Mechanisms of Diabetic Skeletal Fragility
Patients with type 2 diabetes have 2-3 times greater bone fracture risk than non-diabetics. This increased risk occurs despite these patients having normal to high bone mineral density, which usually is protective against fractures. Thus, causes of type 2 diabetic skeletal fragility are largely unknown and there is limited information on which clinicians can base decisions for fracture prevention.
Because bone mineral density is normal or high in type 2 diabetes, deficits in bone quality or microarchitecture have been implicated in diabetic skeletal fragility. In particular, advanced glycation end-products (AGEs), resulting from biochemical reactions between extracellular sugars and amino acid residues on proteins such as collagen, accumulate in tissues involved in the pathogenesis of various diabetic complications. AGE accumulation in bone can deteriorate its mechanical integrity and increase formation of harmful microdamage. Further, studies indicate that cortical porosity is increased in type 2 diabetes, but the relative contribution of AGEs, microdamage, and porosity to diabetic skeletal fragility, and the underlying mechanism remains unclear.
Our overall goal is to determine the biomechanical mechanisms underlying increased skeletal fragility in type 2 diabetes. From age- and sex-matched adult diabetic and non-diabetic patients undergoing total hip replacement surgery, we are collecting femoral head and neck specimens, assessing microarchitecture by microcomputed tomography, measuring mechanical properties by reference point indentation and compression tests, quantifying microdamage by 3D ultra-high resolution computed tomography, and measuring AGEs in bone, serum, and skin by biochemical methods and a non-invasive tool designed to measure skin autofluorescence.
This work will provide a better understanding of the mechanisms contributing to skeletal fragility in type 2 diabetes, may contribute to development of methods to improve fracture risk assessment, and have the potential to improve clinical management of diabetic patients who are susceptible to fractures.
This work is funded by NIH-NIA T32AG023480, NIH-NCRR/NCATS UL1TR001102, and a pilot and feasibility grant from the Boston Area Diabetes and Education Center (NIH P30 DK057521).