The aim of this study is to compare the efficacy and safety between zoledronic acid (ZA) and clodronate (CA) in the treatment of bone metastases for prostate cancer patients. We conducted a prospective study in recruiting 137 prostate cancer patients with bone metastases from 2008 to 2010. All men were well responding to first-line hormone therapy (PSA < 2 ng/mL); Patients were randomly assigned to receive zoledronic acid (4 mg over a 30 min infusion) every 1 month or to take 4 tablets per day of clodronate (1,600 mg) for up to 3 years. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry at femoral neck, lumbar spine, and total hip, together with visual analog scale score were evaluated on baseline and 6, 12, 24, and 36 months, respectively. Toxicity and skeletal-related events (SREs) happened in both groups during this period were recorded down and compared. The ZA group had better bone progression-free survival (BPFS) (31 months vs 22 months, P = 0.04), but no statistical evidence of benefit was observed in terms of overall survival rate. The ZA group significantly increased lumbar spine BMD (4.5 ± 2.3 % vs CA group 2.3 ± 3.9 % P = 0.03), had a better response on pain-relieve effect (92 vs 76 % P = 0.002) and a rapid pain palliation (9 months vs 13 months P = 0.03). The CA group reported more gastrointestinal cases. However, the ZA group required more dose modifications. As compared to clodronate, Zoledronic acid has advantages on extending BPFS, better bone pain control and lumbar spine BMD performance for prostate cancer patients with bone metastases. The overall survival rate and SREs rate are similar.