Osteoclasts in osteoradionecrosis: Pathogenic mechanisms and emerging therapies

Osteoradionecrosis (ORN) is a severe complication of radiation therapy characterized by impaired bone repair and regeneration, disrupting the delicate balance between osteoclast-mediated bone resorption and osteoblast-driven bone formation. Despite significant research, the intricate pathological mechanisms underlying ORN remain incompletely understood. Notably, while radiation therapy generally inhibits the function of most cells in bone tissue, its specific activation of osteoclasts is a key feature of ORN. Recent findings emphasize the pivotal role of excessive osteoclast activity in driving ORN progression. This review provides a comprehensive exploration of osteoclast adaptations within the unique bone microenvironment of ORN, shaped by hypoxia, immune dysfunction, and bacterial infections. It delves into the cellular stress responses-including oxidative stress, metabolic reprogramming, autophagy, and iron regulation-that further influence osteoclast function in ORN. By integrating these insights, we evaluate current therapeutic approaches and propose innovative osteoclast-targeted strategies to mitigate ORN. Through this synthesis of emerging evidence, the review sheds light on the complex interplay of factors contributing to ORN pathogenesis and highlights promising avenues for prevention and treatment, offering hope for improved clinical outcomes.