Background: Up to 75% of advanced breast cancer patients develop bone metastases (BM) that induce increased osteoclast activity resulting in local bone destruction. The ensuing skeletal complications, including fractures, may have serious consequences. Denosumab, a fully human monoclonal antibody, inhibits RANKL, a key mediator of osteoclast activity. Denosumab has been shown to increase bone mineral density and reduce fractures in postmenopausal women with low bone mass. Primary results from a recently completed randomized pivotal study demonstrated that denosumab was superior to zoledronic acid (ZA) in delaying and preventing skeletal-related events (SREs) in breast cancer patients with bone metastases. Here, we describe results of other endpoints from the study.Methods: Patients with breast cancer and BM (N=2046) who had not been treated with intravenous (IV) bisphosphonates were randomized 1:1 to receive either subcutaneous (SC) denosumab 120 mg and IV placebo, or SC placebo and IV ZA 4 mg every 4 weeks. All patients were encouraged to take daily supplemental calcium (≥500 mg) and vitamin D (≥400 IU). The primary endpoint was time to first on-study SRE (predefined as pathologic fracture, radiation to bone, surgery to bone, or spinal cord compression). Other endpoints included time to first radiation of bone; time to first on-study SRE or hypercalcemia of malignancy (HCM); skeletal morbidity rate (SMR; the number of SREs per year); and the proportion of patients with at least 1 on-study SRE. SMR was defined as the ratio of the number of SREs, allowing for one event every 21 days, divided by the patient9s time at risk.Results: As previously reported, denosumab was superior to ZA in significantly delaying the time to first on-study SRE (hazard ratio [HR] 0.82; 95% CI: 0.71, 0.95; P Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 22.