THERAPY IN PRACTICE

Am J Cancer 2002; 1 (3): 179-187 1175-6357/02/0003-0179/$25.00/0 © Adis International Limited. All rights reserved.

Hypercalcemia of Malignancy Pathophysiology Diagnosis and Treatment Sebastien J. Hotte,1 Hal W. Hirte,1 Shafaat A. Rabbani,2 Tobias Carling,3 Geoffrey N. Hendy4 and Pierre P. Major1 1 2 3 4

Hamilton Regional Cancer Centre, Hamilton, Ontario, Canada Departments of Medicine and Oncology, McGill University, Montreal, Quebec, Canada Department of Surgical Sciences, Endocrine Unit, Uppsala University Hospital, Uppsala, Sweden Departments of Pediatrics and Medicine, McGill University, Montreal, Quebec, Canada

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Calcium Homeostasis . . . . . . . . . . . . . . . . . . . . . . . 2. Pathophysiology of Hypercalcemia of Malignancy (HCM) . 3. Clinical Presentations of HCM . . . . . . . . . . . . . . . . . . 4. Treatment of HCM . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Older Treatments . . . . . . . . . . . . . . . . . . . . . . 4.2 Current Management Strategies: The Bisphosphonates 4.3 Emerging Therapeutic Approaches . . . . . . . . . . . . 5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Hypercalcemia of malignancy (HCM) is the most common cause of elevated serum calcium in hospitalized patients and is found with varying frequency in patients with various types of cancer. Calcium homeostasis is finely regulated with day-to-day variations of less than 2%, and the development of HCM stems from various anomalies in homeostatic mechanisms. Hypercalcemia often produces a number of clinical symptoms, including alterations in central nervous system function, symptoms of dehydration and renal dysfunction. Whenever possible and appropriate, the goals of treatment of HCM should therefore be to return the patient to a euvolemic state, to normalize serum calcium and to treat the underlying cause. Almost invariably, however, HCM is a particularly adverse complication for patients with cancer and is almost always associated with a dismal prognosis. Older treatments like mithramycin and calcitonin have recently been replaced with newer management strategies, mostly involving bisphosphonates. These agents are potent inhibitors of osteoclasts which have been found to normalize serum calcium levels in a high proportion of patients with HCM. Emerging therapeutic approaches include monoclonal antibodies to parathyroid hormone related peptide (PTHrP), inhibition of RANK ligand through the use of a soluble form of its receptor osteoprotegerin, analogues of Vitamin D and selective inhibiton of the Ras-Raf-MAPK-ERK signalling pathway. In this article, we review the pathophysiology of tumour osteolysis leading to hypercalcemia of malignancy, and we discuss the physiological basis for the clinical symptoms of hypercalcemia. Past, current and future therapeutic approaches are also reviewed.

Hypercalcemia of malignancy (HCM) is the most common cause of elevated serum calcium in hospitalized patients.[1] It can be defined as a serum calcium level corrected for albumin that is greater than the upper normal range value given by the laboratory and that is associated with concomitant cancer. In many institutions, values higher than 2.8 mmol/L (11.0 mg/dl) are considered

abnormal. Hypercalcemia occurs more frequently in certain malignancies, although there is considerable variability between tumor types in reported series.[2-5] In these studies, patients with lung or breast cancer were frequently found to have hypercalcemia (27.3% and 25.7%, respectively). This was followed by multiple myeloma (7.3%) and head and neck cancer (6.9%). Patients

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with lymphoma/leukaemia, renal cancers and gastrointestinal malignancies had a 4.1 to 4.3% probability of developing hypercalcemia. In the general, non-hospitalized population, an elevated serum calcium level related to hyperparathyroidism is the most common cause of hypercalcemia. Its prevalence in the general population is one to three cases per 100 000. In postmenopausal women, the prevalence increases to 2%.[6] Clinical symptoms of hypercalcemia are usually independent of its underlying cause. Although there is poor correlation between symptoms and serum calcium concentration, disease states in which calcium levels increase more rapidly tend to be associated with more symptoms. This may in part explain the preponderance of symptoms in HCM. In the present review, we will first discuss briefly calcium homeostasis and outline the current understanding of the pathophysiology of HCM. We will then discuss the symptoms and serum biochemical findings of HCM and will finally review the current standard treatment approaches that have superceded previous, more complex and potentially toxic therapies. Experimental therapies entering clinical evaluation will also be mentioned briefly.

(CASR) in the parathyroid glands and kidneys has improved our understanding of calcium homeostasis.[9-14] In vitro studies[9-14] and important information derived from clinical studies of patients with mutations of the CASR gene[15,16] support the calcium regulation model shown in figure 1.[16-19] Detection of a low serum calcium level by the parathyroid cell CASR activates parathyroid hormone (PTH) secretion. Elevation of PTH levels increases both renal retention of calcium and production of

Ca2+

NH2

Ca2+

Ca2+

G proteins

CASR COOH

PLC

PKC

Ins(1, 4, 5)P3 Ca2+ Ca2+ Ca2+

[Ca2+]

Regulation of PTH

ER

Parathyroid cell

1. Calcium Homeostasis Individual serum calcium levels are finely regulated with day-to-day variations of less than 2%. In men, values of total serum calcium usually range from 2.2 to 2.6 mmol/L (9.0 to 10.3 mg/dl or 4.5 to 5.2 mEq/L) while in women, values usually range from 2.2 to 2.5 mmol/L (8.9 to 10.2 mg/dl or 4.4 to 5.1 mEq/L).[7] Calcium is highly bound to albumin, and the normal values mentioned above assume a normal albumin level. Since a significant proportion of patients with cancer are hypoalbuminemic, it is necessary to correct the total plasma calcium level for the level of calcium that would have been measured if the albumin level had been normal. The calculation for this correction is as follows: corrected serum calcium (mmol/L) = patient’s serum calcium (mmol/L) + 0.02 [midrange serum albumin (g/L) – patient’s serum albumin (g/L)] or corrected serum calcium (mg/dl) = patient’s serum calcium (mg/dl) + 0.8 [midrange serum albumin (g/dl) – patient’s serum albumin (g/dl)].[8] Occasionally, elevation of gammaglobulins can lead to an increase in the total serum calcium. Calcium-specific electrodes that measure free, ionized calcium are available and may be appropriate to use in instances where gammaglobulins are elevated, specifically as seen with multiple myeloma. In most other instances, measurements of total serum calcium are sufficient and are reported by most clinical laboratories. The identification of a cell surface calcium sensing receptor © Adis International Limited. All rights reserved.

Systemic effects Bone

Kidney Ca Ca

2+

2+

Ca2+

1, 25(OH)2D3−

25(OH)D3

Small intestine Vitamin D

Liver

Fig. 1. Proposed mechanism of regulation of calcium (Ca2+) homeostasis. The Ca2+ receptor (CASR) is expressed on the parathyroid cell surface and senses fluctuations in the concentration of extracellular Ca2+. Hypothetically, activation of the CASR and interaction with G proteins and PKC leads to activation of PLC, increasing the levels of Ins(1,4,5)P3 which, in turn, enhances the concentration of intracellular Ca2+ which, by post-transcriptional mechanisms, inhibits PTH secretion and release into the bloodstream. In response to hypocalcemia, PTH increases serum Ca2+ levels via enhanced bone resorption and renal Ca2+ reabsorption. Active vitamin D [1,25(OH)2D3] is also important in Ca2+ homeostasis. The hormone precursor undergoes an initial hydroxylation in the liver to 25-hydroxyvitamin D3 [25(OH)D3] and then, under the regulation of PTH, which stimulates 1-α hydroxylase activity in the proximal kidney tubules, is hydroxylated to 1,25(OH)2D3. 1,25(OH)2D3 increases serum Ca2+ levels, mainly by stimulation of intestinal Ca2+ absorption, but also exhibits an important negative feedback mechanism by inhibiting PTH secretion (–). 1,25(OH)2D3 = 1,25-dihydroxyvitamin D3; ER = endoplasmic reticulum; 25(OH)D3 = 25-hydroxyvitamin D3; Ins(1,4,5) P3 = inosito (1,4,5)-triphosphate; PKC = protein kinase C; PLC = phospholipase C; PTH = parathyroid hormone (reproduced from Carling,[18] with permission from Elsevier Science).

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Hypercalcemia of Malignancy

calcitriol, which in turn promotes intestinal calcium absorption. In addition, high PTH levels decrease the incorporation of serum calcium into newly synthesized bone matrix by directly inhibiting bone-forming osteoblasts. Elevation of serum PTH also increases the release of calcium from bone by indirectly activating bone-resorbing osteoclasts. Elevation of serum calcium has the opposite effects. It activates thyroid C cells to release calcitonin, which directly inhibits osteoclasts. The CASR’s response to calcium changes in different segments of the nephron is complex. The CASR is involved in decreasing renal calcium reabsorption in response to elevated serum levels. It also plays a role in the reduced urinary concentrating capacity that is seen with hypercalcemia. A recent study[19] examining the function of the CSAR in the different segments of isolated nephrons has improved our understanding of the renal effects of PTH. This study has also shown that the CASR is distributed in several areas of the brain and gut. This provides some of the physiological basis to explain, in part, the neurological and gastrointestinal symptoms related to rising serum calcium levels. However, research on the function of the CASR in these organs is preliminary and much study remains to be done.

2. Pathophysiology of Hypercalcemia of Malignancy (HCM) Patients with HCM have often been divided into those with humoral hypercalcemia of malignancy (HHM)[20] who do not have clinically detectable bone metastases, and those with HCM associated with bone metastases. Recent findings may provide a pathophysiological basis for unifying these two groups as discussed below. In 1941, Albright hypothesized that a PTH-related peptide (PTHrP) was responsible for the elevated calcium level seen in patients with HHM.[21] However, most of the key experimental observations validating this hypothesis were made during the last two decades,[20,22-29] and have been reviewed recently.[30-32] PTHrP binds functionally to the PTH receptor, which explains its endocrine effects and provides one pathophysiological mechanism for the development of HCM. Recent experimental reports support an additional, paracrine role of PTHrP secreted by breast tumor cells,[32-35] resulting in activation of neighbouring osteoclasts (figure 2). As discussed below, this local paracrine effect of PTHrP can explain tumor-induced destruction and hypercalcemia in the absence of detectable elevations of PTHrP in plasma.[36] A similar mechanism is likely to be operative in metastases from other tumor types[37] and could explain the hypercalcemia secondary to invasion of bone by tumor. A third mechanism for the devel© Adis International Limited. All rights reserved.

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Growth stimulation

Ras Cells in primary tumor

Activation of PTHrP gene expression

Bone derived growth factors (TGF-β)

PTHrP

OAFs (IL-6, IL-1β)

Myeloma

Osteoclasts

RANKL

Raf MEK ERK-1,2 PTHrP gene

Osteoblasts

PTHrP

Tumor cells (direct invasion)

Fig. 2. Mechanisms of pathophysiology of hyperclacemia of malignacy. PTHrP is produced locally in bone or at a distance and stimulates osteoblasts to produce RANKL which binds to its receptors on osteoclasts which are activated to destroy bone. In this process, tumor growth factor β (TGFβ) which is found in high concentrations in bone marrow stroma, is liberated and further stimulates the proliferation of tumor cells in bone to increase their secretion of PTHrP leading to a vicious circle of bone destruction. The activation of PTHrP production by tumor cells following stimulation by growth factors involves the Ras-Raf signaling pathway. Tumour cells can also destroy bone directly. A third mechanism involves the secretion by lymphoma and myeloma cells of factors that directly stimulate the activity and proliferation of osteoclasts, also leading to bone destruction. IL = interleukin; OAFs = osteoclast activation factors; PTHrP = parathyroid hormone-related peptide; RANKL = receptor activator of NF-KKB ligand.

opment of hypercalcemia is through direct destruction of bone by tumor cells.[38-40] These three mechanisms are illustrated in figure 2. In multiple myeloma as well as certain lymphomas and leukaemia, local production of cytokines,[41-44] prostaglandins[42] and vitamin D[45,46] appears to be responsible for osteoclast activation. Lymphomas can also produce vitamin D metabolites that promote bowel calcium absorption leading to hypercalcemia. Other mechanisms promoting tumor-induced osteolysis have been proposed.[47,48] However, their relevance to the clinical pathophysiology of malignant hypercalcemia remains to be defined. More than 80% of first episodes of hypercalcemia respond to treatment with potent inhibitors of osteoclast function.[49] This suggests that HCM is caused initially by osteoclast activation. The proportion of cases that do not respond to such treatment may represent instances where osteoclast activation cannot be suppressed with tolerable doses of currently available osteoclast inhibitors or may be due to direct tumor erosion of bone. Although Am J Cancer 2002; 1 (3)

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this latter hypothesis was initially suggested 25 years ago,[38-40] it is only recently that clinical[50] and experimental[51] observations have demonstrated the capacity of tumor cells to directly erode bone. The ‘resistance’ to initial or subsequent treatment of hypercalcemia with inhibitors of osteoclast function may be explained in some cases by a shift from hypercalcemia due to osteoclast-mediated bone resorbtion to hypercalcemia to direct bone erosion by tumor cells. The bone matrix contains a number of growth factors that, as a consequence of bone resorbtion by PTHrP, are released in active form into the bone microenvironment.[52-54] These osteolytic cytokines and growth factors include interleukin-1 and 6, transforming growth factor-beta (TGFβ) and tumor necrosis factor (TNF), which can be produced as a consequence of the presence of oncogenes in the cancer cell.[55] For example, the ras-raf-mapk-erk signalling pathway is involved in stimulating PTHrP production by tumor cells. Of the tumor-derived growth factors, TGFβ appears to be particularly important. TGFβ enhances the production of PTHrP by tumor cells, fuelling the process of bone destruction.[37] PTHrP can be produced by tumor cells locally from bone metastases[55] or distantly, reaching bone through the systemic circulation,[22-25] and induces osteoblasts to produce RANK ligand, which stimulates osteoclastic bone resorption by activating the NFκB receptor on osteoclasts.[35] This is better visualized in figure 2. The bone resorbing effects of PTHrP are mediated through binding with the PTH receptor[26] on osteoblast stromal cells, where it regulates the expression of a TNF-like molecule, RANKL.[28] When bound to its receptor on stromal cells, RANKL promotes their maturation into bone resorbing osteoclasts.[28] Additionally, PTHrP has been shown to decrease the level of the decoy soluble receptor osteoprotegrin (OPG), which binds to RANKL, thus blocking its access to its receptor (RANK) located on osteoclasts. This complex regulatory network remains the subject of research by several groups. Finally, PTHrP also causes hypercalcemia by increasing kidney absorbtion of calcium by interacting with the renal PTH receptor. It is easy to explain the deposition of calcium complexes in the pancreas and kidney seen with chronic calcium elevation. On the other hand, support for a direct role of elevated calcium levels in mediating the systemic neurological and gastrointestinal symptoms of hypercalcemia comes from clinical observations. Two clinical studies have observed a close correlation between the degree of central nervous system and gastrointestinal symptoms and the level of elevated calcium and the proportional improvement with decreases in elevated calcium levels.[56,57] The recent localization of the CASR in several regions of the brain and gastrointestinal system may provide a physiological expla© Adis International Limited. All rights reserved.

Hotte et al.

nation for the propensity of these symptoms in hypercalcemia. Other recent animal studies suggest a direct role of PTHrP in mediating the general symptoms of loss of appetite, fatigue and cachexia that are seen in hypercalcemia and advanced malignancy.[58]

3. Clinical Presentations of HCM Hypercalcemia is often divided into mild (serum calcium >2.8 to <3.2 mmol/L), moderate (>3.2 to <3.5 mmol/L) and severe (>3.5 mmol/L) disease. Severe hypercalcemia is almost always symptomatic and patient comfort is usually improved by correcting the elevated calcium. Approximately 50% of moderate cases of hypercalcemia are symptomatic. Unfortunately, HCM is often an undiagnosed and undertreated disease.[59] Its differential diagnosis includes excess vitamin D and alkali intake, use of thiazide diuretics, tamoxifen or estrogens and granulomatous diseases. Multiple endocrine neoplasia (MEN) is a rare familial condition with a high prevalence of HCM secondary to increased PTH production by tumors of endocrine glands. Primary hyperparathyroidism has been reported in a few patients with other cancer types and elevated serum calcium.[60] Rare cases of PTHproducing tumors have also been reported.[60,61] An assay to measure serum PTH has been developed and will identify these rare cases.[62] On the other hand, assays for PTHrP are not routinely available in most clinical laboratories and are technically demanding. Clinically, the hypercalcemia associated with PTHrP is often accompanied by hypokalemic, hypochloremic metabolic alkalosis while hyperchloremic metabolic acidosis is usually seen with PTH-associated hypercalcemia. Retrospective case series of HCM diagnosed by general medical services show that approximately 40 to 60% of patients present with hypercalcemia as the initial manifestation of malignancy.[56,57] Although the percentage of cancer types in HCM varies among series, breast and lung cancer account for approximately 50% of cases; multiple myeloma and head and neck cancers account for approximately 7% of cases each; leukaemia, lymphomas, gastrointestinal, esophageal, gynecological, renal, other urological tumors, and cancers of unknown primary origin all account for less than 5% of cases each.[2-5] HCM is rarely seen in other malignancies.[49,56,57] Although bone invasion and clinically detectable metastases often complicate the course of prostate cancer, hypercalcemia is rarely observed. Patients with HCM have symptoms reflecting a more rapid rise in serum calcium rather than those symptoms associated with more chronic hypercalcemia, such as renal and pancreatic calcifications. Results from case series show that approximately 70% of patients with HCM have non-specific symptoms such as faAm J Cancer 2002; 1 (3)

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tigue, decrease in appetite and weight loss. Although these symptoms could be secondary to advanced malignancy, correction of the elevated calcium often improves these and other symptoms associated with HCM,[56,57] supporting a causal role of elevated calcium levels. Sixty percent of patients with hypercalcemia have symptoms of dehydration (polydypsia, concentrated urine, dry oral mucosa, poor skin turgor, hypotension), which is at least in part due to a reversible renal tubular defect resulting in loss of urinary concentrating ability and ensuing loss of body water. Furthermore, decreased proximal reabsorption of sodium, magnesium and potassium may occur as a result of salt and water depletion and cause electrolyte abnormalities. Occasionally, renal insufficiency causing elevation of creatinine levels may arise from this pre-renal azotemia or from diminished glomerular filtration, a complication observed most commonly in patients with multiple myeloma. HCM is associated with many other symptoms. In 50% of cases, altered central nervous system (CNS) function varying from confusion to obtunded sensorium and coma is seen. The level of neurological dysfunction correlates somewhat with the calcium elevation. Gastrointestinal (GI) symptoms of nausea, vomiting and constipation are seen in a quarter of patients. As mentioned above, the CASR has been identified in the CNS and GI systems;[19] however its role in causing CNS and GI symptoms is still unknown.

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diuretics increase this effect and may be necessary in patients with cardiac dysfunction to avoid fluid overload but should be restricted to patients that have been adequately rehydrated. The objective of treatment in most clinical trials is to reduce serum calcium to <2.8 mmol/L (11.0 mg/dl), a level at which most patients have no symptoms.[56,57] Improvements in symptoms tend to correlate with the decrease in calcium levels. Approximately 70% of patients who achieve normal serum calcium levels can be discharged from hospital.[56,57] Unfortunately, survival benefits from treating hypercalcemia are usually seen only in patients where effective anti-cancer therapy is available.[63,64] The common pathway for hypercalcemia is efflux of calcium from bone. In the majority of cases, control of the hypercalcemia can be achieved by inhibiting osteoclasts. This suggests that, at least initially, osteoclast-mediated bone resorbtion is the predominant cause of the hypercalcemia. Some cases are resistant to treatment with osteoclast inhibitors from the onset. In many cases, subsequent episodes of hypercalcemia can no longer be treated with osteoclast inhibitors. This might be explained by an overwhelming activation of osteoclasts that cannot be suppressed with safe doses of osteoclast inhibitors. Alternatively, direct bone erosion by tumor cells may become the primary mechanism. This latter hypothesis has received support from recent experimental and clinical observations.[50,51] Therapies for inhibiting osteoclasts may be classified into: (i) those that have been used in the past; (ii) current standard treatments; and (iii) emerging new approaches.

4. Treatment of HCM Whenever appropriate, the goals of treatment of HCM are: (i) to return the patient to a euvolemic state; (ii) to normalize serum calcium; and (iii) to treat the underlying cause, where possible. As previously mentioned, HCM is an often undiagnosed and undertreated disease, which is associated with a number of symptoms that decrease quality of life.[59] Normalization of plasma calcium often improves these symptoms. On the other hand, in some cases where the underlying tumor can no longer be effectively treated, consideration should be given to not correcting the hypercalcemia, thereby allowing the patient to die in relative comfort if other supportive measures to mitigate the symptoms of hypercalcemia are in place. Such discussions should ideally involve the patient, the caregivers, and the medical staff, and should be undertaken prior to the development of severe symptoms. When active therapy is deemed appropriate, volume repletion is usually the initial step. Almost invariably, patients with symptomatic hypercalcemia are clinically dehydrated and require intravenous fluid administration with 2 to 6 liters of normal saline solution. Rehydration promotes calcium excretion; loop © Adis International Limited. All rights reserved.

4.1 Older Treatments

Mithramycin, a mainstay in the treatment of HCM in the past, is now infrequently used because of hematological toxicity. Parenteral phosphate infusions may cause precipitation of calcium complexes in tissues such as the kidney and worsen renal function; they are no longer used to treat HCM. Calcitonin is a direct and rapid inhibitor of osteoclasts that may be used as initial therapy to reduce calcium levels, especially over the first 24 hours. Doses of 2 to 8 units per kilogram given subcutaneously every 6 to 12 hours for up to 48 hours are used but tachyphylaxis prevents long term use.[65-68] 4.2 Current Management Strategies: The Bisphosphonates

In the majority of cases, inhibition of osteoclasts will control calcium levels, and the bisphosphonates have emerged as the most potent osteoclast inhibitors. Bisphosphonates are rapidly cleared from the circulation by absorption into bone cavities lying under osteoclasts. In order to be active, they must be absorbed Am J Cancer 2002; 1 (3)

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by osteoclasts;[69] as a result, their inhibitory activity only becomes evident after several days. The inhibitory effect of bisphosphonates was identified 30 years ago.[70,71] The inhibitory mechanisms of bisphosphonates on tumor-induced osteolysis have recently been reviewed elsewhere.[72,73] An alternative or complementary hypothesis for the mechanism of action of bisphosphonates suggests that they inhibit osteoblasts, which in turn suppresses osteoclast activity.[73] Residual bisphosphonates are excreted renally and, in animals, very high renal concentrations can cause kidney toxicity. In humans, renal dysfunction associated with bisphosphonate treatment has occasionally been reported in clinical trials and case studies[74,75] and tends to be related to the speed of administration. Very limited information is available on the safety of bisphosphonates in severe renal dysfunction since most trials were limited to patients with serum creatinine of 400 mmol/L or less. Overall, bisphosphonates are generally very well tolerated; the most common toxicities are irritation at the site of injection and fever with the more potent amino-bisphosphonates. Among first generation bisphosphonates, intravenous clodronate has been most widely used for the treatment of hypercalcemia.[76] More recently, amino-bisphosphonates have proven more effective, and one of its members, pamidronate,[77-79] can be infused safely over 2 to 4 hours and has become the most widely used bisphosphonate to treat hypercalcemia. Doses of 30, 60 or 90mg are used to treat mild, moderate or severe hypercalcemia, respectively.[77-81] Treatment can be repeated as needed. A large international trial has recently demonstrated that a third generation amino-bisphosphonate, zoledronate, which can be infused over 15 minutes is more effective than pamidronate and is likely to replace it as the standard of care.[49] Other third generation amino-bisphosphonates like ibandronate[82] and alendronate[83] do not appear to be as potent as zoledronate in HCM. The recent trial comparing pamidronate and zoledronate[49] is the largest trial ever done in patients with HCM and reported safety results in 287 patients as well as efficacy results in 275 patients. This larger sample size increases the likelihood that the reported effects mirror those seen in the general population, and does so with adequate statistical power. The complete response rate (defined as a corrected serum calcium ≤2.7 mmol/L) was almost 70% for pamidronate and higher than 85% for zoledronate given at a 4 or 8mg dose. Tolerability was similar for both drugs. Median response durations were 18 days for pamidronate 90mg and 32 and 43 days for zoledronate 4 and 8mg, respectively. Furthermore, zoledronate can be administered as a 15-minute infusion compared to a 2- to 4-hour infusion for pamidronate. This added convenience along with improved efficacy and a longer duration of response will likely make zoledronate (4mg © Adis International Limited. All rights reserved.

Hotte et al.

for initial treatment, 8mg for relapsed or refractory disease) the standard of care as the drug becomes available for clinical use. Bisphosphonates with direct anti-tumor activity would be ideally suited for treating hypercalcemia resulting from invasion of bone by tumor by both inhibiting osteoclast activity and destroying tumor cells. Preliminary animal experiments suggest that zoledronate may have anti-tumor and anti-angiogenic activity.[84,85] This property may well allow potent bisphosphonates like zoledronate to be used to delay or prevent the development of bone metastases but has not yet been demonstrated in humans. In extreme situations (severe CNS depression or coma), or in patients with severe renal dysfunction, renal dialysis can be used to rapidly decrease serum calcium on a short-term basis.

4.3 Emerging Therapeutic Approaches

A number of new treatment approaches are emerging. One shortcoming of bisphosphonates is their delayed onset of action of a few days. Monoclonal antibodies to PTHrP are being evaluated for their ability to rapidly inhibit the bone-resorbing activity mediated by PTHrP. In animals, serum calcium levels decreased within a few hours of antibody administration.[86] Combined with bisphosphonates, or as a single modality, monoclonal antibodies will hopefully prove to be a more rapid and effective treatment of HCM. Inhibition of osteoclastic activation can be done by inhibiting RANK ligand through the use of a soluble form of its receptor, known as osteoprotegerin (OPG). Comparison of OPG administration with pamidronate in a murine model found OPG to be as effective in inhibiting osteoclasts with faster onset.[87] OPG might represent an effective therapeutic option for diseases associated with excessive osteoclast activity.[88] Vitamin D and its low calcemic analogues can inhibit PTHrP production. This steroid hormone has been used to reduce tumor growth and hypercalcemia in syngenic mice and xenograft models of several malignancies. Leydig tumor H-500 bearing animals were infused with Vitamin D and its analogue, EB-1089. These injections resulted in significant reductions in tumor volume, tumor PTHrP, serum PTHrP and serum calcium compared to control animals receiving vehicle alone.[89] This treatment also led to a marked prolongation of survival of experimental animals. These analogues have therefore not only been shown to prevent the development of hypercalcemia but are also highly effective in normalizing established hypercalcemia and reducing the incidence of osteolytic skeletal metastasis in these tumor-bearing animals.[89-91] Growth factors and cytokines regulate PTHrP expression via the Ras-Raf-MAPK-ERK signalling pathways.[92] Additional Am J Cancer 2002; 1 (3)

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therapeutic approaches aimed at these mechanisms in order to block the production of PTHrP by tumor cells will be available in the future. In one animal study, inhibition of these pathways resulted in decreased PTHrP production and normalization of serum calcium of tumor-bearing animals[92]. A number of highly selective chemical inhibitors of the Ras-Raf-MAPK-ERK signalling pathway are currently in late stages of clinical development.

5. Conclusion In summary, a better understanding of the molecular pathophysiology of bone remodelling and the mechanisms involved in tumor mediated bone destruction have allowed the identification of targets which may be used therapeutically. Although the development of third generation bisphosphonates, such as zoledronate has resulted in more effective, simple and convenient treatment of HCM, emerging new approaches may further improve the management of this disease, and may also play a role in the treatment and prevention of bone metastases.[93,94]

Acknowledgements Dr Hotte is a clinical scholar supported by a fellowship grant from the Canadian Institute of Health Research (CIHR), the Canadian Association of Medical Oncology (CAMO) and Eli Lilly Pharmaceuticals. Dr Major is an investigator for several clinical trials with bisphosphonates supported by Novartis and has served as an advisor to Novartis for a FDA meeting. P. Major and his collaborator, R. Cook have received a grant to pursue statistical studies on the methods of analysis of recurrent skeletal events.

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Correspondence and offprints: Dr Sebastien J. Hotte, Hamilton Regional Cancer Centre, 699 Concession Street, Hamilton, ONT, L8V 5C2, Canada. E-mail: [email protected]

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