Beyond Glycemic Control in Diabetes Mellitus: Effects of Incretin-Based Therapies on Bone Metabolism

Abstract

Diabetes mellitus (DM) and osteoporosis (OP) are common disorders with a significant health burden, and an increase in fracture risk has been described both in type 1 (T1DM) and in type 2 (T2DM) diabetes. The pathogenic mechanisms of impaired skeletal strength in diabetes remain to be clarified in details and they are only in part reflected by a variation in bone mineral density. In T2DM, the occurrence of low bone turnover together with a decreased osteoblast activity and compromised bone quality has been shown. Of note, some antidiabetic drugs (e.g., thiazolidinediones, insulin) may deeply affect bone metabolism. In addition, the recently introduced class of incretin-based drugs (i.e., GLP-1 receptor agonists and DPP-4 inhibitors) is expected to exert potentially beneficial effects on bone health, possibly due to a bone anabolic activity of GLP-1, that can be either direct or indirect through the involvement of thyroid C cells. Here we will review the established as well as the putative effects of incretin hormones and of incretin-based drugs on bone metabolism, both in preclinical models and in man, taking into account that such therapeutic strategy may be effective not only to achieve a good glycemic control, but also to improve bone health in diabetic patients.

Pharmacology, Physiology, and Mechanisms of Action of Dipeptidyl Peptidase-4 Inhibitors

“…Several DPP4 substrates including GIP, GLP-1, PYY, NPY, and GLP-2 regulate bone formation or resorption in rodents (220). Dpp4 Ϫ/Ϫ mice exhibited normal bone formation (221), and treatment of high-fat-fed mice with sitagliptin had no effect on bone quality (221); however, sitagliptin increased trabecular bone mineralization and architecture.…”

Pleiotropic effects of the dipeptidylpeptidase-4 inhibitors on the cardiovascular system

“…Since impaired angiogenesis and rarefaction is associated with obesity/T2DM and contributes to impaired diastolic dysfunction and renal injury, the efficacy of various DPP-4i in promoting SDF-1␣-mediated effects may significantly contribute to improved CV outcomes. Incretin signaling has been shown to modulate bone remodeling (28). Therefore, DPP-4i may also improve bone repair by their effects on EPCs and SDF-1␣, in addition to their actions on bone cells (28).…”

“…Incretin signaling has been shown to modulate bone remodeling (28). Therefore, DPP-4i may also improve bone repair by their effects on EPCs and SDF-1␣, in addition to their actions on bone cells (28). Furthermore, DPP-4i may act to increase EPC numbers by potentiating the bone marrow mobilizing effects of granulocyte-colony stimulating factor-1 (53,54).…”

A Review of the Mechanisms, Diagnosis and Preventative Treatment of Osteoporotic Fragility Fractures in Patients With Type 2 Diabetes Mellitus

“…These have shown early potential in T2DM treatment for improving glycemic control but also having an anabolic effect on bone health (which could perhaps be enhanced by concurrent thiazolidinedione use), although the mechanisms behind this are not fully understood [35,36]. Thiamine derivatives have also been suggested as a potential solution to reverse bone mineral reductions in patients with T2DM [20].…”