Osteonecrosis of the Jaw Caused by Denosumab in Treatment-Naive and Pre-Treatment with Zoledronic Acid Groups: A Time-to-Onset Study Using the Japanese Adverse Drug Event Report (JADER) Database

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-kappa B 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-naive (naive 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 naive group and 86 reports of the post-zoledronic acid group were analyzed. The median onset in the naive 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 naive 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 naive 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.

Automated summary

This study evaluated and compared the time-to-onset profile for medication-related osteonecrosis of the jaw associated with denosumab in treatment-naive and pre-treated patients with zoledronic acid. The results showed a shorter onset time in the post-zoledronic acid group and highlighted the importance of considering the early risk of medication-related osteonecrosis of the jaw when switching patients from zoledronic acid to denosumab treatment.