Osteoclast-targeted agents were studied in men with mCRPC and bone metastases. In a phase III, double-blind, placebo-controlled trial, Saad et al.158 randomized patients with mCRPC to receive zoledronic acid at 4mg or placebo every 3 weeks for 15 months; the primary endpoint was the proportion of men experiencing at least 1 SRE. Men receiving zoledronic acid had significantly lower rates of SREs (33% with zoledronic acid versus 44% with placebo; p=0.021) and longer time to first SRE (>410 days with zoledronic acid and 321 days with placebo; p=0.011). The rate of pathologic fractures was also lower compared to placebo (13.1% with zoledronic acid versus 22.1% for placebo). Fizazi et al.159 performed a non-inferiority trial of 1,904 men with mCRPC with bone metastases randomized to receive denosumab or zoledronic acid with the primary endpoint of outcome of time to SRE. In addition to demonstrating that denosumab was non-inferior to zoledronic acid (20.7 versus 17.1 months;  p=0.0002), this trial also showed that denosumab was superior to zoledronic acid in improving time to first SRE in a secondary analysis (p=0.008). Rates of hypocalcemia were higher with denosumab than zolendronic acid; as such, clinicians should monitor calcium levels prior to infusions, and repletion of vitamin D prior to starting these agents, along with SOC calcium and vitamin D maintenance. In terms of schedule, CALGB 70604160 was a phase III, open-label trial that randomized 1,822 patients with metastatic breast or prostate cancer (n=686) or multiple myeloma to receive zoledronic acid every 4 weeks or every 12 weeks for 2 years. The trial demonstrated non-inferiority of 12-week dosing intervals for prevention of SREs. No differences were shown for secondary endpoints such as pain scores or performance status or toxicity including ONJ or renal dysfunction. In the randomized, double-blinded, placebo-controlled phase III CALGB 90202 trial,161 645 mHSPC patients were assigned 1:1 to receive either zoledronic acid (4mg intravenously every 4 weeks) or placebo. After progression to CRPC, all patients crossed over to open-label zoledronic acid. Median time to first SRE was 32.5 months in the zoledronic acid group and 29.8 months in the placebo group (HR=0.96; 95% CI: 0.76 to 1.22; p=0.74). OS was similar between groups (HR=0.89; 95% CI: 0.70 to 1.14; p=0.34). The study concluded that early treatment with zoledronic acid in men with HSPC and bone metastases was not associated with lower risk for SREs or death.