Effect of anti-diabetic drugs on bone metabolism: Evidence from preclinical and clinical studies

Diabetes mellitus is associated with abnormal bone health and an increased risk of fracture even though patients have normal or higher BMD. The mechanisms behind diabetes mellitus- induced various skeletal disorders remain unclear. Anti-diabetic drugs may have negative or positive impact on bone metabolism. For instance, thiazolidinediones increases the bone loss and risk of fracture possibly through PPARγ activation in bone marrow cells and hamper osteoblastogenesis via decreasing Runx2 transcription factor, IGF-1 and Wnt signalling pathways. In contrast, metformin and sulfonylureas have a neutral or positive effect on bone health and reduced risk of fracture. Results from the preclinical and clinical studies convey conflicting findings over insulin safety profile on bone health. Incretin-based therapy (GLP-1 receptor agonist and DPP-4 inhibitors) and SGLT2 inhibitors are currently marketed anti- diabetic drugs. While evidence from animal studies suggest that incretin-based therapy have anabolic effect on bone, limited clinical data of DPP-4 inhibitors and GLP-1 receptor agonist indicated a neutral effect on the bone health and risk of fracture. SGLT2 inhibitors may cause bone loss or increase fracture risk due to altered calcium, phosphate and sodium concentration. Therefore, safety concerns of anti-diabetic drugs are crucial for the management of diabetes mellitus. In this review, analysis of the available evidence for effect of anti-diabetic drugs on the bone metabolism and fracture risk in diabetes mellitus is described.