Iron dysregulation, ferroptosis, and oxidative stress in diabetic osteoporosis: Mechanisms, bone metabolism disruption, and therapeutic strategies.

Abstract

Diabetic osteoporosis (DOP) is a common complication in diabetes, driven by hyperglycemia-induced metabolic disturbances, chronic inflammation, and oxidative stress. This review describes the critical role of iron metabolism dysregulation in DOP pathogenesis, focusing on ferroptosis, a novel iron-dependent cell death pathway characterized by lipid peroxidation and reactive oxygen species (ROS) overproduction. Diabetic conditions exacerbate iron overload, impairing osteoblast function and enhancing osteoclast activity, while triggering ferroptosis in bone cells. Ferroptosis not only accelerates osteoblast apoptosis but also amplifies osteoclast-mediated bone resorption, synergistically promoting bone loss. Furthermore, chronic inflammation and oxidative stress disrupt the balance between bone formation and resorption, with elevated pro-inflammatory cytokines (e.g., tumor necrosis factor-α, interleukin-6) and ROS exacerbating cellular dysfunction. Therapeutic strategies targeting iron metabolism (e.g., deferoxamine) and ferroptosis inhibition (e.g., nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway activation, antioxidants like melatonin) demonstrate potential to mitigate DOP progression. Future research should prioritize personalized interventions, clinical trials of iron chelators and antioxidants, and mechanistic studies to refine therapeutic approaches. This review provides a comprehensive framework for understanding DOP pathogenesis and highlights innovative strategies to improve bone health in diabetic patients.