Effect of Rosiglitazone on Bone Quality in a Rat Model of Insulin Resistance and Osteoporosis
- Laura D. Sardone1,2,
- Richard Renlund3,
- Thomas L. Willett2,3,
- Ivan G. Fantus2,4 and
- Marc D. Grynpas1,2⇓
- 1Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- 2Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
- 3Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- 4Department of Medicine, Mount Sinai Hospital, University of Toronto, Ontario, Canada
- Corresponding author: Marc D. Grynpas, .
OBJECTIVE Rosiglitazone (RSG) is an insulin-sensitizing drug used to treat type 2 diabetes mellitus. The A Diabetes Outcome Progression Trial (ADOPT) shows that women taking RSG experienced more fractures than patients taking other type 2 diabetes drugs. These were not osteoporotic vertebral fractures but, rather, occurred in the limbs. The purpose of this study was to investigate how RSG treatment alters bone quality, which leads to fracture risk, using the Zucker fatty rat as a model.
RESEARCH DESIGN AND METHODS A total of 61 female 4-month-old rats were divided into six groups. One Sham group was a control and another was administered oral RSG 10 mg/kg/day. Four ovariectomized (OVX) groups were dosed as follows: controls, RSG 10 mg/kg, alendronate (ALN, injected at 0.7 mg/kg/week), and RSG 10 mg/kg plus ALN. After 12 weeks of treatment, bone quality was evaluated by mechanical testing. Microarchitecture, bone mineral density (BMD), cortical bone porosity, and bone remodeling were also measured.
RESULTS OVX RSG 10 mg/kg rats had lower vertebral BMD and compromised trabecular architecture versus OVX controls. Increased cortical bone porosity and decreased mechanical properties occurred in these rats. ALN treatment prevented decreased BMD and architectural and mechanical properties in the OVX model. Reduced bone formation, increased marrow adiposity, and excess bone resorption were observed in RSG-treated rats.
CONCLUSIONS RSG decreases bone quality. An unusual finding was an increase in cortical bone porosity induced by RSG, consistent with its effect on long bones of women. ALN, an inhibitor of bone resorption, enhanced mechanical strength and may provide an approach to partially counter the deleterious skeletal effects of RSG.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db10-1672/-/DC1.
- Received December 10, 2010.
- Accepted August 20, 2011.
- © 2011 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.