Review
Type 2 diabetes and the skeleton: new insights into sweet bones

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Summary

Substantial evidence shows that skeletal fragility should be considered among the complications associated with type 2 diabetes. Individuals with type 2 diabetes have increased fracture risk, despite normal bone mineral density (BMD) and high BMI–factors that are generally protective against fractures. The mechanisms underlying skeletal fragility in diabetes are not completely understood, but are multifactorial and likely include effects of obesity, hyperglycaemia, oxidative stress, and accumulation of advanced glycation end products, leading to altered bone metabolism, structure, and strength. Clinicians should be aware that BMD measurements underestimate fracture risk in people with type 2 diabetes, and that new treatments for diabetes, with neutral or positive effects on skeletal health, might play a part in the management of diabetes in those at high risk of fracture. Data for the optimum management of osteoporosis in patients with type 2 diabetes are scarce, but in the absence of evidence to the contrary, physicians should follow guidelines established for postmenopausal osteoporosis.

Introduction

Diabetes is a chronic disease associated with substantial comorbidities. The widely recognised complications of this disease include neuropathy, nephropathy, and retinopathy, all of which can result in substantial morbidity, leading to recurrent admissions to hospital and increasing health-care costs. Notwithstanding, a very high prevalence of coexistent cardiovascular disease in patients with type 2 diabetes is the most serious comorbid disorder. Our patient in the case study (panel) has borderline hypertension, and only fair control of her diabetes, obesity, hypercholesterolaemia, and neuropathic changes. Targeted therapy should include control of the patient's lipids, reduction in blood pressure, and tightened glycaemic control. So what should be done, if anything, about this patient's two fractures and the likelihood that she might have increased skeletal fragility? On one hand, osteoporosis management in patients with type 2 diabetes frequently takes a back seat to the more life-threatening complications of middle-aged postmenopausal women for example heart disease and stroke. On the other hand, fractures can have a profound effect on quality of life and can lead to substantial disability. Although recent studies have provided some insight into the pathophysiology of skeletal fragility in diabetes,1, 2, 3 a considerable void is still present in our understanding of how obesity and diabetes affect the adult skeleton. In particular, defining the progression of bone changes during the evolution of this disease from prediabetes to overt diabetes through to insulin dependency will be essential when considering possible therapeutic interventions to mitigate skeletal fragility. Hence, now assessment of the bone disease associated with obesity, insulin resistance, microvascular disease, and type 2 diabetes is fully warranted.

Section snippets

Increased fracture risk in type 2 diabetes

Evidence accumulated during the past two decades suggests that type 2 diabetes is associated with up to a three times increased risk of hip and other non-vertebral fractures, depending on the skeletal site and disease severity.4, 5 For instance, the Health, Ageing, And Body Composition Study6 prospectively assessed incident non-traumatic fractures in community-dwelling men and women and reported that type 2 diabetes was associated with a 64% increase in fractures at all sites compared with

Structural and material contributions to diabetic skeletal fragility

A fracture occurs when the forces applied to a bone exceed its strength. Whole bone strength is determined by bone mass, bone microarchitecture and macroarchitecture, and the intrinsic properties of the bone matrix, such as the extent of mineralisation, collagen content, and the degree of collagen cross-linking.37 Increased fracture risk despite normal, or even increased, bone mass in people with type 2 diabetes implicates: (1) altered bone microarchitecture or deficits in bone material

Osteoblast function in type 2 diabetes

Type 2 diabetes is a disease of disordered glucose use and enhanced energy storage. In muscle and adipose tissue, insulin resistance is increased, such that insulin-mediated glucose uptake is impaired.49 This dysfunction is due to suppression of the glucose transporter, GLUT4, in muscle, resulting from changes in the signalling molecule, IRS1, fatty acid accumulation, and oxidative stress. In adipocytes, a similar process occurs and is associated with large fatty acid toxic effects. By

Pathophysiology of bone disease in type 2 diabetes: early stages of disease

The pathogenesis of diabetic skeletal fragility is multifactorial, and includes factors such as obesity, hyperinsulinaemia, hyperglycaemia, accumulation of AGEs, and presence of microvascular disease. These disorders are either counterbalanced or potentiated by each other and by other factors at various times in the natural history of the disease. As such, the pathophysiological changes of diabetic bone disease can be broadly discussed by separately considering the factors that affect the

Accelerated ageing, microvascular disease, and muscle dysfunction

Ageing is associated with the gradual accumulation of mitochondrial DNA alterations secondary to progressive oxidative damage. This process leads to impairment of respiratory chain complexes and an increased production of reactive oxygen species producing a cascade of deleterious metabolic events including the formation of AGEs. In addition to changing collagen structure, AGEs might interact with the receptor for advanced glycation end products on cell membranes, leading to increased oxidative

Pathophysiological model: bone metabolism throughout the evolution of diabetes

Although in the earlier discussion of this Review, we have attempted to broadly categorise bone disease into early and late phases of type 2 diabetes, this distinction is arbitrary and many of the pathophysiological factors, such as obesity, are often present throughout the course of type 2 diabetes. However, indirect evidence of the importance of the evolution of type 2 diabetes and of hyperinsulinaemia independent of obesity on the skeleton stems from several clinical observations in patients

Effect of type 2 diabetes therapies on bone metabolism

Growing medical literature has described the effects of diabetes drugs on bone metabolism and fracture risk. The effect of the most widely used diabetes drugs on bone metabolism is summarised below and in table 2.

How to predict fracture risk?

Clear evidence suggests that people with type 2 diabetes have an increased fracture risk despite BMD values that are generally not in the osteoporotic range. This situation poses considerable challenges for the primary prevention of fragility fractures in these patients since identification of adults at increased fracture risk is primarily on the basis of BMD T scores. Fracture risk assessment methods, such as the WHO Fracture Risk Assessment Tool (FRAX) combine important clinical risk factors

Conclusions

This Review highlights that despite normal to high bone mass, patients with type 2 diabetes have a moderately increased risk of fracture irrespective of sex and race or ethnicity. BMD measurements underestimate skeletal fragility in type 2 diabetes and, therefore, health-care providers should factor the presence of diabetes into their assessment of fracture risk. The pathophysiology of diabetic bone disease is poorly understood, but is certainly multifactorial, associated with a complex

Search strategy and selection criteria

We searched MEDLINE, Embase, and the Web of Science for studies from January, 1980, to April 30, 2015, with the terms “diabetes” or “T2D” or “T2DM” or “type 2 diabetes mellitus”, and “bone density”, “BMD”, “bone microarchitecture”, “osteopenia”, “osteoporosis”, or “fracture”. We also searched the reference lists of obtained studies and published reviews. In the selection and review of studies, we gave the greatest weight to systematic reviews and meta-analyses, or randomised controlled trials.

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