Effect of Dipeptidyl Peptidase-4 Inhibitors on Bone Metabolism and the Possible Underlying Mechanisms

Abstract

Diabetes mellitus has been demonstrated to be closely associated with osteoporosis. Accordingly, hypoglycemic therapy is considered effective in treating metabolic bone disease. Recently, the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors, a new type of antidiabetic drug, on bone metabolism have been widely studied. This review mainly describes the effects of DPP-4 inhibitors on bone metabolism, including their effects on bone mineral density, bone quality, and fracture risk. In addition, the potential underlying mechanisms are discussed. Based on the current progress in this research field, DPP-4 inhibitors have been proved to reduce fracture risk. In addition, sitagliptin, a strong and highly selective DPP-4 inhibitor, showed its beneficial effects on bone metabolism by improving bone mineral density, bone quality, and bone markers. With regard to the potential underlying mechanisms, DPP-4 inhibitors may promote bone formation and reduce bone resorption through DPP-4 substrates and DPP-4-related energy metabolism. Vitamin D and other related signaling pathways also play a role in affecting bone metabolism. Although these assumptions are controversial, they provide a translational pharmacology approach for the clinical use of DPP-4 inhibitors in the treatment of metabolic diseases. Prior to the use of these drugs in clinic, further studies should be conducted to determine the appropriate type of DPP-4 inhibitor, the people who would benefit the most from this therapy, appropriate dose and duration, and the effects of the treatment.

Diabetes pharmacotherapy and effects on the musculoskeletal system

“…DPP‐4 inhibitors have been reported to have neutral or beneficial effects on bone by the majority of studies and have not been associated with increased risk of fracture, with the exception of sitagliptin and saxagliptin, for which contradictory clinical studies exist. Sitagliptin has been associated with greater therapeutic potential in bone metabolism compared with saxagliptin, based on pre‐clinical data as it has been shown to promote bone formation, bone healing and suppress osteoclastogenesis in animal models . Clinical studies have shown that sitagliptin positively affects markers of bone turnover, but has a neutral or potentially harmful effect on fracture risk.…”

“…Clinical studies have shown that sitagliptin positively affects markers of bone turnover, but has a neutral or potentially harmful effect on fracture risk. On the other hand, saxagliptin has been shown to have negative effects on bone in both pre‐clinical and clinical studies . Further prospective studies, designed specifically to evaluate fracture risk, are necessary to demonstrate the musculoskeletal safety of these drugs in persons with diabetes.…”

“…DPP‐4 inhibitors are effective and well tolerated when used as monotherapy, although when used in combination with other oral antidiabetic agents, such as metformin and SUs, their efficacy is improved . Their mechanism of action on bone is still largely undiscovered but due to their effect on prolonging endogenous GLP‐1 and GIP action, improved glucose tolerance and enhanced GLP‐1 and GIP action on bone are two of the proposed mechanisms . GLP‐1 has been shown to affect bone metabolism, specifically by promoting osteoblast proliferation and inhibiting osteoblast apoptosis in murine osteoblasts .…”

“…Additionally, saxagliptin (as monotherapy or add-on therapy), in recent data from pooled analysis of 20 randomized control studies demonstrated a higher incidence of fracture with saxagliptin, 301 Sitagliptin has been associated with greater therapeutic potential in bone metabolism compared with saxagliptin, based on pre-clinical data as it has been shown to promote bone formation, bone healing and suppress osteoclastogenesis in animal models. 277 Clinical studies have shown that sitagliptin positively affects markers of bone turnover, 170 but has a neutral or potentially harmful effect on fracture risk. On the other hand, saxagliptin has been shown to have negative effects on bone in both pre-clinical and clinical studies.…”

“…On the other hand, saxagliptin has been shown to have negative effects on bone in both pre-clinical and clinical studies. 277…”