# Effect of metformin on inflammation and bone damage in a rat model of medication‐related osteonecrosis of the jaw

## TL;DR

This study shows that metformin reduces inflammation and bone damage in rats with medication-related jaw bone disease.

## Contribution

The study demonstrates metformin's protective effects against osteonecrosis of the jaw in a rat model.

## Key findings

- Metformin reduced empty bone lacunae and apoptotic osteoclasts in MRONJ rats.
- Metformin decreased inflammatory markers like IL-1β and myeloperoxidase activity.
- TRAP expression increased with metformin without affecting osteoclast numbers.

## Abstract

This study investigated how chronic metformin administration modulates the cellular profile and inflammatory markers in a zoledronic acid‐based rat model of medication‐related osteonecrosis of the jaw (MRONJ). Male Wistar rats were allocated to different treatments: (i) naïve, (ii) MRONJ (zoledronic acid, 0.2 mg/kg, i.v. on days 0, 7, 14, and 49), or (iii) MRONJ + metformin (250 mg/kg, by gavage, daily for 70 days). All rats had the inferior first molar extracted on day 42. Mandibular arches were harvested for analyzing their gums on day 70. Additionally, RAW 264.7 cells were incubated with zoledronic acid or metformin for cell viability tests and analysis of interleukin‐1β (IL‐1β) production. MRONJ was characterized by increased numbers of empty osteocyte lacunae, osteoclasts, and apoptotic osteoclasts, and by high expression of tartrate‐resistant acid phosphatase (TRAP) and F4/80 (a macrophage marker). Zoledronic acid‐incubated RAW 264.7 macrophages showed increased IL‐1β expression. Metformin reduced the number of empty bone lacunae, apoptotic osteoclasts, leukocyte infiltrate, and F4/80 positive cells in the alveolar bone. It increased TRAP expression levels without altering the number of osteoclasts. Metformin also reduced the myeloperoxidase activity and decreased IL‐1β levels in vitro. In conclusion, metformin reduced the severity of MRONJ by mitigating the inflammatory response.