# Rescuing Mitochondrial Dysfunction in Macrophages Prevents Osteonecrosis of the Jaw in Anti‐Resorptive Therapy

## TL;DR

Fixing mitochondrial issues in macrophages can prevent a jaw condition caused by anti-resorptive drugs used in osteoporosis treatment.

## Contribution

A novel therapeutic strategy using nanoparticles to rescue mitochondrial dysfunction and prevent bisphosphonate-related osteonecrosis of the jaw.

## Key findings

- Zoledronic acid disrupts mitochondrial function in macrophages, increasing reactive oxygen species and inflammation.
- Inhibiting autophagy through TLR4-MyD88/PI3K-AKT-mTOR pathway worsens bisphosphonate-related osteonecrosis of the jaw.
- ZDPR nanoparticles effectively prevent BRONJ and show therapeutic benefits for osteoporosis and osteolysis.

## Abstract

Mitochondria‐driven macrophage dysregulation contributes significantly to inflammatory disease progression; however, the mechanism underlying bisphosphonate‐related osteonecrosis of the jaw (BRONJ) remains unclear. This study demonstrates that zoledronic acid (ZA) disrupts mitochondrial bioenergetic function in macrophages, leading to elevated mitochondrial membrane potential, excessive mitochondrial reactive oxygen species (mtROS), and increased HIF‐1α expression, which together promote a pro‐inflammatory transition in macrophages. ZA further inhibits autophagy by activating the TLR4‐MyD88/PI3K‐AKT‐mTOR pathway, preventing the clearance of dysfunctional mitochondria and sustaining superoxide production. Genetic loss of Atg5 in innate immune cells disrupts autophagosome maturation and markedly worsens ZA‐induced BRONJ development. To restore mitochondrial degradation and biofunction, ZA‐loaded nanoparticles incorporating the mTOR inhibitor rapamycin (ZDPR) are developed. ZDPR effectively prevents BRONJ and exerts therapeutic benefits in osteoporosis and osteolysis. These findings highlight bone‐targeted mitochondria rescue as a promising strategy to enhance antiresorptive therapy.

Schematic model showing the suggested mechanism that ZA induces classical activation of macrophages by impairing mitochondrial biofunction and inhibiting mitochondrial clearance to contribute to the pathological process of BRONJ. RAPA‐loaded nanoparticles ZDPR has shown potential in alleviating BRONJ lesions as well as treating osteoporosis or osteolytic bone metastases.