Androgen-deprivation-therapy-induced fractures in men with nonmetastatic prostate cancer: what do we really know?

Androgen-deprivation-therapy-induced fractures in men with nonmetastatic prostate cancer: what do we really know? Celestia S Higano SUMMARY Androgen deprivation therapy (ADT) alone or in combination with radiation therapy or other drugs is increasingly used for the treatment of localized, high-risk, or biochemical relapse of prostate cancer (PC). Bone mineral density (BMD) loss is rapid during the first year of ADT; up to 4.6% of total hip, femoral neck, and lumbar spine BMD loss has been reported in PC patients without bone metastases (nonmetastatic PC). In prospective studies, concurrent administration of a bisphosphonate or selective estrogen receptor modulator stabilized or increased BMD. Results of retrospective studies of ADT-treated patients who did not receive antiresorptive therapy have demonstrated a 21 37% increase in fracture risk. Because of the documented bone loss and increased fracture risk, patients should receive adequate counseling, monitoring, and therapy aimed at preventing or treating ADT-induced bone loss. Future studies should address the long-term impact of antiresorptive therapy on actual fracture rate and the impact on quality of life and healthcare costs. Keywords androgen deprivation therapy, bone loss, fractures, osteoporosis, prostate cancer Review criteria A comprehensive PubMed search of the English language literature from January 1950 to June 2007 for relevant articles was performed using the MeSH term prostate neoplasm with search terms including diphosphonates, bone density, osteoporosis, metabolic bone diseases, androgen antagonists, hormonal antineoplastic agents, bone fractures, orchiectomy, leuprolide, and goserelin, estrogens, raloxifene, toremifene, and selective estrogen receptor modulators, and the keywords pamidronate, zoledronic acid, and bisphosphonate. The bibliographies of retrieved articles were evaluated for additional citations. Articles were limited to patients without bone metastases. cme CS Higano is Associate Professor, Medicine and Urology, University of Washington, Seattle Cancer Care Alliance, Seattle, WA, USA. Correspondence University of Washington, Seattle Cancer Care Alliance, 825 Eastlake Avenue East, Mailstop G4-830, Seattle, WA 98109, USA thigano@u.washington.edu Received 10 July 2007 Accepted 5 October 2007 www.nature.com/clinicalpractice doi:10.1038/ncpuro0995 Continuing Medical Education online Medscape, LLC is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit. Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide CME for physicians. Medscape, LLC designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credits. Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To receive credit, please go to http://www.medscape.com/cme/ncp and complete the post-test. Learning objectives Upon completion of this activity, participants should be able to: 1 List side effects associated with androgen deprivation therapy (ADT). 2 Describe the rate of bone loss expected in men with nonmetastatic prostate cancer on ADT. 3 Identify factors that predispose to bone loss and fracture in men with nonmetastatic prostate cancer on ADT. 4 Describe strategies that reduce rate of bone loss in men with prostate cancer on ADT. 5 Identify the most commonly used method for assessing bone mineral density in men with prostate cancer on ADT. Introduction In 2007 nearly 220,000 men are expected to be diagnosed with prostate cancer. 1 Many of these men will eventually receive androgen deprivation therapy (ADT), such as orchiectomy or gonadotropin-releasing hormone (GnRH) agonist therapy (with or without antiandrogen therapy), for treatment of locally advanced or metastatic disease. 2,3 ADT has been shown to improve survival times when given in combination with radiation therapy in men with localized prostate cancer and when given after radical prostatectomy in men with node-positive disease. 4 7 Although ADT is also commonly used in men with biochemical relapse, to date there are no prospective trials showing that ADT confers a survival benefit for all patients with this stage of disease. Because ADT suppresses testosterone levels, numerous adverse effects, such as sexual 24 nature clinical practice UROLOGY january 2008 vol 5 no 1

GnRH agonist in premenopausal early-stage BCa 8.2% Chemotherapy-induced amenorrhea in early-stage BCa 6.4% ADT in nonmetastatic PC 4.6% Hormonal therapy in postmenopausal early-stage BCa a 2.6% Early menopause 2% Late menopause 1% Normal men 0.5% 0 2 4 6 Percentage BMD loss per year 8 10 Figure 1 A comparison of cancer-therapy-induced bone loss versus normal bone loss in men and women. a Hormonal therapy consisted of the aromatase inhibitor anastrazole. 2,17 26,33 35 Abbreviations: ADT, androgen deprivation therapy; BCa, breast cancer; BMD, bone mineral density; GnRH, gonadotropinreleasing hormone; PC, prostate cancer. dysfunction, cognitive and mood changes, hot flashes, metabolic changes and skeletal complications, can occur. 3,8 27 Clinicians must have a thorough understanding of these adverse effects and how they should be managed. Skeletal complications, such as bone loss and fractures, have emerged as important adverse effects associated with ADT in men with prostate cancer. Bone loss results from ADT-induced testosterone and estrogen deficiencies. 2 During ADT, testosterone and estrogen levels fall to <95% and <80%, respectively, of normal levels and usually rise gradually after therapy is discontinued. 2,28 Return of normal testosterone levels is variable, and in some cases, the original testosterone level never recovers. 28,29 The time to recovery of initial testosterone levels after discontinuation of ADT is generally longer in men with lower baseline testosterone levels (i.e. <212 ng/ml), men over 65 years of age, and men receiving ADT for more than 24 30 months. 29 31 Testosterone exerts its effects on the bone remodeling process by stimulating proliferation of osteoblasts (bone-formation cells) and inhibiting apoptosis of osteoblasts and osteoclasts (bone-resorption cells). 32 Testosterone might also indirectly affect bone remodeling via aromatization of testosterone to estrogen. 32 Estrogen is the dominant steroid regulating bone resorption. A deficiency of estrogen shifts the balance of bone remodeling towards increased bone resorption by activating osteoclasts, decreasing osteoclast apoptosis, and possibly by decreasing osteoblast formation, proliferation, and function and increasing osteoblast apoptosis. 32 This process results in the formation of resorption cavities that are usually beyond the capacity of osteoblastic repair, resulting in net bone loss. 32 The results of prospective studies show that men with nonmetastatic prostate cancer experience annual reductions in the bone mineral density (BMD) of the femoral neck, lumbar spine, and total hip bone of up to 4.6%, a rate that equals or exceeds bone loss in other populations at risk of declining BMD (Figure 1). 2,17 26,33 35 BMD loss and microarchitectural deterioration of bone can decrease bone strength and increase the risk of bone fractures. 36 39 Fractures have been associated with significant morbidity, reduced quality of life (QOL), and increased mortality, although the impact of fractures per se has not been evaluated in men with nonmetastatic prostate cancer. 40,41 This article reviews what is known and what is implied from other high-risk populations about the prevalence, risk factors, consequences, prevention strategies, and monitoring recommendations for bone loss and fractures in men with nonmetastatic prostate cancer receiving ADT. january 2008 vol 5 no 1 HIGANO nature clinical practice UROLOGY 25

Table 1 Percentage change in bone mineral density in men with nonmetastatic prostate cancer receiving androgen deprivation therapy. a Type of ADT ADT duration (months) Mean % change in BMD per year by skeletal site Lumbar spine Total hip Femoral neck GnRH agonist 17 20 12 to 36 2.1 to 4.6 1.9 to 3.3 2.3 to 3.9 GnRH agonist + antiandrogen (4 6 weeks) 21,22 12 2.3 to 3.3 0.6 to 1.8 NR b or NS c GnRH agonist ± antiandrogen 23,24 12+ 2.0 to 2.2 2.1 to 2.8 2.1 or NR d GnRH agonist, orchiectomy, antiandrogen, 15 to 49 1.4 to 4 0.7 to 2.5 0.7 or NR e or LHRH agonist + antiandrogen 25,26 Intermittent ADT + antiandrogen 35 9 4.5 2.5 NR a Includes the minimum and maximum percentage changes reported in the literature. b Not reported in Berruti 2002. c No significant change reported from baseline in Smith 2001. d Not reported in Israeli 2006. e Not reported in Greenspan 2005. Abbreviations: ADT, androgen deprivation therapy; BMD, bone mineral density; GnRH, gonadotropin-releasing hormone; LHRH, lutenizing hormone-releasing-hormone; NR, not reported; NS, not significant. Prevalence of Bone Loss and Fractures in Men Receiving ADT Aging in men is associated with a decrease in bioavailable testosterone and estradiol levels that results in a gradual bone loss of 0.5 1% per year. 32,42 Bone loss with ADT, however, is much more rapid. Several prospective studies have demonstrated a 0.6 4.6%-yearly BMD loss in men with nonmetastatic prostate cancer receiving ADT (Table 1); annual bone loss rates are similar among different types of ADT. 17 26,35 Interestingly, our experience shows that BMD loss may be somewhat attenuated with intermittent ADT, with stabilization of lumbar spine and total hip BMD occurring during the offtreatment period; however, data evaluating the long-term effects of intermittent ADT on BMD and fracture risk are lacking, and hence the true benefit of this approach is unknown. 35 Compared with prostate cancer patients not receiving ADT, men with nonmetastatic prostate cancer receiving ADT experience a 5 10-fold higher rate of bone loss within the first year of therapy. 25 This rate of bone loss not only exceeds normal male and perimenopausal female bone loss, but might rival that observed in postmenopausal women with early-stage breast cancer treated with an aromatase inhibitor, a hormonal therapy known to decrease BMD and increase fracture risk (Figure 1). 2,43 Although the greatest loss of BMD occurs within the first year of ADT, the duration of ADT has also been directly linked to the magnitude of bone loss. 25,44 47 T score is used to interpret results of BMD tests; it compares the BMD measured with that expected for a young, healthy adult (T score = [Measured BMD young adult BMD]/Young adult standard deviation). 48 In one study, the prevalence of osteoporosis (T score < 2.5) increased progressively during ADT with approximately 50% of patients developing osteoporosis by 4 years and 80% by 10 years. 45 After 10 years of ADT, none of the patients had a normal BMD, and BMD decreases were greater in men who had received ADT for longer durations. 45 A low baseline BMI (i.e. <25 kg/m 2 ) might also increase the risk for decreased BMD in men with prostate cancer before ADT initiation. 49,50 Furthermore, one study has suggested that a higher BMI might lessen the risk of bone loss once ADT is initiated in men with prostate cancer. 46 However, bone loss in men with prostate cancer might be secondary to causes other than ADT. Secondary causes of bone loss such as hyperthyroidism, hyperparathyroidism, liver disease, calcium or vitamin D malabsorption should, therefore, be considered and/or treated in these men. 51 For example, vitamin D deficiency (serum 25-hydroxyvitamin D <15 ng/ml) has been reported in 17% of ADT-naive men with locally advanced prostate cancer. 52 Additionally, many men with prostate cancer have an inadequate calcium intake. In one study, more than 90% of men with prostate cancer reported a daily calcium intake of less than 1,000 mg per day, the National Institute of Health recommendation. 53 Prospective studies reporting bone loss with ADT in men with nonmetastatic prostate cancer have not evaluated fracture risk associated with ADT; however, the results of three large retrospective studies have demonstrated that these patients are 21 37% more likely to experience a fracture (Table 2). 36 38 The 26 nature clinical practice UROLOGY HIGANO january 2008 vol 5 no 1

Table 2 Fracture risk in men with nonmetastatic prostate cancer receiving GnRH agonist therapy compared with those not receiving GnRH agonist therapy. Fracture type Fracture risk by study (relative risk [95% CI]) Shahinian et al. (2005) 37,a Smith et al. (2005) 36,c Smith et al. (2006) 38,d Any fracture 1.37 (1.20 1.57) b P = NR 1.25 (1.09 1.45) P <0.0001 1.21 (1.09 1.34) P <0.001 Hip/femur NR 1.36 (1.14 1.62) P = 0.0006 1.76 (1.33 2.33) P <0.001 Vertebral NR 1.50 (1.21 1.83) P = 0.0001 1.18 (0.94 1.48) P = 0.155 a Retrospective study using data from Surveillance, Epidemiology and End Results program and Medicare databases. b After 9 doses of GnRH agonist during first year following prostate cancer diagnosis. c Retrospective study using data from Medicare databases. d Retrospective study using data from an employer database of health insurance billing claims. Abbreviation: NR, not reported. results of a multivariate analysis conducted by Smith and colleagues 38 demonstrated that men with prostate cancer receiving GnRH agonists were 13% more likely to experience a fracture despite controlling for age, comorbidity, income, observation period, geographic region, and type of insurance. In this study, age >65 years and comorbidity were also independent risk factors for fracture. Risk Factors for Fractures Decreased BMD BMD is a strong predictor of fracture risk in men. 54 56 In one study, total hip BMD was strongly associated with hip fracture risk in more than 5,000 men aged 65 years or older (3.2-fold increased fracture risk per sex-specific standard deviation decrease in BMD; 95% CI 2.4 4.1). 56 Low BMD is the strongest predictor of fracture in women, with a 4-fold and 1.8-fold increase in fractures occurring in osteoporotic (T score 2.5) and osteopenic (T score < 1 and > 2.5) women, respectively. 57 In healthy men, an increased fracture risk has been positively correlated with decreased BMD. 42,55,58 One study reported that men 70 years of age or older had a 40 50% increase in the 10-year probability of experiencing nontraumatic fractures for each standard deviation decrease in T score. 55 Another study of more than 2,400 healthy men aged 55 years and older suggested that even men with osteopenia (T score between 1 and 2.5) experience significant fracture risk. 39 Although no prospective studies in men with nonmetastatic prostate cancer receiving ADT have followed patients for long enough to establish an association between fracture risk and low BMD, several studies have reported preexisting osteopenia (T score < 1 and > 2.5) in 20 56% of patients and pre-existing osteoporosis in 5 35% of ADT-naive patients. 18,22,25,45,49,50,52 Increased ADT duration An increased ADT duration also increases the risk of fractures in men with nonmetastatic prostate cancer. 36,44 The results of one study showed that the hazard ratio for fracture risk associated with GnRH agonist therapy increased from 1.10 (95% CI 0.97 1.21; P = 0.08) in men receiving ADT for less than 1 year to 1.16 (95% CI 1.08 1.26; P <0.0001) in those receiving therapy for 1 year or more. 36 In a prospective study of men with nonmetastatic prostate cancer, the relative risk (RR) of hip fractures was estimated using a formula derived from BMD measurements and fracture rates in postmenopausal women. 44 In this study, the estimated RR of hip fractures was higher for men with nonmetastatic prostate cancer receiving ADT (ADT for 12 36 months, RR = 2.4 [95% CI 1.2 3.6]; ADT for >60 months, RR = 3.9 [95% CI 1.8 9.6]) than in men with nonmetastatic prostate cancer who were not receiving ADT (RR = 2 [95% CI 1.5 2.6]). 44 Consequences of fractures In the US, 1.5 million osteoporosis-related fractures occur each year. 59 Nearly 30% of patients with a hip fracture are institutionalized in the year following the fracture. 59 Vertebral fractures have been associated with difficulty in performing activities of normal daily living, increased risk for fragility fractures, and increased physician visits for back pain. 59 Men with nonmetastatic prostate cancer receiving ADT are more likely to require fracture-related hospitalizations than are patients not receiving ADT (4.9% vs 2.2%, P <0.001); loss of muscle mass and strength due to ADT are thought to contribute to increased fracture rate in these men. 36 38,60 january 2008 vol 5 no 1 HIGANO nature clinical practice UROLOGY 27

Although the consequences of ADT-induced fractures have not been formally evaluated, inferences for mortality, morbidity, and QOL can be made from osteoporosis outcome studies. In a 5 year observational study, osteoporotic fractures were associated with an increased mortality rate in men compared with the general population and also compared with women with osteoporotic fractures. 41 The Canadian Multicentre Osteoporosis Study (CaMos) reported that hip, spine, wrist/forearm, pelvic, or rib fractures in men and women over 50 years of age are correlated with decreases in physical functioning (i.e. walking, climbing stairs, carrying groceries) and role-physical functioning (i.e. difficulty performing work or other activities, or limited to the kind of activities or work as a result of the patient s physical health) QOL domains ( 4 [95% CI 6 to 2] and 5.8 [95% CI 9.5 to 2.2], respectively). Men who experienced hip fractures had profound decreases in their role-physical domain scores ( 35.7; 95% CI 60.4 to 11.1). 40 In another CaMos study, the decrease in health-related QOL associated with osteoporosis in men and women at least 65 years of age was similar to other chronic medical conditions including arthritis, diabetes mellitus, heart disease, and chronic obstructive pulmonary disease. 61 The costs for osteoporosis-related fractures in the US (2005) have been estimated to be $16.9 billion, with fractures in men accounting for $4.1 billion. 62 In a retrospective study using medical claims (1997 2001) for inpatient and outpatient services of more than 61,000 osteoporotic men and women, osteoporosis patients with concurrent fracture had more than twice the overall healthcare costs compared with patients with osteoporosis without concurrent fracture ($15,942 vs $6,476) and more than three times those of patients without osteoporosis ($15,492 vs $4,658). 59 Furthermore, results of an observational study of men and women with hip fractures showed that men are undertreated for osteoporosis following discharge, with only 27% of men receiving any type of osteoporosis therapy within 1 5 years following discharge compared with 71% of women (P <0.001). 63 Preventing ADT-Related Fractures Whether lifestyle or pharmaceutical interventions prevent fractures in men with nonmetastatic prostate cancer receiving ADT is unknown; however, in other high-risk populations such as the elderly or men and women with osteoporosis, interventions have proven effective for reducing fracture risk. 64 68 Loss of BMD due to ADT can be prevented with bisphosphonate, estrogen, or selective estrogen receptor modulator (SERM) therapy, although the value of prophylaxis in this setting is unknown. Prophylactic treatments to prevent bone loss have been shown to decrease fracture risk in patients treated with corticosteroid therapy and might, therefore, be useful in preventing or minimizing fracture risk in patients treated with ADT. 19 21,23,24,26,51,69 Lifestyle modifications and exercise Studies evaluating the impact of lifestyle changes on ADT-related loss of BMD are lacking, and studies evaluating risk factors for bone loss, such as smoking, alcohol consumption, calcium supplementation, and exercise, in prostate cancer patients receiving ADT have produced conflicting results. 22,44,46,47,49,50 However, because smoking and possibly excessive alcohol consumption have been shown to increase the risk of bone loss and fractures in various populations, counseling men with prostate cancer receiving ADT on the possible skeletal and overall health benefits of smoking cessation and reduced alcohol consumption is recommended. 22,27,46,50,70,71 Weight-bearing and muscle-strengthening exercises can increase BMD and reduce the risk of fracture. According to the results of a prospective cohort study, increasing levels of physical activity reduces the RR of hip fracture in elderly women. 64 These results confirm those of other studies showing that routine exercise, including walking, weight training, or highimpact exercise, can increase BMD by 1 2% at some skeletal sites. 72 Resistance exercise programs initiated during ADT can increase muscle strength, which may further decrease the risk of fall and fracture. 60 Men with prostate cancer receiving or initiating ADT should, therefore, be encouraged to participate in a routine (20 45 min/session, 2 4 sessions/week), customized exercise program that includes resistance exercise. 2,70 Pharmaceutical interventions Calcium and vitamin D Vitamin D deficiencies and inadequate calcium intake are commonly found in men with prostate cancer and are associated with bone loss. 49,52,53 Daily calcium and vitamin D supplementation 28 nature clinical practice UROLOGY HIGANO january 2008 vol 5 no 1

Table 3 Clinical trials evaluating pharmaceutical interventions for the prevention of bone loss in men with nonmetastatic prostate cancer receiving androgen deprivation therapy. a Study Number of patients (controls) b Bone loss prevention therapy c Greenspan 56 (56) Alendronate (70 mg/week PO for (2007) 26,f 1 year) vs placebo Smith (2001) 21 21 (22) Pamidronate (60 mg IV every 12 weeks for 48 weeks) vs control group Smith (2003) 24 42 (37) Zoledronic acid (4 mg IV every 3 months for 1 year) vs placebo Ryan (2006) 19 50 (51) Zoledronic acid (4 mg IV every 3 months for 1 year) vs placebo Israeli (2007) 23 106 (109) Zoledronic acid (4 mg IV every 3 months for 48 weeks) vs placebo Michaelson 22 (22) Zoledronic acid (4 mg IV 1 dose in (2007) 20 1 year) vs placebo Mean % change in BMD after 12 months d,e Lumbar spine Total hip Femoral neck 3.7 vs 1.4 (P <0.001) No change vs 3.3 (P <0.001) 5.6 vs 2.2 (P <0.001) 4.6 vs 2.1 (P <0.0001) 0.7 vs 0.7 (P = 0.002) No change vs 1.8 (P = 0.005) 1.1 vs 2.8 (P <0.001) 1.4 vs 2.4 (P <0.0001) 4.7 vs 2 1.6 vs 2.1 NR vs NR (P <0.0001) (P <0.0001) 4 vs 3.1 (P <0.001) 0.7 vs 1.9 2 vs 0.1 (P = 0.005) 1.6 vs 0.7 (P <0.001) No change vs no change (P = 0.56) 1.2 vs 2.1 (P <0.001) 1.3 vs 2.4 (P = 0.0004) Eriksson (1995) 75 16 (11) Estrogen g vs control group NR vs NR NR vs NR 1.2 vs 9.6 (P = NR) Smith (2004) 69 19 (22) Raloxifene (60 mg/day PO for 1 year) vs control group 1 vs 1 (P = 0.7) 1.1 vs 2.6 (P <0.001) 0.3 vs 1.7 (P = 0.06) a ADT consisted of GnRH agonist, GnRH agonist ± antiandrogen, or orchiectomy. b Patients assessable for efficacy analysis. c All patients received calcium and vitamin D supplementation, unless otherwise noted. d BMD measured by dual-energy x-ray absorptiometry. e P value provided for between-group comparison. f Interim, 12-month results. g All 16 patients received polyestradiol phosphate 160 mg intramuscularly every 4 weeks for 3 months then 80 mg every 4 weeks thereafter; additionally 9 of the 16 patients received ethinyl estradiol 1 mg PO daily for 2 weeks followed by 0.15 mg PO daily and the other 7 patients did not begin oral estrogen therapy until after 3 months of polyestradiol phosphate intramuscular injections. Abbreviations: ADT, androgen deprivation therapy; BMD, bone mineral density; GnRH, gonadotropin-releasing hormone; IV, intravenous; NR, not reported; PO, orally. has been shown to moderately increase BMD (by between 0.5 2%) and reduce osteoporotic fractures in elderly men and women. 68 Daily calcium (500 1,500 mg) and vitamin D (800 IU) supplementation should, therefore, be strongly considered for all men with prostate cancer receiving ADT; the supplemental dose can be determined by a nutritionist on the basis of the individual patient s daily dietary consumption of calcium and vitamin D. While daily calcium and vitamin D supplementation can reduce the loss of BMD, supplements alone have not proven to prevent or treat bone loss in men with prostate cancer receiving ADT. 2,3,19 21,23,24,26,68 70,73,74 Bisphosphonates Bisphosphonates reduce bone resorption by inhibiting osteoclast activity and are available in oral and intravenous (IV) formulations. 70 The results of several studies show that bisphosphonates prevent ADT-related bone loss effectively in men with prostate cancer (Table 3). 19 21,23,24,26,69,75 While most evidence supporting the use of bisphosphonates for ADT-related bone loss prevention in men with prostate cancer is derived from studies evaluating IV bisphosphonates, significant increases in BMD in men with prostate cancer receiving ADT and once-weekly oral alendronate (70 mg) were observed in one recently published study (Table 3); this study was not powered to detect a difference in fracture rates between treatment groups. 26 Ringe and colleagues 66 also observed a 57% decrease in vertebral fractures in osteoporotic men receiving alendronate (10 mg once daily for 3 years) compared with men receiving vitamin D. Whether this can be extrapolated to men with prostate cancer receiving ADT is unknown. Both alendronate and risedronate are Food and Drug Administration (FDA)-approved and commonly used for increasing BMD in osteoporotic men or for the treatment of glucocorticoid-induced osteoporosis. However, they are not FDA-approved for the treatment of ADT-induced osteoporosis; ibandronate is FDAapproved for the prevention and treatment of postmenopausal osteoporosis. 2,76 78 The IV bisphosphonates pamidronate and zoledronic acid prevent ADT-related bone loss effectively in men with nonmetastatic prostate cancer (Table 3). 19 21,23,24 Results from one study evaluating IV pamidronate in men with january 2008 vol 5 no 1 HIGANO nature clinical practice UROLOGY 29

prostate cancer initiating ADT showed that pamidronate (60 mg IV every 12 weeks) prevents bone loss by maintaining BMD at baseline values (Table 3). 21 Zoledronic acid (4 mg IV every 3 months), however, not only prevented bone loss, but increased BMD in patients who initiated or had received up to 12 months of ADT at study entry (Table 3). 19,23,24 Results from a more recent study evaluating a single annual dose of zoledronic acid (4 mg) suggest that less frequent administration of zoledronic acid might provide similar benefits to those observed with more frequent administration; however, further study is required to confirm these results and to determine the impact on fracture risk of different dosing schedules (Table 3). 19,20,23,24 Because studies completed thus far have not been powered to quantify differences in fractures rates between treatment and control groups, whether the positive effects on bone loss are associated with a decreased fracture risk in this population is unknown. 19 21,23,24,26 BMD is inversely related to fracture risk in men with prostate cancer; it is, therefore, conceivable that maintaining or increasing BMD will correlate with decreases in the risk and incidence of fragility fractures in men with prostate cancer receiving ADT to a similar extent to results reported in studies on osteoporotic postmenopausal women. 55,67 Black and colleagues 67 found that a single annual dose of zoledronic acid (5 mg) reduced the risk of vertebral and hip fractures by 70% and 41%, respectively, in osteoporotic postmenopausal women after 3 years. Studies designed to evaluate the effects of IV bisphosphonates on fracture incidence in men with prostate cancer receiving ADT are ongoing. 79 Estrogens Estrogen has a central role in bone homeostasis in men, so it is reasonable to evaluate estrogen therapy for bone loss and fracture prevention in men with prostate cancer receiving ADT; however, studies to date evaluating estrogen therapy in these patients are small. 75,80,81 Eriksson and colleagues 75 evaluated changes in BMD in men with nonmetastatic prostate cancer receiving orchiectomy or estrogen therapy in doses that usually result in castration levels of testosterone (see Table 3). Although no changes in BMD were observed in patients receiving estrogens, those receiving orchiectomy experienced a loss of BMD in the femoral neck, suggesting that estrogen therapy might prevent the bone loss that commonly occurs when testosterone is reduced to castration levels. More recently, two small studies reported decreases in markers of bone resorption in men with prostate cancer receiving ADT who were treated with estrogens (diethylstilbestrol 1 mg/day or ethinyl estradiol 1 mg/day), suggesting that estrogens might be effective in preventing bone loss associated with ADT, but neither BMD nor fractures were evaluated in these studies. 80,81 Estrogen therapy, therefore, seems to spare bone loss associated with ADT, but the studies are small and the known cardiovascular and thromboembolic toxicity of oral estrogens are of concern. 27 Transdermal estrogen formulations might minimize these complications, but additional studies evaluating the effects on BMD or fracture rates are needed. 27 Selective estrogen receptor modulators SERMs, such as raloxifene and toremifene, selectively bind to estrogen receptors in bone and mimic the beneficial effects of endogenous estrogen on bone metabolism while avoiding the potential toxicity (cardiovascular and thromboembolic) associated with estrogens. 69 Study results indicate that raloxifene, compared with placebo, significantly increases BMD and decreases bone resorption markers in men with prostate cancer receiving ADT (Table 3); studies evaluating toremifene are ongoing. 69,82 Research evaluating the effect of SERMs on fracture risk has only been conducted in postmenopausal women with osteoporosis; a 30 50% decrease in vertebral fractures was observed in women receiving daily raloxifene (60 120 mg once daily for 36 months). 65 Additional studies evaluating the use of SERMs for the prevention of ADT-related fractures are needed. Monitoring For Bone Loss and Fractures Identifying patients at the highest risk for bone loss is essential for preventing fractures caused by ADT. Before ADT is initiated, all patients should undergo a physical examination and complete a detailed medical history in order to identify existing risk factors. Because BMD is a robust predictor of fracture risk, determination of a patient s baseline BMD is necessary to effectively monitor for ADT-related bone loss, to better counsel patients on risk, and follow response to 30 nature clinical practice UROLOGY HIGANO january 2008 vol 5 no 1

For patients initiating ADT a Determine risk group: Low-risk no high-risk characteristics High-risk 1 or more of the following characteristics: Duration of ADT >6 months, previous fractures, family history of osteoporosis, low BMI, tobacco smoking, excessive alcohol consumption, corticosteroid use, medical comorbidities, low vitamin D levels Encourage lifestyle modifications (e.g. cessation of alcohol, cigarette consumption) Recommend resistance exercise training plan Measure baseline BMD (DEXA of hip ± spine or QCT of spine) Normal: T score: > 1 Osteopenia: T score: 1 to 2.5 Osteoporosis: T score: < 2.5 Daily calcium (1,200 1,500 mg) and vitamin D (800 IU) intake Initiate bisphosphonate therapy for all patients who experience a fracture regardless of BMD Daily calcium (1,200 1,500 mg) and vitamin D (800 IU) intake Consider bisphosphonate b or SERM c therapy Initiate bisphosphonate therapy for all patients who experience a fracture regardless of BMD Daily calcium (1,200 1,500 mg) and vitamin D (800 IU) intake Consider bisphosphonate therapy b,d Initiate bisphosphonate therapy for all patients who experience a fracture regardless of BMD Low-risk patients: repeat BMD and review clinical riskfactor status every 24 months High-risk patients: repeat BMD and review clinical riskfactor status every 12 months Low-risk patients: repeat BMD and review clinical riskfactor status every 12 months High-risk patients: repeat BMD and review clinical riskfactor status every 6 months Low or highrisk patients: repeat BMD measurement and clinical history every 6 months Figure 2 Bone loss management algorithm for men with nonmetastatic prostate cancer initiating androgen deprivation therapy. a BMD assessment and monitoring and/or treatment according to this algorithm should be considered for patients already receiving ADT. b Some studies evaluating bisphosphonates for the prevention of bone loss initiated bisphosphonate and ADT concurrently. c SERM refers to raloxifene or toremifene therapy; final results from studies evaluating toremifene have not been published. d A SERM may be a reasonable alternative for those with contraindications to bisphosphonate therapy, but SERMs are not FDA approved for treatment of osteoporosis in men. Abbreviations: ADT, androgen deprivation therapy; BMD, bone mineral density; BMI, body mass index; DEXA, dual energy X-ray absorptiometry; QCT, quantitative computed tomography. This figure was adapted from that originally published in Higano CS (2004) Understanding treatments for bone loss and bone metastases in patients with prostate cancer: a practical review and guide for the clinician. Urol Clin North Am 31: 331 352, (2004) Elsevier, Inc., and Diamond TH et al. (2004) Cancer 100: 892 899, (2004) American Cancer Society. This material was reproduced with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc. 2,3,71 therapy when initiated. 55 Measuring a patient s baseline BMD is, therefore, now recommended in national guidelines (Figure 2). 2,3,71,83 Several techniques for measuring BMD exist, with the most common method being dual energy X-ray absorptiometry (DEXA) of the lumbar spine and total hip. Sclerotic changes in bone, especially in the lumbar spine, can confound the BMD reading and should be taken into account. 2 Quantitative computed tomography (QCT) of the lumbar spine is also suitable, but is not as widely available as DEXA; also, QCT evaluates trabecular BMD rather than the cortical BMD measured in most clinical trials. 2 Follow-up BMD scans, ideally done on the same machine and at the same skeletal site(s), should be routinely repeated every 6 24 months depending on the patient s baseline BMD and number of existing risk factors (Figure 2). 2,83 Unlike BMD, biochemical markers of bone turnover are dynamic, rather than static, indicators of whole-body bone metabolism; january 2008 vol 5 no 1 HIGANO nature clinical practice UROLOGY 31

therefore, serum and/or urinary levels of bone resorption (e.g. N-telopeptide) and bone formation (e.g. bone-specific alkaline phosphatase) markers are commonly used to follow the effectiveness of therapy (as secondary endpoints) in clinical trials evaluating bone loss prevention and treatment strategies in men with prostate cancer. 2,19 21,23,26 The feasibility of using markers of bone turnover to monitor for ADT-related bone loss and response to bone loss prevention therapies in clinical practice is unknown. However, because measuring markers of bone turnover is noninvasive and can provide evidence of change in BMD within the first 3 months of therapy, and is potentially less costly than BMD scans, additional studies evaluating the clinical usefulness of bone turnover marker levels in conjunction with BMD measurements are warranted. 2,84 Currently, Medicare in the US does not routinely reimburse the costs of baseline BMD measurements in men with prostate cancer initiating ADT. Medicare and other payers may, however, provide coverage for baseline and subsequent BMD measurements on an individual basis depending on the patient s existing risk factors. 85 Because individual Medicare contractors have different reimbursement standards, verification of the coverage policies is recommended before BMD measurements are completed; however, once ADT is initiated, patients are considered at high risk, and reimbursement is usually not an issue. Conclusions Use of ADT, administered on a short term, long term or intermittent basis, is common in men who have either localized or biochemical relapse of prostate cancer. In this population of men, who will live for many years, increasing awareness of ADT-associated adverse effects, particularly bone loss and fractures, and effective strategies to manage these adverse effects are required to maintain good QOL. Whether lifestyle modifications or pharmaceutical interventions prevent ADT-related fractures is currently unknown; however, results from several studies in men with prostate cancer initiating or receiving ADT demonstrate that loss of BMD, a strong surrogate marker for fracture risk, can be prevented in patients receiving a bisphosphonate or raloxifene. 19 21,23,24,26,55,69 Evidence indicates that bone loss prevention strategies, including risk factor assessments, BMD monitoring, encouraging appropriate lifestyle modifications and exercise, ensuring adequate calcium and vitamin D intake, and bisphosphonate or SERM therapy when appropriate, should be the standard of care so that the risk of ADT-associated fractures is significantly reduced or eliminated. 2,3,70 Future studies should address the long-term impact of antiresorptive therapy on actual fracture rate and the impact on QOL and healthcare costs. The appropriate duration of therapy and monitoring schedule of prostate cancer patients receiving long-term ADT should be determined in the course of future prospective trials. Key Points Prospective data show that ADT significantly increases the risk of BMD loss in men with nonmetastatic prostate cancer Men initiating ADT should have an assessment of risk factors, calcium and vitamin D intake, lifestyle modification counseling, and baseline and follow-up BMD assessments Men with established osteoporosis are candidates for treatment with a bisphosphonate; a SERM would be a reasonable alternative for those men with contraindications to bisphosphonate therapy Bisphosphonate or SERM therapy to prevent further bone loss should be considered for men with osteopenia and/or other high-risk factors for bone loss Prospective trials on fracture risk due to ADT have not been completed, however, low BMD is a robust predictor of fracture risk in other populations, and data from these populations should be used to inform treatment strategies until prostate cancer-specific data is available References 1 Jemal A et al. (2007) Cancer statistics, 2007. CA Cancer J Clin 57: 43 66 2 Higano CS (2004) Understanding treatments for bone loss and bone metastases in patients with prostate cancer: a practical review and guide for the clinician. Urol Clin N Am 31: 331 352 3 The NCCN Prostate Cancer Clinical Practice Guidelines in Oncology (version 2.2007). 2006 National Comprehensive Cancer Network, Inc. [http://www.nccn.org] (accessed 15 May 2007) 4 Bolla M et al. (2002) Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 360: 103 108 5 Pilepich MV et al. (2005) Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 61: 1285 1290 32 nature clinical practice UROLOGY HIGANO january 2008 vol 5 no 1

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