Effect of rosiglitazone on bone quality in a rat model of insulin resistance and osteoporosis

Abstract

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.

FIG. 1.

Representative three-dimensional images showing porosity in cross sections of rat femora obtained with MicroCT. Porosity analysis showed a significant increase in femoral porosity for OVX rats treated with an RSG dose of 10 mg/kg (P = 0.023): OVX controls (A), OVX RSG 10 (B), OVX ALN (C), and OVX RSG 10 + ALN (D).

FIG. 2.

Representative static histomorphometry images of rat proximal tibiae. Sections stained with Goldner’s Trichrome so that trabeculae appear green and bone marrow appears pink. White space represents space occupied by adipocytes: OVX controls (A), OVX ALN (B), OVX RSG 10 (C), and OVX RSG 10 + ALN (D). (A high-quality digital representation of this figure is available in the online issue.)