Zoledronic Acid Significantly Reduces Pathologic Fractures in Patients with Advanced-Stage Prostate Cancer Metastatic to Bone

Comprehensive Review

Zoledronic Acid Significantly Reduces Pathologic Fractures in Patients with Advanced-Stage Prostate Cancer Metastatic to Bone Fred Saad

Abstract

Centre Hospitalier University of Montreal Montreal, Quebec, Canada

The skeletal complications of metastatic bone disease secondary to advanced prostate cancer result in significant morbidity. In particular, pathologic fractures often require clinical intervention and are independent predictors of mortality in men with advanced prostate cancer. Before the introduction of zoledronic acid, bisphosphonates had been shown to provide pain palliation in patients with prostate cancer and bone metastases but were not efficacious in preventing skeletal complications. Zoledronic acid is the first bisphosphonate to show efficacy in reducing skeletal complications associated with the predominantly osteoblastic bone lesions characteristic of prostate cancer. In a large phase III randomized trial, zoledronic acid 4 mg every 3 weeks for 15 months significantly reduced the percentage of men who experienced a skeletal complication and reduced the incidence of pathologic fractures. Additionally, zoledronic acid 4 mg significantly decreased the annual incidence of skeletal complications, including fractures, and provided better control of bone pain compared with placebo. Adverse events with zoledronic acid were primarily limited to the flu-like, acute-phase symptoms previously reported with intravenous bisphosphonates, namely fever, myalgia, nausea, and anemia. These adverse events were mild to moderate and easily managed with supportive care. Zoledronic acid is the first and only bisphosphonate shown to reduce skeletal morbidity, including fractures, in patients with advanced prostate cancer and bone metastases.

Clinical Prostate Cancer, Vol. 1, No. 3, 145-152, 2002 Key words: Bisphosphonate, Bone metastases, Prostatic carcinoma, Skeletal complications Submitted: Nov 1, 2002; Revised: Nov 27, 2002; Accepted: Nov 29, 2002 Address for correspondence: Fred Saad, MD Department of Surgery/Urology Centre Hospitalier de l’Université de Montréal Hôpital Notre-Dame 1560 Rue Sherbrooke East Montréal, Quebec, Canada H2L 4M1 Fax: 514-412-7620 e-mail: [email protected]

Introduction Prostate cancer is one of the most common cancers in North America and will affect an estimated 1 in 5 American men.1 Worldwide, prostate cancer is the fourth most common cancer in men and comprises 6% of all cancer deaths among men.2 Bone is a frequent site of metastasis in advanced disease, and it has been estimated that 85%-100% of men who die of prostate cancer have evidence of bone metastases at autopsy.3 Bone metastases can lead to serious skeletal complications, including severe bone pain, pathologic fracture, and spinal cord compression. These complications have important clinical implications because they frequently require surgery to bone to correct or stabilize a fracture or radiation therapy to palliate bone pain.4 These skeletal complications occur frequently in men with prostate cancer. One recent report showed that 30% of men with advanced prostate cancer experience skeletal complications and that the median time to first complication is 9.5

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Table 1

The Efficacy of Bisphosphonates in Randomized, Placebo-Controlled Trials in Patients with Bone Metastases Secondary to Prostate Cancer Number of Patients

Drug

Dose

Efficacy Results

Smith27

57

Etidronate

7.5 mg/kg I.V., days 1-3, then 400 mg/day p.o.

No significant benefits

Elomaa et al28

75

Clodronate

3200 mg/day (first month), then 1600 mg/day p.o.

↓ Pain and analgesic use (first month only) ↓ Serum calcium levels

Kylmala et al29

57

Clodronate

300 mg/day I.V., days 1-5, then 1600 mg/day p.o.

↓ Pain by 10% (nonsignificant)

Ernst et al30

208

Clodronate

1500 mg I.V. every 3 weeks

↓ Pain (nonsignificant)

Study

↓ Proportion of patients with ≥ 1 SRE (P = 0.021) Saad et al31

643

Zoledronic acid

4 mg I.V. every 3 weeks

Time to first SRE (P = 0.01) ↓ Rate of skeletal morbidity (P = 0.006)

Strang et al32

55

Clodronate

300 mg/day I.V., days 1-3 then 3200 mg/day p.o.

No significant benefits

Lipton et al33

236

Pamidronate

90 mg I.V. every 3 weeks

No significant benefits in pain or proportion of patients with SREs

Abbreviation: SRE = skeletal-related event

months.5,6 The osteoblastic bone lesions characteristic of prostate cancer are associated with elevated bone resorption, as evidenced by elevated biochemical markers of resorption.7 In addition, the increased osteoblastic activity typical of prostate cancer creates strong calcium demand (bone hunger syndrome), which in turn increases parathyroid hormone levels and osteoclast activity, thereby resulting in generalized osteopenia. Additionally, the ablation of androgens in patients receiving long-term hormonal therapy can cause osteoporosis and can further compromise bone integrity, leaving men with prostate cancer at high risk for fractures.8-11 These data provide a strong rationale for bisphosphonate therapy in patients with prostate cancer. Pathologic fractures, in particular, result in significant morbidity and mortality. For example, men who experience hip fractures have an increased risk of mortality (hazard ratio [HR] = 3.2).12 In a study conducted at the Mayo Clinic among men who experienced a hip fracture, only 41% of men recovered full function after the fracture and 16% died within 30 days.13 Of those who survived, 79% still required assisted living after 1 year (either in nursing homes or with in-home care). Other studies have suggested that skeletal fractures are an independent and negative predictor of overall survival in men with prostate cancer.14,15 Thus, the prevention of skeletal fractures remains an important clinical endpoint in the treatment of bone metastases and prostate cancer. Palliative treatments for bone metastases and the resulting skeletal complications include analgesics, radiotherapy, boneseeking radionuclides, and bisphosphonates.16 However, because bone pain tends to escalate with progression of disease,

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analgesic therapy eventually fails to completely control bone pain.17 Radiotherapy or bone-seeking radionuclides are effective in palliation of bone pain but can also cause bone marrow suppression.17,18 Intravenous (I.V.) bisphosphonates are the standard of care for patients with multiple myeloma and bone metastases from breast cancer and have been shown to palliate bone pain and to reduce skeletal complications in that patient population.19-24 However, their use in patients with prostate cancer has been less extensively investigated.

The Efficacy of Bisphosphonate Therapy in Bone Metastases and Prostate Cancer Bisphosphonates are analogues of sodium pyruvate that preferentially bind to bone surfaces undergoing active remodeling. Bisphosphonates have been shown in vitro to be potent inhibitors of osteoclast activity, to inhibit osteoblast proliferation, and to enhance differentiation.25,26 Bisphosphonates have been successfully used for the treatment of osteolytic bone metastases in patients with breast cancer and multiple myeloma. Oral clodronate (1600 mg/day) can prevent bone metastases and improve survival in women with breast cancer.20 Monthly administration of 90 mg pamidronate I.V. has been shown to be safe and effective in reducing skeletal complications with long-term treatment in patients with bone metastases and breast cancer or multiple myeloma.21,22 Similarly, the new-generation bisphosphonate zoledronic acid (4 mg via 15-minute I.V. infusion) is safe and effective in reducing skeletal complications in patients with multiple myeloma and bone metastases secondary to breast

Fred Saad

Figure 1 A

50% 40%

Zoledronic Acid (4 mg) Significantly Decreased Skeletal Complications Compared with Placebo Zoledronic acid 4 mg Placebo P = 0.021

44%

Clodronate

Patients (%)

33% 30% 20 20% 10%

(n = 214)

(n = 208)

0%

All Skeletal Complications

B 50%

Patients (%)

40% 30%

Zoledronic acid 4 mg Placebo P = 0.029

37%

27% 20

20% 10%

(n = 214)

significantly different from placebo in the palliation of bone pain in patients with advance prostate cancer.27 In general, etidronate cannot be considered an effective treatment for bone metastases and prostate cancer.

(n = 208)

0%

All Skeletal Complications Excluding Asymptomatic Fractures Figure 1 shows all skeletal complications (A), and all skeletal complications excluding asymptomatic fractures (B).

cancer.24 However, the outcomes of clinical trials of bisphosphonates for the treatment of prostate cancer have been mixed. Although the incidence of fractures is an objective clinical endpoint, few of the earlier studies of bisphosphonates in prostate cancer focused on such objective clinical endpoints. Instead, biochemical measures of bone resorption or the softer endpoints of pain perception and analgesic use were often used. Nonetheless, a review of the efficacy of first- and second-generation bisphosphonates in the palliation of bone pain provides a general assessment of the effectiveness of these bisphosphonates in patients with prostate cancer. The results of trials conducted with bisphosphonates in patients with prostate cancer and bone metastases are summarized in Table 1.27-33

Etidronate Etidronate is an early-generation, non–nitrogen-containing bisphosphonate that was shown to be clinically useful in the treatment of hypercalcemia of malignancy.34 Small, uncontrolled studies such as that conducted by Carey and Lippert35 showed etidronate to be effective in pain palliation in patients with prostate cancer, but larger, double-blind studies did not confirm these results. Etidronate administered orally (400 mg/day) or I.V. (7.5 mg/kg body weight) for 1 month was not

Clodronate, also a non–nitrogen-containing bisphosphonate, has been investigated extensively in the treatment of metastatic bone disease. In osteolytic metastases, oral clodronate (1600 mg/day) has been shown, in a double-blind, placebo-controlled trial, to significantly reduce skeletal complications in patients with bone metastases secondary to breast cancer.19 Additionally, oral clodronate (1600 mg/day) for 2 years can prevent the development of bone metastases in patients with metastatic breast cancer.20 In contrast to studies in breast cancer, studies of clodronate in bone metastases associated with prostate cancer demonstrated lower response rates in the prevention of skeletal morbidity and pain associated with bone metastases. For example, in an openlabel, uncontrolled study of 85 patients with advanced prostate cancer, I.V. clodronate (300 mg/day) followed by oral maintenance (1600 mg/day) showed significant reduction from baseline pain in 75% of patients.36 However, 2 placebo-controlled studies of clodronate in patients with advanced prostate cancer failed to show significant improvement in bone pain compared with placebo.28,29 Similarly, a placebo-controlled study of 208 men with advanced prostate cancer receiving mitoxantrone and prednisone with or without clodronate 1500 mg I.V. every 3 weeks for a median duration of 21 weeks also failed to show significant reductions in either pain or skeletal complications in patients receiving clodronate.30 Overall, like etidronate, clodronate has not been shown to be effective in significantly reducing either pain or skeletal complications in patients with prostate cancer and bone metastases.

Pamidronate Pamidronate is a nitrogen-containing bisphosphonate indicated for use in patients with multiple myeloma and bone metastases secondary to breast cancer.23,37 Pamidronate is highly effective in these patients for reducing pain and for preventing skeletal complications and is safe and efficacious with longterm treatment.21,22 However, similar to clodronate, pamidronate has failed to demonstrate objective clinical benefit for the prevention of skeletal complications of bone metastases in randomized, clinical trials in patients with prostate cancer. Two separate studies demonstrated that pamidronate (60 or 90 mg I.V.) can prevent the loss of bone mineral density associated with androgen deprivation therapy in men with prostate cancer.38,39 Nevertheless, in a recent double-blind, placebo-controlled study of pamidronate 90 mg I.V. administered every 3 weeks for 27 weeks in 350 men with advanced prostate cancer, there was no reduction of skeletal complications compared with placebo.40 Furthermore, there were no significant between-group differences in change from baseline pain score or analgesic use for pamidronate versus placebo. Therefore, although pamidronate

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Zoledronic Acid Decreases Fractures in Prostate Cancer is a potent bisphosphonate with proven efficacy in patients with breast cancer and bone metastases, it has not demonstrated efficacy in patients with prostate cancer.

Figure 2

Treatment with Zoledronic Acid 4 mg Significantly Reduced Pathologic Fractures Compared with Placebo

30% P = 0.015

Zoledronic Acid

22%

Zoledronic acid 4 mg (n = 214) Placebo (n = 208)

Patients Without Event (%)

Patients (%)

Zoledronic acid is a new-generation 20% bisphosphonate with 2 nitrogen atoms 16% that was developed based on improved 13% potency compared with other bisphos10% 10% phonates in preclinical studies.41 In addi8% tion, clinical trials have demonstrated 4% that zoledronic acid is more effective than pamidronate for the treatment of hyper0% All Fractures Vertebral Fractures Nonvertebral Fractures calcemia of malignancy in patients with 42 breast cancer and multiple myeloma. Furthermore, in a large phase III trial in with placebo (median not reached for zoledronic acid vs. 321 days patients with multiple myeloma or bone metastases secondary for placebo; P = 0.011). to breast cancer, zoledronic acid (4 mg) was at least as effective Although the study was not powered to show statistically sigas pamidronate in reducing skeletal complications and delaying 24 nificant reductions in individual skeletal complications, the efonset in patients with breast cancer. Therefore, zoledronic acid fect of zoledronic acid on the incidence of pathologic fractures was investigated in men with prostate cancer and bone metaswas also significant. Only 13% of men treated with zoledronic tases with the hope that its increased potency would translate acid 4 mg experienced pathologic fractures compared with 22% into improved efficacy where other bisphosphonates have failed. of patients in the placebo group (P = 0.015; Figure 2). CorreSimilar to the results of one study of pamidronate, zoledronic sponding reductions were noted for both vertebral fractures and acid has been shown to prevent bone loss in men undergoing an43 nonvertebral fractures. Moreover, the time to first pathologic drogen deprivation therapy for prostate cancer. Treatment with fracture was significantly delayed by treatment with zoledronic zoledronic acid 4 mg every 3 months for 1 year led to significant acid. The median time to first pathologic fracture was not increases in lumbar, hip, and femoral neck bone mineral density reached in the zoledronic acid 4 mg group, compared with 321 compared with a loss of bone mineral density in men treated days for the placebo group (P = 0.011; Figure 3). However, as with placebo. However, this study was not large enough to the study was conducted for 15 months, this delay is at least 4 demonstrate an effect of zoledronic acid on the incidence of fracmonths in duration. tures and other skeletal complications. The annual incidence of skeletal complications (skeletal morZoledronic acid was also compared with placebo in a large bidity rate) is the number of skeletal complications divided by prospective, randomized, double-blind trial of 643 men with advanced prostate cancer and bone metastases.31 Compared with placebo, zoledronFigure 3 Zoledronic Acid 4 mg Significantly Delayed the Onset of ic acid 4 mg (administered every 3 weeks Pathologic Fractures via 15-minute infusion) decreased the per100% centage of men who developed a skeletal complication by 25% (33% for zoledron90% ic acid 4 mg vs. 44% for placebo, P = 80% 0.021; Figure 1A). Skeletal complications 70% were defined as pathologic fracture, spinal 60% cord compression, radiation to bone, sur50% gery to bone, or change of antineoplastic 40% therapy to palliate bone pain. This reduc30% tion in skeletal complications was clinicalMedian Time (Days) 20% ly important, as the difference remained Zoledronic acid 4 mg NR P = 0.011 statistically significant when asympto10% Placebo 321 matic fractures were excluded from the 0 analysis (27% for zoledronic acid 4 mg vs. 60 120 180 240 300 360 420 480 37% for placebo, P = 0.029; Figure 1B). Time After Start of Study Drug (Days) Additionally, treatment with 4 mg zoledronic acid significantly increased the time Shown are Kaplan-Meier estimates of time to first pathologic fracture for zoledronic acid 4 mg and placebo. to first skeletal complication compared Abbreviation: NR = not reached

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Fred Saad tal complication; an HR of < 1 indicates a decreased risk. The HR between 4 mg zoledronic acid and placebo was 2.5 0.64 (Figure 5). This represents a 36% decreased risk of developing a skeletal Zoledronic acid 4 mg (n = 214) Placebo (n = 208) 2.0 P = 0.006 complication for patients treated with zoledronic acid 4 mg compared with 1.49 1.5 placebo (P = 0.004). Another symptomatic hallmark of 1.0 0.80 bone metastases is the severe and inP = 0.009 P = 0.071 creasing bone pain reported by patients P = 0.048 0.45 0.5 0.31 with progression of disease. Whereas 0.21 0.17 0.16 0.04 bone pain, as assessed by Brief Pain In0 ventory pain scores, increased throughAll Skeletal All Pathologic Vertebral Nonvertebral Complications Fractures Fractures Fractures out the study in both treatment groups, men treated with zoledronic acid 4 mg Abbreviation: SRE = skeletal-related event reported less increase in pain scores compared with placebo, and these differences were significant at time on study in years. The mean annual incidence of skeletal months 3 and 9 (P < 0.05; Figure 6).31 Therefore, zoledronic complications for men treated with 4 mg zoledronic acid was acid has demonstrated immediate and durable effects on bone 0.80 event/year (95% CI, 0.57%-1.03%) compared with 1.49 pain. events/year (95% CI, 1.03%-1.94%) in the placebo group As noted, the reduction in skeletal complications remained (P = 0.006; Figure 4). A corresponding and significant reducsignificant when asymptomatic fractures were excluded from the tion in the annual incidence of fractures was also observed. The analysis. Asymptomatic fractures (detectable only on radiannual incidence of fractures for men treated with zoledronic ographs) do not typically require clinical intervention. Howevacid 4 mg was 0.21 fractures/year versus 0.45 fractures/year in er, in this study, men treated with zoledronic acid 4 mg demonthe placebo group (P = 0.009). The incidence of vertebral fracstrated a 45% relative reduction in nonvertebral fractures comtures, which is associated with risk of spinal cord compression pared with placebo. Nonvertebral fractures are often acutely and neurologic damage, was also significantly reduced from symptomatic and require clinical intervention such as surgery. 0.16 vertebral fractures/year in the placebo group to 0.04 verteTherefore, the marked reduction in symptomatic fractures with bral fractures/year in the zoledronic acid 4 mg group zoledronic acid is clinically relevant. (P = 0.048). Furthermore, the reductions in the incidence of pathologic Finally, the Andersen-Gill multiple-event analysis incorporates fracture and pain accomplished with zoledronic acid treatment both the rate and timing of skeletal complications to provide a represent significant clinical benefits that may have quality-ofsensitive measure of skeletal morbidity. The analysis provides a life implications. Pathologic fractures are often devastating to a HR between treatment groups for the risk of developing a skelepatient. Vertebral fractures can cause loss of height, kyphoscoliosis, and neuFigure 5 Zoledronic Acid 4 mg Significantly Decreased Risk of Skeletal ral damage, whereas rib fractures may Complication Compared with Placebo create restriction of the lungs.4 The majority of pathologic fractures do not heal properly and require surgical intervention resulting in lengthy hospital Multiplestays and extensive rehabilitation.44,45 Event Furthermore, surgical intervention itAnalysis P = 0.004 self can cause further complications in Hazard ratio = 0.64 almost one fourth of cases and overall fatality rates as high as 8% have recently been reported.45 Lastly, only 50% of nonambulatory patients recover walking ability after surgical treatment of 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 the fracture.46 Thus, preventing fracHazard Ratio (Zoledronic Acid 4 mg Versus Placebo) tures or delaying their onset by > 100 days with zoledronic acid is an imporIn favor of zoledronic acid In favor of placebo tant advance in the treatment of metastatic bone disease in men with This figure shows the multiple-event analysis of the risk of developing a skeletal compliation between patients treated with zoledronic acid 4 mg and placebo. prostate cancer.

Annual Incidence of Skeletal Complications Was Reduced in Men with Prostate Cancer Treated with Zoledronic Acid 4 mg Compared with Placebo

Mean SREs/Year

Figure 4

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Zoledronic Acid Decreases Fractures in Prostate Cancer

Least Square Mean Change from Baseline in Pain Score

This trial included a second Figure 6 Least Squares Mean Change from Baseline of Brief Pain Inventory Scores for zoledronic acid treatment arm Patients Treated with Zoledronic Acid 4 mg or Placebo for 15 Months (8 mg). This dose of zoledronic 1.2 acid was associated with increases in serum creatinine in some paZoledronic acid 4 mg 1.0 Placebo tients. The protocol was consequently amended to reduce the 0.8 * dose of zoledronic acid for that treatment arm to 4 mg (the 8/40.6 mg group). At that time, the protocol was amended to exclude pa* 0.4 tients in the 8/4-mg group from * efficacy analyses but include 0.2 them in safety analyses. Efficacy results for the 8/4-mg group were * 0 presented in the original publication for the sake of completeness, -0.2 but the 8-mg dose is not recommended for clinical use. Al-0.4 though the efficacy results for the 3 6 9 12 15 Time (Months) 8/4-mg group did not achieve statistical significance compared *P < 0.05 for the between-group comparison at that time point with placebo, a combined analysis of the 4-mg and 8/4-mg zoledronic acid 4 mg and zoledronic acid 8/4 mg, with the exgroups did remain statistically significant when compared with ception of a higher incidence of bone pain, nausea, vomiting, placebo. The results from the 8/4-mg group are likely secondary and constipation in the 8/4-mg group. The incidence of serious to a combination of factors, including the heterogeneity of the adverse events was similar between both zoledronic acid groups dosing and the higher dropout rate that occurred in this treatand placebo. Moreover, in this study, zoledronic acid 4 mg (via ment arm. 15-minute infusion) demonstrated a renal safety profile compaAdditionally, the suppression of bone metabolism exerted by rable with placebo. In consultation with the Renal Advisory zoledronic acid may have been maximized with the 4-mg dose, Board, the criterion for renal dysfunction was defined as inas evidenced by the similar changes in biochemical markers of creased serum creatinine. When zoledronic acid 4 mg was inbone resorption and formation in the 2 treatment arms. Urinary fused in 100 mL over 15 minutes, the HR for experiencing an measures of N-telopeptide:creatinine decreased approximately increase in serum creatinine was 1.07 between zoledronic acid 4 70% from baseline in both the 4-mg group and the 8/4-mg mg and placebo (95% CI, 0.46%-2.47%; P = 0.882), indicatgroup within one month of treatment (P = 0.001 vs. placebo for ing a comparable risk. The renal HR for the 8/4-mg group was both groups) whereas the placebo group demonstrated a 6% in1.76 (95% CI, 0.79%-3.93%); while this result was not signifcrease from baseline at 1 month. These differences were mainicantly different compared with placebo (P = 0.165), the 8-mg tained consistently throughout the trial. Furthermore, the dose is, nonetheless, not recommended for clinical use. serum marker of bone formation, bone alkaline phosphatase, reThis trial of zoledronic acid enrolled patients with advanced mained consistently at or below baseline in the zoledronic acid prostate cancer who had already failed at least 1 round of hortreatment groups throughout the study period but steadily inmonal therapy. Patients who have failed hormonal therapy typcreased in the placebo group from 6% above baseline at month ically experience more skeletal-related events than patients with 1 to 33% above baseline at month 15 (P = 0.001 for zoledronless advanced disease. Therefore, it was expected that a treatic acid 4 mg and P = 0.003 for zoledronic acid 8/4 mg, comment effect could be detected in this patient population in a pared with placebo). shorter time frame than in patients who are responding to horThe treatment benefits of zoledronic acid 4 mg were accommonal therapy. However, > 30% of patients in this study had alpanied by a minimal increase in adverse events compared with ready experienced at least 1 skeletal complication before study the placebo group. Zoledronic acid exhibited a safety profile entry, indicating that bone metastases had already caused consimilar to that of pamidronate and other I.V. bisphosphonates. siderable morbidity in these patients before study enrollment. Specifically, 5%-10% increases in the incidence of flu-like, Based on the inclusion criteria defined in this pivotal phase III acute-phase symptoms (fever, fatigue, myalgia, anemia, and trial, the US Food and Drug Administration approved zolelower-limb edema) were reported for zoledronic acid 4 mg, dronic acid for patients with prostate cancer who have procompared with placebo. These symptoms were transient, mild gressed after treatment with at least 1 hormonal therapy. In conto moderate in severity, and were easily managed with supporttrast, the recommendation of the European Committee for Proive care. The incidence of adverse events was similar between

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Fred Saad prietary Medicinal Products included all prostate cancer patients with bone metastases. Because zoledronic acid has the added benefit of preventing both fractures and declines in bone mineral density,43 initiation of zoledronic acid therapy at the first sign of bone metastases in patients with prostate cancer, regardless of prior hormonal therapy status, may provide significant clinical benefit and is preferred

Conclusion Zoledronic acid is the first bisphosphonate to demonstrate an objective clinical benefit in patients with advanced prostate cancer, leading to a significant reduction in skeletal complications, including fractures. Furthermore, men treated with zoledronic acid 4 mg experienced more time without fractures and other complications and a decreased annual incidence of skeletal complications compared with men treated with placebo. Additionally, treatment with zoledronic acid 4 mg provided better control than placebo of the severe pain that is characteristic of prostate cancer and bone metastases. After 15 months of treatment, zoledronic acid was safe and well tolerated with long-term use. Zoledronic acid exhibits antiosteoporotic effects that prevent the loss of bone mineral density in men receiving androgen-deprivation therapy and has been demonstrated to be efficacious in this advanced-stage patient population. Therefore, intervention with zoledronic acid at the first indication of bone metastases, especially in the hormone-refractory setting, might be expected to exhibit greater clinical benefits in preventing the development of skeletal complications such as fractures and, therefore, reduce the often severe morbidity that is associated with prostate cancer and bone metastases.

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