Deciphering the Immune–Bone Interaction Network in Diabetic Bone Fragility: Inflammatory Mechanisms and Precision Therapeutics

Diabetes mellitus increases fracture risk and impairs skeletal repair even when bone mineral density is normal or elevated, indicating that diabetic bone fragility cannot be explained by bone mass alone. This review examines how chronic metabolic stress reshapes the immune–bone microenvironment and disrupts bone remodeling and regeneration. We summarize evidence linking hyperglycemia, advanced glycation end product–RAGE signaling, oxidative stress, mitochondrial dysfunction, and cellular senescence to persistent inflammatory activation within the diabetic bone niche. Particular emphasis is placed on macrophage metabolic remodeling, excessive neutrophil extracellular trap formation, Th1/Th17-associated inflammation, and impaired regulatory T cell-mediated resolution. We further discuss how these immune abnormalities suppress osteogenesis, enhance osteoclastogenic signaling, and delay the transition from inflammation to tissue repair. Emerging therapeutic approaches, including macrophage state remodeling, NETosis modulation, restoration of immune resolution, antidiabetic drug-informed intervention, and biomaterial-assisted local delivery, are critically evaluated according to their mechanistic rationale and current level of evidence. By distinguishing findings supported by diabetic bone studies from those inferred from related inflammatory models, this review presents diabetic bone fragility as an immunometabolic disorder and highlights opportunities for stage-specific and precision therapeutic strategies.