The increasing use of thiazolidinediones for the treatment of type 2 diabetes mellitus, coupled with the potential for fractures in the aging population, poses a significant concern for health care providers. This concern is based on many reports of postapproval adverse musculoskeletal effects, particularly bone changes and fractures. To better understand the effects of thiazolidinediones on bone health, we conducted a PubMed search of articles published from January 1966-June 2009. We reviewed the hypothesized mechanisms for thiazolidinedione-induced adverse effects on bone, studies that evaluated thiazolidinedione use and fracture risk, potential treatment options for fracture minimization, and future directions for research. Thiazolidinedione-induced bone changes may stem from the ability of these drugs to reduce the activity of osteoblasts without an appreciable effect on osteoclasts, shifting the balance of bone homeostasis to favor bone loss. Clinical data suggest that treating patients who have type 2 diabetes with thiazolidinediones has detrimental effects on bone health, as measured by reduced bone mineral density and increased fracture rates, notably distal extremity fractures in female patients. Thiazolidinediones are selective peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists; thus, continued pursuit of PPAR system selectivity and investigation of other PPAR agonists are crucial to understanding and avoiding these detrimental effects. Clinicians, particularly pharmacists, must take an active role in educating colleagues on the importance of screening thiazolidinedione-treated patients for fracture risk, counseling patients on adequate calcium and vitamin D intake and fall prevention, and appropriately selecting therapy for secondary prevention of fracture.