Mechanisms of diabetes mellitus-induced bone fragility

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Abstract

Diabetes mellitus is associated with an increased risk of fragility fractures. Here, Napoli and colleagues discuss the complex interactions between glucose homeostasis and bone fragility, the epidemiology of fractures in patients with diabetes mellitus and the effects of antidiabetic drugs on bone health.

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Most cited references 132

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Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia.

C Weyer, T. Funahashi, S. Tanaka … (2001)

Plasma concentrations of adiponectin, a novel adipose-specific protein with putative antiatherogenic and antiinflammatory effects, were found to be decreased in Japanese individuals with obesity, type 2 diabetes, and cardiovascular disease, conditions commonly associated with insulin resistance and hyperinsulinemia. To further characterize the relationship between adiponectinemia and adiposity, insulin sensitivity, insulinemia, and glucose tolerance, we measured plasma adiponectin concentrations, body composition (dual-energy x-ray absorptiometry), insulin sensitivity (M, hyperinsulinemic clamp), and glucose tolerance (75-g oral glucose tolerance test) in 23 Caucasians and 121 Pima Indians, a population with a high propensity for obesity and type 2 diabetes. Plasma adiponectin concentration was negatively correlated with percent body fat (r = -0.43), waist-to-thigh ratio (r = -0.46), fasting plasma insulin concentration (r = -0.63), and 2-h glucose concentration (r = -0.38), and positively correlated with M (r = 0.59) (all P < 0.001); all relations were evident in both ethnic groups. In a multivariate analysis, fasting plasma insulin concentration, M, and waist-to-thigh ratio, but not percent body fat or 2-h glucose concentration, were significant independent determinates of adiponectinemia, explaining 47% of the variance (r(2) = 0.47). Differences in adiponectinemia between Pima Indians and Caucasians (7.2 +/- 2.6 vs. 10.2 +/- 4.3 microg/ml, P < 0.0001) and between Pima Indians with normal, impaired, and diabetic glucose tolerance (7.5 +/- 2.7, 6.1 +/- 2.0, 5.5 +/- 1.6 microg/ml, P < 0.0001) remained significant after adjustment for adiposity, but not after additional adjustment for M or fasting insulin concentration. These results confirm that obesity and type 2 diabetes are associated with low plasma adiponectin concentrations in different ethnic groups and indicate that the degree of hypoadiponectinemia is more closely related to the degree of insulin resistance and hyperinsulinemia than to the degree of adiposity and glucose intolerance.

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From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis.

Stavros C. Manolagas (2010)

Estrogen deficiency has been considered the seminal mechanism of osteoporosis in both women and men, but epidemiological evidence in humans and recent mechanistic studies in rodents indicate that aging and the associated increase in reactive oxygen species (ROS) are the proximal culprits. ROS greatly influence the generation and survival of osteoclasts, osteoblasts, and osteocytes. Moreover, oxidative defense by the FoxO transcription factors is indispensable for skeletal homeostasis at any age. Loss of estrogens or androgens decreases defense against oxidative stress in bone, and this accounts for the increased bone resorption associated with the acute loss of these hormones. ROS-activated FoxOs in early mesenchymal progenitors also divert ss-catenin away from Wnt signaling, leading to decreased osteoblastogenesis. This latter mechanism may be implicated in the pathogenesis of type 1 and 2 diabetes and ROS-mediated adverse effects of diabetes on bone formation. Attenuation of Wnt signaling by the activation of peroxisome proliferator-activated receptor gamma by ligands generated from lipid oxidation also contributes to the age-dependent decrease in bone formation, suggesting a mechanistic explanation for the link between atherosclerosis and osteoporosis. Additionally, increased glucocorticoid production and sensitivity with advancing age decrease skeletal hydration and thereby increase skeletal fragility by attenuating the volume of the bone vasculature and interstitial fluid. This emerging evidence provides a paradigm shift from the "estrogen-centric" account of the pathogenesis of involutional osteoporosis to one in which age-related mechanisms intrinsic to bone and oxidative stress are protagonists and age-related changes in other organs and tissues, such as ovaries, accentuate them.

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Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture.

Mohsen Janghorbani, Rob Van Dam, Walter C. Willett … (2007)

The authors conducted a systematic review of published data on the association between diabetes mellitus and fracture. The authors searched MEDLINE through June 2006 and examined the reference lists of pertinent articles (limited to studies in humans). Summary relative risks and 95% confidence intervals were calculated with a random-effects model. The 16 eligible studies (two case-control studies and 14 cohort studies) included 836,941 participants and 139,531 incident cases of fracture. Type 2 diabetes was associated with an increased risk of hip fracture in both men (summary relative risk (RR) = 2.8, 95% confidence interval (CI): 1.2, 6.6) and women (summary RR = 2.1, 95% CI: 1.6, 2.7). Results were consistent between studies of men and women and between studies conducted in the United States and Europe. The association between type of diabetes and hip fracture incidence was stronger for type 1 diabetes (summary RR = 6.3, 95% CI: 2.6, 15.1) than for type 2 diabetes (summary RR = 1.7, 95% CI: 1.3, 2.2). Type 2 diabetes was weakly associated with fractures at other sites, and most effect estimates were not statistically significant. These findings strongly support an association between both type 1 and type 2 diabetes and increased risk of hip fracture in men and women.