Osteoporosis is a major public health concern with origins in childhood and is potentially linked to childhood obesity. This study used novel approaches in bone imaging to characterize skeletal development in girls and to assess the influence of whole body and regional soft tissue composition on bone material, structural and geometric properties, the primary determinants of bone strength, controlling for important covariates such as maturation, diet and physical activity. Prospective analyses were conducted to assess associations between measures of total body fat (TBFM) and android fat masses (AFM) and skeletal muscle fat (SMF) content on bone mineral content, density and strength. The results showed that higher TBFM and AFM were inversely associated with changes in cortical bone sites of the femur and tibia. These findings suggest that gains in abdominal adiposity during the pre- and early- pubertal years may contribute to suboptimal bone development and skeletal fragility later in life. The analyses also showed inverse associations between baseline muscle density of the thigh and calf with 2-year changes in bone strength and bone density of the metaphyseal and diaphyseal sites of the femur and tibia. This paradoxical relationship between SMF and bone outcomes was explained by subsequent analyses showing that girls exhibiting larger gains in muscle density experienced larger increases in bone density and strength compared to girls who did not significantly increase muscle density. These findings suggest that fatty infiltration of skeletal muscle contributes to suboptimal bone development in peri-pubertal girls. Further longitudinal analyses were conducted to examine the individual effects of the muscle-bone unit components on 2-year changes in bone strength. These results showed that muscle size contributed to gains in bone strength, independent of its mechanostat effect on BMC. These results underscore the importance of muscle size for promoting bone development and bone strength during growth. A final set of analyses were conducted to examine the effects of dietary fatty acids on bone development. The results of these analyses suggest that while decreasing intakes of AA n-6 FA may benefit bone health, higher intakes n-3 FAs may benefit tibia bone density development in young girls.

There is a pressing need for better assessment of bone strength as current clinical tools do not directly measure bone mechanical properties, but offer only surrogate measures of bone strength. We conducted an ex-vivo study of emu bones to examine how two investigative devices, hr-pQCT and MRTA, compare to current clinical tools (DXA and QUS) in predicting true bone mechanical properties. We found that hr-pQCT parameters were able to assess bone strength as well as DXA and better than QUS, while MRTA was able to predict bone strength well in low-density but not high-density bones. Our results suggest that both hr-pQCT, which has the unique ability to specifically assess the various determinants of bone strength, and MRTA, which measures a bone mechanical property (stiffness), have great potential for use as clinical tools that can assess various components of bone strength not measured by current devices.

Extended periods of mechanical unloading are known to be detrimental to bone health. Astronauts who spend months in microgravity aboard the International Space Station (ISS) are at particular risk. It is anticipated that NASA will not drastically increase the size of the astronaut corps, and this will mean increased likelihood of repeat missions for more astronauts. Thus, it is important to better understand the effects that prolonged, multiple bouts of unloading have on bone. This study utilized the hindlimb unloaded (HU) rat model to examine bone loss and recovery for single and double unloading bouts. Adult male Sprague-Dawley rats (6 months old) were randomized into the following groups: baseline (sacrificed at 6 months), 1HU7 (unloaded for 1 month, weight-bearing recovery for 3 months), 2HU10 (unloaded for 1 month, recovered for 2 months, unloaded for another month, and then recovered 2 months), 1HU10 (normal cage activity until 1 month HU ending at month 10, 2 month recovery followed), and aging controls (remained ambulatory throughout experiment). Every month (28 days), animals were terminated and the left femurs were excised, resulting in n=15 per group for each time point. Mineral and geometric properties were measured using peripheral quantitative computed tomography (pQCT) at the distal femur metaphysis, and quasi-static reduced platen compression (RPC) was used to estimate the mechanical properties of cancellous bone. Strength indices based on pQCT parameters were calculated as predictors of mechanical properties. Bone mass properties decreased due to HU and recovered within 2-3 months post-HU. A combination of increased periosteal apposition and endocortical resorption also occurred during HU. The initial HU bout suppressed normal age-related increases in mechanical properties and recovered within 1-2 months. Cancellous compressive strength index (CSI) most closely matched changes in mechanical properties. A second HU bout after two months recovery had a less detrimental effect on pQCT parameters but a greater negative impact on mechanical properties, when compared to pre-HU values. The opposite is true for mechanical properties if loss is characterized relative to aging controls. Recovery after the second HU period did not appear to be significantly affected by a previous bout of HU.

There is a pressing need for better assessment of bone strength as current clinical tools do not directly measure bone mechanical properties, but offer only surrogate measures of bone strength. We conducted an ex-vivo study of emu bones to examine how two investigative devices, hr-pQCT and MRTA, compare to current clinical tools (DXA and QUS) in predicting true bone mechanical properties. We found that hr-pQCT parameters were able to assess bone strength as well as DXA and better than QUS, while MRTA was able to predict bone strength well in low-density but not high-density bones. Our results suggest that both hr-pQCT, which has the unique ability to specifically assess the various determinants of bone strength, and MRTA, which measures a bone mechanical property (stiffness), have great potential for use as clinical tools that can assess various components of bone strength not measured by current devices.

Osteoporosis is an age-related skeletal disease characterised by an increased incidence of fragility fractures. In this thesis I develop a new technique capable of measuring the thickness of the previously unmeasured endocortical region, and providing an improved measure of the cortical bone mineral density (cBMD) from in-vivo clinical CT scans. These features are of interest as both have been linked to fracture risk. \\ The new technique is developed within the cortical bone mapping (CBM) framework so that it provides localised architectural measurements over a bone's surface. Its performance is assessed using simulated QCT data from three simulated phantoms with differing bone architecture, and two paired datasets of ex-vivo QCT and HR-pQCT scans across the proximal femur and the lumbar spine. The simulated data allows for inaccuracies in CBM measurements caused by beam hardening effects to be considered for the first time: I show that beam hardening leads to an underestimation in cortical thickness and an overestimation in trabecular BMD and that these inaccuracies can be reduced through adjustments to the CBM optimisation process. \\ A new technique of analysing HR-pQCT scans is also developed, for the validation of the new CBM method. It was used in place of other established HR-pQCT techniques for its ability to provide localised measurements of the endocortical region. A comparison with the well known full-width half-maximum (FWHM) method shows that it is less susceptible to errors caused by beam hardening. It also measures the mean cBMD, which has a greater clinical relevance than the peak cBMD measured by the FWHM method as it includes the impact of porosity. I demonstrate that the endocortical thickness can be measured to an accuracy of \(-0.15\pm0.71\thinspace\mathrm{mm}\), and that local cBMD measurements are possible down to \(300\thinspace\mathrm{mg/cm}^3\) from QCT scans over the proximal femur. I also validate CBM methods over the vertebrae for the first time and demonstrate that the cortical thickness and endocortical thickness can be measured with accuracies of \(0.10\pm0.30\thinspace\mathrm{mm}\) and \(-0.20\pm0.53\thinspace\mathrm{mm}\). \\ Two clinical trials involving Teriparatide are used to demonstrate that the new CBM method is able to detect significant regional changes in the dense cortical and endocortical bone over the proximal femur and lumbar spine, which can be attributed to changes in intracortical remodelling and endosteal apposition. The analysis of a cross-sectional fracture discrimination trial shows that fracture incidence is associated with significant decreases in endocortical thickness over specific regions.

An alarming reduction in the numbers of several species of seals in the Baltic Sea was observed during the second half of the 1900s. Organochlorines, particularly PCBs, were found to cause the decline, inducing sterility and severe bone loss. If bone tissue is affected by PCBs, bone could be used as a biomarker for exposure to environmental contaminants. To isolate the effects of PCBs from other factors, experimental studies have been conducted on model species, such as mink. In this study, 58 mink femurs from three different treatment groups and one control group were analysed. Altogether 14 different parameters were measured using peripheral quantitative computed tomography (pQCT). Mink treated with a low dose of PCBs develop increased content, area and thickness of cortical bone. Mink treated with a high dose of PCBs do not show the same effects but have a cortical area similar to that of non-exposed animals. The trabecular density and content is increased in all groups that have been exposed to PCBs. The observed effects may be the result of dioxin-like PCBs binding to the aryl hydrocarbon receptor (AhR). The activation of AhR leads to disruptions in endocrine systems, that in turn impacts bone modelling and remodelling. However, other pathways cannot be ruled out, including the effects of non-dioxin-like PCBs. Further analyses are needed in order to fully understand how PCBs affect bone tissue properties.

<p>Background: Increased physical activity has a modest effect on the spatial distribution of bone mineral. The risks and benefits of exercise for women with osteoporosis at high risk to fracture are not known. The decompression of aquatic exercise is an option to increase exercise compliance. The dual energy absorptiometry (DXA) vertebral fracture assessment (VFA) images 2D bone geometry however measurement properties have not been established for this outcome.</p> <p>Purpose: To determine relative and absolute intra-rater reliability of DXA-based vertebral height (VH) measures and to assess the feasibility of investigating bone outcomes in women with established osteoporosis before and after a 6 month aquatic exercise program.</p> <p>Methods: DXA VFA scans of 32 women over 60 years old were analyzed on 2 occasions, 4 weeks apart. Relative reliability, intraclass correlation coefficient (95% CI) and absolute reliability, standard error of measurement (95% CI) were estimated for visible anterior, middle and posterior VHs from T4 to L4. Women with osteoporosis at high risk to fracture (clinical practice guidelines used) were recruited from two osteoporosis clinics. Feasibility of recruitment, adherence to the exercise, adherence to the assessment protocols (DXA, pQCT, physical performance measures), safety and retention were assessed.</p> <p>Results: Intra-rater reliability ICC >0.87 (0.74, 0.94) and SEM <1.17 from T10 to L4. Recruitment of 9 women in 10 weeks; average adherence 68%; pQCT data loss 46%; 1 fracture after class; retention 89% at 12 months.</p> <p>Conclusion: Further study of measurement properties of VH and protocols for recruitment, data management and safety are required.</p> / Master of Science Rehabilitation Science (MSc)

La microarchitecture osseuse est un des déterminants de la qualité osseuse qui peut maintenant être évaluée in vivo au radius et au tibia distaux avec une résolution isotropique de 82μm par un nouveau scanner à haute résolution (XtremeCT, SCANCO Medical AG). Par ailleurs, l’utilisation d’analyse en éléments finis sur les volumes 3D obtenus permet d’évaluer les propriétés biomécaniques de l’os comme la résistance osseuse. Nous avons montré qu’il s’agissait d’une technique prometteuse pour évaluer la densité, la microarchitecture et les propriétés biomécaniques osseuses au niveau des sites périphériques, notamment parce que ces mesures étaient associées chez la femme avec des fractures ostéoporotiques de toutes sortes. Nous avons également montré que les mêmes mesures étaient tout aussi pertinentes chez l’homme, alors qu’il est moins sujet à l’ostéoporose. Les résultats étaient associés aux fractures ostéoporotiques de toutes sortes, notamment les fractures vertébrales. L’analyse en éléments finis permet donc la mesure in vivo de la résistance osseuse, ce qui pourrait fournir des informations sur la fragilité osseuse et le risque de fracture non accessible par les seules mesures de densité ou de microarchitecture osseuse. / Bone microarchitecture is one of the determinants of bone quality that can now be evaluated in vivo at the distal radius and tibia with an isotropic resolution of 82μm with a new high-resolution peripheral scanner (XtremeCT, SCANCO Medical AG). Moreover, the use of finite element analysis on the 3D bone volume acquired allows the assessment of bone biomechanical properties such as bone strength. Our studies show that this technique is promising to assess bone density, microarchitecture and strength at peripheral skeletal sites. Indeed those measures were associated with osteoporotic fractures of all kinds in women. We also demonstrated that those same measures were associated with osteoporotic fractures of all kinds, including vertebral fractures, in men, who are less prone to be affected by osteoporosis. Finite element analysis allows in vivo measurement of bone strength, which might provide additional information about bone fragility and fracture risk that are not assessed by measures of density or microarchitecture.

La microarchitecture osseuse est un des déterminants de la qualité osseuse qui peut maintenant être évaluée in vivo au radius et au tibia distaux avec une résolution isotropique de 82μm par un nouveau scanner à haute résolution (XtremeCT, SCANCO Medical AG). Par ailleurs, l'utilisation d'analyse en éléments finis sur les volumes 3D obtenus permet d'évaluer les propriétés biomécaniques de l'os comme la résistance osseuse. Nous avons montré qu'il s'agissait d'une technique prometteuse pour évaluer la densité, la microarchitecture et les propriétés biomécaniques osseuses au niveau des sites périphériques, notamment parce que ces mesures étaient associées chez la femme avec des fractures ostéoporotiques de toutes sortes. Nous avons également montré que les mêmes mesures étaient tout aussi pertinentes chez l'homme, alors qu'il est moins sujet à l'ostéoporose. Les résultats étaient associés aux fractures ostéoporotiques de toutes sortes, notamment les fractures vertébrales. L'analyse en éléments finis permet donc la mesure in vivo de la résistance osseuse, ce qui pourrait fournir des informations sur la fragilité osseuse et le risque de fracture non accessible par les seules mesures de densité ou de microarchitecture osseuse.

L'ostéoporose est une maladie du squelette caractérisée par une dégradation de la qualité osseuse conduisant à une majoration du risque fracturaire. Le seul examen permettant actuellement de prédire ce risque est l'ostéodensitométrie à double rayonnement X (DXA) par la mesure de la densité minérale osseuse (DMO). Cependant, la DMO seule ne rend compte que de 40 à 70% de la variation de la résistance mécanique osseuse. Les 3 buts ce travail étaient : 1/ d'évaluer les rôles respectifs de la microarchitecture corticale et trabéculaire dans le comportement mécanique vertébral, 2/ d'évaluer le rôle propre de l'hétérogénéité de la microarchitecture trabéculaire et 3/ de décrire le comportement mécanique vertébral post-fracturaire et d'en identifier les déterminants. Nous montrons que la mesure de l'épaisseur de la corticale antérieure et de son rayon de courbure ainsi que la détermination de la variation régionale de la microarchitecture trabéculaire améliorent significativement la prédiction du risque fracturaire. Il existe une variation marquée du comportement mécanique vertébral après une fracture de grade 1 de Genant. La microarchitecture osseuse, et non la masse osseuse, explique les propriétés mécaniques vertébrales plastiques et élastiques post-fracturaires.