Drugs for type 2 diabetes: role in the regulation of bone metabolism.

Until a few years ago, the possibility that glucose-lowering drugs affect glucose metabolism and fracture risk was not even considered. The increased incidence of fractures with thiazolidinediones in women was a causal finding. This phenomenon, which has been demonstrated by large-scale clinical trials, is associated with a reduction in bone density. Thiazolidinediones stimulate adipocyte differentiation, and inhibit osteoblast differentiation, from bone marrow stromal cells; other mechanisms could also be involved in the thiazolidinedione-induced reduction of bone density. Insulin has an anabolic effect on the bone, but it is nonetheless associated with an increased incidence of fractures in observational studies. Although this finding could be partly due to unaccounted confounders, it is likely that insulin-induced hypoglycemia, and consequent falls, produce a higher risk for fractures, at least in the elderly. Among older drugs, metformin and sulfonylureas do not appear to produce any beneficial or detrimental effects on the bone. Of newer agents, DPP4 inhibitors have been associated with a possible protective effect in earlier trials, but this result has not been confirmed in larger scale studies on patients with a higher level of comorbidities. Considering that the increase in active incretin levels determined by DPP4 inhibitors could theoretically improve bone density, further clinical studies are needed to assess more clearly the effect of this class of drugs. GLP-1 receptor agonists also increase bone density in experimental models, but human data are still insufficient to draw any conclusion.