ObjectiveTo compare the efficacy and safety between denosumab and zoledronic acid for advanced cancer with bone metastasis.MethodsMEDLINE, EMBASE, and the Cochrane library databases were searched for randomized controlled trials up to December 2020 that compared denosumab and zoledronic acid in the treatment of advanced cancer with bone metastasis. The following clinical outcomes were extracted for analysis: time to first skeletal-related event, time to first-and-subsequent skeletal-related events, overall survival, and disease progression. Safety outcomes including incidence of adverse events, serious adverse events, acute-phase reactions, renal toxicity, osteonecrosis of the jaw, and hypocalcemia were also extracted.ResultsFour randomized controlled trials involving 7201 patients were included. The overall analysis showed that denosumab was superior to zoledronic acid in delaying time to first skeletal-related event (hazard ratio = 0.86; 95% confidence interval, 0.80-0.93; P < 0.01) and time to first-and-subsequent skeletal-related events (risk ratio 0.87; 95% confidence interval 0.81-0.93; P < 0.01). Denosumab was associated with lower incidence of renal toxicity (risk ratio 0.69; 95% confidence interval 0.54-0.87; P < 0.01) and acute phase reaction (risk ratio 0.47; 95% confidence interval 0.38-0.56; P < 0.01), but higher incidence of hypocalcemia (risk ratio 1.78; 95% confidence interval 1.33-2.38; P < 0.01) and osteonecrosis of the jaw (risk ratio 1.41; 95% confidence interval 1.01-1.95; P = 0.04). No significant differences were found in overall survival, time to disease progression, or incidence of adverse events and serious adverse events between denosumab and zoledronic acid.ConclusionsCompared with zoledronic acid, denosumab is associated with delayed first-and-subsequent skeletal-related events, lower incidence of renal toxicity, and acute phase reaction, but higher incidence of hypocalcemia and osteonecrosis of the jaw. Hence, denosumab seems to be a promising choice for advanced cancer with bone metastasis. Nonetheless, more randomized controlled trials are needed for further evaluation.