Introduction: The role of muscle forces in determining bone micro-architecture and strength in children is poorly understood as limited evidence relies on surrogate measures of muscle force such as muscle size. The objective of this thesis was to explore the role of muscle area, peak forces from neuromuscular performance tests and physical activity in determining bone properties at the radius and tibia in children. Methods: 37 boys and 42 girls (mean age 10.5; SD 1.6y) had their dominant forearm and lower leg imaged using peripheral quantitative computed tomography (pQCT) and high resolution pQCT (HR-pQCT). Bone mass, density, area and estimated strength were assessed. Muscle area was determined from the pQCT scans and grip strength measured via a handheld dynamometer. Peak force from a single maximal push-up performed on force platforms and the number of standard push-ups completed in a single attempt were recorded. Countermovement and standing long jump maximal forces were recorded, impulse and power were calculated, and average standing long jump distance was measured. Physical activity was measured using the Physical Activity Questionnaire for Children. Sex, maturation (estimated age from peak height velocity), weight and limb length (ulna and tibia) were controlled in the linear regression models. Variance predicted (R2) by models using muscle area, neuromuscular performance measures as independent predictors (squared partial r) of bone properties are reported. Results: Grip strength and muscle area independently predicted 14-18% of the variance in bone area at the distal radius and 9-22% of the variance in bone strength at the distal and shaft sites of radius. Peak push-up force predicted 10% of the variance in trabecular number at the distal radius. Muscle area independently predicted 5-28% and countermovement and standing long jump forces and impulses predicted 6-10% of the variance in bone area, cortical content or density at the tibia shaft. Standing long jump power predicted 5-8% of the variance in bone area and cortical density at the tibia shaft. Physical activity predicted 9% of the variance in trabecular number at the distal tibia. Discussion: Thesis findings support the use of muscle area as a surrogate for muscle forces and identified neuromuscular performance measures that will guide targeted exercise interventions aiming to optimize bone strength development in children.

Introduction. Osteoporosis is a chronic disease characterized by the loss of bone mass and the deterioration of bone micro-architecture leading to a subsequent increase in fracture risk. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides non-invasive measures of bone micro-architecture and strength in live humans but its ability to monitor small skeletal changes is yet poorly understood. The objectives of this thesis were to 1) determine HR-pQCT precision for volumetric density, geometry, cortical and trabecular micro-architecture, as well as estimates of bone strength; 2) determine the monitoring time interval (MTI) and least significant change (LSC) metrics; and 3) to characterize annual changes in bone area, density, and micro-architecture at the distal radius and tibia using HR-pQCT in postmenopausal women. Methods. To determine precision error as well as monitoring and change metrics of the distal radius and tibia, 34 postmenopausal women (mean age 74, SD±7 years) from the Saskatoon cohort of the Canadian Multicentre Osteoporosis Study (CaMos) were measured using HR-pQCT. To characterize the annual change in bone outcomes of this same cohort, 51 women (mean age±SD: 77±7 years) were measuring at baseline and again 1 year later. Precision errors were calculated as coefficient of variation (CV% and CV%RMS). The LSC was determined from precision errors and then divided by the median annual percent changes to define MTIs for bone area, density, and micro-architecture. Repeated measures analysis of variance (ANOVA) with Bonferroni adjustment for multiple comparisons were used to characterize the mean annual change in total density, cortical perimeter, trabecular and cortical bone area, density, content, and micro-architecture. Significant changes were accepted at P<0.05. Results and Discussion. HR-pQCT precision errors were <10% for bone densitometric, geometric, and mechanical properties; while precision errors were <16% for cortical and trabecular micro-architectural outcomes. Further, the use of either automatic or modified contour methods for the dual-threshold technique for cortical micro-architectural analysis provided similar precision. Densitometric and geometric outcomes had longer monitoring times (>3 years), while micro-architecture had monitoring times of ~2 years. The observed annual changes were statistically significant for several outcomes; however, only cortical and trabecular area, as well as cortical density at the distal tibia changed beyond the LSC. Overall, thesis findings will assist design and interpretation of prospective HR-pQCT studies in postmenopausal women.

Fractures are a major public health concern and there is an urgent need to identify high-risk individuals. This study used novel approaches in bone imaging to characterize optimal skeletal development in girls and enhance our understanding of the structural and functional deficits that contribute to skeletal fragility and fracture risk during growth. The findings indicate that fracture in girls is associated with lower trabecular bone density, but not bone macro-architecture at metaphyseal regions of weight-bearing bones, which is consistent with findings reported in children at the distal radius. These findings suggest that lower trabecular density at metaphyseal regions of long bones track throughout the appendicular skeleton and may be an early marker of skeletal fragility.Obese children are overrepresented in childhood fracture cases. Nevertheless, the effects of fat on bone during growth remain unclear. This study showed that skeletal muscle was a stronger determinant of bone parameters in girls than total body adiposity, although fat mass had a persistent, albeit weak association with bone parameters. Furthermore, fatty infiltration of skeletal muscle, which is associated with type 2 diabetes mellitus, was inversely associated with bone strength in girls. These findings are consistent with the proposed functional model of bone development which posits that forces from muscle contractions are the main mechanical challenges to which bones adapt.Physical activity during growth is critical for optimal bone development. The findings from this study support this premise and suggest that regular physical activity enhances bone strength in girls. Nevertheless, for exercise to be accepted as an important public health osteoporosis prevention strategy, lasting adaptations must be shown. Plausible biological explanations have been offered in support of the peri-pubertal years as a "window of opportunity" for maximizing the response to exercise. Findings from this study suggest that a two year school-based high-impact jumping intervention was not an effective means to enhance bone parameters in girls. Controlled dose-response trials will be necessary to test questions regarding the types, bouts, and durations of exercise required to define the "dose" of exercise needed to elicit meaningful skeletal adaptations during growth.

L’objectif de ce travail était d’étudier certains aspects de la géométrie ou macroarchitecture afin de mieux comprendre la contribution de la géométrie sur le risque de fracture. Pour les os tubulaires, l’apposition périostée tente de compenser la perte osseuse après la ménopause et il existe peu d’études pour les vertèbres. Dans une étude prospective, les dimensions des corps vertébraux augmentent significativement à 3 ans chez les femmes ménopausées ostéoporotiques et que cette augmentation est fortement associée à la taille initiale des os suggérant que les os plus grands ont besoin d’une expansion périostée plus importante pour maintenir la résistance osseuse. Des études antérieures ont suggéré qu’il fallait évaluer la géométrie du rachis dans sa globalité en étudiant le rôle des courbures rachidiennes. Dans une deuxième étude prospective de 3 ans chez des femmes ménopausées ostéoporotiques, la cyphose thoracique est un facteur de risque de fractures vertébrales même après ajustement sur la présence de fractures vertébrales prévalentes. Une troisième étude prospective qui a cherché à identifier les paramètres géométriques associés au risque de fracture de hanche chez les femmes ménopausées ostéoporotiques non traitées montre que l’épaisseur corticale fémorale mesurée par l’outil HSA (Hip Structural Analysis) améliore la prédiction du risque de fracture de hanche indépendamment de la mesure de la densité minérale osseuse (DMO). L’outil géométrique que nous avons développé pour s’affranchir de l’influence de la DMO montre que l’augmentation de la distance intertrochantérienne est associée à une augmentation du risque de fracture indépendamment de la DMO. En revanche l’outil actuel est peu reproductible pour la mesure de la corticale fémorale. / The aim of the study was to study certain aspects of bone geometry or macroarchitecture to understand better the contribution of bone geometry on the risk of fracture. For tubular bones, periosteal apposition can occur to compensate bone loss after the menopause and there is no data concerning the prospective changes in vertebral body dimensions. In a prospective study of women with postmenopausal osteoporosis, vertebral body dimensions increase over 3 years in women and the bigger bones need more periosteal expansion to maintain bone strength. Previous studies showed that whole spine geometry and especially the spinal curvatures need be evaluated to understand the role of vertebral geometry on the risk of fracture. In a second prospective study in postmenopausal osteoporotic women, thoracic kyphosis is a risk factor for vertebral fractures over 3 years, even after adjusting on presence of prevalent fractures. A third prospective study aimed at identifying the geometric parameters associated with an increase risk of hip fracture in postmenopausal osteoporotic women untreated. Femoral cortical thickness measured by HSA tool (Hip Structural Analysis) is associated with an increase risk of hip fracture, independently of bone mineral density (BMD). The geometrical tool which we developed to eliminate the influence of the BMD shows that increase in the intertrochanteric distance is associated with an increase risk of hip fracture.

Larger and stronger muscles are positively associated with bone strength in the growing skeleton; however, less is known about the role of muscle properties on bone strength later in life. The primary objective of this study was to examine the relationship between muscle cross sectional area (MCSA), muscle force and rate of torque development (RTD) with bone strength indices (bone strength index (BSI) and strength strain index (SSI)) in the radius of healthy middle-aged adults. All bone and muscle measurements were determined in the non-dominant forearm in a sample of 40 healthy adults (23 men, 17 women: mean age 49.5, SD 2.3 yrs). Peripheral quantitative computer tomography (pQCT) was used to scan the distal and shaft sites of the radius bone in the forearm. MCSA was determined from the forearm shaft scan. Forearm muscle force was measured by hand grip dynamometry and RTD was obtained from isometric wrist flexion from an isokinetic dynamometry protocol. Hierarchical regression analyses were used to identify whether muscle properties (MCSA, grip force, and RTD) independently predicted radius bone strength indices (BSI and SSI), after adjusting for the confounders of sex, height and weight. Steps of the regression models that included sex, height, weight and a muscle property explained between 66% and 71% of variance in distal radius BSI and between 74% and 78% variance of estimated bone strength (SSI) at the shaft site (all steps p<0.001). MCSA explained a significant amount of variance in BSI (R2=0.08; p<0.01) and SSI (R2=0.04; p<0.05) at the radius. Grip force was also a significant predictor of SSI (R2=0.05; p<0.01) but not distal radius BSI (R2=0.03; p=0.07). Conversely, RTD explained a significant amount of variance in bone strength at the distal radius (R2=0.04; p<0.05), but not at the shaft (R2=0.01; p=0.17). These cross sectional findings support the theory that regional muscle size, force, and rate of torque development are related to estimated bone strength in the forearm at midlife. Further research should focus on targeted interventions to help determine which muscle property elicits a greater osteogenic response to optimize bone strength at distal and shaft sites of the radius.

Larger and stronger muscles are positively associated with bone strength in the growing skeleton; however, less is known about the role of muscle properties on bone strength later in life. The primary objective of this study was to examine the relationship between muscle cross sectional area (MCSA), muscle force and rate of torque development (RTD) with bone strength indices (bone strength index (BSI) and strength strain index (SSI)) in the radius of healthy middle-aged adults. All bone and muscle measurements were determined in the non-dominant forearm in a sample of 40 healthy adults (23 men, 17 women: mean age 49.5, SD 2.3 yrs). Peripheral quantitative computer tomography (pQCT) was used to scan the distal and shaft sites of the radius bone in the forearm. MCSA was determined from the forearm shaft scan. Forearm muscle force was measured by hand grip dynamometry and RTD was obtained from isometric wrist flexion from an isokinetic dynamometry protocol. Hierarchical regression analyses were used to identify whether muscle properties (MCSA, grip force, and RTD) independently predicted radius bone strength indices (BSI and SSI), after adjusting for the confounders of sex, height and weight. Steps of the regression models that included sex, height, weight and a muscle property explained between 66% and 71% of variance in distal radius BSI and between 74% and 78% variance of estimated bone strength (SSI) at the shaft site (all steps p<0.001). MCSA explained a significant amount of variance in BSI (R2=0.08; p<0.01) and SSI (R2=0.04; p<0.05) at the radius. Grip force was also a significant predictor of SSI (R2=0.05; p<0.01) but not distal radius BSI (R2=0.03; p=0.07). Conversely, RTD explained a significant amount of variance in bone strength at the distal radius (R2=0.04; p<0.05), but not at the shaft (R2=0.01; p=0.17). These cross sectional findings support the theory that regional muscle size, force, and rate of torque development are related to estimated bone strength in the forearm at midlife. Further research should focus on targeted interventions to help determine which muscle property elicits a greater osteogenic response to optimize bone strength at distal and shaft sites of the radius.

Purpose: To evaluate the course of recovery in fall-risk and functional status over the first year following a distal radius fracture (DRF), and evaluate differences in fall and fracture risk factors in women over the age of 50 years with a DRF compared to their non-fractured peers. Methods: Two cohorts of participants volunteered in two sub-studies of the thesis. The first was seventy-eight women recruited from a DRF Clinic within the first week after their fracture, and followed up in concert with standard clinic appointments at week three, nine, 12, 26, and 52 post-fracture. The second cohort consisted of women aged 50 years or older, with and without a recent distal radius fracture, being at least 6 months post-DRF, but no more than 2 years post-fracture. Seventy-seven women age 50-78 with (Fx, n = 32) and without (NFx = 45) a history of DRF were assessed on two occasions within 4 weeks apart using a battery of fall and fracture risk tools, including balance, mobility, gait speed, fracture risk assessment, as well as bone quality assessment using peripheral quantitative computer tomography (pQCT) and dual x-ray absorptiometry (DXA). Results: Fall-risk status (strength, balance, mobility) gradually improved over the first year post-fracture, with balance confidence remaining high even immediately post-fracture. In the second study, women with a recent DRF, compared to women without, demonstrated higher fall and fracture risk. Women with a recent DRF had lower bone and muscle strength in both the upper and lower extremities compared to the non-fractured controls, with no differences in DXA derived aBMD at the femoral neck or spine. Significance of findings: The results of these studies will help clinicians understand the normal course of functional recovery post-fracture, and assist in determining appropriate fall risk assessment and interventions for post-menopausal women at risk of fragility fracture. Results demonstrate the importance of studying women at risk of DRF as an important first indicator of bone fragility and risk of future fracture. These findings also strengthen the notion that DXA alone may not be the best predictor for fracture risk.

Introduction: Osteoporotic fractures, a major public health problem in aging populations, can lead to increased disability and mortality. Though rheumatoid arthritis (RA) patients have a higher risk for fractures than healthy populations, it is not known how hip structural geometry and body composition, two factors associated with bone strength, affect fracture risk in this population. The overall goal of this dissertation is to examine the association between RA, fracture, hip structural geometry, and body composition, in the participants of the Women's Health Initiative (WHI).Methods: The association between probable RA and fracture risk was tested using the entire WHI cohort (n=161,808). The association between probable RA and hip structural geometry was tested, both cross-sectionally and longitudinally, in a smaller sample (n=11,020) of participants from the WHI Bone Density Centers (WHI-BMD). The last study, testing the association between probable RA and body composition was also conducted in the WHI-BMD cohort.Results: In comparison to the non-arthritic group, the probable RA group had a significant 50%, 2-fold, and 3-fold increase in any, spine, and hip fracture, respectively. The association was not mot modified by age or ethnicity, but glucocorticoid use altered the association between RA and spine fractures. In terms of geometry, the probable RA had a significantly lower (p<0.05) mean hip BMD, outer diameter, cross-sectional area, and section modulus at the narrow neck region compared to control groups, indicating reduced bone strength. Body composition changes were present between the probable RA and the control group, with the probable RA group having statistically lower estimate of lean mass and statistically higher estimates of fat mass compared to the non-arthritic control group cross-sectionally and over the study.Conclusion: These studies confirm the increased risk for fracture among RA patients, while providing evidence that RA alters bone strength, especially at the hip, and negatively effects body composition by reducing lean mass and increasing fat mass. Additional research is needed link structural geometry and body composition to bone strength to lead to tailored interventions to minimize decreases in bone strength in this high fracture risk population.

The objective of this research was to evaluate the relationships between greater adiposity and bone development during adolescence. Bone was evaluated from age 11 to 17 years in the Iowa Bone Development Study using peripheral quantitative computed tomography (pQCT). Body composition (fat and lean mass) was estimated by dual energy x-ray absorptiometry (DXA). The first research aim evaluated the associations between greater overall adiposity and subsequent maturation and bone strength in 135 girls and 123 boys. Greater adiposity was defined according to age 8 Body Mass Index (BMI) to categorize participants as overweight (OW) or healthy-weight (HW). Maturation was defined as the age of peak height velocity (PHV). Bone strength was assessed at the radius and tibia (bone strength index, BSI, and strength-strain index, SSI). Differences in bone strength between OW and HW were evaluated with sex-specific multi-level regression models to account for individual growth and correlation between repeated measurements. Analyses were adjusted for centered age (measurement visit age - grand mean age of cohort), change in fat mass, and limb length in Model 1, with additional adjustment for lean mass in Model 2. Analyses were repeated using biological age (visit age - age PHV). BMI was positively associated with age of maturation in girls and boys (p< 0.05). HW versus OW girls had significantly lower BSI and SSI at the radius and tibia (p< 0.05) in Model 1. Results remained significant except for radial BSI in Model 2. HW versus OW boys had significantly lower BSI and SSI (all p< 0.05) at the tibia, but not radius, in Model 1. Significant differences were sustained in Model 2. Analyses were repeated using biological age, which yielded similar results for boys, but reduced parameter estimates were observed in girls, with only tibial SSI significant in Model 2 (p< 0.05). These findings support a stronger role for greater adiposity in the occurrence of earlier maturation and greater bone strength in girls than boys while greater lean mass appeared to play a greater role in boys. The second research aim evaluated associations between abdominal adiposity and bone in 132 girls and 122 boys. Visceral adipose tissue area (VAT, cm2) and subcutaneous adipose tissue area (SAT, cm2) were estimated from DXA scans. Sex-specific analyses evaluated the fat-bone relationship with growth models using biological age as the time variable adjusted for limb length and lean mass. There were no significant associations between bone parameters and VAT or SAT in girls. In boys, greater VAT was associated with lower trabecular bone density (tBMD) and BSI (all p< 0.05) at the tibia, but not radius. Greater VAT and SAT were associated with smaller cortical bone size and thickness (all p< 0.01) at the radius, but not tibia. Analyses limited to overweight participants showed VAT was negatively associated with periosteal circumference at the radius and tibia, cortical bone thickness at the tibia and SSI (all p< 0.05) at the radius in girls. In boys, the results were relatively unchanged for VAT, while SAT was only significantly associated with lower tBMD (p< 0.05) at the tibia. These results suggest the bone-fat relationship may vary depending on adiposity and bone site. The third research aim evaluated the longitudinal association between intramuscular fat and cortical bone at the tibia from age 11 to 17 years in 153 girls and 143 boys. Muscle density (MD) was used to estimate intramuscular fat (IMF). Lower MD indicates greater IMF. The relationships between muscle density and cortical bone parameters were modeled using multi-level regression models adjusted for biological age, limb length and muscle cross-sectional area measured by pQCT. In the adjusted multi-level regression models, MD was positively associated with cortical bone parameters, but only reached statistical significance for BMD, bone mineral content (BMC), bone cross-sectional area, cortical thickness and SSI in girls, while only SSI was significant in boys (all p< 0.05). These results suggest that greater fat content within muscle may be harmful to weight-bearing cortical bone during adolescence. In conclusion, findings from the first aim suggest there are sex- and site-specific differences in the relationship between adiposity and bone during adolescence. Findings from the second and third aims indicate these differences could be explained, in part, by the existence of specific fat depots (abdominal more so than intramuscular fat) that could be harmful to bone and that may be more apparent in boys due to a sex-specific fat distribution pattern that favors accumulation of abdominal rather than peripheral fat.

Mechanical response tissue analysis (MRTA) provides a noninvasive means of estimating the cross-sectional bending stiffness (EI) of long bones, and thus can serve as a predictor of bone strength. Estimates of bone bending stiffness are derived from the point impedance response of a long bone to low frequency (70-500Hz) stimulation according to beam vibration theory. MRTA has demonstrated the ability to reliably estimate human ulnar bending stiffness with between-test coefficients of variation of 5%, and in vivo measurements of monkey tibiae have been validated with ex vivo 3-point mechanical bending tests. Human tibial MRTA measurement has achieved between-trial coefficients of variation of only 12%, so a new physical MRTA configuration and improved computer algorithms have been developed in an attempt to improve upon this level of reliability. The new configuration removes the rigid proximal and distal tibial restraints and models the tissue behavior with a 12-parameter algorithm that accounts for free vibration at the ankle and knee joints. Initial testing with only the hardware changes and application of the 7-parameter model of tissue behavior used in earlier systems yielded unacceptable variation. Subsequent reliability testing with application of 6-, 9-, and 12-parameter models demonstrated modest improvements, prompting the development of the more robust 12-parameter model used in the present study. Evaluation of 110 college-age females (age 20.2±1.8 yr, height 163.3±5.9 cm, weight 60.7±9.3 kg, BMI 22.8±3.1 kg·m⁻²) with the current MRTA system has demonstrated an improvement in within-trial reliability for unsupported tibial EI measurement with a coefficient of variation of 11.2%. These results demonstrate the ability of the system to measure tibial response characteristics when both proximal and distal ends are free of rigid support. Long-term measurement reliability is still problematic with a coefficient of variation of 36.5% for a set of 4 measurements spanning 21 months. / Ph. D.