Prostaglandins (PGs) are important signalling factors for bone mechanotransduction. The inhibition of cyclooxygenase, responsible for the synthesis of PGs, with non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to influence bone formation induced by mechanical stimulation. The purpose of this study was to examine the timing effects of NSAID administration on: 1) bone formation induced by multiple mechanical loading events in a rat model and 2) the PGE2 response of MLO-Y4 osteocyte like cells stimulated by fluid shear stress. The rat forelimb compression model was used to induce bone formation in male and female rats using a 1-month loading protocol (12 loading sessions). The right forelimbs were loaded and the left forelimbs served as non-loaded controls. NSAIDs were administered orally either before or after loading. Fluorochrome labels were administered to the rats to determine mineral apposition rate (MAR). The NSAIDs examined (indomethacin, NS-398 and ibuprofen) did not significantly affect periosteal MAR, administered either before or after loading, suggesting NSAIDs do not affect bone adaptation to multiple mechanical loading events. To examine in vitro effects of NSAIDs on PGE2 production, an orbital shaker was used to apply fluid shear stress to MLO-Y4 cells seeded in 6-well culture plates. Indomethacin was added to the culture media either before or after loading and media PGE2 concentrations were determined at various time points by enzyme immunoassay. Fluid shear stress increased PGE2 production of MLO-Y4 cells and indomethacin administration inhibited that response when administered both before and after fluid flow. However, PGE2 production was influenced by the media changes that occurred in the in vitro experiments, making it difficult to differentiate between indomethacin effects and media change effects. The in vitro experiments revealed the difficulties of modeling the timing effects of NSAID administration on MLO-Y4 PGE2 production in response to fluid flow. / Thesis / Doctor of Philosophy (PhD) / Bone is a dynamic tissue that can adapt to mechanical loading. Prostaglandins (PGs) are important signalling factors produced by osteocytes, the bone mechanosensing cells, that help to activate various cells and cell processes leading to changes in bone structure. Blocking PG signalling with non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to influence bone formation induced by mechanical stimulation in animals and humans. The purpose of this study was to examine the timing effects of NSAID administration on: 1) bone formation induced by multiple mechanical loading events in rats and 2) the PG production of osteocyte like cells in response to fluid flow stimulation. The results of this study suggest that NSAIDs, administered either before or after loading, do not affect bone responses to multiple mechanical loading events. Further investigation is needed to determine the translatability of these findings to NSAID use around the time of exercise in humans.

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Background Running is a popular form of exercise that more than 55 million Americans actively participate. Endurance running like marathon and half- marathon is getting increasingly popular among active runners. Although the effect of running is considered beneficial to bone health, the direct relationship between strains and strain gradients occurred during long distance running and bone changes is still not clear. Especially, given a high rate of injury associated with the first-time marathon, understanding the direct effect of strain stimuli on bone health is an important issue. Based on the previous studies, we hypothesized that the higher values of strain will induce bone adaptation more effectively and will lead to higher bone osteogenic changes. Since osteocytes sense shear stress caused by the interstitial fluid flow, which is created by the deformations, and regulate activities of osteoblasts and osteoclast that govern bone adaptation, we also hypothesized that the local strain gradient will create pressure differences within the interstitial fluid network and will increase fluid flow. Furthermore, due to that increased fluid flow, the regions with the higher strain gradient will experience a higher amount of bone adaptation. Thus, in this study, our purpose was to define the effect of the strains and strain gradients on bone changes within distal tibia, which is the most prone anatomical site to low risk stress fracture, during training for first-time marathon. Methods High-resolution and low-resolution computed tomographic (CT) images of the distal tibia were obtained before and after a self-selected training from runners who were actively training to participate in their first-time marathon in the next calendar year. The low resolution scan covered a 69.864 mm length of the distal end of the tibia while the high resolution CT scan covered a 9.02 mm region of the distal tibia. Using low resolution CT image based subject specific finite element (FE) models, the strains and strain gradients of the distal tibia at the instance of the peak ground reaction force (GRF) were calculated. The baseline and follow-up high resolution CT scans were used in high resolution peripheral quantitative CT (HRpQCT) analysis and the estimation of bone changes over the training period. Finally, the effect of strains and strain gradients on the distal tibia bone changes was estimated based on the FE model driven strain values and HRpQCT analysis driven bone changes. We used a linear mixed model to define the relationship between strain values and bone changes in the distal tibia. Results The strain values that occurred during marathon training had significant effects on bone changes in the distal tibia. Particularly, the strain gradients showed a higher effect than the strains. In the cortical compartment, the strain gradients, which were calculated as a strain difference of a node from the surrounding nodes (Strain Gradient-1), affected the bone mineral density (BMD) negatively, and per 1000 µε increase resulted in 2.123% decrease in the cortical BMD. The strain gradients, which were calculated as a strain difference of a node from the surrounding nodes normalized to distance to surrounding nodes (Strain Gradient-2), presented a positive effect on the cortical bone volume with a slope of 4.335% / 1000 µε. In the trabecular compartment, the strain gradient-1 showed negative effects on the percent change in BMD and bone mineral density (BMC), whereas the strain gradient-2 showed positive effects on the percent change in BMD and BMC. Conclusion The linear mixed model analysis revealed a statistically significant (p < 0.05) relationship between strain gradients that occurred during running and distal tibia bone changes. The strains, biometrics, and initial parameters of bone did not show any significant effect on the bone changes. The connection between local strain environment and bone changes in the distal tibia investigated in this study is an important step to understand the mechanism of mechanically induced bone adaptation.

Background Running is a popular form of exercise that more than 55 million Americans actively participate. Endurance running like marathon and half- marathon is getting increasingly popular among active runners. Although the effect of running is considered beneficial to bone health, the direct relationship between strains and strain gradients occurred during long distance running and bone changes is still not clear. Especially, given a high rate of injury associated with the first-time marathon, understanding the direct effect of strain stimuli on bone health is an important issue. Based on the previous studies, we hypothesized that the higher values of strain will induce bone adaptation more effectively and will lead to higher bone osteogenic changes. Since osteocytes sense shear stress caused by the interstitial fluid flow, which is created by the deformations, and regulate activities of osteoblasts and osteoclast that govern bone adaptation, we also hypothesized that the local strain gradient will create pressure differences within the interstitial fluid network and will increase fluid flow. Furthermore, due to that increased fluid flow, the regions with the higher strain gradient will experience a higher amount of bone adaptation. Thus, in this study, our purpose was to define the effect of the strains and strain gradients on bone changes within distal tibia, which is the most prone anatomical site to low risk stress fracture, during training for first-time marathon. Methods High-resolution and low-resolution computed tomographic (CT) images of the distal tibia were obtained before and after a self-selected training from runners who were actively training to participate in their first-time marathon in the next calendar year. The low resolution scan covered a 69.864 mm length of the distal end of the tibia while the high resolution CT scan covered a 9.02 mm region of the distal tibia. Using low resolution CT image based subject specific finite element (FE) models, the strains and strain gradients of the distal tibia at the instance of the peak ground reaction force (GRF) were calculated. The baseline and follow-up high resolution CT scans were used in high resolution peripheral quantitative CT (HRpQCT) analysis and the estimation of bone changes over the training period. Finally, the effect of strains and strain gradients on the distal tibia bone changes was estimated based on the FE model driven strain values and HRpQCT analysis driven bone changes. We used a linear mixed model to define the relationship between strain values and bone changes in the distal tibia. Results The strain values that occurred during marathon training had significant effects on bone changes in the distal tibia. Particularly, the strain gradients showed a higher effect than the strains. In the cortical compartment, the strain gradients, which were calculated as a strain difference of a node from the surrounding nodes (Strain Gradient-1), affected the bone mineral density (BMD) negatively, and per 1000 µε increase resulted in 2.123% decrease in the cortical BMD. The strain gradients, which were calculated as a strain difference of a node from the surrounding nodes normalized to distance to surrounding nodes (Strain Gradient-2), presented a positive effect on the cortical bone volume with a slope of 4.335% / 1000 µε. In the trabecular compartment, the strain gradient-1 showed negative effects on the percent change in BMD and bone mineral density (BMC), whereas the strain gradient-2 showed positive effects on the percent change in BMD and BMC. Conclusion The linear mixed model analysis revealed a statistically significant (p < 0.05) relationship between strain gradients that occurred during running and distal tibia bone changes. The strains, biometrics, and initial parameters of bone did not show any significant effect on the bone changes. The connection between local strain environment and bone changes in the distal tibia investigated in this study is an important step to understand the mechanism of mechanically induced bone adaptation.

L'étude de l'os est d'un intérêt majeur en Anthropologie. Constituant la charpente des vertébrés, le squelette est le reflet de l'activité motrice. En effet, chaque élément du squelette a une fonction dictée par sa forme et un rôle autorisé par sa morphologie. C'est l'illustration la plus visible de l'adaptation. Ce processus est largement étudié dans la lignée humaine et ce dogme est au cœur de nombreuses recherches en Anthropobiologie. Ces caractères sont inscrits dans la forme de l'os. Chaque courbure, apophyse ou crête témoignent au moins en partie de l'action d'un muscle ou d'une fonction dictée par un lent processus évolutif voire adaptatif. Cette évolution se fait par l'évolution de caractères externes de l'os par sa forme ou l'anatomie " visible " d'une part et par l'évolution de caractères plus internes, subtils et directement lié aux propriétés biomécaniques de l'os à savoir l'os trabéculaire. L'os trabéculaire est un matériau plus fragile, déformable que l'os cortical. Il constitue une trace indirecte des contraintes appliquées squelette. C'est ainsi que les activités locomotrices, alimentaires ou occupationnelle seront inscrite dans l'endostructure osseuse. C'est la théorie développée par Wolff dès 1870 dans " The law of bone remodelling ". Il développa cette conception d'un processus actif, évolutif par l'observation macroscopique des travées de l'extrémité supérieure du fémur chez l'homme. Si la contrainte exercée sur un os en particulier augmente, il va se remodeler pour devenir plus rigide et résister à la charge dans ce segment d'os particulier et pour cette force particulière de contrainte. Nous avons étudié cette théorie sur deux modèles chez le vivant au niveau du membre supérieur et au niveau du membre inférieur pour caractériser les contraintes asymétriques appliquées à l'os trabéculaires. La latéralité ou préférence manuelle est un exemple d'activité asymétrique. Ses effets sur l'os sont bien connus lors de la pratique de sports intensifs ou d'activités très latéralisées. Cependant peu de données existent sur les activités usuelles et la préférence manuelle de l'homme jeune sans activité particulière. Par une étude en microscanner avec des coupes de 41 microns, des volumes d'intérêt dans les os du squelette carpien radial ont été réalisés sur des individus d'âge jeune sans antécédent particulier de façon bilatérale. Plusieurs variables cliniques et anthropométriques ont également été recueillis. Nous avons pu mettre en évidence des caractères endostructuraux expliquant la variabilité interindividuelles en les comparant avec des éléments anthropomorphiques et la force de serrage manuelle. Par ailleurs, les défauts d'axe en varus ou en valgus exercent des contraintes asymétriques également sur les articulations portantes. La chirurgie prothétique du genou croit ces dernières années de façon exponentielle par un effet conjoint de l'amélioration des techniques, et l'augmentation de l'incidence de l'arthrose. / The study of bone is of major interest in Anthropology. The skeleton is an image of motor activity. Indeed, every element of the skeleton has a function dictated by its shape and role and then by its morphology. This illustrates the most visible adaptation of the bone. This process is widely studied in the human lineage. This theory is an important path of research in Anthropology. These characters are inscribed in the shape of the bone. Each curve, or crest reflect the action of a muscle or a function dictated by a slow evolutionary process. This change is by changing external characteristics of the bone by its form or anatomy "visible" on the one hand and by the evolution of more internal character, subtle and directly related to the biomechanical properties of bone namely trabecular bone. Trabecular bone is a more brittle material, deformable than cortical bone. It is an indirect trace of the stresses applied to the bone. Thus locomotion, feeding or occupational activities can be analyzed into the bone endostructure. This is the theory developed by Wolff in 1870 in "The law of bone remodeling." He developed this idea of ??an active, evolving process by macroscopic observation of the spans of the proximal femur in humans. If the stress on a particular bone increases, it will remodel to become more rigid and withstand the load in that particular bone segment and for this particular force of constraint. We studied this theory on two models in the living human being. One concerned the upper limb and the second the lower limb to characterize asymmetrical forces on trabecular bone. Laterality or handedness is an example of asymmetrical activity. Its effects on bone are well known in the practice of intensive sports or very lateralized activities. However, little data exist on the usual activities and the handedness of the young man with no particular activity. We performed a microCT study with cuts 41 microns slices. Volumes of interest in radial carpal bones were performed on both sides on young human adults without particular medical history. Several clinical and anthropometric variables were also collected. We were able to highlight endostructural patterns explaining the interindividual variability in comparison with anthropometric parameters and crush or pinch grip. Furthermore, axis deviations in varus or valgus exert asymmetric constraints also on weight-bearing joints. The prosthetic knee surgery increases exponentially in the last decades by a combined effect of improved techniques and the increased incidence of osteoarthritis. The OA is multifactorial but the weight has a major effect on cartilage wear. We further know that the morphology and deformation of members influence this phenomenon. We wanted to characterize the response of the bone to endostructure these asymmetrical stresses on the tibial plateau. We collected tibial plateaus during total joint replacement surgeries for knee and compare the bone under chondral internal and external with microCT 7.4 micron slices. Some parameters highlight the major effect weight and body mass such as bone volume fraction BV/TV, structure model index SMI, trabecular space Tb. and trabecular number Tb.N. Subchondral densification during osteoarthritis is associated with a reduction in its elastic modulus, which could increase cartilage stress, and accelerate cartilage loss.

The mechanical loading affects the long bone cross-section geometry (CSG). The aim of this thesis was to examine experimentally the relationship between the locomotory parameters and cross-sectional properties of long bones, and to test some partial knowledge of the bone mechanical adaptation. Two groups of B6CBA mice were examined: (a) Lurcher type (model of olivocerebellar degeneration; n = 10) and (b) control (normal mice; n = 10). We analyzed the motor characteristics and the bone cross-sectional geometric properties. The motor tests included the test of spontaneous motor activity (Open field), strength properties (horizontal bar) and motor coordination (rotarod). Cross-sections were taken in 50 % of the left tibia biomechanical length and further processed for fluorescence confocal microscopy. We analyzed the biomechanical properties of cortical bone cross-sections (software ImageJ). There were nonsignificant differences in CSG parameters (TA, CA, Imax, Imin, J, Imax/Imin) between Lurcher and control mice. The results did not support our assumption about the effect of motor disorder on CSG properties. We did not demonstrate the effect of local factors on the bone biomechanical adaptation. The results of this thesis may be useful to find new testing possibilities of cortical bone in...

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