Protective Effects of Vildagliptin against Pioglitazone-Induced Bone Loss in Type 2 Diabetic Rats

Abstract

Long-term use of thiazolidinediones (TZDs) is associated with bone loss and an increased risk of fracture in patients with type 2 diabetes (T2DM). Incretin-based drugs (glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors) have several benefits in many systems in addition to glycemic control. In a previous study, we reported that exendin-4 might increase bone mineral density (BMD) by decreasing the expression of SOST/sclerostin in osteocytes in a T2DM animal model. In this study, we investigated the effects of a DPP-4 inhibitor on TZD-induced bone loss in a T2DM animal model. We randomly divided 12-week-old male Zucker Diabetic Fatty (ZDF) rats into four groups; control, vildagliptin, pioglitazone, and vildagliptin and pioglitazone combination. Animals in each group received the respective treatments for 5 weeks. We performed an intraperitoneal glucose tolerance test (IPGTT) before and after treatment. BMD and the trabecular micro-architecture were measured by DEXA and micro CT, respectively, at the end of the treatment. The circulating levels of active GLP-1, bone turnover markers, and sclerostin were assayed. Vildagliptin treatment significantly increased BMD and trabecular bone volume. The combination therapy restored BMD, trabecular bone volume, and trabecular bone thickness that were decreased by pioglitazone. The levels of the bone formation marker, osteocalcin, decreased and that of the bone resorption marker, tartrate-resistant acid phosphatase (TRAP) 5b increased in the pioglitazone group. These biomarkers were ameliorated and the pioglitazone-induced increase in sclerostin level was lowered to control values by the addition of vildagliptin. In conclusion, our results indicate that orally administered vildagliptin demonstrated a protective effect on pioglitazone-induced bone loss in a type 2 diabetic rat model.

Novel skeletal effects of glucagon-like peptide-1 (GLP-1) receptor agonists

“…Kim and coworkers have indeed shown that sclerostin levels are increased in diabetic rats compared to controls and can be downregulated by exenatide treatment (Kim et al 2013). More recently, they demonstrate that the DPP-4 inhibitor vildagliptin lowers the increased levels of sclerostin induced by thiazolidinedione (Eom et al 2016). Our own results showed that exenatide but not liraglutide decreased sclerostin levels in OVX mice (Pereira et al 2015).…”

“…However, not all studies are showing a positive effect of DPP-4 inhibitors on fracture risk, BMD and bone turnover (Monami et al 2011, Driessen et al 2014. Recent preclinical studies showed protective effect of DPP-4 inhibitors on the skeleton of diabetic rats (Glorie et al 2014, Eom et al 2016 while others have shown no effect (Gallagher et al 2014). In vitro studies have also indicated neutral effects of DPP-4 inhibitors on bone formation (Gallagher et al 2014).…”

Diabetes pharmacotherapy and effects on the musculoskeletal system

“…Interestingly, pharmacologic reduction in DPP‐4 showed an improvement in the bone phenotype of mice, whereas genetically induced reduction of DPP‐4 (DPP‐4 knockout mice) was not associated with such changes . Vildagliptin was also found to have beneficial effects on BMD and bone microacrchitecture and has even been shown to restore bone changes induced by pioglitazone treatment in a T2D animal model . Another DPP‐4 inhibitor, MK‐0626, had neutral effects on bone in a T2D mouse model .…”

“…289 Vildagliptin was also found to have beneficial effects on BMD and bone microacrchitecture 292 and has even been shown to restore bone changes induced by pioglitazone treatment in a T2D animal model. 293 Another DPP-4 inhibitor, MK-0626, had neutral effects on bone in a T2D mouse model. 286 Sitagliptin has not been associated with an increased risk of fracture based on published studies 265,298 and a meta-analysis that included 27 trials evaluating sitagliptin use 299 ; however, a recent cohort study with 1578 participants concluded that sitagliptin use for longer than 250 days was associated with increased risk for fracture (aHR: 1.32).…”

Practical strategies for improving outcomes in T2DM: The potential role of pioglitazone and DPP4 inhibitors

“…Actually, preclinical studies have suggested a protective effect of DPP4i on bone metabolism in animals treated with pioglitazone. The administration of vildagliptin to T2DM diabetic rats restored bone mass density, trabecular bone volume and trabecular bone thickness, all parameters decreased by pioglitazone . Also, the risk of fracture can be mitigated by fall prevention and by screening and treatment of osteoporosis.…”