Thiazolidinedione-induced Skeletal Fragility

INTRODUCTION

Thiazolidinediones (TZDs) are insulin-sensitizing drugs that activate the gamma isoform of the peroxisome proliferator-activated receptor (PPAR) family of nuclear transcription factors. Rosiglitazone and pioglitazone, the TZDs currently in clinical use, are widely prescribed in the management of type 2 diabetes mellitus (T2DM), accounting for more than 20% of oral hypoglycemic medication use in the United States []. In T2DM, TZDs improve glycemic control [], are more effective than other oral hypoglycemic agents in maintaining adequate glycemic control [], and slow the progression of coronary artery atherosclerosis more effectively than other oral therapies []. The use of TZDs may increase further as a result of recent evidence that treatment with rosiglitazone slows the rate of progression from impaired glucose tolerance to T2DM []. In addition to an established role in the management of T2DM, TZDs have potential and emerging applications in other disorders characterized by insulin resistance, such as polycystic ovarian syndrome []. Both rosiglitaonze and pioglitazone increase the risk of non-fatal congestive heart failure [, ]. Rosiglitazone may also increase the risk of other cardiovascular events [, ], while pioglitazone may favorably affect the incidence of vascular events [, , ]. Current prescribing trends in the United States indicate that pioglitazone is the preferred TZD [].

The frequent use of TZDs, the likelihood that treatment will be for prolonged periods of time, and the knowledge that PPAR is expressed in many tissues mandate a careful evaluation of their safety. PPAR is expressed in skeletal tissue, and there is now a considerable body of evidence that PPAR signaling regulates skeletal function []. Recent evidence suggests that TZD use is associated with accelerated bone loss and an increased risk of fractures, at least in women with T2DM. The purpose of this review is to summarize current knowledge of the skeletal effects of TZD therapy.

Thiazolidinediones (TZDs) are commonly used as insulin-sensitizing agents in the treatment of type 2 diabetes mellitus, a disorder in which fracture risk is increased. The molecular target of TZDs, the gamma isoform of the peroxisome proliferator-activated receptor (PPAR), is expressed in skeletal tissue, where its activation promotes differentiation of mesenchymal stem cells into adipocytes at the expense of osteoblasts, and increases osteoclastogenesis. Administration of TZDs to rodents consistently decreases bone formation and variably increases bone resorption, thereby causing bone loss. Randomized trials in humans have demonstrated that TZDs decrease markers of bone formation and promote bone loss. Data from randomized trials of both rosiglitazone and pioglitazone have shown an increase in risk of limb fractures in women assigned to TZD therapy. An emerging body of observational evidence suggests that fracture risk is also increased in the axial skeleton and in men exposed to TZDs. Fracture risk should be assessed in individuals for whom TZD therapy is being considered and an alternative hypoglycemic agent prescribed in those at moderate to high risk. Few data are available on the efficacy of osteoporosis therapies in managing TZD-induced bone loss, but antiresorptive therapy may be effective.

Keywords

Thiazolidinedione, type 2 diabetes mellitus, fracture, bone, osteoporosis, bone formation, bone resorption,