Diabetes, bone and glucose-lowering agents: basic biology

Abstract

Skeletal fragility often accompanies diabetes and does not appear to correlate with low bone mass or trauma severity in individuals with diabetes. Instead (and in contrast to those with osteoporotic bone disease), bone remodelling and bone turnover are compromised in both type 1 and type 2 diabetes, contributing to defective bone material quality. This review is one of a pair discussing the relationship between diabetes, bone and glucose-lowering agents; an accompanying review is provided in this issue of Diabetologia by Ann Schwartz (DOI: 10.1007/s00125-017-4283-6). This review presents basic science evidence that, alongside other organs, bone is affected in diabetes via impairments in glucose metabolism, toxic effects of glucose oxidative derivatives (advance glycation end-products [AGEs]), and via impairments in bone microvascular function and muscle endocrine function. The cellular and molecular basis for the effects of diabetes on bone are discussed, as is the impact of diabetes on the stem cell niche and fracture healing. Furthermore, the safety of clinically approved glucose-lowering therapies and the possibility of developing a single therapy that would be beneficial for both insulin sensitisation and diabetes bone syndrome are outlined.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-017-4269-4) contains a slideset of the figures for download, which is available to authorised users

Cardiovascular autonomic neuropathy and bone metabolism in Type 1 diabetes

“…Our analyses of bone turnover markers show that a higher E/I ratio was associated with lower serum levels of osteoprotegerin and higher values for the Valsalva manoeuvre were associated with lower sclerostin levels. As osteoprotegerin is an osteoclast inhibitor, which downregulates bone resorption, and sclerostin is an osteoblast inhibitor, downregulating bone formation , our findings suggest that autonomic dysfunction may be associated with both reduced bone resorption and bone formation, which coincides with recent studies showing that both bone resorption and bone formation may be hampered in people with diabetes . As mentioned above, it is not possible to attribute these associations to either of the two branches of the autonomic nervous system.…”

Osteoprotegerin in diabetic osteopathy

“…The higher fracture risk described in T2DM, despite the elevated mean values of BMD and T-score, suggested the hypothesis that T2DM is associated with an impaired bone quality [33], which could be defined as "diabetic osteopathy". Several mechanisms may contribute to the pathogenesis of diabetic osteopathy [34e36], as a possible consequence of chronic hyperglycaemia, which directly or indirectly reduces bone turnover, leading to a poor bone quality [7].…”

“…Type 2 diabetic patients have an increased fracture risk, despite normal or greater bone mineral density (BMD) than non-diabetic subjects [6]. This observation suggested the hypothesis that chronic hyperglycaemia of T2DM affects bone metabolism, leading to a reduced bone turnover and consequently to a poor bone quality, and higher fracture risk [7].…”

Chronic stress and body composition disorders: implications for health and disease

“…In obesity, GLP-1 and other protective gut molecules decrease and the process of osteopenia and/or osteoporosis intensifies progression to osteosarcopenia [91]. Insulin resistance increases, advanced glycation end-products are produced, and reactive oxygen species are formed, and these negatively affect the skeletal muscle causing sarcopenia [92][93][94].…”