Replacing Zoledronic Acid With Denosumab Increase the Risk of ONJ

Objectives: Intravenous zoledronic acid (ZA) administration is often replaced with subcutaneous denosumab administration for patients with bone metastatic cancer because of their clinical load. Both denosumab and ZA have osteonecrosis of the jaw (ONJ) as the side effect. ZA is a bisphosphonate with a high affinity for hydroxyapatite and a strong ability to inhibit osteoclast action over a long time period. Denosumab is an anti-RANKL antibody that inhibits osteoclast maturation by binding to and inhibiting RANKL. Their pharmacological mechanisms are completely different; thus, replacing ZA with denosumab may affect ONJ development. Considering the known risk factors, this study aimed to evaluate the risk of developing ONJ when replacing ZA with denosumab.
Methods: In total, 149 consecutive Japanese patients who were administered ZA for bone metastatic cancer during 2012–2015 were enrolled. All patients underwent a dental examination before ZA administration and were followed up. ONJ was diagnosed according to the AAOMS position paper, 2014 update. The risk of developing ONJ was evaluated by logistic regression analysis using the following factors: age, sex, cancer type, angiogenesis inhibitors, steroids, and replacement of ZA with denosumab.
Results: Twenty-one patients (14.0%) developed ONJ. A single regression analysis revealed significant differences in age, cancer type, angiogenesis inhibitors, and replacement of ZA with denosumab. A multiple regression analysis revealed significant differences in angiogenesis inhibitors (OR=3.6, 95%CI: 1.3-10.0, P=0.014)and replacement of ZA with denosumab (OR=3.5, 95%CI: 1.3-10.2, P=0.017).
Conclusions: Replacing ZA with denosumab is a major risk factor for developing ONJ. Bisphosphonate binding to the bone and RANKL inhibition could increase the risk of developing ONJ. Additionally, our result showing high frequency of ONJ development suggests racial differences and/or prevalence of unknown ONJ patients who are not receiving dental examinations.