Gallagher Emily Jane, Sun Hui, Kornhauser Caroline, Tobin-Hess Aviva, Epstein Sol, Yakar Shoshana, LeRoith Derek
Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA.
Diabetes Metab Res Rev. 2014 Mar;30(3):191-200. doi: 10.1002/dmrr.2466.
Individuals with type 2 diabetes (T2D) are at greater risk of bone fractures than those without diabetes. Certain oral diabetic medications may further increase the risk of fracture. Dipeptidyl peptidase-IV (DPP-IV) inhibitors are incretin-based therapies that are being increasingly used for the management of T2D. It has been hypothesized that these agents may reduce fracture risk in those with T2D. In this study, we used a mouse model of T2D to examine the effects of the DPP-IV inhibitor, MK-0626, on bone.
Male wild type (WT) and diabetic muscle-lysine-arginine (MKR) mice were treated with MK-0626, pioglitazone, alendronate or vehicle. The effects of treatment with MK-0626 on bone microarchitecture and turnover were compared with treatment with pioglitazone, alendronate and vehicle. Osteoblast differentiation was determined by alkaline phosphatase staining of bone marrow cells from WT and MKR mice after treatment with pioglitazone, MK-0626 or phosphate buffered saline.
We found that MK-0626 had neutral effects on cortical and trabecular bone in diabetic mice. Pioglitazone had detrimental effects on the trabecular bone of WT but not of diabetic mice. Alendronate caused improvements in cortical and trabecular bone architecture in diabetic and WT mice. MK-0626 did not alter osteoblast differentiation, but pioglitazone impaired osteoblast differentiation in vitro.
Overall, the DPP-IV inhibitor, MK-0626, had no adverse effects on bone in an animal model of T2D or directly on osteoblasts in culture. These findings are reassuring as DPP-IV inhibitors are being widely used to treat patients with T2D who are already at an increased risk of fractures.
2型糖尿病（T2D）患者比非糖尿病患者骨折风险更高。某些口服降糖药物可能会进一步增加骨折风险。二肽基肽酶-IV（DPP-IV）抑制剂是基于肠促胰岛素的疗法，越来越多地用于T2D的治疗。据推测，这些药物可能会降低T2D患者的骨折风险。在本研究中，我们使用T2D小鼠模型来研究DPP-IV抑制剂MK-0626对骨骼的影响。
雄性野生型（WT）和糖尿病肌肉赖氨酸-精氨酸（MKR）小鼠接受MK-0626、吡格列酮、阿仑膦酸盐或赋形剂治疗。将MK-0626治疗对骨微结构和骨转换的影响与吡格列酮、阿仑膦酸盐和赋形剂治疗进行比较。在用吡格列酮、MK-0626或磷酸盐缓冲盐水治疗后，通过对WT和MKR小鼠骨髓细胞进行碱性磷酸酶染色来确定成骨细胞分化。
我们发现MK-0626对糖尿病小鼠的皮质骨和小梁骨具有中性作用。吡格列酮对WT小鼠的小梁骨有不良影响，但对糖尿病小鼠没有。阿仑膦酸盐使糖尿病和WT小鼠的皮质骨和小梁骨结构得到改善。MK-0626没有改变成骨细胞分化，但吡格列酮在体外损害成骨细胞分化。
总体而言，DPP-IV抑制剂MK-0626在T2D动物模型中对骨骼或直接对培养中的成骨细胞没有不良影响。由于DPP-IV抑制剂被广泛用于治疗已经具有较高骨折风险的T2D患者，这些发现令人安心。
