Thiazolidinediones on PPARγ: The Roles in Bone Remodeling

Abstract

Thiazolidinediones (TZDs) are synthetic PPARγ (peroxisome proliferator-activated receptor gamma) agonists and a class of drugs for diabetes mellitus type 2 that can decrease blood sugar efficiently by enhancing insulin sensitivity. However, increased bone fracture risk in diabetic individuals treated with TZDs is one of the reported side effects. Recent studies show that TZDs such as rosiglitazone simultaneously inhibit osteoblast differentiation and activate osteoclast differentiation, leading to bone loss due to decreased bone formation and increased bone resorption. Furthermore, TZDs may activate PPARγ in tissues other than bone, such as the hypothalamus-pituitary-gonad (HPG) axis to indirectly regulate bone mass. This paper will focus on current new developments that implicate potential mechanisms for how PPARγ modulates skeletal homeostasis and how TZDs exert bone-loss side effects.

Figure 1

Potential mechanisms for TZD-induced bone loss. In vivo studies in both clinical trials and using animal models demonstrate that TZDs, a class of diabetic drugs that functions as PPARγ agonists, cause bone loss and increased fracture risk, especially in postmenopausal women, by simultaneously inhibiting bone formation and stimulating bone resorption. In addition to the well-documented direct effects of TZDs on bone cell differentiation and function, emerging evidence indicate that TZD may also exert its detrimental skeletal effects via several potential indirect effects, which provokes further investigation in future preclinical and clinical studies.