Combined Effects of Romosozumab and Zoledronate on the Development of Osteonecrosis of the Jaw

OBJECTIVE: This study aimed to assess the occurrence of medication-related osteonecrosis of the jaw (MRONJ) in mice following the sequential administration of romosozumab and zoledronate and to confirm their inhibitory effects on osteoclast differentiation in vitro. MATERIALS AND METHODS: Thirty-five female C57BL/6 mice were divided into three groups: romosozumab followed by zoledronate (ROM+ ZOL), saline followed by zoledronate (ZOL), and control (Con) group receiving saline. After drug administration, the maxillary first molars were extracted. Bone healing and necrosis were evaluated using micro-computed tomography, histomorphometry, and immunohistochemistry. To investigate the mechanism underlying the in vivo study results, the effects of romosozumab and zoledronate were evaluated by analysing tartrate-resistant acid phosphatase staining and actin ring formation after differentiation of RAW 264.7 cells. RESULTS: The ROM+ZOL group exhibited more severe bone necrosis than the ZOL and Con groups. The ROM+ZOL group demonstrated a lower bone volume fraction and a reduction in the number of sclerostin-positive cells, suggesting enhanced osteonecrosis when romosozumab was administered before zoledronate. Moreover, both zoledronate and romosozumab effectively suppressed osteoclast differentiation and function in vitro. CONCLUSIONS: Sequential administration of romosozumab followed by zoledronate may exacerbate the risk of MRONJ, underscoring the need for careful consideration in clinical applications.