Osteonecrosis of the Jaw Caused by Denosumab in Treatment-Naïve and Pre-Treatment with Zoledronic Acid Groups: A Time-to-Onset Study Using the Japanese Adverse Drug Event Report (JADER) Database
Shiori Hasegawa, Hiroaki Ikesue, Riko Satake, Misaki Inoue, Yu Yoshida, Mizuki Tanaka, Kiyoka Matsumoto, Wataru Wakabayashi, Keita Oura, Nobuyuki Muroi, Tohru Hashida, Kazuhiro Iguchi, Mitsuhiro Nakamura
Abstract
BACKGROUND: Medication-related osteonecrosis of the jaw is a serious adverse event associated with bone-modifying agents, such as injectable bisphosphonate (zoledronic acid) and the anti-receptor activator of nuclear factor-κB ligand antibody (denosumab). OBJECTIVE: This study aims to evaluate and compare the time-to-onset profile for medication-related osteonecrosis of the jaw associated with denosumab between treatment-naïve (naïve group) and pre-treatment with zoledronic acid (post-zoledronic acid group) patients using the Japanese Adverse Drug Event Report database. METHODS: Medication-related osteonecrosis of the jaw was defined according to the Medical Dictionary for Regulatory Activities. The medication-related osteonecrosis of the jaw onset profiles were evaluated using the Weibull shape parameter and the log-rank test. RESULTS: The Japanese Adverse Drug Event Report database contains 632,409 reports published between April 2004 and March 2020. In the time-to-onset analysis, after extracting the combinations with complete information for the treatment start date and the medication-related osteonecrosis of the jaw onset date, 272 reports of the naïve group and 86 reports of the post-zoledronic acid group were analyzed. The median onset in the naïve and post-zoledronic acid groups was 487.0 (25-75%: 274.0-690.8) and 305.5 (25-75%: 158.3-508.5) days, respectively. Medication-related osteonecrosis of the jaw occurred earlier in the post-zoledronic acid group than in the naïve group, and the log-rank test demonstrated a significant difference in their time transitions (p < 0.0001). CONCLUSIONS: The results indicated a risk of medication-related osteonecrosis of the jaw in naïve and post-zoledronic acid groups and a shorter onset time in the latter than in the former. Thus, healthcare professionals should take the early risk of medication-related osteonecrosis of the jaw into account when switching patients from zoledronic acid to denosumab treatment.