Medicine (Austin & Northern Health) - Theses
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ItemApplication of High Resolution Peripheral Quantitative Computed Tomography to the Study of Bone Microstructure and Matrix Mineral Density in Health and Disease( 2023-06)Longevity increases the proportion of elderly persons in the community. Advancing age is accompanied by bone loss which compromises the volume, microarchitecture, and strength of both cortical and trabecular bone, particularly in women after menopause. Increasing fragility fracture risk is likely to be due to trabeculae thinning, perforation of trabeculae or reduction of trabecular numbers, thinning of the cortex and increased cortical porosity. Bone also becomes fragile due to changes in the material composition such as increased matrix mineral density, glycation of collagen and accumulation of unrepaired microdamage. These changes impact the mechanical properties of bone and make bones less able to resist loading, leading to an increased risk of fragility fractures. The diagnosis of bone fragility is currently based on evaluation of clinical risk factor and with measurement of areal bone mineral density (aBMD) of the lumbar spine, and proximal hip using dual-energy X-ray absorptiometry (DXA). BMD is normally distributed. Over 10% of people in the community have ‘so-called’ normal BMD (T-score more than - 1.0 SD), around 60% of persons have osteopenia (T-score - 1.0 to -2.5 SD) and around 30% have a BMD T-score less than - 2.5 SD below the young normal mean, the diagnostic threshold for ‘osteoporosis’. Because of the population distribution of BMD, most patients with fragility fractures in the community and most patients with diseases affecting the skeleton such as chronic kidney disease who suffer fragility fractures have osteopenia or normal BMD, not osteoporosis, so the use of aBMD threshold of less than – 2.5 SD has led to underestimation of the burden of bone fragility in the community. High-Resolution peripheral Quantitative Computed Tomography (HR-pQCT) with 82 or 61-micron isotropic voxel size is an in-vivo imaging modality. HR-pQCT enables quantifying bone microarchitecture, distinguishing trabecular and cortical compartments, and measuring cortical and trabecular microarchitecture with minimal radiation exposure (5 micro-Sv, equivalent to one day of background radiation) has made it an important modality to identify bone fragility in persons independent of their BMD level. HR-pQCT is used in musculoskeletal research to quantify bone microstructure of appendicular regions of interest, both in normal and pathological conditions. However, there are limitations in the application of this imaging method and in the interpretation of findings, that need to be recognised such as accurate segmentation of cortical from trabecular bone using threshold or non- threshold-based image analysis algorithms and challenges in the correct choice of a region of interest (ROI) which is chosen as a fixed distance from the distal joint line. This region differs in persons differing in arm length; it is more distal in taller individuals, more proximal in shorter individuals. For this reason, sex differences, racial differences and growth related differences in microarchitecture may be the result of differences in the positioning of the region of interest. The aim of this thesis was to address several of these technical limitations in methodology by using a non-threshold-based HR-pQCT image analysis and standardising the location of the ROI, so that sex- and race-specific differences in bone morphology could be correctly determined free of positioning errors. This method was applied in various disease states to establish the effects of disease on bone microarchitecture. We investigated distal radius bone morphology of 158 healthy Asians and Caucasian women and men aged from 21 to 53 years using HR-pQCT. Errors in positioning the region of interest misrepresents accurate quantification of bone microarchitecture because it varies point by point (slice-by slice) along the length of a bone. For example, adjusting the scanned ROI resulted in a 0.51 SD higher cortical porosity in Asian women and 0.32 SD higher cortical porosity in Caucasian women. Failure to correct the ROI overestimated porosity by 0.21 SD in Asian men and by 0.39 SD in Caucasian men. Failure to correct the ROI comparing older Caucasian women, 33 postmenopausal women aged from 73 to 95 years, underestimate the age-related increase in porosity by 0.40 SD. We investigated the effects of spinal paralysis on bone microstructure of distal radius and distal tibia and fibula of individuals with spinal cord injury. In this study, 32 men, 12 with tetraplegia and 20 with paraplegia, that were within 0.5 to 18.5 years of paralysis, were scanned by HR-pQCT. We report that following unloading caused by spinal cord injury, weight bearing regions adapted to accommodate greater peak strains, and strain rates changes had more severe microarchitectural deterioration than non-weight bearing regions that are normally adapted to lower peak strains and strain rates prior injury. These observations highlight the site specificity of the strain thresholds regulating the cellular activity of mechano-transduction. The rapidity of the change and irreversible microarchitectural deterioration suggest prompt intervention with antiresorptive, anabolic therapy, or both, warrants consideration. We also studied the effect of chronic kidney disease (CKD) on bone microstructure of 128 patients with CKD and compared them with 275 age- and sex-matched controls. We report that most patients with CKD stages 4-5D and kidney transplant recipients had osteopenia or normal femoral neck BMD, not osteoporosis. Despite these modest deficits in femoral neck BMD, distal tibial and distal radial microarchitecture and estimated failure load were compromised, even in patients with normal BMD. Cortical and trabecular distal tibia and distal radius microarchitecture, not femoral neck BMD, were independently associated with estimated failure load and accounted for over 85% of the variance in failure load estimated at these metaphyseal locations. Resistance to fracture is achieved by modelling and remodelling adding bone to, or removing bone from, its periosteal (external) and endocortical, intracortical, and trabecular components of its endosteal (internal) surfaces. Quantification of macro/micro-structure of 18 radii and 5 femora human post-mortem specimens show that bone mass is constant along the radius, femur, and femoral neck. Along the metaphyseal regions, the constant mass was fashioned with a large void volume and high surface area/matrix volume forming mainly trabecular bone. At the middiaphyseal regions the same mass was fashioned with small intracortical and medullary void volumes and low surface area/matrix volume forming cortical bone. In addition, quantification of distal radius and tibia of 94 women, using HR-pQCT, showed that bigger bones are assemble with relatively less cortical mass of higher porosity and lower matrix mineral density. In conclusion, the aging population is at higher risk of fragility fractures due to age-related bone loss and deteriorated bone microstructure. HR-pQCT provides three-dimensional bone microstructure analysis of human extremities as in-vivo, with minimal radiation exposure and high-resolution images. We offered a methodological solution for standardizing positioning and scanning of ROI and accurately quantifying bone microarchitecture, and in pathological conditions. We investigated the impact of spinal cord injury on bone microstructure and the effects of chronic kidney disease on bone strength, highlighting the significance of cortical and trabecular microarchitecture in assessing bone health.