Fluvastatin enhances healing of medication−related osteonecrosis of the jaw (MRONJ) via macrophage polarization in a rat MRONJ−like model

Medication−related osteonecrosis of the jaw (MRONJ), a serious adverse effect of antiresorptive agents, remains difficult to manage. Our previous studies showed that statins, widely prescribed for dyslipidemia, promote healing in MRONJ−like lesions, however, the mechanisms underlying their therapeutic effects remain unclear. This study investigated the efficacy of the therapeutic effect of fluvastatin (FS) in a rat MRONJ−like model, with particular attention to macrophage polarization. Four−week−old female rats were allocated to three groups. Two groups received zoledronic acid (ZOL) and dexamethasone (DEX) for two weeks prior to extraction of maxillary first molars. After extraction, one group was treated with a single local injection of FS near the extraction site, whereas the other received saline. A control group underwent identical procedures, but received saline instead of ZOL, DEX, and FS. All animals were evaluated two weeks after treatment. The control (saline) group showed complete socket healing. In contrast, ZOL/DEX−treated rats exhibited incomplete epithelial closure and exposed necrotic bone. However, local FS administration in ZOL/DEX−treated rats extensively promoted healing, resulting in smaller epithelial gaps and reduced bone exposure, and decreased areas of necrotic bone. Total macrophage numbers were significantly higher in both experimental groups compared with the control group. The ZOL/DEX group showed a predominance of pro−inflammatory M1 macrophages, whereas the FS−treated group exhibited relatively increased proportions of tissue−reparative M2 macrophages. Local FS administration enhances bone healing of MRONJ−like lesions by promoting macrophage polarization toward M2 phenotype.