Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Diabetes. 2011 Dec;60(12):3271-8. doi: 10.2337/db10-1672. Epub 2011 Oct 12.
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.
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.
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.
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.
罗格列酮（RSG）是一种用于治疗 2 型糖尿病的胰岛素增敏药物。A 糖尿病结局进展试验（ADOPT）表明，服用 RSG 的女性比服用其他 2 型糖尿病药物的患者发生更多骨折。这些骨折不是骨质疏松性椎体骨折，而是发生在四肢。本研究旨在使用 Zucker 肥胖大鼠作为模型，探讨 RSG 治疗如何改变导致骨折风险的骨质量。
共将 61 只 4 月龄雌性大鼠分为 6 组。1 个 Sham 组作为对照，另 1 个给予口服 RSG 10mg/kg/天。4 个卵巢切除（OVX）组的剂量如下：对照组、RSG 10mg/kg、阿伦膦酸钠（ALN，每周注射 0.7mg/kg）和 RSG 10mg/kg 加 ALN。治疗 12 周后，通过机械测试评估骨质量。还测量了微结构、骨密度（BMD）、皮质骨孔隙率和骨重建。
与 OVX 对照组相比，OVX RSG 10mg/kg 大鼠的椎体 BMD 较低，骨小梁结构受损。这些大鼠的皮质骨孔隙率增加，机械性能降低。ALN 治疗可预防 OVX 模型中 BMD、结构和机械性能的降低。在 RSG 治疗的大鼠中观察到骨形成减少、骨髓脂肪增多和骨吸收过度。
RSG 降低骨质量。一个不寻常的发现是 RSG 引起的皮质骨孔隙率增加，这与其对女性长骨的作用一致。ALN，一种骨吸收抑制剂，增强了机械强度，并可能为部分抵消 RSG 对骨骼的有害影响提供一种方法。
