Background: Zoledronic acid (ZA) has been used as the standard treatment for patients with solid cancer or myeloma that has metastasized into bone. A new potential therapeutic strategy, denosumab, is being investigated in a variety of tumors. We conducted a systematic review with meta-analysis of randomized clinical trials assessing the efficacy and safety of denosumab in comparison with ZA in patients with bone metastases secondary to malignancy. Methods: A systematic literature search of several electronic databases till July 2011 and a review of reference lists of relevant articles was conducted. Summary relative estimates and 95% confidence intervals (CIs) were calculated using a fixed-effects or random-effects model, depending on the heterogeneity of the included studies. Results: Seven reports from 3 randomized controlled trials involving 5723 patients were identified. The pooled analysis showed that denosumab significantly delayed time to first on-study skeletal-related event [hazard ratio (HR) = 0.83; 95% CI, 0.76-0.90, P < 0.001], time to multiple skeletal-related events (HR = 0.83; 95% CI, 0.76-0.90, P < 0.001), and pain worsening (HR = 0.92; 95% CI, 0.86-0.99, P = 0.026) for patients with bone metastases compared with ZA. Similar results of the 2 groups were obtained with respect to overall survival (HR = 0.98; 95% CI, 0.91-1.06), disease progression (HR = 1.02; 95% CI, 0.96-1.09), and pain improvement. Summary of the adverse effects revealed similar safety profiles for the 2 drugs. Conclusions: Denosumab is superior to ZA in preventing complications for patients with bone metastases. However, further studies are still needed to assess longer-term safety and efficacy of denosumab.