Bone metastases are associated with a major patient and healthcare burden resulting from the impact and the management of associated skeletal-related events (including spinal cord compression, pathologic fracture and surgery or radiation to bone). In preclinical studies, RANK Ligand inhibition has been shown to prevent the development of bone and some visceral metastases. Clinical studies are ongoing to evaluate whether the fully human monoclonal antibody denosumab, which targets RANK Ligand, can prevent the development of bone metastases in high-risk patients. Findings from a phase 3 study in men with high-risk non-metastatic castration-resistant prostate cancer demonstrated that denosumab (120 mg every 4 weeks) significantly increased bone metastasis-free survival (primary endpoint) by 4.2 months (median) versus placebo (HR 0.85 [0.73, 0.98]; P = 0.028). This is the first study to demonstrate the clinical benefit of a bone-targeted agent in this setting. Further evaluation of denosumab in the prevention of metastatic disease is warranted and ongoing in other tumor types.