake, sedentarism, personal history of atraumatic fracture, recent fracture, familiar history of fracture, loss of height, concomitant diseases, chronic use of glucocorticoids, alcohol and tobacco consumption. We designed a questionnaire to evaluate the predictive value of each factor and to determine if they are useful to forecast the diagnosis of osteoporosis (WHO criteria). Results 666 patients (84,84%) were in postmenopausal state. Osteoporosis was diagnosed in 205 women ( 26.11%) (CI 95%– :23.07–29.34). Data analysis are shown in table 1. We designed a predictive score including factors shown in table 1 giving one point to those factors with an odds ratio 4 2 and 0.5 point if the odds ratio was 4 2. Maximun score was 9 points. We conclude that in our population the probability of diagnosing osteoporosis when the score is 4 5 is greater than 85%. risk factor

Odds ratio

p

age 4 65 years recent fracture age between 50–65 years BMI 5 25 atraumatic fracture height 5 155 cm weight 5 50 Kg glucocorticoids

7.944 3.492 3.218 2.893 2.748 2.558 2.550 2.080

0.000 0.035 0.000 0.000 0.001 0.000 0.011 0.040

concomitant disease (OR 1.703, p 0.050), early – onset menopause (OR 1.643, p 0.016).

P268SU. THE BURDEN OF OSTEOPOROSIS IN LATIN AMERICA Morales-Torres J1, Gutie´rrez-Uren˜a S2; 1Hospital Aranda de la Parra, Leon, Mexico, 2Hospital General, Guadalajara, Mexico Osteoporosis causes considerable morbidity, mortality and resource utilization in industrialised nations. Its burden is

S84

Abstracts

relatively well estimated in the United States and Canada, but poorly studied in most countries in Latin America. Aim: To know the burden of osteoporosis in Latin America through a review of literature and publicly available information. Methods: Information from 20 countries in the Latin American region was collected from published and electronic sources. Rheumatologists and Bone Specialists were asked for additional information by a questionnaire. Results: In year 2000, the population of Latin America and Caribbean region was 524 million from diverse ethnic origins. Currently, on average 5.5% of the population is 65 years and older. In only 2 countries, people over 65 years constitute more than 10% of national population. However, with life expectancy of more than 70 years in most countries in this region, a significant growth of elderly population is anticipated. Studies using WHO criteria for osteoporosis report 12 to 18% of women 50 years and older have vertebral osteoporosis. Proximal femur osteoporosis affects 8 to 22% of women in this age category. Community based studies in Argentina reported between 263 and 331 hip fractures per 100,000 people 50 years and older. Hospital based studies in Colombia, Chile, Brazil, Mexico, Panama and Venezuela reported between 79 and 175 hip fractures per 100,000 persons aged 50 and more. Between 17 and 37% of hip fracture sufferers die in the year following it. Direct costs of a hip fracture ranged from 4,500 to 6,000 US Dollars. National gross income per capita in the different countries ranges from 410 to 7,550 US Dollars. Conclusions: The burden of osteoporosis varies across countries with differences in populations and health resources. Numerous gaps in knowledge need to be filled to face the anticipated explosive growth in osteoporotic fractures.

P269MO. RELATION BETWEEN PULMONARY FUNCTION TESTS AND BONE MINERAL DENSITY IN YOUNG ADULTS WITH CYSTIC FIBROSIS 1

2

1

2 1

Pache I , Udry E , Lamy O , Sauty A ; Department of Osteology, University Hospital, Lausanne, Switzerland, 2Department of Pulmonology, University Hospital, Lausanne, Switzerland Aims: To determine the relation between bone mineral density (BMD) and forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and steroids use in young adults with cystic fibrosis (CF). Methods: 25 patients with a stable disease or on a waiting list for lung transplantation. Results: Mean age was 26.4 + 5.8 years. Twelve (48%) patients had osteoporosis on 4 1 site, 8 (32%) had osteopenia on 4 1 site and 5 (20%) a normal BMD. Seven (87.5%) out of 8 patients on a waiting list for lung transplantation had osteoporosis and one had osteopenia. None of the patients with normal BMD had been prescribed long term steroids. No difference in the frequency of steroids administration was found between the patients with osteoporosis compared with those with osteopenia. We did not found any relationship between the presence or absence of colonisation with Pseudomonas aeruginosa and BMD. Conclusions: Low BMD is a frequent problem in young adults with CF and is more prevalent in patients with low FEV1 and FVC. It can be explained by more frequent use of steroids and a lower nutritional status. There was however no correlation between BMD and Pseudomonas aeruginosa colonisation in the airway.

FEV1 (% ± SD) FVC (% ± SD)

Osteoporosis

Osteopenia

Normal BMD

p value

40.6 ± 18.1 63.5 ± 16.3

59.4 ± 21.4 76.9 ± 17.4

73.2 ± 21.7 92.2 ± 14.6

0.02 0.02

P270SA. EARLY GREYING OF THE HAIR DO NOT INDICATE OSTEOPOROSIS LATER IN LIFE. Albertsdottir K1, Gudbjornsson B1,2; 1The Osteoporosis Clinic, Akureyri Hospital and, 2The Center for Rheumatology Research, University Hospital, Reykjavik, Iceland Aim: To elucidate whether early greying of hair in women indicate osteopenia or osteoporosis later in live in Scandinavian female population. Methods: Questionnaire based study on consecutive series of 350 unselective women at the age of 50–79 years, who were refereed for bone mineral density measurement by DEXA (Lunar 2000X) at the Osteoporosis Clinic in Akureyri Hospital, Iceland. All participants answered a standardised general health questionnaire and gave information on previous history of fragility fractures. Results: 281 women (82.6%) returned the questionnaire by mail. Their mean age was 64 ± 8 years and 244 of these woman had reached menopause (87%). The mean T-score for the whole group was in lumbar spine (L1–L4) –1.21 ± 1.61 (–5.43– +2.59) and in the femoral neck –2.22 ± 1.28 (–5.25– +1.27). Premature greying of hair was defined as those who have more than half of their hair grey at age, which were below the 95% confidential interval. According to this 19 women had history of premature greying of their hair (before the age of 43 years). Six of these women (35%) had osteopenia (T-score –1.0 – –2.5) in their lumbar spine and five (26%) had osteoporosis (T-score 5–2.5), in comparison to 35% and 24% in the whole greoup. Further stastistical analysis (ANOVA) by grouping the participating women by the decade of age when their hair turned grey or when half of their hair had turned grey did not result in significan differences between the groups. Conclusions: The present study does not indicate that Scandinavian women who get prematurely grey in their hair have an increased risk for osteoporosis later in life.

P271SU. THE BONE AND JOINT DECADE MONITOR PROJECT: THE BURDEN OF MUSCULOSKELETAL CONDITIONS AT THE START OF THE NEW MILLENNIUM Woolf AD1, A˚kesson K2, Hazes JMW3, and the WHO Scientific Group on The Burden Of Musculoskeletal Conditions A1,2,3; 1 Royal Cornwall Hospital, Truro, UK, 2Malmo¨ University Hospital, Malmo, Sweden, 3Academisch Ziekenhuis Rotterdam, Rotterdam, The Netherlands This project aims to 1) collate data on the global burden of musculoskeletal conditions and compliment the WHO Global Burden of Disease estimates; 2) establish outcome measures to be used to monitor change in these conditions in all populations. Osteoporosis, rheumatoid arthritis, osteoarthritis, spinal conditions and limb trauma have been focused on. Estimates of incidence and prevalence have been made for different geographic and economic areas but is impeded by variability in reporting, lack of data and inconsistency of definitions used. Agreements were sought for diagnostic criteria for use in epidemiological studies. Summary measures of health are used to estimate the burden and these require the definition of the course, stages and associated health status. Most conditions were staged by structural change and time. For osteoporosis such were low bone mass, presence of and site of fracture, and whether acute. Pain, mobility, activities of daily living and participation were used to describe health status that is well modeled by the new WHO Classification of Functioning and Disability. It was agreed that the impact at a societal level should be measured by relating the utilisation and cost of healthcare resources and social support to the agreed diagnostic groups. It was agreed that the impact on the individual is best measured by the domains: physical health (sub-domains; pain and physical function (mobility and ADL)), social health and mental health (subdomains; energy/vitality and anxiety). The most useful generic

Abstracts and specific instruments were considered for each condition but none were found to capture all of important domains nor were globally applicable. Data reflecting the burden of musculoskeletal conditions has been collated but there needs to be an improvement in data that is collected and reported for this to truly reflect the burden.

P272MO. OSTEOPOROSIS IN GENERAL PRACTICE: FAILURE TO LINK FRACTURES TO THE DIAGNOSIS OSTEOPOROSIS Versluis RGJA, Papapoulos SE; Leiden University Medical Center, Leiden, The Netherlands In a large primary care health center a random cohort of 494 women aged between 55 and 84 years (mean 67.6 yrs) was investigated for methods to identify those with osteoporosis. In the Dutch health care system practically every individual is registered in a general practice regardless of medical condition and electronic records of diagnoses and treatments are kept. The most frequent diagnosis was hypertention registered in 24% of the women, followed by gynaecological diagnoses (fibroids, prolapse etc) in 22% and osteoarthritis of the hip or the knee in 18% of the women. The most commonly prescribed drugs were CNS preparations (21%), diuretics (18%) and beta-blockers (17%). Osteoporosis was diagnosed in 2.3% of the women and antiosteoporotic treatments, other than vitamin D and calcium, were prescribed to 0.8%. Further analysis of the electronic records revealed that 19% of the women had one or more fractures (mainly of the wrist but also of the hip). Thus, fractures were among the top 3 most common diagnoses but they were not linked to osteoporosis. Subsequently, practically all women at the highest risk for further fractures were not treated. Despite efforts to increase the awareness of the disease, fractures in elderly women were rarely linked to the diagnosis of osteoporosis in this general practice.

P273SA. SAFETY PROFILE OF RISEDRONATE SODIUM ASSESSED FOR POST-MENOPAUSAL OSTEOPOROSIS IN MEDICAL PRACTICE: A NON-INTERVENTIONAL OBSERVATIONAL STUDY WITH 9188 PATIENTS Ringe JD1, Wick BC2, Grauer A2, Griek H2, Eggenweiler S2; 1 Akademisches Lehrkrankenhaus der Universitat zu Koln, Leverkusen, Germany, 2Procter & Gamble Pharmaceuticals, Weiterstadt, Germany Objective: To confirm the safety of risedronate sodium (Actonel*) used in daily clinical practice for the treatment of women with post-menopausal osteoporosis. Methods: Office-based physicians in Germany were asked to enroll 3 to 6 female patients with postmenopausal osteoporosis. The patients were initiated with risedronate 5 mg daily therapy and were followed for 6 months. The physicians documented the course of the treatment on a questionnaire, which included documentation of adverse drug reactions (ADR). ADRs, defined as adverse events that in the physician’s opinion have a causal relationship to risedronate, were collected and coded in the MedDRA classification system. A descriptive statistical analysis of the data collected for the observation period has now been performed. Results: 2739 physicians enrolled 9188 patients. 7735 (84.2%) patients were followed at least 6 months. Only 583 (6.4%) patients discontinued therapy due to adverse drug reactions. 488 (5.3%) patients discontinued treatment for other reasons or were lost to follow up. A total of 667 (7.3%) patients experienced ADRs which was similar in incidence and nature to those seen in pivotal trials. 18 (0.2%) experienced serious ADRs. Physicians assessed the tolerability of risedronate for 86.4% of patients as excellent, or good, and 4.1% as satisfactory.

S85 Conclusion: These results demonstrate, that 6 months after initiation the adherence to risedronate therapy under clinical practice conditions – very close to ‘real life’ – is very high. This is likely to be attributable to the high physician ratings for tolerability and the low incidence of ADRs observed. The results of this observational study confirm the good safety and tolerability profile of risedronate in daily clinical practice in a large number of patients.

P274SU. THE SHORT TERM EFFECT OF NASAL SALMON CALCITONIN ON VIT-D AND PARATHORMONE LEVEL Cerrahoglu L1, Duruo¨z MT1, Uyanik BS2; 1CBU Medical School PM&R Department, Manisa, Turkey, 2CBU Medical School Biochemistry Department, Manisa, Turkey Aims: To assess the short term effect of two different doses of salmon calcitonin on blood vit-D and PTH level. Methods: Subjects with postmenopausal osteoporosis were recruited randomly into our study. Seconder osteoporosis, vit-D treatment, renal and hepatic insufficiency and hormon replacement therapy were the exclusion criteria. First and second groups were taken 100 UI and 200 UI nasal salmon calcitonin respectively. The vit-D and PTH levels were assessed at baseline and 6th months. The change was assessed by ‘effect size’. The t test was performed to evaluate the relationship between groups. p50,05 accepted as significant. Results: 17 subjects for each group were recruited randomly (mean ages: 58,53; SD:6,61 and 58,29; SD:7,18). Groups were similar at baseline. Vit D levels were increased significantly in 100 UI (%12,04) and 200 UI (%26,83) groups (p50,0001 and p = 001). PTH levels were decreased significantly in both groups (%25,97 and %43,24 respectively) (p = 0,001). The Effect sizes for vit-D were 0,70 (100UI) and 1,92 (200UI) and for PTH were –0,57 (100UI) and –0,71 (200UI). Conclusion: Salmon calcitonin affects significantly vit-D and PTH levels adversely in short term. This effect is more evident in 200 UI group.

P275MO. OSTEOPOROSIS IN CLINICAL PRACTICE. ONE-YEAR SURVEY IN A RHEUMATOLOGICAL UNIT Geusens PP1,2, Vanhoof J1; 1BIOMED, LUC, Diepenbeek, Belgium, 2University Hospital, Maastricht, The Netherlands Few data are available on the diagnosis of osteoporosis in clinical practice. Information about osteoporosis has mainly been obtained via epidemiological studies. We evaluated the characteristics of patients who were diagnosed with osteoporosis in a rheumatological unit over a period of one year. Patients who had osteoporosis diagnosed by DEXA during one year were selected for this survey. The diagnosis of osteoporosis was based on a T-score 5–2.5 in either the spine, the femoral neck or the trochanter and further specified as primary or secondary osteoporosis. 3751 patients were included in the survey (2068 women and 1075 men). 607 (16%) had osteoporosis diagnosed, 516 in women (25% of women) and 91 in men (8% of men). Of these patients, 461 (76%) had primary osteoporosis and 146 (24%) had secondary osteoporosis. Secondary osteoporosis was more found in men (47%) than in women (18%) with osteoporosis (p50.001). GIO accounted for most of the secondary osteoporosis cases (54%), in 45% of men with secondary osteoporosis and in 58% of women. Rheumatoid arthritis and polymyalgia rheumatica/giant cell arteritis were the most frequent conditions that required glucocorticoid treatment. We conclude that osteoporosis is a frequent diagnosis in rheumatological practice. The frequency of secondary osteoporosis is high, especially in men and is mainly associated with glucocorticoid therapy.

S86 P276SA. INDIAN NURSES AND OSTEOPOROSIS: KNOWLEDGE AND ATTITUDE TOWARDS PREVENTION Kabir SR, Handa R, Dey AB, Dwivedi SN; All India Institute of Medical Sciences, New Delhi, India Aims: Osteoporosis is a growing but neglected health problem in India. The level of awareness is generally low even amongst the health care personnel. This study, the first of its kind from India, aimed to assess the awareness about osteoporosis among nurses. Methods: Four hundred self administered questionnaires were distributed randomly to the female nurses working at a tertiary care teaching hospital in New Delhi. The structured questionnaire included questions about the disease, its preventive strategies, and desire for more information. Results: A total of 348 questionnaires were returned (response rate 87%). Age of the participants ranged from 22–59 years. Nearly 98% respondents had heard about osteoporosis, books and journals being the commonest source of information. Almost 97% could tell that it was a disease affecting the bones. However, as many as 25% had no idea whatsoever about the disease process or its consequences. Female preponderance was mentioned by 96% nurses while only 38% could mention the vulnerable age group. Two thirds of the nurses felt that osteoporosis may affect them. Only 78% knew that the disease could be prevented. Knowledge about preventive strategies useful included calcium supplementation (71.8%) and regular exercise (23.2%). The role of HRT and milk in prevention of osteoporosis was known only to 9.1% and 7.6% respondents respectively. An overwhelming 99% nurses wanted to have more information about osteoporosis but as many as 29% did not know whom to approach for the same. Conclusions: Osteoporosis awareness especially about preventive strategies is inadequate in female nurses in India. Health education programmes to fulfill the lacunae in knowledge are the need of the day.

P277SU. A/P RATIO IS USELESS AND MISLEADING, C/P RATIO IS ENOUGH FOR THE ASSESSMENT OF VERTEBRAL FRACTURES Okamoto ST1, Morii H2, Okamoto S3; 1KS Okamoto Naika Clinic, Shimabara, 2Aino Gakuin College, Osaka, 3Sanyo Osteoporosis Research Foundation, Oita, Japan Introduction: For the diagnosis of vertebral fractures, the ratio between the anterior marginal height and that of posterior vertebral body(A/P) or the central portion to posterior (C/P) are assessed. But A/P ratios of front margin widely affected by the variation of physiologically declining front edges or the presence of osteophytes. We also noted horizontal rotations of the vertebral bodies are commonly seen in elderly cases, that causes the error of the lateral height measurement instead of frontal one. Anterior maximum height measurement is recommended, but then A/P ratios always exceeds C/P ratio above 5% in any cases of wedge fractures. Methods: To avoid oblique radiational view of the vertebral body, TV-X ray fluoroscopy with the postural adjustment was performed in 128 normal volunteers and 1,249 female osteoporosis patients. We also calculated A/P or C/P ratio from the autopsy data, and compared them with the measurement of DXA Morphometry, CT, MRI or Laser Stereolithographic Plastic Models of vertebra. Results: As deformities are common in elderly female, over 65 years of age, less than 5% of vertebra becomes proper projection for the measurement without this maneuver. The mean C/P ratios of normal female coincide with the reported autopsy data, which means are about 10% lower than that of reported conventional X ray measurements. For example, mean C/P ratio of L2 vertebra is 83% anatomically while the mean of plain X-ray assessment is

Abstracts 98%. In all osteoporotic cases, the C/P ratio was enough and A/P ratio is not necessary for the fracture detection. Discussion: The mean height measurement error of 15% in conventional fracture assessment come from random pointing in oblique X ray view and from midpointing based on the idea to consider the terminal plate as flat. In conclusion, measurement of A/P ratios are useless if vertebral X rays are taken properly.

P278MO. A BRIEF QUESTIONNAIRE FOR SCREENING WOMEN WITH OSTEOPOROSIS Silveri F1, Morbidelli C2, Sfrappini M4, Pozone M5; 1Department of Rheumatology, University of Ancona, Italy, 2Department Medicine, INRCA, Ancona, Italy, 3Department of Endocrinology, University of Ancona, Italy, 4Department of Geriatric, Hospital of S. Benedetto del Tronto, Italy, 5Department of Geriatric, Hospital of L’Aquila, Italy The aim of the study was to evaluate the discriminant validity of a brief questionnaire for screening women with osteoporosis. The screening was performed by a questionnaire that was used by Albrand in French women from Lyon area (Osteoporos Int 1998;8; P278). The questionnaire values seven variables: age, years since menopause, weight, history of fragility fractures after 45 years, estrogen and glucocorticoid therapy, disorders associated with osteoporosis (hypothyroidism, intestinal malabsorption, hyperparathyroidism, Cushing’s syndrome, and chronic renal failure). The score of this questionnaire range from 1 to 19. We studied 568 consecutive ambulatory Caucasian postmenopausal women (45-80 years old) from middle Italy (Adriatic coast). All patients were valued by questionnaire and bone mineral density (DXA; Hologic QDR 4500) at the lumbar spine and proximal femur. The area under receiver operating characteristic (ROC) curve was employed to evaluate the screening method’s performance. For screening test the area under the curve is 0.814 ± 0.02 (SE) (95% CI 0.785 to 0.842), and an optimal cut-off point of 3 comes close to maximizing both sensitivity (73.4%) an specificity (75.9%). A strong relation was found between questionnaire score and proximal femur BMD (p 5 0.001) and lumbar spine BMD (p 5 0.001). In conclusion, in our preliminary data, this brief questionnaire can be used to identify postmenopausal women who are at risk of osteoporosis.

P279SA. POPULATION-BASED ANALYSIS OF OSTEOPOROSIS TREATMENT AND PREVENTION USING A COMBINATION OF ADMINISTRATIVE DATABASES, A CLINICAL BONE MINERAL DENSITY DATABASE AND SURVEY DATA Caetano PA1, Metge CJ1, Leslie WD2; 1University of Manitoba, Faculty of Pharmacy, Winnipeg, Canada, 2University of Manitoba, Faculty of Medicine, Winnipeg, Canada Introduction: Administrative databases are commonly used to analyze osteoporosis treatment and prevention patterns. In Manitoba, Canada, a unique situation presents itself since all patients are universally covered for health care under the Canada Health Act. This universal coverage allows researchers using administrative databases to collect and analyze data on the entire population. As well, in Manitoba, all bone mineral density scans are regulated and all results are recorded in a separate database. Linkage of this database to the pharmaceutical, medical and hospital databases allows for analyses into treatment and prevention patterns. Furthermore, an ongoing population-based study in Manitoba has collected patient-specific survey data that can also be linked to the aforementioned databases. Hence, the objectives of this study are to combine information and data from all of the above databases to: (a) analyze factors contributing and

Abstracts

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influencing initiation and persistence on osteoporosis therapy and (b) model lifetime and five-year age-specific risks of fracture. Methods: All female residents of Manitoba (identified as having continued coverage in the Manitoba registry database between April 1st,1995 and March 31st, 2001) are included in the analysis (n4400,000). Treatment patterns are analyzed for all women receiving a prescription for osteoporosis prevention or treatment, or listed as suffering a fracture due to osteoporosis, or with a bone mineral density measurement in the osteoporotic or osteopenic range (WHO standards). Propensity to receive treatment or BMD test is calculated from variables in the above mentioned databases and from survey data. Models to determine likelihood of fracture are constructed and compared for both users and non-users of osteoporosis medications. Conclusions: Unlike other models which attempt to predict fracture incidence from a limited number of data sources and/or amongst specific populations, this study links several populationbased databases. Furthermore, the combination of survey and bone mineral density databases provides information previously unreported in claims data.

as a part of physical check-up or as a control subject in prior studies were investigated retrospectively. BMD was measured at the lumbar spine and proximal femur using dual energy x-ray absorbtiometry (Lunar DPX-IQ). Subjects were studied in 4 groups [ages 20–29 (n = 43), 30–39 (n = 28), 40–49 (n = 118), 50–59 (n = 101)]. BMD of the lumbar spine (L2–L4) had its peak at ages 30-39 (1.192 ± 0.140), however the peak for the proximal femur was between the ages of 20 and 29 (femoral neck: 1.116 ± 0.146, Ward’s triangle: 1.013 ± 0.143, trochanter: 0.945 ± 0.122, femur total: 1.109 ± 0.134). There was a tendency to decrease in BMD at both sites (lumbar spine and proximal femur) after these peak values with increasing age. Linear regression analysis indicated a non-significant relation between age and L2–L4 BMD (R2 = 0.009, p = 0.109, beta = –0.0014), whereas a statistically significant linear negative relation was found at proximal femur (femur neck R2 = 0.192, p = 0.000, beta = –0.0061; Ward’s triangle R2 = 0.290, p = 0.000, beta = -0.0088; trochanter R2 = 0.093, p = 0.000, beta = –0.0037; total femur R2 = 0.105, p = 0.000, beta = –0.0043). In conclusion, there was a significant correlation between age and proximal femoral BMD in males.

P280SU. BONE MINERAL DENSITY AND OSTEOPOROSIS IN POLISH WOMEN. COMPARISON BETWEEN RURAL AND URBAN POPULATION

P282SA. CARDIOVASCULAR RISK FACTORS IN PATIENTS WITH OSTEOPOROSIS

Filip R, Zagorski J; Institute of Agricultural Medicine, Lublin, Poland

Carbonell C1, Olmos C1, Yanovsky N1, Cama A1, Carrazoni C1, Perpin˜a E2, Romero C1; 1ABS VI´A ROMA, Barcelona, Spain, 2ABS HORTA, Barcelona, Spain

Aims: The aim of the study was determination of the values of bone mineral density (BMD L2–L4) and evaluation of occurrence of osteoporosis between normal women living in rural and urban environment (especially postmenopausal) in comparison to other populations. Methods: Subjects of the study were 503 normal women aged 30–79 (mean 49.5 years), all residents of Lublin Region. Analysed population was divided into two subgroups: urban (n = 282, 56%) and rural (n = 229, 44%). 65 (12.9%) women worked as farmers, 107 (21.3%) were retired, other occupations were 325 (64.6%). The lumbar spine (L2-L4) of all subjects was examined in a-p position using dual X-ray absorptiometry (LUNAR Corp.) at the Densitometric Laboratory of Institute of Agricultural Medicine in Lublin (Poland) from November 1999 to June 2000. Results and Conclusion: Statistically significant differences in mean values of BMD between urban and rural populations, as well as between farmers and other occupations were not observed. Mean values of BMD in every age range were similar to the populations of North America and Northern Europe. The prevalence rates of osteoporosis according to WHO criteria in whole analysed population were calculated as 6.9%, and osteopenia as 25.4%. The prevalence of osteoporosis and osteopenia increased with advancing age. In women younger than 45 years osteoporosis was not observed, the prevalence of osteopenia was 12.6%. In women between 45 and 55 years prevalence of osteoporosis was 5.7% and osteopenia 25.6%. In women older than 55 years of age osteoporosis was observed in 18.5% and osteopenia in 40.7%.

Aims: To know cardiovascular risk factors (CVRF) in postmenopausal women with osteoporosis (OP). Design: Cross-sectional descriptive study. Methods: 178 medical records were reviewed. Women who had a measurement of bone mass by DEXA, by a clinical criteria, in the last year, were selected for the study. We registered: age, weight, height, BMI, hypertension (AH4140/90), total cholesterol (TC) considering hypercholesterolaemia a TC4240 mg/dl. Thiazides, Statins and antiresortive treatment for OP (calcium, D vitamin, bisphosphonates, raloxifene, hormonal replacement therapy (HRT), calcitonin). Results: 76 women of 178 presented OP by DEXA. Mean age: 74.64 years old (range 53–90); mean height: 150 cm; weight: 58.75 kg and BMI 26. The other CVRF registered were as follows: 41 (53.9%) hypertension; 32 (42.1%) hypercholesterolaemia and 10 (13.2%) diabetes. 20 women (48.8%) with osteoporosis and hypertension were treated with thiazides. 16 (50%) with osteoporosis plus hypercholesterolaemia were treated with statins. Referring to osteoporosis treatment: 42 (56.5%) took calcium with or without D vitamin, 17(22.4%) bisphosphonates, 4(5.3%) raloxifene, 7 (9.2%) calcitonin and 2 (2.6%) HRT. Prevalence of diabetes in OP group was 11,7% versus 11,3% in non osteoporotic group. Prevalence of hypercholesterolaemia was 46,6% in osteoporotic group vs. 50,7 in non OP group and hypertension prevalence was 46,6% in women with osteoporosis vs. 33,8% in the women group without osteoporosis. Conclusions: There is a high prevalence of CVRF (hypertension, diabetes, hypcholesterolaemia) in our patients with osteoporosis, higher compare to the population with same age and sex of the rest of Spain.

P281MO. BONE MINERAL DENSITY OF LUMBAR SPINE AND PROXIMAL FEMUR IN HEALTHY MALES Akin S, Korkusuz F, Ungan M, Isikli S; METU Medical Center, Ankara, Turkey There are few population studies on males on the relation of bone mineral density (BMD) and age. The aim of this study was to investigate the relationship between BMD and age at lumbar spine and proximal femur (femoral neck, Ward’s triangle, trochanter, total femur) in Turkish males. Two hundred ninety healthy males (aged 20–59 years) with no history of diseases and therapy affecting bone metabolism who underwent BMD testing

P283SU. INVESTIGATION OF THE INCIDENCE OF PERIPHERAL BONE FRACTURES AMONG COHORT INDIVIDUALS 50 YEARS AND OVER Mikhailov EE, Benevolenskaya LI; Institute of Rheumatology RAMS, Moscow, Russia Aim of the study was to investigate incidence of peripheral bone fractures among 221 males and 300 females in period 1990- 1999. All persons lived in Moscow.

S88 The fractures were confirmed by X-ray examination. Every year persons were questioned.The questionnaire include: date of fracture (Day, Month, Year), place of treatment, site of fracture according ICD-9, number of fractures, level of trauma Level of trauma was divided: 1-minimal trauma (fall from standing height or less), 2-fall from greater than standing height (excluding 3), 3fall down stairs, 4-involved in accident (for example road traffic accident), 5-spontaneous fracture. There were 51 cases of fracture ( 6 among male and 45 among female) in period 1990– 1999 years. Incidence of fractures was 0,7/100 000 person/years (p/y) among males and 3,8/100 000 p/y among females (p50,00004). Incidence of fractures was significantly more among females (4,2/100 000 p/y) than among males (0,3/100 000 p/y) in groups 60 years and over (p50,0001). Maximal incidence of fractures was at age 60–69 years among females. The main site of the fractures was the distal third of the forearm (40,4%) and 90,5% of them were among females. Incidence of the distal third of the forearm was 195,3/100 000 p/y among males and 1290,8/100 000 p/y among females in groups 50 years and over. We found out only 2 new cases of the hip fracture among females (135,9/100 000 p/y). All fractures among males were high energy fractures: 80% fall down stairs, 20% fall from greater than standing height. There were 84,5% fractures in a minimal trauma, 8,9% in an accident (as a rule in a road traffic accident), 4,4% due to fall down stairs, 2,2-fall from greater than standing height among women. Important predictors of fracture were reducing of hip BMD and falls.

P284MO. EFFECT OF CLASSICAL OSTEOPOROTIC RISK FACTORS ON BONE MINERAL DENSITY IN A YOUNG MALE POPULATION

Abstracts P285SA. DIETARY CALCIUM CONTENT AND BONE MASS IN PORTUGUESE ADULTS Tavares V1, Godinho F2, Pimentel Santos F2, Branco JC1; 1 APOROS, Lisboa, Portugal, 2S. Reumatologia, H. Garcia Orta, Almada, Portugal Aim: To evaluate the average dietary calcium content and possible correlation with BMD in a sample of an adult working Portuguese population. Methods: Included in an awareness and screening program led by APOROS (Portuguese patient-oriented osteoporosis society) we studied an adult population working at the same place (National Mint and Press). A standard questionnaire was used to evaluate average weekly dietary calcium content. Wrist BMD was assessed using LUNAR Pixi. Work activity level was defined as active or sedentary according to type of work. Young adults were defined as under or equal to 30 years. Results: Total population was 484 adults (241 females; 22.1% young adults; 60.8% sedentary workers) with a mean age of 41.3 yrs (minus/plus 11.4 yrs). Mean dietary calcium content in total poulation was 4614.8 mg/week, with a significant higher content in young adults (p = 0.035) due to a significant difference in young males compared to older males (p = 0.004). Dietary calcium and BMD had a positive correlation in young adults (R = 0.136;p50.0002). Sedentary workers had significant lower BMD (p50.0001) and although a significant difference in age between sedentary and active workers was present (p50.0001) we found no correlation between age and BMD. Conclusions: Average dietary calcium content in our study population was below the daily recommended intake for adults. The positive correlation between dietary calcium and bone mass in young adults suggests, as previously described, the importance of dietary calcium in peak bone mass.

Costa Dias F, Fonseca JE, Canha˜o H, Resende C, Pereira da Silva JA, Viana Queiroz M; Unidade de Reumatologia, Hospital de Santa Maria, Lisbon, Portugal Aim: Male osteoporosis is a prevalent disease with important socioeconomic impact. Although most of the clinical aspects of male osteoporosis are similar to women osteoporosis, there are growing differences between genders being detected in bone metabolism and risk factors. However, this field is still not completely clarified. The aim of this study was to analyze the effect of several classical osteoporotic risk factors on bone mineral density (BMD) in a young male population. Methods: 57 men, working in the Portuguese navy, randomly selected, with a mean age of 36,6 9,2 years, were submitted to a BMD measurement with a dual photon densitometer (DXA, Hologic-R) and inquired about osteoporotic risk factors. The protocol for the assessment of osteoporotic risk factors included evaluation of body mass; tobacco (number of cigarettes per day), coffee (number of cups per day) and ethanol consumption (grams per day); calcium ingestion (mg per day); duration (minutes per week) of weight bearing sport activity. Statistical analysis was performed using multiple regression analysis for the evaluation of the effect of the osteoporotic risk factors on DXA results. Results: Lumbar BMD was 1,076 0,145 g/cm2; femoral neck BMD was 0,957 0,141 g/cm2; body mass was 25,3 2,5; consumption of tobacco, coffee and ethanol was respectively 5,0 8,9 cigarettes/day, 2,1 1,8 cups/day, 19,6 22,9g/day; calcium ingestion was 772,0 581,0 g/day; weight bearing sport activity was performed during 241,2 216,3 minutes/week. Regression analysis depicted a significant positive effect of body mass both on lumbar and femoral neck BMD and a significant effect of weight bearing sport activity only on femoral BMD. All the other factors did not influence significantly BMD. Conclusion: This study confirms the importance of anthropometric parameters and of weight bearing exercise on male BMD.

P286SU. A LACK OF PHYSICAL ACTIVITY AND LOW CALCIUM INTAKE LEADS TO OSTEOPOROSIS IN YOUNG ADULTS Lissens MA1, Akuyz G2; 1Department Health Care and Chemistry, KHK University, Geel Belgium, 2Department Physical Medicine and Rehabilitation, Marmara University, Istanbul, Turkey The incidence of osteoporosis is known to increase exponentially after the age of 50 years. In women bone loss accelerates around the menopause. In recent years however, low bone mineral density (BMD) is seen more and more in young adults, as well males as females. In this study, BMD was determined in 50 healthy young adults (age 20 to 45), 28 females and 22 males (mean age 31.18 ± 8.51 years) using dual-energy X-ray absorptiometry (DXA) of the lumbar spine (L2–L4). The mean BMD was found to be 1.013 ± 0.199 g/cm2. The mean T-score was 87.56 ± 13.46% (ranging from 59 up to 127%) or –1.21 SD (ranging from –4.04 to +1.2 SD). Twenty eight or 56% of these young adults showed a T-score below –1 SD. Eight of them (16%) fulfilled the WHO-criteria of osteoporosis and 20 (40%) of osteopenia. The changing life style of young adults, including a lack of physical activity, a lack of exposure to sunshine, low calcium and high caffein dietary intake, alcoholic beverages, soft drinks, smoking and drugs might at least partially explain these findings. In an attempt to test this hypothesis, BMD values were correlated with physical activity (walking, sports and exercise) and with daily calcium intake. A nearly significant positive correlation with calcium intake (p = 0.058) and with physical activity (p = 0.073) was found. However, calcium dietary intake was estimated only semi-quantitatively and retrospectively, and physical activity (type and duration) was very difficult to quantify. Moreover, other influencing factors that might be important were not taken into account.

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P287MO. THE RELATION BETWEEN DIETARY CALCIUM INTAKE AND BONE MINERAL DENSITY IN POSTMENOPAUSAL OSTEOPOROSIS

as well as dental state and calls for arrangements of primary and secondary prophylaxis of osteoporosis and fluorosis.

Cerrahoglu L, Duruo¨z MT, Tikiz C, Olcenler S, Tulukoglu N; CBU Medical School PM&R Department, Manisa, Turkey Aim: To assess the relation between dietary calcium intake and bone mineral density (BMD) in postmenopausal osteoporosis (PMO). Methods: Subjects with PMO who had not got any treatment previously were recruited randomly. Secondary osteoporosis, and up to 70 years of age were the exclusion criteria. The standard questionnaire was filled out by a physician to determine the daily calcium intake for each patient. Bone mineral density (BMD), T and Z scores of L1–L4 region, L3 lateral, femur neck, trochanter and Ward’s triangle were assessed. Spearman’s nonparametric rank correlation coefficient was used to evaluate the relation between two quantitative variables. Results: Eighty-seven subjects with PMO were recruited. The mean age was 58.54 (SD: 7.44; min–max: 41-70) and the mean of daily calcium intake was 1110,93 mg (SD:770,19). There were a significant relation between calcium intake and BMD and Z score at L1–L4 level. Other correlation coefficient values were nonsignificant (Table). Conclusion: There is a significant relation between dietary calcium intake and L1–L4 BMD and Z score. Region

BMD

Z score

T score

L1–L4 L3 lateral Femur neck Trochanter Ward’s triangle

0,521*¨ 0,170 0,201 0,032 –0,031

0,482** 0,239 0,240 –0,147 0,161

0,382 –0,011 –0,033 –0,172 –0,065

* p = 0,015; ** p = 0,027

P288SA. IMPACT OF INCREASED FLUORIDE CONCENTRATIONS IN WATER ON BONE TISSUE FUNCTIONAL STATE, TEETH, ANTHROPOMETRIC PARAMETERS AND PHYSICAL DEVELOPMENT OF TEENAGERS 1,2

2

1,2

Povoroznjuk VV , Zhovinsky EY , Grygoreva NV , Vilensky AB1,2, Bidenco NV2; 1Institute of Gerontology, Kiev, Ukraine, 2 Ukrainian Center of Osteoporosis, Kiev, Ukraine The aim of this research is to study structural-functional state of bone mass, teeth, state of factual feeding, anthropometric parameters and physical development of children and teenagers residing in regions with high Fluoride content in water. 103 children, aged 10–15 years (48 boys and 55 girls) from the residential areas A, B and C where Fluoride content in environment was increased were inspected during the study. It was discovered that the Fluoride level in the water of towns B and C was 2–5 times higher than normative, and in local wells the level differed within bounds of residential area. Lower level of calorie content, insufficient protein consumption and low level of microelements, unbalanced consumption of carbohydrates and fats characterize a daily ration of teenagers from all towns. The excessive F concentration in water (max – up to 3,51 m/I in town C) leads to development of dental fluorosis, frequency and degree of which depends on Fluoride level in drinking-water, on the background of normal indexes of structural–functional state of bone tissue. For children residing in region with increased Fluoride content in drinking-water delay of physical development of boys and disharmonious physical development of girls are rather typical. The anthropometric examination of children revealed particular somatotypes of children from different towns, but to study them would be the task of further investigations. The increased Fluoride content in water negatively influences peak bone mass formation and physical development

P289SU. AGE CHANGES OF DXA ABSORPTIOMETRY IN HEALTHY PORTUGUESE WOMEN Bernardes M1, Pereira S2, Valente P1, Bernardo A1, Mariz E1, Cardoso A1, Vaz C1, Barros H2, Lopes-Vaz A1; 1Department of Rheumatology, S. Joa˜o Hospital, Porto, Portugal, 2Department of Hygiene and Epidemiology of Porto Medical School, Porto, Portugal Background: Cross-sectional studies reported a decline in bone mineral density (BMD) with age using a variety of methods. However these reports are based largely on measurements at appendicular sites of the skleleton. Low bone mineral density is associated with increased risk of fracture and it appears to decline with increasing age. Objective: The aim of this study was assess age changes in dual X-ray absorptiometry (DXA) in a large sample of healthy portuguese women. Participants and Methods: Bone densitometric parameters were measured at the proximal femur and lumbar spine by DXA absorptiometry (Hologic QDR 1500) in 768 randomly selected healthy community women. A structured questionnaire comprising information on demographic, social, familial, anthropometric and behavioural characteristics was used. Results: Bone mineral density at the femoral neck decreased significantly by 16,0% between late adolescence (20–24 years) and old age (484 years). Bone mineral density at the lumbar spine decreased significantly by 16,9% between late adolescence (20–24 years) and old age (484 years). Bone mineral density at lumbar spine increase until 45 years, although this increase was not statistically significant and decrease significantly after. Conclusions: Bone mineral density measured by dual X-ray absorptiometry decrease significantly after twenties suggests that the accretion of peak bone mass increase about this period.

P290MO. PATIENTS’ PERSPECTIVE ON IMPAIRED QUALITY OF LIFE DUE TO OSTEOPOROSIS Hren R1, Breznik M1, Strah D2, Cokolic M3; 1University of Ljubljana, Ljubljana, Slovenia, 2Outpatient Clinic Domzale, Domzale, Slovenia, 3Teaching Hospital Maribor, Maribor, Slovenia When treating osteoporosis, it is important that clinical measures of therapeutic management are correlated with the patient concern for quality of life. In this study, we examined patient perception of suffering and impaired quality of life due to osteoporosis. Women who participated in the study were required to have been previously diagnosed with osteoporosis. Quality-of-life survey included three questions on pain, activities of daily living, and mood. Each question was ranked on a five-point scale, in which a rating of 1 respresented the worst possible function and rating of 5 the best possible function. The total score could vary from 3 to 15, and women were accordingly subdivided into one of the three categories: severely affected by osteoporosis (3–6), moderately affected by osteoporosis (7–11), and mildly affected by osteoporosis (12–15). In the survey, we also collected the fracture status, age, body mass index, lumbar spine (L2–L4) BMD, and treatment choice. The survey was conducted at 10 centers. We prospectively enrolled 945 women with postmenopausal osteoporosis, with a mean age (SD) of 64 (9) years, mean body mass index of 26 (4) kg/ m2, and mean T-score at lumbar spine of –3.3 (0.8). The fracture status of the study group was as follows: 18% of women suffered the wrist fracture, 3% the hip fracture, and 18% had kyphosis. In total, 22% of women were severely affected by osteoporosis and 55% were moderately affected. The survey revealed that 44% of

S90 women had either always (12%) or often (32%) serious problems in undertaking activities of daily living; 23% of women always (5%) or often (18%) felt unhappy because of osteoporosis. Results of our survey suggest that osteoporosis is associated with considerable morbidity (only 23% of women were mildly affected) that needs to be taken into account when treating the disease.

P291SA. THE INFLUENCE OF THE BODY MASS INDEX AND OF THE HISTORY OF HYPERTHYROIDISM, HYPERCORTISOLISM AND AMENORRHOEA ON BONE MINERAL DENSITY Francucci CM, Mancini T, Camilletti A, Riccialdelli L, Kola B, Massi F, Boscaro M; Division of Endocrinology, Department of Internal Medicine, University of Ancona, Ancona, Italy The pathogenesis of osteoporosis is complex and many risk factors are involved. In order to select the patients at higher risk of osteoporosis, different questionnaires have been used. The questionnaire we have been using aims especially to look for conditions such as amenorrhoea, hyperthyroidism and hypercortisolism, which are well known risk factors for the osteoporosis. In this study we have evaluated the effects of these risk factors and of the body mass (BMI) on bone mineral density (BMD) in 766 women who were referred to our centre to perform a dual-energy X-rays absorptiometry (DPX Lunar V 3.61, Madison, Wisconsin). These women presented a mean age ± SD of 46.2 ± 2.5 (range 40–49 years), a mean BMI ± SD of 25 ± 4,4 and didn’t present any other risk factors. A positive correlation between BMI and BMD was observed (r = 0,4 and P 5 0,001). The patients were subsequently divided in four categories depending on risk factors (amenorrhoea, hypercortisolism, hyperthyroidism and controls). All groups didn’t differ for age and BMI. We observed that amenorrhoic patients presented BMD significantly lower versus both hyperthyroid and controls (**p 5 0,001). In conclusion our data show that underweight and amenorrhoic women have the lowest BMD. Amenorrhea is an important osteoporosis risk factor, independently of the weight.

P292SU. A COMPARISON OF RISK FACTORS AND BONE MINERAL DENSITY MEASUREMENTS IN TURKISH POSTMENOPAUSAL WOMEN WITH OSTEOPOROSIS Ofluoglu D, Kul E, Gunduz OH, Akyuz G; Marmara University School of Medicine, Department of Physical Medicine and Rehabilitation, Istanbul, Turkey Osteoporosis is a metabolic bone disease characterized by a decrease in bone mass and a deterioration in bone microarchitecture. The aim of this study was to investigate the risk factors of osteoporosis in Turkish postmenopausal osteoporotic women and to compare the relations with bone mineral density (BMD) measurements. Postmenopausal osteoporotic women admitted to the outpatient clinic were included. The patients were asked to complete a questionnaire related to demographic variables, lifestyle characteristics and risk factors related to osteoporosis. After complete physical examination, thoracic and lumbar X-Rays were obtained. Routine hematological and biochemical investigations were performed to exclude other conditions and secondary causes of osteoporosis. Assessment of pain was performed using 10-cm visual anologue scale (VAS) and modified face scale. BMD’s were evaluated with DEXA. The mean age of 176 patients was 66.86±8.61 years, and the mean age at menopause was 45.86±6.63 years. Baseline T scores were –2.44±1.22 in L1–4, –2.69±0.86 in femur Ward’s region, – 2.14±0.89 in femur neck. Their VAS and modified face scores were 3.36±1.98 cm and 4.93±2.39, respectively. Only one fourth of our patients stated that they walked regularly. Thirty-nine per cent

Abstracts of the patients consumed more than 3 cups of coffee per day, and 24,7% of them were accepted heavy smookers. Nineteen per cent of patients had less than or equal to 2 months of immobilization after menopause, and 2,9% were immobilized 42 months due to various reasons. In our patients, 27% had at least one fracture during their lifetime. We have shown that regular walking was positively correlated, and coffee consumption, smoking, history of fracture, family history of fracture, and immobilization were negatively correlated with bone mineral density. We concluded that besides genetic factors and medical history, lifestyle has one of the important factors on BMD measurements.

P293MO. OSTEOPOROSIS AWARENESS AMONG BOTH GENDER PORTUGUESE YOUNG ADULTS AND ADULTS OVER 50 YEARS Canhao H, Fonseca JE, Resende C, Castelao W, Romeu JC, Pereira Silva JA, Viana Queiroz M; Santa Maria Hospital, Lisbon, Portugal Aim: To characterise osteoporosis (OP) knowledge and awareness among Portuguese young adults and adults over 50 years. Methods:Transversal study using a written questionnaire. The studied population included healthy university students, hospital employees, gynaecology and urology outpatients. Individuals with significant or rheumatological diseases were excluded. Results: 244 individuals distributed in 4 groups: A-102 females 18-25 yrs; B-59 males 18–25 yrs; C-50 females450 yrs; D-33 males450 yrs. The mean age for each group was: A-20,3±2,2 yrs; B-20,3±2,1 yrs; C-57,3±7,2 yrs; D-64,5±8,6 yrs. 99% young females, 100% young males, 98% females 450years and 97% males 450years ‘have already heard about osteoporosis’. None of young females nor young males have ever actively sought a doctor due to OP; on the opposite, 26% females and 9% males over 50 years sought a medical visit because OP. Concern about the disease was high in group C, moderate in groups A and D and mild in group B. Only 1% of young males and females and 9% of males 450years have done a densitometry; by contrary 55% of older females have done at least 1 densitometry. 22% in group C, 6% in group D and none in groups A and B were submitted to specific therapy for osteoporosis. 36% of patients in group C had been submitted or were currently under hormonal replacement therapy. Conclusion: In our study, despite the extended knowledge of OP, only a minority of individuals looked for a doctor specifically for this disease. We reported a significant difference on the number of densitometries performed in females and males over 50years, with more than half of the former having done at least one exam. Women showed greater concern about becoming affected by OP than men and the degree of concern increase with age. Despite public awareness being considered the first step towards OP prevention and treatment, we have observed a discrepancy between awareness and active search for care. This fact should be considered in future health authorities campaigns.

P294SA. OSTEOPOROSIS AWARENESS AMONG INDIAN PATIENTS Kabir SR, Dey AB, Handa R, Bhatla N; All India Institute of Medical Sciences, New Delhi, India Aims: Though an emerging public health problem in India, osteoporosis has not yet received the attention it deserves. The primordial prevention of osteoporosis in general population should be to make them aware of the disease, risk factors and preventive measures. We carried out a prospective study to determine the awareness of osteoporosis and its prevention among Indian patients.

Abstracts Methods: 400 adult patients from the Geriatric and Gynaecology Clinics at a tertiary care hospital in New Delhi were randomly given self administered questionnaires. The structured questionnaire included questions about the disease, preventive measures and desire for information. Results: A total of 374 patients (age 20–82 years; female 284, male 90) responded (response rate 93.5%). A mere 21% patients had heard about osteoporosis. Of these, 94% knew that osteoporosis was a disease affecting the bones. However, 78% had no idea about the disease process or its consequences. Nearly 75% knew it was more common in females while 42% could identify correctly the vulnerable age group. Of the patients who had heard about osteoporosis, nearly two thirds felt that they might be affected themselves, but as many as 38% did not know that the disease could be prevented. Only one respondent knew the role of HRT. An overwhelming 333 patients (89%) wanted to have information about osteoporosis, but 75% of them did not know whom to approach for the same. Conclusions: The knowledge about osteoporosis, its risk factors and preventive measures is very poor amongst the patient population of Geriatrics and Gynaecology Clinics – two ‘at risk’ groups. With the elderly population in India projected to cross 160 million by 2025, educational initiatives involving osteoporosis are urgently required in the country.

P295SU. PREVENTION ACTIVITIES AGAINST OSTEOPOROSIS IN MUNICIPALITIES IN JAPAN Satomura K1, Nakahara T1, Miyagishima K1, Noami M1, Yamada S2, Sakurami T3; 1Kyoto University, Kyoto, Japan, 2Aichi Medical University College of Nursing, Aichi, Japan, 3Hayato-Cho Medical Center for Doctors’ Association, Kagoshima, Japan In Japan number of patients with osteoporosis is gradually increasing. One of the reasons is that the calcium intake is lower than it should be. By Health and Medical Service Law for the Aged, screening test for osteoporosis is performed to forty- and fifty-year-old female. Municipalities have plans to disseminate knowledge about osteoporosis. We surveyed their prevention activities against osteoporosis. Objects and Method: A questionnaire asking their prevention activities against osteoporosis was sent to all municipalities in Japan. Results: 1583 out of 3252 municipalities replied the questionnaire. 12.3% of the municipalities held only lectures about osteoporosis, 33.0% of them held only series of health education classes about it and12.0% of them held both lectures and series of health education classes. The lectures were held 2.7 times in a year. The series of health education classes consisted of 2.3 classes. In 25.2% of these classes, the bone density of participants was measured. Total number of participants in these classes was 17,208 in a year. 95.4% of municipalities which had these classes used three or less kinds of media for advertising them. 36.6% of the municipalities that had no lectures or classes planned to have them in the near future. Discussion: Only 57.3% of municipalities disseminated information aggressively by lectures and/or classes. 98.1% of the municipalities with lectures and/or classes gave advices about osteoporosis anytime if they were requested. Even in municipalities that held classes which give more profound knowledge about osteoporosis than lectures, total number of participants was small and kinds of methods for public relation was few. To diffuse knowledge about osteoporosis effectively, new strategies should be improved. Conclusion: In Japan, to decrease number of patients with osteoporosis, municipalities have to develop striking methods for diffusing the knowledge about the disease.

S91 P296MO. RISK FACTORS FOR OSTEOPOROSIS IN HEALTHY WOMEN Pilipovic N, Vujasinovic-Stupar N, Palic-Obradovic D, Vukojevic P, Radunovic G, Brankovic S; Institute of Rheumatology, Belgrade, Yugoslavia Out of 667 citizens of Belgrade, randomly selected from the population register, we chose 101 healthy premenopausal women aged 20–40 yrs and 102 healthy postmenopausal women, aged 41–60 yrs, to establish risk factors for osteoporosis using standardized questionnaire. The study was carried out in Institute of Rheumatology in Belgrade and bone mineral density (BMD) of lumbar spine was measured using a Lunar DPX-L device. Osteopenia was found in 12 (11,88%) premenopausal (pre) and in 41 (40,20%) postmenopausal women (post); osteoporosis was found in 2 (1,98%) premenopausal and in 11 (10,78%) postmenopausal women. We were assessing 24 risk factors for osteoporosis and 11 of them were detected in woman with low BMD: sedentary type of work (50% pre and 78,85% post), sedentary type of life (64,3% pre and 73,1% post), smoking (78,6% pre and 30,8% post), alcohol abuse (7,1% pre and 5,8% post), coffee abuse (100% pre and 59,6% post), low calcium intake (50% pre and 21,2% post), low sun exposure (14,3% pre and 59,6% post), late menarche (50% pre and 19,2% post), nulliparae (35,7% pre and 13,5% post), long breast feeding (35,1% pre and 51,9% post), low or normal BMI (92,9% pre and 42,3% post). Statistical analyses (Chi square test, T-test) confirmed, that extensive smoking and low BMI have significant negative effect on BMD in premenopausal healthy women and in postmenopausal healthy women, beside menopausis, sedentary type of life, sedentary type of work and low or normal BMI have significant negative effect on BMD.

P297SA. EVALUATION OF RISK FACTORS AND MEASUREMENT OF CALCANEAL ULTRASOUND IN TURKISH WOMEN Dinc¸er G1, Atalay F2, Go¨kc¸e-Kutsal Y3, Yavuzer G1, Sonel B1, Elhan A4, Osteoporosis Society A5; 1Ankara University Medical School, Department of Physical Medicine and Rehabilitation, Ankara, Turkey, 2Gazi University Medical School, Department of Physical Medicine and Rehabilitation, Ankara, Turkey, 3Hacettepe University Medical School, Department of Physical Medicine and Rehabilitation, Ankara, Turkey, 4Ankara University Medical School, Department of Biostatistics, Ankara, Turkey, 5 Osteoporosis Society, Ankara, Turkey Objective: To investigate bone mass in Turkish women, and to determine the predictive values of certain putative sociodemographic, behavioral, genetic, and relevant life style parameters on bone mass. Method: A total of 684 women aged 30–75 years from 5 different regions of Turkey were evaluated. Antropometric measures were recorded. Risk factors of osteoporosis were assessed by a detailed questionnaire including demographic, social, reproductive and life style parameters. Stiffness index (SI, expressed as the % in young adults) of the calcaneous was measured using the Achilles Express Ultrasonometer (Lunar Corp., Madison, WI, USA). Subjects (n = 338) with a history of any medication or diseases known to affect bone metabolism were excluded. Further statistics were performed on remaining 346 subjects. Results: The mean age was 41.1 ± 9.2 years. Thirty-seven percent of the subjects were in postmenopausal state. According to T scores, 175 subjects (51%) had normal bone mass, 134 (38%) had osteopenia and 37 subjects (11%) had osteoporosis (70% of these osteoporotic women were postmenopausal). The average SI in pre- and postmenopausal state was 90,7 ± 15,2 and 81,2 ± 16,7, respectively and the diffence was statistically significant (z = –4,9, p50,001). SI was weakly associated with age (r = –0,26),

S92 physical activity (r = 0,21), number of pregnancies (r = –0,16), and monthly income (r = 0,16). Stepwise regression analysis revealed that none of the parameters had predictive value on bone mass. Conclusion: This study presents the high prevalence of osteoporosis in Turkish postmenopausal women. The weak correlation between SI and assessed risk factors revealed that measurements of bone mass is mandatory for the diagnosis and treatment approach of osteoporosis.

P298SU. THE DIAGNOSTIC CRITERIA OF PRIMARY OSTEOPOROSIS IN CHINA

Abstracts Diet was found to have mostly major variables: Women with osteoporosis consume: less white meat: in special chicken with no skin and fish, less vegetables rich in carotene, as well as onions. The osteoporosis profile consumes: more salt with their food and fat food of animal origin types. We don’t find significant differences in the consumption of dairy products, nor in the calcium support of food. We found that osteoporotic women within the ages studied have lived longer in cities, have lower educational level, lower IMC, lower body weight and do less physical exercise. The urban conditions of Uruguayan women was found associated with osteoporosis. There was no association found with osteoporosis in women which remained in their origin place.

Liu Z, Piao J, Pang L, Pan ZA, Guo Y, Li F, Liu J; China Osteoporosis Foundation, Beijing, P.R.China From over 10 years clinical practice and epidemiological studies, we realize that the appropriate diagnostic criteria are the most important thing among basic research, clinical studies of the prevention and therapy for osteoporosis. In this paper, we will discuss the following two problems for using dual energy X ray absorptiometry (DEXA). Which part of the bone is the better place to be measured? We can easily find that the results of bone mineral density in different areas are different. One of the reasons is the effect of bone size, shape and the direction. Hip neck is considered to be the best place for BMD measurement and osteoporosis diagnosis, because it has less artificial influences from the analysis based on our data. And we can see that ward’s area (early bone loss, 425% at age 50) can not provide the accurate data for osteoporosis diagnosis. For L2–4 one should consider that soft tissue calcification can cause artificial high reading. What are the best diagnostic criteria we should use for Chinese people? In 1985, WHO suggested that osteoporosis can be diagnosticed for white women while a T-score of a value for BMD or BMC more than 2.5SD below the young adult average value. In Japan, Dr. Orimo and Japanese bone mineral society defined the osteoporosis diagnostic guidelines. If BMD is 70% below the mean value of young adult of the same gender, it is osteoporosis. We suggest the following criteria for Chinese people: the cumulated bone loss 425% than the mean value of young adult of the same gender in Chinese can be diagnosed having osteoporosis, the cumulated bone loss between 1–12% is normal BMD, the cumulated bone loss between 13–24% is osteopenia, the cumulated bone loss 437% and the presence of one or more fragility fractures is severe osteoporosis.

P299MO. OSTEOPOROSIS – LIFE AND DIET HABITS INFLUENCE IN A URUGUAYAN POPULATION OF 40–59 YEARS OLD WOMEN Herna´ndez J, Ronco A, Souto R, Moyano M, Bairo L, Uboldi C, Tuso L, Calegari M, Ramagli A; Uruguayan Society of Reumatologhy, Montevideo, Uruguay Materials and Methods: 256 40–59 years old women were interviewed between March 2000 and May 2001. Two groups of patients were identified: 162 with densitometry of minus 2.5 SD, 94 controls with normal. Both groups were interviewed personally by a rheumatologist and later by a trained researcher. Based in a questionnaire including sections over variables: Social – Demographic – Tobacco – Alcohol – Occupation – Present and past height and weight – osteoporosis family background – Menstrual and reproductive characteristics – Feeding frequency over 100 items. Frequency and consumption of each type or dietary item was registered twice a day, per week and on a monthly basis, and converted over times per year. Numerous factors were found associated with an increase and reduction of osteoporosis risk in middle aged Uruguayan women.

P300SA. PREVELANCE OF VERTEBRAL FRACTURES IN POSTMENOPAUSAL OSTEOPOROTIC WOMEN AND THE RELATIONS BETWEEN BONE MINERAL DENSITY AND MEUNIER INDEX Cerrahoglu L, Olcenler S; CBU Medical School PM&R Department, Manisa, Turkey Aims: To determine the prevelance of vertebral fractures in postmenopausal women according to meunier index. Methods: Subjects with osteoporosis according to WHO criteria and back pain were recrutied randomly into our study. Patiens with secondary osteoporosis, under osteoporotic therapy, a diagnosis other than the osteoporosis which might explain the patients’ back pain. Vertebral fracture prevelance was studied using Meunier Index. T7-L4 vertebrae bodies were analysed at lateral dorsolomber X-Ray. DEXA was used to assess the BMD, T and Z scores at L2-4 and L3-lateral regions. Statical analysis was made by student t test and pearson corelation coefficient. Results: The 62 subjects were recruited into the study. The mean age of patients with and without osteoporotic vertebral fractures were 62.5±5 and 60.9±6 respectively. The age and menapausal ages of two groups were not diferent significantly. The prevelance of vertebral fracture was %35 in postmenopausal women according to Meunier Index. Vertebral fracture was established in 22 patients. There was significant statical relation between the BMD of L2-4 vertebrae and Meunier Index. According to Meunier Index, BMD with vertebral fracture were found low. The mean BMD of L2-4 vertebrae with and without osteoporotic fractures were 0.814±0,1 and 0.915±0.1 respectively (p = 0.03). T and Z scores were insignificantly lower in patients with vertebral fractures. No statically significant difference of L3-T score was found between two groups although Z scores of L3 vertebrae was statically significantly low in patients with vertebral fractures. Conclusion: The loss of bone mineral density causes a risk of fracture. A significant corelation between Meunier Index and bone mineral density was found. Meunier Index was evaluated as a valid method for detemining vertebral fractures. It recomended that BMD should be measured with patients with a total score of higher than 10 due to Meunier Index.

P301SU. FRAGILITY FRACTURES – A GROWING PUBLIC HEALTH PROBLEM IN SLOVENIA Komadina R1, Rok – Simon M2; 1Teaching Hospital Celje, Celje, Slovenia, 2Institute of Public Health, Ljubljana, Slovenia As a part of Bone & Joint Decade project, National Action Network Slovenia prepared a report on osteoporotic fractures in Slovenia. In the analysis, we studied data from the Slovenian Institute of Public Health. Mortality rate: In 1999, 1476 people died because of injuries and intoxications. In 11.8% of cases death was caused by injuries of femur and hip. 322 people died because of musculosceletal

Abstracts injuries (171 femoral fractures, 39.2% of them due to femoral neck fractures and 35.7% due to pertrochanteric fractures). Hospitalization rate: In Slovenia every year 16.859 people with musculo-sceletal injuries are hospitalized (2.759 hip fractures). 40.8% of hip fractures are due to neck fractures and 39.1% of them are pertrochanteric fractures. 89.3% of fractures appeared as a result of fall from standing position. Rate of hospitalization increases with average age (13.3/1000 inhabitants of 80–84 years; 25.4/1000 inhabitants of 85–89 years; 833.7/1000 inhibitants older than 90 years). During hospitalization, 155 patients (6%) died because of femoral fractures. Their death was in most cases caused by heart failure (78) and lung embolism (12). The number of patients who died while hospitalized rises with their age (50–54 years: 1.4%, 60–64 years: 4.3%, 70–74 years: 4.2%, 80–84 years: 7.7%, above 90 years: 13.9%). Treatment outside hospital and medical rehabilitation are most often required because of back pain. Among all muscolo-skeletal disorders, fractures of the hip are the most frequent cause of death in Slovenia. Above the age of 70, people are at higher risk to have a broken hip. In women mortality rate is twice as high as in men and osteoporosis is one of the most frequent risk factors. Almost 90% of all hip fractures appear as a result of fall. 20% of women and 30% of men die in the first year after the fracture.

P302MO. OSTEOPOROSIS: LACK OF AWARENESS AMONG AFRICAN PHYSICIANS PERPETUATES THE MYTH THAT THIS CONDITION IS ABSENT IN AFRICA Zebaze MRD1, Ebah LM2, Djeumen CW2, Magny ET3, Watsop DC1, Choukem S4, Seeman E5; 1Mfou District Hospital, Yaounde´, Cameroon., 2University teaching centre, Yaounde´, Cameroon., 3 Nkondjock District Hospital, Nkondjock,Cameroon., 4Faculty of Medicine, Yaounde´ University, Cameroon., 5Austin and Repatriation Medical centre, University of Melbourne, Melbourne, Australia. With modernization, aging and changing lifestyle, osteoporosis is becoming a growing public health problem in developing countries and Africa. As it is a largely preventable and treatable disease, awareness can lead to a reduction in the incidence of fractures. Therefore it is important to know how far Medical Doctors who are those taking care of patients and community health are aware of the disease. To assess the level of awareness of osteoporosis among African Medical Doctors a cross sectional survey of 70 Doctors of diverse background, specialty, age, practice and set up working in Yaounde´, the political capital of Cameroon was done. All were enrolled in a Knowledge and Attitudes study after a friendship meeting. Very low scores in all the items investigated were found. For example, concerning the epidemiology of the disease, 10% of respondents do not know that it is mostly a disease of postmenopausal women and up to 11.4% of the physicians think that osteoporosis affect only white women. Only 17.1% of the physicians knew the definition of osteoporosis while 45.7% chose estrogen replacement therapy as a treatment of osteoporosis, 7% knew biphosphonates is a treatment of osteoporosis, 27.1% of the physicians responded that Physical activity could help to prevent osteoporosis and 8.5% answered that good calcium intake plus activity is a way of preventing osteoporosis. Concerning hip fractures, 52% of the physicians had seen a hip fractures following a minimal trauma in an elderly, only 29.7% could associate those hip fracture with osteoporosis. Our data suggests that African physicians are unaware of osteoporosis. It brings out the necessity to increase the awareness of African physician in other to tackle the upcoming osteoporosis problem in this part of the world. It also indicate that a lack of awareness among physicians is likely to lead to under-estimation of cases of osteoporosis contributing to the perpetuation of the myth that this disorder does no occur in Africa.

S93 P303SA. RESULTS OF ADMINISTRATION OF MINI OSTEOPOROSIS QUALITY OF LIFE QUESTIONNAIRE IN TURKISH POSTMENOPAUSAL OSTEOPOROTIC PATIENTS Bolgen-Cimen O, Bagis S, Sahin G, Yapici Y, Bicer A, Karabiber M, Erdogan C; Mersy´n Univercity, School of Medicine, Depart. PMR, Mersy´n, Turkey Results of Administration of Quality of Life Questionnaire in Turkish Postmenopausal Osteoporotic Women Health related quality of life has been an important outcome criterion in the assessment and follow-up of osteoporotic patients. Osteoprosis Quality of Life Questionnaire (OQLQ) was validated in previous studies in patients with osteoporosis with vertebral fractures. But quality of life in osteoporotic patients who don’t have any vertebral fractures has not been widely investigated. The aim of this study was to evaluate OQLQ in Turkish postmenopausal osteoporotic women without vertebral osteoporosis. Two hundred twenty six postmenopausal osteoporotic women were included in this study. Mean age of total patients was 57,98± 8,26, mean duration of menopause was 12,11±9.19, mean BMI was 27,39±4.38. Patients were divided into three subgroups (osteoporotic, osteopenic and normal) according to their BMD. We analysed the effect of age, BMI, number of childbirth, menarche age, duration of menopause, lumbar, total femur BMD and osteoporosis risk questionnare on OQLO using multivariate analysis. OQLO did not show any significant relationship with these parameters. Although several lengthy health status instruments exist, shorter questionnaires must be developed to promote health status assessments in routine clinical practice. Other aspects than BMD have important influence on quality of life in patients with osteoporosis without any vertebral fractures. Further reliability and validity studies of OQLQ is needed for Turkish osteoporosis women.

P304SU. BONE MINERAL DENSITY AND RISK FACTORS: THE ROLE OF AMENORRHEA Mancini T, Camilletti A, Biondi E, Kola B, Massi F, Francucci CM, Boscaro M; Division of Endocrinology, Department of Internal Medicine, University of Ancona, Ancona, Italy Many risk factors contribute to the pathogenesis of osteoporosis. Typical examples include lifestyle and constitutional factors, low body mass, low levels of physical activity, prolonged immobility, alcool abuse, estradiol deficiency, long term corticosteroid use and hypertiroidism. Many studies have shown that these factors predict low bone mass at any skeletal site. Between 4.040 women (mean age±SD 55.2±10.1, BMI 25.8±5.1 and BMD 1.070±0.1g/cm2) arrived at our center, at the first time from 1996 to 2000, to effect a dual-energy X-ray absorptiometry (DXA) for bone mineral density evaluation, we have selected 775 women with a middle age of 46.2±2.5 that are the whole group of patients with an age range of 40 to 49 years. Since these women had a significant reduction of spinal BMD at lumbar spine (L2-L4) vs 715 healthy women with the same range of age of DPX Lunar V 3.61 (mean BMD±SD 1.149±0,15g/cm2 vs 1,170±0.12g/cm2; p = 50.001), we have excluded 283 women that had a history of amenorrhea (n8217), hypercortisolism (n830), hyperthyroidism (n825), renal illnesses (n89) and hyperparathyroidism (n82). The others 492 women (without no other osteoporosis risk factors referred to us) had a bone mass like controls of DPX Lunar V 3.61 (mean BMD±SD 1.170±0.1g/cm2 vs 1.170±0.12g/cm2; p = 0.8). Even if the women with hypercortisolism had a bone mass reduced vs controls, only the patients with amenorrhea had a significantly lower BMD vs 492 healthy women and vs controls of DPX Lunar V 3.61 (mean BMD±SD 1.099±0.14g/cm2 vs 1.170±0.1g/cm2 vs 1.170±0.12; p = 50.001). Our data show that amenorrhea is an osteoporosis risk factor more important than endogenous or iatrogenic hypercortisolism, that hypertiroidism don’t give rise to significant reduction of bone

S94 mass at vertebral level and that healthy women of middle Italy (Adriatic coast) and controls of DPX Lunar V 3.61 have the same BMD at lumbar spine.

P305MO. OSTEOPOROSIS SCREENING IN PRIMARY CARE Aragones R1, Orozco P1, Carbonell C2, Olmos C2; 1ABS Go´tic, Barcelona,Spain, 2ABS Vı´a Roma, Barcelona, Spain Aims: To asses osteoporosis screening at primary care in Spain, and to know if physicians can do any measurement of bone mass. – Contact with professionals interested in osteoporosis and it study. Design: a descriptive observational study. Method: We mailed a majority of Spanish physicians a selfadministered questionnaire asking for their daily screening of osteoporosis. Dates: July and august 2000. Results: 414 physicians answered our questionnaire from all Spanish sites except Soria and Zamora. Most of them doesn’t included osteoporosis in their daily preventive activities (67.6% versus 32.4%). About risk factors, the most often investigated were aged of menopause and personal past fracture. Only 26.1% can do bone densitometry and half of them investigated de suspected diagnosis of osteoporosis and the other half send patients to specialist. 64.7% answered that they are interested in OP multicentric studies. The other results are listed in table 1. Conclusions: 1. Osteoporosis is included only in one third of primary health care centres as a preventive activity; 2. Only a few physicians can do bone densitometry for OP diagnosis; 3. More than a half of physicians are interested in OP studies in primary care. Table 1 Questionnaire NO (%)/YES (%) Is Osteoporosis included in your preventive daily activities?/67.6/32.4 Do you ask always about: Family history of OP/64.5/35.5 Do you ask always about: Age at menopause/5.1/94.9 Do you ask for personal past fracture?/16.9/83.1. Do you do screening for OP in patient with: Vertebral deformity/fracture/ 17.1/82.9 Do you do screening if Hip fracture/21.7/78.3; Colles fracture/53.4/46.6 Therapy with corticosteroids/40.6/59.6; Anticonvulsivant therapy/88.2/11.8 Can you make a bone densitometry?/73.9/26.1

Abstracts contactable. Of those offered treatment 5 were taking bisphosphonates, 3 Calcium and vitamin D, 1 refused treatment and 6 were not offered treatment. The mean percentage increase in the treatment group was BMD spine 3.68%, NOF 1.48% and the corresponding decrease in the untreated group was –2.77% spine, 1.04% NOF. 2 sustained further fragility fractures 1 vertebral and 1 metatarsal. In this study 47% of the men shown to be at risk for osteoporosis were either not offered or refused treatment.

P307SU. TO ASSESS THE QUALITY OF LIFE IN POSTMENOPAUSAL OSTEOPOROTIC WOMEN WITH AND WITHOUT VERTEBRAL FRACTURES Olcenler S, Cerrahoglu L; CBU Medical School PM&R Department, Manisa, Turkey Objective: To compare the quality of life of postmenopausal osteoporotic (PMO) with and without vertebral fractures. Method: Subjects with osteoporosis according to WHO criteria (T-score 5–2.5) were recrutied randomly into our study. Fortyeight women with back pain at postmenopausal period were taken into account. We excluded patients with secondary osteoporosis, under osteoporotic therapy. The back pain which has other origin than the osteoporosis (eg. Neoplasmes, lumbar disc disease . . .) and some major illness which would substantially influence the patient’s quality of life (eg. congestive heart failure, stroke . . .) were in the exclusion criteria. T7-L4 vertebrae bodies (Meunier Index) were analysed at lateral dorsolumber XRay. DEXA was used to assess the bone mineral density (BMD), T and Z scores at L2-4 and L3-lateral levels. We administered the 36 item short form (SF-36) of the medical outcomes survey instrument. Statical analysis was made by student t test and Pearson corelation coefficient using SPSS 10.0 logistic package. Results: Vertebral fracture was established in 17 patients using Meunier Index. The mean age of women with and without vertebral fractures were 62,9 ± 5 and 60,9 ± 6 respectively. No significant difference of the menapausal age was observed between patients with and without vertebral fractures. No difference was found after evaluating with SF36 instrument between symptomatic patients with and without vertebral fractures. Conclusion: No statistically significant difference between quality of life at osteoporotic women with and without vertebral fractures was observed.

P306SA. FRACTURE PREVALENCE AND TWO YEAR FOLLOW UP IN THE ELDERLY MALE POPULATION Thomas J, Steel S, Doherty SM; Centre for Metabolic Bone Disease, Royal Hull Hospitals & Hull University, Kingston upon Hull, East Yorkshire, UK This is part of a continuing study comparing the logistical feasibility of undertaking diagnosis, risk assessment and treatment of osteoporosis in a male population over 60 years of age in an UK urban general practice. The study involved attendance at the practice where a questionnaire was completed and also at the hospital for DXA scan of lumbar spine and femoral neck (NOF). 198 (52%) men aged 60–90 attended for DXA. 20 men were found to be osteoporotic or severely osteopenic. 2 were being treated with a biphosphonate. 7 were osteoporotic (BMD T-score 4–2.8) at spine and NOF, 3 NOF only and 1 spine only. 1 was severely osteopenic (T-score4–2.3 and 5–2.8) at spine, 5 NOF only and 1 spine only. The family doctors were advised to offer bone protective treatment and lifestyle advice. A 2 year review was conducted with an invitation for a repeat DXA and questionnaire 15 men attended for a repeat DXA scan. 2 were too frail, 2 were unwilling to attend, as they had been informed by their doctor that their bone density did not require treatment and one was not

P308MO. RISK FACTORS FOR HIP FRACTURE IN WOMEN Anikin SG, Benevolenskaya LI; Institute of Rheumatology The aim of our study was to determine risk factors for hip fracture in minimal trauma among women aged 50 years and over. All of them lived in Electrostal town (suburb of Moscow, population 150 000). There were investigated 180 women: 60 women with hip fracture (confirm by x-ray examination) in period 1992–1999 years and 120 women in control group. The questionnaire includes 35 factor of hip fracture in women. To analyses data we used statistical program EpiInfo 2000. We found out the next significant risk factors. Lower weight (P50,005) and body mass index (P50,001). Impairment cerebral circulation (OR = 5,1, P50,001), intake sedative and soporific drags (OR = 2,8, P50,05), low physical activity at the work in 25–50 years (OR = 4,1, P50,001). Intake dairy produce one time a week or more rarely at age up to 25 years (OR = 2,7, P50,05). History of maternal hip fracture after 50 years (P50,001). Our data may be useful for selecting individuals with high risk of hip fracture and for creating prevention program.

Abstracts P309SA. BULGARIAN WOMEN’S KNOWLEDGE ABOUT OSTEOPOROSIS Manolova A, Ribarova F, Sider L; National Center of Hygiene, Medical Ecology and Nutrition, Sofia, Bulgaria One of the essential issues in osteoporosis prevention (OP) is the knowledge about the disease, major risk factors involved in its etiopathogenesis, prevention and treatment methods. The aim of this study is to assess the osteoporosis related knowledge in Bulgarian female population. Methods: A self administrated questionnaire (Bulgarian adaptation of OPQ, developed by a team from the Dept. of Psychology, WHO Collaborating Center for Metabolic Bone Disease, University of Sheffield Medical School, published in Maturitas, 00,237,75-81) is administrated to a nation-based sample of women (1000). The studied population was divided in to 3 age groups – premenopausal, menopausal and post menopausal. A subgroup comprising 120 women from the regional sections of the Foundation ‘Women without osteoporosis’ was formed. An informed consent was obtained from all women participating in the study. Results: The Bulgarian version of the OPQ shows significant consistency and construct-validity (Cronbach alfa = 0.87). As a whole the results show relatively low awareness of Bulgarian women about the disease (items for general information and consequences), osteoporosis risk factors, prevention and treatment. There is an interesting finding that younger women (under 45 years) are the least informed (P50.01). This, together with the fact that they do not actively search for specialized information shows the poor awareness of the young women toward the disease. The Foundation ‘Women without osteoporosis’ representatives in all three age groups show the significantly highest level of OP related knowledge. Conclusion: The study results show the necessity of conducting formal and informal educational programs through medical lectures, education materials and mass media.

P310SU. AGE-RELATED BONE LOSS IN NORMAL POPULATION OF UKRAINE: DATA OF ULTRASOUND BONE DENSITOMETRY Povoroznjuk VV; Institute of Gerontology, Kiev, Ukraine The bone tissue state in the residents of Ukraine, subjects of both sexes, was studied. The total of 1866 persons (1364 women and 502 men; 20–89 years old) were included. Patients with diseases influencing their bone tissue metabolism were excluded from the study. The heel bone examinations were performed by means of an ultrasound bone densitometer ‘Achilles+’ (Lunar Corp.,

S95 Madison, WI). The speed of sound (SOS, m/s), broadband ultrasound attenuation (BUA, dB/MHz) and a calculated ‘Stiffness’ index (SI, %) were measured. It was found out that the ultrasound parameters characterizing state of spongy bone tissue, and its density decrease after the age of 45 years old in women and after the age of 70 years old in men (Fig. 1). SI lower than the fracture threshold was found in: 2,4% – men; 13,4% – women in age group of 50–59 years; 9,6% – men; 24,6% – women in age group of 60–69; 22,6% – men; 50,0% – women in age group of 70–79 years, 20,1% – men; 53,3% – women in age group of 80–89 years. Thus, in the process of aging ultrasound parameters characterizing bone tissue state decrease significantly and number of the examined with indices lower than the fracture threshold increases.

P311MO. CALCANEAL STIFFNESS INDEX OF WOMEN: THE LEBANESE REFERENCE POPULATION Maalouf GH1, Abou Jaoude PA2, Atallah PA1, El Hage AN3, Nehme AL4, Wehbe JO1, Bedran FA5; 1St Georges University Hospital, Beirut, Lebanon, 2Mount Lebanon Hospital, Beirut, Lebanon, 3 Beit Chabab Hospital Lebanese College for Handicapped, Beit Chabab, Lebanon, 4CHU Rangueil, Toulouse, France, 5Serhal Hospital, Beirut, Lebanon We determined the Calcaneal Stiffness Index of a randomized women reference population, measuring 3454 female calcanea. The measurement was done using four ultrasound machines (Achilles, Lunar), and performed on women with age ranging between 20 and 90 years. Females were asked randomly to take part in a nationwide screening program using media, conferences, telephone calls, etc . . . and all were called to take measurements at the red cross centers spread all over the country. No inclusion or exclusion criteria were used. Nevertheless women had to be ambulant. Age related Lebanese Stiffness Index curve was delineated and found to be different from the American and the European curves used by the manufacturer. The shape of the curve was more similar to the Japanese curve. The ‘young adult reference’ of the Lebanese curve is lower than the U.S. and European reference curves. This decrease seems to be consistent in pre and post- menopausal periods. Other acessory results were obtained from this population namely the effect of weight on the Stiffness Index and the prevalence of osteoporosis and osteopenia in the Lebanese population. T-score correlation between Stiffness Index results and Femur BMD results was found to be good all over the range.

P312SA. LIFE HABITS, MARKERS AND DENSITOMETRY IN 40– 59 YEARS OLD WOMEN – CONTROL STUDY CASE Chijani V, Gonzalez G, Barreto G, Moyano M, Teijeiro R, Albanese M, Gomez E, Tuso L, Bairo L, Uboldi C; Uruguayan Society of Reumathology, Montevideo, Uruguay

Fig. 1. SI values in population of Ukraine associated with age and sex.

Aims: A personal research was performed with a questionnaire specifically designed comprising medical aspects on one hand, and on the other hand, social demographic, dietary and reproductive history factors. On a preliminary side, statistics basic analysis was performed on numerical variables with research purposes. Methods: The sample chosen was 255 women, 128 of wihch were healthy controls and 127 were cases. Cases were defined as those patients with DPD values and/or abnormal densitometry. Controls were those presenting normal values. Protocol: a) Personal data base, clinical aspects. Standard customized form, address, family composition. Osteo reabsortive marker: DPD. Conventional Radiology. DEXA Densitometry.

S96 Criteria: T Score, upon OMS criteria. Present treatment. b) Diet, excercise, gineco-obstetrics history. Conclusions: The education factor was the major discriminatory factor, over all the queries to patients, as in the quest over osteoporosis risk factors. Weight evolution on 40–44 years olds was significantly associated with the condition case or control (osteoporosis or normal). Osteoporosis – (T Score of –2,5) was present on 25.94% of densitometries. 74.06% showed osteopenia.

Abstracts that exercise to some agree affects accretion of bone mass during childhood and adolesence.

P315SA. DETERMINATION OF BONE MINERAL DENSITIES OF LUMBAR VERTEBRAE IN MENTAL WORKERS IN ELECTRIC POWER ENTERPRISES IN HENAN Liu Z, Wang X; Orthopaedic Society of Henan, Zhengzhou, China

The population of Egypt is rising steadily by an annual increase of 2.2% and expected to reach to 3 million by the year 2010. 4% of this population will be well over the age of 65 years, which will result in an increase in the prevalence of osteoporotic fractures. More than 100 studies have been carried out among Egyptians between 1989 and 2001 to have an idea of the problem and its impact on the life style among Egyptians. These studies will be critically analyzed and its results presented and discussed.

Objective: Bone mineral densities (BMD) of lumbar vertebrae in 316 mental workers of the 36 electric enterprises in Henan were determined. Methods: BMD of anterior-posterior and lateral lumbar vertebrae were measured by dual energy X-ray absorptionmetry with emphasis on BMD of area of interest (ROI) in lumbar vertebrae. Results: Peak values of BMD of lumbar verebrae occurred in age group 30–39 years of both sexes, and BMD gradually diminished with increasing age. Slight osteoporosis (OP) in 64 (20.5%), and severe OP in 25 (7.91%), the total OP incidence being 39.9%. Conclusion: Determination of BMD in ROI of lateral lumbar vertebrae can reveal early change of BMC. OP in mental workers is attributed to rather little outdoor activity and physical labor.

P314MO. CORRELATION BETWEEN MAXIMAL EFFECT (VMAX) DELIVERED DURING FITNESS TEST AND BONE MINERAL DENSITY (BMD) IN CHILDREN AND ADOLESCENTS

P316SU. INCIDENCE OF OSTEOMALACIA IN PATIENTS WITH HIP FRACTURES

P313SU. OSTEOPOROSIS IN EGYPT/ DO WE HAVE A PROBLEM? El Badawy SA; Cairo University, Cairo, Egypt, President Pan Arab Osteoporosis Society, President Egyptian Prevention Osteoporosis Society, Secretary General ILAR

Kramme K1, Mortensen L2, Froberg K3, Beck-Nielsen H1, Brixen K1, Charles P2; 1Dep. of Endocrinology, Odense University Hospital, Denmark, 2Dep. of Endocrinology, Aarhus University Hospital, Denmark, 3Institute of Sports Science and Clinical Biomechanics, University of Southern Denmark Previous studies have suggested that exercise may be one of the most important modifyable factors for accretion of bone mass in childhood and adolescence. Thus, some studies in adults have reported a positive correlation between VO2max and BMD. VO2max, however, depends on body weight which in itself is closely related with BMD. To circumvent this interdependence we evaluated the association between the maximal effect delivered during fitness test and lumbar spine and whole-body BMD in children and adolescents. This cross-sectional study comprised 157 females and 149 males aged 8 to 21 years (median 14 years). Participants were tested on an ergometer bicycle, and BMD subsequently measured using a Norland DXA-scanner. The relationship between BMD and Emax, body weight, height, age, and sex was evaluated using multiple backwards regression analysis. Results are shown in the table. Data are shown as partial correlation coefficients. (* p50.05, **p50.01, ***p50.001. n.i = not included in the final model) BMD Lumbar Spine BMD Whole Body Sex 0.33*** n.i Age 0.46*** 0.44*** Body weight 0.23*** 0.55*** Height 0.17** n.i. Emax 0.15* 0.18** Combined model 0.87*** 0.89***

In conclusion, the maximal effect delivered during exercise test correlates significantly with BMD in the lumbar spine and whole body in children and adolescents. Our study supports the idea

Riaz S, Alam M, Ahmed M, Umer M; The Aga Khan University Hospital, Karachi, Pakistan Background: The high incidence of moderate to severe osteoporosis in the elderly patients is a major cause of hip fractures after trivial trauma. Some of them also have dietary deficiency of calcium causing osteomalacia. Western studies have shown a 1– 2% prevalence of osteomalacia in the population with hip fractures. The incidence of osteomalacia in our population is not known. Objectives: This study was designed to find out the prevalence of osteomalacia in patients with hip fracture who presented at The Aga Khan University Hospital since September 1998 to September 2000. Materials and Methods: The total number of patients was 168 with 61 males and 107 females. Ninety-one patients presented with intracapsular fracture and 77 had intertrochanteric fractures. All patients were classified according to Garden and Boyd & Griffin’s classification, respectively. The degree of osteoporosis was assessed using the Singh’s Index. Laboratory investigations included serum Calcium, Phosphorus and Alkaline phosphatase. During surgery, small amount of curetted cancellous bone was taken and sent for histopathology. An elaborate questionnaire was completed for every patient. The average age was 61 years with 77% of the female patients being postmenopausal. Most of the patients (94.5%) had low velocity trauma. Results: Singh’s index for most of the fractures was II (30.8%) and III (46.2%). Thirty five percent of the patients showed abnormal values of serum Calcium, Phosphorus and Alkaline Phosphatase. Bone biopsy showed osteomalacia to be present in 12 patients (7.1%). Among these twelve patients, 7 had abnormal values of serum Calcium, Phosphorus and Alkaline phosphatase. There were 3 males and 9 females, seven being postmenopausal. Conclusion: Although the number of patients was small, this study showed an alarmingly high incidence of osteomalacia in Pakistani population compared with a very low prevalence of osteomalacia presented in western literature.

Abstracts

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P316AMO. INCREASED FRUIT AND VEGETABLE INTAKE REDUCES BONE TURNOVER IN EARLY POSTMENOPAUSAL SCOTTISH WOMEN Macdonald HM1, New SA2, Fraser WD3, Black AJ1, Grubb DA4, Reid DM1; 1University of Aberdeen, Woolmanhill Hospital, Aberdeen, UK, 2University of Surrey, Guildford, UK, 3Royal Liverpool University Hospital, Liverpool, UK, 4Rowett Research Institute, Aberdeen, UK We previously demonstrated that higher intakes of nutrients suggesting a diet rich in fruit & vegetables were associated with increased bone mineral density (BMD) in late premenopausal women (mean age 47.5 years). Subjects were selected from APOSS, a study on 5119 women who had a first BMD scan in 1990–3, 3883 of whom returned for a second scan in 1997–2000. At the follow-up visit 3239 women completed a validated food frequency questionnaire. Fruit intake was associated with greater BMD in premenopausal women (n 325). We now examine the effect of fruit and vegetable intake on urinary markers of bone resorption. At the follow-up visit most women provided a urine sample for measurement of free pyridinoline (fPYD) and deoxypyridinoline (fDPD) cross-links by HPLC (expressed relative to creatinine). Women taking bisphosphonates or suffering from thyroid disease were excluded. However, data from under- and over-reporters were included. Low intakes of vegetables (unadjusted or adjusted for energy intake as shown in table) were associated with increased levels of fPYD and fDPD, but no associations were seen with fruit intake. Women were divided into 4 categories according to menopausal status/HRT use: pre/perimenopausal (still menstruating), postmenopausal, past HRT user and present HRT user. The relationship was statistically significant for postmenopausal women and current HRT users. These results support recent findings of the DASH II trial and provide further confirmation that a high consumption of alkaliforming foods may benefit the skeleton. The possibility that a particular nutrient found in vegetables such as folate, vitamin K or specific phytochemical may explain these results requires further investigation. Menopausal group

All women (n 2744) Pre/Perimenopausal women (n 288) Postmenopausal women -no HRT (n 863) Past HRT users (n 570) Present HRT users (n 1023)

Energy adjusted vegetable intake fDPD/CRE

fPYD/CRE

Pearson r P

Pearson r P

–0.074 –0.064 –0.099 –0.034 –0.098

–0.073 –0.040 –0.118 –0.038 –0.081

50.001 0.293 0.005 0.435 0.002

50.001 0.515 0.001 0.382 0.011

Controlling for age, weight, height, smoking status, socio-economic status and physical activity level

P317SA. ROLE OF SERUM INTERLEUKIN-6 AND SOLUBLE INTERLEUKIN-6 RECEPTOR IN POSTMENOPAUSAL BONE LOSS Korzh IV; Sytenko Institute of Spine and Joints Pathology, Kharkov, Ukraine The aim of this study was to investigate the role of serum interleukin-6 (IL-6) and soluble interleukin-6 receptor (sIL-6R) in postmenopausal bone loss. Methods: It was examined in a population-based, longitudinal study of 216 women, 25–80-year-old at baseline, including 22 centenarians. Serum IL-6 and soluble interleukin-6 receptor were measured in baseline blood specimens. Repeat standardized measures of bone mineral density (BMD) at the femur (total hip) and the lumbar spine (L2-L4) were taken by dual x-ray absorptiometry an average of 2.8 yr apart.

Results: Crude and age-adjusted mean serum IL-6 levels were significantly lower in postmenopausal women with than without hormone replacement therapy at baseline. Statistical interaction between serum IL-6 and menopausal age or menopausal age group indicated that the effect of IL-6 on bone loss weakened with increasing distance from menopause and was no longer significant in women more than 10 yr after menopause. Among women up to 10 yr past menopause (n = 39), serum IL-6 was the single most important predictor of femoral bone loss, accounting for up to 34% of the total variability of change in BMD. Serum sIL6R and showed an increase until the seventh decade and a progressive decrease in older ages (r = 0.39, p50.0001 and r = 0.26, p = 0.008, respectively). IL-6 and sIL-6R were significantly higher in women within 10yr of menopause as compared to premenopausal subjects (1.62 vs. 1.27 pg/ml, p = 0.014; 48.1 vs. 41.2 ng/ml, p = 0.002; and 264.5 vs. 241.8 ng/ml, p = 0.008, respectively). In postmenopausal women, a negative correlation was found between sIL-6R and the lumbar BMD (r = –0.28, p = 0.002) even after adjusting for age and weight. Conclusions: The serum levels of IL-6 and sIL-6R exhibit different patterns of age- and menopause-related changes, and that the biological activity of IL-6 may be increased with age with potential implications in the age-related diseases such as osteoporosis.

P318SU. ARE THE SERUM VITAMIN D CUT-OFF LEVELS CURRENTLY USED IN AGED PEOPLE ACCURATE ENOUGH TO AVOID THE DEVELOPMENT OF SECONDARY HYPERPARATHYROIDISM? Go´mez C, Naves ML, Ferna´ndez JL, Dı´az JB, Coto MT, Cannata JB; Bone and Mineral Research Unit, Intituto Reina Sofia de Investigacio´n,Hospital Central de Asturias, Oviedo, Spain Serum 25-hydroxyvitamin D (25OHD), the main circulating vitamin D metabolite, is a good indicator of the vitamin D status. However, there is still some controversy related to ‘normal’ and ‘abnormal’ values. It is accepted that levels of 25OHD 55 ng/ml leads to osteomalacia, 510 ng/ml may induce secondary hyperparathyroidism, and 418 ng/ml might be considered ‘normal’. The purpose of this study was to assess the vitamin D status and the prevalence of secondary hyperparathyroidism in a random sample of 312 people (159 women and 153 men, 68±9 years old; ranged 54 to 89) who participated in the European Vertebral Osteoporosis Study (EVOS). We included in this analysis only those people who never received any kind of treatment for osteoporosis. There were no differences in age, sex or season of blood withdrawal between the 44 treated and the 268 non-treated people. In the 268 people analysed in this abstract, serum 25OHD showed a significant seasonal relationship: (13.7± 6.8 ng/ml) in winter/spring vs (19.4±10.3 ng/ml) in summer/autumn. This seasonal relationship was also observed with PTH and osteocalcin. Serum 25OHD levels were ‘deficient’ (510 ng/ml) in 27% of people, ‘borderline’ (10–18 ng/ml) in 40% and ‘normal’ (418 ng/ ml) in 33% of people. The prevalence of secondary hyperparathyroidism (iPTH 465 pg/ml) according to 25OHD group levels was 33% (510ng/ml), 16% (10–18 ng/ml) and 12%(418 ng/ml). There was no cases of secondary hyperparathyroidism with 25OHD levels 440ng/ml. The independent predictors for PTH values were 25OHD and serum creatinine in both sexes, and age in men. In conclusion, in people older than 54 years the 25OHD levels currently used in clinical practice to define ‘normal’ or ‘abnormal’ status needs to be reviewed and redefined in order to avoid a non negligible amount of secondary hyperparathyroidism likely due to ‘inadequately low’ levels of 25OHD in this population.

S98 P319MO. FEMUR BONE MINERAL DENSITY AND BLOOD MARKERS OF PROTEIN NUTRITION: GENDER SPECIFIC ASSOCIATIONS IN ELDERLY HIP-FRACTURED PATIENTS Di Monaco M1, Vallero F1, Di Monaco R2, Mautino F1, Cavanna A1; 1 Presidio Sanitario San Camillo, Osteoporosis Research Centre, Torino, Italy, 2I.R.E.S. L. Morosini, Torino, Italy Protein depletion is detrimental in bone health, but the association between bone mineral density (BMD) and serum albumin is controversial. We recently showed a positive association between femur BMD and total lymphocyte count (TLC), a validated marker of protein nutrition, in hip-fractured women. The aim of the study was to investigate the associations among femur BMD and both serum albumin and TLC in hip-fractured men and women. 435 patients consecutively admitted to a rehabilitation hospital following their first hip fracture were evaluated. 54 subjects were ruled out in agreement with the following exclusion criteria: impossibility to undergo BMD assessment, treatment with corticosteroid drugs, presence of haematological diseases which could alter TLC, total white cell count out of the normal range, presence of clinically detectable infections, chronic liver diseases, chronic renal failure. Finally 381 patients (335 women and 46 men) were included in the study. BMD was measured by DEXA (Hologic QDR 4500W) at the unfractured femur. In women a positive correlation was observed between TLC but not albumin and BMD measured at five sites: total femur (r = 0.23; p50.001), femur neck (r = 0.17; p50.01), trochanter (r = 0.19; p50.001), intertrochanteric area (r = 0.22; p50.001) and Ward’s triangle (r = 0.15; p50.01). Conversely in men a positive correlation was found between albumin but not TLC and BMD measured at the five sites: total femur (r = 0.46; p50.01), femur neck (r = 0.49; p50.01), trochanter (r = 0.34; p50.05), intertrochanteric area (r = 0.49; p50.01) and Ward’s triangle (r = 0.48; p50.01). Linear multiple regression showed that the associations were independent of age, weight, height, body mass index, time between surgery and blood sample collection and type of hip fracture (cervical or trochanteric). Our results support the role of protein nutrition in bone health, at least in elderly frail patients. TLC and serum albumin were suitable markers, however sex-related differences in their usefulness were observed.

P320SA. VERTEBRAL SIZE AND VOLUMETRIC DENSITY IN YOUNGER AND OLDER MEN WITH SPINE FRACTURES Wang XF, Duan YB, Seeman E; Austin & Repatriation Medical Centre, Melbourne, Australia Reduced peak bone accrual, excessive bone loss and impaired age-related periosteal apposition may variably contribute to the smaller vertebral size and lower volumetric BMD (vBMD) in men with spine fractures. We hypothesized that younger men with spine fractures would have smaller vertebral size due to reduced growth while older men would have normal bone size and reduced vBMD due to bone loss. We studied 44 men aged 54.3 yrs (45–65), 64 men aged 75.2 yrs (66–90) with nontraumatic spine fractures, and 395 healthy men aged 17 to 91 yrs without fractures. Vertebral width, height, and vBMD of the third lumbar vertebra were measured by postero–anterior scanning using dual x-ray absorptiometry. Vertebral volume (V) was estimated as: V = (scan area of L3)3/2. Vertebral vBMD was estimated as BMC/ V. The data were expressed as Z scores (Mean ± sem). Advancing age was associated with increased vertebral width (r = 0.17, p50.001) but not vertebral body height in healthy men. Vertebral width was reduced in younger (–0.25 ± 0.15 SD, p = 0.10) and older patients with fractures (–0.57 ± 0.11 SD, p50.001). Vertebral height was similarly reduced in younger and older patients (–0.30 ± 0.16 vs –0.29 ± 0.12 SD, NS). After adjusting for standing height and body weight, vertebral width was reduced only in older patients (–0.33 ± 0.11 SD, p50.01). vBMD deficit was similar in younger and older patients before (–1.30 ± 0.13 vs –1.37

Abstracts ± 0.10 SD, NS) and after adjusting for height and weight (–1.37 ± 0.13 SD vs –1.45 ± 0.10 SD, NS). We infer that, contrary to our hypothesis, younger men with spine fractures do not have reduced bone size but only reduced vBMD, probably due to reduced accrual of bone. Older men have both smaller bone size and reduced vBMD, both may be the result of reduced periosteal apposition. The pathogenesis of spinal fragility may different in younger and older men.

P321SU. EFFECTS OF ESTROGEN AND ESTROGEN RECEPTOR ALPHA GENE POLYMORPHISMS ON RENAL CALCIUM HANDLING IN ELDERLY WOMEN Jamieson E1, Taylor A1, Devine A1, Dick IM1, Beilby J2, Prins A2, Wilton S4, Duff R4, Ly T4, Dhaliwal SS3, Prince RL1,3,5; 1Dept. Medicine, Univ. Western Australia, 2The Western Australian Centre for Pathology & Medical Research, 3Dept. Endocrinology & Diabetes, Sir Charles Gairdner Hospital, 4Australian Neuromuscular Research Institute, QEII Medical Centre, 5Western Australian Institute of Medical Research, Australia There is clear evidence for the importance of postmenopausal endogenous estrogen production on bone mass. The potential mechanisms of action include direct-effects on bone, kidney or bowel. This study investigates the interaction between ERa gene polymorphisms and estrogen concentrations in relation to bone metabolism and the renal handling of calcium. Markers of bone turnover and calcium, phosphate, kidney and ovarian related biochemical parameters were measured in 259 postmenopausal women. Results were correlated with estrogen status as assessed by measurement of serum estradiol, sex hormone binding globulin and the ratio of the two, the free estradiol index. Bone turnover markers showed that a high free estradiol index was associated with low concentrations of bone turnover and accounted for 2 to 8% of the variance in these parameters. A high free estradiol index was associated with a high plasma calcium before and after adjustment serum for albumin. Urine calcium excretion and the calcium creatinine ratio were negatively correlated with the free estradiol index independent of PTH concentration. Two ERa polymorphisms were investigated – a TA repeat upstream of ERa gene and a PvuII restriction fragment length polymorphism (RFLP) in intron 1. No association was shown between ERa genotype and bone turnover or renal calcium handling. Thus in elderly postmenopausal women raised endogenous estrogen concentrations were associated with reduced renal calcium and low bone turnover but a raised plasma calcium. The increased plasma calcium under the influence of high estrogen is more likely to be due to a direct stimulation effect on renal calcium reabsorption rather than a direct effect on reduced bone resorption which would be expected to result in a reduction in plasma calcium.

P322MO. BIOCHEMICAL, HORMONAL AND GENETIC DETERMINANTS OF TRANSMENOPAUSAL BONE LOSS DIFFER ACCORDING TO SKELETAL SITE Panyakhamalerd K1, Guthrie JR2, Erbas B2, Poon C1, Dennerstein L2, Ebeling PR1; 1The Royal Melbourne Hospital, Parkville 3050 Australia, 2The University of Melbourne, Parkville 3050, Australia The menopause transition is characterised by variable rates of bone loss. Identification of women at risk of rapid bone loss could target preventative therapy. We measured rates of spinal (LS) and femoral neck (FN) bone loss over 4 years in 409 pre-, peri- and post-menopausal women aged (mean ± SD) 50 ± 2.3 yrs from the Melbourne Women’s Midlife Health Project. 82% and 67% of women, respectively, attended 25 and 48 months later for repeat bone density (BMD) scans. Baseline measurements of urine and

Abstracts serum biochemical bone markers; serum estradiol and FSH; and estrogen (ER) and androgen receptor (AR) and aromatase (AROM) genotypes were related both to rates of bone loss and progression through the menopause transition. Rates of LS and FN bone loss were highest in the group progressing from pre- to post-menopause (2.6% and 1.6%/year, respectively). Bone loss also occurred in women who remained postmenopausal (0.9% and 0.4%/year, respectively). Urine Ctelopeptide (CTx) and total and free deoxypyridinoline (Dpyr) cross-links were higher at baseline in the group that progressed through the menopause transition than in those women who remained premenopausal. In the best general linear model for LS bone loss, urine CTx and body mass index were positively related to bone loss, while age, transition from pre- to post-menopause, serum estradiol, urine total pyridinoline; and AR and AROM genotypes were negatively related to bone loss. In the model for FN bone loss, age, transition from pre- to post-menopause, serum FSH and ER genotype all were negatively related to bone loss.The effects of biochemical, hormonal and genetic factors and rates of transmenopausal bone loss differ according to the skeletal site studied. Effects of bone turnover markers, estradiol and AR and AROM genotypes predominate at the spine, while the effects of age, FSH and ER genotype are more important at the femoral neck.

P323SA. HISTOPATHOLOGY OF SUBCHONDRAL INFLAMMATORY BONE LOSS AND JUXTA / ARTICULAR LOW TURNOVER OSTEOPOROSIS IN RHEUMATOID ARTHRITIS [RA] Dreher R1, Schulz A1,2; 1Hospital for Rheumatic Diseases, Bad Kreuznach, 2Pathology Department Justus Liebig University of Giessen, Germany The X ray finding of juxta-articular osteopenia in early RA is explained as an early collateral phenomenon of developing arthritis. Histological descriptions of initial changes in rheumatoid joint structures [cartilage, subchondral bone plate, juxta-articular bone] are rare and normally restricted to case reports. Objective: Histological examination of high numbers of operated joints in patients with rheumatoid arthritis, who had a therapeutic resection of the metatarsophalangeal joint. [method: Clayton operation] to compare histopathology and radiology of the resected joints. Method: Fixation of the resected joints in Carnoy solution, embedding the whole undecalcified joint samples in methacrylate. Microscopic analysis of the sections stained by the MassonGoldner and Kossa technique with special regard to early changes in the joint cartilage, subchondral bone plate, cartilage – cortical bone- synovial membrane border and juxta-articular cancellous bone. Results: Resorption of the subchondral bone plate occurs from below, bone resorbing cells being predominanty mono-or oligonucleated osteoclasts. In the more advanced stage, joint destruction is characterized by perforation of the subchondral bone plate from below and cartilage resorption starting at the peripheral cartilage-bone-synovial membrane border. In the mutilating late stage of joint destruction, joint structures were more and more replaced by granulation tissue, the osteoclasts and chondroclasts being mainly from the mono-or oligonuclear type. Signs of bone formation of newly formed osteoid on the trabecular surface are common. Very early in the disease and corresponding to the juxta-articular radiological osteopenia, the juxta-articular canncellous bone shows a significant disintegrated microarchitecture with change of the plate structure into a barlike pattern, lacking trabecular interconnectivity. Bone turnover is low. The medullary tissue shows no signs of inflammation. Conclusion: Serious microscopic changes occur in rheumatoid joints prior to radiological signs of joint destruction. The early juxta-articular osteopenia corresponds to a noninflammatory advanced low turnover osteoporosis probably in consequence of a pain dependent disuse of the affected joints.

S99 P324SU. DIVERGENT EFFECTS OF INTERLEUKIN (IL)-6 AND IL11 ON THE CONCENTRATIONS OF GLUCOCORTICOID RECEPTOR IN HUMAN OSTEOBLAST-LIKE CELLS Dovio A1, Sartori ML1, Masera RG1, Ceoloni B1, Prolo P2, Racca S1, Chiappelli F2, Angeli A1; 1Department of Clinical and Biological Sciences, University of Turin, Turin, Italy, 2Laboratory of Oral and Molecular Immunology, UCLA School of Dentistry, Los Angeles, USA Aims: Glucocorticoid (GC)-induced osteoporosis is admittedly the most frequent secondary osteoporosis. The pathogenesis still has many unresolved issues. While the effects of GC on cytokine production and recognition have been extensively studied, little is known on the effects of cytokines on GC action at the target level. Cytokines belonging to the so-called interleukin (IL)-6 or gp130 cytokine family, notably IL-6 and IL-11, are known as proresorptive cytokines, in that they promote osteoclastogenesis. We have focused on the effects of IL-6 and IL-11 on GC receptor type II (GR) in two human osteoblast-like cell lines (Saos-2 and MG-63) which have remarkably different constitutive expression of these cytokines and GR as well. Methods: GR concentration and equilibrium dissociation constant (Kd) were measured by [1,2,4,6,7-3H]Dexamethasone radioligand binding assay and Scatchard analysis; IL-6, IL-11 and osteoprotegerin (OPG) concentrations in cell media were measured in duplicate by sensitive ELISAs using commercially available kits. Results: We have provided evidence that IL-6 upregulates GR binding sites, while IL-11 downregulates these sites. GR affinity did not change after exposure to both cytokines. In further experiments we have found that while modulating GR concentrations, neither IL-6 nor IL-11 significantly modified GC sensitivity of the GC-responsive gene OPG. Conclusions: The lack of effect of IL-6 and IL-11 on GCsensitivity could be explained by redundancy of GR for inducible changes of OPG transcription. Alternatively, the effect on GR number could be counteracted by opposite effects on other molecular determinants of GC-sensitivity. We suggest that complex effects of GC on the system(s) of proinflammatory/ antiinflammatory cytokines and conversely of these cytokines on GC action could account for the dynamics of bone loss in patients given GC and conceivably having high concentrations of these cytokines in the bone microenvironment.

P325MO. DEVELOPMENT OF A NEW ANISOTROPY INDEX ON TRABECULAR BONE RADIOGRAPHIC IMAGES USING THE FOURIER TRANSFORM Brunet-Imbault B, Lemineur G, Lespessailles E, Benhamou CL; Equipe INSERM ERIT-M 0101, Orle´ans, France Among the parameters conditioning bone strength, anisotropy is considered as very important. Parameters determined on 3D volumes or 2D slices for the microarchitecture assessement can not be currently used in clinical practice. This study presents the development of 2D anisotropy indices performed on radiographic images using the Fourier transform. The population included 66 post-menopausal women: 22 osteoporotic fracture cases (all types of fractures were included) versus 44 age-mached control cases. Calcaneus radiographic images were analyzed by the Fast Fourier Transform (FFT). All the FFT spectrums were cross-like. 6 parameters were measured: the radius of the amplitude expansion in high frequencies named rL for the longitudinal trabeculae and rT for the transverses, the spreading angles of the amplitudes named thetaLr and thetaLl (branch of the longitudinal trabeculae), thetaTh and thetaTb (branch of the transverse trabeculae). The reproducibility of the measures has been evaluated between 2 and 4%. Indices as rL/rT and SDTI (Spectral Dispersion Trabecular Index) = 360 deg – (thetaLr + thetaLl + thetaTh + thetaTb) were calculated.

S100 Differences in rL/rT and SDTI values were found between the fracture and control groups: respectively rL/rT = 1.93 ± 0.62 versus 1.60 ± 0.36 (p = 0.0215) and SDTI = 166.20 ± 16.90 versus 148.29 ± 21.27 (p = 0.0006). SDTI which directly reflects the anisotropy of the structure is lower in control cases. Furthermore rL/rT 41 in fracture cases could be due to a preferential alteration of the tranverse trabeculae in osteoporosis. This preliminary study suggests that: – anisotropy indices determined from spectral analysis are able to separate fracture from control cases; – the structural changes of post-menopausal osteoporosis are characterized by a higher anisotropy at the calcaneus.

P326SA. EFFECTS OF THYROXIN AND ESTROGEN ADMINISTRATION ON BONE MASS,MINERAL CONTENT AND BONE STRENGTH IN MALE RATS

Abstracts measured by a dynamometer for hand and arm) for the nondominant forearm. Results: Younger adults: no correlations between hand-/arm strength and BMD, but significant correlation between total area and maximum strength of the hand (men: r = 0,35, p = 0,01, women r = 0,28, p = 0,02) resp. of the arm (only in men, r = 0,36, p = 0,02).Older adults: significant correlation of hand strength and trabecular BMD in women (r = 0,32, p = 0,003), only trend towards a relation of hand strength with cortical/total BMD and with BMD in the group of men (p between 0,08 and 0,16), no correlations between arm strength and bone parameters. Conclusions: Bone parameters of the distal radius are characterized more by the maximum hand strength than by the arm strength. In younger adults, maximum strength shows a relation to geometric parameters (cross-sectional areas), whereas a correlation with BMD is missing. In contrast, there are significant correlations between maximum strength of the hand and BMD in older adults.

Broulik PD1, Rosenkrancova J2; 13rd Internal Clinic Prague Czech Republic, 2Technical School Prague Czech Republic Thyrotoxicosis increases bone turnover in favor of net bone resorption. Estrogens show a profound effect on bone homeostasis by protecting the skeleton against resorbing action of parathormone. The present study was undertaken to find out the effects of a standart dose of estradiol upon bone metabolism in adult male rats with and without hyperthyroidism. We had four groups of rats. Controls, treated with thyronine, treated with estradiol and treated with thyronine and estradiol. The volume and density of the femurs were calculated by the method of Kalu. Morphometric measurements were performed directly on the X rays after magnification with fine caliper. Second femurs were tested mechanically by the three point bending test in MINI Bionix testing system. Bone density, bone mass were significantly decreased in thyronine treated rats. The decrease in bone density and bone mass in the thyronine treated rats was completely prevented by administration of estrogen. Femoral length and outer diameter were not different between the groups. The decrease in cortical widths in thyroxine treated rats was prevented by administration of estrogen. Bone strength decreased in thyronine treated rats compared with intact controls. The administration of estrogen completely reversed negative effects of thyronine on bone strength. Estrogen in intact rats was found to cause increase inbone strength compared to the intact animals. Estrogens have positive skeletal effects in male rats. Our results support theory that estrogens in vivo are important to retaining bone mass in male rats. Estrogen replacement in thyreotoxic male rats prevents bone loss and a loss of bonestrength. This work was supported by a grant IGA MZ5953-3.

P327SU. RELATIONS BETWEEN MUSCLE STRENGTH AND BONE PARAMETERS OF THE FOREARM Eidner T, Ko¨ltzsch J, Lehmann G, Hein G; Dpt. of Internal Medicine IV, Rheumatology & Osteology, Friedrich-SchillerUniversity of Jena, Germany Aims: The architecture of bone is influenced by biomechanical strain during bone growth and lifelong bone remodeling. Therefore, muscle strength is important for bone physiology and pathophysiology. Our aim was to characterize the interaction between muscles and bone by measuring muscle strength and bone density of the distal forearm. Methods: For a group of younger adults (52 men, 69 women, mean age 23,3±2,0 y.) and a group of older adults (81 men, 81 women, 63,2±6,8 y.) we determined bone parameters by pQCT (Stratec XCT 900, bone mineral density – BMD, bone mineral content – BMC, cross-sectional area – A, each trabecular – cortical – total) and muscle parameters (maximum strength

P328MO. ABSENCE OF A CHANGE IN CIRCULATING LEVELS OF OSTEOPROTEGERIN IN RESPONSE TO SUBCUTANEOUS ESTRADIOL IMPLANT IN POSTMENOPAUSAL WOMEN Rogers A, Pereda CA, Naylor KE, Eastell R, Blumsohn A; Bone Metabolism Group, University of Sheffield, Sheffield, UK Estrogen in vitro enhances osteoprotegerin (OPG) mRNA expression and production of OPG protein in human osteoblastic cells. However the effect of estrogen therapy on circulating levels of OPG has yet to be determined. The aim of this study was to determine the effect of estrogen therapy on serum levels of OPG in postmenopausal women. Subjects were 10 hysterectomised postmenopausal women (ages 60 to 75 years, mean 64 years) receiving a subcutaneous estradiol implant (25mg) at baseline and after 6 and 12 months. OPG concentrations were determined by ELISA (Biomedica, Austria), a sandwich assay, which detects monomeric, dimeric and ligand bound forms of OPG. Serum OPG and estradiol (E2) were measured at baseline and at 4, 8, 12, 24, 52, 78 and 103 weeks. Markers of bone turnover (bone alkaline phosphatase (bone ALP), procollagen type I-N terminal propeptide (PINP), osteocalcin (OC), free deoxypyridinoline (iFDPD), Ntelopeptide of type I collagen (NTX) were measured at baseline and at 4, 8, 12 and 24 weeks. Baseline concentrations of E2 (67.4 (3.0) pmol/L) increased fourfold by 4 weeks and sixfold by 103 weeks. PINP, bone ALP and OC increased by 28%, 7% and 9% (P50.01) respectively during the first 4 weeks of treatment and then decreased significantly. NTX decreased by 46% over the first 24 weeks (P50.01) and iFDPD by 17% (P = NS). Despite the marked increase in serum estradiol levels and significant reduction in bone turnover, there were no changes in the mean circulating concentration of OPG from baseline (92.7 (4.6) pg/ml) at any time point (P = 0.98, ANOVA). Our observations suggest that circulating OPG levels do not change in response to estrogen therapy. However the reliability and specificity of the currently available methods for measuring OPG in a serum matrix is uncertain. Measurements made in serum might also not reflect OPG activity within the bone microenvironment.

P329SA. THE STUDY CONCERNING ETIOPATHOGENESIS OF IDIOPATHIC OSTEOPOROSIS AND OSTEOPENIA IN CHILDREN – THE ROLE OF INSULIN-LIKE GROWTH FACTOR I Chlebna-Soko´l D, Rusinska A; Department of Paediatric Propedeutics, Institute of Paediatrics, Lodz, Poland Objective: The aim of this work was to determine whether insulinlike growth factor I (IGF-I) was able to influence on development of idopathic abnormalities in skeletal mineralization in children.

Abstracts Subjects and methods: The study comprised 44 patients aged 7–18 years, including 12 with idiopathic osteoporosis, 20 with osteopenia and 12 controls. Bone mineralization disorders were diagnosed on the basis of complex clinical, densitometric and biochemical evaluation. Serum concentration of IGF-I by radioimmunoassay, and the third fraction of IGF binding proteins (IGFBP3) by immunoradiometry were evaluated. In children with osteoporosis serum levels of osteocalcin, activity of bone isoenzyme of alkaline phosphatase (bone formation markers) and urine concentration of pyridinoline, deoxypyridinoline and collagen type I crosslinked C-telopeptyde (resorption markers) were also assessed. Results: It was found that children with osteoporosis and osteopenia have a statistically significantly lower concentration of IGF-I (mean values were 583 and 686 ng/ml, respectively) than in the control group (850 ng/ml, p50,05). These differences were independent on biological age of the studied children and were present in all adolescence stages. Concentations of IGFBP3 did not differ significantly between groups (3593 v. 3957 v. 3955 ng/ ml). The concentration of IGF-I correlated positively with total and spinal bone mineral density. In children with osteoporosis there was also a significant negatively correlation between IGF-I concentration and elimination of pyridinoline and deoxypyridinoline with urine. There was no significant relationship between the concentration of IGF-I and IGFBP3 and other studied bone metabolism markers. Conclusions: The conducted study revealed that lower IGF-I concetrations correlate with higher bone resorption markers values and decreased mineralization. These results suggest the importance of insulin-like growth factor I in etiopathogenesis of idiopathic osteoporosis, which needs to be confirmed in further studies. Acknowledgment: The study has been supported by Medical University of Lodz (grant No 502-11-578).

P330SU. BONE CELL ACTIVITY IN CELIAC DISEASE: AN IN VITRO STUDY Teti A1, Bianchi ML2, Bardella MT3, Taranta A4, Longo M4, Saraifoger S2; 1Dipartimento Medicina Sperimentale – Universita` dell’Aquila, L’Aquila, Italy, 2Istituto Auxologico Italiano – IRCCS, Milano, Italy, 3Cattedra di Gastroenterologia – Universita` di Milano, Milano, Italy, 4Dipartimento di Istologia e Embriologia Medica – Universita` La Sapienza, Roma, Italy Celiac disease (CD) is often associated with low bone mass. We are now presenting the first results of a study on the influence of CD on bone cell activity. The in vitro response of human osteoblasts to the sera of patients affected by celiac disease and normal subjects was evaluated. The CD patients were divided in two groups: the first group included patients in a stable condition, on a gluten-free diet (GFD) for at least 2 years, with no sign of disease activity and with no anti-gliadin and anti-endomisium antibodies; the second included newly diagnosed patients, whose sera were obtained before starting GFD (no-GFD). Cell proliferation (tritiate-thymidine incorporation), activity of bone alkaline phosphatase (ALP), mineralization of bone matrix and transcriptional expression of cytokines were measured. Osteoblast proliferation was much higher with the sera of both groups of CD patients than with those of controls (p50.01). ALP activity was significantly increased only with the sera of the noGFD patients (p50.005). Matrix mineralization, as measured by a semiquantitative analysis, was higher with the sera of CD patients than of controls, and the highest levels were observed for no-GFD patients. Active osteoblasts can stimulate bone resorption by releasing cytokines or other growth factors influencing osteoclast differentiation or function. Transcriptional expression of IL-1b, IL-6 and osteoprotegerin (OPG, a specific inhibitory factor of osteoclasts) was evaluated. While mRNA for IL-1b and IL-6 was similar in all

S101 groups, the mRNA for OPG was significantly reduced in the osteoblast cultures treated with the sera of no-GFD patients (p50.01). This suggests that the osteoclast function block by OPG may be suppressed, thus increasing bone resorption activity. These preliminary data seem to indicate that bone remodeling is altered in celiac patients, and the next step in our study will be to evaluate osteoclast activity and bone resorption.

P331MO. BODY SEGMENT LENGTHS AND ARM SPAN IN NORMAL MEN AND WOMEN AND PATIENTS WITH SPINE FRACTURES Duan YB, Wang XF, Edmonds J, Kim BT, Seeman E; Austin & Repatriation Medical Centre, Melbourne, Australia Men and women with spine fractures are shorter and leaner and have smaller vertebral szie. Whether the shorter stature in fracture cases is due to the fracture is not clear. We asked: (i) What are the age- and gender-specific differences in upper or lower body segment length in men and women? (ii) Do men and women with spine fractures have shorter body segment length compared to controls? We studied 101 healthy men and 233 healthy women aged 18 to 92 years, and 34 men and 67 women with spine fractures. Standing height, sitting height and leg length were measured by using a Holtain stadiometer. Arm span was measured by an extended ruler. The results were expressed in absolute term and Z scores (mean ± sem). Arm span was greater by 1 and 5 cm than standing height in young men and young women, respectively (women, 164.6 ± 0.6 vs 163.8 ± 0.6 cm; men, 180.5 ± 1.4 vs 175.8 ± 1.6 cm, p50.01). Advancing age was associated with decreased sitting height in healthy men and women (r = –0.29 to –0.36, both p50.01); leg length was independent of age in both genders (r = –0.03 to –0.12, NS). Sitting height and leg length were 6% and 9% higher in young men than young women, and 8% and 9% higher in elderly men than elderly women, respectively (all p50.01). Men with spine fractures had lower sitting height (Z = –1.02 ± 0.13 SD, p50.01) not leg length (Z = 0.05 ± 0.14 SD, NS) or arm span (Z = – 0.22 ± 0.14 SD, NS) relative to age-predicted mean. Women with spine fractures have lower sitting height (Z = –0.81 ± 0.16 SD, p50.01), leg length (Z = –0.36 SD, p50.05) and arm span (Z = –1.46 ± 0.53 SD, p50.01). We concluded that women, not men with spine fractures, come from a population with short stature.

P332SA. LOW VIT. D AND BONE METABOLISM IN CENTENARIANS Passeri GP1, Pini GP2, Troiano LT3, Vescovini RV1, Sansoni PS1, Pedrazzoni MP1, Franceschi CF2,4, Passeri MP1; 1Dept.of Internal Medicine and Biomedical Sciences, University of Parma, Italy, 2 Dpt. of Experimental Pathology, University of Bologna, Italy, 3 Dept. of Biomedical Sciences University of Modena, Italy, 4 INRCA- Italian National Research Center for Aging, Ancona, Italy One hundred and four subjects (90 females and 14 males), range 97–105 y., living in Northen Italy were visited, at home or in retirement facilities. After a complete assessment history (physical examination, cognitive and performance tests), blood samples were drawn to evaluate bone metabolism and phalangeal (DBM Sonic, Igea, Italy) or calcaneal (Sahara, Hologic, USA) ultrasonography was performed: None of the centenarians had any acute illness, 30 were self-sufficient, 38 were disabled due both cognitive and physical impairmets. In the 12 months prior our visit 28 sustained hip fractures, 14 of which occured within the last 5 years. 25OH vitamin D was detectable in only 5 centenarians; below the sensitity of the method in all others. Serum calcium was below 9 mg/dl in 75% of the subjects, serum PTH was increased with values above the upper normal limit in 64%, PTH was negatively

S102 correlated with calcium (r = -0,33, p = 0.001). Serum cross-lapd (CTX), were 3 times upper normal in 81%. IL-6 was positively correlated with PTH (r = 0.24, p = 0.019) and CTX (r = + 0.37, p50.001) and negatively with calcium (r = -0.35, p50.001): Bone ultrasonography at the phalanxes (62 subjects) and at calcaneus (28 subjects) showed that most centenarians had a severe state of osteopenia. Ultrasonographic parameters showed a correlation with bone resorption markers: phalangeal Ultrasound Bone Profile Index was negatively correlated wit PTH (t = –38, p = 0.032) and with TCX (r = 0.28, p = 0.036), calcaneal Speed of Sound with CTX (r = 0.4, p = 0.05). This findings indicate that extreme longevity is characterized by vitamin D deficiency, secondary hyperparthyroidism with increased bone resorption and severe osteopenia. Since half of the hip fracture recorded in centenarians had occured within the last five years, these data suggest that the correction of secondary hyperparathyroidism and elevated bone turn-over, may reduce the risk of bone loss and fracture-induced disability even in the oldest olds.

P333SU. INTESTINAL CALCIUM ABSORPTION ASSESSED BY STABLE STRONTIUM TEST IN ELDERLY MEN Gonnelli S, Gennari L, Montagnani A, Campagna MS, Franci MB, Lucani B, Mangeri M, Merlotti D, Cepollaro C, Gennari C; Institute of Internal Medicine, University of Siena, Italy The mechanisms leading to bone loss in men are still poorly understood. In particular, the role of calcium malabsorption in male osteoporosis remains controversial. Recently, stable strontium (Sr) has been proposed as an alternative to dual tracer procedure for the assessment of intestinal calcium absorption. The aim of this study was to assess the determinants of intestinal Sr absorption in elderly men. In 111 consecutive men (aged: 51–85 yrs) we performed a Sr absorption test using an oral load of 2.5 mmol, without additional calcium or meal. Sr was measured by graphite furnace atomic absorption spectrophotometry and both fractional absorption (Fc240) and the area under the concentration time curve (AUC 0300) were evaluated. Testosterone (TT), estradiol (E2), 25OHD, insulin-like growth factor 1 (IGF-1), IGF binding protein 3 (IGFBP3) were measured. Bone mineral density at lumbar spine (BMD-LS) and at femur (BMD-F) by DXA, and dietary calcium intake by a validated self-reporting questionnaire were also assessed. On the basis of BMD-F men were classified as osteoporotics, osteopenics or normals. The precision was 7.8% for AUC0-300 and 11.2% for Fc240. Both Fc240 and AUC0-300 negatively correlated with age (r = –0.31 and –0.30 respectively) and with calcium intake (r = 70.45 and –0.31 respectively). 25(OH)D significantly correlated with AUC0-300. AUC0-300 showed a positive, but not significant, correlation with BMD-LS, BMD-F, E2 and TT. No significant correlation were found between IGF-1, IGFBP3 and Sr absorption, whereas E2 and IGF1/IGFBP3 ratio were lower in osteoporotics. For its better reproducibility AUC0-300 seems to result more appropriate than FC240 in evaluating Sr intestinal absorption. Moreover, in males Sr absorption decreases with advancing age and it is related to 25(OH)D and calcium intake, but not with TT, IGF-I and E2 serum levels.

P334MO. MEN WITH IDIOPATHIC OSTEOPOROSIS AND THEIR FATHERS HAVE REDUCED VERTEBRAL WIDTH de Vernejoul MC1,2, Ostertag A1, Cohen-Solal ME1,2, Baudoin C1; 1 INSERM U349, Paris, France, 2Fe´de´ration de rhumatologie, Paris, France We have shown previously that bone density is decreased in the families of men with idiopathic osteoporosis. On the other hand it has been suggested that the bone size could be an important

Abstracts determinant of bone fragility. Our aim was to assess whether the size of the vertebrae was changed in the males with osteoporosis and their family members. We studied 40 males with idiopathic osteoporosis defined by a T-score 5–2.5 with or without fractures and aged less than 65. Mean ± SD age was 48 ± 10 years old. 26/40 patients had a vertebral fracture (VF) and 7 had peripheral fracture but none had femoral neck fracture. Lumbar spine bone mineral density (BMD) and width of L3 were measured on a Lunar DPX-L. The 40 patients were compared to 79 age and sex matched controls. Width (4.14± 0.31 vs 4.43±0.38 cm, p50.0001) of L3 was decreased in the patients independently of the presence of a VF. We studied 6 relatives subgroups: 10 fathers, 17 mothers, 32 sisters, 19 brothers, 22 daughters and 20 sons that were each compared with an age and gender matched control group. BMD was decreased in each relative subgroup compared to its control group, differences ranging from 7 to 19%. The width of L3 was significantly decreased only in the fathers compared to their controls (4.23 ± 0.36 vs 4.65 ± 0.62 cm p50.005) but was identical to controls in the sibs and children. There was an increase in vertebral width with age (range 20-80, n = 180) in the control men but not in the male members of the family of the patients (sons, brothers and fathers, range 20-80 n = 49). In conclusion our data show that the decreased bone density and width of males with osteoporosis is not associated with change in bone size in their children. However, the normal periosteal bone apposition occuring with age in adulthood was not observed in the family of the patients.

P335SA. PREDICTION OF BONE MINERAL DENSITY BY ESTROGEN PRECURSORS, ESTRADIOL, SHBG AND BMI IN ELDERLY WOMEN AT RISK FOR OSTEOPOROTIC FRACTURES Goemaere SJAG1, Zmierczak H1, Van Pottelbergh I1, Toye K1, Daems M1, Zegels B2, Reginster JY2, Kaufman JM1; 1Unit for Osteoporosis, Ghent University Hospital, Ghent, Belgium, 2Bone & Cartilage Metabolism Unit, Ulg, Lie`ge, Belgium. We assessed the relationship between dehydroepiandrosterone sulphate (DHEA-S), delta-4 androstenedione (delta-4-A), total estradiol (E2), free estradiol (FE2), sex hormone binding globulin (SHBG) and body mass index (BMI) with bone mineral density (BMD) in two groups of elderly ambulatory Caucasian women; group 1: 70–80 years old and low BMD (n = 158), group 2: more than 80 years old with low BMD and / or other clinical risk factors for osteoporotic fractures (n = 270). Hip BMD was measured by Hologic DXA, hormones and SHBG by immunoassays, FE2 was calculated by a validated formula. Data were analysed by multiple linear regression after ln transformation of hormones and SHBG. BMI was a positive determinant of BMD (standardized beta coefficients: 0.21 to 0.41), SHBG a negative determinant of BMD (beta: –0.16 to –0.21). Both, BMI and SHBG predicted independently BMD at the femoral neck, trochanter and total hip in both study groups (p50.05). DHEA-S and FE2 were independent predictors of BMD at the femoral neck, trochanter and total hip after adjustment for BMI in group 2; in group 1 BMD was not significantly associated with DHEA-S nor FE2. Total E2 and delta4-A did not contribute significantly to BMD in either group. The data confirm prior reports of SHBG being a negative determinant of BMD and of BMI and FE2 as positive determinants of BMD in elderly women. That FE2 and DHEA-S were independent predictors of BMD in the older group but not in the 70-80 years group may be explained by the different inclusion criteria, with the latter group including only women with low BMD. BMI and SHBG were relatively strong determinants of BMD, independent of FE2, indicating that only part of the impact of BMI and SHBG on BMD is mediated by E2.

Abstracts

S103

P336SU. INCREASED CORTICAL WIDTH IN WOMEN TREATED WITH HIGH DOSES OF OESTROGEN 1

2

2

3

4

Vedi S , Bell KL , Loveridge N , Garrahan N , Purdie DW , Compston JE1; 1Bone Research Group,University of Cambridge, Cambridge, UK., 2Bone Research Group (MRC), University of Cambridge, Cambridge, UK., 3University of Wales College of Medicine, Cardiff, UK., 4Centre of Metabolic Bone Disease, Hull Royal Infirmary, Kingston Upon Hull, UK Investigations of the skeletal actions of oestrogen have mainly focused on cancellous bone: in this study we have examined effects on cortical bone. Transiliac biopsies were obtained from 10 premenopausal women with endometriosis aged 23–38 yrs, 9 post-menopausal women aged 54–71 yrs before and after 2 years conventional HRT and 7 women aged 52–67 yrs after long-term high-dose oestradiol implant therapy. Cortical width was lowest in the pre-HRT group (1.36±0.60 mm; mean ± SD) and highest in the high-dose oestrogen group (2.29±0.78 mm; p = 0.014). Intermediate values were seen in the endometriosis group and women treated with conventional HRT (1.75±0.48 and 1.83±0.71mm respectively). No significant differences between groups were observed in canal area, density or porosity. The proportion of canals with a resorption surface was lowest in the high-dose oestrogen group (3.03±3.7% vs 11.1±7.1%, 10.5±8.6% and 13.6±7.8% in the pre- and post HRT and endometriosis groups respectively). Wall width was significantly higher in women with endometriosis than in the pre-HRT group (47.7±7.2 microns vs 60.2±13.7; p = 0.025), values in women treated with conventional HRT and high-dose oestrogen being 52.1±7.7 and 54.3±10.2 microns, respectively. Our results demonstrate that high doses of oestrogen have significant positive effects on cortical width, predominantly related to inhibition of bone resorption.

P337MO. EVIDENCE THAT POSTMENOPAUSAL WOMEN WITH VERTEBRAL FRACTURES DUE TO TYPE I OSTEOPOROSIS HAVE ENHANCED RESPONSIVENESS OF BONE TO ESTROGEN DEFICIENCY Riggs BL1, Melton, III LJ1, Atkinson EJ1, O’Fallon WM1, Dunstan C2, Khosla S1; 1Mayo Foundation, Rochester, MN, 2Amgen Corporation, Thousand Oaks, CA Osteoporosis (OP) has been divided into type I and type II fracture syndromes (Am J Med 75:899, 1983). Type I osteoporosis occurs within 20 years after menopause and may be due to estrogen (E) deficiency plus some additional factor predisposing to excessive bone loss. One such factor might be a greater degree of sex steroid deficiency. This could not be excluded in earlier studies because previous assays were relatively insensitive. Thus, we studied 40 women with typical high turnover type I osteoporosis and vertebral fractures and 40 normal postmenopausal women using newly developed ultrasensitive assays (detection limits of 1 and 5 pg/ml for estradiol [E2] and estrone [E1], respectively and 5 ng/dl for testosterone [T]). Bone turnover was assessed by measuring serum osteocalcin (OC) and bone alkaline phosphatase (BAP) and 24h excretion of urinary pyridinoline (PYD) and deoxypyridinoline (DPD). Although levels of serum sex steroids were identical in both groups, bone turnover was increased by up to 50% in the osteoporotic women. Moreover, compared with controls, the osteoporotic women had 13% lower (P50.05) serum PTH and 53% higher (P50.01) serum osteoprotegerin levels, which were likely compensatory responses to the increased bone turnover. Thus, women with type I osteoporosis may have a geneticallydetermined, increased responsiveness of bone to E deficiency that is evident in the presence of low E levels but is overcome by high E levels. This hypothesis is consistent with recent reports that postmenopausal women with polymorphisms of the E receptor genes have low bone density and fractures.

Variable (mean ± SEM)

Controls

Type I OP

P (rank sum)

Age, yrs Yrs after menopause E2, pg/ml E1, pg/ml T, ng/dl OC, ng/ml BAP, U/L PYD, nmol/mmol Cr DPD, nmol/mmol Cr

68.4 16.7 6.3 15.9 24.8 9.0 20.3 42.7 13.0

64.6 17.3 6.1 16.8 27.6 10.2 30.4 55.5 18.8

NS NS NS NS NS <0.02 <0.001 <0.001 <0.001

± ± ± ± ± ± ± ± ±

0.9 1.1 0.8 0.9 1.6 0.3 1.0 2.1 0.6

± ± ± ± ± ± ± ± ±

0.8 1.4 1.2 2.2 1.8 0.4 1.9 2.5 0.9

P338SA. THE ROLE OF HIP GEOMETRICAL PARAMETERS AND BONE MINERAL DENSITY IN EVALUATING RISK FACTORS FOR OSTEOPOROTIC HIP FRACTURES Yildiz A1, Bankaoglu M2, Parlar D1, Senerdem N1, Durlanik G1, Sahin F1, Ku¨zgu¨n U3, Oztu¨rk I3, Basak M2, Ku¨ran B1; 1Sisli Etfal Teaching Hospital Physical Medicine and Rehabilitation Depatrment, 2Sisli Etfal Teaching Hospital Radiology Department, 3 Sisli Etfal Teaching Hospital Ortopedics Department In this study, we aimed to search the role of hip geometry and bone mineral density (BMD) in osteoporotic hip fractures. Twenty-six cases with hip fracture and 180 cases as a control group were included. All cases were postmenopausal women above age 50. Fifty percent of the hip fractures was trochanteric and the other half was neck. Both of these groups were compared besed on geometric parameters and BMD’s.CT was used to determine the geometric characteristics and DEXA method was used to measure BMD’s. As a pre-study, geometry and BMD of right and left hips were compared with each other in the control group. Since there was no difference between the right and left hips except in the femoral axis length and the neck width/shaft width ratio, we used the uninvolved hips in the fracture group to compare with the hips in the control group. When the unmatched groups were compared, shaft cortical width, cortical width/shaft length, cortical width/ shaft width ratios and shaft width were significantly lower, the hip axis length (HAL)/shaft width ratio was significantly higher and the BMD was significantly lower in the fracture group than in the control group. In the age-matched comparison, cortical width and its associated ratios were significantly different in fracture and control groups before age 70, though not significantly different after age 70. When the fracture cases were subgrouped according to fracture types and were compared with the control group, the significance and priority of parameters were again variable.Using logistic regression analysis, independent risk factors were determined. These factors and their odds ratio (OR) values were as follows: age:10.5, weigth:6.6, cortical width:4.7, HAL/shaft width:3, cortical width/shaft width:3.4, cortical width/shaft length:3.8, BMD:15-30. In conclusion, we observed that, unlike other studies, proportional parameters were more important in evaluating risk factors for hip fractures.

P339SU. UNRECOGNIZED PATHOLOGY MAY CONTRIBUTE TO THE ASSOCIATION OF VERTEBRAL DEFORMITIES WITH INCREASED RISK OF HOSPITALIZATIONS AND MORTALITY Versluis RGJA, Papapoulos SE; Leiden University Medical Center, Leiden, The Netherlands Nearly two thirds of patients with morphometric vertebral fractures are asymptomatic. There is evidence, however, that such deformities, among other, are associated with increased rik of hospitalizations and mortality but no causality has been identified. In epidemiological studies there is usually no attempt

S104 to link abnormal radiographs to individuals. In a study of methods to identify women with osteoporosis in general practice a cohort of 449 women aged between 55 and 84 years had lateral spine radiographs and vertebral morphometry was performed by the method of Eastell et al. Forty four women (10%) had severe (grade II) vertebral deformities. These women were invited to the practice for further evaluation and 42 attended. The most common abnormality found was vitamin D deficiency/insufficiency that was present in 24% of the women. In 22 women history, clinical examination and laboratory tests excluded underlying diseases. The rest were invited to a bone clinic for further evaluation and 19/20 attended. In 5 of these women (12% of those with grade II vertebral deformities) the following diagnoses were made: multiple myeloma, chronic lymphatic leukemia, coeliac disease, Paget’s disease and primary hyperparathyroidism. Thus, in this random cohort of postmenopausal women previously unrecognized pathology was identified in 12% of those with grade II vertebral deformities. These results that underscore the clinical significance of morphometric vertebral fractures, indicate that such associations should be sought in other cohorts and may provide clues to the currently unknown association of vertebral deformities with increased risk of hospital admissions and mortality.

P340MO. IS HYPERLIPIDEMIA A CO-FACTOR IN THE PATHOGENESIS OF OSTEOPOROSIS IN ELDERLY WOMEN? La´szlo´ B. Tanko´ LBT, Yu Z. Bagger YZB, Henrik B. Hansen HBH, Claus Christiansen CC; Center for Clinical and Basic Research, Ballerup, DK Aims: Recent case-controlled studies indicate that statins offer benefits in the preservation of bone mineral density (BMD). However, it is unclear whether these effects are direct effects or due to lipid-lowering. The aim of the present study was to investigate the influence of serum cholesterol on BMD and markers of bone turnover in postmenopausal women. Methods: Longitudinal analysis of 422 healthy postmenopausal women stratified into quartiles of baseline serum cholesterol. None of the participants received treatment for osteoporosis (HRT, SERM, bisphosphonate) or hypercholesterinemia during the observation period (1992-2001). Serum cholesterol at baseline and at the end of the follow-up period was measured by an automatic colorimetric assay. BMD in the lumbar spine (L1-L4), distal arm and total hip was measured by DEXA. ELISA was used to measure serum markers of bone turnover (osteocalcin and CTx). Results: At baseline, BMD at all sites showed an inverse linear relationship to serum cholesterol (lumbar spine: p50.001, distal arm: p50.001, total hip: p50.05). The univariate correlation between serum cholesterol and BMD in the spine, distal arm and total hip were characterized by Pearson’s r-values of 0.185 (p50.001), 0.148 (p50.001) and 0.128 (p50.05), respectively. The changes in serum cholesterol during the follow-up period were correlated to the simultaneous changes in BMD measured in the lumbar spine (r = 0.17, p50.001). Serum markers of bone turnover could not capture the effect of serum cholesterol on bone turnover. Conclusions: These results further support the notion that lipids do contribute to the determination of BMD as a co-factor.

P341SA. OSTEOPOROSIS IN MEN Conradie M, Hough FS; Endocrinology and Metabolism Unit, Tygerberg Hospital and University of Stellenbosch, Cape Town, South Africa Background: Osteoporosis in men is an important and costly problem in clinical medicine. One third of the estimated 1.7 million hip fractures worldwide occur in men. It appears to be as

Abstracts heterogeneous an entity in males as in females with hypogonadism and bone toxins (i.e. alcohol, nicotine and steroids) regarded as the major contributing risk factors. Methods: We analysed the clinical, biochemical, densitometric and histomorphometric data obtained in 88 men admitted consecutively to our Metabolic Unit from 1988 to date, with apparent primary vertebral osteoporosis. Aims: In this descriptive study we aimed to characterize the male osteoporotic population we serve with regard to demographic, clinical, biochemical and histomorphometric findings, to evaluate the ability of historic risk factors to predict the underlying histological subtype, to determine possible correlation between estrogen status, androgen status and presence of hypercalcuria with densitometric and histological findings and to document differences in clinical, dietary, biochemical and densitometric data amongst the three histologically distinct subgroups i.e. high turnover osteoporosis, low turnover osteoporosis and the group with evidence of reduced mineralization. Results: In this group of young, mostly white osteoporotic males (age 46 ± 11), osteoporosis without any evidence of reduced mineralization was present in 72 males, 41 men had evidence of high turnover disease and 29 men had low turnover bone disease. Histological evidence of reduced mineralization was present in 16 males. Poor calcium-nutrition and daily alcoholintake were more prevalent in those with defective mineralization. Fracture prevalence, biochemical data and hormonal status was similar in the different histological subgroups. Conclusion: Idiopathic osteoporosis is an important clinical entity. It appears to be as heterogeneous a condition in men as in women. A significant percentage (18%) of male osteoporotic patients in this study had histological evidence of defective mineralization.

P342SU. CONTRIBUTING FACTORS TO BONE MINERAL DENSITY CHANGES IN NORMAL PERIMENOPAUSAL WOMEN Krahe C1, Sisson de Castro JA2, Friedman R2, Gross JL2; 1 Gynecology and Obstetrics Department, PUC-RS, 2 Endocrinology Division, Universidade Federal RGS, Porto Alegre, Brazil Aims: To evaluate the contributing factors for BMD changes in perimenopausal women. Methods: 56 caucasian women, 40 to 50 years of age, followed for 4 years in a private office according to standard gynecological recommendations. Lumbar (L2L4) and femoral BMD measurements were performed in a same DXA (Lunar) scan. Food intake, physical activity, smoking habits, alcohol ingestion, routine biochemical tests, estradiol, SHBG, T4, TSH, PTH were also determined at the beginning and at the end. Bone alkaline phosphatase, osteocalcin, N-telopeptide and deoxypiridinoline were measured only at the end. Results: Significant changes were: L2L4 BMD loss of 1,46% (p = 0.005), femoral neck (FN)BMD gain of 1.48% (p = 0.04)and great trochanter (GT)BMD gain of 2.35% (p50.001), as well as weight gain, height loss, caffeine and vitamin D intake reductions and rise of FSH levels. By multiple regression analysis L2L4 BMD reduction was associated to rise of FSH (p = 0.004), osteocalcin (p = 0.002)and to osteopenia at the entrance. FN BMD increases were associated to vitamins D and B12 ingestion, to exercise and to osteocalcin levels. GT BMD changes were associated to ingestion of magnesium and vitamin C. All these associations remained significant controling for changes in age and weight. Conclusions: BMD changes in healthy perimenopausal women are small, variable and depend on factors that may affect a specific skeletal region. Losses at L2L4, a trabecular region, were related mostly to the rise of FSH, presumably due to the reduced estradiol production. Positive changes at the proximal femur, a weight bearing region, could be related to more exercise and better nutrition. These findings could help to manage perimenopausal women and to prevent osteoporosis.

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P343MO. THE EFFECT OF DYDROGESTERONE ON INSULIN SENSITIVITY AND OXIDATIVE STRESS IN POSTMENOPAUSAL DIABETIC WOMEN

P345SU. HYPOVITAMINOSIS D AND HYPERPARATHYROIDISM IN PHYSICALLY INACTIVE ELDERLY JAPANESE LIVING IN NURSING HOMES

Borissova AM, Tankova T, Kamenova P, Dakovska L, Kirilov G, Kovatcheva R, Genov N, Koev D; Hospital of Endocrinology and Gerontology, Sofia, Bulgaria

Nakamura K, Nashimoto M, Yamamoto M; Department of Community Preventive Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Physiologically estrogens improve carbohydrate metabolism. This is not the case with the different progestogens. There are four main progestogens, which are usually added to estrogens in the different combinations of HRT – Levonorgestrel (with clear diabetogenic effect), medroxyprogesterone acetate (known to decrease glucose tolerance by 30%), norethisterone acetate (with no effect on glucose tolerance) and Dydrogesterone (potentiating the effect of estrogens). Ten type 2 diabetic females, of mean age 55+5 years, in menopause since mean 5 years were enrolled in the study. Transdermal 17-beta estradiol (Systen TTS 50, Janssen Cilag) and 10 mg daily for 10 days a month Dydrogesterone (Duphaston, Solvay) was applied for three-month period. Insulin sensitivity was determined with the manual method of euglycaemic hyperinsulinaemic clamp technique, as well as the blood samples for lipids and parameters of oxidative stress were estimated at the beginning and end of three-month period. Insulin sensitivity increased by 50%, fasting hyperinsulinaemia was normalized and parameters of oxidative stress (TAOCS) were significantly raised (p50.01). Conclusion: HRT should be prescribed in type 2 diabetic postmenopausal women because of its favourable effect on existing pathophysiological disturbances. Dydrogesterone in combination with a transdermal estrogen should be recommended in cases with leading insulin resistance.

Aims: The purposes of this study were to investigate the prevalences of hypovitaminosis D and hyperparathyroidism in physically inactive elderly people living in Japanese nursing homes and to determine any correlations with demographic, environmental and/or lifestyle factors. Methods: We targeted 220 elderly people living in nursing homes for the physically disabled in Japan. Of them, 133 (female, 113; male, 20) subjects who agreed and met our inclusion criteria were studied. The average age of the subjects was 84.6 years (SD 8.2). Serum 25-hydroxyvitamin D3 (25[OH]D3), intact parathyroid hormone (intact PTH), creatinine, and albumin concentrations were measured in each subject. Total hours of sunshine during the previous 5 weeks, activities of daily living (ADL) levels, and dietary vitamin D intake were also measured. ADL levels were evaluated using the Physical Self-Maintenance Scale (5-point scale). The examinations were performed between October and December, 1999. Results: The average concentrations of the serum 25(OH)D3 and intact PTH were 29.9 nmol/l (SD 13.1) and 5.04 pmol/l (SD 2.27), respectively. The prevalences of hypovitaminosis D (25[OH]D3530 nmol/l) and hyperparathyroidism (intact PTH46.90 pmol/l) were 77/133 (57.9%) and 21/133 (15.8%), respectively. Serum 25(OH)D3 concentrations were positively associated with the hours of sunshine (R2 = 0.371, p50.001) and the serum albumin concentrations (R2 = 0.086, p50.001) but not with age (p = 0.075) or total ADL score (p = 0.527). A negative association between serum intact PTH and 25(OH)D3 concentrations was found in subjects who were 80 years or older (p50.001) but not in subjects under the age of 80 years. Conclusions: Hypovitaminosis D and hyperparathyroidism are commonly seen in elderly Japanese with low ADL levels. Hypovitaminosis D seems to adversely affect PTH levels, especially in the very elderly.

P344SA. THE EFFECTS OF GH AND IGF-1 ON BONE MINERAL DENSITY AND BONE METABOLISM IN POSTMENOPAUSAL WOMEN WITH ACROMEGALY

P346MO. THE SPINE LOAD MODELLING

Bolanowski M, Zatonska K, Jedrzejuk D, Milewicz A; Department of Endocrinology and Diabetology, Wroclaw University of Medicine, Wroclaw, Poland The results of experimental and clinical studies show significant influence of GH and IGF-1 on bone mineral density (BMD) and bone metabolism. Aim: The question is if the risk of osteoporosis in postmenopausal women with acromegaly (high GH and IGF-1 levels) is lower than in healthy age-matched ones? Methods/patients: Femur BMD, serum levels of osteocalcin (OC), carboxyterminal telopeptide of type I collagen (ICTP), TNFalpha, GH, IGF-1 were studied in two groups of postmenopausal women (acromegaly, No 15 vs controls No 45). Results: No significant differences were shown in femoral neck, Ward’s triangle nor trochnater BMD among groups studied. In control group 2 cases with osteoporosis and 3 with osteopenia were detected. None of acromegalic patients was osteopenic nor osteoporotic. Mean OC and ICTP levels were statistically significantly higher in acromegaly than in controls, but TNFalpha was higher in control group. Conclusion: Our results indicate higher bone turnover, both formation and resorption in women with acromegaly. It could suggest protective effects of excess GH and IGF-1 against osteoporosis in women with acromegaly.

Wendlova J; Derer’s University Hospital, Bratislava, SR Aim of the study: Modelling of the influence of abduction and adduction of the upper limb on spinal load with the help of the laws of theoretical mechanics and the application of its results in clinical medicine. Biomechanical solution: Biomechanical model of an upper limb is demonstrated as a construction consisting of a lever arm and a joint connection in articulatio humeri. Based on three general conditions of the balance of force plane system in theoretical mechanics we calculated the magnitude of three reaction forces induced in shoulder joint during abduction and adduction of the upper limb. These reaction forces originating during a load upon shoulder joint are transferred through mm. spinohumorales to the spine as the so-called action forces, which are of the same magnitude but of the opposite direction. The first force is transferred to the spine as a horizontal tensile force, the second as a horizontal compressive force and the third as a vertical compressive force. Conclusion: The results of the calculation of forces applied to the spine show that during the abduction of both upper limbs the spine is stressed only by the sum of two vertical compressive forces, in contrast to the abduction of only one upper limb when there is an unfavourable effect upon the spine of the sum of two twisting moments of forces and one vertical compressive force. Our application of results of the spine load modelling in relation to excess upper limbs load: A) setting up the methodology of active therapy aimed at exercising upper limbs for osteoporotic

S106 patients; B) the application of basic principles of motoric activity in daily life; C) the draft design of a rehabilitation aid for patients with acute painful fractures of vertebrae in thoracic area.

P347SA. CORRELATION BETWEEN REDUCTION OF STATURE AND VERTEBRAL FRACTURE IN PATIENTS WITH POSTMENOPAUSAL OSTEOPOROSIS Morii H1, Okamoto S2, Kiriyama T2, Nakamura T3; 1Aino Gakuin College, Osaka, Japan, 2Sanyo Osteoporosis Research Foundation, Oita, Japan, 3Oita Kosairen Health Care Center, Oita, Japan Introduction: The reduction in stature is one of serious signs associated with vertebral fractures mainly due to osteoporosis. Although it has not been well defined what is vertebral fracture, we evaluated number of vertebral fractures and grade of osteoporosis may have effect on the reduction of stature on the basis of our criteria of vertebral fracture in addition to age. Methods: Number of vertebral fractures was counted from lateral views of X ray pictures in 2 cohorts: 2,874 women in a health survey center (Study 1) and 1,249 female patients with osteoporosis at one outpatient clinic in Oita (Study 2), Japan. The questionnaire survey was performed regarding stature at 20 years of age. Results: In both studies the greater was the decrease of stature, the greater was the decrease of BMD. Even in fracture 0 group in Study 2, the decrease of stature was significantly greater and BMD was significantly more reduced in female patients older thab 55 years of age. The greater was the number of fractures of vertebrae, the greater was the decrease of BMD. ROC analysis showed better utility of the stature changes among other parameters associated with vertebral fractures in predicting number of fractures. Conclusion: It was demonstrated that the decrease of stature can occur in postmenopausal women with osteoporosis even without vertebral fractures. ROC (receiver operated characteristics) analysis showed that the decrease of stature is more sensitive than BMD in predicting vertebral fractures.

P348SU. OSTEOPOROSIS IN PEOPLE WITH DEVELOPEMENTAL DISABILITIES Dittberner K; St. Amant Center, Winnipeg, Canada Osteoporosis and resulting spontaneous fractures in residents with developemental disabilities living in institutions have not received much attention. Identification of risk factors that lead to osteoporosis in this population would greatly help the caregivers in their daily handling of these individuals and promote a framework for specific treatment. We reviewed 218 (20% were children) residents at St. Amant Center, a facility for people with moderate to severe mental and physical handicaps. Of the 218 residents, 30 had one or more spontaneous fractures due to osteoporosis in the past 15 years. Per year we averaged 3–4 new spontaneous fractures,which was consistent with other similar facilities. As this group represents those at highest risk, we looked at various factors that may have contributed to their severe osteoporosis. Based on available current literature and after reviewing the residents’ history, medications, x-rays, and lab data, the following risk factors were identified, not necessarily in order of severity: immobility, anti-seizure medications, joint contractures, documented osteopenia on x-ray or osteomalacia biochemically aboriginal ancestry, post-op immobilization, hypogonadism, female gender and specific genetic and nutritional issues.Using these risk factors, we then classified the residents as ‘high risk’ if three or more risk factors were present,‘moderate risk’ if two factors were present, and ‘low risk’ if fewer than two factors were present. Of the 218 residents, 115 (53%) were considered to be

Abstracts high risk and 63 (29%) were considered moderate risk. Subsequently, warning stickers were placed in the rooms of residents classified as moderate or high risk, alerting their caregivers to their fragile status. We also ensured they had adequate calcium and vitamin D. Since implementing this system 18 months ago, there have been no further spontaneous fractures. Further work will be done to correlate bone densitometry results with this risk classification system.

P349MO. OSTEOPOROTIC VERTEBRAL FRACTURES PRECEDES SPINAL OA Okamoto S1, Morii H2, Kiriyama T1, Okamoto ST1; 1Sanyo Osteoporosis Research Foundation, Oita, 2Aino Gakuin College, Osaka, Japan Introduction: We propose a new concept, OP-OA syndrome, that is, spinal osteoporosis becomes a risk factor of spinal osteoarthritis (OA). Spinal osteophytes frequently and specifically appear with vertebral compression fractures, especially in elderly women. An inverse relationship between osteoporosis and spinal OA has been emphasized as a matter of common sense, which interferes the idea and the search for the high prevalence of osteoporotic fish vertebral fractures concealed in the terminal plate sclerosis or osteophytes. Methods: The TV X ray fluorosxopy was performed in 1,249 female patients with osteoporosis in one outpatient clinic in Oita. As is almost impossible to differ fracture lines from vertebral rim lines by the conventional oblique radiational view, each patient was asked to change the position, so that the middle tangential fracture lines of vertebra appeared in the film. Results: All of 210 patients in whom the decrease of stature was more than 40 mm from the age of 20 years had more than one vertebral fractures. Among them, 174 cases(82.9%) had osteophytes above second degree by Nathan’s classification. Vertebral eburmation was observed in 46 cases (21.9%). The Progressive growth and final fusion of intervertebral osteophytes after fresh fractures were observed in seven cases. Discussion: The narrowing of the intervertebral spaces has been believed to be essential signs in the diagnosis of OA. Although the center of the terminal plates of the vertebral body come far apart, pressed by the nucleus of the discs, these findings have often been overlooked. We admit primary generalized OA with generalized joint involvement might have inverse relationship with osteoporosis but major part of OA are secondary. Fish vertebra type osteoporotic fractures not only coincide with OA frequently, but becomes high risk factor of secondary OA, to induce the narrowing between vertebral edges and cause the instability of the vertebra.

P350SA. LOW BONE TURNOVER IN THE HIP REGION AS A RISK FACTOR FOR OSTEOPOROTIC FRACTURES OF THE NECK OF THE FEMURA: POSSIBLE CHANGE OF PARADIGM Dreher R1, Lingg G1,2, Schulz A1,2; 1Hospital of Rheumatic Disease Bad Kreuznach, 2Insitut of Pathology University of Giessen Objective: For the first time, the histopathological bone remodelling in the trochanter region of the hips were compared with that in the iliac crest in patients with osteoporosis in order to investigate the bone in the region of the maximum osteoporotic fracture risk. Method: In 20 patients with suspicion of osteoporosis, iliac crest biopsies and biopsies from the trochanter region were simultaneously taken. Bone mass, trabecular structure (plates, rods), resorption and osteoid surface of the trabeculae (% trabecular surface) with number and form of activated osteoclasts and osteoblasts, osteoneosynthesis and mineralization of the bone after in-vivo tetracycline labelling were determined semiquantitatively. Bone density was measured by means of DXA in the hip regions: neck of the femur, Ward’s triangle and trochanter.

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Results: Absolute bone density (g/m ): neck of the femur = 0.75 ±617; 0.189, Ward’s triangle 0.591 = 617; 0.214, trochanter = 0.653 ±617; 0.185. The DXA values of the hip regions (trochanter, Ward’s triangle, neck of the femur) are highly correlated (r = 619; 0.90). Compared to the iliac crest, the bone mass and the bone remodelling activity is substantially reduced in all biopsies from the trochanter region. Whereas the cellularity corresponds to a mature hematopoiesis in the medullary space of the iliac crest bone, the medullary cavity of the trochanteric bone is replaced by adipose tissue. Conclusion: Compared to the activity of the iliac crest bone, bone remodelling and osteoneosynthesis in the bone of the trochanter region of the hip is greatly reduced. There may be a correlation between reduced bone mass, reduced bone remodelling acitivity and absent hematopoiesis in the medullary cavity (lack of osteoclastic and osteoblastic precursor cells). The raised risk of neck of the femur fractures in osteoporosis would thus result from a low turnover of the bone tissue and not be due to an increased osteoclastic bone resorption.

P351SU. INFLUENCE OF PREGNANCY AND LACTATION ON ULTRASONOMETRY (QUS) IN POSTMENOPAUSAL WOMEN Hadji P, Gottschalk M, Backhus J, Fischer F, Schmidt S, Schulz KD; Philipps University, Marburg, Germany The aim of this study was to elucidate the relation between parity, lactation, and bone mass assessed by QUS in postmenopausal women. We performed a comparison study and subsequent matched pairs analysis as well as multiple linear regression analysis in five German centres. 2080 postmenopausal women (mean ±SD age, 58.8 ±8.2 years), in whom diseases and drug treatments known to affect bone metabolism had been excluded, underwent QUS measurement at the os calcis. The ultrasonometry variables, speed of sound (SOS), broadband ultrasound attenuation (BUA), and the stiffness index (SI) were compared in nulliparous and parous women and in women who had and had not breast fed. Because of some significant intergroup differences and in order to determine any effect of the number of live births and the duration of breast feeding on QUS results, second analyses were undertaken using an equal size samples, matched for possible confounding variables such as age and body mass index (matched pairs). In these analyses, nulliparous women were compared with parous women grouped according to the number of live births, and women who had never breast fed were compared with women who had breast fed grouped in relation to the duration of breast feeding. Furthermore, a multiple linear regression analysis was performed to examine the combined effects of reproductive factors on QUS variables. No statistically significant associations were found between ultrasonometry variables and parity or breast feeding, even after controlling for confounding variables in matched pairs analysis and in a multiple linear regression analysis. Therefore, reproductive factors such as parity and breast feeding are not associated with subsequent low bone mass assessed by quantitative ultrasonometry at the os calcis in postmenopausal women. Further longitudinal studies are needed to improve our understanding of the mechanism of bone turnover during pregnancy and breast feeding.

female subjects with postmenopausal osteoporosis (fsh 430miu/ l and bone mineral density t-score 4–2.5) were treated with calcitonin 100 iu s.c. every other day for a period of one month, without ca and vitamin D supplementation. ivgtt was performed at the beginning and the end of the treatment to assess the function of beta-cells – first phase (fpis) and second phase of insulin secretion (spis), total area under the curve of insulin secretion. Blood and urine samples for ca, p and bone ap were taken at the same points. there was a significant decrease in fpis with 30% (p50.02), insignificant in spis with 7%, and increase in basal iri secretion with 18%. the calculation of the total area under the curve of insulin secretion shows equal values before and after antiresorptive treatment. Conclusion: The application of antiosteoporotic antiresorptive drugs without ca and vitamin D supplementation leads to some changes in the dynamics of the beta-cell function, but the capacity of beta-cell secretion is preserved. Bone antiresorptive drugs must be administered with obligatory ca and vitamin D supplementation.

P353SA. EVALUATION OF NUTRITIONAL STATE AND BODY COMPOSITION IN CHILDREN WITH OSTEOPENIA AND OSTEOPOROSIS Chlebna-Soko´l D, Loba-Jakubowska E, Rusinska A, Blaszczyk A; Department of Paediatric Propedeutics, Medical University, Lo´dY¨, Poland Objective: The aim of the study was to determine, whether children with osteoporosis or osteopenia demonstrate abnormalities in nutritional state and body composition. Subjects and methods: The study comprised 66 children, aged 5 to 18 years (34 girls and 32 boys). Osteoporosis was diagnosed in 45 cases: in 25 secondary (17 with chronic connective tissue diseases, 2 with asthma and also with cranio-clavicular dysostosis, brain tumor, hydrocephalus, myopathy, colitis and malabsorption syndrome) and primary in 20. In the remaining 21 children osteopenia was diagnosed. Those disorders were diagnosed on the basis of complex clinical, densitometric and biochemical analysis. Nutritional state and body composition were evaluated by anthropometric measurements: body weight, height, 4 skin folds, arm circumference. On the basis of those measurements, body mass index (BMI), Jelliffe index, the content of fatty and non-fatty tissues (lean body mass, LBM) were calculated. Normalization of values for somatic data was performed in relation to the arithmetical mean and standard deviation for the reference group (healthy children). The values were accepted as normal between ± 2,00 SD. Results: A decrease of body weight was observed in 3/66 patients, BMI in 3/66, fatty tissue calculated from the sum of 4 skin folds in 1/66 and from body density also in 1/66, LBM in 7/66 and Jelliffe index in 6/66 cases. An increase in BMI was observed in 3/66 patients, the sum of skin folds in 4/66, LBM in 1/66 and Jelliffe index in 4/66 cases. Conclusions: The analysis revealed slight abnormalities in body copmosition and nutritional state in children with decreased bone mineralization. Those observations may suggest that abnormalities in skeleton mineralizations are not related to the abnormalities in somatic development. Acknowledgement: The study was partly financed from State Committee for Scientific Reaserch grant No. 4P05E 03816.

P352MO. ANTIRESORPTIVE ANTIOSTEOPOROTIC DRUGS WITHOUT CALCIUM AND VITAMIN D SUPPLEMENTATION CHANGE THE DYNAMICS OF BETA-CELL FUNCTION Borissova AM, Dakovska L, Kirilov G, Kovatcheva R, Shinkov A, Ivanova R; Hospital of Endocrinology and Gerontology, Sofia, Bulgaria Antiresorptive drugs decrease the level of serum calcium (ca) by reducing the number and activity of the osteoclasts. The rise in ca ion concentration in a beta-cell leads to insulin secretion. twelve

P354SU. OSTEOPOROSIS AND OBESITY IN POLISH WOMEN Krela-Kazmierczak I, Dobrowolska-Zachwieja A, Linke K; Karol Marcinkowski University of Medical Sciences, Poznan, Poland Introduction: Obesity is considered as a protective factor for osteoporosis. The aim of this study was evaluation relation

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Abstracts

between BMD and: BMI (Body Mass Index), WHR (Waist Hip Ratio), FBM (Fat Body Mass), LBM (Lean Body Mass). Materials and Methods: The participants (n = 101) were healthy postmenopausal women age from 50 to 68 years, who was divided into 3 groups BMD-dependent ( I – osteoporosis n = 43; II – osteopenia n = 43; III – normal bone density – control group n = 15). BMD lumbar spine we measured by DEXA, body weight, high, BMI, body circumferences (waist, hip) and WHR, 4 skin-fat folds by Harpenter’s foldmeter, which was use to estimated FBM) and LBM. Results: The mean value of BMD was: I: 0.762 ± 0.102 g/cm2; II: 0.950 ± 0.079 g/cm2; III: 1.124 ± 0.075 g/cm2. The mean value of BMI and WHR were: I: 24.1 ± 3.5 and 0.77 ± 0.05; II: 27.4 ± 4.6 and 0.79 ± 0.05; III: 28.8 ± 3.9 and 0.79 ± 0.05. The differences of BMI and WHR between this 3 groups were statistically significant (p50.01and p50.05), and BMI correlated with BMD (r = 0.3; p50.05). Obesity % (BMI430) were: I-4.6%; II-23.3%; III-40.0%. The value of FBM and LBM were: I – 26.7% and 73.3%, II – 29.9% and 70.1%, III – 32.9% and 67.1% (defferences between groups – p50.01). We observed significant correlation between: LBM and T – score (r = 0.5; p50.01); FBM and T – score (r = 0.5; p50.01); FBM and BMI (r = 0.8; p50.01). The mean value of fat intake (g/ 24h): I – 78.7 ± 24.9 (131.4 ± 36.8% of RDA), II – 82.4 ± 23.8 (130.3 ± 35.7% of RDA), III – 76.3 ± 20.2 (122.4 ± 33.9% of RDA). Conclusions: Polish osteoporotic postmenopausal women have both lower BMI and FBM then ones with osteopenia and normal BMD. BMI, FBM and LBM are related to BMD. Obesity is common among postmenopausal polish women.

P355MO. DIETARY INTAKE AND SERUM LEVEL OF ASCORBIC ACID IN POLISH OSTEOPOROTIC WOMEN

P356SA. NUTRITION AND BONE TISSUE FUNCTIONAL STATE IN POSTMENOPAUSAL WOMEN DEVELOPMENT OF TEENAGERS Povoroznjuk VV, Grygoreva NV; Institute of Gerontology, Kiev, Ukraine, Ukrainian Center of osteoporosis, Kiev, Ukraine There has been increasing evidence that balanced diet and maintained optimal status significantly reduce morbidity and mortality. High calcium intake prevents bone loss and osteoporotic fractures in postmenopausal women although the association is less obvious in the first years after menopause. Influence of diet on bone tissue functional state was investigated in 247 persons. Bone tissue functional state was determined by ultrasound densitometry (I – osteoporosis, II – osteopenia, III – normal bone tissue). The diet of Ukrainian postmenopausal women is characterized by a reduced intake of proteins, especially animal; fats, especially vegetable; vitamins, main mineral macro- and microelements. The intake of main mineral element, necessary for bone turnover – calcium – is lower than recommended. Results for main nutrients are presented in the table. It is evident that all elements essential for the bone are below the recommended values. It is advised that the diet must be rich in proteins, calcium and vitamin D. Age

G

n

Ca (mg/d)

Mg (mg/d)

P (mg/d)

Vitamin D (mcg/d)

50-69 years 50-69 years 50-69 years 70 and more year 70 and more year 70 and more year

I II III I II III

54 40 43 63 40 47

476,1+73,5 471,3+37,01 373,9+42,9 486,2+36,77 431,6+23,09 439,3+84,83

283,9+18,5 287,6+18,8 290,5+38,6 264,0+10,1 290,8+17,0 273,9+25,8

891,9+61,8 863,9+61,77 768,4+44,51 865,7+38,78 834,5+30,21 876,4+78,41

0.72+0,18 0,44+0,07 0,36+0,09 0,38+0,07 0,42+0,05 0,36+0,08

Krela-Kazmierczak I, Dobrowolska-Zachwieja A, Linke K; Karol Marcinkowski University of Medical Sciences, Poznan, Poland Introduction: Ascorbic acid deficiency is considered as a factor which may lead to osteoporosis. The aim of this study was evaluation relation between dietary intake and serum level of ascorbic acid (vitamin C) and bone mineral density (BMD). Materials and Methods: BMD spine was measured using DEXA. We observed 101 Polish postmenopausal women age from 50 to 68 years, who was divided into 3 groups BMD-dependent: I: osteoporosis n = 43; II:osteopenia n = 43; III:control group (normal bone density) n = 15. They did not use pharmacological vitamins supplementation during last 3 months. We evaluated daily vitamin C intake by 24 hours nutritional history. We assessed daily intake of vitamin C using computer programme FOOD. We estimated achievement of Polish Recommended Daily Allowances (RDA). We evaluated serum vitamin C level (S) using colorimetric methods of Roem’s and Homolka’s (normal range: 0.4-1.5 mg/dl). Results: The mean values of BMD were: I – 0.762 ± 0.102 g/cm2; II – 0.950 ± 0.079 g/cm2; III – 1.124 ± 0.075 g/cm2. The mean values of vitamin C intake were: I – 29.4 ± 21.7 mg/24h; (45.8 ± 34.9% of RDA), II – 31.9 ± 17.8 mg/24h; (47.8 ± 29.7% of RDA), III – 25.5 ± 23.6 mg/24h; (38.9 ± 38.5% of RDA). The mean values of serum vitamin C level (mg/dl) were: I – 0.62 ± 0.26; II – 0.59 ± 0.27; III – 0.75 ± 0.32 (I, II, III – NS). Conclusion: Polish women intakes not enough vitamin C in their diet and have low serum vitamin C level. There was no relation between vitamin C diet intake and serum level to BMD. Group

n = 101 I osteoporosis II osteopenia III control group * I. II. III

Vitamin C (mg/dl) x (mg/dl)

SD

50.2 n (%)

0.2–50.4 n (%)

0.63 0.62 0.59 0.75 NS

0.28 0.26 0.27 0.32

5 (5.0) 17 (16.8) 3 (7.0) 6 (13.9) 2 (4.7) 9 (20.9) 0 2 (13.3)

0.4–1.5 n (%)

41.5 n (%)

79 34 32 13

0 0 0

(78.2) (79.1) (74.4) (86.7)

0

P357SA. BODYWEIGHT IS A KEY DETERMINANT OF BONE MINERAL DENSITY IN ELDERLY WOMEN, WHILE THE EFFECT OF PHYSICAL ACTIVITY, MUSCLE STRENGTH AND MUSCLE MASS IS LIMITED Gerdhem P, Ringsberg K, A˚kesson K, Obrant K; Department of Orthopedics, Malmo¨, Sweden Aims: To elucidate, in elderly women, the independent influence of current body-weight, weight-change, physical activity, muscle strength and muscle mass on bone mineral density (BMD). Methods: In the Malmo¨ Osteoporosis Prospective Risk Assessment (OPRA) study 1044 women, all of the same age – 75 years, were recruited from the population files. 995 of the women were examined with DXA (total body, hip- trochanter -neck and lumbar spine- LII- LIV). Isometric muscle strength (knee extension and flexion) was tested by a computerized dynamometer and the present activity level was assessed as an activity score. From the total body scan mode, total fat mass and lean body mass were assessed. Results: We found body-weight to have a substantial influence, 16-34% (i.e. r2 = 0,16-0,34) depending on skeletal site, on the total variability of BMD. Given body-weight (forward stepwise regression), none of the other variables contributed to more than 1% of the variability of BMD in any of the skeletal regions. For example: With the percentage figures given, body-weight (32%), physical activity (0,8%), muscle strength (0,7%) and lean mass (0,5%) all contributed significantly, to total body BMD. When body-weight (including fat and lean mass) was replaced by weight-change (from age 50 to the time of assessment at age 75), weight-change was more determining for BMD (4-13%, p50,0000) than physical activity and muscular strength. Each 10 kg weight-change predicted a change in T-score between 0.40- 0.65 SD. The effect of weight-gain on BMD was most pronounced for lowweight women, but also women in the upper-weight quartile increased their BMD with weight-gain. Conclusions: Our findings suggest that in elderly women, high body-weight or weight-gain, irrespective if caused by increased

Abstracts muscle or fat mass, overrule by far the effect of increased muscle strength and activity level on bone mineral density.

P358SU. THE INFLUENCE OF AGE, TESTOSTERONE AND ESTROGEN ON QUANTITATIVE ULTRASONOMETRY (QUS) OF THE OS CALCIS IN HEALTHY GERMAN MEN Hadji P, Saeger U, Kalder M, Gottschalk M, Bock K, Schulz KD; Philipps-University, Marburg, Germany The aim of this study was to evaluate the influence of age, testosterone and estrogen levels on quantitative ultrasonometry (QUS) of the os calcis in a large sample of healthy German men. 484 healthy men aged 20 to 80 years (mean age, 54.4 ± 15.4 years) not on medication known to effect bone metabolism were randomly recruited. Before entry to the study, all men had answered a detailed questionnaire on important risk factors. Speed of sound (SOS), broadband ultrasound attenuation (BUA) and stiffness index (SI) of the os calcis were measured using the Achilles ultrasonometer (GE/Lunar). Additionally, serum testosterone and estrogen levels were determined. BUA, SOS and SI decreased continuously from age 20. The total age-related decline was 17% for BUA, 2.4% for SOS and 17.4% for SI (p50.001). This occurred over a 47-year period. The annual decrease derived from age regressions was -0.4% for BUA, 70.05% for SOS, and –0.39% for SI. There was a significant decrease of serum testosterone with age (p50.001), while estrogen showed no such association. There was a significant correlation of testosterone to SOS and SI (p50.01), but non of estrogens to QUS variables. This significant correlation diminished after performing a multiple linear regression analysis. Hereby only age remained as a significant predictor of QUS variables. Like in women, men show a significant age related decline of QUS variables. In contrast to women, the QUS variables decline continuously from the age of 20 years. There is no age-independent influence of testosterone or estrogens on QUS variables.

P359MO. DO RISK FACTORS PREDICT WHICH OSTEOPOROTIC WOMEN SHOULD HAVE A X-RAY TO CONFIRM PREVALENT VERTEBRAL FRACTURE: THE IMPACT STUDY Delmas PD1, Eastell R2, Watts N3, Le-Moigne-Amrani A5, Grauer A4, van de Langerijt L5, Cahall DL5; 1University Claude Bernard, Lyon, France, 2Univeristy of Sheffield, Sheffield, United Kingdom, 3 Univeristy of Cincinnati, Cincinnati, Ohio, USA, 4Procter and Gamble Pharmaceuticals, Geneva, Switzerland, 5Aventis Pharma, Bridgewater, NJ, USA Although 2 out of 3 vertebral fractures are not diagnosed, they are associated with significant morbidity and an increased risk of subsequent fracture. The aim of this analysis was to test whether risk factors (RFs) can predict which osteoporotic women should have a x-ray to detect prevalent vertebral fractures (PVF). We assessed this in women enrolled in the IMPACT trial, designed to evaluate the impact of physician’s reinforcement with bone marker data on patients’ compliance and persistence on risedronate treatment. We studied 1842 osteoporotic women (low BMD:T score l5 –2.5 hip and/or spine), 65–80 yr., not receiving glucocorticoids who had lateral spine radiographs; 588 (32%) osteoporotic women had PVF versus 1254 (68%) osteoporotic women with no PVF. Using a logistic model, we retained low trauma fragility fracture after 45 yr. (LTF), age, and height loss from age 25 yr. (HL) as the risk factors of highest discrimination capability from 30 RFs (area under the curve of the receiver operating characteristic curve was 0.636). Judging it was more important to predict the fractures, we fixed a sensitivity rate of 90%. The model correctly predicts 90% of osteoporotic women with PVF but only 19% of osteoporotic women with no fracture. We conclude that vertebral fractures are common in women with

S109 a T score less than or equal to –2.5 and in this population, the use of this combination of 3 RFs, which only decreased by 16% the total number of x-rays to detect 90% of PVF, does not justify the use of this model in the selection of postmenopausal women to be screened for PVF.

P360SA. ASSESSMENT OF SKELETAL STATUS USING DEXA AND PQCT METHODS IN PAEDIATRIC SUBJECTS – NORMALIZATION FOR BONE AGE Pludowski P1, Lebiedowski M1, Chadzynski P2, Lorenc RS1; 1 Departament of Biochemistry and Experimental Medicine. Children’s Memorial Health Institute, Warsaw, Poland, 2Medical Academy, Warsaw, Poland The assessment of skeletal age is an important factor for the analysis of biological maturity, growth and its disorders. Bone density measurements using DEXA as well as pQCT methods became questionable in paediatric patients because of influence of body and bone size on the BMD values. In this study we have measured 200 children aged 5–19 years (mean age 12,4) using DPX-L densitometer for assessment of skeletal status, pQCT (4%, radius) for assessment of volumetric density and geometry and Expert- XL for assessment of bone age. Several cases of young patients with different bone disorders such as OI, IJO, Hypercalciuria, Multihormonal Pituitary Deficiency were also included. The purpose of the study was the evaluation of differences between Z-score values calculated on the basis of chronological age vs. bone age in healthy children and children with different bone disorders. The study was focused on relation between bone maturity status (bone age), muscle status (lean mass, grip strength) and the skeletal status (BMD, BMC, volumetric density, SSI) assessed directly by DEXA and pQCT methods. Strong correlation between lean body mass, Strength Strain Index (R2 = 0,78; p50,001) and grip strength (R2 = 0,87; p50,001) was stated in the group of healthy children. The weaker relationship was found in children with bone disorders. In those children, marked differences in BMD Z-score values after normalization for bone age (as compared to chronological) were found especially in the Multihormonal Pituitary Deficiency Subjects. The lack of marked differences in other bone disorders suggests the need for application of the additional parameters for normalization of BMD Z-scores. On the basis of this study we suggest that bone age should be taken into consideration in the diagnosis of bone disorders. Nevertheless, further studies are needed for selection of specific parameters characteristic for various bone disorders with the subsequent normalization of their BMD Z-scores values.

P361SU. USING THE OST INDEX TO IDENTIFY WOMEN AT RISK OF OSTEOPOROSIS: A VALIDATION STUDY IN BELGIUM Ben Sedrine W, Reginster JY; WHO Collaborating Center for Public Health Aspects of Rheumatic Disorders, Liege, Belgium We previously reported that the Osteoporosis Self-Assessment Tool (OST) performed well for identifying women at risk of osteoporosis, who would benefit from further evaluation using BMD measurements. The OST index was developed using a sample of women in Asia (Koh etal, Osteoporos Int 2001;12:699705), and was later validated in other populations in Asia and Caucasians in the US. The final index contained only 2 variables (age and body weight) and achieved 91% sensitivity and 45% specificity for predicting osteoporosis (femoral neck BMD T472.5). We examined the performance of the OST tool in a separate validation sample of 4035 postmenopausal Caucasian women in Belgium, ages 45-96 (mean = 61y); the overall prevalence of osteoporosis was 19%. When increased risk was defined as OST52, the sensitivity for identifying femoral neck T4–2.5 in this sample was 88%, and the specificity was 43%. The area under the ROC curve (AUC) was 0.76 (95% CI = 0.74,0.78). A

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very high risk category was defined as OST5–4; in this group (3.4% of all women), the prevalence of osteoporosis was 67%, and the prevalence of osteopenia (T5–1) was 23%. Thus, 90% of women in this very high risk group had osteoporosis or osteopenia. A moderate risk group was defined as OST = –1 to –4, representing 30% of all women; 73% of the women in this moderate risk category had either osteopenia (41%) or osteoporosis (32%). We conclude that the OST index performed well in this sample of women in Belgium; these results serve to validate the OST risk index. The prevalence of osteoporosis in the moderate and high risk categories is high enough to justify measuring BMD. OST is a free and simple risk assessment tool which can help clinicians and patients actively assess osteoporosis and determine the need for BMD measurements and intervention before fractures occur.

P362MO. FREQUENCY OF SPINE FRACTURES ASSESSED WITH LVA IN NORMAL, OSTEOPENIC, AND OSTEOPOROTIC POSTMENOPAUSAL WOMEN Faulkner KG1, Barden HS1, Weynand L1, Burke P2; 1GE Medical Systems LUNAR, Madison WI USA, 2Osteoporosis Diagnostic and Treatment Center, Richmond VA, USA This study determined the prevalence of spine fractures/ deformities assessed with dual-energy Lateral Vertebral Assessment (LVA) in normal, osteopenic, and osteoporotic postmenopausal women. Measurements were performed with the Lunar Prodigy bone densitometer (GE Medical Systems) utilizing a digital, CZT detector. LVA defines fractures as vertebral heights and ratios greater than 3 SD (moderate) or 4 SD (severe) below expected values. Osteopenia and osteoporosis were defined using WHO guidelines. Bone mineral density (BMD) was measured at the spine and both femora in 231 subjects (mean age 65 + 11.9 years). Osteopenia was found in 46.7% and osteoporosis in 26.4% of women at one or more sites. More than half (53.2%) of the 231 women had spine fractures. Fractures were found in 72.1% of women with osteoporosis and 49.1% of women with osteopenia at any of the three sites. Surprisingly, 41.9% of women with normal T-scores and 46.5% of women without osteoporosis had vertebral fractures by LVA. Women who were osteoporotic at the total femur were just as likely to have vertebral fractures as women osteoporotic at the lumbar spine. 40-45% of women who had normal T-scores at central DEXA sites had a spine fracture/deformity. These women would be considered low risk based on BMD T-scores but regarded as high risk for future fracture based on LVA measurements. We conclude that LVA can play an important role in assessing fracture risk in women over 65, regardless of BMD T-score. Percentage of women with fractures based on T-score diagnosis

All Sites Spine (L2-L4) Total Femur (Left) Total Femur (Right)

Normal (T 4 = –1.0)

Osteopenia (–2.55T5–1.0)

Osteoporosis (T4–2.5)

41.9% 45.8% 41.4% 41.6%

49.1% 51.1% 59.0% 57.8%

72.1% 74.4% 76.0% 73.9%

P363SA. CAN HEIGHT LOSS OR BODY WEIGHT BE USED AS A SURROGATE OF BMD MEASUREMENT FOR THE DIAGNOSIS OF OSTEOPOROSIS? Roux C1, Pols H2, Ringe J3, Le-Moigne-Amrani A4, Cahall DL4, Delmas PD5; 1Hoˆpital Cochin, Paris France, 2Erasmus University, Rotterdam, The Netherlands, 3Klinikum Leverkusen, Leverkusen, Germany, 4Aventis Pharma, Bridgewater, NJ, USA, 5University Claude Bernard, Lyon, France Low body weight (LBW) and low body mass index (BMI) have been shown to be associated with postmenopausal osteoporosis

(PMO) and low BMD. In this analysis, we examined whether LBW, BMI, or height loss could be used instead of a DXA confirmation of low BMD in PMO women with no history of low trauma fragility fracture after 45 yr. We assessed risk factor (RF) models in 5477 PM women, 65–80 yr., not previously diagnosed for osteoporosis, and not receiving glucocorticoids, enrolled in the IMPACT trial with risedronate treatment. This trial is designed to evaluate the impact of bone marker data on physician’s reinforcement of patient’s compliance and persistence. 1763 PM women (32%) were osteoporotic (T score, less than or equal to –2.5 at the spine and/or hip). The final model selected confirmed that LBW and height loss were the most effective RFs to discriminate women with/without osteoporosis, with an area under the curve (AUC) of 0.728. By choosing a cutoff point of less than or equal to 64Kg (63% Vs 29%) and greater than or equal to 3cm of height loss (57% Vs 50%) of women with and without osteoporosis respectively, we were able to predict 88% of osteoporotic women and 31% of non-osteoporotic women, (AUC = 0.682). These preliminary results do not support LBW, BMI or height loss as reliable surrogates of BMD measurement for the diagnosis of osteoporosis, but stresses the importance of these risk factors in the clinical evaluation of the PM women suspected of osteoporosis. A higher low weight cutoff (less than or equal to 64Kg), which selected 63% of our osteoporotic women, should be considered when evaluating PM women greater than or equal to 65yr for a diagnosis of osteoporosis since the usual cutoff of less than or equal to 57Kg selected only 33%.

P364SU. RELATIONSHIP BETWEEN BONE MINERAL DENSITY AND VERTEBRAL FRACTURE RISK IN CARDIAC TRANSPLANT RECIPIENTS Ho¨fle G1, Holzmu¨ller H1, Gouya G1, Hergan K2, Langer P1, Drexel H1; 1Department of Internal Medicine and Vorarlberg Institute of Vascular Investigation and Treatment (VIVIT), LKH Feldkirch, Austria, 2Department of Radiology, LKH Feldkirch, a teaching hospital affiliated with the University of Innsbruck, Austria Osteoporosis and increased incidence of fractures, particularly vertebral fractures (vfx), are a common problem after cardiac transplantation (CTX). Fractures occur even before Osteodensitometry (DXA) detects osteoporosis. Therefore we studied the characteristics associated with the presence/absence of vfx in cardiac transplant recipients. We performed a cross-sectional analysis of male and female CTX patients in a late post-transplantation period (4.4 years ± 2.5 SD after CTX, n = 27). We measured bone mineral density (BMD) by Osteodensitometry (DXA, Lunar) as well as by quantitative heel ultrasound (Sahara, Hologic). Vfx prevalence and bone turnover markers were also studied. Osteopenia was frequent (51.9%) in these patients and many even had osteoporosis (29.6%). Only 18.5% had bone density in the reference range of young adults. Vfx were present in 13 of 27 patients (48.2%, n = 51 vfx). They were observed in 1 out of 4 patients with normal DXA results, 7 out of 14 osteopenic and 5 out of 8 osteoporotic cardiac transplant recipients. Femoral neck bone mineral density and corresponding T scores were significantly lower in vfx patients (BMD 0.816 g/cm2 ± 0.093 SD versus BMD 0.903 g/cm2 ± 0.091 SD in patients without vfx; p50.023). We found similar differences in Ward’s triangle (patients with vfx: BMD 0.587 ± 0.102 SD versus BMD 0.754 ± 0.119 SD in patients without vfx; p50.001) and total hip (p50.033). However, none of the quantitative heel ultrasound parameters distinguished between patients with and without vfx, neither did Osteodensitometry in lumbar spine nor bone turnover markers. There is considerable overlap between BMD levels of patients with and without vertebral fractures. Our findings propose a superior validity of DXA measurements of the hip over the analysis of lumbar spine BMD, heel ultrasound parameters or bone turnover markers in defining vertebral fracture risk in posttransplantation bone disease.

Abstracts

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P365MO. VALIDATION OF RISK INDICES TO IDENTIFY POSTMENOPAUSAL WOMEN WITH AN INCREASED LIKELIHOOD OF OSTEOPOROSIS

Although longitudinal correction factor based on the daily calibration has not yet been used to correct the ESP phantom prior any analysis, exceptional stability between the 3 X-cal suggests that in the future the number of cross-calibration could be reduced except in case of hardware modifications.

Hochberg MC1, Thompson DE2, Ross PD2; 1University of Maryland, Baltimore, MD, 2Merck Research Laboratories, Rahway, NJ, USA Several risk indices, including Osteoporosis Self-assessment Tool (OST), SOFSURF, Osteoporosis Risk Assessment Instrument (ORAI), and the Simple Calculated Osteoporosis Risk Evaluation (SCORE) have been developed for identifying postmenopausal women with osteoporosis (OP). We evaluated the performance of these indices among 17,572 Caucasian women ages 45-81 who were screened for the Fracture Intervention Trial (FIT); 3637 (21%) had OP, as defined by a femoral neck bone mineral density (BMD) T score 4–2.5. All of the risk tools yielded reasonably good specificity when sensitivity was set to approximately 90% for diagnosing OP (Table); similar results were obtained using T 472.0. Three risk categories have been previously reported using the OST. A high risk subgroup was identified (OST5–3, 1309 [7%] of women) that had a high prevalence of osteoporosis (59%), while OP prevalence was 26% in a medium risk group (OST = –3 to 0, 9474 [54%]), and only 6% in a low risk group (OST40, 6789 [39%]). These results are similar to those reported in the original Asian sample (Osteoporos Int 2001;12:699-705), except that the risk category cutoffs were shifted up by one unit. While the women who were screened for FIT may not be representative of the general population as they were selected on certain characteristics, the performance of these risk tools was similar to that in the original development populations. We conclude that these free and simple risk assessment tools could help increase awareness of OP in women, and encourage the appropriate use of BMD measurements to diagnose OP before fractures occur. Index

Cutoff

Sensitivity

Specificity

LR (+)

LR (–)

OSTA ORAI SOFSURF SCORE

51 vs 4=1 410 vs 4=10 41 vs 4=1 411 vs 4=11

89 92 86 89

46 26 46 39

1.65 1.24 1.60 1.45

0.24 0.31 0.30 0.30

P366SA. IS MULTIPLE CROSS-CALIBRATION NEEDED IN A MULTI-CENTER STUDY?: THE PHASE 3 STRONTIUM RANELATE PROGRAM Perron C, Tahintzi-Zawadynski S, Hans D, Barada M, Gumy C, Slosman D; GEQAP, Geneva University Hospital, Geneva, Switzerland Because of the diversity of DXA devices generally involved in multi-centre studies, it is well accepted that one crosscalibration(X-cal) of scanners is needed to allow the pooling of the data. Whether several X-cal are essential to guaranty the quality of the study is still debated. In our study’s quality control program, we investigated the consistency of results found between three types of Hologic DXA scanners (QDR 1000, 2000 and 4500), over several cross-calibrations using the European Spine Phantom (ESP). During the phase 3 program of Strontium Ranelate, a new compound for the treatment of osteoporosis, involving 9196 postmenopausal women. DXA measurements were performed in 77 Hologic DXA scanners. Those were cross calibrated three time using 3 ESP phantoms measured 20 times at each visit. Since no significant difference was found between the 3 ESP phantoms, results were pooled. Results from the 3 Xcal are given in the following table and expressed in percentage difference between DXA of 3 types. No significant difference was found between the successive crosscalibrations for the diverse DXA. The maximum observed difference did not even reach the precision of the ESP phantom (0.47%, 0.56% and 0.42% for QDR1000, 2000 and 4500 respectively).

Xcal 1 – g/cm2 Xcal 2 – g/cm2 Xcal 3 – g/cm2 Diff 1–2% Diff 2–3% Diff 1–3%

QDR1000 N = 24

QDR2000 N = 19

QDR4500 N = 34

0.945 0.946 0.946 –0.02 –0.03 –0.06

1.028 1.030 1.034 –0.27 –0.31 –0.58

1.001 1.000 1.003 0.05 –0.25 –0.20

P367SU. THE ASSOCIATION BETWEEN FEMUR BONE MINERAL DENSITY AND HIP FRACTURE TYPE VARIES WITH AGE: A CROSS SECTIONAL STUDY OF 435 HIP-FRACTURED PATIENTS Di Monaco M1, Vallero F1, Di Monaco R2, Mautino F1, Cavanna A1; 1 Presidio Sanitario San Camillo, Osteoporosis Research Centre, Torino, Italy, 2I.R.E.S. L. Morosini, Torino, Italy The aim of the study was to evaluate the association between femur bone mineral density (BMD) and the hip fracture type at different ages. 435 patients consecutively admitted to a rehabilitation hospital following their first hip fracture were evaluated. All the fractures were either spontaneous or sustained as a result of minimal trauma. 22 out of 435 patients could not undergo BMD measurement and were ruled out. The fractures of the remaining 413 patients were classified as either cervical (N = 195) or trochanteric (N = 218). The BMD of the unfractured femur was assessed by DEXA (Hologic QDR 4500W), 21.5 ± 10.1 days (mean ± SD) after fracture occurrence. The patients with trochanteric fracture had significantly lower BMD than those with cervical fracture at all the five sites assessed: total proximal femur (p50.001), femur neck (p50.05), trochanter (p50.001), intertrochanteric area (p50.001) and Ward’s triangle (p50.01). Logistic multiple regression showed that the association between the hip fracture type and BMD measured at each of the five sites was independent of age, weight, height, body mass index, time between fracture occurrence and DEXA assessment and number of both concomitant diseases and drugs in use. Age stratification showed that the association between femur BMD and hip fracture type was actually found in the 209 patients aged 80 years and older and in the 50 patients aged 69 years and younger, but not in the 154 patients belonging to the intermediate age group (70–79 years). Our data confirm previous reports showing that cervical and trochanteric fractures are associated with different levels of BMD. Moreover we show that the role played by BMD as determinant of the hip fracture type varies with age, adding an interpretation key to the knowledge of the etiological differences between cervical and trochanteric fractures.

P368MO. THE DISCRIMINATION POWER OF QUANTITATIVE ULTRASOUND AT THE HAND PHALANGES IN THE DETECTION OF THE DIFFERENT TYPES OF NON-TRAUMATIC FRACTURES Pluskiewicz W2, Drozdzowska B1; 1Dept. and Chair of Pathomorphology, Zabrze, Poland, 2Metabolic Bone Diseases Unit, Zabrze, Poland The aim of the study was to determine whether quantitative ultrasound at the hand phalanges has the ability to discriminate between individuals without and with non-traumatic fractures. All women (n = 1205) (age range 51–88 years) were divided into controls and women with non-traumatic fractures (n = 747). Fractured women were divided on the basis of the types of fractures: with hip, spine, wrist or other fractures. All non-hip fractured women (n = 442) created group 2 with three subgroups:

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Abstracts

with spine, wrist or other fractures. These subgroups were comparable in terms of age and years since menopause between each other and with control group 1 created for them by 744 women. For significantly older women with hip fractures (group II, n = 19) separate comparable control group was created (group I, n = 146). Skeletal status was assessed using DBM Sonic 1200 (Igea,Italy) which measures Ad-SoS [m/s]) at the proximal phalanges. Women with spine, wrist or other fractures had significantly lower Ad-SoS than controls (1828.8 57.1 m/s, 1861.6 61.2 m/s, 1862.5 55.3 m/s, respectively vs. 1902.6 63.4 m/s, p50.001) just as hip fractured women (1814.2 60.0 m/s vs. 1876.9 65.2 m/s, p50.0001). Vertebrally fractured women had significantly lower Ad-SoS than higher and comparable values in those with wrist or other fractures. Ad-SoS revealed the following areas under the ROC curve: 0.796 in women with hip fractures, 0.753 in those with spine, 0.664 in those with wrist and 0.675 in those with other fractures. By multiple logistic regression analysis the risks of fracture, estimated as Odds Ratios (ORs) for each 1 SD reduction in Ad-SoS, were: 2.66 (1.50-4.72) for hip, 2.63 (1.803.82) for spine, 1.94 (1.67-2.26) for wrist and 1.86 (1.52-2.26) for other fractures. The present study demonstrates the ability of phalangeal QUS to discriminate between healthy individuals and subjects with different types of non-traumatic fractures as well as of phalangeal parameter to identify vertebrally fractured women from those with wrist or other fractures. Both ROC analysis and Odds Ratios proved the usefulness of the method in fracture risk assessment.

P369SA. CANCELLOUS BONE TEXTURE ANALYSIS: SYSTEMATIC EVALUATION OF RUN LENGTH ON 20 BONE SAMPLES 1,3

2

3

3

Guggenbuhl P , Chappard D , Bezy-Wendling J , Garreau M , Chale`s G1, Rolland Y3,4; 1Rheumatology Unit, University Hospital, Rennes (France), 2Histology-Embryology laboratory, Angers University (France), 3Signal and Imaging Treatment Laboratory, INSERM emi 9934, Rennes University (France), 4Radiology Unit, University Hospital, Rennes (France) Goal: Bone microarchitecture alteration in osteoporosis is assessed by histomorphometry. In order to overcome the need of biopsy, a lot is made to describe bone microarchitecture from X-ray, TDM or MRI using texture analysis (TA). TA showed promising results, but suffers from a lack of reproducibility. Our goal is to evaluate the impact of acquisition conditions on the variation of TA parameters. Materials and Method: We studied 20 normal animal cancellous bone samples of 15/25/8 mm; CT scan acquisitions were made on a Somaton Siemens1 with optimal conditions for bone (120 KV, 240 mA, 5122 matrix, FOV 50 mm, convolution filter (AB90)); 4 different slice thickness were performed at 1, 3, 5 and 8 mm. Each sample was measured 5 times at each slice thickness after repositioning. TA was performed with Mazda1 software; we present the results of the run length analysis (short run length, long run length) measured at 4 different angles (horizontal, vertical, 458 and 1358); a 300 mm2 region of interest was used for all the sample. Results: There was a decrease of the short run length with the increase of the slice thickness. At the opposite, there was an increase of the long run length with the increase of the slice thickness. The mean variation coefficient was included between 1,05 and 3%. But when the analysis was performed at each slice thickness, the best reproducibility was found at 3 mm : 0,8 to 2,5%. When different angles were studied, we found a strong correlation between the different directions measurements (R2 = 0,7 to 0,9). Conclusion: Our results suggest that (1) TA parameters vary with slice thickness (2) a good reproducibility can be achieved with run length methods if slice thickness is constant. In our series, the best reproducibility is obtained with 3 mm slice thickness.

P370SU. COMPARISON OF THREE TYPES OF DXA HOLOGIC DEVICES USING THE ESP PHANTOMS IN THE LONGITUDINAL MULTICENTRE STRONTIUM RANELATE TRIALS Tahintzi-Zawadynski, S, Perron C, Hans D, Pittet N, Slosman D; GEQAP, Geneva University Hospital, Geneva, Switzerland In order to pool in vivo data acquired on diverse DXA devices in a multicentre clinical trial, cross-calibration is usually required. While variation of results between DXA devices of different manufacturers is expected, one would assume that intra-brand difference would be minimum. In the present study, we investigated the impact of three type of Hologic DXA scanners on the cross-calibration assessed by the European Spine Phantom (ESP). In the Strontium Ranelate phase 3 studies involving 9196 postmenopausal women, DXA measurements were performed using 77 Hologic DXA densitometers: 24 QDR1000, 19 QDR2000 and 34 QDR4500. Those were cross calibrated using three ESP phantoms (138, 140 and 142) measured 20 times each. Differences between phantoms and between apparatus were determined. The ESP precision is 0.47%, 0.56% and 0.42% for QDR1000, 2000 and 4500 respectively. No significant difference was found between the three ESP phantoms for each type of device and results were pooled. As listed below (see table), percentage of differences between two types of devices (DXAdiff) were significantly different from zero between pairs of devices. In addition, these inter-types differences (QDR1000 vs 2000, etc) were larger than the observed intra-types variability. Our results confirm the importance of a stringent crosscalibration procedure in multicentre clinical trials involving different types of devices. DXAdiff

QDR1000/2000

QDR1000/4500

QDR2000/4500

ESP 138 ESP 140 ESP 142 Mean diff.

–8.2 –7.7 –10.2 –8.7*

–5.3 –6.1 –6.2 –5.9*

2.7 1.5 3.6 2.6*

DXAdiff = [(meanBMD DXA1-meanBMD DXA2)/ meanBMD DXA1]*100; *p50.05

P371MO. THE ROLE OF DENSITOMETRY IN CLINICAL PRACTICE. RESULTS OF A HEALTH INSURANCE SPONSORED SCREENING PROGRAM Chapurlat RD1, Albrand G1, Duboeuf F1, Maillet B2, Gosselin M2, Delmas PD1; 1INSERM Unit 403, Lyon, France, 2Osteoporosis Center, Moulin, France Despite potentially severe consequences, the prevention of osteoporotic fracture is often neglected, and most women who sustain osteoporotic fracture do not receive adequate therapy. So strategies to screen and treat postmenopausal women need to be defined, specifically with health insurances. To assess the role of densitometry to screen postmenopausal community-dwelling women in clinical practice, we measured femoral and spine bone mineral density (BMD) among affiliates of a local French health insurance (Mutualite´ Bourbonnaise), which sponsored this screening, using a Lunar DPX device, in a regional osteoporosis center in Moulin, France. Women affiliated to this insurance were systematically invited. During the same visit, clinical risk factors for fracture such as age, time since menopause, fracture history, body weight, use of glucocorticoids or of hormone replacement therapy (HRT), were also collected. Among the 708 women of this population-based sample (mean age 61 ± 5.7), we found that BMD decreased with age (femoral BMD was 4% lower in women 60-69 years of age and 19% lower in women 70-79, both compared to women 560, p50.001). Women 557 kg had femoral BMD 12% lower than that of women 460 kg (p50.001). Femoral BMD of women who had taken glucocorticoids regularly was 3% lower than that of other women (p50.001). Femoral BMD of women with a history of vertebral

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fracture was 12% lower than that of other women (p50.001). Women with history of wrist fracture had 8.5% reduced femoral BMD compared to other women (p50.001). In conclusion, our results – obtained in a population-based sample – are consistent with those of epidemiological studies, indicating that some easily identified clinical risk factors (age, low body weight, history of fracture, glucocorticoid use) are associated with decreased BMD. Whether or not such a screening program results in higher treatment rate of osteoporotic women needs to be assessed prospectively.

P372SA. ACCURACY OF AUTOMATED DETERMINATION OF REGIONS OF INTEREST IN FOREARM DENSITOMETRY. THE HUNT STUDY, NORWAY Lilleeng SE, Forsmo S, Langhammer A; Inst. of Community Medicine and General Practice, Norwegian University of Science and Technology, Trondheim, Norway Aims: In a population-based multipurpose health study during the years 1995-97 in the county of Nord-Trøndelag, Norway (HUNT study), forearm BMD was measured in 18265 men and women above 19 years of age with three single X-ray absorptiometry devices (DTX-100 Osteometer). Regions of interest (ROI) were automatically determined by Osteometer software. Due to problems in the automated determination of the radius endplate or the 8-mm radius/ulna distance, all measurements were recalculated after manual assessment of ROI. The purpose of the present study was to analyse the discrepancies between automated and manual determination of ROI and to assess the clinical impact of the differences. Methods: Pre- and post-adjustment BMD results from two machines and 6267 women (mean age 55) were analysed. The association between BMD discrepancies ± 1 SD from the mean and adjusted BMD, age, weight and height was analysed in a logistic regression model, controlling for device. T- and Z-scores were determined in both pre- and post-adjustment data to assess the validity of the primary determination. Results: Mean difference in g/cm2 at distal and ultradistal site was 0.0004 and 0.007, respectively. In logistic regression of ultradistal data, odds ratio of BMD was 51, and 41 for age, weight and height, given discrepancies ± 1 SD. No association was found at distal site. The table shows validity of T- and Zscores based on primary determination. Conclusion: Accuracy of forearm SXA-densitometry is good, however, ultradistal BMD is often estimated too high, thus sensitivity is lower than at distal site.

Sensitivity Specificity Pos. predictive value

Distal radius

Ultradistal radius

Z-score

T-score

Z-score

T-score

0.97 1.00 0.98

0.98 1.00 0.99

0.80 0.99 0.95

0.88 0.99 0.97

P373SU. COMPARISON OF PENCIL-BEAM AND CONE-BEAM DUAL X-RAY ABSORPTIOMETERS FOR THE EVALUATION OF BONE MINERAL CONTENT IN EXCISED RAT BONE Libouban H1, Simon Y2, Silve C3, Legrand E2, Basle MF1, Audran M2, Chappard D1; 1Lhea-Gerom, Fac. Medicine, Angers, France, 2 Rheumatology, CHU, Angers, France, 3Inserm U426, Fac. Medicine, Paris, France The aim of the present study was to assess the precision and accuracy of excised rat bone mineral content (BMC) measurements in three different generations of DXA densitometers: Hologic QDR2000 pencil-beam, Hologic QDR4500 fan-beam and Lunar PIXImus cone-beam. BMC was measured on tibias and

femurs obtained from 79 male Wistar rats. Hologic QDR2000 and Hologic QDR4500 measurements were performed using small animal software with a proximal high resolution option. For each scan-mode, the reproducibility of the BMC measurements was evaluated by scanning four isolated bones on five consecutive days. The coefficients of variation of BMC were 0.62 and 0.85% for pencil-beam, 1.73 and 3.59% for fan-beam, 0.70 and 1.52% for cone-beam respectively for femur and tibia. Accuracy of BMC measurements was assessed by comparing BMC results obtained on each different scan-mode with the true values obtained from ash weight. The linear regression between BMC and ash weight showed high linear correlation coefficients: 0.998 for pencil-beam, 0.984 for fan-beam and 0.995 for cone-beam. However, comparative analysis revealed that the three densitometers overestimated BMC by respectively 10.9%, 12.6% and 3.1% vs. ash weight. Overestimation was found to be dependent on the net bone mineral content. The relationship between the data obtained from the 3 scanmodes was evaluated. The highest coefficient of correlation was found between BMC measurements from pencil-beam and conebeam (r = 0.995). The mean differences between paired measurements were: 0.002g (fan-beam vs. pencil-beam), 70.054g (cone-beam vs. pencil-beam), 70.051g (cone-beam vs. fan-beam). Data from cone-beam DXA were respectively 8.8% and 9.2% lower than those from pencil-beam and fan-beam. We conclude that the three DXA instruments precisely and accurately measure BMC in excised rat bone; however, DXA overestimates BMC with a dependence on the net bone weight. This dependence was less pronounced with the cone-beam technology.

P374MO. THE USEFULNESS OF BONE ULTRASONOGRAPHY IN THE ASSESSMENT OF CORTICOSTEROID-INDUCED OSTEOPOROSIS Cepollaro C, Gonnelli S, Montagnani A, Bruni D, Rossi B, Mangeri M, Breschi M, Caffarelli C, Gennari C; Institute of Internal Medicine, University of Siena, Italy Few data are present in literature on the usefulness of quantitative ultrasound (QUS), a technique that could theoretically provide information on bone structure, in the management of corticosteroid-induced osteoporosis. The aim of the present study was to investigate the usefulness of QUS at calcaneus and phalanxes, compared to DXA, for detecting bone status in patients taking corticosteroids. We studied 198 patients (mean age 58.1±13; 130 women and 68 men) in chronic treatment with corticosteroids and 198 sex and age-matched controls. The patients were being treated with oral prednisone or equivalent at a dose of 47.5 mg/ day for at least 1 year. In all subjects we measured ultrasound parameters at calcaneus: speed of sound (SOS), broadband ultrasound attenuation (BUA) and Stiffness, by Achilles + (Lunar Corp.), and at phalanxes: amplitude dependent speed of sound (AD-SoS) and characteristic graphic trace parameters: fast wave amplitude (FWA) and the bone transmission time (BTT), by DBM Sonic (Igea). We also measured bone mineral density at lumbar spine (BMD-LS) and at femoral subregions (femoral neck: BMD-FN, total hip: BMD-T, trochanter: BMD-TR, intertrochanter: BMD-ITR, Ward’s triangle: BMD-W) by DXA (QDR 4500, Hologic, USA). All densitometric and ultrasonographyc parameters, expressed as T scores, were significantly lower (P50.05 for SOS, P50.001 for the others) in patients treated with corticosteroids with respect to controls. In corticosteroid-treated patients, the Tscores were -2.4 for BMD-LS, -2.3 for BMD-FN, -1.5 for BMD-TR, BMD- ITR and BMD-T, -2.6 for BMD-W, -1.6 for SOS, -2.4 for BUA, -2.6 for Stiffness and -2.8, -1.4 and -2,4 respectively for FWA, BTT and AD-SoS. In conclusion QUS at the heel and at phalanxes could be considered a useful tool in the management of glucocorticoidinduced osteoporosis.

S114 P375SA. VERTEBRAL BODY SIZE MEASURED BY POSTEROANTERIOR AND LATERAL DUAL-ENERGY X-RAY ABSORPTIOMETRY IN WOMEN WITH AND WITHOUT VERTEBRAL FRACTURES Ferrar L, Henry Y, Eastell R; University of Sheffield, UK There is evidence to suggest that vertebral bone volume is smaller in patients with vertebral osteoporosis compared to healthy controls. In these studies, volume was estimated as postero-anterior (PA) bone area measured by dual-energy x-ray absorptiometry (DXA) raised to the power of 1.5. We aimed to compare this approach with estimation of volume as lateral bone area 1.5, where lateral area is derived from paired PA and supine lateral DXA scans of the lumbar spine. We studied a populationbased sample of 128 women (ages 50 to 87 years) with no radiological evidence of vertebral fractures (normal group), and 49 women (ages 50 to 84 years) with osteoporotic vertebral fractures. We compared PA and lateral bone area, and PA and lateral bone volume (area 1.5) for vertebrae L2 to L3 in the normal and fracture groups. Fractured vertebrae were excluded from analysis. Women with vertebral fractures were older and had lower lumbar spine BMD (p50.0001) compared to women with no fractures. Mean PA vertebral bone area (14.29 ± 0.25 cm2 for the normal, 13.21± 0.44 cm2 for the fracture group) and volume (54.20 ± 1.45 cm3 for the normal, 48.22 ± 2.41 cm3 for the fracture group) were significantly smaller in women with fractures (p50.0001). There was no significant difference (p = 0.957) between groups for lateral bone area (10.31 ± 0.21 cm2 for the normal, 10.30 ± 0.33 cm2 for the fracture group) or volume (33.26 ± 1.05 cm3 for the normal, 33.22 ± 1.57 cm3 for the fracture group). We conclude that previous findings of smaller vertebral volume in patients with osteoporosis compared to controls may be attributed to measurement error associated with PA DXA (possibly in relation to the influence of the spinous processes), rather than a true difference.

P376SU. LONGITUDINAL QUALITY CONTROL METHODOLOGY FOR THE QUANTITATIVE ULTRASOUND ACHILLES + IN CLINICAL TRIAL SETTINGS Hans D1, Wacker W2, Genton L1, Paris E3, Slosman D1; 1Geneva University Hospital, Geneva, Switzerland, 2GE-Medical Systems Lunar-Madison USA, 3Synarc Inc-Copenhagen, Denmark Appropriate Quality Assurance and Quality Control (QC) procedures have not been well developed and validated for Quantitative ultrasound technologies. In addition, because of external factors (e.g. temperature, aging of the phantom) the confidence we may have in the external black rubber phantom (used with the Achilles+) is too limited to consider this phantom as a good indicator of device stability. The goal of this study is to define the right QC parameters and develop the QC methodology for the QUS Achilles+ device. We scrutinized 4 Achilles + QC files known to have multiple stable/unstable behaviours, as well as the malfunction history log from GE-Lunar. We selected several QC parameters known to be influenced by potential malfunctions. There are phantom temperature-adjusted speed of sound (PSOS-TC) and broadband ultrasound attenuation (PBUA-TC), water speed of sound error (WSE), water spectrum slope (WSS) and water gain (WG). For each of these parameters, the optimum thresholds have been calculated (table) and combined into a whole QC process meant to detect malfunction in the daily QC. Given the currently available phantom and parameters, the best possible QC procedures to detect long-term drift in the daily QC of the Achilles + has been developed and will be applied to large clinical trials in osteoporosis.

Abstracts

CV% 95% CI

PSOS-TC

PBUA-TC

WSE*

WSS**

WG**

0.22% ± 0.6%

0.67% ± 1.9%

– ± 6.8 m/s

– ± 5.3%

– ± 7.3%

*alarm thresholds have been calculated based on the in vivo precision given by the manufacturer and the ratio 1.33 to 1 (in vivo-in vitro)** the 99.7% confidence internal has been taken.

P377MO. QUANTITATIVE ULTRASOUND TECHNIQUE IN THE EVALUATION OF SKELETAL STATUS IN NEWBORNS Montagnani A1, Gennari L1, Gonnelli S1, Cepollaro C1, Martini S1, Perrone S2, Muraca M2, Bonocore G2, Bagnoli F2, Gennari C1; 1 Institute of Internal Medicine, University of Siena, Italy, 2 Neonatology, University of Siena, Italy One of the most debated issues in paediatric bone research is the optimal technique for determining bone mass in growing children. Dual energy X-ray (DXA) absorptiometry is widely used as a method for assessing bone mass in children, even though it shows some limits for accuracy and radiation exposure. Quantitative ultrasound (QUS), widely employed in evaluating skeletal status in adults, is also an emerging method to evaluate paediatric bone mineral, since it is portable and requires no ionising radiation. However, a sufficient experience in the application of QUS to newborns is lacking. The aim of the present study was to evaluate the pattern of QUS parameters in newborns. In 115 newborns (gestational age: 39.2±1.3 weeks) amplitude dependent speed of sound (ADSOS), fast wave amplitude (FWA) and the bone transmission time (BTT) have been assessed at distal metaphyses of humerus using Bone Profiler. Since such device is normally used for measurements at fingers in adult subjects, it has been appropriately adapted by manufactory to perform the measurements at newborns’ humerus. AD-SOS resulted within 1646 m/s and 1850 m/s, with a mean of 1746.8, FWA and BTT means were 1.68±1.63 mV and 0.23±0.1 ms, respectively. The study of relationships between QUS parameter and anthropometric characteristics of newborns showed a weak negative correlation between AD-SOS and height, whereas we found a positive relationship between weight or height and BTT (r = 0.30 and 0.25, respectively). No correlation was found between AD-SoS, BTT and gestational age. Moreover, AD-SoS and BTT showed a significant correlation (r = 0.61). Our data show that QUS methods, after appropriate technical adaptation, could be used in the assessment of skeletal status in newborns. However, this new potential application of bone ultrasonography needs further studies, namely in regard to normative data, precision characteristics and longitudinal pattern of QUS parameters in newborns.

P378SA. VALIDITY OF QUANTITATIVE CALCANEAL ULTRASOUND AS A SCREENING TOOL IN THE MEASUREMENT OF BONE MINERAL DENSITY IN AMERICAN INDIANS Power DJ, Lisse JR, Yocum DE, Villanueva I, Botzong B, Lampert KJ; Arizona Arthritis Center, University of Arizona, Tucson, USA Aims: To test the validity of quantitative calcaneal ultrasound (QUS) as a screening tool for the presence of low bone mineral density in American Indian poplulations as compared with dual energy x-ray absorptiometry (DEXA). This is the first such study in American Indians. Methods: Patients seen in Arizona Indian Health Service Rheumatology Clinics were evaluated with both QUS (Achilles Express, Lunar) and DEXA (QDR 4500W, Hologic) at the spine (L2L4) and hip (total hip). Results: 235 patients were analyzed (200 women and 35 men). Mean age was 49.03 years (17-91). Using QUS, 59.7% of the

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patients were osteopenic (T-score 5–1.0), while with DEXA at the hip, 26.4% and at the spine, 38.4%. Using QUS, 19.5% were osteoporotic (T-score 5–2.5), but with DEXA, only 5.6% were osteoporotic at the hip and 6.9% at the spine. Correlation of QUS T-scores to hip T-scores was.598 (p50.001) and.519 for QUS Tscore to spine T-score (p50.001). The table below shows the results when comparing QUS to DEXA at the spine and at the hip for the diagnosis of osteopenia (OPN) and osteoporosis (OPS). Conclusion: QUS is more sensitive for identifying osteopenia and osteoporosis at the hip than at the spine and more specific for determining osteoporosis rather than osteopenia at both the spine and hip in American Indians. The negative predictive value is very good, while the positive predictive value is not optimal. The data suggest that patients with low T-scores by QUS should have DEXA prior to the initiation of antiresorptive medications. Test

OPN: Heel-Spine

OPN: Heel-Hip

OPS: Heel-Spine

OPS: Heel-Hip

Sensitivity Specificity Positive predictive value Negative predictive value Area ROC

75.31% 56.41% 64.21% 68.75% 0.72(0.64–0.80)

85.71% 51.81% 44.21% 89.06% 0.79(0.71–0.87)

47.82% 84.56% 34.37% 90.55% 0.75(0.64–0.86)

90.00% 85.23% 29.03% 99.21% 0.89(0.81–0.98)

P379SU. INFLUENCE OF SOFT TISSUE THICKNESS ON BONE MINERAL DENSITY MEASUREMENTS PERFORMED WITH A NEW CONE BEAM DXA BONE DENSITOMETER Duboeuf FD1, Dinten JM2, Gonon G2, Delmas PD1, Meunier PJ1; 1 Inserm Unit 403, Hoˆpital Edouard Herriot, Lyon, 2CEA-LETI, Direction de la recherche technologique, de´partement syste´mes pour l’information et la sante´, Grenoble, France Aim: To evaluate the influence of soft tissue thickness on bone mineral density (BMD) measurements obtained with a new cone beam DEXA bone densitometer (LEXXOS)TM (1). Material: The device associates a conic X rays beam with a bidimensional X rays digital flat panel detector. This new detector has a 20 cm square acquisition area and provide pixels of 400 microm. This technology realizes hip, spine and forearm acquisition without scanning in two X rays flashes. Acquisition time is less than 2 seconds. Method: Five measurements of a human lumbar spine embedded in polymethymetacrylate (PMMA) were performed with 15, 20 and 25 cm of water. Similarly, five measurements were performed with 5 cm (2.5 under and 2.5 above) of PMMA together with water up to 17.8, 20 and 25 cm from bottom, corresponding to 18.8, 21, and 26 cm of soft tissue attenuation. For each given thickness, measurements were performed in standard and high resolution mode. Results: In standard mode, values are stable until 21 cm of soft tissue attenuation (from 0.982 g/cm2 at 18.8cm to 0.973 g/cm2 at 21 cm), and decrease with soft tissue values of 25 to 26 cm (0.952 and 0.941 g/cm2 respectively). Stability is observed with the high resolution mode in the whole range of soft tissue attenuation thicknesses. (Range from 0.977 to 0.997g/cm2). At 25 and 26 cm of soft tissue attenuation in standard mode, variability increases (cv range 1.57–1.88 versus 0.30 to 0.48 for lower thichnesses), and is reduced using the high resolution mode (cv range 0.71– 0.92). Conclusion: LEXXOS prototype in vitro performances are in the same range as performances (2) obtained with currently commercialized osteodensitometers.

References 1. Dinten JM, Robert Coutant C, Darboux M. SPIE Medical Imaging. San Diego, February 2001. 2. Barthe N, Braillon P, Ducassou D, Basse-Chatalinat The British Journal of Radiology 1997:70:728–739.

P380MO. VALIDATION OF A SIMPLE CLINICAL RISK INDEX TO IDENTIFY POSTMENOPAUSAL ASIAN WOMEN WITH OSTEOPOROSIS: THE OSTEOPOROSIS SELF-ASSESSMENT TOOL FOR ASIANS (OSTA) Hochberg MC1, Thompson DE2, Ross PD2; 1University of Maryland, Baltimore, MD, 2Merck Research Laboratories, Rahway, NJ, USA Risk assessment tools have been developed for identifying Caucasian postmenopausal women with osteoporosis (OP), as defined by low bone mineral density (BMD). The Osteoporosis Self-assessment Tool for Asians (OSTA), was developed using a sample of women in Asia (Koh et al, Osteoporos Int 2001;12:699– 705). OSTA only requires age and weight. We evaluated the performance of the OSTA among 140 Asian women who were screened for eligibility for the Fracture Intervention Trial (FIT). These Asian women had a mean (SD) age of 67 (7) yr (range 5579); 22 (16%) had OP, as defined by a femoral neck BMD T score 4–2.5 of the young mean for Asian women (40.528 g/cm2). Using an OSTA cutoff of 40 vs 4=0, the sensitivity was 96% and specificity was 37%. The likelihood ratio positive (LR+) was 1.52, while the LR- was 0.12 (the post-test odds equals LR*[pre-test odds]). Three risk categories have been previously defined using the OSTA index; a high risk subgroup (OSTA 4–4, [n = 13] 9% of women) with a high (38%) prevalence of OP, a medium risk group (OSTA = –4 to –1, [n = 82] 59% of women) with a moderate (20%) prevalence of OP, and a low risk group (OSTA 4=0, [n = 45] 32% of women) with a low (2%) prevalence of OP. These results are very similar to those reported in the original Asian sample using the same index cutoffs. While the women screened for FIT may not be representative of the general population, the performance of the OSTA was similar to that in the original development population. We conclude that this free and simple risk assessment tool could help increase awareness of OP in Asian women, and encourage the appropriate use of BMD measurements to diagnose OP before fractures occur.

P381SA. LOW DIAGNOSTIC SENSITIVITY OF T-SCORE OF THE HIP USING NHANES REFERENCE DATA SET Ortolani S, Cherubini R, Saraifogher S; Istituto Auxologico Italiano IRCCS, Milan, Italy T-score is widely used to express bone density data and, following WHO proposal, –2.5 T-score threshold is increasingly accepted for densitometric diagnosis of osteoporosis. Moreover, T-score is intended to provide a standardised index to overcome differences in BMD absolute values among skeletal sites and/or brands of bone densitometers. To further improve standardisation of densitometric data of the hip, major bone densitometry manufacturers have since a few years moved from in-house normative data to the NHANES III reference database to calculate hip bone density T-scores. NHANES III is a recent population based survey made in US that should provide more reliable reference data, but some studies have questioned the applicability at least to non US populations of the T-scores generated from NHANES data. We tested the effect of switching from previous normative data set provided by Hologic in 1991 (HOLO) to NHANES III normative data set (NH) in a sample of 258 postmenopausal osteoporotic women (mean age 69.5, range 42-91) with at least one major fragility fracture (vertebra, hip, homerus), who had bone density of lumbar spine and hip measured with Hologic QDR 2000. The table shows the number and percentage of patients captured as osteoporotic, according to WHO definition, by DXA at different skeletal sites, depending on the normative data used. NH based T-scores of the hip show a better consistency between total hip and neck ROIs, but capture as osteoporotic only 50% of the patients with prevalent osteoporotic fractures, an unacceptably low sensitivity for a diagnostic test. This poor diagnostic

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performance must be taken in account when proposing total hip or femoral neck T-score based on NHANES III as the gold standard for the diagnosis of osteoporosis.

T-score 4–2.5 (N) T-score 4–2.5 (%)

Spine L2-L4

Total Hip Neck HOLO HOLO

Total Hip NH

Neck NH

192 74.4%

174 67.4%

128 49.6%

136 52.7%

223 86.4%

P382SU. TEXTURE ANALYSIS OF X-RAY RADIOGRAPHS IS CORRELATED WITH BONE HISTOMORPHOMETRY Chappard D1, Guggenbuhl P2, Legrand E3, Basle´ MF1, Audran M3; 1 LHEA-GEROM, Faculty of Medicine, Angers, France, 2 Rhumatologie, CHU, Rennes, France, 3Rhumatologie, CHU, Angers, France Recent studies have found that alteration of the 3D trabecular microarchitecture is a risk factor for vertebral fractures, especially in male patients. Histomorphometry allows microarchitectural analysis of bone; however, the invasive character of transiliac bone biopsy limits its use in large series of patients. X-Ray films are commonly used in routine practice and constitute a 2D projection of the trabecular architecture. Blocks of trabecular bone were prepared from calf bone. They were selected from different parts of the femoral condyle to provide various densities and architectures. All blocks (25 x 15 x 8 mm) were radiographed on a numerized system, with the same acquisition parameters. Texture analysis was appreciated by several methods: (skeletonization, run lengths and fractal techniques). 2D sections of the blocks were obtained and analyzed by histomorphometric methods: BV/TV, trabecular characteristics and 2D descriptors of architecture (star volumes, index of connectivity). Significant correlations were obtained for BV/TV with run length parameters describing the X-ray image: (hRSE: r = –0.73, hLSE: r = 0.70). Skeletonization parameters (axis r = –0.77) and fractal dimension with the blanket method (r = –0.69) were also significant by correlated. The trabecular characteristics were found highly correlated with texture parameters describing the Xray image (e.g., Tb.N /axis: r = –0.76; / hGRE: r = –0.72; Tb.Sp/ vGLN r = –0.78). Although the relationships between the 2D/3D trabecular architecture are not fully elucidated from a stereological point of view, the texture analysis of X-ray films might be a suitable approach to explore the disorganization of bone in osteoporosis.

and increased thereafter. In Caucasian boys, QUS parameters had a similar profile but increased two years later than girls. QUS parameters, in black child group increased at 11 yr in both sex. By Spearman’s correlation coefficient, in Caucasian girls, age, puberty, height, weight and physical activity influenced QUS parameters. In boys, SOS was influenced by age, height and weight. BUA wasn’t affect by these factors. In black child we didn’t observe correlation with any of the parameters analyzed. Diet didn’t influence QUS parameters in both groups. Conclusion: QUS is a good technique for measuring young people bone mass. However reference data ranges must be developed for each population. The factors that influences bone mass in different race and sex can be studied by QUS.

P384SA. IDENTIFYING OSTEOPOROSIS IN A COHORT OF SINGAPORE WOMEN USING A SIMPLE CLINICAL TOOL Koh LKH; Singapore General Hospital, Singapore The objective of this study was to determine if a simple scoring index for predicting osteoporosis among postmenopausal Asian women would apply to a cohort of Singapore women. The index had been developed previously, which achieved 91% sensitivity and 45% specificity, with AUC of 0.79, using only 2 variables (age and body weight). We applied this model to a cohort of 294 normal Singapore women aged 59 ± 7.4 years (range 50–89 years) who met the same inclusion criteria as the scoring index. The index based on age and weight was calculated for each subject, and ranged from –10 to 7. Based on the original scoring index cutoffs of –4 and –1, three osteoporosis risk categories were defined: 4% were categorized as high risk, 41% as moderate risk, and 55% as low risk. Forty-six percent of women with high risk, 10% with moderate risk, and only 1% with low risk had osteoporosis (femoral neck DXA T 4–2.5 SD). The index achieved a sensitivity of 90%, specificity of 58%, and AUC of 0.82. Using scoring index cut-offs of –3 and 0, the proportion of women was 10%, 54% and 36% and proportion having osteoporosis was 27%, 7% and 1% respectively for high, moderate and low risk categories. The scoring index had acceptable predictive ability for detecting osteoporosis. Different cut-offs on the index could be chosen for our population depending on whether testing more women, or having a higher yield for detecting osteoporosis was desired.

P385SU. PREDICTING OSTEOPOROSIS FROM RISK FACTORS WITH DATA MINING ENSEMBLE P383MO. QUANTITATIVE ULTRASOUND (QUS) OF THE CALCANEUS IN A PORTUGUESE YOUNG POPULATION Costa M, Nero P, Santos Z, Branco E, Branco J; Rheumatology Unit, Hospital Egas Moniz, Lisboa, Portugal Objectives: To determine the value range of QUS parameters for Portuguese children and adolescents by age, sex and race groups. Methods: The study included 758 healthy children (92.9% caucasian and 7.1% black) coming from four Lisboa schools. There were 411 (54.2%) girls and 347 (45.8%) boys. Mean age was 10.6+2.4 yrs, range 6-17 yrs. The Sahara Clinical Sonometer of Hologic was used to performed QUS measurement of the nondominant calcaneus. Patient examination was performed by two rheumatologists. All subjects filled out questionnaires about diet habits and physical activity. Statistical analysis, was done using SPSS version10. Results: BUA and SOS mean values were: 71.101+18.9 dB/ MHz, 1562.94+25.05 m/s. These parameters were significantly higher in black (p50.001) and no statistical differences between sex was found. In Caucasian girls, BUA increased from 12 to 14 yrs. SOS had an higher value at 7 yr, then a reduction until 12 yr

Rae S1, Wang W2; 1Dept. of Rheumatology, Bedford Hospital, Bedford, MK42 9DJ, UK, 2Dept. of Computing, University of Bradford, Bradford, BD7 1DP, UK Prediction of osteoporosis from risk factual assessment is gaining creditability [1]. In this research the ensemble methodology of artificial intelligence (AI) data mining techniques is explored to quantify the relevance of risk factors associated with osteoporosis and then predict the disease with the most salient risk factors identified. An ensemble, also known as multi-version system, is defined as a system that is composed of a number of models (namely versions) in order to achieve a better overall performance than that of individual models. The overall output is determined by a decision fusion strategy. The models were implemented by artificial neural nets in this research. The individual neural nets were trained with the half of the data we collected from 709 patients (mean age = 63.2, SD = 11.3) screened by QUS. Then two ensembles were constructed with those trained neural nets. The ensembles developed along with the individual versions were tested with another half of the data which is not used for training. Their performances were assessed with the ROC curves (shown

Abstracts

S117 Conclusions: Although BMD of both hips are correlated, a significant number of postmenopausal women without scoliosis have difference between both sides.

A) Femoral N B) Ward C) Troch D) Total Hip

43%

45%

410%

40.5 D.St

41.0 D.St

44.6% 44.6% 48.7% 34.0%

23.3% 20.0% 26.0% 12.7%

4.0% 4.7% 2.7% 1.3%

18.7% 8.7% 12.7% 6.7%

1.3% 0.7% 0.7% 0.7%

% of patients with difference between both sides

P387SA. COMPARISON OF THE PHALANGEAL ULTRASOUND AND DUAL ENERGY X-RAY ABSORPTIOMETRY IN THE ASSESSMENT OF THE SKELETAL STATUS OF ADOLESCENTS ROC curves of the ensembles (two multi-net systems: MNS1, MNS2) and logistic regression (L_Regr) for predicting osteoporosis. The Boolean outputs of the decision trees are plotted by scattered solid triangles.

in the Figure) and compared with other two methods, i.e. automatically induced decision trees and the conventional logistic regression. The solid suqare on the curve indicates the best decision threshold point which represents about 80% correct prediction for abnormal cases and 10% mis-predcition for normal cases. It is clear that the ensembles outperformed any of other two methods over the whole region. Thereby concern this type of AI technology is a suitable for prediction of osteoporosis from risk factors.

Reference 1. Black DM, Steinbuch M, Palermo L. et al. (2001): An Assessment Tool for Predicting Fracture Risk in Postmenopausal Women. Osteoporos Int 2001;12(7):519–528.

P386MO. DIFFERENCE OF BONE MINERAL DENSITY BETWEEN BOTH HIPS Mansur JL, Cianciosi MC; Centro de Endocrinologia y Osteoporosis, La Plata, Argentina Bone mineral density (BMD) of both hips is similar, not as in upper extremities, where the dominance of one of them explains the difference. Although BMD of both sides are highly correlated in same reports, it is not described how many people have significant differences. We prospectively study the BMD of both hips (Lunar Prodigy) of 150 postmenopausal women. The presence of scoliosis in the image of spine scans, and previous treatments with drugs that affect bone metabolism were exclusion criteria. We report the difference between both sides in 1) % and 2) T-Score, in four regions: A) Femoral neck (FN), B) Ward area (W), C) Trochanter (Troch), and D) Total Hip (TH). We study the group as a whole, and divided in tertils of age and weight. Results: n:150, age: 58.6 (9.0) years, Weight: 68.9 (14.0) Kg. Differerence mean: 3.84% in FN, 3.75% in W, 4.11% in Troch, and 3.08% in T.H.I.). Nearly half of patients have a difference 43%, and nearly 25% have a differnce 45% in FN (see Table) while in TH 34% and 13% have that differences.II). Dividing them in tertiles, women with more weight (471 Kg) have more difference between both sides in all regions (p40.01), and there were no difference in tertiles of age.

Konstantynowicz J1, Pluskiewicz W2, Halaba Z2, Kaczmarski M3, Jastrzebska J1; 1Department of Auxology and Pediatrics, Medical Academy, Bialystok, Poland, 2Metabolic Bone Diseases Unit, Silesian School of Medicine, Zabrze, Poland, 33rd Department of Pediatrics, Medical Academy, Bialystok, Poland The objective of the study was to compare the utility of quantitative ultrasound of the phalanges (QUS) and dual energy x-ray absorptiometry (DXA) for the evaluation of the skeletal status in adolescents. Materials and Methods: 164 healthy white subjects (93 boys and 71 girls) aged 14 – 19 years (mean age 16.7 ± 1.5) were examined with DXA (DPX-L Lunar) and QUS of the proximal phalanges (DBM Sonic 1200, Igea). The lumbar spine bone mineral density (S-BMD), total body bone mineral density (TBMD) and specially calculated regional bone mineral content of the arm (ARM-BMC) were measured and compared to the amplitude dependent phalangeal speed of sound (SOS). Anthropometric measurements and pubertal stage assessment according to Tanner were also carried out. Results: All densitometric variables correlated positively with age, height, body mass index (BMI) and, especially, with weight, whereas SOS was unrelated to weight but it correlated negatively with BMI (r = minus 0.32) only in girls. Tanner stage influenced bone mass based on DXA and SOS comparatively. Both, in boys and girls, SOS and T-BMD, as analyzed separately, showed comparable correlations with chronological age (r = 0.56 versus r = 0.55 in males; r = 0.42 versus r = 0.41 in females). SOS correlated positively with T-BMD and S-BMD uniquely in boys (r = 0.47 and r = 0.4 respectively). Such relationship was not found in girls. However, all subjects demostrated significant association between regional DXA results (ARM-BMC) and SOS (r ranged from 0.31 to 0.46). Conclusion: Although the results are incoherent in some aspects, the phalangeal QUS as a fast technique of good acceptance should be investigated furthermore in pediatrics and it could serve as the pre-examination for the assessment of skeletal status. DXA remains, at the moment, the best and most available densitometric method in adolescents’ medicine.

P388SU. COMPARISON OF THE USEFULNESS OF DIFFERENT TECHNIQUES AND MEASUREMENT SITES IN ASSESSING RISK FOR COLLES’ FRACTURE. Rodrı´guez M, Go´mez C, Naves ML, Ferna´ndez JL, Cannata JB; Bone and Mineral Research Unit, Intituto Reina Sofia de Investigacio´n, Hospital Central de Asturias, Oviedo, Spain Colles’ fracture is one of the most frequent and the earliest osteoporotic fracture. The aim of this study was to assess the odds ratio associated to axial and appendicular bone measure-

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Abstracts

ments using dual X-ray absorptiometry (DXA), quantitative ultrasounds (QUS) and digital X-ray radiogrammetry (DXR). We conducted a case-control study: cases were women 445 years and at least one year of menopause with Colles’ fracture in the previous six months, controls were age-matched from a based population sample (1 case: 2 controls). We included 28 cases (64±9 years) and 56 controls (63±9 years)in whom lumbar spine and hip DXA (Hologic QDR 1000), heel QUS (Sahara sonometer, Hologic) and contralateral forearm DXR (Pronosco system) were performed. The standardized odds ratios (OR) for predicting Colles fracture were calculated for the different techniques and measurement sites using logistic regression. As the table shows for DXA, femoral neck was the best and lumbar the worst predictor. For QUS, BUA was the best predictor and for DXR the cortical porosity achieved the highest value. In addition, in multivariate analysis porosity was the best predictor. Among the quantitative variables the femoral neck BMD was the stronger power to predict fracture. By contrast, BUA with the higher OR mean value but it was not the best predictor due to its high dispersion. These data indicate that all the tested methods, except lumbar spine – likely due to age related artifacts – were able to assess the increased risk for Colles’ fracture. Site

Method

OR related to Colles’ fracture (95% CI)

p value

F. Neck Total hip Lumbar Heel Heel Forearm porosity Forearm BMD Forearm striation

DXA DXA DXA BUA SOS DXR DXR DXR

1.89 (1.18–3.02) 1.65 (1.10–2.47) 1.28 (0.94–1.76) 2.00 (1.19–3.34) 1.59 (1.14–2.21) 1.65 (1.18–2.30) 1.41 (1.06–1.89) 1.49 (1.04–2.13)

0.007 0.01 0.12 0.008 0.007 0.003 0.02 0.03

P389MO. PQCT EVALUATION IN ADULT PATIENTS WITH OSTEOGENESIS IMPERFECTA (OI) Fracassi E, Gatti D, Braga V, Prizzi R, Rizzardi L, Adami S; Rheumatological Rehabilitation, University of Verona, Italy In patients with OI bone mineral density (BMD) as compared to age and gender-matched controls, was found low in some studies and normal in others. In most of these studies the bone densitometric results are expressed per unit area (areal BMD) rather than per unit volume (volumetric density). Since bone sizes are lower in OI patients, the areal density measurements underesteem the volumetric density and overesteem some mechanical properties. Quantitative computed tomography (QCT) is the only available method for directly measuring both cortical and trabecular density and the cross-sectional area of each component. In the table we list the data from DXA (spine and hip) and peripheral (pQCT) (ultradistal and proximal radius) measurements of 27 adult patients affected by OI, mostly of type I, compared with a group of healthy persons by age and sex. In the patients with OI areal BMD values at both femoral neck and lumbar spine were considerably lower than in control subjects (732 and 736% respectively) even after adjusting the values for both body weight and height. The patients with OI had lower trabecular bone density and lower bone mass at ultradistal radius, while the cortical bone density was normal. In conclusion it appears that the most obvious defect in adults with OI is the inability to maintain normal trabecular density and to acquire an adequate thickness of the cortices of long bone, possibly as the results of inadequate periosteal bone growth resulting in marked diminution of bending strength (BBRI).

PQCT

normal (41)

Total ultradistal radius Density (mg/cc) Trab. ultradistal radius Density (mg/cc) Area ultradistal radius (mm2) Cortical proximal radius Density (mg/cc) Area proximal radius (mm2) Cortical Area proximal radius (mm2) Cortical thickness (cm) BBRI (cm3)

423,6 ± 60,3 342,2 ± 80,0 216,4 ± 45,0 146,8 ± 52,4 315,4 ± 82,6 302,7 ± 71,7 1127,5 ± 40,3 1143,1 ± 53,9 128,7 ± 38,7 99,2 ± 25,9 94,5 ± 16,0 73,6 ± 14,3 0,33 ± 0,05 0,28 ± 0,04 1,96 ± 0,74 1,34 ± 4,47

groupo.i. group (27) % p Change –19% –32%

–23% –22% –15% –32%

50.0001 50.0001 N.S N.S. 50.005 50.0001 50.005 50.0001

P390SA. DXA-DUAL FEMUR SCAN AND SIDE DIFFERENCESINFLUENCE OF WEIGHT-BEARING LOAD? Kasalicky P1,2, Rosa J1; 1MEDISCAN Diagnostic Center, Prague, Czech Republic, 2Postgraduate Medical School, Prague, Czech Republic Problems concerning side differences in BMD results of peripheral skeleton have been discussed since various densitometric techniques were introduced into clinical practice. The bone densitometry evaluation result may be strongly affected by the selected extremity. Left extremities are generally accepted as standard for the BMD evaluation. Based on our experiences with considerable side differences of QUS results and taking into account a possibility of simple dual femur scan measurement with Lunar Prodigy densitometer, we decided to measure both femurs routinely. In the sample of 4484 patients we found no statistical differences between T-score of left and right total proximal femur. However, considerable individual differences were observed. The other aim of our investigation was to test the hypothesis that the observed BMD side difference in some patients could be explained by different weight-bearing load on the extremities, for which our method of two scales was used. For detection of difference in side weight-bearing load as potential cause for this difference we used our method of two scales previously used for QUS measurement. Weight distribution was measured by patients standing on two scales (each leg on one scale, with marked weight on each scale), with request to stand as they are used to. By this method we evaluated 2659 patients. Correlation coefficient of T-score side differences (total proximal femur and femoral neck) and weight–bearing load differences was r = 0.06, what was not considered as statistically significant result. So, according our results, side differences in BMD results of left and right proximal femur can not be explained by the differences in weight-bearing load, assessed by the method of two scales.

P391SU. INDICATIONS AND INTERPRETATIONS OF BONE DENSITOMETRY IN THE REGION OF NORTH HOLLAND Staal KP, Roos JC, Manoliu RA, Kostense PJ, Lips P; Free University Medical Center, Amsterdam, The Netherlands Aims: To assess the differences between hospitals in bonedensitometry in North-Holland we studied the indications and interpretations of bone-mineraldensity (BMD) measurements. The findings compared with existing guidelines for osteoporosis will give information on the use and usefulness of these guidelines. Methods: In 12 hospitals in North-Holland we studied the indications as given by the referring doctor, the results of the bonedensitometry and the interpretations of it. This was done in 100 adult patients per center who came for a first measurement before 1 december 1999. The patients were, based on the Tscores of the corresponding DXA-machine and according to the WHO guidelines, divided in 3 groups.

Abstracts

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Results: Up until now 850 female patients were analysed. Of them 48.3% were referred by a general practitioner and 51.7% by a specialist. Osteoporosis was diagnosed in 243 (28.6%) and osteopenia in 356 (41.9%) patients. Normal BMD had 251 (29.5%) women. The rate of osteoporosis was similar in patients referred by a general practitioner or a specialist. The most common indication was lower backpain in the general practitioners (66%) and corticosteroid use (30%) in the specialists. The indication ‘osteoporosis?’ was the most common one (80 cases, 16,5%). Twentyfour of those patients had really osteoporosis. With regard to the reports there was no T-score mentioned in 50% of the cases. The diagnosis according to the criteria of the WHO were missing in 15.6% of the reports. The indication which resulted in the highest rate of osteoporosis (51.9%) was osteoporoticfracture. Conclusion: The diagnosis according to the WHO was missing or incorrect in 15.6% of the reports. The T-score was absent in 50% of the cases. The medical specialists referred more patients at risk because of treatment or concomitant disease and the general practitioners referred more patients with indications as lower backpain, positive family history and early menopause.

P392MO. PREDICTION OF FEMUR FRACTURE BY RADIAL BENDING BREAKING RESISTENCE DERIVED FROM DXA

P393SA. BONE MINERAL DENSITY IN LUMBAR SPINE AND FEMORAL NECK IN RUSSIAN HEALTHY WOMEN Toroptsova N, Demin N, Benevolenskaya L; Institute of Rheumatology, Moscow, Russia Aim: To generate standard curves for bone mineral density (BMD) in healthy Russian women. Method: A study using dual-energy X-ray absorptiometry (DXA, Hologic QDR 4500A) was performed in 394 healthy women aged 15-80 years. The general inclusion criterion was that the subjects should be healthy (if they had any condition affecting bone metabolism or were treated with the drugs affected bone mineralization, they were excluded from the study) and belong to the age groups specified in the sample. Results: The highest value for lumbar spine BMD was found within the 25–34 years age group –1.026 g/cm2, being significantly lower before 25 years and after the age 45 years. The rate of loss of bone mass between 45 and 74 years was 8,8%. The highest value for femoral neck BMD was found in age group less 25 years old –0.842 g/cm2, being significantly lower after the age 55 years. The rate of loss of bone mass between 45 and 80 years was 18.38%. We compared BMD values of healthy Russian women with reference data base of Hologic QDR 4500 based on z-score and found out that our sample of healthy women differed from that data base both in lumbar spine and femoral neck. Conclusion: We received first data on normal bone mass values of lumbar spine and femoral neck in healthy Russian women using dual-energy X-ray absorptiometry.

Gatti D, Braga V, Sartori E, Rossini M, Adami S; Rheumatological Rehabilitation, University of Verona, Italy Bone Mineral Density (BMD) measurement by dual X-ray absortiometry (DXA) is considered the best predictor of fracture risk. BMD takes into account only in part the bone cross-sectional area that is an important determinant of both bone compression strength and of bending breaking resistance. From DXA measurements of proximal radius (Osteoplan1, NIM, Italy) we obtained the projected outer diameter (D) and the mean diameter of the medulla (d), by an algorithm based on the assumption of a constant cortical volumetric density of 1050 g/cm3. The algorithm was validated by the good correlation found (r = 0.8) between calculated d and that actually measured by peripheral quantitative tomography pQCT (XCT 960; Stratec, Italy) at the same radial site. The D and d values were used to calculate a bending breaking resistance index (BBRI = (D4-d4/D)’s). In sixty-eight women with either previous femoral neck (no. 41) or pertrochanteric fracture (no. 27) DXA measurements at proximal and ultradistal radius, lumbar spine and femoral neck were obtained together with the evaluation of proximal radius BBRI. In the table we report the Z- score values for bone measurements and ODD Ratios for a 1 SD decrease in radial measurements adjusted for age in women with hip fracture. Our study shows that the diagnostic accuracy for femoral neck fracture of BBRI was somewhat comparable to that of spine and femoral neck BMD and significantly superior to that of ultradistal and proximal radius BMD and gives additional support to the importance played by that bone geometry, particularly for compact skeletal segments. All hip fractures

Distal R. Proximal R BBRI Spine F. Neck

Neck fractures

Z-score (SD)

Proportion O.R. (95%CI) with Z-score50

Z-score (SD)

Proportion O.R. (95%CI) with Z-score50

–0,20 ± 1,15 –0,64 ± 1,19 *** –0,68 ± 1,02 *** –0,88 ± 1,32 *** –1,02 ± 1,12 ***

62% 72% 80% 67% 80%

+0,04 ± 1,07 –0,31 ± 0,95 * –0,75 ± 0,90 *** –0,77 ± 1,15 ** –0,76 ± 0,86 ***

59% 63% 80% 68% 80%

0,82 (0,57–1,17) 1,09 (0,87–1,37) 2,04 (1,26–3,31)

* = p50,05; ** = p50,01; *** = p50,001 versus zero.

0,80 (0,52–1,23) 1,16 (0,88–1,54) 3,01 (1,61–5,62)

P394SU. ESTIMATION OF BONE MINERAL DENSITY WITH THREE COMMERCIAL ULTRASOUND INSTRUMENTS Saarakkala S1, Jurvelin JS2, Kro¨ger H1, To¨yra¨s J2; 1Department of Surgery, Kuopio University Hospital, POB 1777, FIN-70211 Kuopio, Finland, 2Department of Applied Physics, University of Kuopio, POB 1627, FIN-70211 Kuopio, Finland Aims: Several ultrasound instruments have been introduced for clinical analysis of bone quality. Bone size affects both ultrasound and DXA parameters and may improve correlations between these methods. Methods: In this study three commercial ultrasound instruments (Achilles+, UBIS 5000 and Sahara (only in vivo)) were compared. The ability of these instruments to estimate BMD of human bone in vivo (n = 121) and bovine bone in vitro (n = 35) was evaluated. In addition, effect of bone size on the reliability of measurements was investigated by calculating size corrected ultrasound and DXA parameters. Ultrasound parameters were corrected based on the subject height (Wren et al. 2000, Proceedings of 2nd VA National Department of Veterans Affairs Rehabilitation Research and Development Conference), while DXA parameters were corrected along Kro¨ger et al. 1992 (Bone and Mineral,17:75–85). Results: In vivo, values of calcaneal BUA and SOS were different although linearly correlated (BUA: r = 0.56–0.65, SOS: r = 0.78–0.87) between instruments. In vitro, correlations were 0.62 and 0.96 for BUA and SOS, respectively. In vivo, correlations between US parameters and BMD in calcaneus, femoral neck and lumbar spine (L2-L4) were 0.62–0.64 (BUA, calcaneus), 0.31–0.38 (BUA, femoral neck), 0.44–0.52 (BUA, spine), 0.59–0.67 (SOS, calcaneus), 0.38–0.43 (SOS, femoral neck) and 0.41–0.46 (SOS, spine), respectively. In contrast to human bone BMD-BUA relation was negative in high density bovine bone. When the size corrections were introduced the correlations between DXA and US parameters decreased systematically. Correspondingly, subject height and shoe number showed positive linear correlations (r = 0.34–0.36) with BMD in femoral neck or spine. Conclusions: Present study suggest that the absolute values of US parameters are different although moderately correlated between instruments. SOS was found to be superior over BUA in prediction of BMD. Our results suggest that correlations

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Abstracts

between BMD and BUA or SOS may be partially transmitted through the size dependence of DXA and US parameters.

P395MO. FRACTAL ANALYSIS OF TEXTURE ON BONE RADIOGRAPHS: CHANGES IN MALE OSTEOPOROSIS AND INFLUENCE OF ITS RISK FACTORS Lespessailles E, Courteix D, Perrin E, Benhamou CL; Equipe INSERM ERIT-M 0101, Orle´ans, France The respective roles of trabecular bone microarchitecture alterations and bone loss in male osteoporosis (OP) are debated. We have developed a fractal analysis of texture on bone radiographs, and validated its close relationships with the 3D microarchitecture. The objective of this study was to evaluate the influence of male OP and its risk factors on BMD and on the fractal parameter Hmean. The calcaneus radiographs were very standardized and the analysis was performed using the maximum likelihood estimator applied to the Fractional Brownian Motion model. 31 fracture cases (vertebrae, hip, radius or miscellaneous) were compared to 171 control cases. The Hmean value was significantly lower in OP (0.686 ± 0.035) versus controls (0.702 ± 0.032) : p = 0.01. There was 33.3% of fractures in the upper tertile of Hmean versus 12.9% in the two lower tertiles. The correlation with age was low (r = –0.22) but significant (p = 0.0006) in the global population. The influence of Body Mass Index (BMI) was of similar amplitude (r = –0.19, p = 0.002), as well as alcohol use (r = –0.26, p = 0.0009). In a multiple regression analysis the factors explaining Hmean were first alcohol, second BMI then age. The femoral neck BMD was lower in OP versus controls : 0.684 ± 0.15 g.cm2 versus 0.842 ± 0.14 g.cm2 (p50.0001). The combination BMD Tscore 5–2.5 + lower tertile of Hmean improved the Odds Ratio of fracture versus other combinations. In conclusion, the fractal parameter of texture Hmean was lower in case of male OP and the risk factors of male OP significantly influenced this parameter. It could be an useful parameter to assess the probability of fracture in association to BMD.

P396SA. BONE MINERAL DENSITY OF PORTUGUESE POPULATION BY QUANTITATIVE ULTRASOUND Vilar A, Micaelo M, Simoes E, Oliveira F, Vaz Patto J; Metabolic Bone Diseases Unit – Portuguese Institute of Rheumatology – Lisbon, Portugal Quantitative Ultrasound (QUS) it is becoming widely used for screening and surveys of osteoporosis. No reference data is available yet for Portuguese population. We describe here the first attempt to get normative data of Portuguese woman with QUS. A randomly nationwide survey was held through 14 locations representing an appropriate selection of cities as described elsewhere. The inclusion criteria were caucasian woman between 20 and 80 years old without previous fracture of calcaneus or menopause before 45 years. An interview with questionnaire regarding demographic data, nutritional habits, diseases and medications known to affect bone mineral metabolism, maternal history, estrogen status or fragility fractures were recorded. In 501 women height, weight, body mass index, right calcaneal QUS to assess SOS, BUA, QUI and estimated BMD was also performed. For each age group we calculated the Mean and its 95% Confidence Interval. A short term precision test (Glu¨er et al.) for QUS was conducted in 28 individuals to determine precision error and coefficient of variation that were 0.012 g/cm2 and 2.1%. We analyse patient group and subgroups and drug use by age. We tested probability and independence of SD for all ages and then pooled SD to determine the reference ranges for all subjects.

In Figure 1 we present Portuguese caucasian females results. For this heel QUS study our population reference data stands among the European and when pooled together the European data were slightly inferior to the USA reference data.

P397SU. IDENTIFYING OSTEOPOROSIS IN A COHORT OF ASIAN MEN USING A SIMPLE CLINICAL TOOL WHICH IDENTIFIES OSTEOPOROSIS IN ASIAN WOMEN Koh LKH; Singapore General Hospital, Singapore The objective of this study was to determine if a simple scoring index for predicting osteoporosis among postmenopausal Asian women would apply to a cohort of Asian men. The index had been developed previously, which achieved 91% sensitivity and 45% specificity, with an AUC of 0.79, using only 2 variables (age and body weight). We applied this model to a cohort of 98 normal Asian men aged 61 ± 8.8 years (range 50–88 years). The index based on age and weight was calculated for each subject, and ranged from –7 to 8. Based on the original scoring index cut-offs of –4 and –1, 3 osteoporosis risk categories were defined: 4% were high risk, 24% moderate risk, and 72% low risk. Using the male threshold for osteoporosis, DXA FN BMD T4–2.5 SD (MT), 75% of men at high risk, 26% at moderate risk, and 13% at low risk had osteoporosis. At a cut-off of 4–1, sensitivity was 50%, specificity was 78%, and AUC was 0.71. Using the female threshold for osteoporosis (FT), the proportion having osteoporosis was 75%, 9% and 4% for high, moderate and low risk categories respectively. Using the same cut-off of 4–1, sensitivity was 63%, specificity was 76%, and AUC was 0.84. Using a cut-off of 40, sensitivity increased to 72% with MT and 100% with FT. The scoring index developed for Asian women had some predictive ability for detecting osteoporosis in Asian men. The index performed somewhat better if the female threshold for osteoporosis, and a higher scoring index cut-off was used.

P398MO. DISCREPANCY BETWEEN AGE ADJUSTED BONE MINERAL DENSITY VALUES OF THREE REGIONS IN THE UPPER FEMUR Hadjidakis D, Mylonakis A, Katsavochristos P, Sfakianakis M, Raptis SA; 2nd Department of Internal Medicine, «Evangelismos» and «Evgenidion» Hospitals, Research Institute and Diabetes Center, Athens University, Athens, Greece In the upper femur femoral neck (FN), trochanter (TR) and Ward’s triangle (WD) are areas with different bone structure and degree of loading. Age adjusted BMD values (z scores) of these areas are expected to be near zero at any age. Aim: To investigate major discrepancies between z scores of FN and the other 2 areas. Methods: Out of a population of 1178 healthy postmenopausal women with measurements of upper femur BMD, 214 (18.2%) presented either TR or WD z score values at least 1.5 SD different from FN z score in either direction. Four groups were created, group TR(–) (z score TR5FN, n = 75), group TR(+) (TR4FN, n = 31),

Abstracts group WD(–) (WD5 FN, n = 14) and group WD(+) (WD4FN, n = 94), aged 67.3±7.5, 61.3±8.2, 70.4±8.7 and 55±5.6 yrs (mean value±1SD) with years since menopause (YSM) 18.2±8.6, 12.4±6.1, 19.7±8.6 and 6.4±3.2 respectively. Results: TR(–) represented 71% of total TR discrepancies while WD(-) only 13% of total WD discrepancies. TR(–) and WD(–) had significantly higher age and YSM than TR (+) and WD(+) (p50.05 and 50.01 respectively). TR(–) and TR(+) FN BMD and z score values didn’t differ significantly while WD(–) FN BMD and z score were significantly higher than WD(+) (BMD = 0.856±0.220 vs 0.727±0.128 gr/cm2, z score = 1.15±1.8 vs –0.76± 1.14 SD, p50.05). BMI values didn’t differ significantly between groups. Conclusions: A remarkable proportion of postmenopausal women present major discrepancies between z score values of FN, TR and WD. In early postmenopausal ages, when FN z score is low, TR and WD z scores are often favoured. In the older female population with a positive FN z score behaviour, TR and WD z scores didn’t behave similarly. BMI doesn’t seem to influence the relative behaviour of z score at the 3 areas.

P399SA. OSTEOPOROSIS AND NEUROLOGICAL IMPAIREMENT: COMPARING TWO METHODS OF BONE ASSESSMENT Abou Jaoude PA1, El Hage AN2, Hadji PE3, Maalouf GH4; 1 Orthopaedic Surgeon Lebanese College for Handicapped, Beit Chabab, Lebanon, 2Physiatrist Lebanese College for Handicapped, Beit Chabab, Lebanon, 3Departement of Gynecology and Obstetrics, University of Marburg, Germany, 4 Orthopaedic Surgeon St Georges University Hospital, Beirut, Lebanon Objective: To compare the results of bone mineral density (BMD) measured by dual emission x-ray absorptiometry and calcaneal ultrasound (CUS) in a population of physically disabled people in order to determine the reliability of US. Methods: Sixty-one patients being treated at a rehabilitation center had CUS measurements. They had various neurological impairements of variable duration. Only thirty-four of them (13 F, 21 M) could have the DEXA measurements, which were performed at a general hospital. Only their measurements were used for the comparison. Results: The average for males was –2.4 and –2.5 respectively for CUS and DEXA, with the correlation coefficient r = 0.73. For females the figures were –3.0, –3.2 and r = 0.86. Those figures were obtained after excluding patients with other hip conditions that affect DEXA measurements (heterotopic ossification, hip replacement surgery, excision of proximal femur). Conclusion: CUS is a valid method for assessing osteoporosis in people with motor impairments. It is the preferred method in our population because of the lower cost, the easier accessibility, and the higher accuracy in the presence of hip problems that preclude the use of DEXA (heterotopic ossification, hip replacement surgery, excision of proximal femur).

S121 variation of more than 2 kg. The absolute weight variation (better than the percentage) was significantly related to the DXA hip change (delta % BMD total hip = 0.5 + 0.3 x kg of weight variation; p50.01), while there was not any correlation with the spine DXA changes. The hip BMD variations were significantly correlated with the spine BMD only in subjects with weight variations under 2 kg. Conclusions: Weight variations are not rare and are related to significant changes in DXA BMD at the hip. These variations, especially if over 2 kg, can justify discrepancies between the densitometric changes of the hip and the spine. The hip BMD variations found after even minor weight gain can be the same as those observed after some specific pharmacological treatments for osteoporosis and they should be kept into account in the analysis of the results of pharmacological trials. Parameters

Mean

SD

Range

Age, years Years since menopause Weight, kg BMI, kg/m2 T score hip T score spine

65 18 60 24 –2.1 –2.5

9 9 8 3 0.8 1.0

42–84 1–42 41–80 18–32 –4/–0.1 –5.1/+0.7

P401MO. PHYSICAL ACTIVITY MAY INDUCE REVERSIBLE LOW BONE MASS IN UNLOADED AND HIGH BONE MASS IN WEIGHT-LOADED SKELETAL REGIONS Karlsson KM, Magnussson H, Linde´n C, Karlsson C, Obrant KJ; Department of Orthopaedics, University Hospital MAS, SE 205 02 Malmo, Sweden Aims: To evaluate bone mineral density (BMD) in unloaded, partly loaded and weight-loaded skeletal regions in active and retired athletes. Methods: BMD (g/cm2) was measured by dual X-ray absorptiometry (DXA) in the upper part of the skull (unloaded region), the arms (partly loaded region) and the femoral neck (loaded region) in 67 active soccer-players, mean age 23 years, 128 former soccer-players, mean age 54 years and 138 controls, mean age 51 years. The active soccer-players exercised on three levels mean 12, 8 and 6 hours/week, respectively. The controls exercised mean 2 hours/week. Data is presented as mean (SD). Results: Active soccer-players had 10 (10)% lower BMD in the upper part of the skull (p50.001), 1 (6)% higher BMD in the arm (NS) and 13 (10)% higher BMD in the femoral neck (p50.001) compared to age- and gender-matched controls. All three levels of soccer-players demonstrated, independent of activity level, the same discrepancies in BMD compared to controls. Former soccer-players had across age lower BMD in the upper part of the skull until age 70 and higher BMD in femoral neck until age 50 as compared to controls. The BMD of the arm was independent of age no different in former soccer-players compared to controls. Conclusions: Unloaded and weight-loaded skeletal regions may respond differently to increased and decreased physical activity. No residual high BMD are found in weight-loaded skeletal regions after age 50 in former male soccer-players.

P400SU. WEIGHT AND DXA CHANGES IN THE FOLLOW-UP Rossini M1,3, James G1,2, Girardello S1,2, Gatti D1,2, Colapietro F1,2, Biasiucci R1,3, Adami S1,2; 1Osteoporosis Center, Verona, Italy, 2University of Verona, Verona, Italy, 3ASL of Verona, Verona, Italy Aims: We evaluated the variations of body weight and the correlations with the DXA changes at the hip and spine level. Methods: 116 postmenopausal women without specific treatments for osteoporosis were reanalyzed with DXA scan (Hologic QDR2000) after one year. Results: At a years distance 39% of the subjects presented weight variations of less than 1 kg; 43% had a weight variation of 1–2 kg in excess or defect; the remaining 18% had a weight

P402SA. THE EFFECT OF BISPHOSPHONATES ON THE BONE MINERAL DENSITY VALUES OF BONES AFFECTED BY PAGET’S DISEASE Donath J, Poor GY; National Institute of Rheumatology and Physiotherapy, Budapest, Hungary Aims: To study the bone mineral density/BMD/in patients with Paget’s disease of bone and to measure the changes in BMD treated with bisphosphonate. Methods: Dual energy X-ray absorptiometry/DXA/scans on affected and unaffected vertebrae and femoral necks were carried out in 30 patients (12 females: 1 monostotic, 11

S122 polyostotic, mean age 73,0; 18 males: 6 monostotic, 12 polyostotic, mean age 72,0) with Paget’s disease of bone at baseline and 12 months after the start of the treatment.The treatment was pamidronate 30 mg/day for 6 days (13 patients) and tiludronate 300 mg/day for 90 days (17 patients). BMD was measured on pagetic and non-pagetic vertebrae and on pagetic and non-pagetic femoral necks. Results: The BMD values of pagetic vertebrae were significantly higher than the BMD of the non-pagetic vertebrae. Both pagetic and non pagetic vertebrae showed a statistically significant increase in BMD values after treatment. There were no significant differences between the BMD values of the pagetic and nonpagetic femora. Both pagetic and non-pagetic femora showed a significant increase in BMD values after treatment. Conclusions: The BMD values of bone affected by Paget’s disease can be increased both on femora and vertebrae by bisphosphonate treatment. This could decrease the higher fragility of bones observed in Paget’s disease.

Abstracts Methods: A group of 115 girls (11 ± 1.5 years; 142.4 ± 9.9 cm; 34.9 ± 8.3 kg) was studied. Some of them had regular physical activity. Bone mineral content was measured at the lumbar spine, non dominant hip and forearm using DEXA. All subjects were prepubescent with respect to the Tanner’s criteria. Androstenedione and S-DHEA were measured in a 24-hours urinary collection. Results and Discussion: S-DHEA and androstenedione correlated with BMC at all the sites (table) accordingly to previous studies done in adults. But in this study, androstenedione was more linked to BMC than S-DHEA, unlike in adults. Conclusion: In our young subjects, androstenedione and SDHEA is weakly linked to the bone mineral content. These data suggest that androgens can influence the bone mass acquisition during the prepubertal period. BMC (g)

Androstenedione (nanomol/24 hrs)

p

S-DHEA (nanomol/24hrs)

p

Lumbar spine Femoral neck Mid radius

r = 0.41 r = 0.37 r = 0.46

0.001 0.001 0.001

r = 0.30 r = 0.30 r = 0.30

0.01 0.01 0.01

P403SU. OSTEOPOROSIS IN POSTMENOPAUSAL SAUDI WOMEN USING DUAL X-RAY BONE DENSITOMETRY Desouki MI; King Khalid University Hospital, Riyadh, Saudi Arabia Objective: A pilot study to estimate the prevalence of osteopenia and osteoporosis in postmenopausal Saudi women. Methods: Lumbar spine bone density was measured in 802 postmenopausal Saudi women 50-80 years of age (average 59 years), using dual x-ray absorptiometry (DXA). Results: The results of the bone mineral density (BMD) in gm/ cm2 were compared to the peak bone density (PBD) in healthy young women (T-score). Based on the definition of World Health Organization (WHO), the T-score value was considered for analysis. Accordingly, 234 (29%) subjects showed normal result, mean bone mineral density of 1.117 ± 0.11, T-score of –0.66 standard deviation; 247 (31%) subjects showed osteopenia, mean bone density of 0.983 ± 0.11 and T-score of –2.4 standard deviation while 321(40%) subject showed osteoporosis, mean bone mineral density of 0.767 ± 0.11 and T-score of –3.4 and standard deviation. When the 802 subjects were analyzed by decades, there were 42% normals, 34% osteopenia and 24% osteoporosis in age 50–59 years, 11% normals, 27% with osteopenia and 62% with osteoporosis in age 60-69 years while in older age 70–79 (only 4.62% had normal BMD, 21.5% had osteopenia and 73.8% had osteoporosis. Conclusion: Osteopenia and osteoporosis are common among postmenopausal Saudi women and should be considered a matter of public health. Bone densitometry should be used to assess the severity of bone loss, identify those who need therapy and for follow up and early diagnosis of those with osteopenia in order to institute proper therapy and avoid future osteoporosis.

P404MO. RELATIONSHIPS BETWEEN ADRENAL ANDROGENS AND BONE MASS IN PREPUBESCENT FEMALES. Jaffre´ C1, Benhamou CL2, Courteix D1,2; 1Laboratoire de la performance motrice, Orle´ans University, France, 2IPROSINSERM ERIT-M 0101, Orle´ans, France During the last years, the research on osteoporosis aimed to prevent the bone loss by increasing peak bone mass during childhood. The best period for bone mass acquisition is puberty. In this period, sex steroid hormones have major beneficial effects on the development of the skeleton. But, the role of the adrenal androgens (mainly androstenedione and S-DHEA) remains uncertain in a prepubertal female population. Aim of the study: To evaluate the relationships between the androstenedione and S-DHEA urinary concentrations and the bone mineral content (BMC) in prepubertal females.

P405SA. BONE MINERAL DENSITY (BMD) IS NOT LOW IN ACUTE STROKE: NEITHER IS BONE AT THE HEEL, NOR LEAN MASS ON THE STROKE SIDE, LOST IN THE FIRST 12 WEEKS AFTER STROKE Davie MWJ1, Haddaway MJ3, Bainbridge N1, Hill SN2; 1Charles Salt Centre for Human Metabolism, Robert Jones & Agnes Hunt Orthopaedic & District Hospital, Oswestry, UK, 2Department of Geriatric Medicine, School of Postgraduate Medicine, University of Keele, UK, 3Department of Diagnostic Imaging, Robert Jones & Agnes Hunt Orthopaedic & District Hospital, Oswestry, UK About 10% of hip fractures occur in stroke patients. We previously found that calcaneal ultrasound BMD was bilaterally low in female stroke patients. More recently low heel BMD was found in females with acute stroke. We have therefore studied BMD in males and females with acute stroke. BMD was measured in both heels of 25 acute stroke patients, using the PIXI at 4 (±2) wk post stroke, and repeated 8 weeks later together with DXA scans of both hips and whole body. 10 females (age 75, range 64–93 yrs) and 15 males (73, 60–85 yrs) were recruited. Results were expressed as BMD or z-score for the Stroke affected (SS) or Non-Stroke (NS) sides. The initial heel scan showed no difference in BMD z-score between SS and NS for females, but SS in males was lower than NS (p = 0.03). Mean BMD z score at the heel in females (SS and NS) was 0.66 and 0.96; in males 0.69 and 0.89: at femoral neck, females 0.45 and 0.39; males 0.28 and 0.14. The first PIXI scan correlated with femoral neck DXA (SS:r = 0.72; NS:r = 0.76). Heel BMD did not change between scans in either sex. Upper limb BMC was lower in the left side (females p = 50.01; males p = 0.02), but the difference no longer existed when adjusted for side of stroke. Neither BMC nor lean mass of the lower limbs was significantly different between SS and NS sides at 10–12 weeks after stroke. Conclusion: Initial heel BMD z-score was not lower on SS in females but was in males. Neither heel nor femoral neck BMD is low in acute stroke. Heel BMD did not change over 8 weeks and is a surrogate for femoral neck BMD. Lean mass is not lost over the first 10 to 12 weeks after stroke on SS compared with NS.

P406SU. CORRELATION BETWEEN LUMBAR AND VARIOUS FEMORAL SUBREGIONS BMD IN TREATED OSTEOPOROTIC WOMEN Di Stefano M, Isaia GC; Department of Internal Medicine, University of Torino, Italy Aim: To evaluate the correlation between lumbar and femoral bone mineral density (BMD) changes induced by pharmacological treatment in osteoporotic women.

Abstracts Methods: We studied 80 women (age range 52–71 years) with postmenopausal osteoporosis; we examined on the same day both lumbar and femoral BMD at baseline and after 12 and 24 months of regular treatment with various drugs (raloxifen, clodronate, calcium plus vitamin D) affecting phosphocalcium metabolism. Results: After 24 months of treatment, we observed a mean increase of 1.61% of lumbar BMD vs baseline (p50.005), while femoral BMD did not show any significant increase vs basal values. The results obtained (which were expressed as rate of change for year of treatment from baseline, both in terms of absolute and percentage values) at lumbar level and at femoral subregions (neck, trochanter, intertrocanteric region, total, Ward’s triangle) level were correlated by using Pearson’s r correlation coefficient. We observed the better correlation among the rate of change of lumbar BMD and the rate of change of femoral BMD for total subregion (r = 0.299, p50.05 at 12 months, r = 0.36, p50.05 at 24 months), while Ward’s triangle showed the worst correlation (p = n.s.). We observed highly statistically significant correlation between rate of change/year among the femoral subregions, mainly after 24 months of treatment in respect of after 12 months. Conclusions: Our data suggest that pharmacologic treatment of osteoporosis can play a different role on BMD at lumbar and at femoral level; total BMD can be considered the best femoral site for DXA follow up and a duration of 24 months of treatment allows us a more omogeneous evaluation than 12 months about femoral BMD change.

P407MO. COMPARISON BETWEEN DUAL X-RAY ABSORPTIOMETRY AND QUANTITATIVE ULTRASOUND PARAMETERS IN DIFFERENT POPULATIONS Bernardes M1, Pereira S2, Valente P1, Bernardo A1, Mariz E1, Branda˜o F1, Cardoso A1, Vaz C1, Pereira J3, Lopes-Vaz A1; 1 Rheumatology Department, S. Joa˜o Hospital, Porto, Portugal, 2 Department of Hygiene and Epidemiology, porto Medical School, 3Nuclear Medicine Department, S. Joa˜o Hospital, Porto, Portugal Background: The quantitative ultrasound (QUS) is a new technique approach to assess both bone quality and density. The association between QUS and dual X-ray absorptiometry (DXA) is still controversial, such that it remains unclear whether a QUS measurement is simply a surrogate for bone densitometry, or whether the future of the technique depends on this ability to provide structural information or enhanced fracture prediction. Objective: The aim of this study was to evaluate the correlation, agreement, sensitivity and specificity between DXA and QUS parameters in healthy women and in patients with diseases that interfere with bone metabolism. Methods: Calcaneal QUS parameters (Osteometer DTUone) and DXA (LUNAR Expert 1320) at the lumbar spine and proximal femur were measured in 184 healthy women randomly selected from community and seven different pathological groups selected from hospital outpatient clinical routine (50 rheumatoid arthritis, 63 SLE, 57 former hyperthyroid patients, 42 asthmatics, 11 cardiac transplants and 24 hepatic transplants). Results: In healthy controls the correlation between QUS and DXA was statistically significant for all evaluated parameters and ranged from 0.33 to 0.55, p50,001. In the pathological groups evaluated, the correlation remained similar and statistically significant. The agreement between QUS and DXA in healthy controls was strong and statistically significant, particularly at the lumbar spine (K agreement ranged 0,90 to 0,97), and the sensitivity and specificity between the QUS measurements and DXA, at the femur and lumbar spine, were close to 100%. Only in the former hyperthyroid patients, the agreement between QUS and DXA was poor (K agreement ranged 0,18 to 0,56). Conclusions: QUS and DXA measurements were well correlated in all different groups. We conclude that QUS was a

S123 reasonable method to differentiate between osteoporosis and non-osteoporosis when we take DEXA as a gold standard.

P408SA. REGIONAL STRUCTURAL SKELETAL DISCORDANCE ASSESSED BY MEASURES OF COMPLEXITY Gowin W1, Saparin P1, Felsenberg D1, Kurths J2, Zaikin A2, Prohaska S3, Hege HC3; 1Free University, Berlin, Germany, 2 Institute of Physics, University of Potsdam, Germany, 3KonradZuse Institute, Berlin, Germany Aims: The aim of the study was to compare the structural composition of trabecular bone as well as of the whole bone at six different skeletal regions. The bones’ composition was evaluated by measures of complexity. Methods: Bone specimens of thirty human cadavers were examined. The distal radius, the proximal tibia, the vertebral body L3, the femoral neck, the calcaneus, and the midshaft of the humerus were scanned in high resolution mode (20 x 20 micro-m) in 1 mm slice thickness on a XCT-2000 scanner (Stratec, Germany). The acquired images were numerically segmented into trabecular and cortical bone areas using previously described preprocessing techniques. Symbolic dynamics were applied to the images in order to receive simplified and easy to analyze symbol-encoded images. After this image-processing procedure, the segmented data sets were evaluated by five different measures of complexity. The BMD was measured as well. Results: The numerical architectural complexity at each skeletal region is different. Although there is a interpersonal variation affecting all skeletal regions, the variation from region to region is greater. The highest interpersonal variation was found in the calcaneus. Conclusions: The discordance of architectural composition at different skeletal regions can be accurately calculated by measures of complexity. The architectural composition of bones depends among other factors on genetic programming as well as on biomechanical load conditions. Despite of the regional discordance, the bone structure at all six skeletal regions follows the same general rule: Loss of bone density occurs simultaneously with a rapid decreasing structural complexity. This transition is accompanied by an increased degree of disorder within the bone architecture at intermediate bone densities. The high interpersonal variation of structure within the calcaneus is evidence of the difficulties to standardize quantitative measurements at this skeletal site.

P409SU. BONE DENSITY OF THE SPINE AND FEMUR IN ARABIAN WOMEN: RELATION TO QUANTITATIVE ULTRASOUND OF THE CALCANEUS AND VITAMIN D STATUS Saadi HF1, Reed RL2, Carter AO3, Dunn EV2, Qazaq HS4, AlSuhaili AR5; 1Department of Internal Medicine, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates, 2Department of Family Medicine, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates, 3Department of Community Medicine, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates, 4 Department of Nutrition, Ministry of Health, Al Ain, United Arab Emirates, 5Department of Nuclear Medicine, Tawam Hospital, Ministry of Health, Al Ain, United Arab Emirates Aims: Quantitative ultrasound (QUS) of the calcaneus is frequently used to screen for osteoporosis. This technique correlates well with axial dual-energy x-ray absorptiometry (DXA) and predicts fracture risk in older women. The correlation between QUS and DXA in women with vitamin D deficiency however is not known. We assessed the correlation between both techniques in 55

S124 Arabian women, a population with high prevalence of vitamin D deficiency, who had low calcaneal BMD by screening QUS. Methods: BMD of the right calcaneus was estimated by Sahara ultrasound (Hologic). Spine and right femur BMD was determined by DXA (Lunar Expert XL). Serum 25-hydroxyvitamin D (25OHD) was measured by radioimmunoassay (DiaSorin; normal range 3085 nmol/l). Results: The correlation between DXA and QUS was statistically significant in postmenopausal (r = 0.59, p = 0.01 for spine, r = 0.64, p = 0.006 for femur, n = 18) but not in premenopausal women (r = 0.32, p = 0.058 for spine, r = 0.25, p = 0.14 for femur, n = 37). Of the 19 premenopausal women who had 25OHD measurements, 11 (61.1%) had a level below 30 nmol/l. This subgroup (25OHD mean±SD: 21.9±4.5 nmol/l) had significantly lower spine (0.87±0.11 vs. 1.0±0.054 g/cm2, p = 0.003) and femur BMD (0.89±0.059 vs. 0.99±0.11 g/cm2, p = 0.045), and lower average sunlight exposure (32.3±19.2 vs. 110.6±99.2 min/day, p = 0.019) than those with normal 25OHD levels (40.0±8.2 nmol/l). Calcaneal BMD was not statistically significantly different between these 2 subgroups (0.34±0.064 vs. 0.29±0.11 g/cm2, p = 0.31). The correlation between spine DXA and QUS was statistically significant in the subgroup with normal 25OHD (p = 0.033) but not in the subgroup with low 25OHD levels (p = 0.24). The correlation between femur DXA and QUS was not statistically significant in either subgroup. Conclusions: The correlation between DXA and QUS may be influenced by 25OHD status. Low 25OHD level was a common finding in premenopausal Arabian women with low BMD. This may be attributed to inadequate skin exposure to sunlight.

P410MO. CORRELATIONS OF TRABECULAR AND CORTICAL BONE DENSITIES OF RADIUS AND TIBIA Kleinmond C1, Hartard M2, Rittweger J1, Felsenberg D1; 1Centre of Muscle and Bone Research, University Hospital Benjamin Franklin, Berlin, Germany, 2Dept. of Preventive and Rehabilitative Sport Medicine, Technical University, Munich, Germany Aims: Investigation of the correlations of trabecular and cortical bone densities (TrbD / CrtD) of tibia and radius. Methods: This cross-sectional study is based on images from the radius and the tibia assessed by peripheral quantitative computer tomography (pQCT), using a XCT2000 scanner (Stratec, Pforzheim Germany). Measurements were performed in 98 healthy postmenopausal women between 48 and 65 years of age. The images were obtained at shank levels of 4% and 38% from the distal end. TrbD was calculated at the 4% site, CrtD at the 38% site. Results: 1. TrbD of the radius (mean 165mg/ccm) was lower (p50,001) than TrbD (mean 201mg/ccm) of the tibia; 2. In contrast, CrtD of the radius (mean 1184mg/ccm) was greater (p50,001) than CrtD of the tibia (mean 1152mg/ccm); 3. TrbD of the radius and the tibia were significantly correlated (r = 0,66); 4. Likewise a significant correlation was found in the corticalis of the tibia and the radius (r = 0,74); 5. Intra bone correlation between trabecular and cortical BD was considerably weaker: r = 0,29 (radius), r = 0,25 (tibia); 6. No significant correlation, however, was found between DeltaTrbD and DeltaCrtD (p = 0.72), indicating that local effects, occurring either of the forearm or the tibia alone were negligible. Discussion: This results indicate strong correlations of trabecular bone densities at different site in the body. There are only weak correlations of trabecular and cortical BMD even in the same bone. Cortical BMD is influenced by the extent of remodeling (resorption and subsequent mineralisation). Probably the CrtD in the tibia is lower than in the radius because the tibia undergoes more deformation cycles. As a consequence microdamages occur more frequently. Conclusions: It seems, that trabecular and cortical bone density are indicative of different conditions / influences.

Abstracts P411SA. DECREASED BONE MINERAL DENSITY ASSOCIATED WITH ANDROGEN DEFICIENCY IN YOUNG HYPOGONADIC MALES Vargas G1, Monteiro M1, Almeida M1, Castro R3, Santos MJ2, Carvalho R1, Bacelar C1; 1Dept of Endocrinology, Hospital Geral Santo Antonio, Porto, Portugal, 2Dept Nuclear Medicine,Hospital Geral Santo Antonio, Porto, Portugal, 3Dept Clinical Pathology, Hospital Geral Santo Antonio, Porto, Portugal Increases in serum androgens levels during puberty allows for skeletal maturation and the attainment of peak bone mass. Normal testosterone secretion in adulthood is important for maintenance of bone density. Testosterone deficiency is associated with heightened bone turnover and is a major risk factor for osteoporosis in men. Androgen replacement allows the achievement of optimal peak bone mass bone if started before puberty. Aim: To evaluate bone status in young males with hypogonadism. Methods: Retrospective evaluation of bone mineral density (BMD) by DEXA and serum and urinary bone markers of 9 hypogonadic males followed since adolescence in our outpatient Clinic of Growth and Development Disorders. Results: This patients, diagnosed idiopathic hypopituitarism (n = 5), bilateral anorchya (n = 1), bilateral criptorchydia (n = 1), macroprolactinoma (n = 1) and idiopathic hypogonadotropic hypogonadism (n = 1). The mean age of diagnosis and/or beginning of treatment with testosterone was 17.1 years old (10–19). Their mean present age is of 20.7 years old (18–40). The mean BMD is 0.743 g/cm3 (0.56–0.92) in lumbar spine and 0.864 g/cm3 (0.48–0.96) in femoral neck. Mean serum levels of osteocalcin are 60.2 ng/ml (minimum 25 – maximum 126). Mean urinary levels of cross-laps and deoxypyridinoline are 584.9 ug/ mmol of creatinine (266.1–1392.7) and 15.9 nmol/mmol of creatinine (5.5–28.8), respectively. Conclusions: These hypogonadic males with delayed diagnosis and treatment, mean age 17,1 years, present with low BMD, predominantly at the axial skeleton, and enhanced bone turnover markers, despite testosterone replacement. These results are according with recent studies that suggest that late onset therapy is not able to prevent low BMD. We emphasize the need for early diagnosis and treatment of these patients in order to obtain normal peak bone mass in adulthood and to prevent osteoporosis later in life.

P412SU. EVALUATION OF MODERATE LEVELS OF PHYSICAL EXERCISE PROGRAM UPON TESTOSTERONE SECRETION AND LOCOMOTOR SYSTEM FUNCTION IN ELDERLY PATIENTS Revnic F1, Teleki N2, Berteanu M2, Revnic CR3; 1I.N.G.G.‘Ana Aslan’, Bucharest, Romania, 2University Hospital, Bucharest, Romania, 3U.M.F., ‘Carol Davila, Bucharest, Romania Muscle mass strength and power decrease with age, particularly in the lower extremities and it has been atributed in part to a decrease in physical activity. As a result, it is difficult for elderly to perform activities of daily living, increasing the risk for falls and fracture, due to the decrease in bone density. The aim of our study was to evaluate the the effect of physical exercise effect upon sex hormones level, upon skeletal muscle metabolism and physiology as well as upon bone mass density in elderly patients with/without physical activity. 32 male patients aged between 40–70 years old from rehabilitation Clinique admitted for osteoarticular and postraumatic pathologies have been taken in our study: 16 male from group A (adult active patients) and 16 old inactive patiens. CK,CKMB levels of muscle metabolism have been estimated before and after training as well as markers of bone resorbtion and formation and urinary Ca. The osteodensitometry measurements have been performed before and after training as well as testosterone with DELFIA 1234

Abstracts Research Spectrofluorimeter using Eu+ labelled Testosterone kit Pharmacia LKB. Muscle strength during physical training has been estimated with Schwartzer-Piker EMG from biceps and tricepps muscle. The training program has demonstrated a significant improvement in neuromuscular function of skeletal muscle in elderly patients as well as an increase in sex hormone secretion and an increasing in BMD. Conclusion: The most significant benefit of physical training is related with the improvement hormonal status, in neuromuscular function, reducing the risk of falls and fractures, stimulating the bone gain and decreasing the bone loss.

P413MO. DIGITAL X-RAY RADIOGRAMMETRY: COMPARISON OF ROMANIAN WITH OTHER EUROPEAN REFERENCE DATABASES Galesanu C1, Galesanu MR2, Melnic G2; 1University of Medicine and Pharmacy, Iasi, Romania, 2Radiological and Imagistic Center, Iasi, Romania Aims: To estimate the evolution pre- and post-therapeutical of some diseases which are characterized by osteoporosis, the use of statistical data from far-off geographical areas and varied as the economic level could give misinterpreting. The aim of this study is to elaborate the normative reference database investigating some sample of population referring to age, sex, occupation, the place in the Romanian’s geographical areas (plain or mountain) and to compare it with other European populations. Methods: The study based on digital X-Ray radiogrammetry technology (DXR-BMD) estimates the bone density using a fully computerized radiogrammetric and textural analysis of the II, III and IV metacarpal bones. The DXR-BMD value measured by the Pronosco X-posure System is corrected for striation and porosity. The software finishes calculating average bone mineral density of three metacarpal bones displaying the BMD value in g/cm2. The studies are performed on groups of minimum three women for each age in the range of 20–79 years (total 232 healthy women). The observed mean BMD (g/cm2) was: 20–29 years: 0.566; 30–39 years: 0.597; 40–49 years: 0.592; 50–59 years: 0.563. The peak expected DXR- BMD was 0.590 g/cm2 (SD ± 0.040 g/cm2) occuring at age 39. The normative reference curve was generated on a second order polynominal. Results: The results of this study was processed mathematically, statistically and graphically. The date were compared with Scandinavian, British and German reference databases. Conclusion: The data show some differences between our values and other European standards, being closer to German values.

P414SA. DIFFERENCE OF BONE MINERAL DENSITY AMONG VERTEBRAE Mansur JL, Cianciosi MC; Centro de Endocrinologia y Osteoporosis, La Plata, Argentina In spine densitometries is common to inform the mean of BMD of L2-L4 or L1-L4. When the difference among the vertebrae is important, it is usual to exclude one of them and inform the mean value of the remaining ones. Objective: Describe the differences of BMD among vertebrae. Patients: We analyzed prospectively densitometries of 500 postmenopausal women with Lunar DPX. and studied the maximum difference among L2, L3 and L4 according to % of young women. Afterwards we compared the % of L1 with the mean % of L2-L4. We analyzed separately the sample divided in tertils according to age, body weight and BMD. Results: 1) Maximum difference among L2, L3 and L4: Accumulative incidence: 54% in 23.4% of the patients, 56% in 36.6%, 58% in 50.0, 510% in 62.2%, 515% in 83.0%. Average differences: 9.8%. In the tertile of older women the

S125 difference was higher (11.2%) vs other tertiles. No difference in body weight or BMD tertils. 2) Difference between L1 and media L2-L4: Average was 6.4%, the value was 56% in 62.2% of the patients, and 510% in 78.2%. The difference was higher in the older tertile (x: 7.9%) vs other tertiles and in women with normal BMD (x: 7.2%) vs osteoporotic (x: 5.6%). Conclusion: incidence of different BMD among L2, L3 and L4 is high, 50% of women has a difference 48% and 37.8% has a difference of 10% (which is 1 SD of the reference BMD value). But, the precision decreases with less vertebrae analyzed. There is a need for establishing criteria for vertebrae selection. The present research may be helpfull to evaluate this subject.

P415SU. THE INFLUENCE OF CORTICAL AND CANCELLOUS BONE ON THE STRENGTH OF FEMORAL NECK IN OSTEOPOROSIS Rodionova SS, Makarov MA, Kolondaev AF; Central Institute of Traumatology and Orthopaedics, Moscow, Russia Inspite of cancellous bone takes 70% of femoral neck diameter its role in the strength of this segment is still under discussion. Materials and Methods: The separate quantitative CT evaluation was conducted on 24 autopsy specimens of proximal femur with BMD (DEXA, Lunar DPXL, g/cm2) correspondent to osteoporosis (g/cm3) of cancellous and cortical bone. Bone mass was assessed in 3 zones: subcapital, transcervical, basal. The specimens were subjected to mechanical testing (ZWIK1464) until the fracture occurs. Results: In 3 sections total BMD was identical. Ratio between cancellous and cortical bone is listed in a table. During mechanical testing the fractures occurred mainly in subcapital zone, where there is the maximum content of cancellous bone and the minimum content of the cortical bone. Conclusion: The mass of cortical bone is more important for femoral neck resistance to fracture than the mass of the cancellous bone. Zone

Subcapital Transcervical Basal

Cancellous bone (g/cm3)

122.9 84.1 107.9

Cortical bone (g/cm3) Upper plate

Lower plate

473.4 517.0 506.2

757.0 974.9 852.6

P416MO. BONE MINERAL DENSITY AND BONE SCINTIGRAPHY IN CHILDREN AND ADOLESCENTS WITH OSTEOMALACIA Desouki MI1, Jurayyan N2; 1King Khalid University Hospital, Riyadh, Saudi Arabia, 2King Khalid University Hospital, Riyadh, Saudi Arabia In order to demonstrate the role of bone mineral density (BMD) measurements and bone scan in the management of patients with osteomalacia, radioisotope bone scintigraphy using Tc-99m Methyline Diphosphonate (MDP) and BMD measurements of the lumbar spine and femur by means of dual X-ray absorptiometry (DXA) were performed at the time of diagnosis, and six months after therapy in 26 Saudi patients (17 females and 9 males). Their mean age was 13.5 years (range, 5–16). BMD measurements were compared with those of normal Saudi subjects matched for age and sex. Bone scan showed an increase in tracer uptake throughout the skeleton (‘superscan’) in all children and demonstrated multiple stress fractures in eight. The mean BMD for the lumbar spine was 0.53 gm/cm2 (Z-score, –3.1) and for the femoral neck 0.55 gm/cm2 (Z-score, 2.8). Repeated bone scan and BMD after 6 months of therapy with oral Vitamin D, calcium and proper sun exposure, demonstrated significant increase

S126 (P50.001) in BMD and healing of pseudofractures. In conclusion, as a non-invasive method with minimal radiation exposure, measurements of BMD in children with osteomalacia are to be recommended in the initial assessment of the severity of osteopenia and in the follow up to monitor the response to therapy. Bone scintigraphy is valuable in demonstrating the site and severity of stress fractures.

P417SA. NUTRITIONAL RICKETS AND OSTEOMALACIA IN SCHOOL CHILDREN AND ADOLESCENTS (6-18 YEARS) IN A MAJOR TEACHING HOSPITAL IN RIYADH, SAUDI ARABIA Jurayyan N1, Desouki MI2; 1King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia, 2King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia During the period between January 1994 and December 1999, forty-two children and adolescents (25 females and 17 males) were diagnosed to have nutritional rickets or osteomalacia. The diagnosis was based on clinical, biochemical and radiological data. Rickets or osteomalacia associated with Vitamin D dependency, renal and liver, disorders malabsorption or anticonvulsant therapy were excluded by appropriate clinical and laboratory investigations. Their age ranged between 6 and 18 years with a mean of 13.5. Non-specific symptoms, such as bone pain and fatigue were the most presenting symptoms, while skeletal deformities and fractures were the presenting symptoms in only five and three patients, respectively. Lack of direct sun exposure and poor calcium intake were evident. Bone profiles at the time of diagnosis revealed mean serum calcium of 2.1 mmol/ L, range 1.5–2.3 (N; 2.2–2.7), phosphorus 1.1 mmol/L, range 0.7– 1.9 (N; 1.4–2.1) and alkaline phosphatase activities of 1,480 U/L, range 834–2,590 (N; 5600). Serum concentrations of 25-hydroxy Vitamin D were low while that of 1,25 Dihydroxy Vitamin D varied between low to normal. Bone density of the lumbar spine and three femoral sites were performed in 26 patients and showed markedly reduces values, while bone scan demonstrated a so high uptake of tracer throughout the skeleton ‘super scan’. Multiple stress fractures were evident in 8 children. In conclusion, although a community-based study to assess the magnitude of the problem is needed, it seems that rickets and osteomalacia of nutritional origin are not that uncommon and deserves a special attention from all pediatricians and practicing physicians. Further studies are needed to help understanding its pathophysiology and identify the contributing factors for the development of the disorder.

P418SU. DIFFERENTIAL DIAGNOSIS BETWEEN DISUSE AND ‘TRUE’ OSTEOPENIAS ACCORDING TO DEXA-ASSESSED MUSCLE-BONE RELATIONSHIPS Ferretti JL1,2,3, Capozza RF1, Cointry GR1, Rolda´n EJA2, Capiglioni R2, Plotkin H4, Zanchetta JR2,3; 1CEMFoC, Natl. Univ. of Rosario, Rosario, Argentina, 2Metabolic Research Institute (IDIM/FIM), Buenos Aires, Argentina, 3Faculty of Medicine, USAL, Buenos Aires, Argentina, 4Shriners Hospital for Children, Montreal, Canada Introduction: Muscle strength is the main determinant of bone strength. The systemic environment affects that determination, thus all disuse-unrelated osteoporoses show a low bone/muscle strength ratio. DEXA cannot determine bone/muscle strength, so it cannot diagnose osteoporosis. Though, it can assess the anthropometric proportionality between bone and muscle masses as determined by the BMC / lean mass (LM) ratio, so it can differentiate between ‘physiological’, ‘disuse’ and ‘true’ osteopenias according to Frost’s criteria [Bone 20:385,1997]. Material and Methods: We have obtained percentilized curves for whole-body DEXA values of 1. BMC (both crude and logarithmically adjusted to a common, 18-kg value of fat mass, a-BMC) as a function of LM and 2. the BMC/LM or a-BMC/LM

Abstracts ratios related to age of 1,450 boys, girls, men, and pre- and postmenopausal women aged 2-87 years. Results: All BMC (or a-BMC) vs LM curves were lineal and parallel (intercepts for pre-MP women 4 men 4 post-MP women 4 children). The BMC/LM vs age curve increased until puberty reaching constant, higher values in women than men until 50 years, and then declining. Adjustment of BMC values to FM reduced their variance in all instances. Interpretation and application: An adequate percentile obtained from a BMC (or a-BMC) vs LM curve could correspond to either a normal, small individual [‘physiological osteopenia’] or to a ‘disuse’ osteopenia. A low percentile will detect a ‘true’ osteopenia (a low bone mass according to the assessed ‘muscle’ mass) deserving further analysis. The BMC/LM-ratio vs age curves provide t-scores for that condition. Diagnosing osteoporosis requires 1. detecting a ‘true’ osteopenia by DEXA as above stated and 2. demonstrating also a low bone strength (not mass) for the measured muscle strength (not mass) as assessed by suitable technologies (CT, pQCT, NMR, dynamometry, etc).

P419MO. INDIVIDUAL BONE MINERAL DENSITY CHANGES IN THE TRANSITION TO MENOPAUSE Sisson de Castro JA1, Krahe C2; 1Endocrinology Division, UFRGS, Porto Alegre, Brazil, 2Gynecology and Obstetrics Department, PUC, Porto Alegre, Brazil Aims: To assess the individual BMD changes and contributing factors in perimenopausal women. Methods: 56 caucasian women, 40 to 50 years of age followed for 4 years in a private office. Lumbar (L4L2) and femoral BMD were performed in a same DXA (Lunar) device. Precision errors as coefficient of variation at L4L2, femoral neck (FN) and great trochanter (GT) were 0.64%, 1,2% and 2.05%. The least significant variations (LSV) had to be greater than 1.8, 3.5 and 5.8% respectively in the above sites. Food intake, physical activity, smoking habits, alcohol intake, routine biochemical tests, estradiol, SHBG, FSH, testosterone, T4,TSH,PTH, Bone alkaline phosphatase, N-telopeptide and deoxypiridinoline were determined. Results: The whole group significantly lost 1.46% at L2L4 but gained 1.48% at FN and 2.35% at GT. The LSV showed that 24 (43%) lost BMD at L2L4, the rest did not change or gained; 18(32%) gained at FN and 11 (19%) at GT, the rest did not change or lost. Those who lost L2L4 BMD had higher increases of FSH (p = 0.045), higher osteocalcin (p = 0.002), higher calcium excretion (p = 0.024), despite greater BMI (p = 0.042). The women who gained FN BMD ingested more vitamins D and B12, practiced more exercise and had lower osteocalcin (0.022). Those who gained GT BMD had greater BMI (p = 0.045) ingested more magnesium and vitamin B12 and had lower osteocalcin (p50.001). Conclusions: Assessing changes of BMD by LSV in women progressing toward menopause 43% lost L2L4 BMD despite the healthier habits, better nutrition and some hormone replacement. One third gained BMD at FN and GT due to better nutrition and physical activity and weight gain. Osteocalcin was higher in those who lost BMD at L2L4 and lower in those who gained BMD at FN and GT. These observations may help the evaluation and prevention of osteoporosis in perimenopausal women.

P420SA. JOINT HYPERMOBILITY IN CHILDREN: BONE MINERAL DENSITY EVALUATION Terreri MT1, Roberto AM1, Szejnfeld VL2, Len CA1, Hilario MOE1; 1 Department of Pediatrics, UNIFESP, Escola Paulista Medicina, Sao Paulo, SP, Brazil, 2Department of Medicine, UNIFESP, Escola Paulista Medicina, Sao Paulo, SP, Brazil Objective: The relation between hypermobility and low bone density is still unknown. Osteoporosis may be observed in some

Abstracts patients with genetic syndromes associated with joint hypermobility. The aim of our study was to detect the possible relation among joint hypermobility, bone mineral density and limb pain. Patients and Methods: Ninety three prepubertal children from 5 to 10 years old (mean 7.3 years) were evaluated concerning the presence of joint hypermobility (based on the Carter and Wilkinson criteria partially modified by Beighton and Horan) and the presence of limb pain (questionnaire). We also performed densitometry to measure bone mineral density (BMD) (Dexa). We excluded the patients with chronic or atual pathology, in use of bone modifying drugs (corticosteroids) and children with some degree of puberty development. Results: Children were distributed according to the presence or not of joint hypermobility associated or not to limb pain: 29 (31.2%) with hypermobility and limb pain, 20 (21.5%) with hypermobility and without pain, 22 (23.6%) without hypermobility and with pain and 22 (23.6%) without hypermobility and without pain (control group). Among all subjects twenty four (25.8%) children presented reduction in BMD over 10% related to the adequated BMD for age and gender. BMD was significantly lower in relation to the controls in the following groups: with hypermobility (independently of the presence of pain), with pain (independently of the presence of hypermobility), with hypermobility and without pain and without hypermobility and with pain. Conclusion: The BMD was lower in the group with limb pain (independently of the hypermobility) in relation to the controls and can be related to the less fisic activity of the children with pain. Alteration in the colagen in children with joint hypermobility (independently of the pain) could explain the lower BMD in relation to the control group.

P421SU. HAZARDS WITH EVALUATION OF BONE MINERAL DENSITY BY DUAL-ENERGY X-RAY ABSORPTIOMETRY Bolosiu CR; Osteoporosis Unit, Department of Rheumatology, University Hospital, Cluj-Napoca, Romania Dual-energy X-ray absorptiometry (DEXA) is worthily considered as the ‘golden standard’ in evaluating osteoporosis. However, bone mineral density (BMD) values significantly differ under hazardous circumstances, which are to be avoided or corrected during or after the measurement. Aims: To elicit currently encountered error factors in DEXA. Methods: Nine hundred and eighty six consecutive subjects attending our Osteoporosis Unit were measured by DEXA at both lumbar spine (AP) and proximal femur using DPX-alpha (Lunar Corporation) machine. Virtual measurement errors were deduced from carefully analyze of scans, correlation to clinical data, and repeated DEXA evaluation aimed to monitoring patients or eliminate any presumed hazards. Results: The following causes of error have been identified in our group of DEXA-measured subjects: a) technical hazards: bad positioning of the patient, postural instability due to involuntary movements (0.5%), inappropriate selection of the region of interest (ROI), b) interference with clothing accessories: buttons, buckles, stays’ wires etc, c) foreign bodies: calcium tablets into the stomach or small intestine (0.5%), Kerr’s tube (0.1%), d) contrast media: barium, oil and iodide compounds, e) calcifications and/or concretions in situ: calculi (7%), aortic or pancreatic calcifications (3.5% and 1.5% respectively), f) malposition of bone pieces (e.g. scoliosis, l4%) and/or skeletal pathology: osteophytosis (26%), Forestier’s vertebral hyperostosis (2.5%), Pagest’s disease of bone (1%), and general pathology: obesity (l8%), ascites (3%). Conclusion: In the above-mentioned circumstances, DEXA either over-evaluate or under-evaluate BMD. In order to avoid false positive and false negative results, the examiner should eliminate technical errors and carefully analyze images, according to the constitutional and pathologic variables of each patient.

S127 P422MO. ASSOCIATION OF SPONDYLOSIS DEFORMANS AND QUANTITATIVE BODY COMPOSITION: ABOUT INTERVERTEBRAL DISC DEGENERATION AND LUMBAR CANAL STENOSIS. Suzuki T, Matsui Y, Mizuno M, Takemura M, Harada A; Department of Orthopaedic Surgery,Chubu National Hospital, Obu, Aichi, Japan Aims: To examine the correlation between spondylosis deformans (disc degeneration and lumbar canal stenosis) and quantitative body composition (bone and soft tissue). Methods: Lumbar spine magnetic resonance images (MRI) of 278 postmenopausal women without a history of serious diseases or surgery in that area were studied. To evaluate intervertebral disc degeneration, disc area, disc bulging ratio, disc height and disc flattening ratio were measured using sagittal sections of four discs. To evaluate canal stenosis, axial images were used and cross sectional area and flattening ratio of the spinal canal were measured. These measurements were done by personal computer using NIH image. Total bone mineral density (T.BMD), fat mass (Fat), lean mass (Lean) and bone mineral content (BMC) were measured by dual-energy X-ray absorptiometry (DXA). The correlation between these DXA data and those of the disc and canal were statistically analyzed by simple regression. Results: Although weak, disc data and body mass data were correlated as follows. Disc area was negatively correlated with BMC (r = –0.175, p50.05), T. BMD (r = –0.264, p50.0001). Disc bulging ratio was positively correlated with Lean (r = 0.227, p50.05), BMC (r = 0.241, p50.05), T. BMD (r = 0.297, p50.0001). Disc height was negatively correlated with Fat (r = –0.136, p50.05), Lean (r = –0.185, p50.05), BMC (r = –0.307, p50.05), T. BMD (r = –0.145, p50.0001). Disc flattening ratio was negatively correlated with Fat (r = –0.136, p50.05), Lean (r = 70.242, p50.05), BMC (r = 70.306, p50.05), T. BMD (r = 70.375, p50.0001). There was no significant correlation between body mass data and those of the canal. Conclusion: The degree of disc compression was mainly related to BMD and less affected by soft tissue data. High BMD may not cause concave deformity in the vertebral body but may increase pressure on discs, leading to further degeneration. Canal stenosis wasn’t related to body mass data, which may be partly because canal volume is determined by nature (to some extent).

P423SA. MUSCLE-BONE RELATIONSHIPS IN OBESE, EUGLYCEMIC, HYPERINSULINEMIC MEN AND WOMEN Ulla MR1, Stivala M1, Ghiglione F1, Noriega R1, Cointry GR2, Ferretti JL2; 1Centro de Estudios de Osteopatı´as Me´dicas, Co´rdoba, Argentina, 2CEMFoC, Natl. Univ. of Rosario, Rosario, Argentina Introduction: This study aimed to determine whether the metabolic disturbance caused by euglycemic hyperinsulinemia impairs or not the anthropometric and biomechanical relationships between bones and muscles as determined by the homeostatic system that biomechanically controls bone structure and indirectly bone mass in men and women (Bone ‘mechanostat’; Frost, Anat Rec 219:1,1987). Material and Methods: We have analyzed the relationships between the DEXA-assessed, whole-body BMC and lean and fat masses (LM, FM) in 23 men and 97 women with euglycemic hyperinsulinemia classified according to their fasting plasma insulin (FPI) levels lower (i) or higher (I) than 15 uUI/ml, body-mass index values lower (b) or higher (B) than 30, and Insulin Secretion Index (ISI; Matsuda & DeFronzo 1999) values lower (s) or higher (S) than 2.8. Results: The FPI correlated positively with LM and FM but not with the BMC. Correlations between BMC and LM were parallel to those of 400 normal age-controls for each gender but showed lower intercepts for groups I, B, and S than i, b, and s. After adjusting logarithmically the BMC to a common, 18-kg FM value

S128 the groups I, B, and S showed significantly lesser intercepts than controls. Those differences were generally more significant for pre-menopausal women than for post-menopausal women or men. Discussion: Despite of not affecting plasma glucose, the high FPI values would have enhanced all body weight, LM and FM. Assuming that LM reflects muscle mass, they would have also lowered the BMC/muscle proportion, perhaps reducing the mechanical influence of muscles on the skeleton. This would evidence the induction of a shift in the setpoint (a typical, ~0.2% bone tissue strain under the maximal customary loads) of the bone ‘mechanostat’. In addition, the apparent estrogen-dependence of the differences is congruent with the hypothesis that estrogens interact positively with that homeostatic system.

P424SU. VARIATION OF THE BONE MINERAL DENSITY IN WOMEN WITH OSTEOPOROSIS BEFORE AND AFTER THERAPY. COMPARISON OF THE RESULTS BETWEEN DOMINANT AND NON-DOMINANT LIMBS

Abstracts used to prepare scan reports for primary care providers (PCPs) and patient letters. Analysis of time-log data from 114 scans (106 new scans; 8 follow-up scans) showed that the surgeon required 9.8 ± 2.8 minutes to complete a report, and the medical assistant required 5.5 ± 2.5 minutes for clerical/correspondence duties, including addressing and mailing envelopes, making telephone calls about previous bone-density reports, calling patients about their PCP and/or calling the patient’s PCP. Radiology technician time was not analyzed. The surgeon was able to complete 5 to 6 new scan reports per hour. Follow-up scans required 15 to 20 minutes for report preparation. Cost analysis demonstrated that the time required to create reports for initial scans was an efficient use of a surgeon’s time. However, greater than 15 scan reports/ week were considered by the surgeon to be excessively burdensome, and cost analysis revealed that 415/week was an inefficient use of the surgeon’s time. A more cost/time efficient system may be for an adequately trained medical assistant to perform most of the clerical and interpretive (report) duties required in completing DXA reports. This system is considered essential when scan volume exceeds 50–60/month. But for this system to work, close supervision by the orthopaedic surgeon is required to ensure accuracy and quality control.

Lourenc¸o P, Rodrigues A, Ferreira G, Garrett A, Moura E; Unidade ´ sseo do Instituto de Quı´mica Fisiolo´gica da de Metabolismo O FMC, Centros de Sau´de da Sub-Regia˜o de Sau´de de Coimbra Introduction: Adequate physical exercise is a fundamental element in the prevention of osteoporosis and an auxiliary factor in its therapy. Objectives: Evaluation of the influence of the preferred utilization of the dominant limbs in execution of the daily tasks on the variation of the bone mineral density in postmenopausal women with osteoporosis undergoing anti-reabsorbing therapy. Material and Methods: 80 postmenopausal women were distributed randomly to three groups receiving respectively the following therapeutics: 1. Calcium and Vitamin D3, 2. Calcium and Alendronate, 3. Calcium and Calcitonin. Osteodensiometric assessments were performed via DEXA (Hologic QDR 4599 E´lite) of the lumbar column and in the proximal portion of the femur and the distal portion of the forearm before and after 12 months of therapy. At the beginning of the study the mean values of the bone mineral density of the dominant and non-dominant limbs were evaluated. At the end of the survey the mean variation of the mineral osseous density was determined. The statistically significant differences of the mineral osseous density and the percent variation over 12 months between dominant and nondominant limbs were analyzed using the Wilcoxon test. Results: The mineral density of the bones at the beginning and the mean annual variation do not show any statistically significant difference between the dominant and non-dominant limbs. Conclusion: The preferred use of the dominant limbs in execution of daily tasks does not show any relevance/ is not reflected in the variation of the mineral osseous density in postmenopausal women with osteoporosis undergoing antireabsorbing therapy during one year.

P426SA. TOTAL HIP ARTHROPLASTY: CAN WE PREVENT BONE LOSS? Maalouf GH1, Khalil G1, Salem SA2, Abdallah AM3, Eid JO4, Wehbe JO1, Melki RO1, Nehme AL5; 1Orthopaedic Surgeon St Georges UniversityHospital,Beirut, Lebanon, 2Orthopaedic Surgeon Lebanese Canadien Hospital, Beirut, Lebanon, 3 Orthopaedic Resident St Georges University Hospital, Beirut, Lebanon, 4Orthopaedic Surgeon El Arz Hospital, Beirut, Lebanon, 5 Orthopaedic Surgeon Rangueil University Hospital, Toulouse, Lebanon We measured the femoral periprosthetic bone mineral density in 38 total hip arthroplasties. It is a prospective, single center controlled study, comparing 20 patients treated with Alendronate 10 mg (ALN) coupled with 600 mg calcium daily and 18 total hip arthroplasties used as controls. All patients were females, having physiological menopause, free of any disease known to influence bone metabolism, with a mean age for the Alendronate group of 63.3 years and a mean age for the control group of 62.6 years. The component used in all treated hips is cemented 28-mm head prostheses. All patients were followed up for two years. The measurement was performed postoperatively at day four (D 4), 1, 3, 6, 12 and 24 months after the operation. Measurements included the controlateral hip and the A/P spine. Bone resorption in hips treated with ALN was significantly reduced compared to controls. Alendronate might be useful in total hip arthroplasties, in reducing bone resorption and can preserve bone stock at least in early stages.

P425MO. THE ORTHOPAEDIC SURGEON AS A CLINICAL DENSITOMETRIST: EVALUATION OF COST AND TIME EFFECTIVENESS

P427SU. INFLUENCE OF CALCIUM INTAKE, BASDAI AND BASMI INDEXES ON BONE MINERAL DENSITY IN PATIENTS WITH ANKYLOSING SPONDYLITIS

Skedros JG, Milleson NM; Utah Bone and Joint Center, 2490 South State Street, Suite 100, Salt Lake CIty, Utah, USA 84115

Pimentel dos Santos FM, Tavares V, Canas da Silva J; Department of Rheumatology, Garcia de Orta Hospital, Almada, Portugal

We feel an orthopaedic surgeon can efficiently and economically perform the duties of a clinical densitometrist. This hypothesis reflects a philosophy that orthopaedic surgeons must take a more active role in evaluating patients for osteoporosis, and initiating treatment or referring them for treatment. We evaluated the cost/ time effectiveness of an orthopaedic surgeon and his medical assistant in completing reports and related correspondence for dual-energy x-ray absorptiometry (DXA) scans. Templates were

Aims: Patients with ankylosing spondylitis (AS) seem to have a higher risk of osteoporosis. The aim of our study was to look at the influence of dietary calcium content, disease activity and structural status on bone mineral density (BMD) in a group of patients with AS. Methods: We examined 20 patients- 9 men and 11 women, with AS fulfilled the modified New York criteria. BMD was measured

Abstracts with hip and lumbar spine DEXA. We excluded all the patients with lumbar syndesmophytes. Dietary calcium content were evaluated by a standardized questionnaire and factors of disease activity by Bath AS Disease Activity Index (BASDAI) and structural repercussion by Bath AS Metrology Index (BASMI). Results: The mean age of the subjects was 41,913,1 years, mean BASDAI 4,72,0, mean BASMI 2,92,2 and mean dietary calcium intake 5221,52226 mg/week. 55% of patients had low BMD. We did not found any correlations between calcium content and functional and structutal indexes with BMD except a weak correlation between BMD at the hip and BASMI. Conclusions: This study group was a small one. Calcium intake do not seem to inflence BMD. There are some indications that structural status may compromise BMD (at least at the hip).

P428MO. BONE MINERAL DENSITY AND GRIP STRENGTH Sahyn G1, Bagis S1, Bolgencimen O1, Bicer A1, Bolgencimen B2, Yapici Y1, Karabyber M1, Erdogan C1; 1Mersyn Univercity, School of Medicine, Dept. Pmr, Mersyn-Turkey, 2Mersyn University, School of Medicine, Dept. of Biochemistry, Mersyn-Turkey Objective: To assess the correlation between bone mineral density and hand grip strength in postmenopausal women. Methods: Two hundred eighteen (218) postmenopausal women aged 41–83 years on no medical regimen were studied. Of the patients, 138 were osteoporotic (DXA,T less than –2.5SD), and 80 of them were normal (DXA, T score between 1 and –1SD) and accepted as control group. Hand grip strength (non-dominant) were measured by JAMAR hand dynamometer. Bone markers are also measured in the serum of patients and controls, 24 hour urine calcium was also assessed. Bone mineral density was measured by NORLAND at lumbar and femoral (neck) and distal forearm regions. Results: There was positive correlation between hand grip strength and bone mineral density at the femoral (neck) region (r = 0.247 p = 0.005). There was also negative correlation between handgrip strength and age, menopause duration, respectively (r = 70.341, p = 0.01, r = 70.291, p = 0.00). Conclusion: Although it is unclear, the study suggests that handgrip strength as a determinant of bone mineral density can help clinicians to identify subjects at risk.

S129 estimate of fracture risk at least as good as DEXA of the spine and femur. Ultrasound evaluation of the os calcis by this technique is inexpensive, fast, non-invasive, risk free and does not involve ionizing radiation thus making it suitable for bone quality evaluation in childrean and young persons.

P430SU. BONE MINERAL DENSITY IN OOPHORECTOMIZED WOMEN Popov AA, Izmozherova NV, Andreyev AN, Porodnova OY; The Urals State Medical Academy, Ekaterinburg, Russia Aims: Surgical menopause induced by total or partial oophorectomy has been reported to be among the most prominent risk factors of excessive bone loss in women. The aim of the study was to assess bone mineral density (BMD) in oophorectomized women in comparison with naturally postmenopausal ones. Methods: In a case-control study 34 postmenopausal women with no history of bone fractures were included. The main group consisted of 17 oophorectomized women, control group were 17 persons in natural postmenopause. The groups were matched by the body mass index, marital and financial status, menopause duration. BMD of the lumbar spine was assessed by dual energy x-ray absorbtiometry. Chi-squared and Mann-Whitney tests were used to verify differences between the groups. The data are shown as median and 25th and 75th procentiles. Results: The main group was insignificantly younger (50; 36–61) than the control one (52; 45-66). The age of menopause (42; 33– 56) was significantly lower in the main group than in the control one (49; 44–53). Among oophorectomized persons 10 had low BMD (T-score 5–1.5 SD), while in the control group low BMD was found in 3 cases. Conclusions: Oophorectomized women turned out to be younger and began losing their BMD significantly earlier than the control group. Low BMD was significantly more frequent in oophorectomized women then in intact ones. Efficacy of estrogen replacement therapy in prevention of the bone loss after oophorectomy is being studied.

P431MO. RELATION BETWEEN THE SINGH’S INDEX AND THE BONE MINERAL DENSITY P429SA. A NEW TECHNOLOGY FOR MEASURING BONE STRUCTURE Morrison RT1, Cohen P1, Russell AS2, Juby A2, Koblanski J3; 1 University of British Columbia, Vancouver, Canada, 2University of Alberta, Edmonton, Canada, 3Texon Technologies Inc., Vancouver, Canada A device using a new technology for measuring bone quality has been developed by Texon Technologies. It measures the unique interaction of an ultrasound signal with the trabecular structure of the os calcis by means of proprietary transducers and software. This device, in addition to independently and simultaneously measureing the ‘speed-of-sound’ and ‘bone ultrasound attenuation’, also measures the ‘Trabecular Index (TI)’. The TI is a mathematical derivation of the scatter of an ultrasound signal and measures the trabecular interaction with the ultrasound beam, thus providing an evaluation of the trabecular structural component of bone quality. Clinical trials suggest that in addition to speed-of-sound and bone-ultrasound-attenuation (a calculated bone mineral density) the TI may provide a more useful measure of fracture risk. Seven of eight (7/8) with low impact fractures had abnormal TI values while only three (3/8) had osteoporotic values for the spine by DEXA and four (4/8) had osteoporotic values of the femur by DEXA. Based on these data, the TI may provide an

Cerrahoglu L, Duruo¨z MT, Tikiz C, Olcenler S; CBU Medical School PM&R Department, Manisa, Turkey Background: The Singh’s Index for the neck of the femur, devised by Singh determines the scale of values for osteoporosis.AIMS: To assess the relation between the Singh’s Index and the bone mineral density (BMD) in osteoporosis. Methods: Subjects who were diagnosed as osteoporosis according to WHO criteria were recruited randomly. Patients with secondary osteoporosis were excluded. Bone mineral density (BMD), T and Z scores of L1-L4 region, L3 lateral and left femur’s neck, trochanter and Ward’s triangle were assessed. Singh’s Index was assessed blindly by two independent physicians on antero-posterior X ray of the left femur. Spearman’s nonparametric rank correlation coefficient was used to evaluate the relation between two quantitative variables. Intraclass correlation coefficient (ICC) was used to evaluate the interrater reliability of the Singh’s index. Results: Sixty-six subjects with osteoporosis were recruited. The mean age was 64.30 (SD: 7.83). The interrater reliability was 0.52. The Singh’s Index had significant relations with Z scores of femur neck (rho: 0.326; p = 0.021), trochanter (rho: 0.372; p = 0.007) and the Ward’s triangle (rho: 0.289; p = 0.040). Conclusions: There is a significant relation between Singh Index and Z score of DEXA. Singh index is a practical instrument to get an opinion about Z score.

S130 P432SA. EVALUATION OF FOREARM MEASUREMENTS AS OSTEOPOROSIS SCREENING TOOL Matusik H, Kobylinska M, Jaworski M, Pludowski P, Lorenc RS; Department of Biochemistry and Experimental Medicine. Children’s Memorial Health Institute, Warsaw, Poland Around 50% of Polish diagnostic potential is based on measurement of densitometric values in distal forearm location. The aim of the present studies is the evaluation of its diagnostic means for the comparison of densitometric values in of forearm with these performed in spine and hip location. 300 women between 20–80 years of age participated in the densitometric measurements of distal forearm, lumbar spine and hip location. BMC, BMD values were normalized concerning high, weight and BMI values. Nutritional, physical activity and skeleton status were analyzed basing on questionnaire. Parallely T-score and Z-score were calculated. All participants were divided on four age groups (20–40, 41–55, 56–65, 66–80) and subsequent analysis of their densitometric values were performed. Basing on the obtained data it can be concluded that every measured segment correlated with others only in limited range differently in every age group. The correlations decreased with aging. The data indicated on minor value of distal measurements in general diagnostic programme.

P433SU. STUDY OF PERIPHERAL AND AXIAL BONE MINERAL DENSITY AND QUANTITATIVE ULTRASOUND PARAMETERS IN PATIENTS WITH DISH Kiss C1, Paksy A2, Gergely P1, Poo´r G1; 1National Institute of Rheumatology, Budapest, Hungary, 2Semmelweis University, Budapest, Hungary It is hypothesised that enthesealnew bone formation is only of many changes involving bone in patients with DISH. Such patient also develope hyperostosis, increase in the amount of normal bone and heterotopic new bone formation. We measured the amount and quality of normal bone at nonentheseal sites in DISH and normal control group in order to investigate the hypothesis above. Peripheral and axial BMD and BUA, SOS have been measured in 30 patint affected by DISH and the results were compared to those of 30 controls. All subjects underwent radiological examination of the lumbar and dorsal spine. BMD was evaluated using DEXA at the lumbar spine, left femoral neck, trochanter, and at the distal radius. SOS and BUA were measured by ultrasound of calcaneus. In DISH patients the mean value of BMD was significantly than that in controls at femoral neck (p50.05) and distal radius (p50.05). There was significant difference between the two groups regarding SOS (p50.01) and BUA (p50.01). It seems to be possible that in DISH at non-entheseal sites of bone the density could be higher.

P434MO. DIAGNOSTIC OF METABOLIC BONE DISEASES THROUGHOUT THE MEASUREMENT OF THE GEOMETRICAL STRUCTURE OF THE BONE Roma´n CA1, Siller JJ1, Cohen D2, Rosas AM3; 1Cicata-IPN, Me´xico D.F., Me´xico, 2Centro Me´dico Palmas, Me´xico D.F., Me´xico, 3ITESM-CEM, Me´xico D.F., Me´xico Diagnostic of metabolic bone diseases throughout the measurement of the geometrical structure of the bone. In the past a correlation between the value of fractal dimension of trabecular bone and the osteoporosis has been determined. Here we consider other mathematical methods for the characterisation of the structure of trabecular bone as a tool of diagnostic of different metabolic bone diseases.

Abstracts We have determined the structure of bone trabecula from healthful persons and from persons with different metabolic bone diseases. We considered different mathematical measurements and computational procedures in the analysis of images of X-ray tomographies for the determination of geometrical structure of bone trabecula in order to find the best method for its characterisation. We found that fractal dimension and the box counting method give the best results, and that this procedure could be a valuable help to the more traditional ones for the diagnostic of metabolic bone diseases.

P435SA. DIAGNOSTIC VALUE OF A SINGLE DENSITOMETRY Bolanowski M; Dept. of Endocrinology and Diabetology, Wroclaw Medical University, Wroclaw, Poland Bone densitometry has been more available in the clinical practice and it is followed by many confusing results. The description of a single measurement without personal contact with a patient is not uncommon. In some cases, the result of a single densitometry can provide a false conclusion and therapeutic decision. The aim of the study was to compare the results of the different densitometric methods in a healthy man. The results of forearm (SPA, SXA, pDEXA, pQCT), lumbar spine (DEXA, QCT), hip (DEXA), total body (DEXA), os calcis (QUS), tibia (QUS) and phalanx (QUS) were compared. A considerable dispersion in the densitometric results was shown. The methods used in the screening studies provided lower results in contrast to golden standard methods. It suggests to be very careful when the result of a single densitometry is interpreted or described without personal contact with a patient and his history, or without sufficient knowledge of the densitometric methods.

P436SU. COMPARISON OF ULTRASONIC MEASUREMENTS VERSUS DXA IN THE COURSE OF OSTEOPOROSIS PREVENTION AT THE DEPARTMENT OF TRAUMATOLOGY, UNIVERSITY OF VIENNA MEDICAL SCHOOL, AUSTRIA Zobor NA1, Greitbauer M1, Mu¨ller D1, Pietschmann P2, Ve´csei V1; 1 Department of Traumatology, University of Vienna Medical School, Austria, 2Department of Pathophysiology, University of Vienna Medical School, Austria The purpose of the investigation: Comparison of ultrasonic versus DXA measurement in patients who already have suffered a fracture. Method: The bone density was measured in the patients who were of 55 years or older, and have suffered a fracture. The measurements were performed with ultrasonic (on the phalanx, radius and tibia) and by DXA (on the lumbar spine and hip), respectively. From each kind of measurement the worst result was taken for statistical analysis and the patient was treated according to it. Results: In our collective 44 patients could be measured in both ways. The mean age was 76.1 years and we had 87% women and 13% men. According to the DXA measurements 83% of them had osteoporosis and 17% osteopenia, while the ultrasonic measurements showed in 79.4% osteoporosis and 20.6% osteopenia. When comparing the ultrasonic with DXA, the measurements of the phalanx and radius were in 85.7% in good agreement with the DXA results, while on the basis of the tibia measurements only 16% had osteoporosis and 26% osteopenia, and the rest 58% was judged as healthy. Conclusion: In contrast to tibia measurements, in elderly patients with recent fractures ultrasound results at the phalanx and the radius show good agreement with DXA-values.

Abstracts P437MO. COMPARING DENSITY FINDINGS OF BONE MINERAL DENSITY IN PATIENTS UNDERGOING CHRONICAL DIALYSIS AND GENERAL POPULATION MEASURED IN CLINIC FOR OUTER PATIENTS

S131 patients with COPD requiring long-term CS regardless of the regimen used. COPD CS users are clear candidates for secondary prevention because of the potential devastating effects of a new vertebral fracture on an already jeopardised lung reserve.

Misˇkiæ B, Bistroviæ D, Leko N; General Hospital Slavonski Brod, Croatia We have maesured bone mineral density with HOLOGIC QDR 4000. We had 2 groups of patients: 71 patient on chronical dialysis program and second group 2024 persons chosen by random order but randomised according to age, sex and all statistical criteria. We have compared bone mineral density in those 2 groups of patients. Average dose of medics in those 2 groups was CaCO3 1.5 g per day, and avarige dose of Rocaltrol was 0.5 micrograms. Bone density was measured on hip, spine and forearm and results were compared by T score which is defined by WHO. According to the results, we had 3 groups of patients undergoing dialysis (13%) compared to general population (26%). Osteopenia is more frequent in patients on dialysis (42%) and 39% in general population. 45% of patients on dialysis had osteoporosis and 35% in general population. On the hip, we had 46.4% on normal findings on the patients on dialysis, according to 63% in general population. We had almost similar percentage of osteopenia (39.6 vs. 31%) and significant difference in osteoporosis (14%) for patients on dialysis and 6% in general population. On forearm, we had only 18.5% of normal findings in patients on dialysis and 40% in general population. We had very similar percentage of osteopenia 36% vs. 40% and difference in osteoporosis 41.5% vs. 24%. We concluded that osteoporosis is more frequent in patients on chronical dialysis. Severity of osteoporosis correlates with the period on the chronical dialysis. Predilectic locations for fracture are hips and forearms.

P438SA. SIMILAR DELETERIOUS SKELETAL EFFECTS OF INTERMITTENT OR CONTINUOUS ORAL CORTICOSTEROIDS IN PATIENTS WITH COPD ALSO USING INHALATION CORTICOSTEROIDS Banffer D1, McCloskey EV2, Papapoulos SE1, Hamdy NAT1; 1 Leiden University Medical Centre, Leiden, The Netherlands, 2 WHO Collaborating Centre for Metabolic Bone Diseases, Sheffield, UK Corticosteroids (CS) are pivotal in the management of chronic obstructive pulmonary disease (COPD). Inhaled CS are effective in reversing airways obstruction and are the preferred mode of administration because of their mostly local effects. A significant number of patients require additional oral CS and the question arises whether intermittent courses of oral CS are less deleterious to the skeleton than continuous oral CS use. To address this question, we compared the prevalence of osteoporosis and vertebral fractures in 63 COPD patients using inhalation CS and either continuous oral (CCS) or intermittent high dose CS (ICS). There were 20 men and 43 women: 39 postmenopausal (6 using HRT). Mean age was 61 years (range 21–79). Mean dose inhalation CS was 41000 ug/day. 25 patients additionally used CCS (mean dose 12.8mg/day) and 37 patients received ICS, (maximum 3 courses/year and not for at least 2 months before study. Bone mineral density measurements (Hologic QDR-1000) and lateral X-rays of the spine were undertaken in all patients. Xrays were evaluated using the McCloskey methodology. Mean cumulative dose of CS was higher in the CCS-group compared to the ICS-group (45+33 gr vs. 24+22gr; p = 0.005). Osteoporosis was equally prevalent at the femoral neck in CCS and ICS patients (60%), but was less prevalent at the lumbar spine in ICS than CCS patients (37% and 60% respectively). There was, however, no significant difference in prevalence of vertebral fractures between ICS (47%) and CCS (38%) patients. Our data suggest that although there is a trend for ICS to be associated with less spinal osteoporosis, fracture risk remains overall high in all

P439SU. BONE METABOLISM DISEASE IN PRIMARY BILIARY CIRRHOSIS: A LONG-TERM LONGITUDINAL STUDY Benetti A1, Varenna M2, Sinigaglia L2, Massarotti M1, Battezzati PM1, Crosignani A1, Giorgini A1, Podda M1; 1Department of Medicine, Surgery and Dentistry, San Paolo Hospital, Milan, Italy, 2 Department of Rheumatology, G.Pini Orthopedic Institute, Milan, Italy Background/Aims: Alterations of bone metabolism in primary biliary cirrhosis (PBC) are considered to have high prevalence and severity, but prospective studies with adequate control group are lacking. Aims of this study were: 1) to characterize bone disease in PBC patients regularly replaced by oral calcium and vitamin D; 2) to correlate bone disease with PBC stage; 3) to measure changes of bone mineral density over time (BMD). Methods: We enrolled 118 women with PBC with no concomitant disease predisposing to bone loss (mean age±SD: 56±10 yr; 72% postmenopausal; 44% with cirrhosis). We measured BMD (lumbar spine, DEXA-Hologic) at entry in all patients. Serial densitometric measurements were repeated after 1, 3 and 5 years in 62 patients.507 healthy women (74% postmenopausal; mean age±SD: 55±10) matched for age and menopausal status to PBC women were the control group. Laboratory determinations included serum osteocalcin and hydroxyproline urinary excretion. Results: Mean BMD was 0.850±0.141 g/cm2 (T-score: 2.030±1.283) vs 0.857±0.157 g/cm2 in control group with a prevalence of osteoporosis (T-score 5–2.5) of 28% and 29% respectively. As expected a significant relationship was found between BMD and age or post-menopausal condition. There was no association with liver disease stage. Biochemical markers of bone remodelling were elevated in 51% of the patients. The yearly bone loss in PBC was –0.008 g/cm2 (IC 95%: –0.013 to –0.003) similar to that seen in control group (–0.009g/cm2; IC 95%: –0.009 to –0.007). Conclusions: Increased bone turnover was observed in most patients. Prevalence of osteoporosis and yearly BMD loss are similar to those seen in the general population and are not associated with liver disease severity.

P440MO. ANKYLOSING SPONDYLITIS IS A STRONG RISK FACTOR FOR VERTEBRAL FRACTURES Geusens PP1,2, Vosse D1, Vanhoof J2, van der Linden S1; 1 University Hospital, Maastricht, The Netherlands, 2BIOMED, LUC, Diepenbeek, Belgium Ankylosing spondylitis (AS) is an inflammatory rheumatic disease of the spine. Several reports indicate that the prevalence of vertebral fractures is increased in AS and is associated with hyperkyphosis. However, the morphometric criteria for definition of a vertebral fracture differed between these studies. We therefore analysed the prevalence of vertebral wedging (decrease in Ha/Hp, where Ha is the anterior height of the vertebra and Hp the posterior height) in the thoracic spine (T6–T12) on plain lateral X-rays in patients with AS according to the several available definitions, semi-quantitative (Genant, MI) and quantitative (Eastell, MII, McCloskey, MIII) in a group of 69 consecutive patients with AS. Odds ratios were calculated for the presence of a vertebral fracture in patients with hyperkyphosis (occiput-wall distance 40) as compared to patients with AS without hyperkyphosis.

S132 Depending on the level of the vertebra, 74–90% of the vertebrae could be accurately measured. The prevalence of vertebral deformities varied between the different methods of calculation. According to MI, mild deformities (Ha/Hp 50.8) were found in 48 vertebrae and moderate deformities (Ha/Hp 50.75) in 14 patients. According to MII, mild deformities (Ha/Hp 53SD of their control population) were found in 18 vertebrae and moderate deformities (Ha/Hp 54SD) in 4 patients. According to MIII, the Ha/Hp was lower than 3 SD of their control population in 14 vertebrae. The odds ratios for vertebral fractures in the presence of hyperkyphosis was 13.4 (95% C.I.: 1.6, 110.6) for moderate deformities (MI), 5.6 (95% C.I.: 1.1, 27.1) for mild deformities (MII), 3.2 (95%C.I.: 0.4, 29.6) for moderate deformities (method II), and 3.8 (95% C.I.: 0.8, 18.7) for deformities (53 SD, MIII). We conclude that (1) vertebral fractures are common in AS, (2) the prevalence differed according to the different definitions, and (3) the prevalence was highest in patients with AS with hyperkyphosis.

P441SA. LOW PREVALENCE OF OSTEOPOROSIS AND FRACTURES AND NO SIGNIFICANT BONE LOSS AT A YEAR’S FOLLOW-UP IN WELL CONTROLLED CROHN’S DISEASE van Hogezand RA1, Banffer D1, McCloskey EV2, Zwinderman AM1, Papapoulos SE1, Hamdy NAT1; 1Leiden University Medical Centre, Leiden, The Netherlands, 2WHO Collaborating Centre for Metabolic Bone Diseases, Sheffield, UK In Crohn’s disease, the pathophysiology of skeletal disturbances is multifactorial including disease activity, malabsorption and glucocorticoid (GC) use. In a previous cross-sectional study of 146 unselected consecutive patients with Crohn’s disease, we demonstrated that in the presence of reasonably well controlled disease activity, prevalence of osteoporosis was low (15% and 19% respectively at the lumbar spine and hip sites) despite previous or current use of GC and that the main risk factor for developing osteoporosis was ileum resection. The aim of this study was to establish the prevalence of vertebral (VF) and nonvertebral (NVF) fractures in the same population and to evaluate the extent of bone loss and incidence of new fractures after oneyear follow-up. Lateral X-rays of the thoracic and lumbar spine were evaluated in Sheffield, UK, using the McCloskey technique (132 evaluable X-rays). NVF were documented by direct questioning. At base line, 15 patients (10%) had sustained a NVF with inappropriate trauma. Eight patients (6%) had 9 VF. BMD was repeated one year after initial evaluation and the incidence of new VF and NVF documented. The only pharmacological intervention allowed, other than necessary GC dose adjustment, was calcium and vitamin D supplementation. Three patients with severe osteoporosis requiring treatment with bisphosphonates were excluded and 13 patients were lost to follow-up. 62 patients were still using GC at one year. There was no significant change in mean BMD at the lumbar spine or hip sites regardless of continuing use of GC. Our data suggest that GC do not result in significant adverse skeletal effects when optimally used in the management of patients with active Crohn’s disease. In this inflammatory bowel disease, the beneficial effects of using GC to control disease activity may counteract the apparently more important deleterious effects of disease activity on the skeleton.

P442SU. DIFFERENCES IN BONE MINERAL DENSITY BETWEEN PITUITARY AND ADRENAL CUSHING’S SYNDROME Minetto MA, Reimondo GM, Ventura M, Osella G, Angeli A, Terzolo M; Medicina Interna I, Dipartimento di Scienze Cliniche e Biologiche, A.O. San Luigi, Orbassano, Italy Although the association between endogenous glucocorticoid secretion and bone loss has been extensively studied, it is not known if pituitary Cushing’s disease (CD) and adrenal Cushing’s

Abstracts syndrome (ACS) have a different potential of inducing osteopenia. Aim of the present study was to analyze retrospectively bone mineral density (BMD) in 25 patients with CD (3 men, 22 women) and 9 patients with ACS (3 men, 6 women) who underwent measurement of BMD by dual energy x-ray absorptiomety (Hologic QDR 4500 W) and a detailed endocrine work-up. The two groups were comparable for age, estimated duration of disease, BMI, gonadal function, UFC levels. Lumbar BMD values in patients with ACS were significantly lower than in patients with CD (0.740 ± 0.11 SD g/cm2 vs. 0.874 ± 0.12 SD g/cm2; p = 0.01), as well as t-score (–2.99 ± 0.94 SD vs. –1.66 ± 1.16 SD; p = 0.007), and zscore (–2.42 ± 1.06 SD vs. –0.90 ± 1.55 SD; p = 0.001). Conversely, we did not find any significant difference in femoral BMD values. In patients with ACS we also observed a reduction of serum DHEAS evaluated as z-score to take into account sex- and age-related differences (–1.07 ± 0.93 SD vs. 2.36 ± 2.35 SD; p = 0.0001). In the whole group of Cushing patients no significant correlations were observed between BMD and hormonal parameters. In the female patients, we observed significant correlations between total hip BMD and serum testosterone (r = 0.59, p = 0.004), total hip BMD and serum DHEAS (r = 0.45, p = 0.02), lumbar BMD and DHEAS z-score (r = 0.48, p = 0.02). In conclusion, our data suggest that bone loss is greater in ACS than in CD. This figure could be explained by the reduced androgen levels in patients with adrenal adenoma because this tumor secretes cortisol almost exclusively while ACTH-dependent Cushing’s syndrome is usually characterized by elevation of different steroids.

P443MO. PREVALENCE OF OSTEOPOROSIS AND VERTEBRAL FRACTURES AND EFFECT OF ORAL BISPHOSPHONATES IN SUCCESSFUL ORTHOTOPIC LIVER TRANSPLANTATION. A ONE-YEAR OPEN STUDY Banffer D1, van Hoek B1, McCloskey EV2, Lamers CBHW1, Hamdy NAT1; 1Leiden University Medical Centre, Leiden, The Netherlands, 2WHO Collaborating Centre for Metabolic Bone Diseases, Sheffield, UK Skeletal disturbances are a common complication of end-stage liver disease. Orthotopic liver transplantation (OLT) reverts the biochemical abnormalities, but significant skeletal morbidity is reported in a third of patients post-OLT although figures vary widely between different series. In an open study design, we studied the prevalence of osteoporosis and vertebral fractures (VF) in 21 consecutive patients (17 men and 4 women) with various underlying primary liver pathology who underwent successful OLT. Patients were followed-up for one year and changes in BMD and incidence of new VF assessed at 6 and 12 months post-OLT. All patients received conventional triple immunosuppressive therapy and calcium and vitamin D supplementation as required to correct any documented deficiency. Thirteen patients were additionally treated with an oral bisphosphonate for at least 6 months on the basis of prevalent osteoporosis and/or fractures. BMD measurements (Hologic QDR-4500) were obtained before and at 6 and 12M post-OLT. Vertebral fractures were evaluated by the McCloskey methodology. Before OLT, osteoporosis was prevalent in 29% of patients and VF in 19%. Lumbar spine BMD significantly increased in patients using oral bisphosphonates compared to those who did not (+7.41+18.22% vs. –6.89+7.23% and +5.82+5.86% vs 75.85+3.67%) at respectively 6 and 12M post-OLT (p50.05). A similar trend, albeit non-significant was observed at the femoral neck at 12M post-OLT. At the end of the year follow-up, a total of 21 new VF were documented in 6 patients, with 17 occurring in the first 6 months after OLT. Bisphosphonates as used in a high risk population of patients with end-stage liver disease appear to protect against bone loss but do not appear to prevent the incidence of new vertebral fractures up to a year post-OLT. Whether this may be achieved by starting bisphosphonates before OLT in high-risk patients with known prevalent osteoporosis and/or fractures remains to be established.

Abstracts P444SA. SERUM OSTEOPROTEGERIN IN PATIENTS WITH RHEUMATOID ARTHRITIS: CORRELATIONS BETWEEN INFLAMMATORY ACTIVITY, CYTOKINES AND VITAMIN D STATUS Scharla SH, Kamilli I, Lempert UG; Klinikum Berchtesgadener Land, Schoenau am Koenigssee, Germany Recent data indicate a role for osteoprotegerin in the pathogenesis of osteoporosis. Osteoprotegerin is produced by osteoblasts and inhibits osteoclast differentiation. In vitro, osteoprotegerin production is decreased by glucocorticoids and increased by 1,25(OH)2D3. We evaluated the role for osteoprotegerin in bone metabolism in patients with rheumatoid arthritis. 69 patients with rheumatoid arthritis and osteopenia were consecutively included in the study. Bone mineral density at femoral neck and lumbar spine was evaluated by DXA. Serum calcium, phosphate, CRP, 25OHD3, osteoprotegerin, interleukin6, interleukin-12 and TNF-alpha as well as calcium excretion and bone resorption marker in urine were determined at the beginning of the study and after 4 weeks. Patients received either 1000 IE vitamin D (29 patients) or 1 microg alfacalcidol (40 patients) for 4 weeks. Osteoprotegerin levels were between 0 and 222 pg/ml (mean 24.2 ± 4.7 pg/ml). Time since diagnosis of osteoporosis was positively correlated with osteoprotegerin levels (r = 0.56, p50.01). High urinary calcium excretion was associated with low osteoprotegerin concentrations (r = -0.4, p50.005). High CRP levels were associated with high osteoprotegerin levels, however, not significantly (r = 0.24; p = 0.09). A significant positive correlation between serum levels of interleukin-6 and interleukin-12 and osteoprotegerin was found (r = 0.39, p50.007 and r = 0.33 p50.03, respectively). No association of osteoprotegerin with TNF-alpha or vitamin D-status was detected. Likewise, therapy with either vitamin D or alfacalcidol did not influence serum osteoprotegerin. Increased inflammatory activity as indicated by elevated serum levels of CRP and the interleukins –6 and –12 were associated with elevated serum levels of osteoprotegerin. Since mediators of inflammation are known to cause osteoporosis whereas osteoprotegerin is supposed to inhibit bone resorption, this seems to be contradictory. However, the increase in osteoprotegerin might be a compensatory mechanism of protection. In this study, shorttime vitamin D therapy had no effect on osteoprotegerin.

P445SU. COELIAC DISEASE PRESENTING WITHOUT DIARRHOEA IS ASSOCIATED WITH LOWER BONE MINERAL DENSITY Gaywood IC1, Davie MW2, Masud T3, George E4, Summers GD5; 1 Lincoln County Hopital, Lincoln, UK, 2Robert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, UK, 3Nottingham City Hospital, Nottingham, UK, 4Arrowe Park Hospital, Wirral, UK, 5 Derbyshire Royal Infirmary, Derby, UK Aims: To examine the relationship between bone mineral density and mode of presentation in women with coeliac disease. Methods: Two hundred and eighty one women entered into a study of bone health in coeliac disease provided data on mode of presentation of disease, general risk factors for osteoporosis and fracture history. All women underwent DEXA scanning of hip and lumbar spine. Not all history items are available on all women. Results: Overall, mean z-scores were reduced at the lumbar spine (–0.55 ± 0.15, mean ± 95% C.I.) and femoral neck, (–0.60 ± 0.15). Women who reported diarrhoea as a presenting symptom of coeliac disease (n = 185) had significantly higher z-scores at the lumbar spine than women who did not report diarrhoea (n = 59), (–0.43 v –0.87, p = 0.007). Lumbar spine z-scores were significantly lower in women over 60 compared to women under 40, (p = 0.03), with lower z-scores in women without a history of diarrhoea in all age groups. Differences between the groups at the femoral neck were not significant. No significant differences in z-

S133 scores at either site were noted between women presenting with and without weight loss, anaemia or tiredness. There were no other significant demographic differences between women with and without diarrhoea. Discussion: The better lumbar spine BMD seen in women with diarrhoea may have several explanations. We speculate that the reduced BMD in women with coeliac disease is due to a prolonged period of malabsorption prior to diagnosis. The continuing decline in z-scores with increasing age raises the possibility of continuing malabsorption as a result of incomplete gluten exclusion. It seems likely that diarrhoea leads to quicker diagnosis than other symptoms. It is also possible that compliance with a gluten-free diet is better in those who develop diarrhoea in the event of a dietary lapse than in those who do not.

P446MO. ABNORMALITIES OF BONE AND MINERAL METABOLISM IN PATIENTS WITH EATING DISORDERS Conradie MM1, Jordaan G2, Hough FS3; 1Dept Endocrinology, Tygerberg Hospital, 2Dept Psychiatry, University of Stellenbosch, 3 Dept Internal Medicine, University of Stellenbosch Osteopenia is a well documented complication of anorexia nervosa (AN), although its pathogenesis remains poorly defined. We studied, 59 Caucasian (15–45 yr) eating disorder patients, classified as either anorexia nervosa (AN), bulimia nervosa (BN) or eating disorder not otherwise specified (EDNOS). A detailed dietary and general history was obtained. We assessed the prevalence and severity (DEXA), the nature (osteocalcin, deoxypiridinoline) and sites (vertebral/hip) of the osteopenia. The role of nutritional factors and vitamin D deficiency, physical activity, hypercortisolemia and hypogonadism in the pathogenesis of bone loss was also evaluated. A low bone mineral density (BMD) (decreased by more than 1SD below age-matched controls) was documented in 46%, with more marked osteopenia (Z-Score 5–2 SD) present in 15%. Both vertebral and hip osteopenia were present. Sixty four percent of AN, 29% of BN and 35% of EDNOS patients were osteopenic. A history of fragility fractures was present in 24%. Conventional risk factors were similar, except for a significantly longer duration of amenorrhoea (p = 0.009), a lower BMI (p = 0.0001) and greater alcohol consumption (p = 0.05) in the osteopenic patients. Nutritional parameters, 25(OH) vitamin D and cortisol levels were similar in AN and BN subjects, as well as in patients with a low versus normal BMD. Significant bone loss was only documented in patients with a past or current history of amenorrhoea. A significant negative correlation between BMD and duration of amenorrhoea was documented (r = -0.4, p = 0.001). We conclude that osteopenia commonly attends AN, as well as BN and EDNOS. Current nutritional (with the exception of alcohol consumption) and mechanical factors as well as hypercortisolemia did not contribute significantly to bone loss and hypogonadism appeared to be the main cause of the bone loss observed in these patients.

P447SA. ORAL ANTIRESORPTIVE THERAPY PREVENTS BONE LOSS AT THE LUMBAR SPINE ONE YEAR AFTER LIVER TRANSPLANTATION Camacho P, Islam K, Peralta M, Creech S, Bella N, Nabham F, Sizemore G, Van Thiel D; Loyola University of Chicago, Maywood, USA Aim: Previous studies showed rapid declines in bone mineral density (BMD) at the lumbar spine and femur after liver transplantation. Several studies evaluated intravenous bisphosphonates as therapy. We aim to determine whether oral antiresorptive therapy prevents bone loss after liver transplantation. Methods: We evaluated pre and one year post-transplantation BMD of 27 patients having liver transplantation at our institution

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Abstracts

from 1998-2000. 14 patients received oral antiresorptive therapy (Tx group), including alendronate (11), calcitonin (8), estrogen (1) and risedronate (1). Combination therapy with two agents was used in seven of these patients. 13 patients received no antiresorptive therapy (No Tx group). Patients with creatinine above 2 mg/dl, abnormal thyroid stimulating hormone or calcium levels were excluded from the study. Mean BMDs were compared using Wilcoxon Signed-Rank test. Results: There were no differences in baseline characteristics (age, sex, weight, calcium, creatinine, pretransplant liver disease) between the groups. Pretransplant lumbar spine (LS) BMD was not statistically different but femoral neck (FN) BMD was lower in the Tx group (p = .048). Table 1 shows baseline and one year BMD in the two groups. Conclusions: At one year, the No Tx group had significant bone loss at the lumbar spine and femoral neck. The Rx group preserved bone at the LS, but lost bone at the femoral neck. Oral antiresorptive therapy appears to diminish transplantation induced bone loss in the lumbar spine. Femoral neck BMD loss post-transplantation is more marked relative to lumbar spine BMD loss, suggesting predominance of cortical over trabecular bone loss in this population. No Tx Group

Baseline One year

Tx Group

LS BMD

FN BMD

LS BMD

FN BMD

1.234 ± 0.22 1.190 ± 0.19 (p = 0.026)

1.067 ± 0.17 0.952 ± 0.18 (p = 0.008)

1.147 ± 0.25 1.120 ± 0.26 (p = 0.552)

0.929 ± 0.17 0.844 ± 0.09 (p = 0.030)

BMDs are expressed as mean ± SD. P values compare baseline and posttransplantation BMD.

P448SU. BONE MASS IN ALCOHOLIC CIRRHOSIS Bernardes M1, Bernardo A1, Valente P1, Mariz E1, Branda˜o F1, Pereira S3, Cardoso A1, Vieira-Lopes A2, Vaz C1, Lopes-Vaz A1; 1 Rheumatology Department, S. Joa˜o Hospital, Porto,Portugal, 2 Medicine 4 Department, S. Joa˜o Hospital, Porto, Portugal, 3 Department of Hygiene and Epidemiology, Porto Medical School, Portugal Objectives: The aim of the present cross-sectional study was to determine osteoporosis (OP) prevalence and possible causes of bone loss in alcoholic cirrhotic patients. Methods: This study comprise 44 patients with alcoholic cirrhosis (13 male; 13 premenopausal women (premw); 18 postmenopausal women (posmw)), and 44 healthy controls, matched with respect to sex, age, body mass index and menopausal state. Cases were randomly selected in the first outpatient clinic visit after hospital discharge, due to Child-Pugh stage C disease. We evaluated bone mineral density (BMD) with Lunar Expert 1320 DXA and calcaneal quantitative ultrasound (QUS) parameters with Osteometer DTUone, in the two groups. Markers of bone turnover (serum osteocalcin, beta-crosslaps, bone alkaline phosphatase and urinary deoxypiridinoline/U-DPR and cross-linked N-telopeptides of type I collagen/NTX), free testosterone, intact PTH, 25(OH) vitamin D3, creatinine and liver function tests were measured in the patients. Results: According DXA parameters, 13% of premw, 50% of posmw and 12% of men were osteoporotic. Consensually, patients exhibited abnormally high levels of bone resorption markers and a big decreased in osteocalcine titles. All male patients presented subnormal values of free testosterone. Secondary hyperparathyroidism (with only 13% of the cases with mildly raised creatinine), generalized hyperprolactinemia and a universal 25(OH) vitamin D3 deficiency are sufficient to explain the bone loss. Lumbar spine and proximal femur BMDs were positively correlated with testosterone. Conclusions: Cirrhotic patients presented significantly lower lumbar spine and proximal femur BMDs than controls and showed an enhancement in bone turnover. Various hormonal

factors, behind the toxic effect of alcohol, seams to contribute to bone loss in this patients.

P449MO. OSTEOPOROSIS IN RHEUMATOID ARTHRITIS Mariz E1, Cardoso A1, Vaz C1, Valente P1, Bernardes M1, Bernardo A1, Branda˜o F1, Pereira S2, Lopes-Vaz A1; 1Rheumatology Department, S. Joa˜o Hospital, Porto, Portugal, 2Department of Hygiene and Epidemiology, Porto Medical School Aims: To evaluate the frequency of osteoporosis (OP) and reduced bone mass in rheumatoid arthritis (RA), compare with matched healthy controls and to study possible correlations between bone mineral density (BMD), disease parameters and bone markers. Methods: 72 female patients (mean age: 55.3 years; mean disease duration: 15.9 years; post-menopausal: 79.2%; rheumatoid factor (RF)+: 61.4%; history of osteoporotic fractures (OF): 14.1%) randomly chosen from our outpatient clinic were compared with 133 age-, body mass index-, menopausal stateand years since menopause (YSM)-matched controls. BMD was measured by DXA at lumbar spine (LS), femoral neck (FN) and hip. Left calcaneal QUS parameters (BUA and SOS) were determined. In the patients group the following parameters were also assessed: dose and duration of steroid therapy, ESR, CRP, bone markers, disability and pain scores (HAQ). Results: The patients had significantly higher frequency of OP and reduced BMD by DXA as well as by QUS compared to the controls. The RF+ patients had significantly lower BMD at FN and hip and higher osteocalcin. The patients with previous OF had lower BMD by DXA. LS, FN, hip BMD, BUA and SOS were all negatively correlated with age and YSM. BMD at both LS and hip had a negative correlation with ESR (r = –0.35, p50.01). FN and hip BMD had a positive correlation with BMI. SOS also showed a negative correlation with mean daily steroid dose (r = –0.33, p50.05). Among bone markers, osteocalcin inversely correlated only with HAQ score D-pyr positively correlated with ESR (r = 0.40, p50.05) and disease duration (r = 0.35, p50.05); beta-crosslaps correlated positively only with ESR (r = 0.3, p50.05). We found a significant negative correlation between LS BMD and bone markers (osteocalcin, beta-crosslaps, NTx). Conclusions: Rheumatoid Arthritis patients had a decrease in BMD compared to the controls. Our data suggest that disease severity parameters and the steroid therapy increase the bone turnover.

P450SA. FAMILIAL AMILOIDOTIC POLINEUROPATHY (FAP) AS A RISK FACTOR FOR OSTEOPOROSIS Miranda LC1, Simo˜es Me1, Diz A2, Parente M1, Conceic¸a˜o I2, Evangelista T2, Carvalho M2, Sales-Luis ML2; 1Instituto Portugueˆs de Reumatologia, 2Hospital de Santa Maria, Portugal Introduction: FAP Type I (Val30Met) is a rare condition characterized by being a genetic based progressive polineuropathy with major organ involvement by the deposition of amiloid substance. Aim of the study: To compare two similar groups of patients one with FAP and the other with other types of neuromuscular disorders regarding BMD and risk factors for osteoporosis. Methods: We selected 15 patients, men and premenopausal women excluding patients with other chronic diseases or medicated with drugs known to interfere with bone metabolism. All patients had a DEXA scan Group 1–9 FAP patients, Group 2–6 patients with lateral amyothrophic sclerosis (ALS), and chronic hereditary polineuropathy. All patients were ambulatory and the strength of the hip flexion was above 3 MRC. Results: Mean age 43,6±9,2 [26,64] years No statistical differences were found in age, sex, weight at 25 years, alcohol, smoking, calcium intake or exercise between the two groups. The FAP group had lower body mass index. Of the FAP patients 66;7% were osteoporotic against 0% of the other group.

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Conclusion: Despite the small numbers in both groups we found a strong statistical significance in almost every DEXA scan parameters which suggests that FAP patients have a high risk of developing osteoporosis even in early stages of the disease. Amiloidotic renal failure and degree of disautonomy could partially explain the results. Statistic significance

L1-L4

Hip neck

Hip total

Hip wards

Wrist Wrist one third mid

Wrist Ud

Wrist total

BMD T-score Z-score

0.03 0.05 0.05

0.03 0.064 0.01

0.005 0.07 0.005

0.017 0.009 0.007

0.099 0.052 0.045

0.034 0.034 0.029

0.099 0.025 0.116

0.081 0.045 0.034

P451SU. BONE MASS IN SYSTEMIC LUPUS ERYTHEMATOSUS Bernardes M1, Valente P1, Bernardo A1, Mariz E1, Branda˜o F1, Cardoso A1, Pereira S2, Vaz C1, Lopes-Vaz A1; 1Rheumatology Department, S. Joa˜o Hospital, Porto, Portugal, 2Department of Hygiene and Epidemiology, Porto Medical School, Portugal Objectives: The aim of the present cross-sectional study was to determine osteoporosis (OP) frequency and possible causes of bone loss in a SLE female population. Methods: This study comprises 71 females with SLE (age 43 ±12 years; 46 premenopausal (premw); 25 post-menopausal (posmw)), treated with an average daily dose of prednisone (addp) of 8,14±4,96 mg, and 71 healthy females, matched with respect to age, body mass index and menopausal state. We evaluated bone mineral density (BMD) with Lunar Expert 1320 DXA and calcaneal quantitative ultrasound (QUS) parameters with Osteometer DTUone, in the two groups. Markers of bone turnover (serum osteocalcin, beta-crosslaps, bone alkaline phosphatase and urinary deoxypiridinoline/U-DPR and cross-linked N-telopeptides of type I collagen/NTX), C3c, C4, CH100, anti-DNAds antibodies (atb) and SLEDAI were measured in the patients. Results: According DXA parameters, 30% of premw and 36% of posmw were osteopenic; 14% of posmw were osteoporotic. There was only one case of OP in premw. Generally, patients exhibited abnormally high levels of bone resorption markers, either in premw and in posmw. On the other hand, 44% of premw and 64% of posmw showed decreased osteocalcin levels. We have found a significant positive association of bone resorption markers with complement fractions (C4, CH100) titles, antiDNAds atbs and C-reactive protein levels, in premw. Corticosteroid exposure variables (cumulative prednisone dose and addp) correlate negatively with bone formation markers and positively with the resorption ones, in premw. Posmw exhibited a negative correlation between osteocalcin and CH100 (r = –0,738,p50,05). We didn’t find any significant correlation with SLEDAI. Conclusions: SLE patients presented significantly lower lumbar spine BMD, BUA and SOS than controls. These women showed an enhancement in bone resorption and a decrease in bone formation in equal proportions, which apparently seams to be correlated either with the disease and the corticoid use.

P452MO. METABOLISM AND BONE MINERAL DENSITY IN ASTHMATIC PATIENTS TREATED WITH INHALED CORTICOSTEROIDS Bernardo A1, Bernardes M1, Mariz E1, Valente P1, Cardoso A1, Barata L2, Pereira S3, Vaz C1, Lopes-Vaz A1; 1Department of Rheumatology, H. S. Joa˜o, Porto, Portugal, 2Department of Immunoallergology, H. S. Joa˜o, Porto, Portugal, 3Department of Hygiene and Epidemiology, University of Porto Medical School, Portugal Aims: Osteoporosis is a frequent side effect of systemic corticotherapy. The aim of this study was to evaluate bone repercussion of inhaled corticosteroids (IC).

Methods: We studied 42 asthmatic premenopausal women aged 25–41 years. Patients had taken an IC regularly for at least 3 months and had had limited exposure to systemic steroids. Nine patients were treated with beclometasone, 12 with fluticasone and 21 with budesonide. Mean daily dose (MDD) and cumulative dose (CD) were calculated from questionnaires. Biochemical markers of bone turnover (bone specific alkalin phosphatase (BSAP), serum osteocalcin (OC), beta-crosslaps (BCL) and crosslinked N-telopeptides of type 1 collagen (NTX)) were measured. Bone mineral density (BMD) was assessed by DEXA (Lunar Expert 1320). Calcaneal quantitative ultrasound (QUS) was performed with Osteometer DTU-one. Results: According to DEXA’s z-score, 7 patients had osteopenia and 1 had osteoporosis. Considering QUS, osteoporosis was found in 2 patients (SOS t-score 4–2,5); osteopenia was detected in 9 by BUA t-score and in 12 by SOS t-score. BMD was higher in women treated with fluticasone, but the difference was not significant. MDD was significantly higher in osteopenic women (as defined by BUA t-score) than in normal women (p50,001). Decreased OC levels were present in 31% of patients and 60% had decreased BSAP. Abnormally high levels of BCL (24% of patients) and NTX (40% of patients) were found. 14% had at the same time decreased markers of bone formation and increased markers of bone resorption. Women treated with beclometasone and fluticasone had lower levels of BSAP and higher levels of bone resorption markers (BCL and NTX), although the differences were not significant. There was no relation between MDD or CD and biochemical markers of bone turnover. Conclusion: Patients treated with IC tend to have abnormal bone turnover, however changes in BMD are minimal.

P453SA. OSTEOPOROSIS IN ANKYLOSING SPONDYLITIS Valente P1, Bernardes M1, Branda˜o F1, Bernardo A1, Mariz E1, Cardoso A1, Pereira S2, Vaz C1, Lopes-Vaz A1; 1Department of Rheumatology, H. S. Joa˜o, Porto, Portugal, 2Department of Hygiene and Epidemiology, University of Porto Medical School, Portugal Aims: The aim of this study was to investigate the frequence of osteoporosis (OP) and osteopenia in ankylosing spondylitis (AS), and their relation with concentration of acute phase reactants and indices of bone turnover. Methods: This study comprises 54 men with AS, mean age 41,5±13,3 years, who had disease for a mean period of 14,2±9,2 years. Bone mineral density (BMD) (Lunar Expert 1320) and calcaneal quantitative ultrassound (QUS) parameters (Osteometer DTU-one) were evaluated in patients and in a control group (54 men, aged 42,2±13,3 years). Biochemical markers of bone turnover (serum osteocalcin, beta-crosslaps, bone alkaline phosphatase (APb); urinary deoxypiridinoline (U-DPR), crosslinked N-telopeptides of type 1 collagen (NTX) and acute phase reactants were measured. Results: OP and osteopenia were observed in 3 (5,9%) and 11 patients (21,6%) at the lumbar spine, and in 4 (8%) and 19 patients (38%) at the femoral neck, respectively. There were no cases of vertebral or hip OP in the control group. Abnormally high levels of U-NTX (32,6%), U-DPR (50%), beta-crosslaps (69,8%), osteocalcin (17,6%) and APb (22,2%) were found. Syndesmophytes score, APb, U-DPR were strongly associated with disease duration. On the other hand, C-reactive protein was positively correlated with NTX and syndesmophytes score. Also, significant positive correlations between lumbar BMD and body mass index and disease duration were found. A significant negative correlation was obtained between Ward BMD and age. Conclusions: The prevalence of OP in AS men was higher than in the control group, and could be observed in early stages of the disease. In patients with advanced spinal changes, ossifications may yield normal or increased values for the lumbar spine BMD. Enhancement of bone resorption was the hallmark in the mecanism of OP in AS.

S136 P454SU. PROGRESSIVE ANDROGEN DEFICIENCY IN THE MALE AND BONE MINERAL DENSITY Mascarenhas MR1,2, Almeida F2, Qu¨c¸ MA2, Senra MH2, Garcia-eCosta J3, Galvo-Teles A1,3; 1Endocrinology, Lisbons Faculty of Medicine, 2Osteoporosis Unit, Endlab, Lda., Lisbon, 3 Endocrinology, Santa Maria University Hospital, Lisbon, Portugal Although there is no andropause comparable with the abrupt menopause in women, total testosterone (T) levels decline with age in men. Nevertheless, studies regarding bone mineral density (BMD) and T in the male aging are scarce. Objectives: The aim of this study was to evaluate the BMD in different T plasma levels in normal men aged 40 years or older. Population and Methods: In 229 normal men aged 40 years or older (mean age = 55.6 ±s 9.5 years) total testosterone and 17beta-estradiol plasma concentrations were measured by RIA. This group was divided according to the T levels [T 42.0 ng/mL or andropause group (n = 23), 2.0 5 T 43.0 ng/mL (n = 38), 3.0 5T 44.0 ng/mL (n = 57), T 44.0 ng/mL (n = 111)]. The BMD (Kg/ cm2) at the lumbar spine (L1-L4), at the hip (total), at the distal forearm (total) and the total fat (TFM) and lean (TLM) body masses (Kg) were studied using the densitometer QDR 4500 Acclaim (Hologic). Height (m), weight (Kg) and body mass index (BMI, Kg/ m2). Data were statistically evaluated by the multifactorial OneWay Anova, multiple regression analysis and the coefficient of Pearson tests. Results: The mean BMD at the hip (total) was significantly reduced in the andropause group (P50.001); in this group significant TLM/BMD at the hip and at the lumbar spine relationships were detected, as well as a significant 17bestradiol/BMD at the distal forearm relationship (P50.05). Conclusions: The results of this study can suggest that, in the male older than 40 years, the sex steroid plasma levels can also contribute to the variation and the maintenance of the BMD. Probably, in the andropausal individuals, the total lean body mass is also a predictive factor of the BMD in the andropause.

P455MO. SERUM 25-OH VITAMIN D3 IN CHRONIC RHEUMATIC PATIENTS Delle Sedie A, Mazzantini M, Frigelli S, Di Munno O; Rheumatology Unit, Internal Medicine, University of Pisa, Italy Vitamin D3 plays a crucial role in bone mineralization. Vitamin D3 deficiency is an underestimated problem. Low levels of 25-OH D3 (i.e. 5 12 ng/mL) have been documented in both general population and internistic hospitalized patients. A recent Italian study on 799 postmenopausal women, who had been referred to 43 Centers for Osteoporosis (February-March) for their first densitometric test, showed that 74% had 25-OH D3 512 ng/ mL. Aim of our study is the assessment of 25-OH D3 in patients with chronic rheumatic diseases, referred for hospitalization to the Rheumatologic Unit of the University of Pisa. Exclusion criteria were vitamin D supplementation in the previous 6 months and concomitant diseases or drugs that could interfere with bone metabolism, with the exception of glucocorticoids. We measured 25-OH D3 serum levels (25-Hydroxyvitamin D 125I RIA Kit, DiaSorin), 1,25-(OH)2 D3 (Gamma-B 1,25-Dihydroxy Vitamin D RIA Kit, Immunodiagnostic Systems), PTH (Intact PTH IRMA Kit, Nichols Institute Diagnostics), Osteocalcin (ELSA-OST-NAT, CIS Bio International), bone Alkaline Phosphatase (Ostase, IRMA, Beckman Coulter), N-telopeptide of type I collagen (NTx) (Osteomark NTx serum enzyme-linked immunoassay, EIA, Ostex). So far we have examined (November-May) 100 patients (78 females, 22 males), aged 58.8 years (range 22–82), affected with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, osteoarthritis, SLE, polimyositis, Sjo¨gren syndrome, polimyalgia rheumatica and vasculitis. Mean 25-OH D3 values were 14.9±10 ng/mL (range 0.3– 69.1); 44 patients (44%) had 25-OH D3 512 ng/mL and 13 of them had PTH above the upper normal limit; 18 patients (18%) had values 56 ng/mL. Significant correlations were found between

Abstracts 25-OH D3 and PTH (r = –0.27, p50.01), age and PTH (r = 0.45, p50.0001), NTx and PTH (r = 0.39, p50.005), and age and NTx (r = 0.41, p50.002). Our preliminary data show that in chronic rheumatic patients serum levels of 25-OH D3 are frequently low, possibly due to low sun exposure and low-fat diet. Therefore serum levels of 25-OH D3 should be assessed particularly in the case of densitometric evidence of reduced bone mass.

P456SA. DISTURBANCES OF BONE MINERALIZATION IN CHILDREN WITH NEPHROTIC SYNDROME Chlebna-Soko´l D1, Loba-Jakubowska E1, Rusinska A1, Kozlowski J2, Bodalski J2, Lorenc RS3; 1Department of Paediatric Propedeutics, Medical University, Lo´d, Poland, 2Department of Children’s Diseases, Medical University, Lodz, Poland, 3 Laboratory of Bichemistry and Experimental Medicine, Center of Children’s Health, Warsaw, Poland Coricosteroids are fundamental drugs in the treatment of nephrotic syndrome. They have a lot of side effects; e.g. disturbances in bone mineralization and loss of bone mass. The aim of the study was to estimate biochemical markers of bone metabolism and mineralization in children with nephrotic syndrome (NS) on long-term treatment with corticosteroids. Patients and Methods: The study comprised 32 children (23 boys and 9 girls), aged 6 to 19 years. NS patients were treated with corticosteroids (CS) from 6 months to 15 years. Total dose of the drug ranged from 1.07 to 39.3 g. The following examinations were performed in all the children: bone densitometry (DEXA, total body and spine programme), serum calcium, phosphorus, and magnesium concentrations, level of: PTH, 25-OHD, osteocalcin and activity of bone izoenzyme of alkaline phosphatase (BALP). Elimination of calcium ions, concentration of pyridinoline, deoxypyridinoline and collagen type I crosslinked C-telopeptide were determined in urine. Statistical analysis was performed with Statistica 5.0. Results: The study revealed significant decrease in bone mineralization in 13 of the total 32 children. In 5 casesosteoporosis, and in 8-osteopenia were diagnosed. The most frequent abnormalities were: elevated activity of BALP and increased osteocalcin concentration in the blood serum, as well as increased elimination of bone resorption markers. Statistically significant correlation between the dosage of CS per kg of body mass and decrease in bone mineralization (program spine) and also between CS dosage and BALP activity were observed. Conclusions: Corticosteroids in children with nephrotic syndrome may lead to osteoporosis and osteopenia. Decreased skeleton mineralization in DEXA is accompanied with abnormalities in biochemical markers of bone metabolism in these children. Acknowledgement: The study was partly financed from State Committee for Scientific Reaserch grant No. 4P05E 03816.

P457SU. THE PREVALENCE OF SECONDARY CAUSES OF OSTEOPOROSIS Papaioannou A1, Sebaldt R1, Adachi JD1, Petrie A2, Ferko N3, Ioannidis G1, Boulos P1, Stephenson G4, Goldsmith C2; 1McMaster University, Department of Medicine, Hamilton, Ontario, Canada, 2McMaster University, Centre for Evaluation of Medicines, Hamilton, Ontario, Canada, 3McMaster University, Department of Clinical Health Sciences, Hamilton, Ontario, Canada, 4Procter & Gamble Pharmaceuticals Inc, Toronto, Ontario, Canada Aim: The purpose of this study was to determine the prevalence of secondary causes of osteoporosis in tertiary referral centers. Methods: We analyzed CANDOO, a prospective database of osteoporosis and osteopenia Canadian patients. Data were gathered for 561 males and 5604 females with a mean age of 64.1 years.

Abstracts

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Results: Of the 1703 (28%) patients with a fragility fracture within 5 years, 151 had a hip fracture, 539 a wrist fracture, 741 a vertebral fracture, and 281 a rib fracture. Secondary causes of osteoporosis (41 condition) were higher in men, 288/561 (51.3%) than women, 2319/5604 (41.4%), p50.001. The most frequent cause of secondary osteoporosis was corticosteroid use in the past 5 years. In total, 884 of 6165 patients (14.3%) had used oral/ inhaled corticosteroids with greater use in men (27.1%) vs. women (13.1%), p50.001. In fracture patients 249/1703 (14.6%) used corticosteroids. Thyroid disorder occurred in 15.4% of women vs. 4.9% of men, p50.001. The fracture cohort for women, n = 273/1504 (18.2%) had significantly more thyroid disorder, p = 0.01, with no difference in men, n = 10/199 (5%), p40.5. Of patients with osteoporosis, 12.8% had a lung disorder, 3% had liver disease, 2% used anticonvulsants, 0.7% had hyperparathyroidism and 1.1% had monoclonal gammopathy. Hypogonadism was not assessed in men. Conclusion: In our cohort, the most prevalent conditions associated with secondary osteoporosis were corticosteroid use, thyroid disease and lung disease.

P458MO. THE FACTORS INFLUENCE ON BONE MINERAL DENSITY (BMD) IN WOMEN WITH EXOGENOUS HYPERCORTICOIDISM Martchenkova LA, Dreval AV, Poliakova EU, Milov NM; Moscow Regional Research Clinical Institute, Moscow, Russia The purpose of our study was to assess factors influence on BMD in women chronically treated with oral glucocorticoids (OGC). The study comprised 50 women with asthma aged 41–66 years (54.5±6.7 (M±s)) received OGC for 1-34 years. Control group consisted of 129 women 41-66 years old (53.3±8.3) hadn’t ever received any GC therapy. BMD was assessed utilizing DEXA technique at lumbar spine, proximal femur and distal forearm. Results: Premenopausal women used OGC (n = 18) had no difference in vertebral end non-vertebral fracture rates vs. premenopausal controls (n = 52), but incidence of vertebral deformities was 64% in postmenopausal ones vs. 42% in post menopausal controls (p50.05). There was no difference in BMD in premenopausal and postmenopausal groups vs. age-related controls, but BMD (T-score, SD) was lower in all women treated OGC vs. all controls (–1.25±1.5 vs. –0.71±1.5 in spine and 70.45±1.3 vs. 0.04±1.3 in total femur, p50.05). Asthmatic women with osteoporosis vs. normal ones were older (60.6±4.0 vs. 51.9±6.2, p50.001), had more postmenopause (11.5±3.9 vs. 4.49±5.6, p50.05), duration of OGC treatment (15.6±11 vs. 8.83±6.4, p50.05) and lower body weight (68.1±12 vs. 77.9±10, p50.05. Only body weight (kg) showed significant correlation with BMD (g/cm2) in all skeletal sites (r = 0.54–72, p50.05) in premenopausal asthmatic women. Correlation of BMD with risk factors in postmenopause is demonstrated in the table (*p50.05, **p50.01). Conclusions: Prolong OGC therapy increases risk of osteoporosis and vertebral deformities. BMD depends on body weight in premenopause, and on age, duration of postmenopause, duration and dose of OGC, body weight and daily calcium intake in postmenopause. Factors

BMD (g/cm2) L2-L4

Age, years Postmenopause, years Duration of OGC therapy, years Standardized daily dose of OGC, tabs Daily calcium intake, mg Body weight, kg

Femoral Ward’s neck triangle

–0.41* –0.41* –0.47* –0.41* –0.34* –0.41* –0.43* 0.41* 0.4* 0.55** 0.45*

Trochanter Distal forearm

–0.54** –0.39*

–0.37* –0.37*

–0.56**

0.34* 0.47*

0.45* 0.43*

0.48**

P459SA. BONE CHANGES AFTER PARTIAL GASTRECTOMY Payer J, Stenova E, Killinger Z, Hruzikova P, Kratochvilova H, Ondrejka P; University Hospital, 1st. Dept. of internal Medicine, Bratislava, Slovakia Metabolic bone disorder is a recognised complication following partial gastrectomy. The pathogenesis of bone metabolism’s changes is multifactorial: poor dietary intake, rapid transit of food, impaired absorption of vitamin D and calcium and decreased acidity of gastric fluid. The aim of our study was to investigate the incidence of bone changes in patients after gastric surgery. We have examined a group of 31 patients (13 women, 18 men) after partial gastrectomy (operation more than 10 years ago, type Billroth I 8, Billroth II 25 pts., average age 61 years) and compared with a corresponding control group (13 women, 18 men, same average age, in the group of women same average time after menopause). Patients with other causes of metabolic bone disorders were excluded. We have measured bone mineral density (hip and lumbar spine L2-4, Norland XR-36) and bone remodelation’s parameters. We have find out a significant decrease of BMD in the femoral neck (p 0,001), increased levels of ALP-S (p50.05), NTx-U (p50,001). The BMD in the lumbar spine, Ca-S, Mg-S, P-S were insignificantly diminished and CTx-S, CTx-U, Ca-U, Mg-U, P-U, osteocalcin-S and PTH-S were insignificantly elevated. There were no significant differences between patients after Billroth type I and Billroth type II gastrectomy. Our results emphasises the need for regular screening of postgastrectomy patients to detect early changes of bone metabolism. Prophylactic administration of supplemental calcium and vitamin D (or its metabolites) might be reasonable after partial gastrectomy.

P460SU. THYROID AND BONE METABOLISM Bernardes M1, Ramires M2, Bernardo A1, Valente P1, Mariz E1, Cardoso A1, Pereira S3, Vaz C1, Medina L2, Lopes-Vaz A1; 1Rheumatology Department, S. Joa˜o Hospital, Porto, Portugal, 2 Endocrinology department, S. Joa˜o Hospital, Porto, Portugal, 3 Department of Hygiene and Epidemiology, Porto Medical School, Portugal Objectives: The aim of this retrospective cross-sectional study was to investigate whether former hyperthyroid (fh) patients have an increased risk for developing osteoporosis due to reduced bone mass and/or persisting high bone-remodelling activity after euthyroidism was restored. A group with thyrotoxicosis (tt) was also evaluated. Methods: This study comprise 59 fh females (age 39 ±13 years; 24 premenopausal (premw); 35 post-menopausal (posmw)), 7 premw with tt and 65 healthy females, matched with respect to age, body mass index and menopausal state. We evaluated bone mineral density (BMD) with Lunar Expert 1320 DXA and calcaneal quantitative ultrasound (QUS) parameters with Osteometer DTUone in the two groups. Markers of bone turnover (serum osteocalcin, beta-crosslaps, bone alkaline phosphatase and urinary deoxypiridinoline/U-DPR and cross-linked N-telopeptides of type I collagen/NTX), circulating thyroid hormones and antithyroid antibodies (atb) were measured in the patients. Results: In the fh group, according DXA parameters, 18% posmw had vertebral OP and 6% had hip OP. A higher prevalence of OP was detected by QUS. There were no cases of osteoporosis in premw. Bone resorption markers were abnormally high and osteocalcin was decreased. In premw, significant correlations were detected between each biomarker and free T3, free T4 and anti-TSH receptor atbs titles (positive ones) and also with TSH levels (negative ones). In the tt group, proximal femur BMD correlates significantly with free T4. Conclusions: Former hyperthyroid women showed significantly lower lumbar spine and proximal femur BMDs, BUA and SOS than controls. This difference was stronger in hyperfunctioning

S138

Abstracts

adenoma and toxic multinodular goitre than in Graves’ disease. These women presented increased bone turnover in spite being euthyroid. This could signify that normal TSH levels close to the inferior limit of normality and normal free T3 and T4 titles close to the superior limit of normality have some responsibility.

P461MO. BONE DENSITY OF CALCANEUS, LUMBAR SPINE AND HIP IN ANKYLOSING SPONDYLITIS USING QUANTITATIVE ULTRASOUND AND DUAL ENERGY X-RAY ABSORPTIOMETRY: ROLE OF DURATION OF DISEASE Bruyn GAW1, Westra R1, Aarts MHM2, Zaanen S2, Jansen TLTA1; 1 Medisch Centrum Leeuwarden, Leeuwarden, Netherlands, 2Isala Klinieken, Zwolle, Netherlands Aims: To evaluate the bone density of patients with ankylosing spondylitis (AS) both at the axial skeleton and at two peripheral sites using dual energy x-ray absorptiometry (DXA) and the quantitative ultrasound (QUS) technique. To assess whether bone density differed in patients with longstanding disease (410 yrs) from those with shorter disease (510 yrs). Methods: The subjects were adult men and women with definite AS. Bone density of the calcaneus was measured with the Sahara Sonometer. Sahara measured the broadband ulrasound attenuation (BUA, in dB/mHz) and speed of sound (SOS, in m/s) through both heels. BUA and SOS were combined to form the quantitative ultrasound index (QUI). Estimated heel BMD was calculated from the QUI (g/cm2). The BMD in lumbar spine (anterior-posterior view) and femoral neck was measured with DXA. Results: 39 patients (27 male, 12 female) were measured, aged 32-72 years, mean 51 ± 12 (SD) years. Mean calculated T score heel of all patients was –0.63 ± 1.05, mean BMD T-score spine was –1.3 ± 1.5 and mean BMD femoral neck –1.5 ± 1.0. Pearson correlation (r) BMD heel/spine was 0.48 (P50.0005), r BMD heel/ hip was 0.40 (P50.01); r BMD heel/spine short duration was 0.48 (NS), r heel/hip short duration 0.17 (NS); r BMD heel/spine long duration was 0.62 (P50.001), r BMD heel/hip long duration 0.53 (P50.001). Discussion: Both QUS and DXA showed that disease duration accounts for the difference in bone density in patients with AS of similar age. Patients with 410 yrs of disease had significantly more bone loss at all sites compared to those with a disease 510 yrs. These findings indicate that osteoporosis develops gradually with time in AS, not only at the spine, but also at the calcaneus and hip. Mean ± SD

AS510 yrs

AS410yrs

P-value

BUA SOS QUI Estimated density T-score heel T-score spine T-score femoral neck

91 1584 115 0.65 0.12 –1.0 –1.1

71 ± 16 1535 ± 27 91 ± 17 0.50 ± 0.11 –0.91 ± 0.9 –1.4 ± 1.6 –1.6 ± 1.0

50.05 50.05 50.01 50.05 50.001 50.01 50.05

± ± ± ± ± ± ±

22 33 21 0.14 0.59 1.0 1.2

P462SA. VITAMIN-D DEFICIENCY AND SECONDARY HYPERPARATHYROIDISM Galofre´ N, Ravento´s A, Gonza´lez-Ares JA, Castan˜o MC, Vila J, Are´valo MD, Carrasco I, Viles J, Grau J; Hospital Municipal, Badalona, Spain Background: There is no consensus about wich levels of 25hydroxyvitamin D (25-OHD) defines hypovitaminosis associated to secondary hyperparathyroidism. Related to geographical situation, it was the lowest levels of 25-OHD that keeps an adequate parathyroid hormone (PTH) concentration are between 12 ng/ml and 40 ng/ml. We conducted a prospective study to determine the lowest concentration of 25-OHD that keeps PTH into normal ranges.

Material and Methods: The study was done in Badalona (Spain), a city placed in the coast, with a mean of 12 hours/day of sun exposure. We studied outpatients free-living in a General Basic Hospital. We mesured in blood:urea, creatinine, calcium, phosphate, alkaline phosphatase, PTH, 25-OHD,, and in 24 hours urine: creatinine clearance, calcium urinary excretion. Hyperparathyroidism (HPP) was define when PTH concentration was higher than 72 pg/ml. Bone mineral density was determined with Hologic QDR 4500 SL, and the diagnostic of osteoporosis (OP) was made according the criteria of WHO. The statistical analysis were performed using X2 test and ANOVA. Results: 48 patients were analyzed, 47 were women with mean age of 66 years; in two patients PTH was not performed. The levels of 25-OHD are: 16.52 ± 9.75, and PTH 89 ± 68.33. 70% of patients, with 25-OHD levels below 12 ng/ml, had HPP. In the table we show the results (± SD). Conclusions: 1-Mean 25-OHD levels in our environment are deficitary although the high sun exposure.2-The increase in PTH levels are significantly higer with 25-OHD levels below 12 ng/ml. 3- Age, serum creatinine and creatinine clearance are factors that also increases PTH.

n 25-OHD Age Creatinine Clearance

PTH 472

PTH472

p5

26 20.4 ± 62.07 ± 0.89 ± 77.11 ±

20 11.5 71.25 0.99 58.73

0.000 0.011 0.045 0.027

10.8 12.09 0.12 26.81

± ± ± ±

5.5 10.87 0.19 25.20

P463SU. FUNCTIONAL OUTCOME AND QUALITY OF LIFE AFTER HIP FRACTURE IN THE ELDERLY COMMUNITYDWELLING Jongjit J; Department of Rehabilitation Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand Older people return to the community after hip fracture are considered to have the best outcome. However, their functionality and its relationship quality of life over the longer term have not been fully assessed. In a population-basd case-control study living in the community subjects six months after hip fracture. We investigated the association between functionality and quality of life. The outcomes examined in this study were; The Functional Independence Measure (FIM), the Frenchay Activities of Daily Living Index (FAI), and the Berg Balance Scale (BBS) were used to measure physical function and quality of life was measured by completing a Short Form-36 (SF-36). Seventy-two hip fractures and 72 controls (mean age 79±4.5, range 50–102) selected ageand sex-matched normal subjects without hip fracture. The hip fracture subjects scored significantly (p50.05) less than the controls in all measures of functions (FIM 95.54 vs 103.5; FAI 23.68 vs 30.76; BBS 46.21 vs 54.25). The SF-36 scores after six months still showed that all 8 domain were significant difference between the control group and the hip fracture group (SF-36: 72% vs 60%, p50.05). The diminish in function in the fracture group was reflected in reducing the quality of life. Thus, clinically reported hip fractures impair both the functionality and quality of life of these subjects. The adverse impact of hip fracture on quality of life and functionality need to be recognized by medical practitioners, and every health person in the community, so that adequate health resources can be devoted to the prevention and treatment of this debilitating condition.

P464MO. BONE MASS IN CARDIAC TRANSPLANT RECIPIENTS Bernardes M1, Martins E2, Valente P1, Bernardo A1, Mariz E1, Branda˜o F1, Cardoso A1, Vaz C1, Silva-Cardoso J2, Lopes-Vaz A1; 1 Rheumatology Department, S. Joa˜o Hospital, Porto, Portugal, 2 Cardiology Department, S. Joa˜o Hospital, Porto, Portugal Objectives: The aim of the present retrospective cross-sectional study was to determine osteoporosis (OP) prevalence and to

Abstracts assess changes in bone metabolism in a cohort of cardiac transplant recipients. Methods: Twelve patients (7 males; 5 females), who received a cardiac transplant during the past 10 years, due to dilated cardiomyopathy, were studied. The association of cyclosporin, azathioprine and prednisone was their immunosupressive therapy. We evaluated bone mineral density (BMD) with Lunar Expert 1320 DXA and calcaneal quantitative ultrasound (QUS) parameters with Osteometer DTUone and compare them with those of 12 controls, matched with respect to age, body mass index and menopausal state. Markers of bone turnover (serum osteocalcin, beta-crosslaps, bone alkaline phosphatase and urinary deoxypiridinoline/U-Dpyr and cross-linked N-telopeptides of type I collagen/NTX), free testosterone, intact PTH and creatinine were measured, in the patients. Results: According DXA parameters, the OP prevalence was 14% in men and 20% in women. OP frequency was higher with QUS (50%). Abnormally high levels of osteocalcine (42%), betacrosslaps (33%), NTX (22%), U-Dpyr (11%) and PTH (17%) were found. In spite of 3 men presented raised serum creatinine levels, only one showed secondary hyperparathyroidism. One woman presented high PTH levels, although creatinine was in normal range. We have found a significant positive correlation of NTX with cumulative cyclosporin dose (cpd) (r = 0,900; p50,05) and a negative one with age at the procedure (r = 70,975; p50,001). Proximal femur BMD was also negatively correlated with cpd (r = 70,886; p50,05). Conclusions: Cardiac transplant recipients presented significantly lower lumbar spine BMD, proximal femur BMD, BUA and SOS than controls. Lower proximal femur BMD and enhancement in bone turnover supported the leading causal role of cyclosporin therapy.

P465SA. BONE MINERAL DENSITY PREDICTORS IN JUVENILE SYSTEMIC LUPUS ERYTHEMATOSUS Terreri MT1, Castro TCM1, Szejnfeld VL2, Castro CHM2, Fisberg M1, Len CA1, Hilario MOE1; 1Department of Pediatrics, UNIFESP, Escola Paulista Medicina, Sao Paulo, SP, Brazil, 2Department of Medicine, UNIFESP, Escola Paulista Medicina, Sao Paulo, SP, Brazil Objective: This study aimed at evaluating spine bone mineral density (BMD) in juvenile systemic lupus erythematosus (JSLE) Brazilian children, searching potential predictors for reduction in bone mass. Patients and Methods: A cross-sectional study of BMD at lumbar spine (L2-L4) was conducted in 16 female JSLE aged 6-17 years. A group of 32 age-matched healthy girls was used as controls. BMD at lumbar spine was measured by dual-energy Xray absorptiometry (DXA). Weight (kg), height (cm) and pubertal Tanner stage were determined in all patients and controls. Disease duration, mean daily steroid doses (mg prednisone/kg/ day), mean cumulative steroid doses (g of prednisone) and JSLE activity measured by SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) were determined in all JSLE patients from medical charts. All parameters were used as potential determinant factors for bone loss. Results: Lumbar BMD in the JSLE patients was lower than agematched healthy control girls, however this difference did not reach statistical significance. In JSLE girls we did not observe significant correlation between BMD and age, height, Tanner stage, disease duration, corticosteroid use and disease activity. We found correlation between BMD and weight. In JSLE group we were not able to find significant parameters to correlate with reduced bone mass. Conclusion: Reduced bone mass was found in JSLE female patients and might contribute to further skeletal fragility. Disease activity and mean cumulative steroid doses were not important to determine BMD values in these patients. Our results suggest that

S139 reduced bone mass in JSLE children can be related to other intrinsic mechanisms and not only to steroid treatment.

P466SU. BONE MINERAL DENSITY IN MALES WITH CHRONIC INFLAMMATORY RHEUMATIC DISEASES Savickiene A, Baranauskaite A; Kaunas Medical University, Rheumatology Dept., Lithuania Rheumatoid arthritis (RA) and seronegative spondyloarthropathies (SSA) differs principally by inflammatory damage of peripheral and axial skeleton. 27 males with rheumatoid arthritis and 55 males with seronegative spondyloarthropathies were examed to determine the relation between the bone mineral density (BMD) and the duration, inflammatory activity of disease and the treatment with glucocorticosteroids. BMD was evaluated by DEXA according to WHO Study Group recommendations (1994). The mean disease duration of RA was 100,37±94,31 and of SSA 128,09±113,31 month (p = 0,3). 25(45,5%) pts in SSA and 7(25,5%) in RA (p = 0,09) were ill more than 120 month. The active disease was diagnosed in 15(55,6%) RA pts and in 32(58,2%) SSA pts (p = 0,8). 17(62,9%) pts with RA and 16(29,1%) pts with SSA have used the glucocorticosteroid therapy (p = 0,004). BMD was lower in the hip than in the spine in both RA and SSA patients but differences was not significant. Low bone density (osteopenia or osteoporosis) according to T-score was diagnosed in 16(59,3%) RA pts in the spine and 10(37,0%) in the hip and in 26(42,3%) and 17(30,9%) SSA pts respectively but difference was not significant. Osteoporosis was found in similar frequency in RA and SSA when the disease was active or disease duration was more than 120 month or the glucocorticosteroid therapy was used (in about 20%). In the univariate analysis significant influence of these variables for osteoporosis was not found. Conclusions: Low bone mass was diagnosed frequently in males with chronic inflammatory disorders. The frequency of osteoporosis and osteopenia did not differ significantly between RA and SSA patients in both skeleton sites. The glucocorticosteroid therapy, the active disease or disease duration more than 120 month had not significant influence for osteoporosis.

P467MO. BONE MINERAL DENSITY PREDICTORS IN JUVENILE DERMATOMYOSITIS Terreri MT1, Castro TCM1, Szejnfeld VL2, Fonseca AS1, Len CA1, Hilario MOE1; 1Department of Pediatrics, UNIFESP, Escola Paulista Medicina, Sao Paulo, SP, Brazil, 2Department of Medicine, UNIFESP, Escola Paulista Medicina, Sao Paulo, SP, Brazil Objective: This study aimed at evaluating bone mineral density (BMD) in juvenile dermatomyositis (JDM) children, considering multiple factors as possible predictors for reduction in bone mass. Patients and Methods: A cross-sectional study of BMD at lumbar spine (L2-L4) was conducted in 10 female JDM children aged 7–16 years. A group of 20 age-matched healthy girls was used as controls. BMD at lumbar spine was measured by dualenergy X-ray absorptiometry (DXA). Weight (kg), height (cm) and pubertal Tanner stage were determined in all patients and controls. Disease duration, mean daily steroid doses (mg prednisone/kg/day) and mean cumulative steroid doses (g of prednisone) were calculated in all patients from medical charts. JDM activity was based on the presence of muscle weakness, cutaneous vasculitis and elevation of the serum concentration of the skeletal muscle enzymes. Results: Lumbar BMD in the JDM patients was significantly reduced compared with BMD in age-matched healthy control girls. In JDM girls we did not observe significant correlation

S140 between BMD and age, height, Tanner stage, disease duration, corticosteroid use and disease activity. We found correlation between BMD and weight. In JDM group we were not able to find significant parameters to correlate to reduced bone mass. Conclusion: Patients with JDM may be at risk for significant reduction in bone mineral density that might contribute to further skeletal fragility. Disease activity and mean cumulative steroid doses were not important to determine BMD values in these patients. Our results suggest that reduced bone mass in JDM children can be related to other intrinsic mechanisms and not only to steroid treatment.

P468SA. CORTICOTHERAPY AND BONE MINERAL DENSITY IN PORTUGUESE CHILDREN WITH JUVENILE SYSTEMIC LUPUS ERYTHEMATOSUS Castelao W, Canhao H, Resende C, Fonseca JE, Costa JCT, Pereira Silva JA, Viana Queiroz M; Santa Maria Hospital, Lisbon, Portugal Chronic corticotherapy is a well known cause of osteoporosis in adult patients, however there are few data about how glucocorticoid treatment affect bone mineralisation in our children. We evaluated the spinal bone mineral density (BMD) of ten Portuguese children with juvenile systemic lupus erythematosus (JSLE) treated with glucocorticoids using densitometry. Cumulative steroid dosage, mean steroid dosage, corticotherapy age onset and duration, concomitant medication and clinical and laboratorial features were studied. Female:male ratio was 9:1. Mean disease onset age was 10.1±4.1 years, mean follow-up time was 6.1±2.9 years, mean steroids onset age was 12.3±3.6 years, mean prednisone dosage was 13.5±9.8 mg/day, mean steroid therapy duration was 76.4±43.5 months, mean cumulative prednisone dose was 25304±16455 mg and mean cumulative dose/weight ratio was 580.6±350.2 mg/kg. Mean spine Z-score by was –2.7±1.1. We grouped our patients by their cumulative prednisone doseweight ratio (5 or 4500mg/kg) in two five patients groups. The mean BMD in the first group (5500) was –2.46±0.86 and in the second (4500) –2.93±1.33. There was a significant (p50.02) difference in the corticotherapy duration. Mean prednisone doseweight ratio, mean age of disease onset and mean steroid onset age were not significantly different. Four of the patients from the second group and only one from the first group were medicated with anti-reabsortive therapy. Severity of JSLE was similar. We divided the patients according to disease onset age in two groups to compare their mean BMD. Children younger than 12 years had a spine Z score of 73.47±2.02 and older than 12 years of 72.17±0.80. Most children had a reduced BMD for age. BMD tended to be lower in patients with higher cumulative dosage or earlier steroid onset, but not significantly. However patients under these circumstances were submitted to a more effective prevention therapy. Larger group studies are required.

P469SU. EFFECT OF TESTOSTERONE ADMINISTRATION ON PHOSPHO-CALCIUM METABOLISM AND ON BONE MINERAL DENSITY IN PATIENTS WITH KLINEFELTER’S SYNDROME Sabino T1, Vale S1, Martins JM1, Gardete Correia L1, Correˆa JN1, Rocha T2, Carvalho MJ2, Sa´ Melo P2; 1Endocrinology Department, Hospital Curry Cabral, Lisbon, Portugal, 2Maternidade Alfredo da Costa, Lisbon Portugal Aim: To determine the effect of testosterone replacement therapy on phospho-calcium metabolism and on bone mineral density (BMD) in patients with Klinefelter’s syndrome. Methods: The authors examined 10 subjects with Klinefelter’ s syndrome (29–40 yr.). The parameters evaluated (before and after testosterone administration) include: the serum total and free

Abstracts testosterone levels, the serum FSH, LH, 17- beta Estradiol levels, the serum and urinary calcium and phosphorus levels, the serum alkaline phosphatase, osteocalcin and parathormone levels and urinary desoxi-piridinoline levels. BMD at femoral neck and lumbar spine (L1-4) were assessed by dual-energy x-ray absorptiometry (Hologic QDR-4500SL (S/N 45544). Results: We evidenced lower BMD in 6 patients at lumbar spine (which in 2 cases also had lower BMD at femoral neck). The lower BMD was associated to an increment of bone resorption as showed by the elevation of urinary excretion of calcium and phosphorus and increment of urinary desoxi-piridinoline levels. The serum osteocalcin levels were normal in all patients. After 3 months of treatment (testosterone enanthate 250 mg im 3/3 weeks), an increment of lumbar spine BMD was observed associated to a normalisation of urinary calcium and phosphorus levels. We also observed an increment of urinary desoxi-piridinoline levels in 6 patients which 2 of them had normal values before treatment (probably related to an increment of bone remodeling). Conclusions: These findings suggest that decreased bone density occur in patients with Klinefelter’s syndrome probably related to an increased bone resorption which can be partially reverted with testosterone substitution.

P470MO. RISK FACTORS OF DIABETIC OSTEOPENIA IN IDDM PATIENTS Katushkina AP, Mokhort TV, Rudenko EV, Zabarovskaja ZV; Balarussian State Medical University, Minsk, Belarus Background and Aims: Diabetic Osteopenia (DO) is a recognized complication of Diabetes Mellitus, but the precise DO pathogenesis remains unclear. In our study we have tried to reveal and to estimate correlation of general, peripheral DO and next parameters: age, sex, DM duration, DM manifestation, HbA1c level, autonomic neuropathy (AN), distal polyneuropathy (DP), smoking. Materials and Methods: We have examined 130 IDDM patients (m = 63, age: 41,81+0,16 y.; f = 67, age: 32,65+0,2 y.), duration of disease: 12,88+0,07 y., Hba1c: 8,6+0,1%. Control group consists of 30 matched normal individuals. AN was estimated by cardiovascular autonomic tests (Pickup & Wilkins), DP was measured by Neuropathy Disability Score. Bone mineral density (BMD) was estimated by dual-energy x-ray absorptiometry and QCT. Results: General DO (gDO) was verified in 42%, local DO (l DO) – 56%. There were next correlations: gDO and age (r = 0,35), GDO and sex (r = 0,22), DO and DM duration (r = 0,48), gDO and DM manifestation (r = 0,5), gDO and HbA1c level (r = 0,68), gDO and AN (r = 0,5), gDO and DP (r = 0,22), gDO and smoking (r = 0,21); l DO and age (r = 0,38), lDO and sex (r = 0,35), lDO and DM duration (r = 0,48), lDO and DM manifestation (r = 0,51), lDO and HbA1c level (r = 0,66), lDO and AN (r = 0,54), lDO and DP (r = 0,32), lDO and smoking (r = 0,2). Conclusions: 1. The frequency of the spreading of local DO prevails with general DO; 2. The early age of the DM manifestation, DM duration, AN presence, bad glucose control increases the risk of the DO evolution.

P471SA. PREGNANCY ASSOCIATED OSTEOPOROSIS: A CASE REPORT Biondi M1, Boschi F1, Zoli A2, Pedone V1; 1Osteoporosis Center, AUSL Forli, Italy, 2Rehabilitation Department, AUSL Forli, Italy Pregnancy-associated osteoporosis is a rare condition; etiology and pathogenesis are not yet defined. A 33 old years women, two months later the second delivery, during the breast-feeding complained of back pain at the lumbar spine. She went to our Center and the X-ray shows three vertebral hollows (L1-L3). The NMR and blood and urinary tests to exclude a cancer disease are negative. The bone mineral content was measured with DEXA

Abstracts (LUNAR MD): BMC L1-L4 = 38.62 g; T-score = –2.8; index of bone turn over are also tested (urinary cross links = 16.1 nm/mM; BALP = 39 U/L). A pregnancy-associated osteoporosis was diagnosed. The patient was treated with risedronate 5 mg/die, calcium 1000 g/die and vitamin D 880 UI/die. After six months the value of BMC was increased of 14% (BMC = 45.84 g) and blood and urinary index was normalized. The back pain became less intense and by the X-ray examination new fractures were not found.

OSTEOARTHRITIS SYMPOSIUM OA1. OSTEOARTHRITIS: EPIDEMIOLOGY, RISK FACTORS, BURDEN OF DISEASE AND PREVALENCE C Cooper, K Walker-Bone, E M Dennison, M K Javaid, D Coggon, N Arden; MRC Environmental Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK Osteoarthritis (OA) is the most common joint disorder in the world [1]. It has been found in skeletal remains from periods in evolution as far back as neolithic times. In western populations, radiographic evidence of OA occurs in the majority of people by 65 years of age, and in about 80% of those aged over 75 years. In the US, it is second only to ischaemic heart disease as a cause of work disability in men over 50 years of age, and accounts for more hospitalisations than rheumatoid arthritis each year.

S141 evidence of OA was considerably stronger for the hip and knee than for the hand.

Classification Two major systems have been proposed for the classification of OA: aetiologic and articular. The recognition that pathologic and radiologic features of the disorder could follow almost any established joint pathology led to the suggestion that OA might be classified as primary (idiopathic) or secondary. The disorders recognised as causes of secondary OA may be divided into four main categories: metabolic disorders such as ochronosis; anatomic derangements such as slipped epiphysis; major trauma or surgery to a joint; and a previous inflammatory arthropathy. However, the distinction between primary and secondary OA is not always clear. It has been shown that after meniscectomy, 20–25% of people will develop premature OA in the operated knee joint some 20 years later. There is also evidence that the 20% who do get secondary OA have some generalised predisposition to the disorder. The second basis of sub-classifying OA relates to the number and distribution of joint sites affected. Just as there is great heterogeneity in the effects and manifestations of OA at one joint, there is variation in the pattern of joint distribution in different individuals. The condition shows a particular predilection for the DIP joint of the hand, the thumb base, the knee, hip and intervertebral facet joint. Involvement of more than one joint is common and many population surveys have reported that subjects with OA in one joint had a frequency in other joints which cannot be explained by chance or age alone [6]. This polyarticular variant of the disorder is known as generalised osteoarthritis.

Prevalence Definition Any working definition of OA entails consideration of pathologic, radiologic, and clinical components. The key pathological features of the disorder have been recognised for many decades, and include focal destruction of articular cartilage, followed by changes in subchondral bone. This paired process, variably accompanied by synovial inflammation, is now viewed as the reaction pattern of a joint in response to insult or injury [2]. The American College of Rheumatology [3] currently defines OA as a heterogeneous group of conditions that lead to joint symptoms and signs which are associated with defective integrity of articular cartilage, in addition to related changes in the underlying bone at the joint margins. The radiographic features conventionally used to define OA include joint space narrowing, osteophyte, subchondral sclerosis, cyst formation and abnormalities of bone contour. These features were originally selected to measure various aspects of cartilage loss and subchondral bone reaction. Although several radiographic systems have been proposed, most epidemiological studies have utilised that developed by the Empire Rheumatism Council, first described by Kellgren and Lawrence [4]. This assigns one of five grades (0 to 4) to osteoarthritis at various joint sites: knee, hip, hand and spine. The criteria for increasing severity of OA relate to the assumed sequential appearance of osteophyte, joint space narrowing, sclerosis and cyst. To ensure standardisation of radiographic methods, recent studies have broken up the overall grading system into its component features, quantified each feature more precisely, and assessed the reproducibility and clinical correlates of each. These individual radiographic features are now included in atlases of standard radiographs which ensure a more consistent approach to the grading of OA [5]. Two broad clinical areas are relevant to any definition of OA: the symptoms associated with the condition, and the degree of disability constituting its longer term sequel. Joint pain is the dominant symptom of OA. The prevalence of joint pain rises markedly with age in the general population. However, the association between joint pain and radiographic features of OA is not constant. In studies performed during the 1950s in the north of England, the relationship between pain and radiographic

In an autopsy series of 1000 cases in 1926, Heine documented almost universal evidence of cartilage damage in people aged over 65 years.1 More recent studies report that cartilage lesions, subchondral reaction and osteophyte are present in the knees of 60% of men and 70% of women who die in the seventh and eighth decades of life. Prevalence estimates from such studies tend to be higher than those from radiographic surveys, partly because relatively mild pathologic change is not apparent on radiographs. Most currently available information on the epidemiology of OA comes from population-based radiographic surveys. These demonstrate that the prevalence of radiographic OA rises steeply with age at all joint sites. Thus, in a Dutch study of 6585 men and women randomly selected from the population, 75% of women aged 60-70 years had OA of their distal interphallengeal joints; even by age 40 years, 10-20% of subjects had evidence of severe radiographic disease in their hands or feet [7]. Knee disease appears less frequent than hand involvement; population-based studies in the United States suggest comparable prevalence rates to those in Europe, rising from less than 1% for severe radiographic disease among people aged 25–34 years, to 30% in those 75 years and above. Both hand and knee disease appear to be more frequent among women than men, although the female to male ratio varies among studies. Hip OA is less common than knee OA, and prevalence rates in men and women appear more similar. Some, but not all, studies have reported a male preponderance at this site. Although OA is worldwide in its distribution, geographic differences in prevalence have been reported. These are often difficult to interpret because of differences in sampling procedure and radiographic consistency. Hand involvement is particularly frequent among native American populations such as the Pima and Blackfoot. American-African females have a higher ageadjusted prevalence of knee OA than Caucasian females, but are less likely to have Heberden’s nodes on physical examination.

Incidence Few studies have examined the incidence of osteoarthritis and most available data have been obtained in the United States. In the hand, observations in the Baltimore Longitudinal Study of Ageing suggest an incidence rate of 4% per year. This rises

S142 steeply with age, reaching 10% per year among subjects aged 75 years and over. More recently, incidence data for symptomatic hand, hip and knee OA were obtained from the Fallon Community Health Plan [8], a health maintenance organisation located in the northern United States. In this study, the age and sexstandardised incidence rate of hand OA was 100 per 100,000 p-y; for hip OA 88 per 100,000 p-y; and for knee OA 240 per 100,000 p-y. The incidence of hand, hip and knee disease increased with age and women had higher rates than men, especially after age 50 years.

Individual risk factors The individual risk factors for OA may be conveniently viewed as acting through two major pathogenetic mechanisms: (a) factors influencing or marking a generalised predisposition to the disorder; and (b) factors resulting in abnormal biomechanical loading at specific joint sites. Among the systemic predisposing factors are included heredity, obesity, reproductive variables, hypermobility, and the negative association with osteoporosis. The mechanical risk factors include trauma, joint shape, and overuse as a consequence of occupational or leisure physical activity. Among these, obesity and joint injury appear to exert the greatest individual effects. Adiposity is clearly associated with the development of knee OA in both sexes [9]. Population-based studies suggest that the increase in risk of knee OA between the highest and lowest fifths of the distribution of body mass index lies between four and seven-fold, and there appears to be a linear dose response relationship. Furthermore, obesity is more strongly associated with bilateral than with unilateral knee OA, and the strength of the association is not diminished by adjustment for potential confounding variables. It is also clear that obesity precedes (rather than follows) the incidence of osteoarthritis; thus, analysis of the Framingham data in the US has revealed that body mass index measured at initial study predicts the occurrence of radiographic knee OA some 36 years later. The association of obesity with hand OA remains controversial. Studies based on the US Health Examination Survey and the Baltimore Longitudinal Study of Ageing, failed to demonstrate statistically significant associations among men or women. However, the trends in several studies point consistently towards an association which is simply less marked than that observed for knee OA. The gradient of risk between obesity and hip OA appears intermediate between that for hand and that for knee disease. Major injury is a common cause of knee OA [10]. Two specific types of injury are associated: cruciate ligament damage and meniscal tears. Follow-up studies of patients with cruciate rupture have reported cartilage loss, even in young patients. For meniscectomy, most studies have reported an increased frequency of subsequent OA. The risk rises with advancing age, prevalence of a generalised predisposition to OA and time since meniscectomy. Major injury, particularly fracture, may alter mechanical function and predispose to OA at other sites.

References 1. Cooper C. Epidemiology of osteoarthritis. In: Klippel JH, Dieppe PA eds. Rheumatology (second edition). London: Mosby 1998: Chapt 8.02. 2. Hutton C. Osteoarthritis: the cause not result of joint failure? Ann Rheum Dis 1989;48:958–961. 3. Altman R, et al. The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hand. Arthritis Rheum 1986;29:1039–1049. 4. Kellgren JK, Lawrence JS. Radiological assessment of osteoarthritis. Ann Rheum Dis 1957;15:494–501. 5. Altman RD, Hochberg M, et al. Atlas of individual radiographic features in osteoarthritis. Osteoarthritis & Cartilage 1995;3(Suppl A):3–70. 6. Cooper C, Egger P, Coggon D, Hart DJ, Masud T, Cicuttini F, Doyle DV, Spector TD. Generalised osteoarthritis in women: pattern of joint involvement and approaches to definition for epidemiological studies. J Rheumatol 1996;23:1938–42. 7. van Saase JCLM, et al. Epidemiology of osteoarthritis: Zoerterm-

Abstracts eer survey. Comparison of radiologic osteoarthritis in a Dutch population with that in 10 other populations. Ann Rheum Dis 1989; 48:271–280. 8. Oliveria SA, Felson DT, Reed JI, Cirillo PA, Walker AM. Incidence of symptomatic hand, hip and knee osteoarthritis among patients in a health maintenance organisation. Arthritis Rheum 1995;38:1134–1141. 9. Felson DT, Anderson JJ, Naimark A, Walker AM, Meanan RF. Obesity and knee osteoarthritis: the Framingham study. Ann Intern Med 1988;109:18–24. 10. Cooper C, Snow S, McAlindon T, Kellingray S, Stuart B, Coggon D, Dieppe P. Risk factors for the incidence and progression of radiographic knee osteoarthritis. Arthritis Rheum 2000;43:995– 1000.

OA2. WHAT DO CELLULAR AND ANIMAL MODELS PREDICT FOR THE CLINICAL MANAGEMENT OF OSTEOARTHRITIS Roland W. Moskowitz; Case Western Reserve University, Cleveland, Ohio USA Not too many years ago, osteoarthritis was presumed to be simply a ‘wear-and-tear’ disease, with cartilage breakdown a result of repetitive abnormal mechanical forces. Studies over the past decade, however, have demonstrated a much more complex etiopathogenesis and pathophysiology. Etiologic factors of significance include gender, genetics, obesity, aging and trauma. Pathophysiologic changes relate to an imbalance between catabolic breakdown and anabolic synthetic activity. Catabolic factors considered to play a major role in this imbalance include metalloproteinases, interleukin-1 a (Il-1a), tumor necrosis factor-alpha (TNF-a), and inducible nitric oxide synthase. Anabolic factors such as insulin-like growth factor-1 (IGF-1) and transforming growth factor-b (TGF-b) are anabolic factors of import. Despite the significant advances in our understanding of the etiology and pathophysiology of osteoarthritis which have taken place over the past several decades, much needs yet to be learned if we are to successfully target therapy to abnormal processes affecting cartilage, bone, synovium and other joint tissues. Studies of human OA based on gross and histologic investigations of tissue responses both at time of surgery or at autopsy have been helpful in delineating some of these processes; they are unfortunately hindered by limitation in amounts of tissues studied as well as time of tissue sampling. Our understanding of osteoarthritis has been aided by investigations utilizing in vitro studies of cartilage synthesis and catabolism, both de novo as well as in response to various impacting agents, and by studies in experimental animals [1,2]. Translation of results from animal studies, however, is complicated by the presence of various subsets of human osteoarthritis, with the likelihood that etiopathologic differences exist with respect to the roles played by age, gender, hormones, biomechanical alterations and inflammatory mediators in the initiation and progression of these various disease subsets. In vitro studies of synthetic activity in human OA usually relate to assessment of proteoglycan and collagen production at different times and stages of the osteoarthritic process, with particular attention to tissue responses to various agents targeted at sites of altered pathophysiology. Catabolic processes are similarly assessed, with quantitative and qualitative definition of matrix breakdown products related to the disease process per se, or to therapeutic agents. It is obvious that experimental models of osteoarthritis provide many advantages over studies in humans. Studies in humans are made difficult by the inability to routinely standardize and grade pathologic change in tissues being analyzed; inability to quantitate disease duration; and the inability to study tissue changes at serial timed intervals during the development of the disease itself. When experimental models are available, however, accurate definition of the time of disease induction, and assessment of disease severity and progress on a detailed temporal basis becomes tenable. Further, control tissues are

Abstracts readily available for study, either from other joints of the same animal or from joints of nonoperated animals of the same or different species; metabolic changes based on studies utilizing in vivo radioactive labeling can be performed; environmental, dietary and physical activity perimeters can be controlled; and studies of therapeutic agents can be carried out without concern for possible toxicity that would apply to the investigation of similar agents in humans. Studies in experimental animals, to be effective, must represent a reasonable prototype of the human disease. In this regard, issues of import in defining such models include the consistency of reproducibility of the disease, the ease with which animals can be handled, and, of course, cost. Pathologic changes must occur sufficiently rapidly and frequently to be of value. Although higher mammals such as dogs or pigs are more likely to truly simulate changes occurring in humans, the high cost of animal purchase and daily boarding for extensive studies frequently require that smaller animals such as mice, guinea pigs or rabbits be utilized. Unfortunately, use of smaller animals results in limitation of joint cartilage available for study for evaluations of cartilage pathophysiologic and biochemical responses. Experimental models are most attractive if they not only simulate disease pathology, but also disease etiopathogenesis. For example, models that simulate human disease most completely with development of cartilage breakdown, osteophyte formation and subchondral sclerosis are more likely to be of value than models which produce only limited components of the overall disease process. Trauma models such as OA induced by anterior cruciate ligament section are most likely to simulate secondary OA in humans; conversely, findings in spontaneous OA models may be more applicable to primary disease in the human. Over a period of years, our laboratory has utilized animal models for assessment of osteoarthritic pathophysiology. The most commonly used model in our studies is the partial meniscectomy (Moskowitz) model of osteoarthritis [3]. This model was based on the clinical observation that osteoarthritis occurred not uncommonly as a sequela to meniscal injury in the human. In this model, approximately 1/4 to 1/3 of the anterior aspect of the medial meniscus is excised. Lesions usually begin within several weeks following surgery and are characterized by gross pitting and ulceration, and osteophyte formation. Histopathologic findings include loss of cartilage surface, fissuring, cyst formation, and diminished concentration of matrix proteoglycans. Proliferation of chondrocytes in clones represents an effort at repair. Osteophytes are most marked at the inner aspect of the medial tibial plateau where they occur in approximately 95% of animals studied. Biochemical findings seen in this model demonstrate similarities to the human [4]. Of interest is the demonstration of increased proteoglycan and protein synthesis throughout a 12 week period of study. Cell replication is increased early in cartilage and subchondral bone. Studies of osteophyte pathogenesis in this model revealed early onset of formation of osteophyte-like structures containing bone, fibrocartilage and hyaline cartilage; no evidence of vascular invasion or metaplasia as a forerunner of osteophyte formation was observed [5]. Osteophytes progressively enlarged over time, occurring in up to 95% of tibias and 40% of femurs studied at 12 weeks. The consistent induction of osteophytes in association with structural cartilage findings of pitting, erosions and cellular proliferation demonstrate the similarity of this model to the human disease. Although, as noted, animal models simulate human disease in many aspects, caveats remain as to the validity of transferring findings in animals to human OA. For example, studies with estrogens in rabbits have demonstrated a worsening of OA [6]; in contrast, studies in mice have shown estrogen administration to be salutary. Although usually perceived as a disease primarily involving cartilage, studies support important potential roles for other joint tissues such as bone and synovium in the osteoarthritic process. Examination of trabecular bone within the femoral head of Hartley strain guinea pigs, a strain predisposed to osteoarthritis, demonstrated subchondral trabecular remodelling as an early event [7]. In our studies utilizing the partial meniscectomy rabbit

S143 model, increased cellular replication was noted early (at two weeks) in subchondral bone, with return to normal by five weeks post-partial meniscectomy [8]. Accordingly, in this model, subchondral bony sclerosis and osteophyte formation simulated findings seen in idiopathic human OA. Many additional animal models have been defined [2]. Such models include those based on metabolic and endocrine manipulation; models resulting from intraarticular introduction of various materials into joints; experimental models based on alteration of joint forces such as partial meniscectomy or anterior cruciate ligament resection; and models of spontaneous osteoarthritis. Although intervertebral disc disease differs in many ways from primary osteoarthritis, changes in this entity simulate some aspects of peripheral osteoarthritis. Spondylosis, characterized by intervertebral disc degeneration and hyperostosis, is common in aging sand rats (Psammomys obesus) [9]. Disc-space narrowing and subchondral end-plate sclerosis increase radiologically with age; lesions are most severe in the lower lumbar region. Ligamentous calcifications ventral to involved discs are common. The sand rat appears to be a model of disc degeneration with possible overlap with the syndrome of diffuse idiopathic skeletal hyperostosis. In summary, animal models provide opportunity for study of disease etiopathogenesis and pathophysiology in evaluation of the osteoarthritic process. In studies of therapeutic agents targeted to disease modification, the finding of a salutary therapeutic response in one or more animal models provides optimism that such an agent may be effective in humans. Although failure to demonstrate a successful response in animals does not exclude the potential for efficacy in humans, positive trials in animal models would support the potential benefit of such agents in human trials. Translation of an effect in animal models to human disease is likely more supportive if findings are consistent among multiple animal models. Investigations in higher mammals are thought to be advantageous in translating therapeutic efficacy to human disease. Trials with a number of socalled disease-modifying drugs have shown efficacy in a number of OA animal models, but predictive consistency remains a question from study to study [10].

References 1. Moskowitz R.W.: The relevance of animal models in osteoarthritis. Scand J Rheumatology 1990;(Suppl 81):21–23. 2. Smith MM, Ghosh P. Experimental Models of Osteoarthritis. In: Osteoarthritis- Diagnosis and Management. 3rd Edition. RW Moskowitz, D Howell, R Altman, J Buckwalter, V Goldberg (eds.) Chapter 8, Philadelphia, W.B. Saunders Company, 2001. 3. Moskowitz RW, Davis W, Sammarco J, et al. Experimentally induced degenerative joint lesions following partial meniscectomy in the rabbit. Arthritis Rheum 1973;16:397. 4. Moskowitz R.W., Goldberg VM, Malemud CJ: Metabolic responses of cartilage in experimentally-induced osteoarthritis. Ann Rheum Dis 1981;40:584–592. 5. Moskowitz R.W., Goldberg VM: Studies of osteophyte pathogenesis in experimentally-induced osteoarthritis. J Rheumatol 1987;14:311–320. 6. Rosner IA, Goldberg VM, Moskowitz R.W.: Estrogens and osteoarthritis. Clin Orthop Rel Res 1986;213:77–83. 7. Bendele AM, White SL, Hulman JF. Osteoarthrosis in guinea pigs: histopathologic and scanning electron microscopic features. Lab Anim Sci 1989;39:115. 8. Mayor M, Moskowitz RW. Metabolic studies in experimentallyinduced degenerative joint disease in the rabbit. J Rheumatol 1994;1:17–23. 9. Moskowitz R.W., Ziv I, Denko C, Boja B, Adler J: Spondylosis in Sand Rats: a model of intervertebral disc degeneration and hyperostosis. J Orthop Res 1990;8:401–411. 10. van den Berg WB. Lessons from animal models of osteoarthritis. Current Opinion in Rheumatol 2001;13:452–456.

S144 OA3. IMAGING OF OSTEOARTHRITIS Charles G. Peterfy; Chief Medical Officer, Synarc, Inc., San Francisco, CA, USA The demand for structure modifying therapies for osteoarthritis has grown considerably over the past several years as awareness of the profound human and economic impact of this prevalent and debilitating disorder has become increasingly widespread. The World Health Organization designated this the Bone and Joint Decade, and the National Institutes of Health in the US recently launched the Osteoarthritis Initiative (www.nih.gov/ niams/news/oisg/), an historic collaborative between the public and private sectors to conduct a large prospective study aimed at among other things, elucidating the structural determinants of clinical outcomes in osteoarthritis. This demand has spawned numerous advances in imaging evaluation of joint damage in osteoarthritis including specialized radiographic techniques and positioning devices, computerized methods of measuring radiographic joint-space width, and innovations in MRI that allow direct examination of the articular cartilage, synovium, menisci, intra-articular and periarticular ligaments, bone marrow edema, and other structures not visible with conventional radiography. This ability to visualize all components of the joint simultaneously, allows MRI to examine the joint as a whole organ and osteoarthritis, therefore, as a disease of organ failure. These innovations promise to accelerate the development new therapies for OA, as they reduce uncertainty, time and cost in clinical trials. This presentation will review these innovations in imaging of OA and point to areas where further development can be expected in the near future.

Radiography of OA Because radiography is unable to directly visualize the articular cartilage, cartilage loss in arthritis must be indirectly inferred from changes in the distance between opposing articular cortices, i.e., joint-space width (JSW). However, this measure is valid only where the two articular cartilage surfaces are in direct contact with each other. In many joints, including the knee, this necessitates loading to displace any intervening fluid. Joint loading is easily accomplished in the knee by acquiring the images while the subject is standing. Even then, however, only a small portion of the curved, incongruent articular surfaces of the femur and tibia are in direct contact in any one position. With increasing flexion of the knee, progressively posterior regions of the femoral cartilage articulate with the tibial surface. Thus, JSW as a measure of cartilage thickness is highly dependent on positioning in the knee, and even minor variations in positioning on serial examinations can produce large errors in JSW measurements over time. Another factor complicating JSW measurement is the projectional viewing perspective of conventional radiography. X-ray beam alignment, joint positioning and the distance between the joint space and the radiographic film are, therefore, critical determinants of the accuracy of serial JSW measurements. Four alternatives to conventional extended knee radiography are depicted in Figure 1. Reproducible foot positioning can be accomplished in each of these with foot maps or a fixation frame.

A. B. C. D. Fig. 1 Comparison of techniques for radiography of the knee with flexion.

Abstracts A. The Buckland-Wright fluoroscopic method provides optimal alignment and good fixation of tibia, good fixation of the femur, but only minimal flexion of the knee. The knee-to-film distance is large and variable, and the source-to-knee distance is short and variable, leading to variable magnification, which must be corrected. The x-ray beam is perpendicular to the film, which is ideal. The technique is more expensive than the other three alternatives, which cost approximately the same as each other. Fluoroscopy carries greater radiation exposure to the subject and is difficult to perform in multi-center studies. B. The schuss view offers good alignment and fixation of the tibia, greater flexion of the knee (its main advantage), but poor fixation of the femur (its main limitation). The knee-to-film and source-to-knee distances are optimal and minimize magnification. Caudad beam angulation results in parallax error causing mild (3%) over-estimation of jointspace width, but this cancels out on serial examinations. C. The ‘MTP’ (metatarsophalangeal) technique aligns the film with the MTP joints. It offers good alignment and fixation of the tibia, but only minimal flexion of the knee, and poor fixation of the femur (a potentially serious limitation). The knee-to-film and source-toknee distances are optimal, thus minimizing magnification, and the x-ray beam is perpendicular to the film. D. The fixed-flexion technique provides good alignment and optimal fixation of the tibia, good flexion of the knee (a strength), and good fixation of the femur (its main strength). The knee-to-film and source-toknee distances are optimal, minimizing any magnification. Caudad beam angulation results in mild parallax error, as for the schuss view. Regardless of the technique used to acquire the images, current state-of-the-art involves central digitization of the radiographs to allow safer and more economical archival, recovery and distribution of the images, as well as electronic submission to regulatory agencies. These electronic images are then analyzed with specialized reading software and monitors that allow automated measurement of JSW with better precision than traditional manual measurements. Electronic score sheets with reader sign-off and automatic databasing are used to record the results.

Imaging OA with MRI MRI is well suited to imaging osteoarthritic joints. Not only does it provide direct multiplanar tomography with relatively high spatial resolution, it is unparalleled in its ability to depict soft-tissue detail. Thus, MRI is the only modality that can examine all components of the joint simultaneously and therefore the joint as a whole organ. Moreover, MRI is capable of probing not only the morphology of joint tissues but a variety of compositional and functional tissue parameters relevant to the arthritic process. Because MRI is noninvasive and generally well tolerated by patients, frequent serial examinations can be performed on even asymptomatic patients. With more than 9,000 MRI systems present world wide, lack of availability is less serious a limitation than in the past. Additionally, small special purpose MRI systems have been developed that can image joints at a fraction of the cost of conventional MRI. Morphological markers of OA include both quantitative measures, such as cartilage thickness and volume, and semiquantitative measures, that grade cartilage, osteophytes, marrow edema, subarticular cysts, menisci, synovial effusion and intaand extra-articular ligaments. Several studies have demonstrated high diagnostic accuracy and precision of widely available MRI techniques for identifying areas of cartilage loss in the knee, and quantifying cartilage volume and thickness. However, regardless of how precisely change in cartilage morphology can be measured, its rate of change cannot be driven any faster than the disease process itself. For faster responsiveness, one must look upstream to earlier stages in the disease process of cartilage degeneration. Accordingly, there has been a great deal of interest in MRI markers of cartilage matrix damage. These markers relate principally to the collagen matrix or proteoglycans. The most promising markers of collagen matrix integrity include T2

Abstracts relaxation and magnetization transfer coefficient. Markers of proteoglycan integrity include water diffusion, Gd-DTPA2- uptake and 23Na concentration.

Conclusion Powerful techniques are being developed for imaging evaluation of OA. Much of this development is being driven by the pharmaceutical and biotechnology industries searching for novel therapeutic solutions to the growing problem of disease in our aging society. Accordingly, the imaging tools that ultimately will be used to direct patients to specific therapies and then to monitor treatment effectiveness and safety are currently being refined and validated in rigorous multi-center and multinational clinical trials aimed at gaining regulatory approval of these new therapies. This process represents not only a new pathway for innovation in medical imaging, but one that allows radiology to advance in sync with the rest of medicine.

Bibliography 1. Peterfy C. Imaging Techniques. In: Klippel J, Dieppe P, eds. Rheumatology 2E. 1 vol. Philadelphia: Mosby; 1997:14.1-14.18. 2. Peterfy CG. The role of MR imaging in clinical research studies. Semin Musculoskeletal Radiol 2001;5:365–378. 3. Buckland-Wright JC, Macfarlane DG, Jasani MK, Lynch JA. Quantitative microfocal radiographic assessment of osteoarthritis of the knee from weight bearing tunnel and semiflexed standing views. J Rheum 1994;21:1734–1741. 4. Peterfy C, Li J, Duryea J, Lynch J, Miaux Y, Genant H. Nonfluoroscopic method for flexed radiography of the knee that allows reproducible joint-space width measurement. Arthritis Rheum 1998;41:S361. 5. Buckland-Wright J, Wolfe F, Ward R, Flowers N, Hayne C. Substantial superiority of semiflexed (MTP) views in knee osteoarthritis: a comparative radiographic study, without fluoroscopy, of standing extended, semiflexed (MTP), and schuss views. J Rheumatol 1999;26:2664–2674. 6. Vignon E, Conrozier T, Piperno M, Richard S, Carrillon Y, O F. Radiographic assessment of hip and knee osteoarthritis. Recommendations: recommended guidelines. Osteoarthritis Cartilage 1999;7:434–436. 7. Mazzuca S, Brandt K, Buckland-Wright J et al. Field test of the reproducibility of automated measurements of medial tibiofemoral joint space width derived from standardized knee radiographs. J Rheumatol 1999;26:1359–1365. 8. Peterfy CG, van Dijke CF, Janzen DL et al. Quantification of articular cartilage in the knee by pulsed saturation transfer and fat-suppressed MRI: optimization and validation. Radiology 1994;192:485–491. 9. Eckstein F, Sitteck H, Gavazzenia A, Milz S, Putz R, Reiser M. Assessment of articular cartilage volume and thickness with magnetic resonance imaging (MRI). Trans Orthop Res Soc 1995;20:194. 10. Disler DG, McCauley TR, Kelman CG et al. Fat-suppressed threedimensional spoiled gradient-echo MR imaging of hyaline cartilage defects in the knee: comparison with standard MR imaging and arthroscopy. AJR 1996;167:127–132. 11. Bashir A, Gray ML, Hartke J, Burstein D. Nondistructive imaging of human cartilage glycosaminoglycan concentration by MRI. Magn Reson Med 1999;41:857–865.

OA4. CLINICAL USE OF BIOCHEMICAL MARKERS OF BONE, CARTILAGE, AND SYNOVIUM TURNOVER IN OSTEOARTHRITIS Pierre D. Delmas; Professor of Medicine, Claude Bernard University; Director, INSERM Research Unit 403, Hoˆpital E. Herriot, Lyon, France Osteoarthritis (OA), the most common joint disease, is not only characterized by cartilage destruction, but also by alteration of bone metabolism (subchondral bone sclerosis, cysts, osteophytes) and of synovium tissue metabolism. Cartilage damage

S145 leading to progressive destruction of joint structure is considered to be the most important lesion of OA, and most attention has been focused on it. There is, however, evidence that other tissues, especially the synovium, are important and specific markers of these joint tissues are also being investigated as markers of OA. The relative importance of the contribution of synovitis in the progression of OA is still debated. The most established method for assessing joint damage in OA is joint space width measurement using planned x-rays. However, when radiological diagnosis is established, significant joint damage has often already occurred. In addition, because changes of joint space width are small compared to width precision error of x-rays, at least one year and preferably two years are usually necessary to assess accurately the progression of joint damage or its reduction by treatment in large groups of patients [1]. Clearly, to identify patients with a high risk for destructive OA and to monitor drug efficacy, more sensitive techniques than plain x-rays are needed. Magnetic resonance imaging is currently being optimized for this purpose. Alternatively, specific and sensitive biochemical markers reflecting abnormalities of the turnover of bone, cartilage, and synovium tissues may be used for the investigation and monitoring of OA. Biochemical markers are molecules of connective tissue matrices which are released into biological fluid during the process of tissue turnover. Some of them may reflect the overall tissue turnover, while others may be specific of tissue synthesis or tissue destruction [2]. They can be measured in serum, synovium fluid, and/or urine. Assays and interpretations of markers in the synovium fluid are especially difficult, and synovium fluid collection may often be technically difficult, excepted for the knee. Conversely, marker levels measured in blood and urine reflect the overall activity of all joints, whether or not they are involved in the OA process. Markers reflect the composition of the matrices of joint components. Bone is mainly formed of type I collagen, but also comprises some unique noncollagenous proteins. Proteoglycans and type II collagen are the major constituents of cartilage, but some other proteins have been identified that may be useful markers of cartilage metabolism. In addition to the surface layer of cells and of microvasculature net, the synovium tissue includes an extracellular matrix that contains mainly type I and III collagens, but also types IV, V, and VI collagen, as well as glucosaminoglycan (sulfated GAG and hyaluronic acid) and other structural glycoproteins including fibronectin, laminin, entactin, and tenascin. Although markers of bone turnover may reflect the focal abnormalities of bone metabolism in OA (subchondral osteosclerosis), circulating and urinary levels are more likely to reflect the overall level of skeletal turnover, which may be influenced by a variety of conditions, including age, menopausal status, osteoporosis, and other bone diseases. Thus, most studies have concentrated on the development of specific markers of cartilage and synovium turnover. They are listed in Tables 1 and 2. It has been suggested that these markers might be useful for identifying patients at high risk for progression and for assessing therapeutic response in OA, because of their faster response compared with x-rays [3–9]. However, most previous studies investigating the value of biochemical markers have several limitations, which include (a) the study of only a small group of patients, (b) the measurement of a single marker of either cartilage, bone or synovium turnover - although the association of markers reflecting different events of cartilage and synovium turnover is likely to give a better picture of the pathophysiological pattern of OA [10–12], (c) the absence of the measurement of a marker which reflects specifically type II collagen degradation, a hallmark of OA, and (d) the lack of a quantitative measure of joint destruction. In addition, most of these studies are cross sectional, and longitudinal data on large cohorts of well characterized OA patients are lacking. The lack of specificity of markers for a given tissue is a critical issue. For example, serum COMP, which was initially proposed as a cartilage specific molecule, has subsequently been shown to be synthesized by ligament and synovial fibroblasts [13]. The same holds true for YKL-40, which has been shown to be secreted in

S146

Abstracts

high amounts by chondrocytes and synoviocytes, but is also produced by the liver and is present in several other tissues [14,15]. Obviously, hyaluronic acid and PIIINP are also nonspecific for joint tissues, as they are widely distributed and their levels increased in other conditions, including scleroderma [16]. The lack of specificity of the current markers is likely to account in part for the discordant and disappointing clinical data generated so far. To overcome this limitation, major efforts have been made to develop most specific markers, especially those reflecting type II collagen degradation, which is a hallmark of OA, type II collagen synthesis, as well as synovial activity which may play a pivotal role in the pathogenesis of OA. Along this line, 3 markers have recently emerged. Glucosylgalactosyl pyridinoline (glc-gal-PYD) is a glycosylated analog of pyrodinoline, which is abundant in human synovium tissue, absent from bone and present in minute amounts in cartilage and other soft tissues, such as muscle and liver [17]. The specificity of glc-gal-PYD for synovium has also been demonstrated in ex vivo models of human joint tissue degradation. Its urinary excretion is increased in patients with rheumatoid arthritis, but also in patients with knee OA [18]. Several recent studies, that will be reviewed, suggest that this marker may be a prognostic index of joint degradation in rheumatoid arthritis. Its interest in OA deserves further investigation. An immunoassay recognizing type II collagen c-telopeptide fragments (CTX-II) in urine has been recently developed [19]. Urinary CTX-II is increased in patients with active rheumatoid arthritis and correlates with the progression of joint disease [20]. It is also significantly increased in patients with knee OA [18], and is higher in patients with rapidly destructive hip OA than is those with slowly progressing hip OA. The rate of synthesis of cartilage can be assessed by the measurement of type II collagen propeptide, which exists in 2 forms, PIIANP and PIIBNP. Using specific antibodies, we have found that both of these circulating markers are decreased in patients with knee OA [21,22]. The observation of decreased cartilage synthesis and increased cartilage degradation in patients with knee OA allows to define an ‘uncoupling index’, which is the ratio between these resorption and the formation markers. In a cohort of patients with knee OA evaluated prospectively with arthroscopy at baseline and after one year of follow up, we have found that this uncoupling index is significantly correlated with joint space narrowing assessed by xray and with the progression of chondropathy measured by arthroscopy. In conclusion, new markers of cartilage and synovium turnover have been developed, that appear to be specific of these tissues. Although they are unlikely to be clinically useful for the identification and staging of OA patients, they have the potential to be predictive of the progression of OA, independently of other parameters. With the develop of potential structure modifying OA drugs, their utility in the monitoring of OA treatment should be investigated. Table 1. Biochemical markers of cartilage turnover*

Aggrecan

Type II collagen

Nonaggrecan and noncollagen proteins

Synthesis

Degradation

Chondroitin sulfate (epitopes 846, 3-B-3[-], 7-D-4) Type II procollagen propeptides (PIICP, PIIANP and PIIBNP)

Core protein fragments Keratan sulfate (epitopes 5-D-4, AN9P1) Pyridinoline (+ in urine) Type II collagen telopeptide: CTX-II (urine) Type II collagen a chains (collagenase epitope [+ in urine]) COMP

YKL-40

*Most markers shown can be measured in serum or synovial fluid. PIICP = carboxy-terminal type II procollagen propeptide; PIIANP and PIIBNP = amino-terminal type IIA and IIB procollagen propeptide; COMP = cartilage oligomeric matrix protein; CTX-II = c-telopeptide fragment of type II collagen

Table 2. Biochemical markers of synovium turnover* Synthesis

Degradation

Types I and III collagens

Types I and III Pyridinoline (S, SF, and U) procollagen propeptides N- andC-telopeptides(Sand U) (PIIINP) (S and SF) Glucosylgalactosyl pyridinoline (glc-gal-PYD) (U) Noncollagen proteins Hyaluronan (S) YKL-40 (S and SF) COMP (S and SF) MMP-1, MMP-3, and TIMP (S and SF) *PIIINP = amino-terminal type III procollagen propeptide; S = serum; SF = synovial fluid; U = urine; COMP = cartilage oligomeric matrix protein; MMP = matrix metalloproteinase; TIMP = tissue inhibitor of metalloproteinases

References 1. Ravaud P, Giraudeau B, Auleley GR, et al. Variability in knee radiographing: implication for definition of radiological progression in medial knee osteoarthritis. Ann Rheum Dis 1998; 57(10):624–9. 2. Garnero P, Rousseau JC, Delmas PD. Molecular basis and clinical use of biochemical markers of bone, cartilage, and synovium in joint diseases. Arthritis Rheum 2000;43(5):953–68. 3. Moller HJ. Connective tissue markers of rheumatoid arthritis. Scand J Clin Lab Invest 1998;58(4):269–78. 4. Lohmander LS, Felson DT. Defining and validating the clinical role of meolecular markers in osteoarthritis. In: Brandt DD, Doherty M, Lohmander LS, eds. Osteoarthritis. Oxford: Oxford University Press, 1998:519–530. 5. Poole AR. Immunochemical markers of joint inflammation, skeletal damage and repair: where are we now? Ann Rheum Dis 1994;53(1):3–5. 6. Mansson B, Carey D, Alini M, et al. Cartilage and bone metabolism in rheumatoid arthritis. Dierences between rapid and slow progression of disease identified by serum markers of cartilage metabolism. J Clin Invest 1995;95(3):1071–7. 7. Petersson IF, Boegard T, Svensson B, Heinegard D, Saxne T. Changes in cartilage and bone metabolism identified by serum markers in early osteoarthritis of the knee joint. Br J Rheumatol 1998;37(1):46–50. 8. Thompson PW, Spector TD, James IT, Henderson E, Hart DJ. Urinary collagen crosslinks reflect the radiographic severity of knee osteoarthritis. Br J Rheumatol 1992;31(11):759–61. 9. Lohmander LS, Ionescu M, Jugessur H, Poole AR. Changes in joint cartilage aggrecan after knee injury and in osteoarthritis. Arthritis Rheum 1999;42(3):534–44. 10. Dodge GR, Poole AR. Immunohistochemical detection and immunochemical analysis of type II collagen degradation in human normal, rheumatoid, and osteoarthritic articular cartilages and in explants of bovine articular cartilage cultured with interleukin 1. J Clin Invest 1989;83(2):647–61. 11. Hollander AP, Heathfield TF, Webber C, et al. Increased damage to type II collagen in osteoarthritic articular cartilage detected by a new immunoassay. J Clin Invest 1994;93(4):1722–32. 12. Billinghurst RC, Dahlberg L, Ionescu M, et al. Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage. J Clin Invest 1997;99(7):1534–45. 13. Muller G, Michel A, Altenburg E. COMP (cartilage oligomeric matrix protein) is synthesized in ligament, tendon, meniscus, and articular cartilage. Connect Tissue Res 1998;39(4):233–44. 14. Johansen JS, Hvolris J, Hansen M, Backer V, Lorenzen I, Price PA. Serum YKL-40 levels in healthy children and adults. Comparison with serum and synovial fluid levels of YKL-40 in patients with osteoarthritis or trauma of the knee joint. Br J Rheumatol 1996;35(6):553–9. 15. Hakala BE, White C, Recklies AD. Human cartilage gp-39, a major secretory product of articular chondrocytes and synovial cells, is a mammalian member of a chitinase protein family. J Biol Chem 1993;268(34):25803–10. 16. Sondergaard K, Heickendor L, Risteli L, et al. Increased levels of type I and III collagen and hyaluronan in scleroderma skin. Br J Dermatol 1997;136(1):47–53. 17. Gineyts E, Garnero P, Delmas PD. Urinary excretion of glucosylgalactosyl pyridinoline: a specific biochemical marker of synovium degradation. Rheumatology (Oxford) 2001;40(3):315–23. 18. Garnero P, Piperno M, Gineyts E, Christgau S, Delmas PD, Vignon E. Cross sectional evaluation of biochemical markers of bone,

Abstracts

19. 20.

21.

22.

cartilage, and synovial tissue metabolism in patients with knee osteoarthritis: relations with disease activity and joint damage. Ann Rheum Dis 2001;60(6):619–26. Christgau S, Garnero P, Fledelius C, et al. Collagen type II Ctelopeptide fragments as an index of cartilage degradation. Bone 2001;29(3):209–15. Garnero P, Gineyts E, Christgau S, Finck B, Delmas PD. Baseline levels of urinary glucosyl-galactosyl-pyridinoline and type II collagen c-telopeptide are associated with progression of joint destruction in patients with early rheumatoid arthritis. Arthritis Rheum 2001 (in press). Rousseau JC, Miossec P, Vignon E, Garnero P, Delmas PD. Serum levels of type II B amino terminal propeptide (PIIBNP) are decreased in patients with knee osteoarthritis. Arthritis Rheum 2001;44(Suppl 1):S309. Rousseau JC, Zhu Y, Miossec P, et al. Serum levels of type II A procollagen amino terminal propeptide (PIIANP) are decreased in patients with knee osteoarthritis and rheumatoid arthritis. Arthritis Rheum 2000;13(Suppl 1):S351.

OA5. THERAPEUTIC TARGETS IN OSTEOARTHRITIS: NEW CHALLENGES Jean-Pierre Pelletier and Johanne Martel-Pelletier; Professors of Medicine, Universite´ de Montre´al, Osteoarthritis Research Unit, Centre Hospitalier de l’Universite´ de Montre´al – Hoˆpital NotreDame, Montre´al, Que´bec, Canada Over the last decade, there have been several interesting advances in the treatment of osteoarthritis (OA). A clearer understanding of the pathophysiology of this disease [1] has facilitated the development of new approaches for treatments aimed at specifically and effectively retarding the disease progress. New classes of molecules that inhibit one or more OA catabolic processes are under evaluation for their potential to alter the degenerative process. One of the most attractive recent findings is the data pointing to an association between inflammation and disease appearance and progression [2]. There are a number of pathways linked to synovial inflammation or inflammation, which represent the most interesting targets. For instance, cytokines, such as interleukin-1b (IL-1b) and other pro-inflammatory cytokines or inflammatory factors, are likely responsible for the signs and symptoms of inflammation present in OA patients. There exist a number of ways by which the reduction of the production or the activity of this cytokine could be managed. For example, the action of the cytokine can be reduced at the cell level by reducing the membrane receptor level or by using receptor antagonists or soluble receptors. The action of the cytokine can also be reduced by blocking the intracellular signaling pathways. We have demonstrated that the natural IL-1 receptor antagonist (IL-1Ra) is capable of reducing several cartilage catabolic processes, which are IL-1 dependent. Moreover, in vivo studies in animal models have demonstrated that the intraarticular injection of IL-1Ra could block the action of IL-1 and reduce disease progression [3]. Recently, studies using gene therapy and different gene transfection methods have allowed for the successful in vivo transfection of the IL-1Ra gene into the OA knee joints of dogs and rabbits [4]. These studies have demonstrated that such therapeutic intervention could reduce the progression of OA lesions. Another interesting target for controlling the activity of the IL-1 system is interleukin-1 converting enzyme (ICE)/caspase-1, which is the enzyme responsible for the conversion from the proform of IL-1 into its active (mature) form [5]. There are a number of studies already underway in rheumatoid arthritis patients with an orally active ICE inhibitor. This form of therapy certainly also represents an interesting potential target for the treatment of OA. The role of proteases in the degradation of the extracellular matrix of cartilage in OA has been well documented, and metalloproteases (MMP) are believed to play a major role in this process. Inhibition of the synthesis/activity of these enzymes as a treatment for OA has been the focus of intensive research [6]. To date, the most promising agents are chemical molecules that can

S147 block the activity of MMP. Certain MMP, such as MMP-13, have been selected as being more attractive targets for the treatment of OA. The main reason(s) for choosing selective inhibition, instead of a broad inhibition, is to avoid a certain number of side effects that could potentially be related to MMP inhibition. Among the different catabolic pathways that are activated by inflammation, nitric oxide (NO) is an interesting one in the context of OA for at least two main reasons [1]. Firstly, NO and its byproducts are capable of inducing the inflammatory component of OA. Secondly, it is also capable of inducing tissue damage and tissue destruction; therefore, it could be responsible not only for the symptoms but also the disease process per se. It has been shown that the excess production of NO generated via an elevation of inducible NO synthase (iNOS) in OA tissues is injurious. This appears to occur through a number of mechanisms. First, it could induce chondrocyte death by apoptosis. It could also stimulate the synthesis and activities of matrix metalloproteases (MMPs) and also reduce the anabolism of cartilage by inhibiting the synthesis of the major matrix components – collagen and proteoglycan. Moreover, NO is also capable of increasing the activity of cyclooxygenase 2 (COX-2) and consequently seems responsible for an increase in the signs and symptoms of the disease. Therefore, it is believed that this molecule is a most interesting target, because reducing its excess production may not only reduce the symptoms but also may likely reduce the progression of disease, thus being able to simultaneously reach two targets at once. This hypothesis is supported by positive findings in recent studies done using the experimental dog model of OA and the oral administration of therapeutic dosages of a specific inhibitor of iNOS [7]. Studies on the effects of eicosanoid overproduction on the metabolism of joint tissues reveal a variety of both catabolic and anabolic activities. The in vivo consequence of the overexpression of COX-2 in OA may lead to the production of a variety of prostanoids, of which the net effect on the disease process may be difficult to assess in vitro. Moreover, the role of products of the lipoxygenase pathways in OA is unclear at present [2]. The level of leukotriene B4 (LTB4) was found to be elevated in the synovial fluid from patients with OA, and both LTB4 and LTC4 production have been reported to be increased in OA synovial tissue. Although the leukotriene mechanism of action is not fully established, LTB4 was reported to induce IL-1b production in synovial cells. This is a field of the utmost interest that merits further investigation in regard to its potential implication of leukotrienes in the genesis of the structural changes of OA. This concept is supported by a recent study in which a combined inhibitor of 5-lipoxygenase (5-LO) and COX, Licofelone, was demonstrated to reduce the progression of experimental OA [8]. Several pharmacologic agents are under investigation to treat OA. Preclinical results are promising and demonstrate the possibility of retarding or inhibiting the progression of joint tissues structural changes. However, the tools to study such effects in the human population remain unsatisfactory. For many years, studies of drug interventions on OA focused essentially on clinical parameters such as pain and joint function without assessing their impact on the structural change of the disease and the possible role of medication in preventing cartilage degradation. Reliable, sensitive and accurate methods for assessment of the progression of OA are key requirements in research efforts to find new ways of controlling the progression of arthritis. Existing radiologic methods used to evaluate the disease progression are useful and allow for several clinical trials to take place. However, these methods are imperfect and time consuming. A faster and more accurate method to evaluate the efficacy of various medications on the progression of OA was required. Current tools lack sensitivity to change over short periods of observation (plain and standardized radiographs) or are invasive (arthroscopy). Based on several recent publications, magnetic resonance imaging (MRI) seems to be the most promising tool for investigating knee OA. Visualization of articular cartilage is now possible with MRI, but quantification of this tissue volume was lacking. We have developed a novel imaging system assessing

S148 cartilage volume/thickness using MRI of the knee. Preliminary data revealed that statistically significant changes in the volume and thickness of OA knee cartilage were detectable at 12 months, which is a considerable improvement over existing X-ray techniques [9,10]. This technology should significantly improve the investigation of new drugs and their potential to modify the progression of OA. This review brings to light that due primarily to recent progress in the understanding of its pathophysiology, several interesting new approaches for the treatment of OA are now being explored. New classes of molecules that inhibit one or more OA disease processes are under evaluation for their potential to alter the degenerative process.

Abstracts When to choose treatment with a COXIB [Ref. Lipsky, p 4S]

References 1. Pelletier, J-P., Martel-Pelletier, J., Howell, D.S.: Etiopathogenesis of osteoarthritis. In: Arthritis and Allied Conditions. A Textbook of Rheumatology (14th ed.), Koopman, W.J., ed., Lippincott, Williams & Wilkins, Baltimore, USA, 2000, chapter 110, pp 2195– 2245. 2. Pelletier, J-P., Martel-Pelletier, J., Abramson, S.: Osteoarthritis, an inflammatory disease: Potential implication for the selection of new therapeutic targets. Arthritis Rheum 2001;44:1237–1247. 3. Caron, J.P., Fernandes, J.C., Martel-Pelletier, J., Tardif, G., Mineau, F., Geng, C., Pelletier, J-P.: Chondroprotective eect of intraarticular injections of interleukin-1 receptor antagonist in experimental osteoarthritis: Suppression of collagenase-1 expression. Arthritis Rheum 1996;39:1535–1544. 4. Fernandes, J., Tardif, G., Martel-Pelletier, J., Lascau-Coman, V., Dupuis, M., Moldovan, F., Sheppard M., Krishnan, B.R., Pelletier, J-P.: In vivo transfer of interleukin-1 receptor antagonist gene in osteoarthritic rabbit knee joints: Prevention of OA progression. Am J Pathol 1999;154:1159–1169. 5. Saha, N., Moldovan, F., Tardif, G., Pelletier, J-P., Cloutier, J-M., Martel-Pelletier, J.: Interleukin-1ß-converting enzyme/caspase-1 in human osteoarthritic tissues: Localization and role in the maturation of IL-1ß and IL-18. Arthritis Rheum 1999;42:1577– 1587. 6. Martel-Pelletier, J., Tardif, G., Fernandes, J., Pelletier, J-P.: Metalloproteases and their modulation as treatment in osteoarthritis. In: Principles of Molecular Rheumatology. Tsokos, G.C., ed., Humana Press Inc., New Jersey, USA 2000, pp 499–514. 7. Pelletier, J-P., Jovanovic, D.V., Lascau-Coman, V., Fernandes, J.C., Manning, P.T., Connor, J.R., Currie, M.G., Martel-Pelletier, J.: Selective inhibition of inducible nitric oxide synthase reduces progression of experimental osteoarthritis in vivo: Possible link with the reduction in chondrocyte apoptosis and caspase 3 level. Arthritis Rheum 2000;43:1290–1299. 8. Jovanovic, D.V., Fernandes, J.C., Martel-Pelletier, J., Jolicoeur, FC., Reboul, P, Laufer, S., Tries, S., Pelletier, J-P.: The in vivo dual inhibition of cyclooxygenase and lipoxygenase by ML-3000 reduces the progression of experimental osteoarthritis. Suppression of collagenase-1 and interleukin-1ß synthesis. Arthritis Rheum. 44: 2320-2330, 2001.8. 9. Martel-Pelletier, J., Raynauld, J-P., Pelletier, J-P.: The quantitative imaging of the structural changes of osteoarthritis: an exciting challenge for the new millennium. Curr Rheum Rep 2001;3:465–6. 10. Raynauld, J-P., Kaumann, C., Beaudoin, G., Berthiaume, M-J., de Guise, J.A., Bloch, D.A., Camacho, F., Godbout, B., Altman, R.D., Hochberg, M., Meyer, J.M., Cline, G., Pelletier, J-P., and J. MartelPelletier: Reliability of a new quantification imaging system using magnetic resonance images to measure cartilage thickness and volume in human normal and osteoarthritic knees. (submitted)

OA6. COX-2SELECTIVE INHIBITORS IN THE TREATMENT OF OSTEOARTHRITIS Marc C. Hochberg, Professor of Medicine and Epidemiology and Preventative Medicine, Division of Rheumatology and Clinical Immunology, University of Maryland, School of Medicine, Baltimore, MD Therapy with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) has long been the cornerstone of pharmacologic management of patients with osteoarthritis (OA). Many patients with OA, however, are at increased risk of developing clinically

*Risk factors for serious upper GI complications from traditional NSAIDs include age above 65 years, the need for chronic high-dose NSAID therapy, history of peptic ulcer disease, concomitant treatment with an anticoagulant or glucocorticoid agent. **Includes discussion of risks and benefits with the patient. Reproduced with permission of the American Journal of Medicine. significant adverse events associated with NSAID therapy, particularly upper gastrointestinal (GI) complications including symptomatic and complicated ulcers. The introduction of cyclooxygenase (COX)-2selective inhibitors (C2SIs) represents a major advance in the pharmacological approach to the signs and symptoms of OA. In numerous clinical trials, C2SIs have been shown to be at least as effective as nonselective NSAIDs in relieving pain and improving physical function in patients with OA, and notably, with a significantly lower risk of NSAID-associated upper GI adverse events. The use of C2SIs to treat patients with OA is recommended as first-line therapy when symptoms of pain and inflammation are present in patients at risk of potential NSAID-associated GI toxicity. . Celecoxib, rofecoxib and valdecoxib are approved for the treatment of patients with OA in the United States. . The efficacy of celecoxib 100 mg twice daily, 200 mg once daily, and 200 mg twice daily in OA is comparable to that of diclofenac 50 mg three times daily and naproxen 500 mg twice daily, and significantly superior to placebo. . The efficacy of rofecoxib 12.5 mg once daily and 25 mg once daily in OA is comparable to ibuprofen 800 mg three times daily, nabumetone 1,500 mg once daily, and diclofenac 50 mg three times daily, and significantly superior to placebo. . In direct comparisons in OA patients, rofecoxib 25 mg once daily was significantly more effective than acetaminophen 1,000 mg four times daily. . Two studies directly compared rofecoxib 25 mg once daily and celecoxib 200 mg once daily in patients with knee OA. In one study, where both drugs were given in the morning, rofecoxib was more efficacious. In the other study, when both drugs were given in the evening, the agents were equally efficacious. . The efficacy of valdecoxib 5 mg once daily, 10 mg twice daily, or 10 mg once daily in OA is comparable to naproxen 500 mg twice daily, and superior to placebo. . Etoricoxib 60 mg once daily and 90 mg once daily are significantly more effective than placebo and comparable to naproxen 500 mg twice daily in the treatment of OA.

Abstracts . COX-189, another investigational coxib, 50 mg, 100 mg, 200 mg twice daily or 400 mg once daily, provided relief of OA symptoms comparable to diclofenac SR 75 mg twice daily, and significantly superior to placebo.

References American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum. 2000;43:19051915. Bensen WG, Fiechtner JJ, McMillen JI, et al. Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc. 1999;74:1095-1105. Cannon GW, Caldwell JR, et al. for the Rofecoxib Phase II Protocol 035 Study Group. Rofecoxib, a specific inhibitor of cyclooxygenase 2, with clinical ecacy comparable with that of diclofenac sodium: results of a one-year, randomized clinical trial in patients with osteoarthritis of the knee and hip. Arthritis Rheum. 2000;43(5):978-987. Clemett D, Goa KL. Celecoxib: a review of its use in osteoarthritis, rheumatoid arthritis and acute pain. Drugs. 2000;59:957-980. Day R, Morrison B, Luza A, et al. for the Rofecoxib/Ibuprofen Comparator Study Group. A randomized trial of the ecacy and tolerability of the COX-2 inhibitor rofecoxib vs ibuprofen in patients with osteoarthritis. Arch Intern Med. 2000;160:17811787. Ehrich EW, Schnitzer TJ, McIlwain H, et al. for the Rofecoxib Osteoarthritis Pilot Study Group. Eect of specific COX-2 inhibition in osteoarthritis of the knee: a 6 week double blind, placebo controlled pilot study of rofecoxib. J Rheumatol. 1999;26:2438-2447. FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med. 2001;345:433-442. Goldenberg MM. Celecoxib, a selective cyclooxygenase-2 inhibitor for the treatment of rheumatoid arthritis and osteoarthritis. Clin Ther. 1999;21:1497-1513; discussion 1427-1428. Lipsky PE. Recommendations for the clinical use of cyclooxygenase2 specific inhibitors. Am J Med. 2001;110(3A): 3S5S. **Matheson AJ, Figgitt DP. Rofecoxib: a review of its use in the management of osteoarthritis, acute pain and rheumatoid arthritis. Drugs. 2001;61:833-865. McKenna F, Borenstein D, Wendt H, Wallemark C, Lefkowith JB, Geis GS. Celecoxib versus diclofenac in the management of osteoarthritis of the knee. Scand J Rheumatol. 2001;30:11-18. Saag K, van der Heijde D, Fisher C, et al. for the Osteoarthritis Studies Group. Rofecoxib, a new cyclooxygenase 2 inhibitor, shows sustained ecacy, comparable with other nonsteroidal antiinflammatory drugs: a 6-week and a 1-year trial in patients with osteoarthritis. Arch Fam Med. 2000;9:1124-1134. Schnitzer TJ, Kivitz AJ, Greenwald M, et al. Rofecoxib provides superior relief of symptoms of osteoarthritis (OA) compared to celecoxib. Ann Rheum Dis. 2001;60(suppl 1):236 (Abstr SAT0089). Truitt KE, Sperling RS, Ettinger WH Jr, Greenwald M, DeTora L, Zeng Q, Bolognese J, Ehrich E; for the Phase III Rofecoxib Geriatric Study Group. A multicenter, randomized, controlled trial to evaluate the safety profile, tolerability, and ecacy of rofecoxib in advanced elderly patients with osteoarthritis. Aging (Milano). 2001;13:112-121. Williams GW, Hubbard RC, Yu SS, Zhao W, Geis S. Comparison of once-daily and twice-daily administration of celecoxib for the treatment of osteoarthritis of the knee. Clin Ther. 2001;23:213227

OA7. STRUCTURE-MODIFYING DRUGS IN OSTEOARTHRITIS Jean-Yves Reginster and Angela Kvasz, Bone and Cartilage Metabolism Unit,University of Lie`ge, Lie`ge, Belgium, WHO Collaborating Center for Public Health Aspects of Rheumatic Diseases, Lie`ge, Belgium

Introduction Until recently, the main aim of pharmacological treatments of osteoarthritis (OA) has been to control the symptoms of the disease, namely pain and limitation of function, especially over short-term periods. This is currently achieved by the use of non-

S149 specific medications, such as analgesics and non-steroidal antiinflammatory drugs (NSAIDs), or of specific compounds such as glucosamine sulfate and others that may interfere with some of the possible disease processes. Irrespectively of their mechanism of action, all of these drugs are currently classified as Symptom Modifying Drugs, as long as they fulfil the clinical research evidence prescribed by scientific organisations and acknowledged by Health Authorities. On the other hand, due to their mechanism of action, specific compounds may not only modify the course of symptoms over long-term treatment periods, but also favourably affect joint structure changes and thus the disease progression, contrary to what has been observed with some NSAIDs that could even worsen progression. If this is the case, such drugs could be classified as Structure Modifying Drugs and therefore indeed as Disease Modifying Drugs in osteoarthritis, as it is currently being tested in different trials in Europe. While in several countries, some of these chemical entities are available as over-the-counter (OTC) or nutriceutical supplements, most of the investigations performed with these molecules have not been undertaken with such products but with molecules registered and marketed as prescription drugs that have fulfilled all the requirements for quality and safety at the level of the health authorities. This article summarizes the evidence indicating that some compounds can effectively interfere with the symptoms of osteoarthritis or with the structural progression of the disease [1].

Chondroitin sulfate Chondroitin sulfate (CS) is a major component of extracellular matrix from many connective tissues, including cartilage, bone, skin, ligaments, and tendons. In particular in the cartilage, the high content of CS in the aggrecan plays a major role in creating a large osmotic swelling pressure that expands the matrix and places the collagen network under tension. The structuremodifying properties of CS were assessed in a double-blind, placebo-controlled trial that included 119 patients with interphallangeal OA. After 3 years, the group taking 400 mg CS three times daily had significantly fewer patients with new erosive OA finger joints (8,8%) compared to the placebo group (29,4%) [2]. More recently, a dose of 800 mg/day of chondroitin sulfate, given for a period of 2 years to patients with primary knee osteoarthritis, prevented the decrease in joint space width and joint space thickness observed in patients having received the placebo for the same duration [3].

Glucosamine sulfate Glucosamine sulfate (GS) is an aminosaccharide that acts as a preferred substrate for the biosynthesis of glycosaminoglycan chains and, subsequently, for the production of aggrecan and other proteoglycans and cartilage. To test the long-term effects of GS on the progression of OA joint structural changes in symptoms of the knee 212 patients with knee OA (American College of Rheumatology criteria) were randomly assigned in a double-blind fashion to a continuous treatment with GS (1500 mg once/day) or placebo for 3 years. Weight-bearing, antero-posterior radiographs of each knee were taken at enrollment and after 1 and 3 years, standardizing patients positioning and radiographic procedures. Total mean joint space width of the medial compartment of the tibio-fermoral joint was assessed by digital image analysis by a validated computerized algorythm, with the narrowest joint space at enrollment being taken for the primary evaluation (signal joint). Patients treated with placebo had an average joint space narrowing (JSN) of approximatively 0.08 to 0.1 mm/year, while no joint space narrowing occurred in the group treated with glucosamine sulfate [4]. These results were later confirmed by another double-blind, placebo-controlled study, performed in 202 patients with knee OA, randomized to either glucosamine sulfate 1500 mg once-a-day or placebo for 3 years. In the glucosamine group, the minimum joint space width of the tibio-femoral joint increased by 0.02 mm after 3 years while it decrease by 0.19 mm in the placebo group [5].

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Diacerein The primary mode of action of diacerein has been reported to be an inhibition of the synthesis and activity of interleukin-1, a proinflammatory catabolic cytokine that plays a key role in the process of cartilage breakdown in osteoarthritis. Diacerein does not inhibit the synthesis of prostaglandins. In a three-year, randomized, double-blind placebo-controlled study, 507 patients with severe to moderate hip osteoarthritis were randomized to receive either diacerein, 50 mg twice daily or identical placebo. At the end of the trial, 62.7% of the placebo and 53.7% of the diacerein treated patients (p = 0.037) had a radiological progression defined as a reduction in the joint space width of at least 0.5 mm. Within the valid completers population (n = 269), the annual joint space narrowing rate was significantly lower in those receiving diacerein than in those receiving placebo (0.018 mm/ year versus 0.023 mm/year; p = 0.042) [6].

Hyaluronic acid Hyaluronic Acid (HA) is synthetized by the synoviocytes and is a key determinant of the viscoelasctic properties of the synovial fluid. HA has been mainly investigated for its symptom-modifying properties. However, in a small-sized study (24 subjects) with knee osteoarthritis where HA (20 mg/2ml once a week for 5 weeks) was compared to methylprednisolone (40 mg/1l once a week for 3 weeks), articular cartilage biopsies showed, under HA, a significant reconstitution of the superficial layer together with an improvement in chondrocyte density and territorial matrix appearance. Chondrocytes also showed an increased extension of the synthetic structures and mithochondria with respect to the organelles having catabolic or storage functions. These results were suggested to reflect a potential structure-modifying activity for HA [7].

Conclusion There is now a convergent body of evidence that several substances acting either through a synthesis of matrix constituants or through an inhibition of catabolic mediators and processus can significantly interact with the progression of osteoarthritis. The most conclusive evidence stands with glucosamine sulfate while chondroitin sulfate and diacerein have also showned promising results in well-conducted longterm trials. The challenge will be now to confirm these structural changes in terms of hard clinical endpoints like a reduction in hip prosthesis or long-term improvement in quality of life of the patients.

References 1. J.-Y. Reginster, V. Gillot, O. Bruye`re, Y. Henrotin. Evidence of nutriceutical eectiveness in the treatment of osteoarthritis. Current Rheumatology Reports 2000;2:472–477. 2. G. Ronca. Antiinflammatory activity of chondroitin sulfate. Osteoarthritis and Cartilage 1997;5:69. 3. B. Michel, E. Vignon, F. de Vathaire, D. Frey, H.-J. Hauselman, G. Stucky, P. Bruhimann, D. Uebelhart. Oral chondroitin sulphate in knee OA patients : radiographic outcomes of a 2-year prospective study. Osteoporosis Int 2001;9:S68. 4. J.-Y. Reginster, R. Deroisy, L.C. Rovati, R.L. Lee, E. Lejeune, O. Bruye`re, G. Giacovelli, Y. Henrotin, J.E. Dacre, C. Gosset. Longterm eects of glucosamine sulphate on osteoarthritis progression : a randomised, placebo-controlled clinical trial. Lancet 2001; 357:251–256. 5. K. Pavelka, J. Gatterova, M. Olejarova, S. Machacek, G. Giacovelli, L.C. Rovati. Glucosamine sulfate decreased progression of knee osteoarthritis in a long-term randomized placebo-controlled, independent, confirmatory trial. Arthritis and Rheum 2000; 43:S384–1908. 6. M. Dougados, M. Nguyen, L. Berdah, B. Mazie`res, E. Vignon, M. Lequesne. Eects of diacerein on the radiological progression of hip osteoarthritis : a three-year placebo-controlled study. Osteoarthritis and Cartilage 2000;43:S336–1619. 7. D.D. Guidolin, I. Pasquali Ronchetti, E. Lini, D. Guerrat, L. Frizziero. Morphological analysis of articular cartilage biopsies from a randomized, clinical study comparing the eects of 500-730 kDa

Abstracts sodium hyaluronate (Hyalgan) and methylprednisolone acetate on primary osteoarthritis of the knee. Osteoarthritis and Cartilage 2001;9:371–381.

SATELLITE SYMPOSIA ABSTRACTS From Research to Clinical Evidence: Defining the Standard for Postmenopausal Women Sponsor: Pfizer Inc. SY1. OSTEOPOROSIS: WHO SHOULD BE TREATED? John A. Kanis, MD; Centre for Metabolic Bone Diseases, University of Sheffield, Medical School, Sheffield, UK The burden of osteoporotic fracture is increasing worldwide, due to the longevity of the population, and in some regions also due to increase in age-specific rates of fracture. With a better understanding of causation and treatment of osteoporosis, intervention strategies require development. Global strategies aimed at the population to decrease fracture risk, such as increase in calcium intake, are attractive but have not been tested. For this reason, greatest attention has been devoted to high risk strategies in segments of the community identified for treatment. There is a poor argument for screening women at the time of menopause using bone mineral density (BMD) assessment. The test has low sensitivity, and many fractures occur in individuals considered to be at low risk. Moreover, specific osteoporosis treatment administered only at the time of menopause is unlikely to prevent fractures in the long term because fracture risk rises when treatment is stopped. The rationale for screening in later life is stronger, but has not been tested. Meanwhile, a case-finding approach is advocated, whereby individuals with clinical risk factors are further identified by BMD assessment. Risk factors include age, family history of hip fracture, prior fragility fracture, high rate of bone turnover, low body mass index, and neuromuscular incompetence. The presence of such factors increases fracture risk beyond that which can be explained on the basis of BMD alone. Therefore, diagnostic thresholds differ from intervention thresholds. Intervention thresholds should be based on the absolute risk of the clinically significant outcomes. Fracture risk is optimally determined as a fracture probability over a relatively long time frame (e.g.,10 years). The setting of intervention thresholds is ultimately dependent upon health economic considerations that have been evaluated in the Swedish population. These require modification in different countries to take account of costs and risks that vary markedly in different regions of the world. In such patients, treatment can be cost-effectively targeted. Cost-effectiveness can be improved still further by patient selection, together with BMD assessment. Current European guidelines are cost-effective, but conservative. The challenge of the future will be to enfranchise a larger segment of the population at risk from osteoporosis.

SY2. ARE PROGESTINS BONE-ACTIVE AGENTS? James H. Liu1, MD, and Ken Muse2, MD; Dept of Obstetrics and Gynecology, University Hospitals of Cleveland1 and Case Western Reserve University,1 Cleveland, Ohio, and the University of Kentucky,2 Lexington, Kentucky, USA Progesterone is the most abundant sex steroid produced by premenopausal and postmenopausal women. Although progestins have been shown to stimulate proliferation of osteoblasts in vitro through their own receptors, its role in bone metabolism is unknown. Progestins utilized in hormone replacement therapy

Abstracts (HRT) include C21 compounds such as micronized progesterone (MiP4) and medroxyprogesterone acetate (MPA) and norethindrone (NET), a 19-nortestosterone derivative. To examine the role of progestins in bone metabolism, 132 early postmenopausal women were randomized to receive orally either placebo, MiP4 (300 mg/d), MPA (10 mg/d), NET (1 mg/d), estradiol (E2) (1 mg/d), or E2 (1 mg/d) + MPA (10 mg/d). All subjects were supplemented with calcium 1000 mg/d and vitamin D 400 IU/d. Endpoints included spine and hip bone mineral density (BMD) determined by serial dual-energy x-ray absorptiometry (DEXA) scans. At the end of 24 months of treatment, changes in BMD at the spine site were: –3% for placebo; –4.3% for MPA (NS); –2.2% for MiP4 (NS); –0.5% for NET (P50.05 vs placebo); +3.2% for E2 (P50.01 vs placebo); and +3.2% for E2 + MPA (P50.01 vs placebo). Changes in BMD at the femoral neck site were: placebo –0.12%; –1.51% for MPA (NS); –0.8% for MiP4 (NS); +1.4% for NET (NS); +3.1% for E2 (NS); and +2.3% for E2 + MPA (NS). These study findings suggest that among the progestins tested, bone activity at the spine site is greatest for NET while MiP4 has intermediate activity and MPA has little or no activity. A similar pattern of progestin response was noted for the hip site, although these changes were not significant. To our knowledge, this is the first randomized study comparing bone activity of the 3 progestins simultaneously. The mechanism of NET’s bone effects is unclear but may be due to: 1) its direct action on progesterone receptors; 2) its crossover activity on androgen receptors; and/or 3) its partial metabolic conversion to EE. Recent studies that have examined various doses of EE in combination with 1 mg of NET acetate have demonstrated that the bone-sparing effects of NET are additive to that of EE. In conclusion, these studies suggest that NET is the most bone-active progestin available among the progestins used in HRT.

SY3. DISCOVERY OF LASOFOXIFENE: THE NEXT GENERATION OF SERMS AND THE LASOFOXIFENE PRE-CLINICAL EVALUATION David D. Thompson; Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut, USA The decline in circulating estrogen in postmenopausal women results in increased risk of osteoporotic fractures, cardiovascular disease (CVD), and an age-related increase in breast cancer risk. The need for effective treatments to prevent osteoporosis, cardiovascular disease, and breast cancer remains high. First generation selective estrogen receptor modulators (SERMs) including tamoxifen and raloxifene, prevent bone loss and breast cancer through their action as estrogen agonists in some tissues and antagonists in other tissues. The results of our drug discovery program produced lasofoxifene, a potent next generation SERM with excellent pharmacokinetic and pharmacodynamic properties and improved efficacy compared to earlier generation SERMs. Lasofoxifene binds selectively and with high affinity to estrogen receptors (ER), ERa and ERb with an IC50 of 0.5 nM and 1.2 nM, respectively, and initiates ER-mediated gene transcription. In vitro, lasofoxifene is a potent inhibitor (IC50 of 0.9 nM) of estrogenmediated breast cell proliferation. In vivo, lasofoxifene inhibits MCF-7 tumor growth in athymic mice, and inhibits the formation and progression of NMU-induced mammary tumors in rats. These data suggest that lasofoxifene has potential to inhibit breast cell proliferation leading to breast cancer. In ovariectomized rats and aged intact female rats, lasofoxifene completely prevented bone loss and reduced serum cholesterol without causing uterine hypertrophy. Efficacy in preventing bone loss was achieved with doses as low as 10 mg/kg/day po, compared to 500 mg/kg/day for raloxifene. Lasofoxifene prevented bone loss by inhibiting osteoclast formation via the mechanism of increased cell apoptosis, in a manner identical to estrogen. In a 2-year ovariectomized primate study, lasofoxifene inhibited bone turnover and prevented bone loss without causing

S151 uterine hypertrophy. Lasofoxifene also prevented bone loss in orchidectomized and aged male rats, similar to findings in ovariectomized and aged female rats. Near identical lasofoxifene doses prevented bone loss and reduced serum cholesterol in both female and male rats. These findings suggest that lasofoxifene has potential to prevent osteoporosis in females and males at significantly lower doses than that of other known SERMs. Lasofoxifene is a potent SERM that acts as an estrogen agonist to prevent bone loss and reduce serum cholesterol, and as an estrogen antagonist to prevent breast cell proliferation. Furthermore, lasofoxifene does not produce uterine hypertrophy. The data suggest that lasofoxifene may have beneficial effects in postmenopausal women.

SY4. EMERGING DATA AND EXPERIENCE WITH LASOFOXIFENE: HIGHLIGHTS FROM CLINICAL TRIALS Alfred Moffett, Jr, MD; University of South Florida College of Medicine, Tampa, Florida, USA Lasofoxifene is an estrogen agonist/antagonist that demonstrates selective binding affinity for the human estrogen receptor (ER) and not for other steroid receptors. It binds to the ER with similar affinity to that of 17b-estradiol. In some tissues, such as the breast and uterus, lasofoxifene receptor binding competes with, and antagonizes, the normal stimulatory actions of estrogen. In other tissues such as bone, because of the tissue-specific cellular environment, binding of lasofoxifene to the ER results in estrogen agonist activity and duplication of many of the effects that occur following estrogen administration. Phase I studies have further characterized the safety, tolerability, and pharmacokinetic profile of lasofoxifene. Single dose studies in males and females have been conducted at doses ranging from 1 to 100 mg; multiple dose studies up to 2 weeks of dosing have been conducted in postmenopausal women at doses ranging from 0.01 mg/d to 20 mg/d. Phase II studies (3 studies) have evaluated lasofoxifene over a 600-fold dose range (0.017 mg/day to 10 mg/day) for up to 1 year in postmenopausal women at risk for osteoporosis. A total of 1,126 subjects have been randomized into these studies. Six- and 12-month data will be reported that demonstrate a significant improvement in bone mineral density (BMD) of the spine and hip at 1 year when compared to placebo controls. In addition, significant reductions in LDL-cholesterol with no adverse effects on other lipid subfractions have been demonstrated as early as 6 weeks and sustained for up to 1 year. Comprehensive endometrial monitoring was done in all phase II study subjects, including end-of-study endometrial biopsies. There were no reported cases of endometrial atypia, hyperplasia, or cancer in any of the subjects. Results from these clinical studies, in addition to the extensive preclinical data, suggest that lasofoxifene is well tolerated and has favorable effects on bone and lipid metabolism.

SY5. EXTRASKELETAL EFFECTS OF HRT AND SERMS IN POSTMENOPAUSAL WOMEN: BREAST CANCER, CARDIOVASCULAR DISEASE, AND COGNITION Elizabeth Barrett-Connor, MD; University of California, San Diego School of Medicine, San Diego, California, USA Breast Cancer: In a reanalysis of data from more than 50 epidemiologic studies, women who used hormone replacement therapy (HRT) for at least 5 years had a 35% increased risk of breast cancer. Recent studies suggest estrogen plus progestogen carries a higher risk than unopposed estrogen. No clinical trial data show that HRT increases the risk of breast cancer. Yet in the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, HRT increased breast density (a strong breast cancer risk

S152 factor), especially in women assigned to estrogen plus progestogen. Raloxifene does not increase breast density. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, osteoporotic older women assigned to raloxifene had a 90% reduced risk of estrogen-receptor–positive breast cancer. Coronary Heart Disease: A meta-analysis of more than 30 epidemiologic studies showed HRT reduced the risk of coronary heart disease by one third. No clinical trial evidence shows estrogen treatment prevents heart disease. In the largest trial, Heart and Estrogen/Progestin Replacement Study (HERS), women with documented heart disease at baseline assigned to HRT had excess number of events in the first year and the same overall risk at 4 years compared to placebo group. Eight other secondary prevention trials failed to show a reduced risk of events, slowed progression of coronary atherosclerosis, or improved outcome after coronary revascularization. In the MORE trial, women with osteoporosis who took raloxifene showed no evidence of early excess heart disease events. After 4 years, fewer events were seen in the subset of women who were at high risk of heart disease. The Raloxifene Use for The Heart (RUTH) trial is comparing raloxifene with placebo in 10,101 women who have known heart disease or are at very high risk. Results are expected in 2007. Cognition and Dementia: A meta-analysis of observational studies and a systematic review of clinical trials concluded that HRT prevents dementia and preserves cognition, particularly verbal fluency and recall. The large HERS trial found no effect of HRT on 6 cognitive function tests, however, and a 1-year clinical trial reported worsening of cognitive function scores in women with early dementia who were assigned to unopposed CEE. In the 3-year MORE trial, women aged 570 assigned to raloxifene showed improvement on 2 of 6 cognitive function tests.

Optimizing Bone Formation and Resorption with Strontium Ranelate: An Innovative Therapeutic Approach to Osteoporosis Sponsor: Servier

Abstracts Bone loss occurs because of the negative balance between the volumes of bone resorbed and formed in each BMU remodeling bone on its endosteal (endocortical, trabecular, intracortical) surface. The negative bone balance is due to an age-related fall in bone formation detectable as a decline in mean wall thickness before menopause. At menopause, estrogen deficiency increases remodeling intensity. Due to the normal lag between the completion of bone resorption and initiation of bone formation in each BMU, bone mass declines rapidly (reflecting the reversible deficit in bone mass). Bone loss continues, more slowly than at menopause but more rapidly than before menopause due to the persisting higher remodeling rate and worsening negative BMU balance as the life span of osteoclasts increases while the life span of osteoblasts decrease. The high remodeling rate results in a higher ‘turn-over’ (replacement) of bone producing a fall in bone mineral mass out of proportion to fall in bone tissue mass (because younger less mineralized bone replaces older more mineralized bone). Structural damage follows (cortical thinning, intra-cortical porosity, trabecular thinning, loss of connectivity). When an antiresorptive drug is given, the mirror image of the changes produced by estrogen deficiency occur; remodeling rate decreases and BMD increases as the delayed bone formation initiated in the BMUs goes to completion. From this higher BMD, bone loss resumes slowly due to the slower remodeling rate, and slower still if there is also a reduction in the negative bone balance (produced by reduced osteoclast lifespan and increased osteoblast life span). If erosion cavities are more shallow, trabecular thinning, perforation, cortical thinning may proceed more slowly. Antiresorptive drugs do not make BMU balance positive; they cannot restore structure or ‘build’ bone (beyond increase in BMD produced reduction in the remodeling space). As bone turnover is reduced due to reduced remodeling, osteons undergo more complete secondary mineralization so that the more slowly declining bone mass becomes more highly mineralized; bone tissue mass falls but its mineral content rises (accounting for the continued BMD increase with antiresorptives). Thus, reduced periosteal and endosteal bone formation has a central role in the pathogenesis of bone fragility. Increasing bone formation is a rational approach to the reversal of bone fragility. Anabolic treatment may increase periosteal and endosteal apposition increasing bone size, cortical and trabecular thickness. If trabecular numbers and connectivity increase and normal bone mineralization follows, it is likely we will cure osteoporosis. Is there progress in this direction?

SY6. REDUCED BONE FORMATION: A RATIONAL TARGET FOR THE TREATMENT OF OSTEOPOROSIS Ego Seeman; Austin and Repatriation Medical Centre, University of Melbourne, Melbourne, Australia Reduced bone formation on the periosteal and endosteal surfaces has a pivotal role in the pathogenesis of bone fragility. The amount of bone lost during ageing is determined by the amount of bone lost on its inner (endosteal) envelope and formed beneath its outer (periosteal) envelope. Sub-periosteal bone formation during ageing has two effects: (i) Bone cross sectional area (CSA) increases so that the bending strength increases and compressive stress (load per unit area) imposed on the bone decreases. (ii) Endosteal bone loss is offset so that bone mass falls less with age. These effects are sex specific. Sub-periosteal bone formation is greater in men than women while the amount of endosteal bone resorbed during ageing is only slightly greater in women than in men. So, net bone loss during ageing is less in men primarily because absolute periosteal bone formation is greater in than in women. Correspondingly, loss of bone strength is less in men primarily because sub-periosteal bone formation is greater than in women. In addition, reduced vertebral CSA and bone mass in women and men with spine fractures may be partly the result of reduced sub-periosteal apposition during growth, ageing or both, not just ‘excessive’ bone resorption. Reduced bone formation in each remodeling or basic multicellular unit (BMU) on the endosteal surface is also important.

SY7. THE CALCIUM-SENSING RECEPTOR AS A MOLECULAR TARGET FOR THE BIOLOGICAL ACTIONS OF STRONTIUM RANELATE Edward M. Brown; Brigham and Women’s Hospital, Boston, MA, USA The Ca2+-sensing receptor (CaR) plays key roles in calcium (Ca2+) homeostasis by permitting specialized cells to ‘sense’ changes in Ca2+. The CaR is also present in osteoblasts and putative osteoclast precursors, where it could potentially mediate the known actions of Ca2+ to stimulate osteoblast function and inhibit osteoclastogenesis. It has been shown that the CaR not only binds Ca2+ but also numerous other cations. Strontium ranelate is the only known therapeutic agents for osteoporosis that both inhibits bone resorption and stimulates bone formation. To determine whether the CaR could serve as a target for the actions of strontium (Sr2+) on bone, Sr2+ activation of the cloned bovine CaR transfected in HEK293 was tested. This activation was assessed by Sr2+-evoked increases in cytosolic Ca2+, accumulation of inositol phosphates or activation of a Ca2+permeable, nonselective cation channel (NCC). Sr2+ activated all three parameters with observed half maximal effects (EC50) between 2 and 3 mM on HEK293 cells. The EC50 for Sr2+ was about 0.5 mM higher than for Ca2+ in HEK293 cells. The maximal

Abstracts

S153 2+

stimulation of these parameters with Sr varied from 70% to 100% of that caused by Ca2+. The differences in the actions of Sr2+ versus Ca2+ on CaR-expressing HEK293 cells may reflect, in part, the relative permeabilities of plasma membrane channels to both ions. These results are in agreement with those previously obtained on Chinese hamster ovary cells transfected with the rat brain CaR.1 In conclusion, Sr2+ is an effective agonist of the CaR, with a lower power than that of Ca2+, and the CaR could potentially mediate, in part, the actions of Sr2+ on bone cells. High local concentrations of Sr2+ in bone close to CaR-expressing cells, combined with low therapeutic concentrations in plasma (~0.13 mM) that do not activate the CaR, may permit therapeutic actions on bone without systemic side effects.

Reference 1. Coulombe et al. J Bone Miner Res. 2001;16(suppl 1):S428 (Abstract SU500).

SY8. OPTIMIZING BONE METABOLISM IN OSTEOPOROSIS: INSIGHT INTO THE PHARMACOLOGICAL PROFILE OF STRONTIUM RANELATE P. J. Marie; INSERM U349, Lariboisie`re Hospital, Paris, France Strontium ranelate (SR) is currently being developed for the treatment of osteoporosis. Its efficacy, observed in preclinical studies, is based on its original mode of action on bone resorption and formation. Pharmacological studies in animal models showed that SR increases bone formation, decreases bone resorption, and improves bone mass. In the model of ovariectomized (OVX) rats, SR limited the reduction in bone mineral content and the decrease in trabecular bone volume (improvement of 36% in comparison with the OVX rats), induced by estrogen deficiency. In this model, SR acted by inhibiting bone resorption whereas bone formation was maintained at a high level, as documented by biochemical markers (alkaline phosphatase +32%, osteocalcin +71% compared with the OVX rats) and histomorphometric indices of bone formation and resorption. In the model of osteopenia induced by hind limb immobilization in rats, SR significantly reduced the histomorphometric parameters of bone resorption (Oc.S/BS, –16%) and partially limited long bone loss, as assessed by bone mineral content (+7.5%), bone volume, and biochemical indices of bone resorption. In normal mice, SR significantly increased bone formation and vertebral bone mass (36% to 59% in males and females, respectively). In normal rats, SR significantly and dosedependently increased the mechanical properties of vertebral, humeral, and femoral bones, associated with an increase in femoral shaft diameter (+4.3%, P50.05). Vertebral bone mineral density and bone strength (energy absorbed) were also significantly increased, whereas stiffness was not altered, underlying the improvement in bone strength without deleterious effects on bone mineralization. In normal adult monkeys, SR was found to decrease bone resorption, by 20% to 60% depending on treatment duration, and to increase bone volume at the iliac crest level (by 22% after 13 weeks of treatment). The unique mode of action of SR on bone formation and resorption is also supported by in vitro studies. In calvaria culture systems and osteoblastic cell cultures, SR enhanced the replication of pre-osteoblastic cells and increased osteoblast collagen synthesis. Moreover, SR was found to inhibit the bone resorbing activity of isolated mouse osteoclasts as well as osteoclast differentiation in chicken bone marrow cultures. Altogether, these pharmacological results suggest that SR optimizes bone metabolism (decreases resorption, increases formation), which may be of potential interest in the treatment of osteoporosis.

SY9. DOSE-RELATED BONE EFFECTS OF STRONTIUM RANELATE IN POSTMENOPAUSAL WOMEN Meunier PJ1, Reginster JY2; 1Department of Rheumatology and Bone Diseases, Edouard Herriot Hospital, Lyon, France and 2 Bone and Cartilage Metabolism Unit, University of Lie`ge, Belgium Two major randomized, multicenter, double-blind, placebocontrolled 2-year studies were carried out to assess the mimimal active dose of strontium ranelate (SR), as curative treatment of postmenopausal vertebral osteoporosis (STRontium Administration for Treatment of OSteoporosis [STRATOS] study) and as preventive treatment of bone loss in early postmenopausal women (PREVention of Osteoporosis Study [PREVOS]). The primary efficacy parameter was percentage variation in lumbar bone mineral density (L-BMD), measured using dual x-ray absorptiometry. STRATOS was carried out in postmenopausal osteoporotic women with at least one previous vertebral fracture and L-BMD Tscore 5–2.4. Three hundred and fifty-three women (66±7 yrs; LBMD 0.699±0.10 g/cm2; mean±SD) were randomized to receive placebo, 0.5 g, 1 g, or 2 g SR per day. All patients received a daily supplement of calcium (500 mg) and vitamin D2 (800 IU). L-BMD, adjusted for bone strontium content, increased in a dosedependent manner, with mean annual slopes ranging from 1.4% for the 0.5 g/day SR dose, to 3.0% for the 2 g/d SR dose, which was significantly higher than placebo (P50.01). There was a significant reduction in the number of patients experiencing new vertebral deformities in the second year of treatment at the 2 g/ day dose (relative risk 0.56; 95% confidence interval [0.35; 0.89]), and a similar effect was observed with 0.5 g/day. In the 2 g/day group, there was a significant increase in bone alkaline phosphatase (bALP), while urinary N-telopeptide of type I collagen (NTX) was lower with SR than with placebo. Bone histomorphometry showed no mineralization defects. All tested doses were well tolerated. The results show that SR 2 g/day offered the best efficacy–safety ratio for the curative treatment of postmenopausal osteoporosis. In PREVOS, 160 healthy, early postmenopausal women (54±3 yrs; L-BMD 0.931±0.14 g/cm2; mean±SD) were randomized to receive placebo, 0.125 g, 0.5 g, or 1 g SR per day. All participants received a calcium supplement of 500 mg daily. SR 1 g/day demonstrated a significant increase in adjusted lumbar BMD compared with placebo (P50.05). The annual increase was 0.7%, compared with –0.5% with placebo, with an overall beneficial effect after 2 years of about 2.4% in the 1 g/day SR group compared with the placebo group. There were no other significant between-group differences in adjusted L-BMD. In the 1 g/day SR group, a significant increase in bALP was observed at M18 (P = 0.048) compared with placebo. No effect on markers of bone resorption was observed. SR was as well tolerated as placebo. The minimum dose at which SR is effective in preventing bone loss in early postmenopausal women is 1 g/day.

SY10. STRONTIUM RANELATE ANTIFRACTURE STUDY PROGRAM: CURRENT DATA Reginster JY1, Meunier PJ2; 1Bone and Cartilage Metabolism Unit, Lie`ge, Belgium and 2Department of Rheumatology and Bone Disease, Edouard Herriot Hospital, Lyon, France Previous studies showed that strontium ranelate (SR), a boneforming and antiresorptive drug, increases bone mineral density (BMD) in postmenopausal women. The antifracture program made up of the Spinal Osteoporosis Therapeutic Intervention (SOTI) trial, coordinated by PJ Meunier, Lyon, France, and the TReatment Of Peripheral Osteoporosis (TROPOS) trial, coordinated by JY Reginster, Lie`ge, Belgium, are multinational, prospective, randomized, double-blind, placebo-controlled 5 year studies designed to evaluate the curative effect of 2 g/day

S154 of SR for the treatment of severe osteoporosis in postmenopausal women, with main statistical analysis after 3 years of follow-up. All patients included in these two studies had previously participated in the Fracture International Run-in Strontium Trial (FIRST) aimed at normalizing the calcium (Ca) and vitamin D (vit D) status before being randomized in either SOTI or TROPOS. The patients received Ca/vit D supplements throughout the studies which were individually adapted according to their deficiencies (0, 0.5 g, or 1 g of Ca, and 400 or 800 IU of vit D). Results of FIRST will be presented. Out of 9196 patients who took part in FIRST, 1649 women (mean age 70 years) with at least one vertebral fracture and a low lumbar BMD were included in SOTI to assess the reduction in the incidence of patients with new vertebral fractures; and 5091 women older than 70 years (mean age 77 years) with a low hip BMD were included in TROPOS to assess the reduction in the incidence of patients with peripheral fractures. The hip fracture relative risk will be evaluated in pooled SOTI and TROPOS patients. The changes in BMD, bone ultrasounds, bone markers, and the tolerance will also be evaluated. The first part of this large phase 3 program is ongoing and expected to end in 2002.

Protecting Bone Health with Lower HRT Doses Sponsor: Wyeth-Ayerst

Abstracts SY12. IMPACT OF LOWER-DOSE HRT ON BONE, CLIMACTERIC SYMPTOMS, AND BODY WEIGHT IN EARLY POSTMENOPAUSAL WOMEN Marco Gambacciani; Department of Obstetrics and Gynecology, University of Pisa, Pisa, Italy Using the lowest effective dose of therapy is sound clinical practice. Research on the influence of lower doses of conjugated equine estrogens (CEE, 0.3 mg) combined continuously with medroxyprogesterone acetate (2.5 mg), dydrogesterone (5 mg) or nomegestrel (2.5 mg) on bone, vasomotor symptoms, body weight changes, and quality of life in healthy, early menopausal women will be presented. A 2-year, open-label trial was conducted in 120 symptomatic women, 45 to 56 years. All participants also received 1,000 mg/day of calcium. Responses were similar between the different progestins evaluated, thus data for the low-dose hormone replacement therapy (LD-HRT) groups were combined for analyses. A total of 15 women in the control group (calcium only) and 63 women in the LD-HRT groups completed the study. LD-HRT resulted in significant improvements in climacteric symptoms within 3 weeks of treatment; these improvements were maintained over the course of the trial. Body weight and BMI at 2 years was unchanged in the women receiving LD-HRT, but was significantly increased from baseline in the control group. LD-HRT significantly reduced biochemical markers of bone turnover from baseline within 6 months of treatment, whereas bone turnover was not altered at any time point in the women who received only calcium. Hip and spine BMD were maintained at baseline levels over the 2-year study in women treated with LD-HRT. By 1 year of therapy, BMD levels were significantly greater in the LD-HRT groups than in the control group. The loss of BMD from baseline was significant for the control group by 1 year. These data suggest that LD-HRT is effective for symptom relief, maintaining BMD, and minimizing side effects (weight gain) in early postmenopausal women. Longer-term treatment with LDHRT on health outcomes requires further study.

SY11. HEALTH AND ECONOMIC IMPACT OF OSTEOPOROSIS PREVENTION Anthony D Woolf; Duke of Cornwall department of Rheumatology, Royal Cornwall Hospital, Truro TR1 3LJ, UK Osteoporosis manifests as fracture which has an enormous health, social and economic impact on the individual and on society. Its prevention is a public health issue. The acute fracture results in pain, disability and acute healthcare costs. A fifth of those who have sustained a Colles’ fractures or clinical vertebral fracture but all who have sustained a hip fracture are hospitalised. There is an excess mortality following hip fracture and also related to vertebral fracture. There are substantial costs associated with healthcare resource utilisation but of the estimated £2 billion cost of osteoporosis in the UK, only a third is for acute care. Many following hip fracture and some after vertebral fracture will not return home and most will have impaired health related quality of life, reduced independence and increased need for social support. Many lose mobility after hip fracture and vertebral fracture is associated with impairment of the various aspects of health related quality of life measured by disease specific and generic instruments, which worsens with the increasing numbers of vertebral fracture and progression of spinal deformity. Asymptomatic vertebral deformities are also associated with reduced functioning. The person has limitation of their activities that restricts their participation in society using the terminology of the new WHO International Classification of Functioning. The incidence of fracture increases with age and the concomitant age-associated increase in comorbidity will worsen the outcome of any fracture. The occurrence of a fracture is also a strong risk factor for further fracture. Identifying and treating those at risk before the first fracture is a priority and prevention will have major health and socio-economic benefits for society and the individual. Strategies for prevention are needed for all stages of life.

SY13. THE WOMEN’S HOPE STUDY: EFFICACY AND SAFETY OF LOWER DOSES OF CONJUGATED EQUINE ESTROGENS AND MEDROXYPROGESTERONE ACETATE IN EARLY POSTMENOPAUSAL WOMEN Robert Lindsay; Chief of Internal Medicine, Helen Hayes Hospital, NY, USA The impact of lower doses of conjugated equine estrogens (CEE) combined with lower doses of medroxyprogesterone acetate (MPA) on vasomotor symptoms, bleeding profiles, vaginal atrophy, endometrial hyperplasia, metabolism, and bone mineral density was investigated in a large, randomized clinical trial of early postmenopausal women. The Women’s Health, Osteoporosis, Progestin, Estrogen (Women’s HOPE) study included 2,805 healthy postmenopausal women (age 40-65 years) with an intact uterus who were randomized to treatment. Patients received CEE 0.625, CEE 0.625/MPA 2.5, CEE 0.45, CEE 0.45/MPA 2.5, CEE 0.45/MPA 1.5, CEE 0.3, CEE 0.3/MPA 1.5 (all doses mg/d), or placebo for 1 year. A metabolic and osteoporosis substudy was conducted over 2 years in 749 of the women enrolled. Lower doses of CEE/MPA resulted in significant reductions from baseline in the number of severity of hot flushes, and vaginal atrophy. Cumulative amenorrhea was higher with lower CEE/MPA doses compared with commonly prescribed doses (CEE 0.625/ MPA 2.5). Endometrial hyperplasia rates ranged from 0% to 0.37% for all CEE/MPA doses. The increase in HDL-cholesterol and decrease in LDL-cholesterol from baseline at 1 year were significant for all CEE/MPA doses, although the greatest changes were observed in the women treated with CEE 0.45/MPA 1.5 and CEE 0.625/MPA 2.5. By 2 years, women assigned to all of the active treatment groups had significant gains in spine and hip BMD, and total body BMC. In contrast women in the placebo

Abstracts group lost spine and hip BMD and total body BMC over the course of the trial. These results suggest that lower doses of CEE/MPA are efficacious and provide endometrial protection for early postmenopausal women with an intact uterus. Using lower doses of both CEE and MPA makes clinical sense and may enhance compliance and initiation of therapy.

Setting the Standard for Treating Osteoporosis: New Evidence for Optimal Patient Management Sponsor: Merck Sharp & Dohme SY14. THE LONG TERM EFFECTS OF ALENDRONATE: BONE QUALITY & SUSTAINED FRACTURE REDUCTION Gideon Rodan; USA Bone quality is an imprecise term referring to properties which contribute to fracture risk, but are not captured by the quantitative parameters of bone mineral density (BMD) or content (BMC). Two quantifiable determinants of bone ‘quality’ include architecture and material properties. The latter can be measured on a sample of compact bone. Fracture risk is obviously related to bone strength, which can be estimated experimentally by measuring the force required to break whole bones or bone specimens ex vivo. With these concepts in mind, let us examine the long-term effects of alendronate (ALN) treatment. Bisphosphonates (BPs) are today the most widely used therapy for the treatment of osteoporosis. ALN has had the largest use, over 4 million patients for up to over 6 years. ALN acts predominantly by reducing bone destruction (resorption) through inhibition of osteoclast activity. In principle, inhibitors of bone resorption should not affect bone quality, since they reduce the destruction of normal bone, provided that they have no deleterious effects on bone formation. Two concerns have been raised regarding BPs: retention in bone and reduced bone turnover. For potent bisphosphonates such as alendronate, risedronate and others, the daily (absorbed) effective dose is in the microgram range. The estimated maximum accumulation of alendronate over 10 years is about 70 mg, a relatively small amount dispersed in 2 kg of calcium hydroxyapatite, albeit not homogenously, mostly buried within the matrix. Its effect on the mineral was shown to be improved crystallinity, probably resulting from more complete mineralization due to reduced turnover. Etidronate, the first clinically used BP, is less potent than the Ncontaining BPs (N-BPs) and is given at higher doses. When initially used at relatively high doses for treating Paget’s disease or ectopic ossification it caused osteomalacia (inhibition of mineralization during bone formation). Osteomalacia causes a substantial deterioration in the material properties of bone; it was reproduced in dogs administered high doses of etidronate and caused fractures. All BPs inhibit mineralization at approximately the same concentration, achieved in vivo by a parenteral dose of approximately 5–10 mg P/kg body weight. The osteomalacia problem has been completely overcome by the development of potent N-BPs, effective at mg/kg levels. For alendronate, the ratio between the osteomalacia producing dose and the therapeutic dose in rats is 46,000. The same should hold for risedronate and for more potent bisphosphonates, such as ibandronate and zoledronate. Thus, based on their mechanism of inhibiting the destruction of normal bone, N-BPs should not cause changes in bone material properties and none have been reported. Consistent with this notion, bone strength in animals treated with NBPs increased in proportion with bone mass, estimated either by DXA or histomorphometry. For alendronate, this was observed in

S155 four different species (baboons, dogs, pigs and rats), dosed with up to 10-fold human therapeutic dose for up to three years. The power of this approach to detect deleterious changes in bone quality is illustrated by an animal study with fluoride. In clinical trials (two in the U.S. and one in Europe) fluoride did not reduce fracture risk, although BMD increased substantially. Similarly, in a pig study, bones from animals receiving fluoride (equivalent to human dose) did not show the expected increase in bone strength with increased bone mass, observed in control and alendronate-treated pigs. Furthermore, the decrease in bone strength was proportional to the increase in fluoride content. These observations support ex vivo biomechanical testing as a predictor of bone strength and the related fracture risk in the clinic. Questions have been raised regarding possible deleterious effects of reduced bone turnover. In the animal experiments described above, none were detected by mechanical testing. To study this question specifically, a rat model of rapid bone formation and resorption following marrow ablation was used. Alendronate dosed up to 25x therapeutic dose had no impact on the bone formation rate. Therapeutic doses had no impact on the bone resorption controlled by mechanical function, while bone formed at 25-fold higher doses was resorbed at about 50% control rate. These findings are pertinent to fracture repair, which is initiated by similar stimuli. Animal studies and clinical observations with N-BPs found that fracture repair was not impaired. In clinical trials ALN and other N-BPs suppress bone turnover, estimated by biochemical markers, into the premenopausal range. This suppression correlates with and was suggested to be necessary for fracture risk reduction, possibly due to effects of bone turnover on architecture. It was recently reported that in dogs treated with a 6x therapeutic dose of alendronate or risedronate, which substantially decrease bone turnover, there was an increase in histological microcracks. However, bone strength, estimated ex vivo as the force needed to break the bone, increased both in the alendronate and risedronate groups, compared to controls. This type of histological microcracks increase with age in human femora. However, no differences in microcracks have been observed between samples from femoral fractures and non-fractured controls. On the other hand, fractured femora were found to have increased porosity, a change usually associated with increased turnover. ALN treatment causes a substantial reduction in the porosity of cortical bones in clinical trials. Taken together, none of the inhibitors of bone resorption, including ALN, for which the largest data base from randomized clinical trials and post-marketing surveillance is currently available, as well as other N-BPs, were found to have deleterious effects on bone quality, estimated by preclinical mechanical testing and clinical fracture risk. This is consistent with their mechanism of reducing the destruction of normal bone without interfering with bone formation.

References/Suggested Reading Balena, R., A. Markatos, J.G. Seedor, M. Gentile, C. Stark, C.P. Peter and G.A. Rodan. 1996. Long-term safety of the aminobisphosphonate alendronate in adult dogs. II. Histomorphometric analysis of the L5 vertebrae. J. Pharmacol. Exp. Therap. 276:277–283. Balena, R., B.C. Toolan, M. Shea, A. Markatos, E.R. Myers, S.C. Lee, E.E. Opas, J.G. Seedor, H. Klein, D. Frankenfield, H. Quartuccio, C. Fioravanti, J. Clair, E. Brown, W.C. Hayes and G.A. Rodan. 1993. The eects of 2-year treatment with the aminobisphosphonate alendronate on bone metabolism, bone histomorphometry, and bone strength in ovariectomized nonhuman primates. J. Clin. Invest. 92:2577–2586. Bell, K.L., N. Loveridge, G.R. Jordan, J. Power, C.R. Constant and J. Reeve. 2000. A novel mechanism for induction of increased cortical porosity in cases of intracapsular hip fracture. Bone 27:297–304. Burkman, R.T., J.A. Collins and R.A. Greene. 2001. Current perspectives on benefits and risks of hormone replacement therapy. Am. J. Obstet. Cynecol. 185:S13–23. Cauley, J.A., D.M. Black, E. Barrett-Connor, F. Harris, K. Shields, W. Applegate and S.R.

S156 Cummings. 2001. Eects of hormone replacement therapy on clinical fractures and height loss: the heart and estrogen/progestin replacement study (HERS). Am. J. Med. 110:442–450. Fratzl, P., S. Schreiber, P. Roschger, M.-H. Lafage, G. Rodan and K. Klaushofer. 1996. Eects of sodium fluoride and alendronate on the bone mineral in minipigs: a small-angle x-ray scattering and backscattered electron imaging study. J. Bone Miner. Res. 11:248–253. Grady, D., N.K. Wenger, D. Herrington, S. Khan, C. Furberg, D. Hunninghake, E. Vittingho and S. Hulley. 2000. Postmenopausal hormone therapy increases risk for venous thromboembolic disease: The heart and estrogen/progestin replacement study. Ann. Int. Med. 132:689–696. Key, T.J. 1999. Serum oestradiol and breast cancer risk. EndocrineRelated Cancer 6:175–180. Lafage, M.-H., R. Balena, M.A. Battle, M. Shea, J.G. Seedor, H. Klein, W.C. Hayes and G.A. Rodan. 1995. Comparison of alendronate and sodium fluoride eects on cancellous and cortical bone in minipigs: a one-year study. J. Clin. Invest. 95:2127–2133. Masarachia, P., M. Weinreb, R. Balena and G.A. Rodan. 1996. Comparison of the distribution of 3H-alendronate and 3H-etidronate in rat mouse bones. Bone 19:281–290. Mashiba, T., C.H. Turner, T. Hirano, M.R. Forwood, C.C. Johnston and D.B. Burr. 2001. Eects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone 28:524–531. Peter, C.P., J. Guy, M. Shea, W. Bagdon, W.F. Kline and W.C. Hayes. 1996. Long-term safety of the aminobisphosphonate alendronate in adult dogs. I. General safety and biomechanical properties of bone. J. Pharmac. Exp. Ther. 276:271–276. Peter, C.P., W.O. Cook, D.M. Nunamaker, M.T. Provost, J.G. Seedor and G.A. Rodan. 1996. Eect of alendronate on fracture healing and bone remodeling in dogs. J. Ortho. Res. 14(1):74–79. Power, J., B.S. Noble, N. Loveridge, K.L. Bell, N. Rushton and J. Reeve. 2001. Osteocyte lacunar occupancy in the femoral neck cortex: an association with cortical remodeling in hip fracture cases and controls. Calcif. Tissue Int. 69:13–19. Renshaw, C.E. and E.M. Schulson. 2001. Universal behaviour in compressive falure of brittle materials. Nature 412:897–900. Roschger, P., P. Fratzl, K. Klaushofer and G.A. Rodan. 1997. Mineralization of cancellous bone after alendronate and sodium fluoride treatment: a quantitative backscattered electron imaging study on minipigs. Bone 20(5):393–397. Toolan, B.C., M. Shea, E.R. Myers, R.E. Borchers, J.G. Seedor, H. Quartuccio, G. Rodan and W.C. Hayes. 1992. Eects of 4-amino-1hydroxybutylidene bisphosphonate on bone biomechanics in rats. J. Bone Miner. Res. 7:1399–1406.

Abstracts higher unit dose did not. Thus, weekly dosing with alendronate may actually reduce any risk of upper GI irritation. A recent study evaluated the safety profile and efficacy of a more convenient alendronate once-weekly dosage schedule in postmenopausal women (ages 40 to 90) with osteoporosis (BMD of either lumbar spine [LS] of femoral neck more than 2.5 SDs below peak (young adult) mean BMD or prior vertebral or hip fracture). In this trial, 1258 patients were recruited and randomized to treatment with once-weekly alendronate 70 mg, twice-weekly alendronate 35 mg or daily alendronate 10 mg in a 1-year, double-blind, multicenter study. The primary efficacy endpoint was the comparability of LS BMD increases. Secondary endpoints included changes in BMD at the hip and total body and rate of bone turnover as assessed by biochemical markers. Mean increases in LS BMD at 12 months were equivalent for all three treatment regimens. The mean increase in lumbar spine BMD was 5.4% in the daily dosing group, 5.1% in the weekly group and 5.2% with twice weekly dosing. Both the weekly and twice weekly groups met the prespecified statistical criteria for therapeutic equivalence compared to daily dosing. BMD increases at other skeletal sites were also similar across the three dosing regimens. The suppression of markers of bone turnover was of a similar magnitude for each dosing group. All treatment regimens were well tolerated. There was no increase in the frequency of esophageal, gastric or other upper gastrointestinal adverse events with the larger weekly dose. Rather, the rate of serious upper GI adverse experiences in the daily treatment group was 1.4%, whereas there were no serious upper GI adverse experiences observed in the weekly or twice weekly dose groups. Continuation of subjects for a second year in this study produced changes in BMD at all sites that were also comparable in all three treatment groups. Importantly 70mg alendronate administered once weekly for 2 years was well tolerated with no increase in GI or other adverse events. In conclusion, 70 mg once weekly alendroanate is therapeutically equivalent to 10mg daily, providing patients with the proven efficacy of alendronate, good tolerability and greater dosing convenience.

SY16. A SYSTEMATIC REVIEW OF OSTEOPOROSIS TREATMENTS: A COLLABORATIVE APPROACH SY15. ALENDRONATE ONCE WEEKLY: STANDARD OF CARE IN TREATING OSTEOPOROSIS

Jonathan Adachi for the Osteoporosis Research Advisory Group (ORAG) and the Osteoporosis Methodology Group, Canada

Philip Sambrook; Australia

We have performed comprehensive systematic reviews of osteoporosis therapies, including alendronate, calcitonin, calcium, etidronate, fluoride, hormone replacement therapy (HRT), risedronate, raloxifene, and vitamin D. We considered the methodological strengths and weaknesses of the individual studies, and summarized the effects of treatments on the risk of vertebral and non-vertebral fractures and on bone mineral density (BMD). Our systematic reviews found the largest treatment effects on lumbar spine BMD with fluoride, alendronate (10–40 mg) and HRT, with intermediate effects seen with risedronate and etidronate. Regarding fracture risk it is likely that a number of drugs reduce the risk of vertebral fractures. These include the bisphosphonates (alendronate, etidronate, and risedronate), vitamin D (hydroxylated), calcitonin, and raloxifene. The inferences regarding reduction of vertebral fractures are strongest for alendronate and risedronate (on the basis of the methodological quality of the studies, the magnitude of the treatment effect, narrowness of the confidence intervals, and the consistency of the results from study to study). There is convincing evidence for non-vertebral fracture risk reduction for only two agents, alendronate and risedronate. Decisions regarding treatment of osteoporosis remain complex, but data from randomized trials have provided great insights into the strength of the evidence for effectiveness of different

Alendronate is a bisphosphonate that potently inhibits bone resorption. Daily administration has consistently been shown to increase bone mass, markedly decrease bone turnover and substantially reduce the incidence of osteoporotic fractures, including hip fractures. Although the majority of patients are compliant with daily therapy, a less frequent dosing regimen, such as weekly, would increase convenience. Bisphosphonates are rapidly bound to sites of active bone resorption and remain there for sustained periods, beyond their initial uptake from the circulation. Weekly dosing is thought to provide continuous inhibition of bone resorption (yielding a sustained effect). This contrasts with intermittent inhibition, as with cyclical etidronate or intravenous ibandronate, in which bone resorption may not be continuously suppressed. Treatment with alendronate at intervals of up to 2 weeks has been shown to increase BMD and bone strength in animal models of osteoporosis. Modeling suggests that weekly administration of alendronate can inhibit bone resorption to an overall extent similar to daily dosing and thereby produce similar effects on bone density. Although daily exposure to potent bisophosphonates (such as alendronate and risedronate) in the presence of an acidic environment can elicit esophageal irritation in a canine model of gastroesophageal reflux, weekly dosing with alendronate at a

Abstracts therapies. In addition to the evidence, other factors such as additional benefits, risks, adverse effects and price, as well as values and preferences will play an important role in decisionmaking regarding anti-osteoporosis therapy.

New Findings on the Eect of Alfacalcidol and D-Hormone Analogs on Fractures Sponsor: Chugai Pharmaceutical Co., Teijin Ltd., and Teva Pharmaceutical Industries Ltd. SY17. RELEVANCE OF BONE MINERAL DENSITY, BONE QUALITY AND FALLS IN REDUCTION OF VERTEBRAL AND NONVERTEBRAL FRACTURES J.Y. Reginster; University of Lie`ge, Belgium The multifactorial pathophysiology of osteoporosis involves the development of low bone mass as well as other skeletal components of fragility and extra-skeletal factors thus leading to fracture and requires as a consequence a multifaceted comprehensive approach to prevention. The most important cause of osteoporosis is the bone loss that occurs after the menopause. Vertebral fractures in postmenopausal osteoporosis can occur spontaneously and are pure osteoporotic fractures. Although bone mass is frequently considered to be the most important determinant of fragility, it explains less than half of the observed fracture risk. Clinical studies have demonstrated that expressed fragility (in the form of a prior fracture) is a stronger predictor of future fractures than is low bone mass. Almost all non-vertebral fractures are fall-related. Increased skeletal fragility or increased occurrence of extra-skeletal factors, such as falling, the type of fall that occurs among the elderly and the loss of protective soft tissue covering, may result in a larger contribution of age and lesser contribution of bone mass in the age-related increase in the frequency of fractures in women and men in later life. Elderly individuals have slower response times and more often fall to the side, thus they more often sustain force directly on the hip. Most of the falls are ‘intrinsic’, not caused by external obstacles. These alterations are the results of a deterioration in gait and postural stability, decreased muscular performance, malnutrition, comorbidity and medications. These extra-skeletal determinants of peripheral fracture risk account for the poorer discrimination between the bone mass of fracture and non-fracture cases in later life compared with vertebral fracture. With continued aging of the population the annual number of fractures is expected to rise dramatically in the coming decades. Global prevention programs for osteoporotic fractures should include not only environmental or pharmacological means to increase bone density and bone strength but also fall prevention programs including pharmacological substances (D-hormones) which have fully demonstrated their ability to improve postural stance, gait and muscular strength.

SY18. MODE OF ACTION OF ALFACALCIDOL VERSUS PLAIN VITAMIN D ON BONE REMODELING AND BONE QUALITY K. Ikeda, National Institute for Longevity Sciences, Aichi, Japan Plain vitamin D deficiency and impaired synthesis and/or action of D-hormone 1,25(OH)2D, with the resultant decline of calcium absorption, increased PTH levels, de-coupled bone remodeling, and reduced muscle strength, are considered a major risk factor of involutional osteoporosis and fractures. Thus, supplementation

S157 with plain vitamin D and calcium is a rational remedy, and its efficacy in vitamin D deficient patients in terms of prevention of osteoporosis is evidence-based. For the treatment of established osteoporosis a monotherapy with plain vitamin D and calcium is not sufficient. On the other hand, the use of D-hormone analogs in the treatment of osteoporosis is more suitable, because they work independent of the vitamin D status, although is more expensive and its advantage over plain vitamin D is not generally accepted. In order to solve some of these problems, we have been studying the effects of D-hormone vs. plain vitamin D on bone remodeling and bone quality in aged ovariectomized (OVX) rats. Our results indicate that 1) D-hormone acts as a potent ‘inhibitor’ of bone resorption in vivo in OVX rats, as opposed to well-known ‘stimulation’ in vitro, 2) unlike typical inhibitors of bone resorption such as estrogens and bisphosphonates, D-hormone does not ‘suppress’ but rather ‘stimulate’ bone formation, and exerts more favorable effects than estrogen on bone strength as well as on BMD, 3) mode of action of D-hormone in vivo involves depletion of osteoclast precursors in bone marrow, no induction of RANKL as established in vitro, and increasing CFU-F as mesenchymal stem cells supplying bone-forming osteoblasts, 4) alfacalcidol increases BMD and bone strength more effectively than plain vitamin D, at a similar level of effects on calcium absorption, i.e. at least in part independently of calcium absorption and PTH levels, 5) ED-71, a second-generation D hormone analog, inhibits bone resorption and increases bone volume more potently than alfacalcidol for a similar level of effects on calcium absorption and PTH. Finally, recent results on the effects of D-hormone vs. plain vitamin D on bone microstructure by micro-CT scanning are presented and discussed in the context of bone quality. Conclusion: These results provide a further rationale for the clinical utility of D-hormone analogs and its advantage over plain vitamin D in the treatment of osteoporosis.

SY19. MULTIFACTORIAL PATHOGENESIS OF FALLS AS A BASIS FOR MULTIFACTORIAL INTERVENTIONS M. Runge; Aerpah Clinic, Esslingen, Germany The pathophysiology of age, falls, bone strength and nonvertebral fractures are inextricably interconnected in a pathogenetic cascade. Osteoporosis does not ‘cause’ the non-vertebral fractures, it is one of several risk factors. The combination of reduced bone strength and increased propensity to falls is responsible for the exponential increase of hip fracture incidence with advancing age. The majority of falls occur without (pre)syncope during normal daily activities with no or minimal external contribution. A patient at high fall risk can be seen as an individual hosting a specific cluster of multiple fall risk factors. Fracture risk assessment identifies and quantifies both reduced bone strength and fall propensity. A fall risk assessment comprises measures of proven independent fall risk factors: 1.) Muscle strength/ muscle power in the lower extremities, 2.) Postural capacity (balance), 3.) Gait disorder, 4.) Vision, 5.) Polypharmacy/psychotropic drugs, 6.) Cognitive impairment. Examining muscle function and gait and balance disorders requires age-, sex- and race-related reference values. Muscle function and balance, which both have been proven independently correlated to fall risk, can be respectively measured with the chair rising test and tandem manoeuvres. The chair rising test correlates well with other parameters of muscle function of the lower extremities; e.g. with measurement of muscle power and velocity by Leonardo force plate. Multifactorial interventions with strength- and balance-training and review of medications have accomplished remarkable success in reducing fall rates. A positive correlation was found between muscle strength and D-Hormone (1,25 (OH)2 D3) serum levels in elderly and this is supported by the fact that D-Hormone receptors exist on skeletal muscle cells. D-Hormone Analogs have well known effects on skeletal muscle cells. There is

S158 emerging experimental evidence that Alfacalcidol, a pro-drug of D-Hormone, can improve proximal muscle strength, neuromuscular function and thereby reduce fall risk. A study has already demonstrated the reduction of falls by D-Hormone in elderly women with normal vitamin D status. Alfacalcidol has a double impact on fall- and osteoporosis-related fractures.

SY20. PHYSIOLOGICAL INTERVENTIONS TO PREVENT BONE LOSS, FALLS AND NONVERTEBRAL FRACTURES IN ELDERLY WOMEN (STOPIT-STUDY) J. C. Gallagher; Bone Metabolism Unit, Creighton University, Omaha, USA In a double blind randomized study, 489 elderly Caucasian women, age 71 years, were randomized to Calcitriol 0.25 mcg twice daily, HRT (conjugated equine estrogens 0.625 mg + MPA 2.5 mg), a combination of Calcitriol and HRT, or placebo and followed for 3 years. The primary outcome was Bone mineral density (BMD), the secondary outcomes were Bone markers, Falls and Fractures. The results showed mean serum 25OHD of 78 nmol/L (31ng/ml), thus, there was no evidence of Vitamin D deficiency in this population. There were significant increases (p50.001) in spine BMD of 1.8% on Calcitriol, 5.7% on HRT and 7% on the combination, the change on placebo was –0.5%. The increase in femoral neck BMD was 0.2% on Calcitriol (p ns), 3.75% on HRT (p50.001), 5.2%(p50.001) on the combination and –0.33% on placebo. The incidence of nonvertebral fractures was 10.7% on placebo, 4.9% on Calcitriol, 11.9% on HRT alone and 7.8% on HRT + calcitriol. The rate of falls per patient year was 0.43 for placebo, 0.27 for Calcitriol alone (P50.001), 0.39 for HRT alone, and 0.35 for the combination HRT + Calcitriol. Although the effect of Calcitriol on BMD was less than that of HRT, the incidence of fractures was 50% lower in the Calcitriol group compared with the HRT and placebo groups. The incidence of falls was 36% lower on Calcitriol compared to HRT or placebo. It is often stated that the larger the treatment effect on BMD the better the efficacy in preventing fractures. However, the effect of falls as a cause of fractures has been underestimated. Thus, the ideal way to reduce osteoporotic fractures is to have a therapy that not only improves bone quality but also reduces falls. In this respect the D-hormone – Calcitriol – is a strong candidate.

Achieving Balance – Encouraging Your Patients Sponsor: Novartis Pharma SY21. MINIMIZING PAIN, MAXIMIZING QUALITY OF LIFE Stuart Silverman; Cedars-Sinai Medical Center, GLA VA Health System, OMC Clinical Research Center and the Department of Medicine, University of California, Los Angeles, USA Osteoporosis is a systemic skeletal condition characterized by decreased bone strength with the consequence of increased susceptibility to bone fracture. Fragility fractures in osteoporosis are often painful and result in disability and decreased quality of life. The most common fragility fractures include vertebral, hip and wrist fractures. Prevalent vertebral fractures are associated with decreases in Health Related Quality of Life (HRQOL) with losses in physical functioning, emotional status, overall quality of life and increases in symptoms such as pain. There is a statistically significant

Abstracts decrease in HRQOL with the first radiographic vertebral fracture with further decreases with each subsequent vertebral fracture and a steep drop off after the second fracture. Incident vertebral fractures are associated with significant decreases in HRQOL and increased number of disability days, although only 1/3 of vertebral fractures come to clinical attention. Both hip and vertebral fractures are associated with increased mortality. Wrist fractures result in acute pain and disability, although, in contrast to hip and vertebral fractures, the pain and disability mostly resolves within 2–3 months with low residual effect. Salmon calcitonin is an effective therapy in the rehabilitation management of patients following osteoporotic vertebral fracture. Salmon calcitonin at 200 IU qd is an antiresorptive agent with efficacy in reducing the risk of vertebral fracture. Both preclinical and clinical studies suggest that salmon calcitonin is analgesic to bone pain following osteoporotic vertebral fracture. Although not conclusively shown, the analgesic effect is most likely due to a central mechanism. The pain relief occurs after one week or less of treatment. Salmon calcitonin in clinical studies reduces pain, improves mobilization and improves function, thus decreasing disability and improving HRQOL. This presentation will 1) review recent studies showing the association of osteoporotic fracture with decreased quality of life; 2) critically review the studies showing the analgesic effect of salmon calcitonin and 3) conclude with a discussion of the role of salmon calcitonin in the management of the patient with osteoporosis.

SY22. INCREASING CONFIDENCE, REDUCING FRACTURES R. Francis; UK Osteoporotic fractures are a major cause of excess mortality, morbidity and health and social service expenditure in older people. It is therefore important that the safety and efficacy of osteoporosis treatments are demonstrated in this age group. A number of studies have shown that calcitonin prevents bone loss or increases bone density. The effect of nasal calcitonin on fracture incidence was investigated in the Prevent Recurrence of Osteoporotic Fractures (PROOF) study, which followed 1,225 postmenopausal women (mean age 68 years) with established osteoporosis for five years. This showed a significant reduction in the incidence of new vertebral fractures with 200 IU nasal salmon calcitonin daily compared with placebo, although the decrease in vertebral fractures with 100 and 400 IU was not statistically significant. The overall number of hip fractures in this study was small, but there was a trend for a lower incidence in women on calcitonin, which was statistically significant with the 100 IU dose. A post-hoc analysis demonstrated a 68% reduction in hip fractures when the marketed doses of 100 and 200 IU were combined, compared with placebo. Among the 105 women over the age of 75 taking part in the PROOF study, there was a 62% reduction in new vertebral fractures with 200 IU calcitonin. The effects of calcitonin in this age group will be investigated further in the Skeletal Protection in Elderly at Risk (SPEAR) study. The primary objective is to assess the efficacy of salmon calcitonin 200 IU nasal spray daily in reducing the frequency of radiographically confirmed clinical fractures in 6,000 women above the age of 70 years with at least one prevalent osteoporotic fragility fracture, who live in a nursing home or in an assisted living facility. The secondary objective is to assess the efficacy of calcitonin in reducing the incidence of multiple new clinical fractures and to evaluate the effect on psychological well-being, quality of life, muscle strength and mobility. Reducing fracture risk and increasing mobility is likely to lead to increased confidence and overall improvement in the health of these elderly patients.

Abstracts SY23. MEASURING BONE QUALITY Charles Chesnut; Osteoporosis Research Group, University of Washington, Seattle, WA, USA Salmon calcitonin nasal spray (SCNS) may have an effect on bone quality (i.e., trabecular microarchitecture and strength) that is independent of, or potentially in combination with, modest effects on BMD and bone resorption and this may further explain the significant fracture reduction demonstrated with salmon calcitonin nasal spray (SCNS) in the five-year PROOF study. A number of questions remain regarding the mechanism of action of salmon calcitonin in reducing fractures. The QUalitative Effects of Salmon Calcitonin Therapy (QUEST) study was initiated to evaluate the effects of SCNS 200 IU daily on bone quality, bone quantity and bone turnover, and also to more fully delineate the actions of SCNS in reducing fracture. The study should define the effects of salmon calcitonin on the trabecular bone architecture and structure, as well as to compare these effects on bone quality to the effects of salmon calcitonin on the other predictors of osteoporotic fracture. This presentation will include an overview of the study design and protocol, including the methodologies that were employed to examine bone quality (BQUAL) and bone quantity (BQUANT) at the various sites. Preliminary analyses of the assessment of the interrelationships of the parameters BQUAL, BQUANT and bone turnover will be presented. These data will provide further elucidation of the hypothesized effects of SCNS on bone quality to explain the observed fracture reduction in PROOF.

Vitamin K and Osteoporosis Sponsor: Eisai SY24. VITAMIN K AND OSTEOPOROSIS Hajime Orimo; Director, Tokyo Metropolitan Geriatric Medical Center, Japan Vitamin K is known as a co-factor for g carboxylase which catalyzes the conversion of specific glutamic acid residue to g carboxyglutamic acid. High levels of Vitamin K were found in bone tissue and Vitamin K plays an important role in bone metabolism. It promotes the formation of g-carboxyglutamic acid (Gla) which is present in 3 proteins of bone matrix: osteocalcin, matrix Gla protein and protein S. Vitamin K stimulates differention and metabolic activity of osteoblasts and induces apoptosis in vitro of osteoclast. Osteocalcin contains 3 Gla residues. Some fraction of circulating osteocalcin is not fully g-carboxylated (undercarboxylated osteocalcin), which is considered as a marker of Vitamin K status. Recently several observations have clearly demonstrated that Vitamin K plays an important role in bone metabolism. Several epidemiologic studies suggest that low reported dietary intakes of Vitamin K1 (phylloquinone) are associated with an increased risk of hip fracture in men and women. It has been shown that Natto (a fermented soybean food product) contains a large amount of Vitamin K2 (menaquinone 7) and Natto intake resulted in a marked, sustain increase of in serum level of Vitamin K2 and serum level of Vitamin K2 was remarkably higher in frequent Natto eater’s. Of particular interest is the fact that there was a significant inverse correlation between the incidence of hip fracture in Japanese women and Natto consumption. It has been reported that serum levels of vitamin K were lower and that of undercarboxylated osteocalcin was higher in patients with hip fractures as compared to control. Furthermore, an increased serum level of undercaboxylated osteocalcin was shown to be a predictor of hip fracture. Oral administration of vitamin K2 has proved to be effective in increasing bone mineral

S159 density in patients with osteoporosis. In this symposium, various topic related to these issues will be discussed.

SY25. REGULATION OF GENE EXPRESSION, SYNTHESIS AND SECRETION OF THE BONE SPECIFIC OSTEOCALCIN PROTEIN Jane B. Lian and Gary S. Stein; Department of Cell Biology, University of Massachusetts Medical School, USA Circulating levels of osteocalcin (OC) remain the only marker of osteoblast specific activity for a noninvasive assessment of bone turnover. Therefore, an understanding of the transcriptional and post-translational modifications that regulate osteocalcin synthesis is important for diagnostic value. Osteocalcin gene expression reflects development of the osteoblast phenotype, responsiveness to vitamin D3, and regulation by several hormones, including glucocorticoids. The gene is silenced in osteoprogenitors and induced in post-proliferative osteoblasts. Osteocalcin transcription and protein are proportional to the mineral deposition in the bone extracellular matrix. At the transcriptional level, the OC gene is activated initially by chromatin remodeling involving the Runx2/Cbfa transcription factor that is essential for formation of mineralized tissues. Synergism of Runx2 with the C/EBPA and *transcription factors contributes to maximal levels of osteocalcin expression in mature osteoblasts. Runx2 coregulatory proteins attenuate osteocalcin expression to precisely regulate cellular levels. Secretion of osteocalcin from the osteoblast is regulated by post-translational processing of the precursor protein to the secreted peptide dependent on the synthesis of a vitamin K dependent calcium binding amino acid (-carboxyglutamate (Gla). The Gla residues mediate binding of OC to hydroxyapatite, thereby accumulating OC in the bone matrix with a small fraction secreted into the circulation. The implications of these properties for OC function in relation to bone resorption and turnover will be presented. Thus to date, our increased understanding OC gene regulation continues to provide insight into OC as a reliable marker of osteoblast activity and potential application of the promoter for targeted therapy to the skeleton.

SY26. THE ROLE OF GLA PROTEIN IN THE CONTROL OF BONE MINERALIZATION Gerard Karsenty; Baylor College of Medicine, USA Bone and teeth extracellular matrix (ECM) are the only ECMs to mineralize physiologically. The molecular mechanisms accounting for bone ECM mineralization are not fully elucidated yet nor do we understand why most other ECMs do not mineralize. Several lines of evidence suggest that bone ECM mineralization may not be a function fulfilled by one or several osteoblast-specific genes. One direct evidence is the fact that inactivation of the matrix gla protein (Mgp) gene leads to ECM mineralization in tissues where Mgp is expressed (arteries and cartilage) and this despite the absence of osteoblast in these tissues. The second evidence is more suggestive, inactivation of most of the genes encoding non collagenous proteins that are expressed in osteoblasts does not result in a quantifiable defect of bone ECM mineralization. Taken together these evidence suggest that ECM mineralization is essentially bone specific without being osteoblast specific. To test this hypothesis we searched for genes encoding inhibitors of MGP action. We identified one such gene and deletion of this gene reverses the phenotype caused by MGP absence. The mode of action of the protein encoded by this inhibitor of MGP suggests a specific biochemical mechanism to explain ECM mineralization. Details will be presented at the meeting.

S160 SY27. WHAT IS THE ROLE OF VITAMIN K DEFICIENCY IN THE PATHOGENESIS OF OSTEOPOROSIS? P.D. Delmas; Professor of Medicine, Claude Bernard University of Lyon, Director, INSERM Research Unit 403, Hoˆpital Edouard Herriot, Lyon, France It has been shown that the circulating levels of vitamin K1 and of the vitamin K2 congeners MK7 and MK8 are markedly reduced in elderly patients with hip fracture. Some epidemiological data suggest that there is an inverse correlation between the risk of an osteoporotic fracture and consumption of green vegetables containing high amounts of vitamin K1. The impact of such a deficiency on bone metabolism can be assessed by measuring the degree of carboxylation of circulating osteocalcin, a bone specific protein that contains three residues of the vitamin K dependent aminoacid GLA. We have previously shown that the serum level of undercarboxylated osteocalcin is a predictor of the subsequent risk of hip fracture in a population of elderly institutionalised women. We have recently confirmed these findings in a large population of elderly healthy women, living at home (the EPIDOS Study), using a new specific immunoassay based on an monoclonal antibody specific for the GLU form of osteocalcin. In vitro and in vivo data suggest that the degree of carboxylation of osteocalcin reflects both vitamin K and vitamin D deficiency, that are highly prevalent in the elderly. Whether these changes only reflect the impaired nutritional status of these patients or are responsible – at least in part – for increased bone loss and fragility in the elderly is not yet clear. The bone mineral density of patients on chronic warfarin therapy has been found to be either normal or low. In both institutionalised and non institutionalised elderly women, we found that serum undercarboxylated osteocalcin was negatively correlated to hip bone mineral density. The overall role of GLA-containing proteins in the physiology of bone remodelling remains to be established. Further research is necessary to better understand the intriguing role of vitamin K in the pathogenesis of osteoporosis.

SY28. DIETARY VITAMIN K INTAKES AND HIP FRACTURE RISK Sarah L. Booth; US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, USA Vitamin K is a potentially modifiable dietary factor in the risk for hip fracture. Vitamin K-dependent proteins have been identified in bone and cartilage, and it is assumed that any role of dietary vitamin K as a protective factor against osteoporosis is mediated through the gamma-carboxylation of these proteins. The predominant dietary source of vitamin K in North America and Europe is phylloquinone (vitamin K-1), which is concentrated in green vegetables and certain plant oils. Average dietary intakes of phylloquinone among adults are below recommended dietary intakes. Several epidemiologic studies suggest that low reported dietary intakes of phylloquinone are associated with an increased risk of hip fracture in men and women. In contrast, the

Abstracts associations between dietary phylloquinone and bone mineral density (BMD) are inconsistent among studies. In at least one study, there appears to be an association between low phylloquinone intakes and low BMD in women, but not in men. A general criticism of these epidemiologic studies has been the overall confounding effect of poor nutrition be dietary phylloquinone intakes have been positively associated with markers of an overall healthy lifestyle. Furthermore, the putative mechanisms of vitamin K action on bone are not well understood, which limits the interpretation of existing studies. To define the potential dietary role of phylloquinone in age-related bone loss, phylloquinone supplementation trials are required.

SY29. VITAMIN K2 EFFECTS ON THE RISK OF FRACTURES AND ON LUMBAR BONE MINERAL DENSITY IN OSTEOPOROSIS – A RANDOMIZED PROSPECTIVE OPENLABEL 3-YEAR STUDY Masataka Shiraki; Research Institute and Practice for Involutional Diseases, Japan We have reported that vitamin K2 (menatetrenone) prevents bone fractures in Japanese women with osteoporosis (JBMR 2000: 15, 515–521). Further extension study to clarify the effects of vitamin K2 on bone mineral density and on bone fracture in women with osteoporosis, was carried out for 3 years. The study design was a randomized prospective open-label study. A total of 362 cases with osteoporosis were divided into two groups: the control group (n = 188, mean age was 69.5 year-old) was given 200mg/ day of calcium and the vitamin K2 treated group (n = 174, mean age was 68.0 year-old) was given 45 mg/day of menatetrenone together with 200mg a day of calcium. The lumbar bone mineral density and all clinical incidental fractures were followed. The background characteristics including age, body size, basal lumbar BMD, prevalent fractures and the level of bone turnover markers were identical between the groups. The mean observation periods for the control and the vitamin K2 treated group were 664 and 662 days, respectively (ns). The basal calcium intakes were 520 and 533 mg/day for the control and vitamin K2 treated group (ns). The serum vitamin K1 (phylloquinone) level for the control and vitamin K2 treated group were 1.1 and 1.5 ng/ml, respectively (ns). The changes in LBMD measured by DXA (Luna DPX-IQ) at 1, 2 and 3years after the treatment were –0.7%, –2.7% and –3.1% for the control and 0.5%, –1.2% and –3.8% for the VK treated group, respectively. There was no significant difference in the change of LBMD between two groups. Although absence of significant increase in LMBD in vitamin K2 treated group was observed, the overall clinical incidental fracture rate over the observation period in vitamin K2 treated group (33 vertebral fractures and 4 long bone fractures) was significantly lower than the control group (54 vertebral fractures and 10 long bone fractures), (p50.0040). These results indicated that vitamin K2 effectively reduces incident clinical fractures without increase in bone mineral density.