The Peroxisome Proliferator-Activated Receptor-γ Agonist Rosiglitazone Decreases Bone Formation and Bone Mineral Density in Healthy Postmenopausal Women: A Randomized, Controlled Trial

Abstract

Context: Thiazolidinediones, which are peroxisome proliferator-activated receptor-γ agonists, are widely prescribed to patients with disorders characterized by insulin resistance. Preclinical studies suggest that peroxisome proliferator-activated receptor-γ signaling negatively regulates bone formation and bone density. Human data on the skeletal effects of thiazolidinediones are currently available only from observational studies. Objective: The objective of the study was to determine whether rosiglitazone, a thiazolidinedione, inhibits bone formation. Design: The study was a 14-wk randomized, double-blind, placebo-controlled trial. Setting: The study was conducted in the general community. Patients: Fifty healthy, postmenopausal women participated in the study. Intervention: Intervention was rosiglitazone 8 mg/d. Main Outcome Measures: The primary end point was biochemical markers of bone formation, and secondary end points were a bone resorption marker and bone mineral density. Results: The osteoblast markers procollagen type I N-terminal propeptide and osteocalcin declined by 13% (P < 0.005 vs. placebo) and 10% (P = 0.04 vs. placebo), respectively, in the rosiglitazone group. These changes were evident by 4 wk and persisted for the duration of the study. There was no change in the serum β-C-terminal telopeptide of type I collagen, a marker of bone resorption (P = 0.9 vs. placebo). Total hip bone density fell in the rosiglitazone group (mean change from baseline rosiglitazone −1.9%, placebo −0.2%; between-group difference 1.7%, 95% confidence interval 0.6–2.7, P < 0.01); lumbar spine bone density fell significantly from baseline values in the rosiglitazone group (P = 0.02 vs. baseline) but was not significantly different between groups (mean change from baseline rosiglitazone −1.2%, placebo −0.2%; between-group difference 1.0%, 95% confidence interval −0.2–2.3, P = 0.13). Conclusions: Short-term therapy with rosiglitazone exerts detrimental skeletal effects by inhibiting bone formation. Skeletal end points should be included in future long-term studies of thiazolidinedione use.