E-Poster Presentation 30th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2020

Localised alterations in bone geometry and cortical porosity predispose fracture site in a mouse model of Paget’s disease of bone (#76)

Alisha C Sharma 1 , Jacob J Trend 1 , Kaz Wanelik 2 , Stephen Brown 3 , Stuart H Ralston 4 , Philipp Schneider 1 , Bram G Sengers 1 , Claire E Clarkin 1
  1. University of Southampton, Southampton, Hampshire, United Kingdom
  2. Diamond Light Source, Didcot, United Kingdom
  3. Institute of Genetic and molecular Medicine, Edinburgh, Scotland
  4. University of Edinburgh, Edinburgh, United Kingdom

Femoral fractures are an impediment in Paget’s Disease of Bone (PDB), with clinical studies demonstrating limitations of bone mineral density measurements for fracture prediction. Recent attention has focused on the impact of bone geometry and microstructure on bone strength. Our aim was to examine whether alterations in longitudinal cortical microstructure comprising of osteocyte lacunae (La) and vascular canals (Ca) underlie fracture risk in PDB. A murine model exhibiting a proline to leucine mutation at codon 394 of Sequestostome-1 (P394L), equivalent to the P392L mutation in humans was used. Synchrotron X-ray computed tomography (CT) focused on microstructural components of the femoral cortex in wildtype (WT) and homozygotes (P394L+/+), at multiple sites (Fig. 1). Bone geometry measurements and four-point bending tests were also undertaken. Differences between WT and P394L+/+ bone microstructure and shape were region-specific. At 30% femoral length P394L+/+ exhibited a larger cortical area fraction (WT 0.776% ± 0.132 and  P394L+/+ 1.167% ± 0.047;  p<0.05) and increased  Lc volume density (WT 0.637% ± 0.100 and  P349+/+ 0.935% ± 0.036; p<0.05) versus WT. P394L+/+ Lc had reduced circumference at  60-70% (WT 16.160µm ± 0.437 and P394L+/+ 14.695µm ± 0.377 p<0.05) versus WT. At 80% there was  increased maximum Ca. thickness (WT 20.359µm ± 0.479 and P349L+/+ 25.145 µm ± 1.771; p<0.05) associated with increased cortical thickness (WT 0.4625mm + 0.06 and P394L+/+ 0.3195mm + 0.4; p<0.001) and reduced polar moment of inertia (WT 1.725mm4 + 0.485 and P394L+/+ 0.396 mm4+ 0.096 ;p<0.05) versus WT. Mechanical testing revealed a lesser force required to break P394L+/+ femora (36.6N) versus WT (42.8N; p<0.05) with P394L+/+ exhibiting  fracture point range between 66-68% femoral length versus 48-53% in WT (p<0.05; Fig.1). Elucidation of skeletal microstructure could be used in combination with DXA scans to better predict fracture risk sites in clinical settings including PDB.

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Figure 1. Longitudinal analyses of cortical microstructure and whole bone geometry in this study represented as % femoral length. Regional alterations in bone composition link to localised fracture points in WT and P394L+/+ femora.