Multiscale Mechanics of Bone Fragility in Type-2 Diabetes

Type-2 (T2) Diabetes is associated with a 3-fold increase in bone fracture risk, despite the fact that bone volume is not reduced. This implies that T2 diabetes impairs bone quality, whereby the intrinsic material properties of the bone matrix are altered. However, current diagnostic techniques are unable to predict fracture probability in T2 diabetes as they are based on measures of bone quantity. While it is believed that non-enzymatic cross-linking of organic proteins (also known as AGE accumulation) in the bone matrix is responsible for bone fragility in T2 diabetes, there is a distinct lack of understanding how altered protein configurations impair whole-bone biomechanics. In this project, the applicant will embark on frontier research that will develop a state-of-the-art multiscale computational framework that couples behaviour from the molecular to whole-bone level, providing a basis to interrogate and elucidate the physical mechanisms that are responsible for diabetic bone fragility. A multiscale experimental framework will, for the first time, establish relationships between AGE crosslink-density and whole-bone fragility in animal and human T2 diabetic bone tissue. Together, this data will inform a probabilistic mutli-level model of hip fracture, which will be used to quantitatively evaluate the relationship between hip fracture probability, bone quantity and bone quality. The research programme will also establish a novel strategy for clinical fracture risk assessment that employs existing protocols to measure bone quantity, in combination with a surrogate measure of bone quality. The surrogate measure of bone quality proposed is a systemic measure of AGE content, which is clinically-obtainable through a blood sample and therefore widely-applicable. Overall, the project will provide a ground-breaking advance in our understanding of bone fragility, with remarkable potential to innovate novel solutions for clinical assessment of T2 diabetic bone disease.

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