Replacing zoledronic acid with denosumab is a risk factor for developing osteonecrosis of the jaw. 
Intravenous zoledronic acid (ZA) is often replaced with subcutaneous denosumab in patients with bone metastatic cancer.  Despite their different pharmacologic mechanisms of action, both denosumab and ZA are effective in bone metastasis but cause osteonecrosis of the jaw (ONJ) as a side effect.  ZA persists in the body almost indefinitely, whereas denosumab does not persist for long periods.  This study evaluated the risks of developing ONJ when replacing ZA with denosumab.  In total, 161 Japanese patients administered ZA for bone metastatic cancer were enrolled in this single-center, retrospective, observational study.  The risk of developing ONJ was evaluated by logistic regression analysis using the following factors: age, gender, cancer type, angiogenesis inhibitors, steroids, and replacement of ZA with denosumab.  Seventeen patients (10.6%) developed ONJ.  Multiple regression analysis indicated a significant difference in rate of ONJ associated with replacement of ZA with denosumab (odds ratio = 3.81; 95% confidence interval 1.04-13.97; P = .043).  Replacing ZA with denosumab is a risk factor for the development of ONJ.  Both binding of bisphosphonate to bone and receptor activator of nuclear factor-κ B ligand inhibition could additively increase the risk of ONJ.  We bring the replacement of ZA with denosumab to the attention of clinical oncologists.