OBJECTIVES: Rigorous critical appraisal of clinical trials to assess bias and chance effects, which can distort trial results, can help evaluate the validity of research findings. In a pre-specified integrated analysis of three phase 3 pivotal trials in patients with bone metastases secondary to breast cancer, prostate cancer, and other solid tumors or multiple myeloma (N=5,723), denosumab was reported to be superior to ZA for the prevention of SREs, with statistically and clinically significant differences. Delfini Group performed critical appraisals of the three individual pivotal trials and the integrated analysis. METHODS: Published trials (Lipton et al, EJC, 2012; Stopeck et al, JCO, 2010; Henry et al, JCO, 2011, Fizazi et al, Lancet, 2011) were analyzed along with supplementary information from study protocols, clinical study reports, and prescribing information. The trials were evaluated for any potential threats to study validity, such as selection bias, performance bias, and assessment bias, as well as the likelihood for chance effects instead of true effects. A detailed analysis of attrition (discontinuation or loss to follow up), which is a frequent issue in oncology studies, was also conducted to assess the presence of attrition bias. RESULTS: The integrated analysis and three pivotal trials were found to be of high-quality evidence and at low risk of bias and chance effects. Important quality features included a robust randomization process, high likelihood of patients remaining balanced and blinded throughout the study, as well as a high degree of adherence to assigned treatments. These and other factors, such as balance in co-interventions and in rates and reasons for discontinuation, make bias from attrition unlikely. CONCLUSIONS: The critical appraisal confirmed that the results of the integrated analysis and three pivotal trials were robust, with denosumab providing clinically meaningful benefit in patients with bone metastases from advanced cancer.