Bone Health in Men Receiving Androgen Deprivation Therapy for Prostate Cancer

Review Articles Bone Health in Men Receiving Androgen Deprivation Therapy for Prostate Cancer James A. Eastham* From the Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, New York

Purpose: Patients with recurrent or metastatic prostate cancer generally receive androgen deprivation therapy, which can result in significant loss of bone mineral density. We explored androgen deprivation therapy related bone loss in prostate cancer, current treatments and emerging therapies. Materials and Methods: Literature published on the pathogenesis and management of androgen deprivation therapy related bone loss was compiled and interpreted. Recent drug therapy findings were reviewed, including treatment guidelines. Results: Men with prostate cancer often present with bone loss and the initiation of androgen deprivation therapy can trigger further rapid decreases. This results in an increased fracture risk, and greater morbidity and mortality. Early detection of osteoporosis through androgen deprivation therapy screening and prompt initiation of therapy are critical to prevent continued decreases. Lifestyle changes such as diet, supplementation and exercise can slow the rate of bone loss. Pharmacological therapy with oral and intravenous bisphosphonates has been demonstrated to prevent or decrease the bone loss associated with androgen deprivation therapy. However, important differences exist among various bisphosphonates with respect to efficacy, compliance and toxicity. Only zoledronic acid has been shown to increase bone mineral density above baseline and provide long-term benefit by decreasing the incidence of fracture and other skeletal related events in men with bone metastases. Conclusions: Androgen deprivation therapy associated bone loss adversely affects bone health, patient quality of life and survival in men with prostate cancer. Increased awareness of this issue, identification of risk factors, lifestyle modification and initiation of bisphosphonate therapy can improve outcomes. Education of patients and physicians regarding the importance of screening, prevention and treatment is essential. Key Words: prostate, prostatic neoplasms, bone and bones, androgen antagonists, osteoporosis

atients with clinically localized prostate cancer are usually treated with radical prostatectomy or radiation therapy. In cases of disease recurrence, most commonly manifesting as increasing prostate specific antigen, ADT is commonly used. This involves hypogonadism induction through orchiectomy, a GnRH agonist alone or combined androgen blockade (GnRH analogue plus antiandrogen).1 While ADT suppresses tumor growth, controls symptoms and extends survival, it is associated with significant side effects, such as weight gain, loss of lean muscle mass, impaired concentration, decreased libido and hot flashes.2 In addition, many patients treated with ADT experience rapid bone loss, which increases the risk of debilitating osteoporotic fractures.3–5 BMD may decrease by 4% to 13% yearly in men receiving such therapy.6 Moreover, men with prostate cancer may experience significant bone loss due to disease even before ADT initiation. Smith et al evaluated 41 patients with prostate cancer and no history of ADT with baseline BMD studies and found that 14 (34%) had osteopenia or osteoporosis.7 This decrease in BMD was associated with

hypogonadism, low vitamin D and insufficient dietary calcium. Similarly another study showed that 42% of men diagnosed with prostate cancer had osteoporosis and 37% had osteopenia before initiating ADT compared with a 27% incidence of osteoporosis in the age matched control group.8 Because many men with prostate cancer are older, BMD losses are superimposed on the progressive decrease in bone density that accompanies normal aging.8 The cumulative decrease in BMD is associated with an increased fracture risk,5,9 which can result in increased morbidity and mortality.10 Earlier diagnosis of prostate cancer resulting from more widespread prostate specific antigen testing, earlier initiation and longer use of ADT, and increased survival in patients with prostate cancer have resulted in a greater number of men receiving ADT and for a longer duration. Moreover, this treatment is not limited to patients with metastatic disease. Therefore, the BMD loss associated with ADT is an increasingly prevalent and important problem in patients with prostate cancer. Urologists must consider the risks of such therapy as well as current approaches to the prevention and treatment of bone loss in patients receiving ADT.

P

Submitted for publication December 23, 2005. * Correspondence and requests for reprints: Department of Urology, Memorial Sloan-Kettering Cancer Center, 353 East 68th St., Suite 527, New York, New York 10021 (telephone: 646-422-4390; FAX: 212-988-0759; e-mail: [email protected]).

PATHOPHYSIOLOGY OF ADT ASSOCIATED BONE LOSS Normal bone is in a state of equilibrium with ongoing bone formation and resorption mediated by osteoblasts and os-

For another article on a related topic see page 359.

0022-5347/07/1771-0017/0 THE JOURNAL OF UROLOGY® Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION

17

Vol. 177, 17-24, January 2007 Printed in U.S.A. DOI:10.1016/j.juro.2006.08.089

18

BONE HEALTH AND ANDROGEN DEPRIVATION THERAPY FOR PROSTATE CANCER

teoclasts, respectively. Estrogens and androgens help maintain this balance between bone synthesis and degradation.11 Estrogens regulate bone remodeling through direct effects on osteoblasts and osteoclasts. They prevent bone resorption by inhibiting osteoclasts and are required to maintain proper osteoblast functioning. Androgens such as testosterone also have direct effects on each cell type and it acts to decrease bone resorption via the aromatization of testosterone to estrogen. However, ADT disrupts this normal hormonal balance required for bone health. Severely hypogonadal men experience decreased BMD and severe bone architecture deterioration.12 This is associated with increased bone resorption but not bone formation, as measured by biochemical markers of bone turnover.13 The rate of loss of BMD occurring with ADT is significantly greater than that in normal aging or female menopause. Normally men lose BMD at a rate of approximately 0.5% to 1.0% yearly starting in middle age.2 Women lose bone mass at a similar rate until menopause, at which point this increases (approximately 3% yearly in the spine) for 5 years. Bone loss in women subsequently decreases to the earlier rate. In contrast, in men with prostate cancer treated with ADT bone loss was determined to be 4.6% and 3.9% at the lumbar spine and femoral neck, respectively, after 1 year with substantial changes evident as early as 6 months after ADT initiation.14 Similar rapid decreases in BMD also occur following orchiectomy with 1 study showing a 15% decrease in trochanter BMD at 1 year.15 Thus, bone loss associated with ADT is more rapid and severe than that in normal aging men or women with rates as much as 10-fold higher than normal. ASSESSING RISK: MEASURING LOSS OF BMD There are various technologies to assess BMD, including DXA, ultrasound, quantitative computerized tomography and radiographic absorptiometry. Although all methods are useful for predicting the fracture risk, the most commonly used measure is central DXA, which can assess BMD changes in the spine, hip, proximal femur and total body.16 Central DXA is preferred to other measurements because it can be performed rapidly in the office and uses radiation doses lower than those of conventional x-ray.16 Results of BMD measurements are typically standardized and reported as a T-score. The T-score is the number of SDs by which patient measured bone mass deviates from the mean of the young normal population of the same sex at a given site.17 T-scores are used to confirm a diagnosis of osteoporosis and assess disease severity as well as predict the fracture risk. According to WHO criteria patients with scores of –1 or greater are considered to be within the normal range. T-scores of –1 to –2.5 indicate osteopenia, –2.5 or less defines osteoporosis and –2.5 or less with at least 1

fracture indicates severe osteoporosis.16 A T-score of –1 represents a 10% to 12% loss of bone mass compared with the mean in normal young adults, which increases the relative risk of fracture 1.5 to 2-fold. Changes in BMD can also be inferred from measurement of bone metabolism biomarkers. Bone continually undergoes formation and resorption, and biochemical markers of the 2 processes can be detected in patient serum or urine. These surrogates may be useful for predicting the outcome or response to therapy.18 Serum markers of bone formation include bone specific alkaline phosphatase and osteocalcin, while indicators of bone resorption that are detectable in urine include pyridinoline, deoxypyridinoline and N-telopeptide of type 1 collagen.19 Changes in the levels of these markers occur in men with prostate cancer following ADT.20 Briefly, the detection of decreases in BMD can be used to identify patients with prostate cancer on ADT who are at increased risk for fracture. Early identification can facilitate prompt therapeutic interventions, such as prevention, lifestyle changes and/or medical therapy, as discussed. IMPACT OF ADT ON BONE HEALTH Numerous prospective studies have demonstrated that substantial bone loss occurs at multiple sites in men with prostate cancer treated with ADT (table 1). At 1 year BMD decreases from the baseline ranges of 1.8% to 3.9% at the hip and 5.3% to 10% at the radius. Other sites may experience even greater losses. For example, after 18 months of ADT the decrease in BMD was 7.1% in the lumbar spine and 6.6% in the femoral neck.14 BMD has also been compared in men with prostate cancer treated with a GnRH agonist vs men in a normal age and sex matched control group. Although men in the control group had no decrease in BMD, men on ADT experienced BMD decreases at several skeletal sites, which attained statistical significance for the total hip and ultradistal radius at 1 year.13 This bone loss associated with ADT results in an exponential increase in the fracture risk. Decreases in BMD of 10% to 15% approximately double the risk of fracture.21 Shahinian et al found that this was also true in men diagnosed with prostate cancer after they determined the incidence of fracture in more than 50,000 patients from 1992 through 1997.9 Of patients who survived 5 or more years after diagnosis fractures occurred in 19.4% and 12.6% of those who did and did not receive ADT, respectively (p ⬍0.001). The fracture risk increased with the number of doses of GnRH agonist received. In another retrospective study fracture rates were evaluated in 288 patients with prostate cancer who received ADT compared with 300 patients in the control group who did not. The incidence of peripheral and vertebral fractures was 4-fold higher with ADT, representing a statistically significant difference.22

TABLE 1. ADT associated BMD decreases References

No. Pts

Treatment

Eriksson et al15 Maillefert et al14 Daniell et al48 Berrut et al3 Higano et al49 Mittan et al13

11 12 26 35 36 28

Orchiectomy GnRH agonist Orchiectomy or GnRH agonist GnRH agonist Luteinizing hormone-releasing hormone agonist ⫹ antiandrogen GnRH agonist

BMD Site (% decrease) Hip Hip Hip Hip Hip Hip

(⫺9.6) (⫺3.9) (⫺2.4) (⫺0.6) (⫺2.7) (⫺3.3)

Radius (⫺4.5) Lt spine (⫺4.6) Lt spine (⫺2.3) Lt spine (⫺4.7) Radius (⫺5.3)

BONE HEALTH AND ANDROGEN DEPRIVATION THERAPY FOR PROSTATE CANCER Therefore, skeletal fractures are common in men with prostate cancer who receive ADT, and these skeletal events can have a significant adverse effect on quality of life and perhaps survival. In a study of 195 men with prostate cancer those with a fracture history had a median survival of 121 months compared with 160 months in those without fractures (p ⫽ 0.04) and a history of fracture was associated with a 7-fold increase in the relative risk of death (fig. 1).10 Skeletal fractures and skeletal metastases were independent negative predictors of survival (p ⫽ 0.007 and 0.002, respectively). Additionally, a history of fracture is associated with an increased risk of future fractures, increased longterm care and other complications, such as decubitus ulcers, urinary tract infections and pneumonia, which can further increase the mortality rate and overall health care costs.23 Therefore, ADT use correlates with significant and rapid decreases in BMD, which can lead to multiple adverse outcomes in patients with prostate cancer. TREATMENT OPTIONS: BISPHOSPHONATES Mechanism of Action of Bisphosphonates Bisphosphonates are nonhydrolyzable pyrophosphate analogues that have shown significant clinical activity in preventing the bone loss and high bone turnover seen in prostate cancer and other diseases. Structurally bisphosphonates are in 2 classes, including those that contain a primary nitrogen atom on the side chain (ibandronate, alendronate, pamidronate, risedronate, neridronate and zoledronic acid) and those that do not (nonnitrogen containing bisphosphonates such as clodronate and etidronate). The presence of nitrogen makes these compounds more active than nonnitrogen containing bisphosphonates. Further modification of the side chain by the addition of a nitrogen bearing heterocyclic ring, as in zoledronic acid, provides the greatest potency.24 For example, in a rat model of tumor induced hypercalcemia the ED50 of zoledronic acid was 850 times as potent as that of pamidronate and several logs stronger than that of many other bisphosphonates.25 Bisphosphonates bind to bone surfaces at active remodeling sites and they are internalized by osteoclasts, which inhibit the activity of these bone degrading cells. Various

FIG. 1. Overall survival in patients with prostate cancer with history of skeletal fracture since diagnosis or no fracture. Skeletal fractures predict worse survival in patients with prostate cancer. Asterisk indicates that curve includes fragility fracture in 19 patients and pathological fracture in 5. Adapted with permission from Oefelein et al.10

19

classes of bisphosphonates act through different mechanisms.26 Nonnitrogen containing bisphosphonates are released during bone resorption and are incorporated into nonhydrolyzable analogues of adenosine triphosphate. Nitrogen containing bisphosphonates disrupt mevalonate metabolism, affecting prenylation of the proteins involved in signaling pathways and other essential cell functions. Nitrogen containing bisphosphonates also inhibit farnesyl diphosphate synthase, which is an enzyme involved in the cholesterol biosynthesis pathway. For the 2 compound types the end result is the same, that is osteoclast apoptosis. BISPHOSPHONATES FOR THE MANAGEMENT OF ADT ASSOCIATED BONE LOSS Alendronate is the only bisphosphonate approved by the United States Food and Drug Administration for age related osteoporosis in men. To our knowledge no bisphosphonate has been approved to date for use in men receiving ADT for advanced prostate cancer. Clinical trials of oral and intravenous bisphosphonates in men receiving ADT have demonstrated that these agents can prevent bone loss, decrease the fracture risk, decrease or prevent SREs such as spinal cord compression and vertebral collapse, and limit bone pain related to metastases.24,26 In a trial of 12 patients treated for 6 to 12 months with a GnRH agonist and an androgen antagonist, treatment with the oral bisphosphonate etidronate (400 mg daily for 2 weeks every 3 months) was able to slow the decrease in BMD in the femoral neck, the trochanter and Ward’s triangle.20 Intravenous bisphosphonates have been similarly evaluated for preventing bone loss in men with prostate cancer receiving ADT and they were found to be more potent than oral forms. In a randomized study of 41 men with locally advanced, node positive or recurrent prostate cancer with no bone metastases pamidronate prevented bone loss in the spine and hip, although it failed to increase BMD significantly above baseline.6 In contrast, zoledronic acid not only prevented BMD loss, but also increased BMD over baseline.27 This trial randomized 106 men with nonmetastatic prostate cancer who were beginning ADT to receive zoledronic acid (4 mg every 3 months for 1 year) or placebo. Significant increases in BMD occurred in the lumbar spine, femoral neck, trochanter and hip with zoledronic acid compared with placebo (each p ⬍0.001, fig. 2). In addition to decreasing the bone loss associated with ADT, bisphosphonates decrease the proportion of patients sustaining an SRE in men with hormone refractory prostate cancer with bone metastases. Saad et al examined 643 men with metastatic hormone refractory prostate cancer who were randomized to 4 mg zoledronic acid or placebo every 3 weeks for 15 months.28 Fewer patients treated with zoledronic acid compared with placebo experienced 1 or more SREs (49% vs 39%, p ⫽ 0.031) and median time to onset of the first SRE was 31% longer with zoledronic acid than with placebo (420 vs 321 days, p ⫽ 0.011). Moreover, zoledronic acid compared with placebo decreased the proportion of patients experiencing pathological fractures (22.1% vs 13.1%, p ⫽ 0.015) and decreased the mean annual incidence of SREs by almost half. The results of these studies indicate that bisphosphonates can prevent the BMD loss that occurs in men with prostate cancer receiving ADT. Only zoledronic acid has

20

BONE HEALTH AND ANDROGEN DEPRIVATION THERAPY FOR PROSTATE CANCER

FIG. 2. Mean percent change from baseline BMD at lumbar spine, femoral neck, trochanter and total hip.27 Zoledronic acid increases BMD in patients with nonmetastatic and metastatic prostate cancer on ADT. Asterisk indicates zoledronic acid statistically significant different vs placebo (p ⬍0.001).

been shown to provide long-term clinical benefit by increasing BMD and decreasing the incidence of SREs in patients with metastatic prostate cancer. Additionally, zoledronic acid may provide limited pain relief from bone metastases.29 However, importantly zoledronic acid has not been shown to affect survival in patients with prostate cancer. Safety of Bisphosphonates Oral and intravenous bisphosphonates are associated with differing toxicity profiles that may factor into choice of therapy. GI absorption of oral bisphosphonates is generally poor (less than 5% of the oral dose) and this absorption can be further decreased by food and coffee. To counter this, large doses must be administered, which in many patients can result in esophagitis, gastric or esophageal ulcers and other GI toxicity. Patients should be advised to ingest oral bisphosphonates on an empty stomach to improve absorption and remain upright 30 minutes after ingestion to decrease the occurrence of GI adverse effects. Bisphosphonates administered by the intravenous route are generally well tolerated and not affected by such pharmacokinetic limitations. Approximately 20% of patients treated with intravenous bisphosphonates have flu-like symptoms, including arthralgia, myalgia, nausea, low grade fever and increased bone pain.30 These symptoms typically occur after the first dose and are generally self-limiting. Hypocalcemia has also been reported, requiring regular assessment of serum calcium, phosphate and magnesium. Patients receiving bisphosphonates should routinely receive calcium and vitamin D supplementation. Acute renal toxicity can occur following rapid intravenous administration of nitrogen based and nonnitrogen based bisphosphonates but

it is exceedingly rare if the drug is properly administered.30 Serum creatinine should be monitored in patients receiving bisphosphonates and, if increased, drug should be withheld until creatinine returns to within 10% of baseline (table 2). The use of zoledronic acid and pamidronate is not indicated in patients with severe renal impairment (creatinine clearance less than 30 ml per minute). Osteonecrosis of the jaw is a rare toxicity that was recently reported in patients receiving long-term therapy with nitrogen based bisphosphonates. The reported incidence rate of osteonecrosis of the jaw in patients receiving bisphosphonates is 0.6% to 10%.31–33 Due to inconsistencies in the literature the true incidence of this condition is not known.34 Risk factors were prior or concomitant chemotherapy, radiotherapy or steroid therapy, trauma, infection and a history of or current dental problems.34 Therefore, physicians should ensure that a thorough oral examination is performed at the start of bisphosphonate therapy with removal of all dental infections before treatment initiation. Physicians should counsel patients regarding the importance of good oral hygiene. Dental procedures and major débridement surgeries should be avoided if possible. Effective treatment of this avascular necrosis has not been determined, although conservative management with penicillin-type antibiotics and chlorhexidine rinses seems effective.34 Although to our knowledge a causal effect of bisphosphonate therapy has not yet been established, increased awareness of the risk of this adverse event would help decrease morbidity in patients receiving this therapy. Compliance Consistent long-term compliance with oral bisphosphonates is critical to ensure optimal efficacy. Poor compliance with oral bisphosphonate therapy is common, which can result in decreased activity and/or discontinuation of therapy.30 Full or partial compliance with oral clodronate was 74% in a study of patients with breast cancer with bone metastases35 and these data are supported by other results.36,37 Early discontinuation of oral bisphosphonate therapy or poor compliance (less than 80% of the prescribed dose) can have a significant negative impact, resulting in decreased BMD, higher fracture risk, longer hospitalization and increased health care costs. Conversely consistent use of oral bisphosphonates was shown to result in a lumbar spine BMD that was 3.3% higher after 3 years compared with inconsistent compliance.38 Several factors may contribute to poor compliance with oral bisphosphonates. Failure to ingest these medications according to instructions, ie not consuming food or drink for 30 minutes after drug administration, can decrease absorp-

TABLE 2. Guidelines for zoledronic acid dose adjustment based on creatinine clearance50 Creatinine Clearance (ml/min) Greater than 60 50–60 40–49 30–39 Less than 30

Recommended Estimated Dose* (mg)

Withdraw From Vial (ml)

4.0 3.5 3.3 3.0 Not recommended

5 4.4 4.1 3.8

* Based on target AUC of 0.66 mg per hour per l (creatinine clearance 75 ml/min).

BONE HEALTH AND ANDROGEN DEPRIVATION THERAPY FOR PROSTATE CANCER tion and decrease efficacy. Drug related toxicity, particularly GI, can cause early withdrawal from therapy or decreased compliance. Patient education coupled with nursing support and prompt, effective management of adverse events would help patients maintain bisphosphonate therapy and, thus, maximize clinical benefit. TREATMENT OPTIONS: SERMS AND ESTROGEN SUPPLEMENTED ADT Other than oral or intravenous bisphosphonate, other pharmacological treatment options for maintaining bone density in men receiving ADT may include the SERM raloxifene and estrogen supplemented ADT. A small, randomized trial showed that 1 year of 60 mg raloxifene daily in men receiving GnRH agonist for prostate cancer significantly increased hip BMD and tended to increase spine BMD.39 In addition, the urological community is beginning to witness a resurgence in estrogen use (1 mg oral diethylstilbestrol40 or transdermal estradiol41) to limit osteoporosis caused by long-term ADT in patients with prostate cancer. Additional studies are necessary to compare the efficacy and safety of SERMs, bisphosphonates and estrogen supplemented ADT in hypogonadal men. RECOMMENDATIONS FOR DIAGNOSING, PREVENTING AND TREATING ADT ASSOCIATED BONE LOSS Early diagnosis of bone loss and prompt initiation of preventive and pharmacological measures to delay or prevent decreased BMD are essential in men with advanced prostate cancer who are initiating ADT. Although no consensus exists on the use and frequency of BMD testing for prostate cancer, a recent literature review resulted in recommendations for screening.4 Diamond et al proposed measuring BMD in patients considered to be at high risk for osteoporosis.4 They suggested that all men at increased risk for fracture (those receiving ADT and/or with a history of fracture) should undergo BMD assessment. The frequency of followup BMD testing depends on the resulting T-score (fig. 3).4 Patients with a T-score of –1 to –2.5, ie with osteopenia or osteoporosis, should undergo followup DXA after 6 to 12 months and those with a T-score of –1 or greater should undergo repeat screening every 2 years. Those with a T-score of –2.5 or less have osteoporosis and should receive active treatment.

21

Lifestyle interventions can have a major impact on bone health and they may delay the onset and severity of ADT associated bone loss. A regular exercise program can decrease bone loss, increase bone and muscle strength, and improve mobility, thus, decreasing the fracture risk.42 This also benefits overall health and well-being, and improves quality of life. Exercise should include a combination of weight bearing aerobic exercise and strength training performed for 30 minutes a day 2 to 4 times weekly.2 Weight bearing exercises include walking, treadmill and stair climbing, and muscle strengthening exercises include weight lifting and exercise machines. Health care professionals should work with qualified personal trainers to develop a suitable exercise program for each patient based on patient needs and ability. Other lifestyle changes that promote bone health are the avoidance of excessive alcohol and caffeine, and smoking cessation. Nutritional intervention is a simple way to ensure that patients are receiving adequate levels of the minerals and vitamins needed to maintain bone formation, especially calcium and vitamin D. Dietary sources of calcium include dairy products, green leafy vegetables and nuts, while sunlight, fortified milk, liver and other foods provide vitamin D. Men with prostate cancer who are initiating ADT should ingest daily supplements to obtain sufficient calcium and vitamin D. Dietary and supplemental calcium intake should be 1,200 mg daily in divided oral doses and the vitamin D intake should be 400 to 800 IU daily.16 Newer data suggest that higher doses of vitamin D may be necessary in older individuals (60 years or older) to decrease the risk of fracture.43 Supplementation to achieve 700 to 800 IU vitamin D daily should be considered in older men with prostate cancer. In addition to implementing changes in lifestyle and nutrition, bisphosphonate therapy should be strongly considered in all men with prostate cancer treated with ADT who have osteopenia or osteoporosis (fig. 3).4,44

FUTURE STRATEGIES FOR PREVENTION AND TREATMENT In addition to bisphosphonate therapy, other approaches are being evaluated for preventing and treating osteoporosis that may have application for ADT associated bone loss. Signaling through RANKL, which has an important role in the differentiation and activation of osteoclasts, is involved in bone loss in several diseases, including osteoporosis and

FIG. 3. Clinical algorithm for assessment and treatment of ADT associated bone loss in men with prostate cancer. Adapted with permission from Diamond et al.4

22

BONE HEALTH AND ANDROGEN DEPRIVATION THERAPY FOR PROSTATE CANCER

prostate cancer.45 Inhibition of RANKL binding to RANK receptor inhibits osteoclast activity and decreases bone turnover. Therefore, therapeutic targeting of RANKL by a human monoclonal antibody, ie AMG 162 or osteoprotegerin, which is a natural soluble RANKL receptor, may retard bone loss. In a dose escalation study subcutaneous injection of AMG 162 in postmenopausal women resulted in a rapid dose dependent and sustained decrease in urinary N-telopeptide of type 1 collagen (maximum of 84%), indicating bone turnover inhibition.46 Therefore, AMG 162 could have potential for treating or preventing ADT associated bone loss in prostate cancer. A randomized trial of this agent has been initiated in patients with advanced solid tumors who have at least 1 bone lesion and are receiving bisphosphonates intravenously. Another approach that can have a major impact on decreasing or preventing ADT associated bone loss is improved education of patients and health care professionals. Patients should be informed about the potential adverse effects of ADT, and the positive role of lifestyle changes and possibly bisphosphonate therapy for preventing some of these complications. If bisphosphonates are used, patients should be aware of the more common side effects. Early recognition and reporting of toxicity can lead to prompt intervention by caregivers, thus, improving compliance and outcomes. Physicians and nurses can counsel patients on specific dietary modifications, vitamins and appropriate exercise regimens that help maintain bone health. Concomitant with patient directed interventions urologists should also initiate early screening and preventive measures that can delay the onset or decrease the severity of bone loss during ADT. Many patients apparently do not receive adequate physician intervention to prevent or treat osteoporosis. For example, in a study of 184 patients on ADT only 15% reported receiving any type of prevention information or therapy to maintain bone health.47 In most cases this was provided by primary care physicians rather than by urologists or medical oncologists. Therefore, urologists and other specialists have a unique opportunity to be more proactive in the treatment of their patients who are likely to have ADT related bone loss. This includes early identification, regular screening and initiation of appropriate interventions, such as education and bisphosphonate therapy, to prevent decreases in bone density and improve outcomes.

benefit by decreasing bone loss in patients with prostate cancer on ADT. These agents differ in their efficacy and toxicity profiles. Although many bisphosphonates slow or prevent BMD loss, zoledronic acid can also increase BMD and decrease SREs and fractures in men with metastatic disease. Differences in absorption, adverse effect profiles and discontinuation rates may also affect the selection of a given agent because many of the oral formulations can result in significant GI toxicity. Continued clinical trials of bisphosphonates would optimize the use of these agents for ADT related bone loss in men with hormone sensitive nonmetastatic prostate cancer as well as in the metastatic setting. These approaches should provide urologists and their patients with effective therapeutic options that serve to maintain and improve bone health during prostate cancer therapy.

Abbreviations and Acronyms ADT BMD DXA GI GnRH RANKL

androgen deprivation therapy bone mineral density dual x-ray absorptiometry gastrointestinal gonadotropin-releasing hormone receptor activator of nuclear factor ␬ B ligand SERM ⫽ selective estrogen receptor modifier SRE ⫽ skeletal related event

REFERENCES 1. 2.

3.

4.

CONCLUSIONS Recent progress in early screening and treatment in patients with prostate cancer has led to the identification of a greater number of men who are candidates for therapy and are surviving longer. This has resulted in an expanding number of patients being treated with or who are eligible for ADT. Additionally, because of the natural history of this disease, many patients have significant bone loss before initiating treatment. The loss of bone density seen with ADT with the resulting increased fracture risk, decreased quality of life and perhaps increased mortality, require urologists to be aware of the scope of this growing problem, and its diagnosis and treatment. Regular screening of patients at risk for bone loss is needed for early detection and treatment. Implementation of lifestyle changes would help prevent bone density loss in all patients with prostate cancer receiving ADT. Bisphosphonates have been shown to have clinical

⫽ ⫽ ⫽ ⫽ ⫽ ⫽

5.

6.

7.

8.

Sharifi N, Gulley JL and Dahut WL: Androgen deprivation therapy for prostate cancer. JAMA 2005; 294: 238. Higano CS: 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 2004; 31: 331. Berruti A, Dogliotti L, Terrone C, Cerutti S, Isaia G, Tarabuzzi R et al: Changes in bone mineral density, lean body mass and fat content as measured by dual energy x-ray absorptiometry in patients with prostate cancer without apparent bone metastases given androgen deprivation therapy. J Urol 2002; 167: 2361. Diamond TH, Higano CS, Smith MR, Guise TA and Singer FR: Osteoporosis in men with prostate carcinoma receiving androgen-deprivation therapy; recommendations for diagnosis and therapies. Cancer 2004; 100: 892. Smith MR, Lee WC, Krupsi TL, Brandman J, Wang Q, Botteman M et al: Association between androgen deprivation therapy and fracture risk: a population-based cohort study in men with non-metastatic prostate cancer. Proc Am Soc Clin Oncol 2004; 23: 382. Smith MR, McGovern FJ, Zietman AL, Fallon MA, Hayden DL, Schoenfeld DA et al: Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 2001; 345: 948. Smith MR, McGovern FJ, Fallon MA, Schoenfeld D, Kantoff PW and Finkelstein JS: Low bone mineral density in hormone-naïve men with prostate carcinoma. Cancer 2001; 91: 2238. Hussain SA, Weston R, Stephenson RN, George E and Parr NJ: Immediate dual energy X-ray absorptiometry reveals a high incidence of osteoporosis in patients with advanced prostate cancer before hormonal manipulation. BJU Int 2003; 92: 690.

BONE HEALTH AND ANDROGEN DEPRIVATION THERAPY FOR PROSTATE CANCER 9.

10.

11.

12.

13.

14.

15.

16.

17. 18.

19.

20.

21. 22.

23.

24.

25.

26.

27.

28.

Shahinian VB, Kuo YF, Freeman JL and Goodwin JS: Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005; 352: 154. Oefelein MG, Ricchiuti V, Conrad W and Resnick MI: Skeletal fractures negatively correlate with overall survival in men with prostate cancer. J Urol 2002; 168: 1005. Leder BZ, LeBlanc KM, Schoenfeld DA, Eastell R and Finkelstein JS: Differential effects of androgens and estrogens on bone turnover in normal men. J Clin Endocrinol Metab 2003; 88: 204. Benito M, Gomberg B, Wehrli FW, Weening RH, Zemel B, Wright AC et al: Deterioration of trabecular architecture in hypogonadal men. J Clin Endocrinol Metab 2003; 88: 1497. Mittan D, Lee S, Miller E, Perez RC, Basler JW and Bruder JM: Bone loss following hypogonadism in men with prostate cancer treated with GnRH analogs. J Clin Endocrinol Metab 2002; 87: 3656. Maillefert JF, Sibilia J, Michel F, Saussine C, Javier RM and Tavernier C: Bone mineral density in men treated with synthetic gonadotropin-releasing hormone agonists for prostatic carcinoma. J Urol 1999; 161: 1219. Eriksson S, Eriksson A, Stege R and Carlstrom K: Bone mineral density in patients with prostatic cancer treated with orchidectomy and with estrogens. Calcif Tissue Int 1995; 57: 97. Physician’s Guide to Prevention and Treatment of Osteoporosis. Washington, D. C.: National Osteoporosis Foundation 2003. Higano CS: Management of bone loss in men with prostate cancer. J Urol, part 2 2003; 170: S59. Lipton A, Costa L, Ali S and Demers L: Use of markers of bone turnover for monitoring bone metastases and the response to therapy. Semin Oncol 2001; 28: 54. Miller PD, Baran DT, Bilezikian JP, Greenspan SL, Lindsay R, Riggs BL et al: Practical clinical application of biochemical markers of bone turnover: consensus of an expert panel. J Clin Densitom 1999; 2: 323. Diamond T, Campbell J, Bryant C and Lynch W: The effect of combined androgen blockade on bone turnover and bone mineral densities in men treated for prostate carcinoma: longitudinal evaluation and response to intermittent cyclic etidronate therapy. Cancer 1998; 83: 1561. Faulkner KG: Bone matters: are density increases necessary to reduce fracture risk? J Bone Miner Res 2000; 15: 183. López AM, Pena MA, Hernández R, Val F, Martin B and Riancho JA: Fracture risk in patients with prostate cancer on androgen deprivation therapy. Osteoporos Int 2005; 16: 707. Kado DM, Browner WS, Palermo L, Nevitt MC, Genant HK and Cummings SR: Vertebral fractures and mortality in older women: a prospective study. Study of Osteoporotic Fractures Research Group. Arch Intern Med 1999; 159: 1215. Dawson NA: Therapeutic benefit of bisphosphonates in the management of prostate cancer-related bone disease. Expert Opin Pharmacother 2003; 4: 705. Green JR, Müller K and Jaeggi KA: Preclinical pharmacology of CGP 42=446, a new, potent, heterocyclic bisphosphonate compound. J Bone Miner Res 1994; 9: 745. Brown JE, Neville-Webbe H and Coleman RE: The role of bisphosphonates in breast and prostate cancers. Endocr Relat Cancer 2004; 11: 207. Smith MR, Eastham J, Gleason DM, Shasha D, Tchekmedyian S and Zinner N: Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 2003; 169: 2008. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L et al: Long-term efficacy of zoledronic acid for

29. 30.

31. 32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

23

the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004; 96: 879. Saad F and Schulman CC: Role of bisphosphonates in prostate cancer. Eur Urol 2004; 45: 26. Conte P and Guarneri V: Safety of intravenous and oral bisphosphonates and compliance with dosing regimens. Oncologist, suppl, 2004; 9: 28. Durie BGM, Katz M and Crowley J: Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005; 353: 99. Van Poznak CH, Estilo CL, Sauter NP, Hudis CA, Williams T, Tunick S et al: Osteonecrosis of the jaw in patients with metastatic breast cancer. Presented at Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, December 8 –11, 2004. Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G et al: Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 2005; 23: 8580. Ruggiero SL, Gralow J, Marx RE, Hoff A, Schubert MM, Huryn JM et al: Practical guidelines for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in patients with cancer. J Oncol Pract 2006; 2: 7. Paterson AHG, Powles TJ, Kanis JA, McCloskey E, Hanson J and Ashley S: Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 1993; 11: 59. Robertson AG, Reed NS and Ralston SH: Effect of oral clodronate on metastatic bone pain: a double-blind, placebo-controlled study. J Clin Oncol 1995; 13: 2427. Kristensen B, Ejlertsen B, Groenvold M, Hein S, Loft H and Mouridsen HT: Oral clodronate in breast cancer patients with bone metastases: a randomized study. J Intern Med 1999; 246: 67. Sebaldt RJ, Shane LG, Pham BZ, Cook RJ, Thabane L, Petrie A et al: Impact of non-compliance and non-persistence with daily bisphosphonates on longer-term effectiveness outcomes in patients with osteoporosis. J Bone Miner Res, suppl 2004; 19: S445. Smith MR, Fallon MA, Lee H and Finkelstein JS: Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab 2004; 89: 3841. Scherr DS and Pitts WR Jr: The nonsteroidal effects of diethylstilbestrol: the rationale for androgen deprivation therapy without estrogen deprivation in the treatment of prostate cancer. J Urol 2003; 170: 1703. Ockrim JL, Lalani E, Kakkar AK and Abel PD: Transdermal estradiol therapy for prostate cancer reduces thrombophilic activation and protects against thromboembolism. J Urol 2005; 174: 527. Hertel KL and Trahiotis MG: Exercise in the prevention and treatment of osteoporosis: the role of physical therapy and nursing. Nurs Clin North Am 2001; 36: 441. Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T and Dawson-Hughes B: Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA 2005; 293: 2257. Clinical Practice Guidelines in Oncology, Prostate Cancer Version 2.2005. National Comprehensive Cancer Network 2005. Hofbauer LC and Schoppet M: Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA 2004; 292: 490. Bekker PJ, Holloway DL, Rasmussen AS, Murphy R, Martin SW, Leese PT et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res 2004; 19: 1059.

24 47.

BONE HEALTH AND ANDROGEN DEPRIVATION THERAPY FOR PROSTATE CANCER

Tanvetyanon T: Physician practices of bone density testing and drug prescribing to prevent or treat osteoporosis during androgen deprivation therapy. Cancer 2005; 103: 237. 48. Daniell HW, Dunn SR, Ferguson DW, Lomas G, Niazi Z and Stratte PT: Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol 2000; 163: 181.

49.

Higano CS, Stephens C, Nelson P, Fearne V, Davies C, Russell K et al: Prospective serial measurements of bone mineral density (BMD) in prostate cancer patients without bone metastases treated with intermittent androgen suppression (IAS). Proc Am Soc Clin Oncol 1999; 18: 314. 50. Zometa® (Zoledronic Acid) Injection Prescribing Information. East Hanover, New Jersey: Novartis Pharmaceutical 2005.