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The nitrogen-containing bisphosphonate zoledronic acid and the monoclonal antibody against RANK, denosumab, are approved for the prevention of skeletal-related events in genitourinary cancers. These agents have different mechanisms of action and pharmacokinetic profiles, and while both are effective in reducing the risk of skeletal-related events, other clinical effects differ. There is evidence for direct and indirect anticancer activity with zoledronic acid from preclinical studies and emerging data from clinical studies suggesting an effect on patient survival. Potential anticancer mechanisms include inhibition of angiogenesis, enhanced immune surveillance via stimulation of \u03b3\u03b4 T cells, and reduction of circulating tumor cells. A synergistic effect of chemotherapy plus zoledronic acid has also been suggested. 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