Skeletal Fragility in Type 2 Diabetes Mellitus: Bone Mechanical Properties, Microarchitecture, and Advanced Glycation End-Products in the Proximal Femur
Robbins, Ann L.
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AbstractOsteoporosis is a metabolic bone disorder characterized by depleted bone mass, remodeling of microarchitecture, and an increased incidence of fractures. Predominantly diagnosed through a measurement of low bone mineral density (BMD), osteoporosis is widely recognized as a highly prevalent condition affecting roughly one in two women and one in five men over the age of fifty.
Diagnostic criteria for osteoporosis, however, fail to accommodate the growing population of patients who suffer from type 2 diabetes mellitus (T2DM), a metabolic disorder characterized by peripheral insulin resistance, high circulating glucose, and insufficient insulin production. Although data on fracture risk is inconsistent, several studies have indicated an increased incidence of fractures in patients with T2DM; paradoxically, BMD is found to be normal or elevated in these patients, even when values were adjusted for BMI.
A possible explanation lies in the perturbed whole body metabolism of T2DM. Many chronic complications from diabetes arise from poor glycemic control and the accumulation of advanced glycation end-products (AGEs). In vitro studies have shown that the non-enzymatic glycation of amine residues on collagen and other proteins leads to increased microdamage in bone. Currently unknown are the mechanical and biological implications of increased AGE content on bone health in diabetic and healthy patients. To address this, the Bouxsein lab at Beth Israel Deaconess Medical Center (BIDMC) have recruited a group of diabetic and non-diabetic patients undergoing elective total hip replacement (THR) as donors of bone and plasma samples. From the samples collected, I hypothesized that AGE accumulation and bone fragility, as assessed through bone biomechanics, will be greater in bone from diabetic patients as compared to non-diabetic controls.
In 20 diabetic and 34 control patients, biomechanical properties and microarchitecture were characterized through cyclic reference point indentation (cRPI) and microcomputed tomography (microCT), respectively. Following completion of AGE quantification in bone and serum samples, correlations between AGE content and structural properties were assessed, with adjustments for confounding factors. Diabetic patients were found to have increased AGE content in cortical bone and increased indentation distances, as assessed by cRPI, although no relationships were found between bone AGE content and cRPI values. A weakly positive correlation between serum AGEs and total bone AGEs was also noted. Although diabetic patient recruitment was limited by surgical criteria to only those with excellent glycemic control, this study is novel for its investigation of AGE accumulation and structural assessment of bone from diabetic patients, and it is the first to note a correlation between serum total AGEs and bone AGEs in a cohort including T2DM patients.
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