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.

Clinical evidence indicates that bone status is affected in patients with type 2 diabetes mellitus (T2DM). Regardless of normal or even high bone mineral density, T2DM patients have increased risk of fractures. One class of antidiabetic drugs, thiazolidinediones (TZDs), causes bone loss and further increases facture risk, placing TZDs in the category of drugs causing secondary osteoporosis. Risk factors for development of TZD-induced secondary osteoporosis are gender (women), age (elderly), and duration of treatment. TZDs exert their antidiabetic effects by activating peroxisome proliferator-activated receptor-γ (PPAR-γ) nuclear receptor, which controls glucose and fatty acid metabolism. In bone, PPAR-γ controls differentiation of cells of mesenchymal and hematopoietic lineages. PPAR-γ activation with TZDs leads to unbalanced bone remodeling: bone resorption increases and bone formation decreases. Laboratory research evidence points toward a possible separation of unwanted effects of PPAR-γ on bone from its beneficial antidiabetic effects by using selective PPAR-γ modulators. This review also discusses potential pharmacologic means to protect bone from detrimental effects of clinically used TZDs (pioglitazone and rosiglitazone) by using combinational therapy with approved antiosteoporotic drugs, or by using lower doses of TZDs in combination with other antidiabetic therapy. We also suggest a possible orthopedic complication, not yet supported by clinical studies, of delayed fracture healing in T2DM patients on TZD therapy.

It is known that insulin resistance and type 2 diabetes mellitus are associated with increased fractures and that brown adipose tissue (BAT) counteracts many if not all of the symptoms associated with type 2 diabetes. By the use of FoxC2_AD^+/Tg mice, a well-established model for induction of BAT, or beige fat, we present data extending the beneficial action of beige fat to also include a positive effect on bone. FoxC2_AD^+/Tg mice are lean and insulin-sensitive and have high bone mass due to increased bone formation associated with high bone turnover. Inducible BAT is linked to activation of endosteal osteoblasts whereas osteocytes have decreased expression of the Sost transcript encoding sclerostin and elevated expression of Rankl. Conditioned media (CM) collected from forkhead box c2 (FOXC2)-induced beige adipocytes activated the osteoblast phenotype and increased levels of phospho-AKT and β-catenin in recipient cells. In osteocytes, the same media decreased Sost expression. Immunodepletion of CM with antibodies against wingless related MMTV integration site 10b (WNT10b) and insulin-like growth factor binding protein 2 (IGFBP2) resulted in the loss of pro-osteoblastic activity, and the loss of increase in the levels of phospho-AKT and β-catenin. Conversely, CM derived from cells overexpressing IGFBP2 or WNT10b restored osteoblastic activity in recipient cells. In conclusion, beige fat secretes endocrine/paracrine activity that is beneficial for the skeleton.