Rethinking Osteonecrosis of the Jaw: Could Cellular Senescence Be the Missing Link Between ORN and MRONJ?

Osteonecrosis of the jaw (ONJ) is a series bone diseases characteristic with similar diagnostic criteria and clinical manifestations. Phossy jaws, medication-related osteonecrosis of the jaw (MRONJ), and osteoradionecrosis (ORN) are major subtypes of ONJ. Though subtypes of ONJ are considered different diseases in clinical practice, similar diagnostic criteria, clinical presentation, and features prompt the possibility that there is a common pathogenesis mechanism for ONJ subtypes. Current pathogenic theories fail to fully explain the delayed onset, persistent progression, and stimulus-independent nature of ONJ. Here, we propose that cellular senescence could be a common pathogenesis mechanism of ONJ. Radiation, antiresorptive agents, and trauma induce persistent DNA damage and activate the DNA damage response, leading to irreversible senescence in jawbone cells. This model explains key clinical observations and offers a rationale for the failure of stimulus withdrawal to reverse disease progression. We outline future directions to validate this hypothesis. If confirmed, this hypothesis may unify ONJ subtypes under a single pathogenic framework and open avenues for targeted interventions.