Most patients with advanced malignancy develop bone metastases during the course of their disease. For the remainder of the patient's life, these bone metastases lead to skeletal-related events such as pathologic fractures and spinal cord compression, as well as bone pain or lesions requiring palliative radiation therapy or surgery to prevent or treat fractures. Skeletal-related events result in increased morbidity, mortality and health care costs. For the past decade, intravenous bisphosphonates (zoledronic acid, pamidronate) have been recognized as the primary pharmacologic options in the prevention or treatment of skeletal-related events in patients with bone metastasis. Recently, the United States Food and Drug Administration approved denosumab, a fully human monoclonal antibody, for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Three prominent clinical trials were conducted to establish the efficacy of denosumab. In two of three trials, denosumab was found to delay the time to first skeletal-related event significantly more than zoledronic acid in patients with breast or castration-resistant prostate cancer with bone metastasis. The third trial found denosumab to be noninferior to zoledronic acid in patients with metastases from solid tumors, excluding breast and prostate solid tumors. Overall survival and progression-free survival were similar between zoledronic acid and denosumab. Thus, evidence is insufficient to prove a greater efficacy of one agent over the other. According to the American Society of Clinical Oncology and the National Comprehensive Cancer Network, patients with bone metastasis should have zoledronic acid, pamidronate, or denosumab (with calcium and vitamin D supplementation) added to their chemotherapy regimen if they have an expected survival of 3 months or longer and have adequate renal function.