Type 2 Diabetes and Skeletal Fragility: Biomarkers and Biomechanical Mechanisms
Individuals with type 2 diabetes (T2D) have up to a 3-fold greater fracture risk than non-diabetics and worse clinical outcomes after a fracture, including higher morbidity and increased mortality rates compared to non-diabetics. Thus, due to the huge and growing number of affected individuals and profound personal and health care costs, diabetic skeletal fragility is an important public health concern. Patients with T2D have normal to high bone mineral density, which usually is protective against fractures. Thus, the mechanisms underlying diabetic skeletal fragility are poorly understood, making it difficult for clinicians to identify those at risk and develop appropriate interventions to prevent fractures. Precisely because BMD is normal or high in T2D, deficits in bone quality or microarchitecture have been implicated in diabetic skeletal fragility. Accumulation of advanced glycation endproducts (AGEs) are involved in the pathogenesis of many diabetic complications, and are likely to also contribute to lower bone strength, though there are limited data in humans. Our overall goals are to determine the biomechanical mechanisms underlying increased skeletal fragility in patients with T2D, and to identify clinical tools that may assist in predicting fracture risk and preventing fractures in T2D. In a cross-sectional study of adults with T2D and age- and sex-matched non-diabetic controls undergoing total hip replacement surgery, we will collect the discarded femoral head and neck specimens, assess bone microarchitecture by microcomputed tomography, measure mechanical properties by reference point indentation and compression testing, and determine bone AGE content by HPLC and fluorometric assays (Aim 1). To determine whether in vivo assessments of glycemic control, AGE accumulation and/or bone quality are associated with bone AGE levels, we will utilize subjects recruited for Aim 1 to correlate serum HbA1c and pentosidine levels, skin AGE content (assessed by non-invasive skin autofluorescence) and bone quality (assessed by reference point indentation) to the concentration of AGEs in the bone itself. This project will have high impact, as the results will provide novel information regarding the mechanisms contributing to skeletal fragility in T2D, and therefore provide rationale for larger studies to improve the identification and management of patients with T2D who are susceptible to fractures.

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