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.
ReviewType 2 diabetes and the skeleton: new insights into sweet bones
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
References (137)
- et al.
Advanced glycation endproducts in diabetes and diabetic complications
Endocrinol Metab Clin North Am
(2013) - et al.
Effects of non-enzymatic glycation on cancellous bone fragility
Bone
(2007) - et al.
Etiology of insulin resistance
Am J Med
(2006) - et al.
Glucose Uptake and Runx2 Synergize to Orchestrate Osteoblast Differentiation and Bone Formation
Cell
(2015) - et al.
Increased serum sclerostin and decreased serum IGF-1 are associated with vertebral fractures among postmenopausal women with type-2 diabetes
Bone
(2013) - et al.
Circulating osteogenic cells: characterization and relationship to rates of bone loss in postmenopausal women
Bone
(2010) - et al.
Visceral adiposity is negatively associated with bone density and muscle attenuation
Am J Clin Nutr
(2015) - et al.
Determinants of bone mineral density in obese premenopausal women
Bone
(2011) - et al.
Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity
Biochem Biophys Res Commun
(1999) - et al.
Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism
Cell
(2010)
Hyperinsulinemia and bone mineral density in an elderly population: The Rotterdam Study
Bone
The association of obesity and glucose and insulin concentrations with bone density in premenopausal and postmenopausal women
Metabolism
Role of oxidative stress in diabetes-mediated vascular dysfunction: unifying hypothesis of diabetes revisited
Vascul Pharmacol
Prevalence of osteoporosis and vertebral fractures in postmenopausal women with type 2 diabetes mellitus and their relationship with duration of the disease and chronic complications
J Diabetes Complications
AMP-activated protein kinase (AMPK) activation regulates in vitro bone formation and bone mass
Bone
Type 2 diabetes and bone
J Bone Miner Res
Effect of type 2 diabetes-related non-enzymatic glycation on bone biomechanical properties
Bone
Determinants of bone strength and quality in diabetes mellitus in humans
Bone
Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes–a meta-analysis
Osteoporos Int
Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture
Am J Epidemiol
Nontraumatic fracture risk with diabetes mellitus and impaired fasting glucose in older white and black adults: the Health, Aging, And Body Composition Study
Arch Intern Med
Risk of fracture in women with type 2 diabetes: the Women's Health Initiative Observational Study
J Clin Endocrinol Metab
Fracture risk in diabetic elderly men: the MrOS study
Diabetologia
Diabetes and fracture risk in older U.S. adults
Bone
Diabetes and risk of hip fracture in the Singapore Chinese Health Study
Diabetes Care
Glycated hemoglobin level and risk of hip fracture in older people with type 2 diabetes: a competing risk analysis of Taiwan Diabetes Cohort Study
J Bone Miner Res
Fracture risk in type 2 diabetes: update of a population-based study
J Bone Miner Res
Diabetes and risk of fracture: The Blue Mountains Eye Study
Diabetes Care
Older women with diabetes have an increased risk of fracture: a prospective study
J Clin Endocrinol Metab
Risk factors for fragility fracture in middle age. A prospective population-based study of 33,000 men and women
Osteoporos Int
Associations among disease conditions, bone mineral density, and prevalent vertebral deformities in men and women 50 years of age and older: cross-sectional results from the Canadian Multicentre Osteoporosis Study
J Bone Miner Res
Prevalent vertebral deformities predict mortality and hospitalization in older women with low bone mass
J Am Geriatr Soc
Associations between baseline risk factors and vertebral fracture risk in the Multiple Outcomes of Raloxifene Evaluation (MORE) Study
J Bone Miner Res
Association between bone mineral density and type 2 diabetes mellitus: a meta-analysis of observational studies
Eur J Epidemiol
Diabetes is associated independently of body composition with BMD and bone volume in older white and black men and women: The Health, Aging, and Body Composition Study
J Bone Miner Res
Type 2 diabetes is associated with increased bone mineral density in Mexican-American women
Arch Med Res
Decreased bone mineral density at the distal radius, but not at the lumbar spine or the femoral neck, in Japanese type 2 diabetic patients
Osteoporos Int
Age-related bone mineral density, osteoporosis rate and risk of vertebral fracture in mainland Chinese women with type 2 diabetes mellitus
J Endocrinol Invest
Bone mineral density and fracture risk in type-2 diabetes mellitus: the Rotterdam Study
Osteoporos Int
High bone mineral density and fracture risk in type 2 diabetes as skeletal complications of inadequate glucose control: the Rotterdam Study
Diabetes Care
Simulated increases in body fat and errors in bone mineral density measurements by DXA and QCT
J Bone Miner Res
Volumetric femoral BMD, bone geometry, and serum sclerostin levels differ between type 2 diabetic postmenopausal women with and without fragility fractures
Osteoporos Int
A bone structural basis for fracture risk in diabetes
J Clin Endocrinol Metab
Bone mass and strength in older men with type 2 diabetes: the Osteoporotic Fractures in Men Study
J Bone Miner Res
Diabetes and change in bone mineral density at the hip, calcaneus, spine, and radius in older women
Front Endocrinol (Lausanne)
Effect of alendronate on bone mineral density and biochemical markers of bone turnover in type 2 diabetic women: the fracture intervention trial
Diabetes Care
Menopausal bone changes and incident fractures in diabetic women: a cohort study
Osteoporos Int
Diabetes and bone loss at the hip in older black and white adults
J Bone Miner Res
Femoral neck bone loss predicts fracture risk independent of baseline BMD
J Bone Miner Res
Identification of osteopenic women at high risk of fracture: the OFELY study
J Bone Miner Res
Cited by (178)
Effect of in vitro ribosylation on the dynamic fracture behavior of mature bovine cortical bone
2023, Journal of the Mechanical Behavior of Biomedical MaterialsN-acetyl-L-cysteine attenuates oxidative stress-induced bone marrow endothelial cells apoptosis by inhibiting BAX/caspase 3 pathway
2023, Biochemical and Biophysical Research Communications