Higher Cortical Thickness Research Articles

Cortical features of distinct developmental trajectories in patients with delusional infestation

BackgroundAlthough there is strong neuroimaging evidence that cortical alterations are a core feature of schizophrenia spectrum disorders, it still remains unclear to what extent such abnormalities occur in monothematic delusional disorders. In individuals with delusional infestation (DI), the delusional belief to be infested with pathogens, previous structural MRI studies have shown prefrontal, temporal, parietal, insular, thalamic and striatal gray matter volume changes. Differential contributions of cortical features of evolutionary and genetic origin (such as cortical thickness, area and folding) which may distinctly contribute to DI pathophysiology are unclear at present. MethodsIn this study, 18 patients with DI and 20 healthy controls (HC) underwent MRI scanning at 1.0T. Using surface-based analyses we calculated cortical thickness, surface area and local gyrification index (LGI). Whole-brain differences between patients and controls were investigated. ResultsSurface analyses revealed frontoparietal patterns exhibiting altered cortical thickness, surface area and LGI in DI patients compared to controls. Higher cortical thickness was found in the right medial orbitofrontal cortex (p<0.05, cluster-wise probability [CWP] corrected). Smaller surface area in patients was found in the left inferior temporal gyrus, the precuneus, the pars orbitalis of the right frontal gyrus, and the lingual gyrus (p<0.05, CWP corr.). Lower LGI was found in the left postcentral, bilateral precentral, right middle temporal, inferior parietal, and superior parietal gyri (p<0.01, CWP corr.). ConclusionThis study lends further support to the hypothesis that cortical features of distinct evolutionary and genetic origin differently contribute to the pathogenesis of delusional disorders. Regions in which atrophy was observed are part of neural circuits associated with perception, visuospatial control and self-awareness. The data are in line with the notion of a content-specific neural signature of DI.

Raloxifene Improves Bone Mechanical Properties in Mice Previously Treated with Zoledronate.

Bisphosphonates represent the gold-standard pharmaceutical agent for reducing fracture risk. Long-term treatment with bisphosphonates can result in tissue brittleness which in rare clinical cases manifests as atypical femoral fracture. Although this has led to an increasing call for bisphosphonate cessation, few studies have investigated therapeutic options for follow-up treatment. The goal of this study was to test the hypothesis that treatment with raloxifene, a drug that has cell-independent effects on bone mechanical material properties, could reverse the compromised mechanical properties that occur following zoledronate treatment. Skeletally mature male C57Bl/6J mice were treated with vehicle (VEH), zoledronate (ZOL), or ZOL followed by raloxifene (RAL; 2 different doses). At the conclusion of 8 weeks of treatment, femora were collected and assessed with microCT and mechanical testing. Trabecular BV/TV was significantly higher in all treated animals compared to VEH with both RAL groups having significantly higher BV/TV compared to ZOL (+21%). All three drug-treated groups had significantly more cortical bone area, higher cortical thickness, and greater moment of inertia at the femoral mid-diaphysis compared to VEH with no difference among the three treated groups. All three drug-treated groups had significantly higher ultimate load compared to VEH-treated animals (+14 to 18%). Both doses of RAL resulted in significantly higher displacement values compared to ZOL-treated animals (+25 to +50%). In conclusion, the current work shows beneficial effects of raloxifene in animals previously treated with zoledronate. The higher mechanical properties of raloxifene-treated animals, combined with similar cortical bone geometry compared to animals treated with zoledronate, suggest that the raloxifene treatment is enhancing mechanical material properties of the tissue.

Defective cancellous bone structure and abnormal response to PTH in cortical bone of mice lacking Cx43 cytoplasmic C-terminus domain

Connexin 43 (Cx43) forms gap junction channels and hemichannels that allow the communication among osteocytes, osteoblasts, and osteoclasts. Cx43 carboxy-terminal (CT) domain regulates channel opening and intracellular signaling by acting as a scaffold for structural and signaling proteins. To determine the role of Cx43 CT domain in bone, mice in which one allele of full length Cx43 was replaced by a mutant lacking the CT domain (Cx43ΔCT/fl) were studied. Cx43ΔCT/fl mice exhibit lower cancellous bone volume but higher cortical thickness than Cx43fl/fl controls, indicating that the CT domain is involved in normal cancellous bone gain but opposes cortical bone acquisition. Further, Cx43ΔCT is able to exert the functions of full length osteocytic Cx43 on cortical bone geometry and mechanical properties, demonstrating that domains other than the CT are responsible for Cx43 function in cortical bone. In addition, parathyroid hormone (PTH) failed to increase endocortical bone formation or energy to failure, a mechanical property that indicates resistance to fracture, in cortical bone in Cx43ΔCT mice with or without osteocytic full length Cx43. On the other hand, bone mass and bone formation markers were increased by the hormone in all mouse models, regardless of whether full length or Cx43ΔCT were or not expressed. We conclude that Cx43 CT domain is involved in proper bone acquisition; and that Cx43 expression in osteocytes is dispensable for some but not all PTH anabolic actions.

Cortical thinning explains changes in sleep slow waves during adulthood.

Sleep slow waves (SWs) change considerably throughout normal aging. In humans, SWs are generated and propagate on a structural backbone of highly interconnected cortical regions that form most of the default mode network, such as the insula, cingulate cortices, temporal lobe, parietal lobe, and medial frontal lobe. Regions in this network undergo cortical thinning and breakdown in structural and functional connectivity over the course of normal aging. In this study, we investigated how changes in cortical thickness (CT), a measure of gray matter integrity, are involved in modifications of sleep SWs during adulthood in humans. Thirty young (mean age = 23.49 years; SD = 2.79) and 33 older (mean age = 60.35 years; SD = 5.71) healthy subjects underwent a nocturnal polysomnography and T1 MRI. We show that, when controlling for age, higher SW density (nb/min of nonrapid eye movement sleep) was associated with higher CT in cortical regions involved in SW generation surrounding the lateral fissure (insula, superior temporal, parietal, middle frontal), whereas higher SW amplitude was associated with higher CT in middle frontal, medial prefrontal, and medial posterior regions. Mediation analyses demonstrated that thinning in a network of cortical regions involved in SW generation and propagation, but also in cognitive functions, explained the age-related decrease in SW density and amplitude. Altogether, our results suggest that microstructural degradation of specific cortical regions compromise SW generation and propagation in older subjects, critically contributing to age-related changes in SW oscillations.

Effect of sclerostin antibody treatment in a mouse model of severe osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that is usually caused by mutations affecting collagen type I production in osteoblasts. Stimulation of bone formation through sclerostin antibody treatment (Sost-ab) has shown promising results in mouse models of relatively mild OI. We assessed the effect of once-weekly intravenous Sost-ab injections for 4weeks in male Col1a1Jrt/+mice, a model of severe dominant OI, starting either at 4weeks (growing mice) or at 20weeks (adult mice) of age. Sost-ab had no effect on weight or femur length. In OI mice, no significant treatment-associated differences in serum markers of bone formation (alkaline phosphatase activity, procollagen type I N-propeptide) or resorption (C-telopeptide of collagen type I) were found. Micro-CT analyses at the femur showed that Sost-ab treatment was associated with higher trabecular bone volume and higher cortical thickness in wild type mice at both ages and in growing OI mice, but not in adult OI mice. Three-point bending tests of the femur showed that in wild type but not in OI mice, Sost-ab was associated with higher ultimate load and work to failure. Quantitative backscattered electron imaging of the femur did not show any effect of Sost-ab on CaPeak (the most frequently occurring calcium concentration in the bone mineral density distribution), regardless of genotype, age or measurement location. Thus, Sost-ab had a larger effect in wild type than in Col1a1Jrt/+mice. Previous studies had found marked improvements of Sost-ab on bone mass and strength in an OI mouse model with a milder phenotype. Our data therefore suggest that Sost-ab is less effective in a more severely affected OI mouse model.

In Obese Postmenopausal Women, Bone Microarchitecture and Strength Are Not Commensurate to Greater Body Weight: The Os des Femmes de Lyon (OFELY) Study

Obesity is associated with higher areal bone density (aBMD) but its protective effect on the risk of fracture is controversial. We aimed to analyze bone microarchitecture and biomechanical properties in obese (OB) postmenopausal French women compared with normal weight (NW) women. A matched case-control study from the Os des Femmes de Lyon (OFELY) cohort was conducted in 63 OB women (body mass index [BMI] > 30, mean age 69 ± 8 years) age-matched with 126 NW women (19 ≤ BMI ≤ 25). Bone architecture was measured with high-resolution pQCT at the distal radius and tibia and bone strength was assessed by micro-finite element analysis (µFEA). aBMD, total body fat mass (FM) and lean mass (LM) were measured by dual-energy X-ray absorptiometry (DXA). aBMD was 15% higher at the total hip in OB compared with NW women. At the radius, OB had 13% and 14% higher volumetric total and trabecular bone densities, 11% higher cortical thickness, 13% greater trabecular number, and 22% lower distribution of trabecular separation compared with NW (p adjusted for height, physical activity, and medication use, <0.01 for all). Differences of a similar magnitude were found at the distal tibia. At both sites, µFEA showed significant higher values of bone strength in OB compared to controls. After normalizing values for individual body weight, we observed that all the parameters were relatively lower in OB compared to NW women. The increase of FM was fourfold greater than the increase of LM in OB. The effect of FM on bone parameters was more pronounced at the tibia compared to the non-weight-bearing site. Nevertheless, the coefficients of correlation were about one-half of those of LM for the biomechanical parameters. We conclude that higher absolute values of bone densities, cortical and trabecular architecture, and strength indices were not in proportion to the excess of BMI and particularly of FM in obese postmenopausal French women.

Youthful memory capacity in old brains: anatomic and genetic clues from the Northwestern SuperAging Project.

The Northwestern University SuperAging Project recruits community dwellers over the age of 80 who have unusually high performance on tests of episodic memory. In a previous report, a small cohort of SuperAgers was found to have higher cortical thickness on structural MRI than a group of age-matched but cognitively average peers. SuperAgers also displayed a patch of ACC where cortical thickness was higher than in 50- to 60-year-old younger cognitively healthy adults. In additional analyses, some SuperAgers had unusually low densities of age-related Alzheimer pathology and unusually high numbers of von Economo neurons in the anterior cingulate gyrus. SuperAgers were also found to have a lower frequency of the ɛ4 allele of apolipoprotein E than the general population. These preliminary results show that above-average memory capacity can be encountered in advanced age. They also offer clues to potential biological factors that may promote resistance to age-related involutional changes in the structure and function of the brain.

Bone structure and fracture risk: Do they go arm in arm?

increased cortical and trabecular thickness and greater cortical density at both the distal radius and the distal tibia. (12,13) In the current study, 29 Chinese-American and 68 white postmenopausal women were evaluated. Areal bone mineral density (aBMD) at the spine, hip, and radius was measured using dualenergy X-ray absorptiometry (DXA), and bone microstructure at the distal radius and tibia was assessed using HR-pQCT. As expected, the Chinese-American women were shorter and weighed less than the white women. Surprisingly, however, aBMD was similar between the two groups at all skeletal sites. Postmenopausal Chinese-American women had approximately 10% smaller bone cross-sectional area but 5% to 6% higher cortical density and 16% to 18% higher cortical thickness than whites. Chinese-American women also had fewer trabeculae at the distal radius and fewer but thicker trabeculae at the distal tibia compared with whites. Differences in bone cross-sectional area were attenuated somewhat after adjusting for the shorter stature and lower weight of the Chinese-American women, whereas differences in cortical and trabecular thickness were largely unaffected. The net result of these differences in bone morphology, evaluated by finite-element analysis (FEA), showed similar compressive stiffness in the two groups, suggesting that the smaller cross-sectional area in Chinese-American women was compensated for by their increased cortical and trabecular thicknesses. The study provides novel insights into differences in bone structure by ethnicity, yet several issues should be considered when interpreting the results, including (1) the modest sample size, (2) the limitations of HR-pQCT measurements and assumptions used for derivation of some microarchitecture features, and (3) lack of information on tissue material properties. The authors examined a relatively small convenience sample of only 29 Chinese-American subjects who were, on average, 2 years younger and tended to be closer to the menopause than the white women. After adjusting the analyses for age and body mass index (BMI), the strength of some of the ethnicity-related differences was attenuated, although most of the differences

Brain Structure in Young and Old East Asians and Westerners: Comparisons of Structural Volume and Cortical Thickness

There is an emergent literature suggesting that East Asians and Westerners differ in cognitive processes because of cultural biases to process information holistically (East Asians) or analytically (Westerners). To evaluate the possibility that such differences are accompanied by differences in brain structure, we conducted a large comparative study on cognitively matched young and old adults from two cultural/ethnic groups--Chinese Singaporeans and non-Asian Americans--that involved a total of 140 persons. Young predominantly White American adults were found to have higher cortical thickness in frontal, parietal, and medial-temporal polymodal association areas in both hemispheres. These findings were replicated using voxel-based morphometry applied to the same data set. Differences in cortical thickness observed between young volunteers were not significant in older subjects as a whole. However, group differences were evident when high-performing old were compared. Although the observed differences in gray matter may be rooted in strategic differences in cognition arising from ethnic/cultural differences, alternative explanations involving genetic heritage and environmental factors are also considered.

Increased bone strength is associated with improved bone microarchitecture in intact female rats treated with strontium ranelate: A finite element analysis study

Strontium ranelate has been previously shown to act on bone metabolism and to be effective in postmenopausal osteoporosis treatment by preventing vertebral and non-vertebral fractures. Animal studies explicitly demonstrated that bone strength was improved with strontium ranelate treatment, but the contribution of either improved bone microarchitecture or intrinsic quality of the bone tissue is not clear. Therefore, the purpose of this research was to address this issue by using the unique capability of finite element (FE) analysis to integrate both intrinsic bone quality properties from nano-indentation and microarchitecture measured by micro-computed tomography (μCT). The two groups included intact female Fischer rats fed a normal diet (controls, N = 12) or a diet containing strontium ranelate (900 mg/kg/day; N = 12) for a period of 104 weeks. The L 5 vertebra was scanned by μCT and a morphological analysis of the vertebral body was performed. Subsequently, those μCT data were the basis of FE models with added virtual endcaps that simulated axial compression tests. The FE models were solved with the vertebral bodies only and repeated with the vertebral processes intact. In the initial stages, the intrinsic bone properties were kept constant between the control and the treated animals in order to independently study the impact of microarchitectural changes on bone strength. Morphological data indicated a significant improvement in bone microarchitecture associated with strontium ranelate compared to controls, including a 40% ( p < 0.01) higher trabecular thickness, a 28% ( p < 0.01) higher cortical thickness, and no significant change in the number of trabeculae ( p = 0.56). The poor correlation of bone strontium content against bone volume fraction (BV/TV) ( R 2 = 0.013, p = 0.74) and BMD ( R 2 = 0.153, p = 0.23) indicated that the morphological data were not biased by the presence of strontium in bone. The FE simulations demonstrated a 22% ( p < 0.01) increase of stiffness and 29% ( p < 0.01) increase in strength compared to controls. The magnitudes were greater, but the relative differences were similar when the entire intact vertebra was modeled compared to the vertebral body alone. Adjusting the FE models to account for differences in intrinsic bone tissue quality between control and treated animals resulted in an even higher bone strength with strontium ranelate. Furthermore, load transfer in strontium ranelate treated animals shifted from an equal distribution between cortical and trabecular compartments to more load being supported by the trabecular bone (a shift of 8%, p < 0.02). Tissue-level stresses were reduced on average (− 7%, p < 0.01) and more homogeneously distributed. Together, these findings indicated that, independently from bone strontium content, microarchitectural adaptations played a major role in the increased bone strength associated with strontium ranelate exposure and that the changes in load distribution resulted in patterns that were more favorable to resisting fracture.

Differences in Macro- and Microarchitecture of the Appendicular Skeleton in Young Chinese and White Women

To identify the racial differences in macro- and microstructure of the distal radius and tibia that may account for the lower fracture rates in Asians than whites, we studied 61 healthy premenopausal Chinese and 111 white women 18-45 yr of age using high-resolution pQCT (HR-pQCT). The Chinese were shorter and leaner. Distal radius total cross-sectional area (CSA) was 14.3% smaller in Chinese because of an 18.0% smaller trabecular area (p < 0.001). Cortical thickness was 8.8% greater in the Chinese, but cortical area was no different. Total volumetric BMD (vBMD) was 10.3% higher in the Chinese because of the 8.8% higher cortical thickness and 2.8% greater cortical density (all p < 0.01). Trabecular vBMD and bone volume/tissue volume (BV/TV) did not differ by race because trabeculae were 7.0% fewer but 10.8% thicker in Chinese than whites (both p < 0.01). Similar results were found at the distal tibia. Lower fracture risk in Chinese women may be partly caused by thicker cortices and trabeculae in a smaller bone-more bone within the bone than in whites.

Neuroanatomy of creativity.

Creativity has long been a construct of interest to philosophers, psychologists and, more recently, neuroscientists. Recent efforts have focused on cognitive processes likely to be important to the manifestation of novelty and usefulness within a given social context. One such cognitive process - divergent thinking - is the process by which one extrapolates many possible answers to an initial stimulus or target data set. We sought to link well established measures of divergent thinking and creative achievement (Creative Achievement Questionnaire - CAQ) to cortical thickness in a cohort of young (23.7 +/- 4.2 years), healthy subjects. Three independent judges ranked the creative products of each subject using the consensual assessment technique (Amabile, 1982) from which a "composite creativity index" (CCI) was derived. Structural magnetic resonance imaging was obtained at 1.5 Tesla Siemens scanner. Cortical reconstruction and volumetric segmentation were performed with the FreeSurfer image analysis suite. A region within the lingual gyrus was negatively correlated with CCI; the right posterior cingulate correlated positively with the CCI. For the CAQ, lower left lateral orbitofrontal volume correlated with higher creative achievement; higher cortical thickness was related to higher scores on the CAQ in the right angular gyrus. This is the first study to link cortical thickness measures to psychometric measures of creativity. The distribution of brain regions, associated with both divergent thinking and creative achievement, suggests that cognitive control of information flow among brain areas may be critical to understanding creative cognition.

Three-dimensional distribution of trabecular bone density and cortical thickness in the distal humerus

One major barrier to osteosynthesis in distal humeral fractures is poor bone quality. This study was an attempt to measure the bone quality in the distal humerus. We measured the distribution of total bone mineral density (BMD), trabecular BMD (tBMD), and cortical thickness (CTh) in the distal humerus using peripheral quantitive computed tomography. Four slices in the infracondylar, supracondylar, and distal disphyseal regions of 25 human cadaver humeri were investigated. Total BMD decreased continuously from the distal diaphysis to the trochlea. Within the infracondylar region, the capitellum was the region of lowest tBMD and CTh (P < .001). Measurements in anterior regions were higher than in most others (P < .001). The tBMD of the medial column in the infracondylar and supracondylar regions was 31% and 36% higher vs the lateral column (P < .001). The medial column had an average 22% higher CTh in the supracondylar and 38% higher CTh in distal diaphyseal regions vs the lateral sides (P < .001). Distal humeral bone properties vary widely, providing stronger bone stock on the medial side. This may improve understanding of implant failure and techniques in surgical treatment.

Histomorphometric and μCT Analysis of Bone Biopsies From Postmenopausal Osteoporotic Women Treated With Strontium Ranelate

Strontium ranelate is a new anti-osteoporotic treatment. On bone biopsies collected from humans receiving long-term treatment over 5 yr, it has been shown that strontium ranelate has good bone safety and better results than placebo on 3D microarchitecture. Hence, these effects may explain the decreased fracture rate. Strontium ranelate's mode of action involving dissociation of bone formation and resorption was shown in preclinical studies and could explain its antifracture efficacy in humans. One hundred forty-one transiliac bone biopsies were obtained from 133 postmenopausal osteoporotic women: 49 biopsies after 1-5 yr of 2 g/d strontium ranelate and 92 biopsies at baseline or after 1-5 yr of placebo. Histomorphometry provided a 2D demonstration of the bone safety of strontium ranelate, with significantly higher mineral apposition rate (MAR) in cancellous bone (+9% versus control, p = 0.019) and borderline higher in cortical bone (+10%, p = 0.056). Osteoblast surfaces were significantly higher (+38% versus control, p = 0.047). 3D analysis of 3-yr biopsies with treatment (20 biopsies) and placebo (21 biopsies) using microCT showed significant changes in microarchitecture with, in the strontium ranelate group, higher cortical thickness (+18%, p = 0.008) and trabecular number (+14%, p = 0.05), and lower structure model index (-22%, p = 0.01) and trabecular separation (-16%, p = 0.04), with no change in cortical porosity. The changes in 3D microarchitecture may enhance bone biomechanical competence and explain the decreased fracture rate with strontium ranelate.

Inactivation of theNa-Cl Co-Transporter(NCC) Gene Is Associated With High BMD Through Both Renal and Bone Mechanisms: Analysis of Patients With Gitelman Syndrome andNccNull Mice

Chronic thiazide treatment is associated with high BMD. We report that patients and mice with null mutations in the thiazide-sensitive NaCl cotransporter (NCC) have higher renal tubular Ca reabsorption, higher BMD, and lower bone remodeling than controls, as well as abnormalities in Ca metabolism, mainly caused by Mg depletion. Chronic thiazide treatment decreases urinary Ca excretion (UVCa) and increases BMD. To understand the underlying mechanisms, Ca and bone metabolism were studied in two models of genetic inactivation of the thiazide-sensitive NaCl cotransporter (NCC): patients with Gitelman syndrome (GS) and Ncc knockout (Ncc(-/-)) mice. Ca metabolism was analyzed in GS patients and Ncc(-/-) mice under conditions of low dietary Ca. BMD was measured by DXA in patients and mice, and bone histomorphometry was analyzed in mice. GS patients had low plasma Mg. They exhibited reduced UVCa, but similar serum Ca and GFR as control subjects, suggesting increased renal Ca reabsorption. Blood PTH was lower despite lower serum ionized Ca, and Mg repletion almost corrected both relative hypoparathyroidism and low UVCa. BMD was significantly increased in GS patients at both lumbar (+7%) and femoral (+16%) sites, and osteocalcin was reduced. In Ncc(-/-) mice, serum Ca and GFR were unchanged, but UVCa was reduced and PTH was elevated; Mg repletion largely corrected both abnormalities. Trabecular and cortical BMD were higher than in Ncc(+/+) mice (+4% and +5%, respectively), and despite elevated PTH, were associated with higher cortical thickness and lower endosteal osteoclastic surface. Higher BMD is observed in GS patients and Ncc(-/-) mice. Relative hypoparathyroidism (human) and bone resistance to PTH (mice), mainly caused by Mg depletion, can explain the low bone remodeling and normal/low serum Ca despite increased renal Ca reabsorption.

Thicker Radial Cortex in Physically Active Prepubertal Girls Compared to Controls

This study was carried out to investigate the effects of physical activity on cortical bone of the radius in a population of prepubertal girls. Forty-nine healthy girls, 17 actives (10.62 +/- 1.56 years) and 32 controls (9.84 +/- 1.23 years) participated in this study. The active group was involved in gymnastics, judo, and dance on average 7.76 +/- 3.94 h/week. Bone mineral content (BMC) and density (BMD) were performed at the distal third of the non-dominant radius using DXA. The lean mass of the non-dominant forearm was derived from the total body analysis performed with DXA. In order to obtain bone cortical thickness, standard radiographs of the non-dominant radius were scanned and computed using a software program based on radiogrammetry. BMD and BMC values were higher in actives than in controls. Cortical thickness at the ulnar side correlated significantly with all the anthropometric and densitometric values as well as the duration of training. In addition, cortical thickness at the ulnar side was significantly higher in the actives compared to the controls. After adjustment for the duration of training per week, cortical thickness of the ulnar side did not differ any more between actives and controls. The same observation was obtained after adjustment for the forearm lean mass. In our active population, physical practice seemed to have induced greater BMC and higher cortical thickness than those observed in the sedentary.

MODERATE EXERCISE DURING GROWTH IN PREPUBERTAL BOYS: CHANGES ON BONE MASS, SIZE, VOLUMETRIC DENSITY, AND BONE STRENGTH: A CONTROLLED PROSPECTIVE STUDY

558 Cross-sectional studies in elite athletes suggest that growth is an opportune time for exercise to increase areal bone mineral density (BMD). However, as the exercise undertaken by athletes is beyond the reach of most individuals, these studies provide little basis for making recommendations regarding the role of exercise in musculoskeletal health in the community. To determine whether moderate exercise increases bone mass, size, areal and volumetric BMD, two schools were randomly allocated to an exercise or control group. Twenty boys (mean age 10.4 yrs,) allocated to 8 mths of 30 min, sessions of weight bearing physical education lessons 3 times/wk were compared with 20 controls matched for age, standing and sitting height, weight, and baseline areal BMD. Areal BMD, measured using DEXA, increased in both groups at all sites, except at the head and arms. The increase in areal BMD in the exercise group was twice that in controls; lumbar spine (0.61±0.11 vs. 0.26±0.09%/mth), legs (0.76±0.07 vs. 0.34±0.08%/mth), and total body (0.32±0.04 vs. 0.17±0.06%/mth), (all p<0.05). In the exercise group femoral midshaft cortical thickness increased by 0.97±0.32%/mth due to a 0.93±0.33%/mth decrease in endocortical (medullary) diameter (both p<0.05). There was no periosteal expansion so that volumetric BMD increased by 1.14±0.33%/mth, (p<0.05). Cortical thickness and volumetric BMD did not change in controls. Femoral midshaft section modulus increased by 2.34±2.35cm2 in the exercise group (NS), and 3.04±1.14cm2 in controls (p<0.05). Moderate and readily accessible weight bearing exercise undertaken before puberty may increase femoral volumetric BMD by increasing cortical thickness. Although endocortical apposition may be a less effective means of increasing bone strength than periosteal apposition, both mechanisms will result in higher cortical thickness that is likely to offset bone fragility conferred by menopause-related and age-related endocortical bone resorption.