Androgen deprivation therapy is commonly used in

Bone Related Events in High Risk Prostate Cancer Sandy Srinivas* and Natalia Colocci From the Division of Oncology, Stanford University School of Medicine, Stanford, California Purpose: We provide recommendations for defining and treating bone related events in high risk prostate cancer. Materials and Methods: A focused literature review was done. Results: Men with prostate cancer often have osteoporosis and osteopenia even before initiating androgen deprivation therapy. After starting androgen deprivation therapy they experience accelerated bone loss. Bone mineral density is the most common tool to assess the degree of bone loss, although the use of bone turnover markers for this purpose is being actively explored. Bisphosphonates are effective for increasing bone mineral density and treating osteoporosis. The benefits derived from bisphosphonates should be weighed against the adverse effects, including the risk of osteonecrosis of the jaw. Treatment is indicated in patients with prostate cancer with osteoporosis and it may be considered in patients with osteopenia and/or additional risk factors. The time of initiation of therapy and duration of treatment have not been conclusively established. Conclusions: Prolonged androgen deprivation therapy results in bone loss and it has a potential to impact quality of life. Additional research is needed to characterize patients who would benefit from therapy and optimize strategies to prevent osteoporosis. Key Words: prostate, bone and bones, prostatic neoplasms, androgen antagonists, osteoporosis Androgen deprivation therapy is commonly used in patients at high risk who have localized disease. 1,2 The adverse effects of ADT have been well described, including anemia, cholesterol and lipid changes, erectile dysfunction, fatigue, hot flashes, weight gain and osteoporosis. 3 We focused on bone related events in patients with localized nonmetastatic prostate cancer undergoing ADT. We address some of the more common clinical questions, including how frequently BMD measurements should be made, which patients should be started on drug therapy, when therapy should be initiated, how long therapy should last and which agents have been used to date for treating ADT induced bone loss. RISK FACTORS FOR BONE LOSS IN THE PATIENT POPULATION Risk factors for osteoporosis have been well described, such as hypogonadism (including that occurring with ADT), a family history of osteoporosis, low body weight, a sedentary life-style, tobacco use, excessive alcohol consumption, corticosteroid use, low vitamin D and previous fractures. 4 Prostate Cancer Osteopenia and osteoporosis are present in 29% to 38% and 5% to 25%, respectively, of men with prostate cancer before ADT initiation. 5,6 Men with prostate cancer appear to have low vitamin D, measured as 25-hydroxy vitamin D, perhaps accounting for the prevalence of osteopenia before starting ADT. 5 Low vitamin D results from aging, low sun exposure with associated decreased vitamin D synthesis and poor * Correspondence: Stanford University, 875 Blake Wilbur Dr., Stanford, California 94305 (telephone: 650-725-2078; FAX: 650-736- 1640; e-mail: sandysri@stanford.edu). dietary habits. Low or inadequate calcium intake may exacerbate the negative effects that vitamin D insufficiency has on bone. ADT and Bone Loss After attaining peak bone mass in the mid third decade of life men normally experience a 0.5% to 1% loss of cortical bone mineral density yearly. 7 Iatrogenic decrease in testosterone by bilateral orchiectomy or an LHRH analogue can accelerate bone loss and may result in osteoporosis or osteopenia. 8 Androgen deprivation interferes with bone metabolism and the normal balance between bone formation and resorption. The result is increased bone resorption due to osteoclast stimulation. With ADT testosterone and estrogen decrease significantly, while biochemical markers of bone turnover increase. 9 BMD has been found to decrease by 1.9% to 4.6% in the lumbar spine and 1.1% to 3.9% in the femoral neck in patients who received LHRH analogues for 12 months. 10,11 Male sex offenders undergoing surgical castration have a spinal bone loss of about 4% yearly. 12 ADT and Fractures The most serious skeletal consequences of ADT are osteoporosis and an increased risk of fractures. According to small retrospective studies the incidence of fractures in men undergoing ADT is 5% to 14%. 13-16 Shahinian et al reported on 50,613 patients with prostate cancer listed in the Surveillance, Epidemiology and End Results, and Medicare databases who were undergoing ADT. 17 There was a 19% incidence of fractures in men undergoing ADT compared to 12% in those not treated with ADT. The relative risk of fracture increased with increasing doses of LHRH analogues and an increased duration of ADT. ADT also decreases lean body mass and increases frailty and the risk of falls. 18,19 0022-5347/06/1766-0050/0 S50 Vol. 176, S50-S54, December 2006 THE JOURNAL OF UROLOGY Printed in U.S.A. Copyright 2006 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2006.06.076

BONE RELATED EVENTS IN HIGH RISK PROSTATE CANCER S51 MEASUREMENT OF BONE LOSS DXA and QCT BMD is a strong predictor of fracture risk. 20,21 BMD can be measured by 2 techniques, including DXA and QCT. DXA has several advantages. It can be used to measure BMD at multiple sites, is associated with low radiation exposure, costs little and can be done in rapid examination time. Its limitation is that it measures the density of cortical and trabecular bone, and for this reason BMD may be falsely increased in the presence of osteoarthritis. 9 QCT can measure cortical or trabecular bone separately and it has greater sensitivity than DXA. However, it is less readily available and more costly, and it requires strict adherence to protocol for reproducibility. The BMD criteria for diagnosing bone loss in men are adapted from WHO T score definitions. Osteopenia is defined as a BMD of between 1.0 and 2.5 SD below the mean in young adults and osteoporosis is defined as a BMD of more than 2.5 SD below the mean in young adults (see table). Baseline measurement of BMD is recommended in all patients with risk factors, such as increased age and prolonged anticipated ADT duration, before starting ADT. The frequency with which patients should be monitored depends on the baseline T score (range 6 to 24 months) (fig. 1). Markers of Bone Metabolism A biochemical approach to assessing bone loss in the presence of metastasis to the bone is via measurements of bone metabolism markers. 22 Bone turnover markers that have been found to reflect bone formation are serum bone specific alkaline phosphatase, osteocalcin, procollagen type 1 carboxyterminal propeptide and procollagen type 1 aminoterminal propeptide. Bone markers reflecting bone resorption are NTx, peptide-bound C-telopeptide of type 1 collagen, pyridinium cross-links and receptor activator of nuclear factor- B ligand. 23 To date a few groups have addressed the clinical usefulness of measuring some of these bone markers for establishing the diagnosis of metastasis to the bone as well as prognosis in patients with prostate cancer. 24,25 The question of whether bone turnover markers can be used to determine response to antiresorptive therapy with bisphosphonates has been addressed in various studies. For example, the measurement of urinary NTx and serum osteocalcin to assess the response to bisphosphonate therapy was found to be useful in a study in approximately 1,200 healthy postmenopausal women receiving alendronate to prevent osteoporosis. 26 In this study changes from baseline of at least 40% in urinary NTx and of at least 20% in osteocalcin 6 months after the initiation of bisphosphonate therapy correlated with the long-term response to treatment with alendronate. A minimum change of 30% to 60% in serum peptide-bound C-telopeptide of type 1 collagen was Classification WHO osteoporosis classification BMD (SD*) Normal Greater than 1.0 Osteopenia 1.0 to 2.5 Osteoporosis Less than 2.5 * Derived from the mean peak value in young adults. FIG. 1. Recommended schedule for monitoring bone loss in patients with prostate cancer undergoing ADT. Adapted from Higano. 45 found to correlate with the response to therapy with bisphosphonates in other studies. 27,28 Briefly, bone turnover markers have been shown to aid in the diagnosis and prognosis of metastatic bone disease in patients with prostate cancer as well as in the assessment of the response to therapy and compliance with bisphosphonates. However, to date they have not been incorporated routinely into clinical practice in the care of patients with prostate cancer. THERAPY Not all men have osteoporosis while on ADT. Differences in peak bone mass and the rate of bone loss vary individually. Careful assessment of risk factors should be made in all patients on ADT. Before starting ADT patients should have calcium and vitamin D measured and adequately replaced. Dietary supplementation with 1,200 to 1,500 mg calcium daily and 400 IU vitamin D daily decreases bone loss in the hip and spine, and decreases the fracture incidence. 29 No oral or intravenous medication has been approved to prevent bone loss from ADT. However, there exists a body of literature on various compounds for treating bone loss from ADT in men with prostate cancer. These agents include bisphosphonates, estrogens and pure antiandrogens. Bisphosphonates Bisphosphonates inhibit osteoclast mediated bone resorption, osteoclast precursor activity and osteoblast induced

S52 BONE RELATED EVENTS IN HIGH RISK PROSTATE CANCER osteoclast activation. They act by direct cellular toxicity or by interference with specific intracellular pathways in osteoclasts. 30 The oral agent alendronate, which is used commonly in patients with osteoporosis, has not been tested in this patient population but it may be effective. Pamidronate The results of an open label, randomized, double-blind study showed that pamidronate prevents bone loss in patients with prostate cancer undergoing ADT. 31 Smith et al evaluated 47 men with prostate cancer randomly assigned to leuprolide alone vs leuprolide in combination with 60 mg pamidronate 12 times weekly. 32 In men treated with leuprolide alone the BMD of the lumbar spine decreased by 3.3% after 12 months of therapy, whereas it remained unchanged in patients receiving pamidronate and leuprolide. Zoledronic Acid Smith et al reported on 106 patients with prostate cancer without bone metastases who were randomly assigned to ADT alone or in combination with zoledronic acid 4 mg every 12 weeks. 11 The end point of the trial was the percent change in BMD in the lumbar spine after 1 year. BMD increased by 5.3% in the zoledronic group compared to a 2% decrease in the ADT alone group for a total treatment effect of 7.3%. Benefit was seen across all groups, including patients with a T score of less than 1 to 3. Estrogens Oral estrogens have been used for decades to treat prostate cancer. Estrogens also have an important role in maintaining bone health. Serum estrogen is positively associated with BMD and negatively associated with fracture risk. Serum estrogen also predicts changes in BMD and bone turnover. 33,34 However, estrogen use has been limited by the thromboembolic toxicity associated with them. Recent evidence suggests that parenteral delivery of estrogens can decrease this toxicity by avoiding the induction of hepatic metabolic pathways responsible for coagulation and fibrinolytic factors. 35-37 Ockrim et al evaluated the impact of estradiol patches on BMD. 38 Mean estradiol greater than 1,000 pmol/l was achieved using 2 patches that were changed 2 or 3 times weekly. The mean increase in BMD was 3.6% in the lumbar spine and 2.1% in the femoral neck. A large randomized trial using transdermal estradiol as primary therapy and as an adjuvant supplementation to ADT is under way. Gynecodynia and gynecomastia were seen 71% and 58%, respectively, of androgen independent patients with prostate cancer treated with transdermal estradiol. 39 SERMs Raloxifene, a SERM, mimics the agonist effects of estrogen in bone. Smith et al reported on 48 patients on ADT who were randomly assigned to 60 mg raloxifene daily or observation. BMD increased in the lumbar spine by 1% in the raloxifene group and decreased by 1% in the observation group. BMD also increased by 1.1% in the hip and decreased by 2.6% in the observation arm. 40 A large national trial is under way evaluating toremifene (another SERM) vs placebo for fracture prevention in 1,200 men undergoing ADT. Bicalutamide Monotherapy Bicalutamide is a nonsteroidal antiandrogen that competitively inhibits dihydrotestosterone binding to androgen receptor. Smith reported a study of bone turnover in 50 patients. 41 It was noted that serum testosterone and estradiol were higher in men receiving bicalutamide monotherapy than in LHRH treated patients. Mean urinary excretion of deoxypyridinoline, urinary excretion of N-telopeptide and serum osteocalcin were also higher in LHRH treated patients than in patients treated with bicalutamide alone, suggesting that bicalutamide monotherapy may maintain BMD and prevent fractures. Sieber et al reported BMD in 103 men with nonmetastatic prostate cancer randomized to medical castration or bicalutamide at 150 mg daily. 42 They noted a 5.4% BMD decrease in the lumbar spine in patients in the medical castration arm and a 2.4% increase in bicalutamide treated patients. The most common side effects reported with high dose bicalutamide are gynecomastia and breast pain. 43 Treatment Selection Based on the combined results of randomized trials in men with prostate cancer on ADT, raloxifene has a 2% effect on lumbar spine BMD compared to a 3.3% effect with pamidronate and 7.3% effect with bicalutamide or zoledronic acid. The benefits of the change in BMD must be weighed against the adverse effects of these agents. The adverse effects of bisphosphonates include renal insufficiency and osteonecrosis. While the pathogenesis of osteonecrosis is not completely known, its overall incidence is 0.03% to 6.2% based on spontaneous reports, a controlled clinical trial, an M. D. Anderson Cancer Center series review 44 and a Web based survey. Preventive dentistry and good hygiene are recommended for prevention. WHO SHOULD BE TREATED WITH DRUG THERAPY? Until it is proved that drug therapy decreases the risk of fractures treatment cannot be routinely recommended in all patients on ADT. Prospective trials evaluating the role of toremifene and antibody to RANKL (AMG-162) in men undergoing ADT are under way and the results are anticipated. All patients on ADT should be encouraged to maintain healthy life-style habits, including exercising regularly, ingesting calcium and vitamin D supplements, and avoiding tobacco and excessive alcohol consumption. Patients with normal baseline BMD who are without additional risk factors need no additional drug therapy. In patients with prostate cancer with osteoporosis the recommendation should be the same as for osteoporosis without prostate cancer, ie bisphosphonates for 5 years, during which status should be monitored closely and reevaluated. In men with osteopenia and in those who are on prolonged ADT therapy and/or have additional risk factors bisphosphonate therapy could be considered after careful counseling. The optimum time to initiate therapy has been addressed in women undergoing treatment with aromatase inhibitors

BONE RELATED EVENTS IN HIGH RISK PROSTATE CANCER S53 in the Z-FAST trial. Women with a BMD T score of less than 2.0 were randomized to up front vs delayed zoledronic acid administered when a decrease in T score to less than 2 or when fracture occurred. Preliminary results showed a 1.5% increase in BMD in the lumbar spine in the immediate therapy group compared to a decrease of 1.8% in the delayed therapy group for an overall effect of 3.3%, suggesting benefit for early treatment. To our knowledge a similar trial to determine when therapy should be initiated has not been performed in men undergoing ADT. HOW LONG SHOULD PATIENTS BE ON DRUG THERAPY? In patients who have osteoporosis BMD measurements should be done to determine how long they must remain on therapy. In patients without cancer safety data on the longterm use of bisphosphonates exist for up to 10 years. Unfortunately in patients on ADT in whom bisphosphonate therapy has been initiated there are no data addressing the issue of therapy duration. Measurements of BMD, bone turnover markers and testosterone may assist in the determination of the duration of therapy. CONCLUSIONS ADT is well known to accelerate bone loss. Bisphosphonates are effective for increasing BMD and treating osteoporosis. The benefits derived from bisphosphonates must be weighed against the adverse effects, including the risk of osteonecrosis of the jaw. Treatment should be reserved for patients with prostate cancer who have osteoporosis and it may be considered in patients with osteopenia and/or additional risk factors (fig. 2). Additional research is needed to characterize those who would benefit from therapy and optimize strategies to prevent osteoporosis. Normal >-1.0 Provide reassurance Osteopenic Osteopenic -1.0 2.5 Provide lifestyle advice Begin calcium and vitamin D Consider drug therapy on an individualized basis Osteoporosis <-2.5 Start bisphosphonate therapy FIG. 2. Guidelines on use of bisphosphonates in men with prostate cancer. 46 Abbreviations and Acronyms ADT androgen deprivation therapy BMD bone mineral density DXA dual energy x-ray absorptiometry LHRH luteinizing hormone-releasing hormone NTx N-telopeptide of type 1 collagen QCT quantitative computerized tomography SERM selective estrogen receptor modulator REFERENCES 1. Hanks, G. E., Hanlon, A. L., Pinover, W. H., Horwitz, E. M., Price, R. A. and Schultheiss, T.: Dose selection for prostate cancer patients based on dose comparison and dose response studies. Int J Radiat Oncol Biol Phys, 46: 823, 2000 2. Bolla, M., Gonzalez, D., Warde, P., Dubois, J. B., Mirimanoff, R. 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