Modulating mechanobiology and blood supply to improve bone strength in Paget's disease

aget's disease of bone (PDB) is a metabolic bone disease characterised by very high rates of bone remodelling which lead to bone expansion, trabecular disorganisation with a consequent decreases in strength and quality. Blood flow to bone lesions present in PDB has been reported to be nine times the normal levels, and warmth to the skin over Pagets bone is common, however targeting the vasculature in the treatment of PDB remains to be investigated. Fracture is a well-recognised complication of PDB and accurate, early diagnosis is key to successful treatment but remains difficult, improving fracture predication in PDB is our long term research goal.
3D image-based computational modelling or finite element (FE) analysis is perceived to be a highly promising tool clinically to predict stresses throughout the bone which are related to impact forces, important determinants of fracture risk. Computed tomography (CT) can provide input to FE analyses, assessing the 3D bone geometry and bone density distribution in order to estimate bone strength in vitro. However, for in vivo application of FE analysis, major methodological challenges are unsolved, since in vivo images are frequently impaired by the presence of soft tissue or motion artefacts and mechanical loading conditions are not known. To combat this problem we have recently developed a novel bone loading system which promotes a robust anabolic response ex vivo. This system allows for CT scans to be undertaken before and after exposure to predetermined strain magnitudes and can better inform FE analyses to accurately predict sites of biomechanical stress and fracture within bone.
The main aim of this interdisciplinary studentship between Biological Sciences and Engineering will be to combine ex vivo loading and finite element analysis in the study of Pagetic bones to better predict fracture risk at local sites during the disease. This will allow us to establish for the first time the role of microstructural organisation and vascularisation in determining bone quality in Paget's disease, as well as offer potential treatments. We will also utilise these techniques to test how effective inhibitors of angiogenesis will be in treating the disease and reducing fractures (in collaboration with Roche).