Zhipeng Li, Cheng Luo, Xue Yu, Liya Ye, Da Sun, Chen Duan, Shiyu Xu, Mei-Qi Zeng, Hui Xu, Ziyao Peng, Peng Wang, Yaobin Wang, Wenjie Ruan, Meng-En Xue, Changjiang Zhang, Dongjuan He
Type 2 diabetes markedly elevates fracture risk despite normal or high bone mineral density, a paradox reflecting qualitative skeletal deficits rather than loss of mass. Chronic hyperglycemia fosters the accumulation of advanced glycation end products in bone; their nonenzymatic crosslinks stiffen type I collagen, impair mineralization, and erode mechanical strength. By engaging the receptor for advanced glycation end products, these adducts activate nuclear factorκB and mitogen-activated protein kinase cascades, amplifying oxidative stress, inflammation, osteoblast dysfunction, and osteoclastogenesis. This review synthesizes epidemiological data from type 1 and type 2 diabetes, highlights the limits of densitybased skeletal assessment, and details the molecular pathology of the glycation-collagen axis. It also appraises antiglycation therapies, including formation inhibitors, crosslink breakers and receptor antagonists, with a particular focus on sodium-glucose cotransporter 2 inhibitors that couple glycemic control with modulation of the glycation pathway. By integrating recent basic and clinical advances, we propose a mechanistic framework for diabetic bone disease and outline strategies to mitigate glycationdriven skeletal fragility.