Bone metabolism in diabetes: a clinician's guide to understanding the bone-glucose interplay

Abstract

Skeletal fragility is an increasingly recognised, but poorly understood, complication of both type 1 and type 2 diabetes. Fracture risk varies according to skeletal site and diabetes-related characteristics. Post-fracture outcomes, including mortality risk, are worse in those with diabetes, placing these people at significant risk. Each fracture therefore represents a sentinel event that warrants targeted management. However, diabetes is a very heterogeneous condition with complex interactions between multiple co-existing, and highly correlated, factors that preclude a clear assessment of the independent clinical markers and pathophysiological drivers for diabetic osteopathy. Additionally, fracture risk calculators and routinely used clinical bone measurements generally underestimate fracture risk in people with diabetes. In the absence of dedicated prospective studies including detailed bone and metabolic characteristics, optimal management centres around selecting treatments that minimise skeletal and metabolic harm. This review summarises the clinical landscape of diabetic osteopathy and outlines the interplay between metabolic and skeletal health. The underlying pathophysiology of skeletal fragility in diabetes and a rationale for considering a diabetes-based paradigm in assessing and managing diabetic bone disease will be discussed.

Keywords: Bone; Diabetes; Fractures; Insulin resistance; Osteoporosis; Review.

Fig. 1

Summary of the clinical features and pathophysiology of skeletal fragility in diabetes. Numerous diabetes-related clinical characteristics are associated with increased fracture risk, although the independent contributors are difficult to ascertain because of significant clinical overlap. The contributing pathophysiological mechanisms are multifactorial, with many overlapping and sometimes conflicting effects. BMD is affected in diabetes (low in type 1 diabetes, normal/near-normal in type 2 diabetes) yet underestimates fracture risk compared with the general population for the same BMD level. Rather, impaired bone microarchitecture and low bone turnover result in impaired strength loading, suggesting a maladaptive response despite skeletal loading. HR-pQCT, high-resolution peripheral quantitative computed tomography; ROS, reactive oxygen species; T1D, type 1 diabetes; T2D, type 2 diabetes. This figure is available as part of a downloadable slideset

Fig. 2

Optimising the management of skeletal fragility in diabetes. There are no prospective RCTs establishing the optimal management of people at risk of diabetic osteopathy. Post hoc analyses suggest that anti-osteoporotic treatments are probably at least as effective in type 2 diabetes as in the general population. Anabolic therapies may have additional benefits in type 2 diabetes given the underlying low bone turnover. The safety and efficacy of anti-osteoporotic medications in normal/near-normal BMD is unknown. With the increasing use of glucose-lowering medications for non-glycaemic benefits (including weight loss and cardiovascular and renal benefits), the effects on the skeleton need to be established and agents with neutral/positive bone effects considered in those at high skeletal risk. AFF, atypical femoral fracture; DPP-4i, dipeptidyl peptidase-4 inhibitors; GLP1-RA, glucagon-like peptide-1 receptor agonist; ONJ, osteonecrosis of the jaw; T1D, type 1 diabetes; T2D, type 2 diabetes. This figure is available as part of a downloadable slideset