Denosumab is a monoclonal antibody that binds RANKL highly specifically and inhibits formation and activation of osteoblasts. Denosumab has been shown to be as effective as zoledronic acid in patients with bone lesions associated with breast or prostate cancers in phase III trials. Denosumab has also been tested in a phase III trial vs. zoledronic acid in bone disease associated with solid tumors, with a small number of patients with myeloma included (about 170 of a total of 1600 patients), and is not inferior to zoledronic acid in delaying or preventing first on-study SRE, with an equal incidence of ONJ after 2 years of treatment. This study shows that ONJ is not the result of bisphosphonates per se, but the result of blocking osteoclast activity and bone remodeling. In a phase II trial in myeloma, single-agent denosumab reduces bone resorption markers with no effect on tumor markers. However, denosumab could enhance anti-myeloma agents. A large randomized phase III trial (N=1000) of denosumab vs. zoledronic acid in patients with newly diagnosed myeloma and at least one bone lesion is planned to begin in September, 2011. Denosumab is administered subcutaneously and requires no adjustment for renal function.