The Journal of Nutrition, Health & Aging© Volume 13, Number 8, 2009

EPIDEMIOLOGICAL DATA AND CONSEQUENCES OF SARCOPENIA

EPIDEMIOLOGY AND CONSEQUENCES OF SARCOPENIA G. ABELLAN VAN KAN Gérontopôle, Department of Geriatric Medicine, CHU Toulouse, F-31059, France

Abstract: Sarcopenia is an evolving concept and the current definition of sarcopenia includes both a loss of muscle strength and loss of muscle mass. However, despite the increasing knowledge and improved technology, a worldwide operational definition of sarcopenia applicable across racial/ethnic groups and populations lacks consensus. As a result the prevalence of sarcopenia (8 to 40% of older people over 60 years) varies depending on the study sample (namely the age of the sample), the definition, and the assessment tool used. DXA is the main assessment method used to evaluate muscle mass, which is further adjusted to height, weight fat mass, or BMI to obtain an index of sarcopenia. Cross-sectional analyses seemed to prove an association between low muscle mass and functional decline, but these results were not consistent when analysed longitudinally over time. This inconsistency could be due to methodological issues as the selected populations in the cohorts where autonomous, community-dwelling, older people. In this highly active population decreases in muscle mass might be not as important as decreases in strength to predict functional decline. The aim of the present paper was to perform a comprehensive review of the literature on the epidemiology of sarcopenia and its consequences to be presented on November 13th and 14th 2008, at the Carla Workshop.

Introduction Sarcopenia is an evolving concept, with nowadays a broader view than just a decrease in muscle mass with aging. Irwin Rosenberg initially described sarcopenia in 1989, as a recognized age-related decline in muscle mass among older people (1, 2). Since then, various definitions of sarcopenia have appeared as our understanding of the aging process and the changes that occur therein progress. Even more, the recent improved techniques to assess body composition and the availability of large representative epidemiological data sets have modified the initial concept of a simple decrease in muscle mass. However, despite the increasing knowledge and improved technology, a worldwide operational definition of sarcopenia applicable across racial/ethnic groups and populations lacks consensus, resulting in a variation of prevalence of sarcopenia depending on the chosen definition of sarcopenia and on the method of assessment (8 to 40% of older people over 60 years). The current definition of sarcopenia includes both a loss of muscle strength and a decline in functional quality in addition to the loss of muscle protein mass (3, 4), but it is unclear whether a decline in functional capacity results from the loss of muscle mass and/or the qualitative impairment of the muscle tissue (5). For example, after 50 years of age, muscle mass is reported to decline at an annual rate of approximately 1 to 2% (6), but strength declines at 1.5% per year and accelerates to, as much as, 3% per year after the age of 60 (7-10). As a result, the age-associated changes in muscle mass explain less than 5% of the variance in the change in strength with aging (11). These rates of decline in strength are even higher in sedentary individuals and twice as high in men as compared to women (12). However, men, on average, have larger amounts of muscle mass and shorter survival than women. This implies that sarcopenia is potentially a greater public health concern Received May 18, 2009 Accepted for publication June 2, 2009

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among women than men (8) with increased health care cost in comparison to non-sarcopenic older people (13). Outstanding is the fact that sarcopenia, by itself or as a major component of frailty, is associated with many adverse outcomes like increased morbidity, falls, institutionalisation, onset of disability, or premature death, increasing the burden of the already increased health care costs and aggravating the decline of quality of life, once it is present (14, 15). Paradoxically, recent epidemiological data suggest that the mentioned adverse outcomes are directly related to a decline in muscle quality (mainly decline in strength) with no relationship to variations in muscle mass (16). The observations show that strength greatly reduces the association between muscle mass and functional decline and early death to a statistically non-significant level, suggesting that the contribution of muscle mass on certain outcomes may be primarily due to its association with strength (17, 18). In the same line, suggestions have been made to separate the age-related decline of muscle strength from sarcopenia to encourage research endeavours focused on strength itself (16). Epidemiological data on Sarcopenia Operational definition of Sarcopenia One reason for the divergent prevalence of sarcopenia within and between subgroups of elderly is due in part to the practical difficulties and changes in assessing muscle mass that have occurred over the past 20 years. This 20-years period has also seen the introduction of very precise body tissue measurement methods such as magnetic resonance imaging (MRI), being nowadays the Dual energy X-ray Absortiometry (DXA) the most accepted method to quantify muscle mass in everyday’s clinical practice and research (19). But, despite the relative agreement among clinicians and epidemiologists on a theoretical definition of sarcopenia, development of a

The Journal of Nutrition, Health & Aging© Volume 13, Number 8, 2009

JNHA: SARCOPENIA consensus operational definition useful across clinics, studies and populations has not occurred (20). The main assessment methods, nowadays available, to evaluate muscle mass in clinical settings are exposed in table 1. Once muscle mass is measured the degree of sarcopenia is evaluated by different indexes taking into account height, weight, fat mass or BMI. As an example, the first to develop a definition of sarcopenia were Baumgartner and colleagues (21). Baumgartner summed the muscle mass of the four limbs from a DXA as appendicular skeletal muscle mass (ASM), and defined a skeletal muscle mass index (SMI) as ASM/height² (as kg/m²). Individuals with a SMI two standard deviations below the mean SMI of a middle-age reference male and female population from the Rosetta study (12) were defined as gender-specific cutpoints for sarcopenia. But all definitions of sarcopenia are arbitrary and open to criticism. An operational definition needs to differentiate those with sarcopenia from those not affected, needs to define standards and be applicable across populations. Some have argued, on the other hand, that the lack of association between the SMI definition of sarcopenia and disability suggests that population-specific thresholds are needed, and that ethnicity along with age or frailty should be considered when setting a cutpoint for sarcopenia. Finally, the use of a young country-specific reference group such as the middle-age population from the Rosetta study is questionable for worldwide application (18). Table 1 Assessment methods of Skeletal Muscle Mass Technique

Measurements

Comments

Circumferences

Calf and mid arm circumfe rences as measures of muscle size Alternating electrical current through body tissue Attenuation of 2 x-ray energies

Frequent estimation errors

Bioelectrical Impedance DXA CT MRI

Cross-sectional muscle size quantification Cross-sectional muscle size quantification

Loss of accuracy and reliability Fairly accurate and reliable, minimal radiation exposure Expensive and radiation exposure Expensive and time consuming

Prevalence of sarcopenia: American Cohorts NMEHS: In the New Mexico Elder Health Survey, sarcopenia was defined as an appendicular muscle mass index less than 2 SD below the mean of a young reference population. Using this definition, 15-25% under the age of 70 years was sarcopenic, whereas beyond the age of 80, over 40% of woman and 50% of men were sarcopenic (21). NHANES III: A statistical significant association was found between sarcopenia (measured by Bioelectrical Impedance) and different functional impairments in a cross-sectional analysis performed with the NHANES III database. The prevalence of sarcopenia in older adults (>60 years) was 7% for men (7% over 80 years) and 10% for women (11% over 80 years) (22). CHS: Sarcopenia was also assessed in the Cardiovascular 709

Health Study (CHS). Baseline analyses of 5036 older people, found a prevalence of sarcopenia of 17.1% for men and 10.7% for women using Bioelectrical Impedance (23). Health ABC Study: 2 sarcopenia definitions (ASM/height2 and residuals) were assessed to evaluate the relationship between them and lower extremity function using data from the Health Aging and Body Composition (ABC) Study. Using ASM/height2 the prevalence of sarcopenia in the overweight (BMI=25-29) and obese (BMI 30) subgroups was 8.9% and 0%, respectively, in men and 7.1 and 0%, respectively, in women. Using residuals, the prevalence of sarcopenia in the overweight and obese group was much higher: 15.4% and 11.5% in men, and 21.7% and 14.4% in women (24). After a follow-up of 5 years, using the 2 sarcopenia definitions, the prevalence of sarcopenia and incident lower extremity limitation was re-assessed. Evaluating 2979 participants, prevalence for sarcopenia, using residuals, was 27.1% for white men, 8.2% for black men, 30.5% for white women and 8.1% for black women. Using the ASM/height2 definition, prevalence for sarcopenia was 25.2% for white men, 11.8% for black men, 31.4% for white women, and 6.8% for black women (25). Other American Studies: Smaller studies also have evaluated prevalence of sarcopenia (using DXA with the ASM/h2 definition) finding a range between 18% and 34% (26, 27, 28). Prevalence of sarcopenia: European cohorts EPIDOS: Using the SMI a prevalence of sarcopenia of 9.5% was found in the EPIDOS cohort (1458 elderly communitydwelling French women). (29). Whole body composition was estimated using DEXA in 1321 older women of the same cohort. The prevalence of sarcopenia increased with age from 8.9% in the 76-80 age group to 10.9% in the 86-95 age group (30). InCHIANTI: Sarcopenia was assessed in the InCHIANTI cohort (1030 community-dwelling Italian), using CT-scan (calf muscle cross-sectional area more than 2 SD below the mean of the population). The prevalence was age-related ranging from 20% at 65 years to 70% at 85 and over in men and from 5% at 65 years to 15% at 85 years and over in women (31). Correlation between muscle area (measured by CT-scan) and frailty (defined by Fried’s criteria) was also assessed. This cross-sectional analysis of 923 participants showed a statistical significant unadjusted correlation between muscle area and 3 of the 5 Fried’s criteria of frailty (exhaustion, low physical activity and low walking speed). Only low physical activity remained correlated after adjustments (32). LASA: Assessment of sarcopenia using DXA was performed in the Longitudinal Aging Study Amsterdam after 520 participants. Sarcopenia was defined as >3% of decline in muscle mass during follow-up. A decline in ASM was experienced by 37.5% of the participants, and 52 (15.7%) met the definition of sarcopenia. No differences in baseline characteristics were observed between the groups (33).

The Journal of Nutrition, Health & Aging© Volume 13, Number 8, 2009

EPIDEMIOLOGICAL DATA AND CONSEQUENCES OF SARCOPENIA Other European Studies: Prevalence of 11% for both men and women and a statistical non-significant lower level of physical activity were found associated to sarcopenic individuals (34). Prevalence of sarcopenia: other cohorts In 527 Chinese participants, using DXA, prevalence of 12.3% and 7.2% was found for men and women (both older than 70 years) respectively (35). Consequences of Sarcopenia (Based on low muscle mass or decline in strength) Decline in functional performances The analyses performed by Visser and colleagues on 3075 older than 70 years participants, revealed that body fat and leg muscle strength, but not leg muscle mass, remained independent determinants of lower-extremity performance. Leg muscle mass measured by DXA (adjusted for body height in regression models) showed no statistically significant association with physical performance measures. Leg muscle strength might mediate the relationship between leg muscle mass and lower-extremity performance (36). Using the LASA cohort, Visser and colleagues performed the same crosssectional analyses on 449 men and women aged 65 years and older. The results, after adjustments, suggest that low muscle strength (assessed by grip strength), but not low muscle mass (assessed by DXA), is associated with poor lower extremity performance (assessed with gait speed and chair stands) in older men and women (37). In the cross-sectional analyses of the InCHIANTI cohort, Lauretani and colleagues showed that the sarcopenic older men had an increased risk of slow walking speed (OR=4.8 [95%CI 1.4-16.8] not found in women and an non-statistically significant increased risk to be unable to walk for 1 km without difficulty in men and women. At the same time, the 3 assessed muscle “variables” (hand grip strength, knee extension torque, and lower extremity muscle power) proved to be associated to slow walking speed and difficulties to walk 1 km in both men and women with OR as high as 11.9 [95%CI 3.1-45.9] for gait speed for men with low muscle power (31). Newman and colleagues using data from the Health ABC Study showed that 2 different definitions of sarcopenia had also different associated risk of impaired lower extremity function (measured as SPPB<10). Using ASM/height2 the risk of impaired lower extremity function was OR= 1.5 (1.1-2.1) for men and OR= 0.9 (0.7-1.2) for women. This risk increased using residual: OR= 1.8 (1.3-2.5) for men and OR= 1.9 (1.42.5) for women (24). In the same cohort, mortality in relation to low lean mass and strength (during 5 years of follow-up) was also assessed by Newman and colleagues. Measures of low muscle strength, both quadriceps and grip, were strong and independent predictors of mortality in older adults, with OR=1.45 (1.23-1.71) and 1.42 (1.17-1.71) respectively. This

association could not be attributed to low lean mass, as neither measures of muscle size (DXA and CT-scan) attenuated the association of strength (38). Delmonico and colleagues evaluated incident lower extremity limitation (defined as difficulty to walk ¼ of a mile or climbing 10 steps without resting) in the same cohort after 5 years of follow-up. Only women, using residuals were found to have an increase risk of onset of limitation with OR=1.34 (1.11-1.61) (25). A statistical significant correlation between sarcopenia (ASM/h2), decline in physical function and lower extremity muscle power was found in a cross-sectional analysis on 137 older adults performed by Ianuzzi-Sucich and colleagues (28). Sarcopenia and its associated factors were also cross-sectional evaluated in a Chinese cohort of 4000 older adults aged 65 years and over. Lee and colleagues found that among men, only weaker grip strength was associated with lower muscle mass and gait speed and chair-stands did not demonstrate any association. On the other hand, women in the lowest tertile of muscle mass performed significantly better in all lower limb performance tests though poorer in grip strength, when compared with those in the highest tertile. Grip strength among all tests showed the strongest association with muscle mass in both men and women (43). Onset of mobility limitations The cross-sectional baseline analyses performed by Baumgartner and colleagues found that sarcopenia was associated to mobility limitations (balance abnormality, using cane or walker), IADL disabilities, and falls during the past year (21). The EPIDOS cohort served Rolland and colleagues to analyze cross-sectional baseline data of 1458 community dwelling woman. In this population, sarcopenia was not found to be association to an increased risk of falls, loss of IADL, mobility limitation or need of walking assistance (29). Janssen found that severe sarcopenia was correlated to onset of IADL disability in the CHS [HR= 1.27 (95%CI 1.07-1.50)] after evaluating 3694 older people during 8 years of follow-up. Subgroup analyses revealed significant effects of severe sarcopenia on disability risk in women (but not men), in both age groups examined (65-74 years and >75 years) and those free of major disease at baseline (23). In the same cohort performing analyses on 4449 older (>60) participants, Janssen established specific cutpoints of muscle mass using Bioelectrical Impedance (and ROC curves). These cutpoints were highly correlated with physical disability, defines as having difficulties in performing ADL. Participants with low skeletal muscle mass had an increased risk of onset of disability with adjusted OR of 4.71 (95%CI 2.28-9.74) for men and of 2.93 (95%CI 1.66-5.19) for women (39). Visser and colleagues evaluated incident mobility limitations (assessed as self-reported difficulty walking ¼ mile and climbing 10 steps without resting) in the Health ABC study during a 2.5-year follow-up. After adjustments, muscle mass 710

The Journal of Nutrition, Health & Aging© Volume 13, Number 8, 2009

JNHA: SARCOPENIA (muscle area evaluated by ct-scan), was associated with incident mobility limitations with OR for men and women of 1.9 (1.27-2.84) and 1.68 (1.23-1.38) respectively. Low muscle strength was associated with a higher risk of mobility limitations. After adjustments, men and women in the lowest quartile of muscle strength were 2.02 (1.39-2.94) and 1.91 (1.41-2.58) times more likely to develop mobility limitations. When muscle mass was adjusted for muscle strength, low muscle area did not remain a significant factor associated with incident mobility limitations. These results, as suggested by Visser, prove that muscle strength mediates the relationship between muscle area and incident mobility limitations (40).

7. 8. 9. 10. 11.

12. 13. 14. 15.

Healthcare cost of sarcopenia Janssen and colleagues performed the only study that has evaluated health care cost of Sarcopenia in 2004. The costs associated with sarcopenia were estimated based on the effect of sarcopenia on increasing risk of physical disability in older persons, and so the population-attributable risk was calculated. The estimated direct a healthcare cost attributed to sarcopenia in 2000 was $18.5 billions ($10.8 billions in men, and $7.7 billions in women). A sensitivity analysis indicated that the costs could be as low as $11.8 billions and as high as $26.2 billions. The excess healthcare expenditures were $860 for every sarcopenic men and $933 for every sarcopenic women. A 10% reduction in sarcopenia would result in savings of $1.1 billion per year (41). To put this in perspective, it has been estimated that the yearly economic cost of osteoporotic fractures in the United States is $16.3 billions (42).

16. 17.

18.

19.

20.

21. 22.

23. 24.

Conclusion

25.

The association between sarcopenia and its consequences need to be further explored in other sets of populations. Frail, but autonomous, older people with baseline low muscle mass and subjectively fatigued should be a target population to assess whether decreased muscle mass is a predictor for subsequent disability before abandoning the idea of non-relationship. An operational definition is highly advisable in order to obtain consistent data on prevalence across different populations and countries, but nowadays no consensual definition can be proposed being the concept of sarcopenia an active area of inquiry.

26. 27. 28.

29.

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31.

32.

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Sarcopenia: its assessment, etiology, pathogenesis, consequences and future perspectives. J Nutr Health Aging. 2008;12(7):433-450 Baumgartner RN, W.D., Sarcopenia and sarcopenic-obesity. Pathy MSJ ed. Principles and Practice of Geriatric Medicine. Vol. 2. 2006, United Kingdom: John Wiley and Sons Ltd. 909-933 Baumgartner RN, Koelher KM, Gallagher D, et al. Epidemiology of sarcopenia among the elderly in New Mexico. Am J Epidemiol. 1998;147(8):755-763 Janssen I, Heymsfield SB, and Ross R. Low relative skeletal muscle mass (sarcopenia) in older persons is associated with functional impairment and physical disability. J Am Geriatr Soc. 2002;50:889-896 Janssen I. Influence of sarcopenia on the development of physical disability: the Cardiovascular Health Study. J Am Geriatr Soc. 2006;54:56-62 Newman AB, Kupelian V, Visser M, et al. Sarcopenia: alternative definitions and associations with lower extremity function. J Am Geriatr Soc. 2003;51:1602-1609 Delmonico MJ, Harris TB, Lee JS, et al. 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functioning older persons. J Gerontol A Biol Sci Med Sci. 2005;60:324-333 Janssen I, Shepard DS, Katzmarzyk PT, et al. The healthcare cost of sarcopenia in the United States. J Am Geriatr Soc. 2004;52:80-85 Ray NF, Chan JK, Thamer M, et al. Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995. Report from the National Osteoporosis Foundation. J Bone Miner Res. 1997;12:24-35 Lee JSW, Auyeung TW, Kwok T, et al. Associated factors and health impact of sarcopenia in older Chinese men and women: a cross-sectional study. Gerontology. 2007;53:404-410

Call for abstracts deadline for Late-breaking News :

2009

September 10, 2009 On line instructions http://www.ctad.fr

Montpellier 08 Las Vegas 09 Toulouse 010 Barcelone 011

Clinical Trials on Alzheimer's Disease

Europeen Alzheimer’s Disease Consortium

Montpellier and Toulouse EADC Centers

October 29-30, 2009 Las Vegas Cleveland Clinic Lou Ruvo Center for Brain Health

http://www.ctad.fr WELCOME

‘‘

Dear Colleague,

After last year’s successful venue in Montpellier, France, we decide to bring CTAD 2009 «Clinical Trials on Alzheimer’s Disease» to Las Vegas for the grand opening of the Cleveland Clinic Lou Ruvo Center for Brain Health in October 2009. This is a great opportunity for joining these two major events. The aims of the meeting are to bring together the current leaders in clinical trials in Alzheimer’s Disease to discuss news results, drugs in development, and future methodological issues (disease modifying, outcomes, biomarkers, health economics). Call for abstracts deadline for Late-breaking News : September 10, 2009. Instruction to authors and additional information on our website : www.ctad.fr

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We look forward to seeing you in Las Vegas.

Organizing Committee http://www.ctad.fr

SCIENTIFIC COMMITTEE Paul AISEN - San Diego Kaj BLENNOW - Molndal Maria CARRILLO - Chicago Bruno DUBOIS - Paris Howard FELDMAN - Vancouver Giovanni B. FRISONI - Brescia Lutz FROELICH - Mannheim Serge GAUTHIER - Montreal Ezio GIACOBINI - Geneva Michael GRUNDMANN - San Diego Zaven KHACHATURIAN - Las Vegas Virginia LEE - Philadelphia Jean-Marc ORGOGOZO - Bordeaux Ronald PETERSEN - Minnesota Lon SCHNEIDER - Los Angeles Peter SNYDER - Rhode Island Eric SIEMERS - Philadelphia Yaakov STERN - New York Jacques TOUCHON - Montpellier John TROJANOWSKI - Philadelphia Bruno VELLAS - Toulouse Michael W. WEINER - San Francisco Bengt WINBLAD - Stockholm

KEY TOPICS NEW CONCEPTUAL MODELS OF ALZHEIMER’S DISEASE ˜ Promote the discovery of early markers in asymptomatic people at risk for dementia ˜ Explore new therapeutic targets for disease modification or prevention ˜ Identify new outcome measures for efficacy of disease modifying treatments

INFRASTRUCTURE NEEDS FOR INTERNATIONAL PREVENTION TRIALS ˜ Harmonization of multi-national, multi-site large scale prevention trials ˜ Recruitment and retention of asymptomatic subject/volunteers for prevention trials ˜ International regulatory issues

METHODOLOGICAL ISSUES ˜ Assessing the impact of clinical trials on today’s medical practice ˜ Design of case report forms and other data-collecting methods for clinical trials ˜ General or specific designs and operating features for data processing systems used for maintaining databases clinical trials ˜ Management of multicenter investigations ˜ Methods for assessing patient’s compliance ˜ Organizational structures for facilitating multicenter investigations

˜ Statistical methods for clinical trials ˜ Study design and clinical endpoints

PREVENTIVE AND DISEASE-MODIFYING TRIALS ˜ ˜ ˜ ˜ ˜ ˜

AD Primary Preventive Trials AD Secondary Preventive Trials AD Disease-modifying trials AD Symptomatic trials Trials in severe dementias Trials in other dementias : Parkinson dementia Vascular dementia - Frontal dementia

VALIDATION OF BIOMARKER & CLINICAL OUTCOME MEASURES FOR PREVENTION TRIALS ˜ CSF Biomarkers ˜ Neuroimaging biomarkers : MRI, fRI, PETscan, SPECT... ˜ Plasma biomarkers

STATUS OF ONGOING CLINICAL TRIALS & UPDATES OF NEW THERAPIES ˜ Immunotherapies ‡ Ơandơsecretase inhibitors

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2000;48(4):381-386 Newman AB, Kupelian V, Visser M, et al. Strenght, but not muscle mass, is associated with mortality in the Health, Aging and Body Composition Study cohort. J Gerontol A Biol Sci Med Sci. 2006;61:72-77 Janssen I, Baumgartner RN, Ross R, et al. Skeletal muscle cutpoints associated with elevated physical disability risk in older men and women. Am J Epidemiol. 2004;159:413-421 Visser M, Goodpaster BH, Kritchesvky SB, et al. Muscle mass, muscle strength, and muscle fat infiltration as predictors of incident mobility limitations in well-

Clinical Trials

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