Prevention and Management of Osteoporosis in Women with Breast Cancer and Men with Prostate Cancer Dawn Hershman, MD, MS* and Rashmi Narayanan, MBBS

Address *Herbert Irving Comprehensive Cancer Center, Columbia University, 161 Fort Washington, Room 1068, New York, NY 10032, USA. E-mail: [email protected] Current Oncology Reports 2004, 6:277–284 Current Science Inc. ISSN 1523-3790 Copyright © 2004 by Current Science Inc.

Advances in cancer treatment have resulted in improved life expectancies for survivors of breast and prostate cancer. As the number of cancer survivors grows, the long-term side effects of treatment play an increasingly prominent role in the routine care of these patients. Due to similar management approaches, survivors of breast and prostate cancer are at increased risk for osteoporosis. This review summarizes the prevention and management of osteoporosis and osteopenia resulting from cancer treatment in survivors of breast and prostate cancer.

Introduction Cancers specific to gender (eg, prostate and breast cancer) are among the most successfully treated malignancies with the largest numbers of survivors. Improvements in diagnosis have meant that more patients are diagnosed during the early stages of these diseases. Furthermore, advances in treatment have resulted in improved life expectancies for survivors of breast and prostate cancer. As the number of cancer survivors increases, the long-term side effects of treatment play a more prominent role in the routine care of these patients. Drugs that abolish secretion of gonadal hormones, or interfere with their actions at target tissues, are central to the management of breast and prostate cancers. The side effects of these drugs, therefore, revolve around conditions caused by sex hormone deprivation. In women with breast cancer, estrogen deprivation is associated with osteoporosis, menopausal symptoms, weight gain, and sexual dysfunction. Androgen deprivation therapy in men with prostate cancer is associated with such long-term consequences as osteoporosis, gynecomastia, and decreased muscle mass, and such short-term consequences as hot flashes and decreased libido [1]. This review focuses on the

prevention and management of osteoporosis and osteopenia resulting from cancer treatment in survivors of breast and prostate cancer.

Osteoporosis Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture [2]. Patients with vertebral fractures experience chronic pain, loss of functional independence, and loss of independent mobility [3]. Decreased bone mineral density (BMD) is the most important known risk factor for fracture [4]. Because no accurate measure of overall bone strength exists, BMD is frequently used as a surrogate measure, accounting for approximately 70% of bone strength [2]. A World Health Organization study group has developed criteria for the diagnosis of osteoporosis by dual energy x-ray absorptiometry (DEXA) [5]. Osteoporosis is defined as a BMD that is greater than 2.5 standard deviations (T score of -2.5) below the young adult mean. Osteopenia is defined as a T score between -1.0 and -2.5. However, these criteria were based on studies of fracture risk in postmenopausal white women. Their applicability to men, premenopausal women, and other races is uncertain. Bone loss in postmenopausal women is caused by increased rates of bone remodeling and an imbalance between the activity of osteoclasts, which resorb or break down old bone, and osteoblasts, which lay down new bone at sites where bone has been resorbed [6]. Modifiable factors that increase the risk of fracture include dietary calcium deficiency, physical inactivity, medications such as steroids and heparin, cigarette smoking, heavy alcohol use, increased propensity for falls, low body weight, weight loss, low bone density, poor bone quality, and low estrogen levels [4,7]. Non-modifiable risk factors include older age, family history, European ethnicity, Asian or Caucasian race [4,7], bone size, and hip geometry [8]. Estrogen and testosterone play important roles in the regulation of bone remodeling (BMD) and bone health. Their effects on bone metabolism are mediated through estrogen and androgen receptors that are present in bone [9] and through the complex relationship between sex hormones and other factors, including insulin-like growth

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factor (IGF)-1, 25-hydroxyvitamin D (25-OHD), parathyroid hormone (PTH), and such bone-resorbing cytokines as tumor necrosis factor (TNF) and interleukin (IL)-6 [10]. During the 4- to 5-year period around menopause, declining ovarian estrogen production results in low serum estrogen levels, associated increases in osteoclast-mediated bone resorption, and subsequent bone loss [11,12]. The conversion of adrenal androgens to estrogens by the enzyme aromatase is the major source of estrogen in postmenopausal women, and exposure to these low levels of estrogen may play an important role in calcium homeostasis through effects on renal and gastrointestinal calcium handling [13,14]. Data on the relationship between fracture risk and BMD in men is contradictory. Prospective studies suggest that increased fracture risk in men occurs at a higher BMD, compared with women [15]. Osteoporotic fractures pose a considerable economic burden, given that they account for 3 billion dollars in annual health-care expenditures [2]. The clinical significance of osteoporotic fractures is reflected in the high rates of mortality and morbidity. One-year excess mortality rates for patients with hip fractures range from 12% to 35% in most studies, with higher mortality rates in men than in women [16]. An Australian study reported that 50% of patients required institutionalized care after hospitalization for hip fracture, and only 30% of patients had returned to baseline functional status after 1 year [17].

Treatment of osteoporosis Treatment of osteoporosis should address its multifactorial causes and aim for early intervention to ensure maximum retention of bone mass and preservation of the structural integrity of the skeleton [11]. Current pharmacologic treatments focus on reducing bone turnover, a major risk factor for fracture that is independent of BMD. Several agents have been approved by the US Food and Drug Administration (FDA) for the prevention and treatment of osteoporosis in postmenopausal women. Drugs approved by the FDA for prevention of osteoporosis are bisphosphonates (alendronate and risedronate), estrogen, and the selective estrogen receptor modifier (SERM), raloxifene. Agents approved for the treatment of osteoporosis are alendronate, risedronate, calcitonin, parathyroid hormone (PTH), and raloxifene. Bisphosphonates are among the most effective agents available for the management of osteoporosis. Bisphosphonates reduce bone turnover by inhibiting osteoclastic bone resorption [18,19]. Alendronate and risedronate have been shown to reduce the risk of vertebral and hip fractures by approximately 50% in postmenopausal women with osteoporosis. Bisphosphonates also prevent bone loss in perimenopausal and postmenopausal women without osteoporosis at baseline [20]. Clinical trials suggest that these drugs prevent bone loss as effectively as the recommended dose of estrogen in standard hormone

replacement therapy (HRT) regimens [21]. In addition, unlike estrogen, these drugs can be discontinued without a rapid acceleration of bone loss. The antifracture efficacy of alendronate has been examined in a 3-year study involving postmenopausal women with and without preexisting vertebral fractures [23]. The incidence of vertebral, hip, and wrist fractures was reduced by 50% in the group with vertebral fractures, whereas the risk of multiple vertebral fractures was reduced by 90%. In women with no prior vertebral fractures, alendronate significantly increased BMD at all measured sites and reduced the vertebral fracture rate by 50% [20]. Two large multicenter randomized, controlled trials evaluating the efficacy of risedronate in the treatment of postmenopausal osteoporosis found that risedronate reduced the incidence of vertebral fractures by 41% to 49% and nonvertebral fractures by 33% to 39% [19,22]. Trials are currently evaluating the efficacy of several newer bisphosphonates in treating osteoporosis [21]. Although salmon calcitonin has been approved for the treatment of osteoporosis, it is less effective than the bisphosphonates in improving BMD and reducing fracture rates (33% vs placebo) [23,24]. Randomized, controlled trials of calcitonin in postmenopausal women with osteoporosis have reported modest reductions in bone resorption (5%–20% vs placebo) and increases in BMD (1%–5% vs placebo) [24]. Parathyroid hormone is an anabolic agent that increases bone formation. Subcutaneous administration of PTH reduces the risk of vertebral fractures in postmenopausal women by 33% and nonvertebral fractures by 47% [25]. Raloxifene is the only SERM approved for the treatment of osteoporosis. It is a nonhormonal agent that binds to estrogen receptors. It behaves as an estrogen agonist in bone and lipid metabolism and as an estrogen antagonist at the breast and uterus. The antifracture efficacy of raloxifene in postmenopausal women with osteoporosis was examined in the MORE (Multiple Outcomes of Raloxifene Evaluation) study [26]. A significant reduction in the incidence of new vertebral fractures was reported in women with and without previous vertebral fractures. Compared with placebo, raloxifene decreased the risk of new clinical vertebral fractures at 1 year by 68%, significantly increased BMD at the lumbar spine and femoral neck, and decreased markers of bone turnover. However, raloxifene did not reduce the risk of nonvertebral fractures. Estrogen replacement in the form of HRT has long been used to treat osteoporosis. Evidence for its ability to preserve bone mass comes from the Postmenopausal Estrogen-Progestin Intervention (PEPI) Trial, which found that women receiving estrogen, or an estrogenprogestin combination, experienced a 5% increase in BMD [13]. Estrogen has not been approved for the treatment of osteoporosis because it had not been shown to reduce fracture incidence until recently. The recently reported, randomized, prospective, placebo-controlled

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trial (Women’s Health Initiative) found that continuous administration of estrogen and a progestin significantly decreased the risk of fractures at all sites [27]. However, the associated increased risk of breast cancer and cardiovascular disease has led experts to conclude that estrogen should not constitute first-line therapy for the prevention or treatment of osteoporosis. Finally, nonpharmacologic measures form a critical part of the recommended approach to treatment of osteoporosis. These include adequate calcium (1500 mg/d) and vitamin D (700–800 IU), smoking cessation, moderating caffeine and salt intake, regular weight-bearing physical activity, and measures for fall prevention. Agents that have been studied for the treatment of osteoporosis in men include bisphosphonates and PTH. Alendronate is associated with significant increases in BMD and decreases in vertebral fractures [28]. PTH has been investigated in two separate randomized, controlled trials [29•,30], which found it to be associated with increases in BMD at the lumbar spine compared with placebo. Although it was expected that the combination of alendronate, which decreases bone resorption, with PTH, which increases bone formation, would have a greater efficacy than either agent alone, a recent trial in women [31] and in men [32] found no evidence of synergy. Moreover, concurrent use of alendronate and PTH may reduce the anabolic effects of PTH [31].

Breast Cancer Osteoporosis in breast cancer survivors Women with a history of breast cancer have higher than average rates of bone loss and fracture. Longitudinal and cross-sectional studies report a higher risk of vertebral fractures and lower bone density in breast cancer survivors [33,34]. Women with a history of nonmetastatic breast cancer have a risk of vertebral fracture nearly five times that of the general population [34]. More recently, a prospective study in postmenopausal women found hazard rates of 1.287 (P=0.05) for spinal fractures, 1.323 (P=0.001) for arm and wrist fractures, and 1.317 (P<0.0001) for all other fractures in breast cancer survivors compared with normal control subjects [35]. Fracture rates may also be higher in premenopausal breast cancer survivors and in all women using aromatase inhibitors. Causes of bone loss in breast cancer Chemotherapy Bone loss in patients with breast cancer may arise from various causes of hormonal deprivation. These include chemotherapy-induced premature ovarian failure, medical or surgical ovarian ablation therapy, partial estrogen agonists, and aromatase inhibition. Other factors that may contribute to the increased risk of osteoporosis in breast cancer survivors include direct effects of various chemotherapeutic agents on bone, inactivity, use of cortico-

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steroids, and inadequate intake of calcium and vitamin D [34,36,37]. Bone loss is greatest in women who become amenorrheic as a result of chemotherapy, suggesting that estrogen deficiency is an important causative factor [34]. In a study of 27 breast cancer survivors, the BMD of women who became amenorrheic was 14% lower than that of women who maintained menstrual function [34]. Several prospective studies have evaluated the effects of chemotherapy-induced ovarian failure on bone loss in premenopausal women with breast cancer [36,38,39]. At 2 years, bone loss at the lumbar spine ranged from 4.4% to 5.9%. Bone loss at the lumbar spine was as high as 9.5% in women who became amenorrheic during chemotherapy [40]. Selective estrogen receptor modulators Selective estrogen receptor modulators, such as tamoxifen and raloxifene, are estrogen-like compounds that bind with high affinity to the estrogen receptor and have either estrogen agonist or antagonist activity depending on the tissue type. Adjuvant tamoxifen therapy preserves bone density in postmenopausal women but is associated with varying degrees of bone loss in premenopausal women. Powles et al. [37] evaluated BMD in 179 pre- and postmenopausal women treated with either tamoxifen or placebo for chemoprevention of breast cancer. Premenopausal women treated with tamoxifen experienced a 1.4% decrease in BMD per year over the 3-year study, compared with a 0.24% increase in the placebo-treated premenopausal women [37]. In contrast, postmenopausal women receiving tamoxifen experienced an increase in BMD compared with postmenopausal women receiving placebo, in whom BMD decreased [37]. These data suggest that the partial agonist effect of tamoxifen confers a net benefit against the backdrop of low circulating estrogen concentrations in postmenopausal women but is too weak to mimic the normal estrogen levels in premenopausal women. The SERM, raloxifene, increases BMD and reduces the risk of vertebral fractures in postmenopausal women, but its effects in premenopausal women are currently unknown [26]. Aromatase inhibitors Steroidal and nonsteroidal aromatase inhibitors are now commonly used as adjuvant therapy for hormone-sensitive breast cancer. These agents almost completely eliminate endogenous estrogen production and abruptly lower serum estradiol levels, resulting in an increase in bone remodeling and turnover and significant amounts of bone loss [40]. This issue was considered in the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial. At 1 year, therapy with anastrozole was associated with a 2.6% reduction in spine BMD in patients, compared with only a 0.4% decrease in healthy control subjects. In contrast, tamoxifen therapy was associated with an increased BMD and decreased markers of bone turnover. Anastrozole was also associated with a higher incidence of vertebral

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fractures than tamoxifen (7.1% vs 4.4%, P<0.001) during the first 2 years of the study, with subsequent stabilization thereafter [41]. BMD was preserved in the group that received both tamoxifen and anastrozole. In premenopausal women receiving ovarian ablation in addition to adjuvant aromatase inhibitors, the mean decrease in BMD at 1 year was 7%. BMD was preserved with the addition of zoledronate [42]. Steroidal aromatase inhibitors may not cause the same degree of bone loss as nonsteroidal agents. Exemestane may be either beneficial or have no effect on bone and lipid metabolism. This may be due to its metabolite, 17-hydroxyexemestan, which has a weak androgenic effect. Exemestane was evaluated in a 12-week, randomized, single-blind, placebo-controlled study of bone turnover in healthy women. Sixty postmenopausal women were randomly assigned to receive exemestane, 25 mg/d; letrozole, 2.5 mg/D, or placebo. At 12 weeks, bone turnover markers were similar to baseline in the placebo and exemestane groups, whereas significant increases occurred in bone turnover markers in women receiving letrozole [45].

Treatment and prevention of osteoporosis in breast cancer survivors Prevention is probably the most important strategy to combat osteoporosis and includes pharmacologic and nonpharmacologic approaches. Measures aimed at minimizing risk factors for fracture, such as low bone mass, rapid bone loss, increased bone turnover, and falls, are recommended. Agents with FDA approval for the prevention of osteoporosis are alendronate and risedronate. In elderly women, calcium (1000–1500 mg/d) and vitamin D (400–800 IU/d) supplementation has been shown to reduce hip and vertebral fractures by 43% and 32%, respectively [44]. Clodronate, a second-generation bisphosphonate, has been evaluated in two British studies of patients with earlystage breast cancer [38,45], most of whom also received chemotherapy and/or HRT. One randomized, placebocontrolled trial found that 1600 mg of daily oral clodronate, taken for 2 years, was efficacious in preventing bone loss. By 1 year, BMD had fallen by 2.2% in the placebo group and had risen by 0.2% in the clodronate group (mean difference, 2.4%). In a second trial conducted in premenopausal women receiving chemotherapy, lumbar spine BMD differed between the clodronate and placebo groups by 3% at 1 year and by 3.7% at 2 years (P<0.01). Among patients who developed ovarian failure, significantly less lumbar spine bone loss was reported in the clodronate group than in the placebo group (5.9% vs 9.5%, P<0.001). Whether bisphosphonates can increase BMD in women with premature menopause due to chemotherapy has also been investigated in a double-blind, placebocontrolled study [46]. In this study, women with breast cancer and premature menopause, stratified based on prior tamoxifen use, were randomly assigned to receive either risedronate (5 mg/d) or placebo for 12 months. A signifi-

cant increase in BMD at the lumbar spine and hip was observed in the risedronate group. However, cessation of risedronate resulted in subsequent bone loss, suggesting that continuous treatment with risedronate may be necessary to maintain bone mass. The benefit was greatest in the patients treated with the combination of tamoxifen and risedronate (P<0.05). The preclinical safety profile of zoledronate, an extremely potent third-generation bisphosphonate, is similar to that of other bisphosphonates [47]. A single intravenous dose of zoledronate appears to suppress bone turnover for over 12 months [48]. Ongoing studies are evaluating the efficacy of zoledronate in preventing bone loss in premenopausal women receiving chemotherapy for early-stage breast cancer. Other investigators are evaluating its use to protect and restore bone in women treated with nonsteroidal aromatase inhibitors. Raloxifene reduces the risk of vertebral fractures in postmenopausal women with osteoporosis [26]. As noted previously, the effects of this agent in premenopausal women are unknown. However, some preliminary data suggest cross resistance between tamoxifen and raloxifene on breast cancer cells; therefore, raloxifene may not be an appropriate preventive agent for osteoporosis in women previously treated with tamoxifen because it may stimulate tumor growth [49].

Screening and treatment recommendations The US Preventative Services Task Force (USPSTF) recommends that BMD screening for osteoporosis be commenced at age 65 in all women and at age 60 in women with one or more risk factor for osteoporosis, such as family history, weight less than 154 pounds, or prior history of nontraumatic fracture [50,51]. Guidelines published by the American Society of Clinical Oncology suggest that screening BMD by DEXA should be performed on an annual basis in high-risk women [51], including women with chemotherapy-related premature menopause and patients receiving treatment with aromatase inhibitors [3]. Calcium and vitamin D should be recommended to all patients. Bisphosphonates should be discussed with all osteopenic patients and recommended for all patients who develop osteoporosis or lose more than 8% of their bone mass yearly. Ongoing studies and future directions Bisphosphonates have shown long duration of action, and this enables simplified dosing regimens. Zoledronate can be administered at intervals of up to a year and produce changes in bone density comparable with those seen with daily oral dosing of alendronate or risedronate [52]. However, concerns have been raised about the harmful consequences of prolonged suppression of bone turnover associated with chronic bisphosphonate therapy, such as acquired osteopetrosis and osteonecrosis of the jaw [53]. Many questions about the management of osteoporosis in patients with breast cancer are yet to be answered. Issues

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under consideration include the optimal time to initiate pharmacologic therapy, the optimal frequency of administration of zoledronic acid, and the negative effects of prolonged oversuppression of bone remodeling that can occur with prolonged high-dose bisphosphonate treatment.

Prostate Cancer Osteoporosis in prostate cancer survivors The survival advantage and effective control of prostate cancer conferred by androgen deprivation therapy (ADT) is offset by several long-term adverse consequences, including osteoporosis [54,55]. A recent cross-sectional study found significantly lower BMD at the lateral spine, total hip, and forearm in men with prostate cancer receiving ADT, compared with eugonadal men with prostate cancer and healthy control subjects. BMD was similar in eugonadal men with prostate cancer and healthy control subjects. Biochemical markers of bone turnover were also elevated in men receiving ADT, compared with eugonadal men with prostate cancer and control subjects. Longitudinal studies have reported significant decreases in BMD in men receiving ADT for prostate cancer and benign prostatic hypertrophy [56–58]. At 1 year, the loss in BMD ranges from 3.1 % to 10% at the lumbar spine and from 3.8% to 8.4% at the femoral neck. Although the studies are small and the degree of bone loss variable, all report significant bone loss. In prostate cancer patients receiving ADT, osteoporotic fractures are more common than pathologic fractures from bone metastases [57]. Several retrospective studies have reported an increased rate of osteoporotic fractures after ADT for prostate cancer. Daniell et al. [57] compared 59 men who underwent orchiectomy with a control group of men with prostate cancer who had not undergone orchiectomy; 14% of the men with orchiectomy had at least one osteoporotic fracture, compared with only 1% of the control group (P<0.001) [59]. Hatano et al. [60] found a 6% incidence of fractures in 218 patients with prostate cancer treated with ADT. A significant association between duration of androgen suppressive therapy and fracture risk has been reported [61]. Causes of bone loss in prostate cancer The pathogenesis of increased bone turnover, bone loss, and fracture in men on gonadotropin-releasing hormone (GnRH) agonists is incompletely understood. Traditionally, estrogen was considered to be the major gonadal steroid regulating bone metabolism in women, and testosterone was thought to play the same role in men. However, recent evidence suggests that estrogen is the dominant sex steroid regulating bone resorption in men, as it is in women, which may have important therapeutic implications [62]. Because most estrogen in men is derived from peripheral conversion of testosterone to estradiol,

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ADT also results in estrogen deficiency. Compelling data suggest that the increased bone turnover and bone loss associated with GnRH therapy may be related, at least in part, to estrogen deficiency. The role of estrogen in bone metabolism was recently demonstrated in a study comparing the effect of estrogen in men on established luteinizing hormone–releasing hormone agonist therapy for prostate cancer. Those randomly assigned to receive estrogen demonstrated significant suppression of biochemical markers of bone turnover compared with those assigned to placebo [62] .

Treatment and prevention of osteoporosis in prostate cancer The options available for the treatment and prevention of osteoporosis in men with prostate cancer include bisphosphonates, estrogen replacement therapy, and SERMs; in addition, men treated with hormone ablation should receive the recommended daily allowance of calcium (1200–1500 mg/d) and vitamin D (400 IU/d). Lifestyle modifications, such as smoking cessation, moderate alcohol intake, and weight-bearing exercise, may also benefit skeletal health in these individuals. However these general measures are unlikely to completely counteract the adverse skeletal effects of hormone deprivation [63]. Bisphosphonates The proven safety and efficacy of bisphosphonates in treating postmenopausal female osteoporosis as well as osteoporosis in men makes these agents an obvious choice to treat osteoporosis in men with prostate cancer. The therapeutic benefit of bisphosphonates in men with primary osteoporosis was evident in a 2-year, doubleblind, placebo-controlled trial of alendronate. BMD increased by 7.1% at the lumbar spine, 2.5% at the femoral neck, and 2% at the total body (P<0.001). A significant decrease in vertebral fractures was reported in the treated versus placebo group (0.8% vs 7.1%, P=0.02) [28]. Several studies have established that bisphosphonates are efficacious in preventing bone loss due to ADT for prostate cancer. Pamidronate and zoledronate have been studied in this setting. In one study, men with advanced or recurrent prostate cancer but without bone metastases were randomly assigned to either leuprolide alone or leuprolide and pamidronate. The men in the leuprolide-alone arm had a significant decrease in BMD at the lumbar spine (3.3%), trochanter (2.1%), and total hip (1.8%), whereas bone mass was preserved at all sites in men on the combination of leuprolide and pamidronate [64•]. Similar results have been observed with zoledronate [65]. Six months of cyclic etidronate and calcium therapy can also reverse bone loss associated with combined androgen blockade, raising questions about the optimal timing of treatment initiation [58].

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Estrogen A retrospective study of men with prostate cancer treated with either high-dose estrogen or orchiectomy found that BMD was significantly decreased in the orchiectomy group but was unchanged in those treated with estrogen [66]. Ongoing trials are evaluating the efficacy of low-dose estrogen, alone or in combination with bisphosphonates, for the prevention of bone loss in this patient population. Bicalutamide Bicalutamide, an androgen receptor antagonist, is an alternative to ADT for prostate cancer. This agent may have fewer effects on bone because it increases serum estrogen and testosterone levels. One cross-sectional study compared markers of bone turnover and levels of gonadal hormones in three groups of prostate cancer patients: those on no hormonal therapy, those receiving leuprolide acetate, and those receiving bicalutamide [67]. Serum estrogen and testosterone levels were higher and biochemical markers of bone turnover were lower in men receiving bicalutamide, compared with the other groups. These observations suggest that bicalutamide may maintain BMD and decrease fracture risk in men with prostate cancer. Additional prospective studies are needed to ascertain the optimal timing of treatment and preventive strategies for osteoporosis in men with prostate cancer. Many recommendations for prevention are based on studies of postmenopausal osteoporosis and encompass pharmacologic and nonpharmacologic measures, as described previously.

Screening and treatment recommendations Several prospective studies have noted that men with prostate cancer had low BMD prior to beginning ADT. A cross-sectional study of prostate cancer patients without bone metastases reported that 29% of the men had T scores in the osteopenic range at one or more skeletal sites, and 63% had osteoporotic T scores by quantitative CT scanning [68]. Therefore, measurement of BMD is recommended prior to beginning ADT and after 1 year. Thereafter, BMD should be measured at 1- to 2-year intervals. Other triggers for BMD screening include a personal history of fracture after the age of 40, significant height loss, smoking, family history of osteoporosis, and long-term use of glucocorticoids. Calcium and vitamin D should be recommended to all patients. Bisphosphonates should be discussed with all osteopenic patients and recommended for all patients who develop osteoporosis or lose more than 8% of their bone mass yearly.

risk, are needed. Low-dose estrogens may be another option for the treatment of bone loss. Further studies are required to identify predictors of bone loss in men with prostate cancer.

Conclusions Cancer treatment has significant long-term adverse effects on the skeleton. The short- and long-term side effects from hormonal deprivation used in the treatment of breast and prostate cancer can have a negative impact on the quality of life of cancer survivors. Improved management of these adverse effects of therapy—and newer treatment options that minimize their negative consequences on the skeleton without compromising antitumor efficacy—are being studied.

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Ongoing studies and future directions Additional options in the management of osteoporosis in prostate cancer remain to be explored. Further studies on osteoporosis in men with prostate cancer, including the long-term effects of bisphosphonates on fracture

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