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

Department of Medicine (A.G., M.B., G.G., D.W., A.H., I.R.R.), University of Auckland, and LabPlus (J.D.), Auckland City Hospital, 1020 Auckland, New Zealand

Address all correspondence and requests for reprints to: Dr. Andrew Grey, Department of Medicine, University of Auckland, Private Bag 92019, 1020 Auckland, New Zealand. E-mail: a.grey{at}auckland.ac.nz.

Context: Thiazolidinediones, which are peroxisome proliferator-activated receptor- agonists, are widely prescribed to patients with disorders characterized by insulin resistance. Preclinical studies suggest that peroxisome proliferator-activated receptor- 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 ß-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.

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