PURPOSE: The purpose of this study was to assess the necessity of post-marketing safety monitoring focused on osteonecrosis of the jaw (ONJ) in patients with bone metastatic cancer treated with denosumab (AMG162). METHODS: The ONJ safety data from three randomized phase III trials were pooled, and risk ratios and power were computed using traditional methods and simulation. RESULTS: A total of 89 ONJ cases (1.57%; 95% CI, 1.26-1.92) were reported with 52 (1.83%; 95% CI, 1.37-2.39) occurring in the denosumab group (n = 2,841) and 37 (1.30%; 95% CI, 0.92-1.79) in the zoledronic acid group (n = 2,836). Overall, the pooled risk ratio (RR) for ONJ was 1.40 (95% CI, 0.92-2.13; p = 0.11). In the trials reporting superior therapeutic efficacy of denosumab, the RR for ONJ was 1.61 (95% CI, 0.99-2.62; p = 0.052). However, neither separately nor pooled had any trial adequate power (>80%) to detect excess relative risks of ONJ of up to 76%, assuming fixed ONJ rates in the control arms. The joint power of the trials to detect the observed excess relative risk of 40% was only 36%. The rate of mucosal healing in patients with ONJ appeared similar in both groups (RR, 1.28; 95% CI, 0.66-2.45; p = 0.5). CONCLUSIONS: Although the overall frequency of ONJ was low, post-marketing risk-benefit studies with this novel compound appear warranted focusing specifically on this rare toxicity, which can potentially have a high impact on quality of life.
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