Frontiers in Endocrinology · Oct 31, 2026
Metabolic Dysfunction Reshapes the Bone–Marrow Niche and Compromises Skeletal Repair
By Ziang Jia, Kuan Liang, Yali Dai
Chronic systemic metabolic dysfunction can increase fracture susceptibility and impair skeletal repair through changes in bone quality and the bone–marrow microenvironment that are not fully captured by bone mineral density (BMD). Type 1 diabetes commonly reduces skeletal acquisition and reserve, whereas type 2 diabetes shows a more heterogeneous phenotype in which BMD may remain preserved despite fracture risk. This discordance reflects variable contributions from intrinsic skeletal deterioration—including matrix glycation, suppressed remodeling, altered material properties, and microarchitectural abnormalities—and extra-skeletal susceptibility related to muscle dysfunction, hypoglycemia, neuropathy, and falls. Glucose and lipid disturbances also reshape the marrow niche by altering stromal and adipogenic-lineage cells, vascular support, and local substrate handling. At the cellular level, impaired metabolic flexibility, mitochondrial and redox stress, dysregulated nutrient sensing, defective quality-control responses, senescence, and ferroptosis may compromise bone-cell function, although several pathways remain supported predominantly by preclinical evidence. This Review integrates these mechanisms with phase-specific fracture repair, clinical risk assessment, and treatment; direct human fracture-healing evidence is concentrated in diabetes. BMD and FRAX remain useful but may incompletely represent risk in selected metabolic phenotypes; interpretation should incorporate disease duration, complications, physical function, and falls. Trial evidence supports established antiresorptive therapy in appropriately selected patients with type 2 diabetes, whereas type 1 diabetes-specific efficacy data remain limited. The skeletal effects of potent weight-loss and glucose-lowering therapies depend on treatment-specific mechanisms, weight trajectory, muscle preservation, and baseline fracture risk. Overall, the evidence supports a phenotype-based framework linking systemic metabolism, bone–marrow niche biology, skeletal quality, repair capacity, and physical resilience.