Medication-related osteonecrosis of the jaw following osteoporosis therapy: A real-world retrospective cohort study using the TriNetX global collaborative network

Abstract

Introduction: Medication-related osteonecrosis of the jaw (MRONJ) was first reported in cancer patients receiving high-dose intravenous bisphosphonates and later linked to other anti-resorptive agents such as denosumab and romosozumab. However, large-scale real-world data on MRONJ risk following these therapies remain limited. This study focuses on the widely used parenteral anti-resorptive agents-ibandronate, denosumab, and zoledronic acid-chosen for their clinical popularity, cost-effectiveness, and convenient dosing. We aimed to assess the risk of MRONJ associated with each agent using real-world data from a global healthcare network.

Methods: This retrospective cohort study was conducted using the TriNetX network. To clarify the causal relationship, cohorts were created to include patients treated with only one anti-resorptive medication. Propensity score matching was applied to adjust for known risk factors associated with MRONJ. Additionally, subgroup analyses were performed for cancer and non-cancer patient populations.

Results: Propensity score matching yielded balanced cohorts (n = 36,983 each) for comparing MRONJ risk. Among matched patients, 106 denosumab users and 41 zoledronic acid users developed MRONJ (HR: 0.378; 95 % CI: 0.264-0.543). No case occurred in the ibandronate group (n = 11,405), which showed substantially lower risk compared to zoledronic acid and denosumab. The incidence of inflammatory condition of jaws share similar trends compared to those of MRONJ among the three groups. In cancer patients, MRONJ risk was 0.294 % with denosumab and 0.525 % with zoledronic acid. Non-cancer patients had much lower risk.

Conclusions: This study used real-world data from the TriNetX platform to evaluate the risk of MRONJ associated with various anti-osteoporosis medications, excluding combination therapies for clarity. Our findings indicate that among the commonly used parenteral anti-resorptive agents, denosumab has been associated with the highest risk of MRONJ, followed by zoledronic acid, with ibandronate showing the lowest risk.

Keywords: Anti-resorptive drugs; Denosumab; Ibandronate; MRONJ (medication-related osteonecrosis of jaws); Osteoporosis; Zoledronic acid.