Dipeptidyl peptidase‐4 inhibitors and prevention of bone fractures: Effects beyond glyemic control

Dipeptidyl peptidase‐4 (DPP‐4) inhibitors improve glycemic control in patients with type 2 diabetes by preventing degradation of two incretin hormones, glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP). GLP‐1 and GIP are secreted from the intestine on ingestion of various nutrients, and enhance insulin secretion from pancreatic β‐cells glucose‐dependently1. Both incretin hormones show various biological functions in addition to their glucose‐dependent insulinotropic action. Thus, DPP‐4 inhibitors are expected to exert extra effects on various tissues and cell types. Among them, their effects on bones are of particular interest. A recent meta‐analysis of randomized clinical trials comparing DPP‐4 inhibitors with placebo or active comparator drugs in patients with type 2 diabetes suggested that treatment with DPP‐4 inhibitors could be associated with a reduced risk of bone fractures2. Type 2 diabetes is associated with higher bone mineral density and, paradoxically, with increased fracture risk, presumably because of impaired bone quality that causes fragility fractures even when bone mass remains normal3. Duration of more than 10 years, presence of diabetic nephropathy, presence of diabetic neuropathy and high serum levels of pentosidine are shown to be risk factors for bone fractures3. One plausible mechanism of increased risk of bone fractures in patients with type 2 diabetes relates to chronic hyperglycemia, raising concentrations of advanced glycation end‐products, such as pentosidine, that increases non‐enzymatic collagen cross‐linking and impairs bone quality. Furthermore, accumulating evidence shows negative impacts of antidiabetic drugs, thiazolidinediones, on bone turnover and bone fractures in patients with type 2 diabetes. However, so far, no oral antidiabetic drugs have been associated clinically with a reduction of bone fractures. Thus, the current finding on DPP‐4 inhibitors by Monami et al. is highly promising despite some limitations, including short duration of the trials included, bone fractures being not principal end‐points, and no discrimination between sexes and between pre‐ and postmenopausal women; and the Monami study provides a premise to initiate randomized, prospective, long‐term clinical trials evaluating the effects of DPP‐4 inhibitors on bone metabolism and bone fractures in patients with type 2 diabetes. The effects of GIP and GLP‐1 on bone metabolism have been well characterized mainly in rodents (Figure 1)1. Investigations on GIP receptor‐deficient mice and GIP transgenic mice showed that GIP increases bone mass by acting on osteoblasts to promote bone formation after meal ingestion, and inhibiting parathyroid hormone‐induced bone resorption. Furthermore, GIP administration has been shown to attenuate ovariectomy‐induced bone loss in rats. In contrast, studies on GLP‐1 receptor‐deficient mice showed that GLP‐1 controls bone resorption, likely through a calcitonin‐dependent pathway. Administration of GLP‐1 receptor agonist exenatide has been shown to promote bone formation in normal and streptozotocin‐induced diabetic rats, suggesting its insulin‐independent action. Although these lines of evidence suggest an association of GIP and GLP‐1 with bone turnover, the effects of GIP and GLP‐1 on human bone turnover are largely unknown. A recent study showed that 44‐week exenatide treatment did not affect bone mineral density in patients with type 2 diabetes4. As aforementioned, GLP‐1 action on the bone is presumably mediated through calcitonin. A series of clinical trials on liraglutide, another GLP‐1 receptor agonist, showed few changes in serum calcitonin levels in patients with type 2 diabetes, suggesting that GLP‐1 might not play a role in human bone metabolism. Regarding GIP, Henriksen et al.5 previously reported that postprandial reduction of bone resorption was not mediated by GIP, but GLP‐2 – another intestinal hormone cosecreted with GLP‐1. However, caution should be taken when interpreting their results, as they investigated the effects of subcutaneous single injections of native GIP that should be rapidly inactivated by DPP‐4 before it reaches the bones. Therefore, further investigations are definitely required to understand GIP and GLP‐1 actions on bone metabolism in humans. Figure 1 The effects of two incretin hormones, glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like polypeptide‐1 (GLP‐1), on bone metabolism. GIP binds to GIP receptors expressed on osteoblasts, thereby . Prevention of bone fractures could be the tip of the iceberg among potentially beneficial effects of DPP‐4 inhibitors in patients with type 2 diabetes. It has been shown that DPP‐4 inhibitors target not only two incretin hormones, GIP and GLP‐1, but also other DPP‐4 substrates, such as pituitary adenylate cyclase‐activating peptide and stromal cell‐derived factor‐1α in patients with type 2 diabetes. Enhancement of these bioactive polypeptides could prevent progression of diabetic micro‐ and macrovascular complications independently of improvement in glycemic control. In the future, clinical trials with adequately powered, prospective, controlled relevant end‐points will clarify the effects of DPP‐4 inhibitors beyond glycemic control.