Sequential Anabolic and Antiresorptive Treatment Promotes Medication‐Related Osteonecrosis of the Jaw in Mice

Objective To investigate the effects of sequential administration of romosozumab and denosumab on post‐extraction socket healing and osteonecrosis development in a murine tooth extraction model. Methods Forty female mice were randomly assigned to four groups: control (Ctrl), romosozumab (Rm), denosumab (Dmab), and sequential romosozumab followed by denosumab (Rm + Dmab). After drug administration, bilateral maxillary first molars were extracted. Extraction socket healing was evaluated by micro‐computed tomography, histological analysis, and immunohistochemistry for receptor activator of nuclear factor κB ligand (RANKL), osteoprotegerin (OPG), and sclerostin. Results The Rm + Dmab group exhibited significantly less new bone formation and more necrotic bone in the extraction sockets than the other groups, accompanied by a marked reduction in osteoclast numbers. The Dmab‐only group showed a lower RANKL/OPG ratio. No significant differences in sclerostin expression were observed among groups. Conclusions Sequential administration of romosozumab followed by denosumab severely impaired extraction socket healing and induced osteonecrotic lesions in mice, resembling medication‐related osteonecrosis of the jaw (MRONJ). These findings suggest that such sequential antiresorptive therapy may increase the risk of MRONJ in patients undergoing dental extractions.