668 Background: In Western populations, zoledronic acid (ZOL) has been proven effective for the prevention of skeletal related events (SREs) from bone metastases. For breast cancer patients, ZOL was shown to be superior to pamidronate. However, the efficacy of ZOL is unknown in Japanese patients. We report here data from the first randomized, placebo-controlled study of ZOL in Japanese patients. Methods: Japanese women with bone metastases from breast cancer were randomized to either ZOL 4mg i.v. infusion over 15 min every 4 weeks or placebo (P). The primary efficacy endpoint was SRE rate ratio (ratio of number of SREs per year for ZOL-treated patients over that for placebo) at 1 year. SREs included pathologic fractures, radiation to bone, spinal cord compression, and surgery to treat or prevent fractures. Secondary endpoints included proportion of patients with ≥1 SRE, time to first SRE and multiple event analysis (MEA: A-G model). Tumor induced hypercalcemia was included in the SRE composite in secondary endpoints. Safety was assessed according to NCI-CTC. Results: 227 patients (median age 53 years) were accrued to the study with 114 in the ZOL arm and 113 in the P arm. Patients were well matched with regard to baseline clinical characteristics. The primary endpoint, SRE rate ratio was 0.61 (p=0.027), indicating that SRE rate was reduced by 39% with ZOL. Proportions of patients with ≥1 SRE were 30.7% and 52.2% for the ZOL and P group, respectively (p=0.001). Median time to first SRE were 360 days in the P group while it did not reach in the ZOL group (p=0.004). Risk ratio of ZOL to P was 0.56 by MEA (p=0.009). ZOL was well tolerated. The most common adverse effects observed more frequently in the ZOL vs. P group were pyrexia (55% vs. 33%), fatigue (44.5% vs. 31.9%) and arthralgia (21.1% vs. 15.9%). One patient in the ZOL group (0.9%) experienced increased serum creatinine. Conclusions: ZOL 4mg demonstrated significant clinical efficacy in Japanese patients for preventing skeletal complications with bone metastases, with an overall 44% reduction in the risk of experiencing SREs as shown by MEA. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharmaceuticals Corp.