Osteoporosis, through its association with age-related fracture, is a major public health concern worldwide. Although osteoporosis was once considered a disease of the elderly, it is now recognized as a condition that has childhood antecedents. The capacity of bone to adapt is the greatest before puberty because of a higher rate of modeling and remodeling. Therefore, the amount of bone gained during childhood and adolescence has the potential to impact lifetime skeletal health. Children who participate in greater amounts of physical activity have greater bone mineral accrual in adolescence as well as a greater peak bone mass in young adulthood. Structured impact loading during growth also positively influences bone parameters. However, the intensity, duration and frequency of loading that is required to elicit skeletal benefits are not well established. Furthermore, although structured physical activity during growth has been hypothesized to delay or prevent the risk of osteoporosis and related fracture later in life there is no clear evidence of a persisting benefit once the loading stimulus has been removed. Therefore, the objective of this thesis was to investigate low-level impact loading during growth and skeletal development as well as to determine the influence of the withdrawal of the loading stimulus on adult bone parameters. Two studies were necessary to realize this objective. The findings should help to determine whether adolescent and adult bone health benefits from structured physical activity during growth. If this is found to be the case then structured gymnastic activity could be promoted as an effective means to optimize adult bone mass, structure and estimated strength.<p> Study 1: The purpose of study one was to investigate whether the differences previously reported in the skeleton of competitive female gymnasts (high level gymnastics exposure) are also demonstrated in young children with a current or past participation history in recreational or precompetitive gymnastics (low level gymnastics exposure). One hundred and sixty three children (30 gymnasts, 61 ex-gymnasts, and 72 non-gymnasts) between 4 and 6 years of age were recruited and measured annually for four years. Total body (TB), lumbar spine (LS) and femoral neck (FN) bone mineral content (BMC) was measured by dual energy x-ray absorptiometry (DXA) at each measurement occasion. Bone mass, density, structure and estimated strength was determined using peripheral quantitative computed tomography (pQCT) at the radius and tibia during the third measurement occasion. Multilevel random effects models were constructed and used to predict differences in TB, LS and FN BMC between groups while controlling for differences in body size, physical activity and diet. Analysis of covariance (covariates of sex, age and height) was used to investigate differences in bone content, density, area, and estimated strength at the radius and tibia. Gymnasts had 3% more TB and 7% more FN BMC than children participating in other recreational sports at the fourth measurement occasion (p<0.05). Gymnasts were also found have 6-25% greater adjusted BMC, volumetric bone mineral density and estimated strength at the distal radius compared to non-gymnasts (p<0.05). These findings suggest that recreational and precompetitive gymnastics participation (low level gymnastics exposure) is associated with greater bone parameters. This is important as beginner gymnastics skills are attainable by most children and do not require a high level of training. Low-level gymnastics skills can easily be integrated into school physical education programs potentially impacting skeletal health.<p> Study 2: The purpose of study 2 was to assess whether the previously reported greater bone mineral content in premenarcheal gymnasts was maintained 10 years after the cessation of participation and removal of the gymnastics loading stimulus. In 1995, thirty elite premenarcheal female gymnasts were recruited into a study investigating the role of high impact physical activity on bone mass in childhood and compared to 30 non-gymnasts. In 2009-2010 gymnasts and non-gymnasts (n=60) were re-contacted and 25 retired gymnasts and 22 non-gymnasts consented to participate. Total body, LS, and FN BMC was assessed at both measurement occasions by DXA. Bone geometric and densitometric parameters were measured by pQCT at the radius and tibia in 2009/10. ANCOVA was used to compare gymnasts and non-gymnasts bone parameters while controlling for differences in age, body composition and maturation. Gymnasts had significantly greater size adjusted TB, LS, and FN BMC (15, 17, and 12%, respectively) at 12 years of age (1995) (p<0.05). At follow-up, retired gymnasts also had significantly greater size adjusted TB, LS, and FN BMC (13, 19 and 13%, respectively) (p<0.05). Furthermore, retired female gymnasts had greater bone area, content and estimated strength at the radius and greater BMC and estimated strength at the tibia compared to non-gymnasts (p<0.05). Premenarcheal gymnasts have bone benefits that were apparent in adulthood after long-term removal of the gymnastics loading stimulus. Low level gymnastics exposure was associated with greater bone parameters in childhood. If these benefits can be maintained, as is suggested in retired competitive gymnasts, recreational gymnastics participation has the potential to positively impact lifetime skeletal health.

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.

Osteoporosis, through its association with age-related fracture, is a major public health concern worldwide. Although osteoporosis was once considered a disease of the elderly, it is now recognized as a condition that has childhood antecedents. The capacity of bone to adapt is the greatest before puberty because of a higher rate of modeling and remodeling. Therefore, the amount of bone gained during childhood and adolescence has the potential to impact lifetime skeletal health. Children who participate in greater amounts of physical activity have greater bone mineral accrual in adolescence as well as a greater peak bone mass in young adulthood. Structured impact loading during growth also positively influences bone parameters. However, the intensity, duration and frequency of loading that is required to elicit skeletal benefits are not well established. Furthermore, although structured physical activity during growth has been hypothesized to delay or prevent the risk of osteoporosis and related fracture later in life there is no clear evidence of a persisting benefit once the loading stimulus has been removed. Therefore, the objective of this thesis was to investigate low-level impact loading during growth and skeletal development as well as to determine the influence of the withdrawal of the loading stimulus on adult bone parameters. Two studies were necessary to realize this objective. The findings should help to determine whether adolescent and adult bone health benefits from structured physical activity during growth. If this is found to be the case then structured gymnastic activity could be promoted as an effective means to optimize adult bone mass, structure and estimated strength.<p> Study 1: The purpose of study one was to investigate whether the differences previously reported in the skeleton of competitive female gymnasts (high level gymnastics exposure) are also demonstrated in young children with a current or past participation history in recreational or precompetitive gymnastics (low level gymnastics exposure). One hundred and sixty three children (30 gymnasts, 61 ex-gymnasts, and 72 non-gymnasts) between 4 and 6 years of age were recruited and measured annually for four years. Total body (TB), lumbar spine (LS) and femoral neck (FN) bone mineral content (BMC) was measured by dual energy x-ray absorptiometry (DXA) at each measurement occasion. Bone mass, density, structure and estimated strength was determined using peripheral quantitative computed tomography (pQCT) at the radius and tibia during the third measurement occasion. Multilevel random effects models were constructed and used to predict differences in TB, LS and FN BMC between groups while controlling for differences in body size, physical activity and diet. Analysis of covariance (covariates of sex, age and height) was used to investigate differences in bone content, density, area, and estimated strength at the radius and tibia. Gymnasts had 3% more TB and 7% more FN BMC than children participating in other recreational sports at the fourth measurement occasion (p<0.05). Gymnasts were also found have 6-25% greater adjusted BMC, volumetric bone mineral density and estimated strength at the distal radius compared to non-gymnasts (p<0.05). These findings suggest that recreational and precompetitive gymnastics participation (low level gymnastics exposure) is associated with greater bone parameters. This is important as beginner gymnastics skills are attainable by most children and do not require a high level of training. Low-level gymnastics skills can easily be integrated into school physical education programs potentially impacting skeletal health.<p> Study 2: The purpose of study 2 was to assess whether the previously reported greater bone mineral content in premenarcheal gymnasts was maintained 10 years after the cessation of participation and removal of the gymnastics loading stimulus. In 1995, thirty elite premenarcheal female gymnasts were recruited into a study investigating the role of high impact physical activity on bone mass in childhood and compared to 30 non-gymnasts. In 2009-2010 gymnasts and non-gymnasts (n=60) were re-contacted and 25 retired gymnasts and 22 non-gymnasts consented to participate. Total body, LS, and FN BMC was assessed at both measurement occasions by DXA. Bone geometric and densitometric parameters were measured by pQCT at the radius and tibia in 2009/10. ANCOVA was used to compare gymnasts and non-gymnasts bone parameters while controlling for differences in age, body composition and maturation. Gymnasts had significantly greater size adjusted TB, LS, and FN BMC (15, 17, and 12%, respectively) at 12 years of age (1995) (p<0.05). At follow-up, retired gymnasts also had significantly greater size adjusted TB, LS, and FN BMC (13, 19 and 13%, respectively) (p<0.05). Furthermore, retired female gymnasts had greater bone area, content and estimated strength at the radius and greater BMC and estimated strength at the tibia compared to non-gymnasts (p<0.05). Premenarcheal gymnasts have bone benefits that were apparent in adulthood after long-term removal of the gymnastics loading stimulus. Low level gymnastics exposure was associated with greater bone parameters in childhood. If these benefits can be maintained, as is suggested in retired competitive gymnasts, recreational gymnastics participation has the potential to positively impact lifetime skeletal health.

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.

Introduction: Metaphyseal inwaisting is a process that occurs during long bone growth and remodelling of epiphyses and results in a proportional increase in growth plate width (GPW) and a decrease in metaphyseal width (MW). The Metaphyseal Index (MI) compares GPW to MW, usually in the distal femur. However, due to bone-age assessments, the most commonly performed radiograph in children is that of the hand/forearm. Previous work showed that gymnasts have a more widened growth plate at the distal radius than normal children, but these studies did not quantify the morphological changes using the MI and pQCT measures. Previous studies have shown that the use of DXA hand/forearm images for the purposes of bone-age assessment were unreliable for children aged 11 and under. Aims: Examine distal radius morphology of 378 Normal subjects (155 male), 36 Gymnast subjects (15 male), 17 NF1 subjects (7 male) and 108 CDGP subjects (83male) to calculate the precision of MI, MW and GPW measurements, to determine a normal reference range for the MI in Normal subjects and use this to compare to the other 3 groups, and to compare longitudinal measurements. Also, to investigate whether DXA software upgrades have improved the ability to make TW3 bone-age assessments, to investigate how closely DXA compares with standard radiographs using 98 (38 male) DXA hand images and radiographs, and calculate the precision (CV%) of the GP and TW3 bone-age assessment methods. Methods: Anthropometric data, Tanner stage, posterior-anterior hand radiographs and pQCT scans of the non-dominant hand/forearm were obtained. MI was measured using a semi-automated computer-assisted method. Statistical analyses were used to compare males and females, and compare the Normal group to other groups. Also, DXA images and radiographs were assessed by the same assessor and the TW3 and GP bone-ageing methods were compared. A CV% was calculated for both comparisons. Results: The CV% of MI, MW and GPW = 1.05%, 0.92% and 1.28% respectively. MI of males and females was not statistically different in any group. The MI of Gymnasts was significantly lower than the Normal group (p = 0.008). The NF1 and CDGP groups were not significantly different from the Normal group. Longitudinal measurements indicated those with a low/high MI at the first visit were likely to have a low/high MI at the second visit, though occasionally the MI would decrease between visits. DXA bone age assessments proved to be reliable in subjects of all ages assessed in this study and showed a CV% only slightly higher than standard radiographs (CV = 2.95% DXA vs2.68% radiograph). The CV% of GP and TW3 methods = 2.68% & 1.61% respectively. Discussion: The CV% of MI, MW and GPW shows these methods to be very precise. The mean MI of gymnasts is significantly lower than in normal children due to a widening of the growth plate and not due to a reduction in metaphyseal width. Insufficient subject numbers and smaller age ranges, particularly in the Gymnast and NF1 groups may play a part in the non-significant differences between them and the Normal group. DXA CV% shows that DXA is almost interchangeable with standard radiographs. The TW3 and GP CVs% show that TW3 bone-age assessment is more precise than the GP method. This confirms the tight control that the MW and GPW have in proportion to each other. This is the first study to quantify changes in distal radius morphology in normal, athlete and disease groups, and create a range of normal reference values, which could be useful for future work in this area.

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.

Bone health in the context of two common maladies, osteoporosis and obesity, has spurred research in the area of physical activity (PA) and bariatric surgery (BarS). Objectives: To examine: 1) relationships between PA and the skeleton utilizing the peripheral Quantitative Computed Tomography (pQCT) and Dual-energy X-ray Absorptiometry (DXA) in pre-menopausal women; 2) effects of adjustable gastric banding (AGB) vs. Roux-en-Y gastric bypass (RYGB) surgeries on pQCT and DXA measures; 3) 6-month time course changes on serum biomarkers of bone turnover and associated adipokines induced by AGB vs. RYGB. Methods: Standard DXA and pQCT measurements were taken for all subjects. PA tertiles (PA-L, PA-M, PA-H) were based on a calculated average MET-min/day determined from 4-d self-reported PA and pedometer step counts. For BarS subjects, bone measurements were taken pre-surgery, 3- and 6-months post-surgery along with serum (or plasma) from fasting blood draws, with ELISA assays for total OC, undercarboxylated OC, CTx, adiponectin, and leptin. Results: Minimal DXA differences between the highest and lowest PA tertiles were seen, while pQCT tibial measures and polar strength-strain index (SSIp) indicated differences along the tibial shaft. Comparing the two instruments and adjusting for BMI, the DXA leg and hip BMD and BMC showed differences (p<0.05) between PA-M and PA-L as well as PA-H and PA-L. Similarly, the pQCT tibial cortical area, BMC, and SSIp were progressively greater for the different levels of PA (p<0.05). 3- and 6-months post-BarS weight, fat-free mass, fat mass, central body fat, tibial and radial subcutaneous fat, and radial MCSA decreased (p<0.05). Comparing the AGB and RYGB and adjusting for weight, DXA BMC showed decreases (p<0.01) at both time points for RYGB. RYGB demonstrated differences (p<0.05) in bone measures at 3- and 6-months post-surgery along the tibial shaft that are indicative of increases in bone strength, and at 6-months, total OC, undercarboxylated OC, and HMW adiponectin increased, while leptin decreased. Conclusions: PA is associated with increases in bone, but pQCT data are more discriminatory and sensitive. 6-months post-RYGB, pQCT measures indicate increases in bone strength parameters, and greater bone adaptation was evidenced by biomarkers of increased osteoblastic activity. / Ph. D.

Le rôle de la microstructure trabéculaire et corticale dans la résistance osseuse et le risque de fracture est bien documenté mais son déterminisme génétique n’a pas encore été étudié. Pour savoir si la microarchitecture osseuse et le métabolisme osseux ont un déterminisme héréditaire, une étude épidémiologique transversale (étude MODAM) a été menée pour évaluer la ressemblance familiale de la microarchitecture osseuse chez les femmes ménopausées et leurs filles non ménopausées en utilisant la tomodensitométrie quantitative périphérique haute résolution (HR-pQCT). Nous avons constaté que les filles des femmes ayant subi une fracture ont une densité osseuse volumétrique totale (vBMD) plus faible, des corticales amincies, et une altération de la microarchitecture osseuse trabéculaire au niveau du radius distal et du tibia comparativement aux filles dont les mères n’ont pas eu de fracture. Une autre étude épidémiologique transversale (étude MINOS) a été menée pour évaluer la corrélation de la densité minérale osseuse (DMO), de la taille des os, des marqueurs du remodelage osseux (BTM) et des hormones de régulation du remodelage osseux dans des paires de frères et des paires d'hommes non apparentés, appariés pour l'âge, le poids et la taille. Nous avons constaté que la taille des os, la DMO à certains sites du squelette et la plupart des BTM étaient plus fortement corrélés chez les frères comparativement aux hommes non apparentés. Ces données suggèrent un déterminisme héréditaire substantiel des niveaux de BTM chez les hommes. En conclusion, nous développons et confirmons l'importance des facteurs familiaux dans la pathogénie de l'ostéoporose chez les femmes et les hommes / The role of trabecular and cortical microstructure in bone strength and fracture risk is well documented, but its genetic determinism has not yet been studied. To find whether the bone microarchitecture, and bone metabolism have a strong hereditary determinism, a crosssectional epidemiological study (MODAM study) was conducted, investigating the familial resemblance of bone microarchitecture in postmenopausal mothers and their premenopausal daughters using high-resolution peripheral quantitative computed tomography (HR-pQCT). We found that daughters of women with fracture have lower total volumetric bone mineral density (vBMD), thinner cortices, and impaired trabecular microarchitecture at the distal radius and tibia, compared with daughters of women without fracture. Another cross-sectional epidemiological study (MINOS study) was conducted to assess the correlation of bone mineral density (BMD), bone size, bone turnover markers (BTMs) and hormones regulating bone turnover in pairs of brothers and pairs of unrelated men, matched for age, weight and height. We found that bone size, BMD at some skeletal sites and most of the BTM levels correlated more strongly in the brothers than in the unrelated men. These data suggest a substantial hereditary determinism of the BTM levels in men. In conclusion, we expand and confirm the importance of familial factors in the pathogenesis of osteoporosis in both women and men

La maladie rénale chronique (MRC) induit des anomalies du métabolisme phosphocalcique, avec des conséquences à la fois osseuses, vasculaires et biologiques. La prise en charge optimale de ces désordres représente un challenge quotidien pour le néphrologue pédiatre, à la fois sur le court terme (équilibre biologique) et sur le long terme (prévention des fractures, optimisation de la croissance et limitation de l’apparition des calcifications vasculaires). Peu d’outils sont actuellement disponibles pour évaluer ces atteintes, et de nouveaux outils prometteurs, à la fois biologiques (FGF23) et radiologiques (HR-pQCT) apparaissent. Néanmoins, les données pédiatriques sur ces outils restent rares. Cette thèse de doctorat a permis d’évaluer ces nouveaux moyens chez ces enfants MRC, notamment en évaluant l’HR-pQCT dans cette population, et en déterminant des valeurs de référence du FGF23 en fonction de l’âge, du sexe et de la fonction rénale. Nous avons pu aussi montrer que les concentrations circulantes de FGF23 ne sont pas dépendantes du sexe dans une population pédiatrique, mais qu’elles augmentent avec l’âge et l’indice de masse corporelle, mais aussi en cas d’antécédent de transplantation d’organe solide ou de traitement par corticostéroïdes. D’un point de vue plus fondamental, nous avons pu montrer que dans des monocytes issus de donneurs sains, une exposition au FGF23 induit une diminution de l’expression des 2 enzymes principales impliquées dans le métabolisme de la vitamine D (1α hydroxylase et 24 hydroxylase), en induisant également une diminution du peptide antimicrobien cathélicidine. Ces résultats permettent donc de décrire un nouveau rôle pour le FGF23 dans la régulation de l’immunité innée / Chronic kidney disease can induce mineral and bone disorders (CKD-MBD), with deleterious consequences for bone and vessels. The management of such abnormalities can be challenging, from the daily biological balance between calcium, phosphorus and PTH levels, to the long-term prevention of morbidities such as fractures, growth impairment and vascular calcifications. Some tools can help to accurately assess CKD-MBD, e.g., new bone imaging techniques (HR-pQCT) and FGF23, but they are rarely used in pediatric populations. In addition to evaluating HR-pQCT in CKD children and healthy controls, this PhD thesis allowed us to determine reference values for circulating FGF23 levels depending on age, gender and renal function; we also showed that FGF23 levels increased not only with age and BMI, but also in cases of solid organ transplant or corticosteroids therapy. We have also showed in vitro that FGF23 could inhibit the two key enzymes of vitamin D metabolism (1α hydroxylase et 24 hydroxylase) in monocytes issued from healthy donors, with in turn a decreased synthesis of the antimicrobial cathelicidin. These later results highlight a new role for FGF23 in innate immunity, and may bring new insights in the understanding of FGF23 deregulation during CKD

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. / Osteoporosis is characterized by altered bone quality and compromised bone strength leading to increased fracture risk. Measurement of areal bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA) is the most widely used index of bone strength. However, BMD alone can only account for 40 to 70% of the variation of bone strength. This study aimed to determine: 1/ the respective role of cortical and trabecular microarchitecture to vertebral mechanical behavior, 2/ the role of trabecular microarchitecture heterogeneity and 3/ the mechanical behavior of a vertebra after simulated mild fracture and its determinants. Our data imply that measurements of cortical thickness and curvature as well as determination of trabecular microarchitecture heterogeneity enhance prediction of vertebral fragility. We found marked variation in the post-fracture load-bearing capacity following simulated mild vertebral fractures. Bone microarchitecture, but not bone mass, was associated with post-fracture mechanical behavior of vertebrae.