Continuing benefit of zoledronic acid in preventing skeletal complications in patients with bone metastases.

PURPOSE: We previously reported the efficacy of zoledronic acid 4 mg versus placebo (every 3 weeks for 24 months) for the prevention of skeletal-related events (SREs) in men with advanced prostate cancer and bone metastases. We conducted several retrospective exploratory analyses to determine whether zoledronic acid has continuing efficacy during long-term treatment. PATIENTS AND METHODS: This report included analysis of the occurrence of SREs during the extension phase only (months 16-24), analysis of skeletal complications excluding the first SRE at 15 months (core phase), and stratified analysis of patients by history of SREs before study entry. RESULTS: Patients (N=422) were randomized to receive zoledronic acid 4 mg or placebo. For the 132 patients who entered the extension phase, zoledronic acid significantly delayed the onset of first SRE (P=.009) and decreased the risk of developing an SRE by 53% compared with placebo (P=.022). Among all 422 patients, zoledronic acid significantly reduced the incidence of a second on-study SRE (P=.017) and significantly delayed the median time to second SRE compared with placebo (P=.006) at 15 months. Among 144 patients (34%) with a history of SREs before study entry, zoledronic acid significantly reduced the skeletal morbidity rate by 65% (P=.036) and reduced the overall risk of developing an SRE by 40% (P=.028) compared with placebo at 24 months. CONCLUSION: This analysis confirms our previously reported results and suggests that long-term treatment with zoledronic acid provides continuing clinical benefit in patients with advanced prostate cancer, even after the occurrence of SREs.

Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer.

In a placebo-controlled randomized clinical trial, zoledronic acid (4 mg via a 15-minute infusion every 3 weeks for 15 months) reduced the incidence of skeletal-related events (SREs) in men with hormone-refractory metastatic prostate cancer. Among 122 patients who completed a total of 24 months on study, fewer patients in the 4-mg zoledronic acid group than in the placebo group had at least one SRE (38% versus 49%, difference = -11.0%, 95% confidence interval [CI] = -20.2% to -1.3%; P =.028), and the annual incidence of SREs was 0.77 for the 4-mg zoledronic acid group versus 1.47 for the placebo group (P=.005). The median time to the first SRE was 488 days for the 4-mg zoledronic acid group versus 321 days for the placebo group (P =.009). Compared with placebo, 4 mg of zoledronic acid reduced the ongoing risk of SREs by 36% (risk ratio = 0.64, 95% CI = 0.485 to 0.845; P =.002). Patients in the 4-mg zoledronic acid group had a lower incidence of SREs than did patients in the placebo group, regardless of whether they had an SRE prior to entry in the study. Long-term treatment with 4 mg of zoledronic acid is safe and provides sustained clinical benefits for men with metastatic hormone-refractory prostate cancer.

Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer.

PURPOSE: A multicenter double-blind, randomized, placebo controlled clinical trial was performed to assess the effect of zoledronic acid, a potent new bisphosphonate, on bone mineral density during androgen deprivation therapy for nonmetastatic prostate cancer. MATERIALS AND METHODS: Men with M0 (no distant metastases) prostate cancer beginning androgen deprivation therapy were randomly assigned to receive 4 mg. zoledronic acid or placebo intravenously every 3 months for 1 year. The primary efficacy variable was the percent change from baseline to 1 year in bone mineral density of the lumbar spine as measured by dual energy x-ray absorptiometry. RESULTS: A total of 106 men were enrolled in the trial. Mean bone mineral density in the lumbar spine increased by 5.6% in men receiving zoledronic acid and decreased by 2.2% in those given placebo (mean difference 7.8%, 95% confidence interval 5.6%-10.0%, p <0.001). Mean bone mineral density of the femoral neck, trochanter and total hip also increased in the zoledronic acid group and decreased in the placebo group. Zoledronic acid was well tolerated. CONCLUSIONS: Zoledronic acid increases bone mineral density in the hip and spine during androgen deprivation therapy for nonmetastatic prostate cancer.

A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma.

BACKGROUND: Bone metastases are a common cause of morbidity in patients with prostate carcinoma. We studied the effect of a new bisphosphonate, zoledronic acid, which blocks bone destruction, on skeletal complications in prostate cancer patients with bone metastases. METHODS: Patients with hormone-refractory prostate cancer and a history of bone metastases were randomly assigned to a double-blind treatment regimen of intravenous zoledronic acid at 4 mg (N = 214), zoledronic acid at 8 mg (subsequently reduced to 4 mg; 8/4) (N = 221), or placebo (N = 208) every 3 weeks for 15 months. Proportions of patients with skeletal-related events, time to the first skeletal-related event, skeletal morbidity rate, pain and analgesic scores, disease progression, and safety were assessed. All statistical tests were two-sided. RESULTS: Approximately 38% of patients who received zoledronic acid at 4 mg, 28% who received zoledronic acid at 8/4 mg, and 31% who received placebo completed the study. A greater proportion of patients who received placebo had skeletal-related events than those who received zoledronic acid at 4 mg (44.2% versus 33.2%; difference = -11.0%, 95% confidence interval [CI] = -20.3% to -1.8%; P =.021) or those who received zoledronic acid at 8/4 mg (38.5%; difference versus placebo = -5.8%, 95% CI = -15.1% to 3.6%; P =.222). Median time to first skeletal-related event was 321 days for patients who received placebo, was not reached for patients who received zoledronic acid at 4 mg (P =.011 versus placebo), and was 363 days for those who received zoledronic acid at 8/4 mg (P =.491 versus placebo). Compared with urinary markers in patients who received placebo, urinary markers of bone resorption were statistically significantly decreased in patients who received zoledronic acid at either dose (P =.001). Pain and analgesic scores increased more in patients who received placebo than in patients who received zoledronic acid, but there were no differences in disease progression, performance status, or quality-of-life scores among the groups. Zoledronic acid at 4 mg given as a 15-minute infusion was well tolerated, but the 8-mg dose was associated with renal function deterioration. CONCLUSION: Zoledronic acid at 4 mg reduced skeletal-related events in prostate cancer patients with bone metastases.