Abstract / Summary
Abstract Background Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse event associated with bone-modifying agents (BMAs) and other therapies. However, its time-to-onset characteristics have not been fully elucidated. This study aimed to comprehensively evaluate the reported onset timing and temporal patterns of MRONJ using a complementary approach integrating a spontaneous reporting database and clinical data. Methods The primary time-to-onset analysis was conducted using the Japanese Adverse Drug Event Report (JADER) database, and onset patterns were evaluated using Weibull distribution analysis. In addition, a single-center retrospective cohort study of patients with lung cancer was conducted to provide supportive real-world observations on MRONJ occurrence, time to onset, and clinical characteristics. Results In the JADER analysis, MRONJ reports exhibited a broad time-to-onset distribution rather than clustering during the early treatment period. MRONJ tended to be reported earlier in the malignancy group than in the osteoporosis group ( p < 0.001). Drug-specific analyses demonstrated significant differences in onset timing among agents used for osteoporosis ( p < 0.001), whereas no significant difference was observed between zoledronic acid and denosumab in the malignancy group. Weibull analysis suggested that MRONJ reports were not restricted to a particular period. In the supportive single-center observations, the observed proportion of MRONJ was 1.5% among patients receiving pharmacological treatment for lung cancer, 4.4% among patients treated with BMAs, and 5.8% among denosumab users. The median time from initiation of BMA therapy to MRONJ onset was approximately 38 months. Most MRONJ cases were initially detected at community dental clinics and subsequently referred for specialist care. Despite differences in absolute time-to-onset estimates between the pharmacovigilance and clinical datasets, both data sources supported the need for prolonged oral monitoring during BMA therapy. Conclusions These findings indicate that reported MRONJ onset was distributed over a broad time range after BMA initiation. Together with the descriptive single-center observations, the results support continuous oral monitoring, patient education, long-term pharmaceutical care, and collaboration with dental care providers throughout long-term BMA therapy.