501Background: Denosumab (Dmab) is a potent RANK ligand inhibitor approved for the management of treatment induced bone loss in early breast (EBC) and prevention of skeletal morbidity associated with metastatic bone disease. Preclinical data suggested that Dmab could prevent development of bone metastases. This trial evaluated the addition of Dmab to standard (neo)adjuvant therapy for high-risk EBC patients (pts). Methods: 4509 pts with EBC (93.5% node+) from 407 centers were randomized to standard loco-regional and (neo)adjuvant therapy plus either Dmab 120mg sc or matching placebo (P) monthly x 6 then 3 monthly for up to 5 years. In addition to routine clinical follow-up, pts underwent annual CT and bone scan imaging to screen for recurrence. Primary endpoint was bone metastasis free survival (BMFS) defined as first bone metastatic event confirmed by central imaging review or death from any cause. Secondary endpoints included disease free survival (DFS), DFS in the postmenopausal (PM) subgroup, overall ...