Fueling bone loss: the immunometabolic reprogramming of the bone microenvironment in diabetic osteoporosis.

Diabetic osteoporosis (DOP) is a serious skeletal complication of type 2 diabetes mellitus (T2DM), characterized by deteriorated bone microarchitecture and elevated fracture risk independent of reduced bone mineral density. Emerging evidence indicates that immunometabolic reprogramming of bone marrow immune cells serves as a core driver of DOP pathogenesis. This review focuses on macrophages and CD4+ Th17/Treg cells, the pivotal immune subsets mediating skeletal immune-metabolic homeostasis. We systematically elaborate how hyperglycemia triggers glycolytic predominance, HIF-1α stabilization, and succinate-SUCNR1 axis activation in macrophages, alongside mTORC1-HIF-1α-dependent Th17/Treg imbalance. Bidirectional immunometabolic crosstalk between these immune cells disrupts the RANKL/OPG and Wnt/β-catenin signaling pathways, thereby disturbing bone formation and resorption. Furthermore, we summarize current immunometabolic-targeted modulators for DOP, stratifying their preclinical and clinical evidence, skeletal benefits, and safety limitations. We also highlight existing clinical diagnostic defects and translational bottlenecks in DOP research. Finally, we prospect emerging research directions including spatial immunometabolic profiling, gut-immune-bone axis regulation, and artificial intelligence-assisted precision intervention, aiming to provide mechanistic insights and novel translational strategies for DOP targeted therapy.