Antiosteoporotic Drugs and Incidence of Type 2 Diabetes Mellitus

Abstract

To the Editor, I read with interest the article by Vestergaard [1] about the potential effect of drugs against osteoporosis such as bisphosphonate and raloxifene on an incidence of type 2 diabetes mellitus (T2DM). The author showed that the risk of newly diagnosed T2DM was significantly reduced in osteoporotic patients treated with alendronate, etidronate, or raloxifene. Moreover, alendronate decreased the risk of T2DM in a dose-dependent manner. It has been shown that undercarboxylated osteocalcin plays an important role in fat and glucose metabolism [2]. Osteocalcin knockout mice displayed higher plasma glucose levels and glucose intolerance caused by decreased insulin sensitivity and its secretion. In addition, administration of undercarboxylated osteocalcin to osteocalcin knockout mice reversed the metabolic abnormalities of the mice. Ferron et al. [3] reported that insulin signaling in osteoblasts favors the activation of osteoclasts and bone resorption by inhibiting osteoprotegerin expression. In addition, when Esp knockout mice, a model of gain of osteocalcin function, were treated with alendronate, osteocalcin carboxylation, insulin secretion, blood glucose, and insulin tolerance were normalized. It is thus assumed that the insulin signal in osteoblasts regulates glucose homeostasis by stimulating osteoclast activity following decarboxylation of osteocalcin. This concept is supported by several clinical studies, including ours [4]. Based on these findings, it was anticipated that the antiresorptive drugs might deteriorate glucose homeostasis. However, in this large-scale cohort study by Vestergaard [1], a favorable effect of the drugs was surprisingly observed. Although bone markers were not measured in the study, bisphosphonate is known to decrease undercarboxylated osteocalcin levels [5]. This fact encourages us to prescribe the drugs for osteoporosis treatment, especially in patients who have a high risk of T2DM such as metabolic syndrome. Also, this is the first evidence showing that antiresorptive drugs might affect glucose metabolism, although the mechanism is not understood to date. Previously, it was reported that bisphosphonate and raloxifene improved arterial compliance in osteoporotic patients [6, 7]. Several studies also demonstrated that bisphosphonate and raloxifene affected lipid profiles [7, 8]. Therefore, the improvement of blood flow and lipid levels by bisphosphonate might be beneficial for insulin sensitivity and glucose uptake in muscle and liver. Improvement of motility by the treatment also might affect the results of the study. Further studies are thus necessary to investigate the effect of bisphosphonate and raloxifene on glucose metabolism.