Impact of reactive oxygen species on bone regeneration in diabetes: Mechanisms and therapeutic strategies

Diabetic bone regeneration is significantly affected by reactive oxygen species (ROS)-induced oxidative stress (OS), which disrupts the balance between osteoclast (OC)-mediated resorption and osteoblast (OB)-mediated formation of bone tissue. This review synthesizes current understanding of how hyperglycemia-driven ROS overproduction dysregulates OB and OC functions, leading to pathological bone remodeling and compromised healing. The key molecular mechanisms involved, such as RANK/RANKL, NF-κB, and MAPK, are discussed, highlighting their role in the ROS-mediated feedback loop that promotes OC differentiation while inhibiting OB survival, differentiation, and activity, worsening bone degeneration. Furthermore, the review addresses ROS-induced cell death pathways (apoptosis, ferroptosis, necroptosis, pyroptosis) along with the pathophysiological changes in the bone marrow microenvironment. Emerging therapeutic strategies to reduce oxidative damage, including antioxidant (AO) therapies and innovative drug delivery systems, offer promise for restoring bone regenerative capacity in diabetic conditions. These innovations aim to restore redox homeostasis, mitigate OS damage, and reactivate endogenous bone regenerative capacity. Understanding these mechanisms provides a foundation for developing targeted interventions to improve clinical outcomes in diabetic bone disease.