Oxidative stress in bone healing: mechanisms, disease contexts, and therapeutic strategies

In the field of bone healing, the fracture microenvironment (FME) dictates repair trajectories through dynamic interactions among osteogenic and osteoclastic lineages, immune cells, and the endothelium. Reactive oxygen species (ROS) act as central redox mediators and are produced by multiple cellular sources, including neutrophils, macrophages, osteoblast-lineage cells, and vascular cells. At physiological levels, ROS support angiogenesis, matrix remodeling, and osteogenesis; when excessive or sustained, they uncouple bone formation from resorption, impair progenitor fitness, and perpetuate inflammatory signaling. Redox-sensitive pathways—Nrf2/Keap1, MAPK/NF-κB, RANKL/OPG, and Wnt/β-catenin/FOXO—govern these processes and intersect with systemic drivers such as diabetes, osteoporosis/estrogen deficiency, cigarette smoking, and aging. Importantly, these comorbidities imprint distinct redox phenotypes in the fracture microenvironment. Diabetes is often dominated by hyperglycemia/AGE-driven oxidative injury with endothelial dysfunction and impaired angiogenesis; osteoporosis/estrogen deficiency features reduced antioxidant buffering and a resorptive bias; cigarette smoking adds an exogenous radical load together with vasoconstriction-related hypoxia; and aging couples mitochondrial decline with senescence/inflammaging that prolongs oxidative and inflammatory signaling. Nevertheless, temporal heterogeneity of ROS flux, cell type-specific responses, and the narrow therapeutic window between signaling and damage remain major hurdles, complicating dose selection, therapeutic timing, and patient stratification for redox-targeted interventions. Elucidating these mechanisms may enable strategies that restore a pro-healing redox milieu while minimizing tissue injury. This review synthesizes the redox-immune-skeletal circuitry regulating fracture repair, evaluates evidence for antioxidants, Nrf2 activation, autophagy modulation, and redox-responsive biomaterials, and underscores the value of single-cell/spatial multi-omics and functional redox biosensors for mechanistic dissection and risk stratification, with the goal of advancing precision adjunctive therapies for high-risk populations.