Diabetic Bone Disease and Fracture Healing: Molecular Mechanisms, Skeletal Fragility, and Emerging Orthopedic Therapeutic Strategies

Diabetes mellitus is increasingly recognized as a disorder of skeletal quality in addition to metabolic dysregulation. Both type 1 and type 2 diabetes are associated with increased fracture risk, impaired fracture healing, and higher rates of orthopedic complications despite preserved or even elevated bone mineral density, highlighting the limitations of conventional densitometric assessment alone. Diabetic bone disease arises through complex and interconnected mechanisms involving osteoblast, osteocyte, and osteoclast dysfunction, accumulation of advanced glycation end products, oxidative stress, chronic inflammation, impaired insulin and insulin-like growth factor-1 signaling, and disruption of bone–pancreas and bone–adipose crosstalk. Here, we review the cellular, molecular, genetic, and epigenetic mechanisms that contribute to diabetic skeletal fragility and examine how these abnormalities impair bone remodeling, fracture healing, and orthopedic outcomes. Particular emphasis is placed on the disconnect between bone mineral density and bone quality, describing how alterations in bone microarchitecture and matrix integrity contribute to skeletal fragility beyond the conventional measures of bone mass. We further review emerging strategies for fracture risk assessment, including advanced imaging modalities and biomarkers that more accurately characterize diabetic bone disease, and discuss the influence of antidiabetic therapies, perioperative glycemic optimization, and emerging biologic and epigenetic therapeutic approaches on fracture healing and musculoskeletal outcomes. By integrating molecular mechanisms with clinical and orthopedic evidence, this review provides a comprehensive overview of diabetic bone disease while highlighting priorities for future research and clinical translation.