Gestational diabetes mellitus and skeletal development in offspring: evidence synthesis and mechanistic perspectives

Gestational diabetes mellitus (GDM) is a common metabolic complication of pregnancy and may influence offspring skeletal development through intrauterine metabolic programming. Available evidence links GDM exposure to altered early linear growth, abnormal bone mass accrual or bone quality, increased fracture risk in later life, and a higher probability of selected skeletal congenital anomalies. However, results from different studies are inconsistent, and it is not yet possible to simply infer a direct causal relationship between GDM and the above skeletal outcomes. A mechanistic sequence can be proposed in which maternal metabolic load initiates placental-interface remodeling, modifies the fetal bone microenvironment, and shifts skeletal developmental programs. The intensity, duration, and timing of intrauterine hyperglycemia may affect mesenchymal stem cell osteogenic-adipogenic balance, growth-plate chondrocyte maturation, osteoblast mineralization, and bone remodeling through mitochondrial dysfunction, oxidative stress, low-grade inflammation, insulin/insulin like growth factor (IGF) -axis disturbance, Wnt/β-catenin and bone morphogenetic protein (BMP) signaling imbalance, impaired placental calcium-phosphate transport, and epigenetic remodeling. Thus, the skeletal impact of GDM is more likely to follow a dynamic pattern characterized by early disruption, partial compensation, and residual risk rather than by a fixed reduction in bone density. Future studies should integrate maternal glycemic trajectories, placental multi-omics, cord-blood bone metabolic markers, offspring bone microarchitecture, and fracture outcomes to develop bone-oriented risk stratification and intervention strategies.