Periosteal Diameter Research Articles

Changes in bone density and structure of proximal humerus with aging in Chinese women

AimsThis study aimed to investigate age- and menopause-related differences in bone mineral density (BMD), bone structure and estimated bone strength at surgical neck of humerus in Chinese female sample. MethodsWe conducted a cross-sectional cohort study of 171 Chinese women. Bone mass, indices of geometric properties and estimated mechanical strength of the surgical neck were evaluated by quantitative computed tomography (QCT). Comparisons were performed across menstrual status categories. Age-related changes in QCT-derived bone parameters were calculated. ResultsThe age-related difference of BMD and cortical thickness was 40.25 % and 32.86 % between the age of 20 and 86 years. Progressive periosteal and endosteal expansion was associated linearly with age. Estimated mechanical strength indexes showed significant quadratic associations with age, with their peak occurred at the age of 46–55 years. The quartile of women with the greatest medullary diameter also had the lowest valve of BMD and cortical thickness and the greatest in skeletal width. Compared to premenopausal individuals, perimenopausal women were distinguished by lower cortical thickness (18.63 %) and BMD (20.05 %). The continued decrease in cortical thickness and BMD was noted after menopause. The medullary and periosteal diameter increased by 17.98 % and 9.34 % respectively in perimenopausal period, but not after menopause. The accelerated loss of the maximum and polar section modulus was observed in late postmenopausal women. ConclusionsThe increase in bone size only occurred during the menopause transition. Obvious loss of resistance to bending was in late postmenopausal period.

Effect of sclerostin inactivation in a mouse model of severe dominant osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a rare bone disease that is associated with fractures and low bone mass. Sclerostin inhibition is being evaluated as a potential approach to increase bone mass in OI. We had previously found that in Col1a1Jrt/+ mice, a model of severe OI, treatment with an anti-sclerostin antibody had a minor effect on the skeletal phenotype. In the present study, we assessed the effect of genetic sclerostin inactivation in the Col1a1Jrt/+ mouse. We crossed Col1a1Jrt/+ mice with Sost knockout mice to generate Sost-deficient Col1a1Jrt/+ mice and assessed differences between Col1a1Jrt/+ mice with homozygous Sost deficiency and Col1a1Jrt/+ mice with heterozygous Sost deficiency. We found that Col1a1Jrt/+ mice with homozygous Sost deficiency had higher body mass, femur length, trabecular bone volume, cortical thickness and periosteal diameter as well as increased biomechanical parameters of bone strength. Differences between genotypes were larger at the age of 14 weeks than at 8 weeks of age. Transcriptome analysis of RNA extracted from the tibial diaphysis revealed only 5 differentially regulated genes. Thus, genetic inactivation of Sost increased bone mass and strength in the Col1a1Jrt/+ mouse. It appears from these observations that the degree of Sost suppression that is required for eliciting a beneficial response can vary with the genetic cause of OI.

Time Trends in Trajectories of Forearm Mineral Content and Bone Size during Childhood-Results from Cross-Sectional Measurements with the Same Apparatus Four Decades Apart.

Evidence suggests that single photon absorptiometry (SPA)-measured forearm bone mineral density (BMD) is lower in contemporary children in Malmö than it was four decades ago, but the fracture incidence in the at-risk population (all Malmö children) has been stable during the same period. The aim of this study was to evaluate if improvements in skeletal structure over time may explain this observation. In 2017-2018 we measured distal forearm bone mineral content (BMC; mg/cm) and periosteal diameter (mm) in 238 boys and 204 girls aged 7-15 using SPA. Based on the SPA measurements, we calculated forearm BMD (mg/cm2), bone mineral apparent density (BMAD, mg/cm3), section modulus, and strength index (BMAD × section modulus). The results were compared with those derived from measurements of 55 boys and 61 girls of the same ages using the same scanner in 1979-1981. We used log-linear regression with age, sex, and cohort as predictors to investigate differences in trait trajectories (trait versus age slopes [mean percent difference in beta values (95% confidence interval)]). SPA-measured forearm BMC was lower at each age in 2017-2018 compared to 1979-1981 (a mean age and sex adjusted relative difference of 9.1%), the forearm BMC trajectory was similar in 2017-2018 to that in 1979-1981 (reference) [0.0%/year (-1.0%, 1.0%)], while the 2017-2018 forearm periosteal diameter trajectory was steeper [1.1%/year (0.3%, 2.0%)]. Since bone size influences both BMD (BMC divided by scanned area) and mechanical characteristics, the forearm BMD trajectory was flatter in 2017-2018 [-1.1%/year (-2.0%, -0.2%)] and the forearm section modulus trajectory steeper [3.9%/year (1.4%, 6.4%)]. Forearm strength index trajectory was similar [1.8%/year (-0.5%, 4.1%)]. The lower SPA-measured forearm BMD trajectory in contemporary children compared to four decades ago may be offset by changes in forearm bone structure, resulting in similar overall bone strength. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Non-Obese MKR Mouse Model of Type 2 Diabetes Reveals Skeletal Alterations in Mineralization and Material Properties.

ABSTRACTObesity is a common comorbidity of type 2 diabetes (T2D). Therefore, increased risk of fragility fractures in T2D is often confounded by the effects of obesity. This study was conducted to elucidate the mechanistic basis by which T2D alone leads to skeletal fragility. We hypothesized that obesity independent T2D would deteriorate bone's material quality by accumulating defects in the mineral matrix and undesired modifications in its organic matrix associated with increased oxidative stress and hyperglycemia. To test this hypothesis, we used 15‐week‐old male non‐obese mice with engineered muscle creatine kinase promoter/human dominant negative insulin growth factor 1 (IGF‐I) receptor (MKR) and FVB/N wild‐type (WT) controls (n = 12/group). MKR mice exhibit reduced insulin production and loss of glycemic control leading to diabetic hyperglycemia, verified by fasting blood glucose measurements (>250 mg/dL), without an increase in body weight. MKR mice showed a significant decrease in femoral radial geometry (cortical area, moment of inertia, cortical thickness, endosteal diameter, and periosteal diameter). Bone mineral density (BMD), as assessed by micro–computed tomography (μCT), remained unchanged; however, the quality of bone mineral was altered. In contrast to controls, MKR mice had significantly increased hydroxyapatite crystal thickness, measured by small‐angle X‐ray scattering, and elongated c‐axis length of the crystals evaluated by confocal Raman spectroscopy. There was an increase in changes in the organic matrix of MKR mice, associated with enhanced glycoxidation (carboxymethyl‐lysine [CML] and pentosidine) and overall glycation (fluorescent advanced glycation end products), both of which were associated with various measures of bone fragility. Moreover, increased CML formation positively correlated with elongated mineral crystal length, supporting the role of this negatively charged side chain to attract calcium ions, promote growth of hydroxyapatite, and build a physical link between mineral and collagen. Collectively, our results show, for the first time, changes in bone matrix in a non‐obese T2D model in which skeletal fragility is attributable to alterations in the mineral quality and undesired organic matrix modifications. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Effects of treatment with a bone-targeted prostaglandin E2 receptor 4 agonist C3 (Mes-1007) 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 synthesis in osteoblasts. Bisphosphonates are widely used to decrease fracture rate but are only partially effective. Bone anabolic compounds, such as prostaglandin E2 receptor 4 (EP4) agonists may be an alternative treatment approach. Here we assessed the effect of Mes-1007, a novel bone-targeted EP4 agonist in Jrt mice, a model of severe OI. Experimental study. Male 8-week old wild type (WT) and OI mice were randomly assigned to 4weeks of three intraperitoneal injections per week with Mes-1007 (25mg per kg body mass), phosphate-buffered saline, zoledronate (5μg per kg), or a combination treatment of zoledronate and Mes-1007. Treatment with Mes-1007 alone did not lead to higher trabecular bone volume per tissue volume (BV/TV) in the distal femur or lumbar vertebra 4 in either WT or OI mice. Treatment with zoledronate alone was associated with a significant increase in distal femur and vertebra BV/TV in both genotypes. In zoledronate-treated WT and OI mice, Mes-1007 increased bone formation rate in vertebral trabecular bone and had an additive effect on BV/TV. Vertebral BV/TV in OI mice that received zoledronate or Mes-1007/zoledronate combination treatment was similar to untreated WT mice (p=0.25). At the femoral midshaft, Mes-1007/zoledronate combination treatment increased cortical thickness in both genotypes and led to higher periosteal diameter in OI mice. Three-point bending tests of femurs showed that Mes-1007/zoledronate combination treatment increased the stiffness, load at yield and maximal load in WT but not in OI mice. Dosing Mes-1007 in combination with zoledronate improved the bone properties in a manner that is consistent with a mechanism of action of EP4 agonists on bone and additive to effects of anti-resorptives typified by zoledronate.

Male mice with elevated C-type natriuretic peptide-dependent guanylyl cyclase-B activity have increased osteoblasts, bone mass and bone strength.

C-type natriuretic peptide (CNP) activation of guanylyl cyclase (GC)-B, also known as NPR2, stimulates cGMP synthesis and bone elongation. CNP activation requires the phosphorylation of multiple GC-B residues and dephosphorylation inactivates the receptor. GC-B7E/7E knockin mice, expressing a glutamate-substituted, "pseudophosphorylated," form of GC-B, exhibit increased CNP-dependent GC activity. Since mutations that constitutively activate GC-B in the absence of CNP result in low bone mineral density in humans, we determined the skeletal phenotype of 9-week old male GC-B7E/7E mice. Unexpectedly, GC-B7E/7E mice have significantly greater tibial and L5 vertebral trabecular bone volume fraction, tibial trabecular number, and tibial bone mineral density. Cortical cross-sectional area, cortical thickness, periosteal diameter and cortical cross-sectional moment of inertia were also significantly increased in GC-B7E/7E tibiae. Three-point bending measurements demonstrated that the mutant tibias and femurs had greater ultimate load, stiffness, energy to ultimate load, and energy to failure. No differences in microhardness indicated similar bone quality at the tissue level between the mutant and wildtype bones. Procollagen 1 N-terminal propeptide and osteocalcin were elevated in serum, and osteoblast number per bone perimeter and osteoid width per bone perimeter were elevated in tibias from the mutant mice. In contrast to mutations that constitutively activate GC-B, we report that mutations that enhance GC-B activity only in the presence of its natural ligand, increase bone mass, bone strength, and the number of active osteoblasts at the bone surface.

Sex- and age-related differences in femoral neck cross-sectional structural changes in mainland Chinese men and women measured using dual-energy X-ray absorptiometry

We investigated age-related changes in estimated bone strength and cross-sectional structure of the femoral neck (FN) in mainland Chinese men and women (according to age and sex) using dual-energy X-ray absorptiometry (DXA). A total of 3855 healthy adults (2713 women, 1142 men; ages 25–91years) were analyzed by FN bone mineral density (BMD) assessment and hip structural/strength analysis (HSA), including cross-sectional moment of inertia (CSMI), cross-sectional area (CSA), section modulus (Z), periosteal diameter (PD), endocortical diameter (ED), and cortical thickness (CT) using DXA. HSA differences between age and sex groups were adjusted for body weight, height and FN BMD. Trends according to age were estimated by linear regression analysis. There was no inverse correlation between HSA parameters and age in young adults. Some HSA parameters (CSMI, CSA, Z, CT) decreased significantly with age, whereas PD and ED increased significantly. Older adults had less estimated bone strength and CT and higher PD and ED (p<0.05) than young adults. Men had greater increases in PD and ED than women across all ages. FN strength decreases with age in both sexes, caused by FN cross-sectional structural deterioration. Indirect comparison of our data with those from other populations showed less age-related FN periosteal apposition in Chinese than Caucasian men, but similar amounts in women. This may partly explain different male/female hip fracture rates among ethnic groups. Chinese men have more structural disadvantages regarding FN geometry during aging than Caucasian men, possibly conferring added susceptibility to hip fracture.

Improving the estimate of the effective elastic modulus derived from three-point bending tests of long bones.

Three-point bending tests are often used to determine the apparent or effective elastic modulus of long bones. The use of beam theory equations to interpret such tests can result in a substantial underestimation of the true effective modulus. In this study three-dimensional, nonlinear finite element analysis is used to quantify the errors inherent in beam theory and to create plots that can be used to correct the elastic modulus calculated from beam theory. Correction plots are generated for long bones representative of a variety of species commonly used in research studies. For a long bone with dimensions comparable to the mouse femur, the majority of the error in the effective elastic modulus results from deformations to the bone cross section that are not accounted for in the equations from beam theory. In some cases, the effective modulus calculated from beam theory can be less than one-third of the true effective modulus. Errors are larger: (1) for bones having short spans relative to bone length; (2) for bones with thin vs. thick cortices relative to periosteal diameter; and (3) when using a small radius or "knife-edge" geometry for the center loading ram and the outer supports in the three-point testing system. The use of these correction plots will enable researchers to compare results for long bones from different animal strains and to compare results obtained using testing systems that differ with regard to length between the outer supports and the radius used for the loading ram and outer supports.

The effects of once-weekly teriparatide on hip geometry assessed by hip structural analysis in postmenopausal osteoporotic women with high fracture risk

Weekly administration of teriparatide has been shown to reduce the risk of vertebral and non-vertebral fractures in patients with osteoporosis at higher fracture risk in Japan. However, its efficacy for hip fracture has not been established. To gain insight into the effect of weekly teriparatide on the hip, hip structural analysis (HSA) based on dual-energy X-ray absorptiometry (DXA) was performed using the data of 209 postmenopausal osteoporotic women who had participated in the original randomized, multicenter, double-blind, placebo-controlled trial assessing the effects of once-weekly 56.5μg teriparatide for 72weeks. The DXA scans, obtained at baseline, 48weeks and 72weeks, were analyzed to extract bone mineral density (BMD) and cross-sectional geometrical indices at the narrowest point on the neck (NN), the intertrochanteric region (IT), and the proximal shaft. Compared with placebo after 72weeks, the teriparatide group showed significantly higher BMD, average cortical thickness, bone cross-sectional area, and section modulus, and lower buckling ratio at both the NN and IT regions. No significant expansion of periosteal diameter was observed at these regions. There were no significant differences in BMD and HSA indices at the shaft region. The results indicate that overall structural strength in the proximal femur increased compared to placebo, suggesting that once-weekly teriparatide effectively reverses changes in hip geometry and strength with aging.

Bivariate Genome-Wide Association Analyses Identified Genes with Pleiotropic Effects for Femoral Neck Bone Geometry and Age at Menarche

Femoral neck geometric parameters (FNGPs), which include cortical thickness (CT), periosteal diameter (W), buckling ratio (BR), cross-sectional area (CSA), and section modulus (Z), contribute to bone strength and may predict hip fracture risk. Age at menarche (AAM) is an important risk factor for osteoporosis and bone fractures in women. Some FNGPs are genetically correlated with AAM. In this study, we performed a bivariate genome-wide association study (GWAS) to identify new candidate genes responsible for both FNGPs and AAM. In the discovery stage, we tested 760,794 SNPs in 1,728 unrelated Caucasian subject, followed by replication analyses in independent samples of US Caucasians (with 501 subjects) and Chinese (with 826 subjects). We found six SNPs that were associated with FNGPs and AAM. These SNPs are located in three genes (i.e. NRCAM, IDS and LOC148145), suggesting these three genes may co-regulate FNGPs and AAM. Our findings may help improve the understanding of genetic architecture and pathophysiological mechanisms underlying both osteoporosis and AAM.

Disruption of the insulin-like growth factor-1 gene in osteocytes impairs developmental bone growth in mice

This study evaluated the role of osteocyte-derived insulin-like growth factor 1 (IGF-1) in developmental bone growth by assessing the bone phenotype of osteocyte Igf1 conditional knockout (KO) mice, generated by crossing the Dmp1-driven Cre-expressing transgenic mice with Igf1 floxed mice containing loxP sites that flank exon 4 of the Igf1 gene. The periosteal diameter of femurs of homozygous conditional KO mutants was 8–12% smaller than wild-type (WT) littermates. The conditional mutants had 14–20%, 10–21%, and 15–31% reduction in total, trabecular, and cortical bone mineral contents, respectively. However, there were no differences in the total, trabecular, or cortical bone mineral densities, or in trabecular bone volume, thickness, number, and separation at secondary spongiosa between the mutants and WT littermates. The conditional KO mutants showed reduction in dynamic bone formation parameters at both periosteal and endosteal surfaces at the mid-diaphysis and in trabecular bone formation rate and resorption parameters at secondary spongiosa. The lower plasma levels of PINP and CTx in conditional KO mice support a regulatory role of osteocyte-derived IGF-1 in the bone turnover. The femur length of conditional KO mutants was 4–7% shorter due to significant reduction in the length of growth plate and hypertropic zone. The effect on periosteal expansion appeared to be bigger than that on longitudinal bone growth. The conditional KO mice had 14% thinner calvaria than WT littermates, suggesting that deficient osteocyte IGF-1 production also impairs developmental growth of intramembraneous bone. Conditional disruption of Igf1 in osteocytes did not alter plasma levels of IGF-1, calcium, or phosphorus. In summary, this study shows for the first time that osteocyte-derived IGF-1 plays an essential role in regulating bone turnover during developmental bone growth.

Femoral Neck Bone Strength Estimated by Hip Structural Analysis (HSA) in Swedish Caucasians Aged 6–90 Years

Dual-energy X-ray absorptiometry hip scans of 1,760 population-based Caucasians, 599 girls and 642 boys aged 6-19 years and 270 women and 249 men aged 20-90 years, were analyzed with the hip structural analysis (HSA) software to present age- and sex-specific normative HSA data of the femoral neck (FN). Measured traits included bone mineral density (BMD), cross-sectional area (CSA), section modulus (Z), periosteal diameter (PD), endosteal diameter (ED), cortical thickness (CT), and cross-sectional moment of inertia (CSMI). When plotting the measured traits versus age, the curves increased with higher ages until statistically significant break points were reached, for all traits at age 17 in girls and age 19 in boys. After the break points, PD and ED increased with higher ages but, as ED increased more than PD, BMD and CT decreased significantly with higher ages. The decline in BMD was counteracted by the increase in bone size so that there was only a nonstatistically significant decrease in bone strength, estimated as Z and CSMI, from break point to age 90. The partial preservation of bone strength was more obvious in men than in women as the decline in BMD was higher in women than in men, while the expansion in PD was larger in men than in women. The sex difference in the normative FN bone strength data seems to be related to sex discrepancies in the development of both bone mass and geometrical parameters during both growth and adulthood.

Bivariate genome-wide association analyses of femoral neck bone geometry and appendicular lean mass.

ObjectiveFemoral neck geometric parameters (FNGPs), such as periosteal diameter (W), cross-sectional area (CSA), cortical thickness (CT), buckling ratio (BR), and section modulus (Z), are highly genetically correlated with body lean mass. However, the specific SNPs/genes shared by these phenotypes are largely unknown.MethodsTo identify the specific SNPs/genes shared between FNGPs and appendicular lean mass (ALM), we performed an initial bivariate genome-wide association study (GWAS) by scanning ∼690,000 SNPs in 1,627 unrelated Han Chinese adults (802 males and 825 females) and a follow-up replicate study in 2,286 unrelated US Caucasians.ResultsWe identified 13 interesting SNPs that may be important for both FNGPs and ALM. Two SNPs, rs681900 located in the HK2 (hexokinase 2) gene and rs11859916 in the UMOD (uromodulin) gene, were bivariately associated with FNGPs and ALM (p = 7.58×10−6 for ALM-BR and p = 2.93×10−6 for ALM-W, respectively). The associations were then replicated in Caucasians, with corresponding p values of 0.024 for rs681900 and 0.047 for rs11859916. Meta-analyses yielded combined p values of 3.05×10−6 and 2.31×10−6 for rs681900 and rs11859916, respectively. Our findings are consistent with previous biological studies that implicated HK2 and UMOD in both FNGPs and ALM. Our study also identified a group of 11 contiguous SNPs, which spanned a region of ∼130 kb, were bivariately associated with FNGPs and ALM, with p values ranging from 3.06×10−7 to 4.60×10−6 for ALM-BR. The region contained two neighboring miRNA coding genes, MIR873 (MicroRNA873) and MIR876 (MicroRNA876).ConclusionOur study implicated HK2, UMOD, MIR873 and MIR876, as pleiotropic genes underlying variation of both FNGPs and ALM, thus suggesting their important functional roles in co-regulating both FNGPs and ALM.

RANKL Inhibition Improves Bone Properties in a Mouse Model of Osteogenesis Imperfecta

Recently, a new class of agents targeting the receptor activator of nuclear factor-κB ligand (RANKL) pathway has been developed for the treatment of osteoporosis and other bone diseases. In the current study, inhibition of the RANKL pathway was evaluated to assess effects on “bone quality” and fracture incidence in an animal model of osteogenesis imperfect (OI), the oim/oim mouse. Juvenile oim/oim (∼6 weeks old) and wildtype (+/+) mice were treated with either a RANKL inhibitor (RANK-Fc) or saline. After treatment, bone density increased significantly in the femurs of both genotypes. Femoral length decreased with RANK-Fc in +/+ mice. Geometric measurements at mid-diaphysis in the oim/oim groups showed increases in the ML periosteal and endosteal diameters and AP cortical thickness in the treated groups. Within +/+ groups, ML cortical thickness and ML femoral periosteal diameter were significantly increased with RANK-Fc. Biomechanical testing revealed increased stiffness in oim/oim and +/+ mice. Total strain was increased with treatment in the +/+ mice. Histologically, RANKL inhibition resulted in retained growth plate cartilage in both genotypes. The average number of fractures sustained by RANK-Fc-treated oim/oim mice was not significantly decreased compared to saline treated oim/oim mice. This preclinical study demonstrated that RANKL inhibition at the current dose improved density and some geometric and biomechanical properties of oim/oim bone, but it did not decrease fracture incidence. Further studies that address commencement of therapy at earlier time points are needed to determine whether this mode of therapy will be clinically useful in OI.

The differences of femoral neck geometric parameters: effects of age, gender and race

This study aims at investigating the effects of age, sex, and ethnicity on five femoral neck geometric parameters (FNGPs): femoral neck periosteal diameter, cross-sectional area, cortical thickness, sectional modulus, and buckling ratio and found that the three factors would influence the FNGPs. Bone geometry is one of the most important predictors of bone strength and osteoporotic fractures. This study aims at investigating the effects of age, sex, and ethnicity on five femoral neck geometric parameters (FNGPs): femoral neck periosteal diameter (W), cross-sectional area (CSA), cortical thickness (CT), sectional modulus (Z), and buckling ratio (BR). In the studied 861 Caucasian subjects and 3,021 Chinese individuals, CSA, CT, and Z displayed trends of decrease with age, but W and BR showed increasing trends with age in both Chinese and Caucasian females and males (p < 0.05). W, CSA, CT, and Z were significantly higher (p <or= 0.001) in Caucasians than in Chinese and higher in males than in females except for BR between Chinese males and Chinese females. In conclusion, the differences of FNGPs according to gender and ethnicity provide important implications in the different prevalence of osteoporotic fracture among different gender and ethnic groups.

A school-curriculum-based exercise intervention program for two years in pre-pubertal girls does not influence hip structure.

BackgroundIt is known that physical activity during growth has a positive influence on bone mineral accrual, and is thus possibly one strategy to prevent osteoporosis. However, as bone geometry, independent of areal bone mineral density (aBMD), influences fracture risk, this study aimed to evaluate whether hip structure in pre-pubertal girls is also affected by a two-year exercise intervention program.MethodsForty-two girls aged 7–9 years in a school-curriculum-based exercise intervention program comprising 40 minutes of general physical activity per school day (200 minutes per week) were compared with 43 age-matched girls who participated in the general Swedish physical education curriculum comprising a mean of 60 minutes per week. The hip was scanned by dual energy X-ray absorptiometry (DXA) and the hip structural analysis (HSA) software was applied to evaluate bone mineral content (BMC, g), areal bone mineral density (aBMD, g/cm2), periosteal diameter, cross-sectional area (CSA, cm2), section modulus (Z, cm3) and cross-sectional moment of inertia (CSMI, cm4) of the femoral neck (FN). Annual changes were compared. Subjective duration of physical activity was estimated by questionnaire and objective level of everyday physical activity at follow-up by means of accelerometers worn for four consecutive days. All children remained at Tanner stage 1 throughout the study. Group comparisons were made by independent student's t-test between means and analyses of covariance (ANCOVA).ResultsAt baseline, the two groups did not differ with regard to age, anthropometrics or bone parameters. No between-group differences were observed for annual changes in the FN variables measured.ConclusionA two-year school-based moderately intense general exercise program for 7–9-year-old pre-pubertal girls does not influence structural changes in the FN.

Bivariate Whole Genome Linkage Analysis for Femoral Neck Geometric Parameters and Total Body Lean Mass

A genome-wide bivariate analysis was conducted for femoral neck GPs and TBLM in a large white sample. We found QTLs shared by GPs and TBLM in the total sample and the sex-specific samples. QTLs with potential pleiotropy were also disclosed. Previous studies have suggested that femoral neck cross-section geometric parameters (FNCS-GPs), including periosteal diameter (W), cross-sectional area (CSA), cortical thickness (CT), buckling ratio (BR), and section modulus (Z), are genetically correlated with total body lean mass (TBLM). However, the shared genetic factors between them are unknown. To identify the specific QTLs shared by FNCS-GPs and TBLM, we performed bivariate whole genome linkage analysis (WGLA) in a large sample of 451 white families made up of 4498 subjects. Multipoint bivariate linkage analyses for 22 autosomes showed evidence of suggestive or significant linkages (thresholds of LOD = 2.3 and 3.7, respectively) to chromosomes 3q12 and 20q13 in the entire sample, 6p25 and 10q24 in women, and 4p15, 5q34-35 and 7q21 in men. Two-point linkage analyses for chromosome X showed strong linkage to Xp22.13, Xp11.4, Xq22.3, Xq23-24, and Xq25. Complete pleiotropy was identified on 10q24 and 5q35 for TBLM and BR in women and for TBLM and CT in men, respectively. Furthermore, chromosomes 5q34-35, 7q21, 10q24, 20q13, Xp22.13, Xp11.4, and Xq25 are also of importance because of their linkage to multiple trait pairs. For example, linkage to chromosome 10q24 was found for TBLM x W (LOD = 2.31), TBLM x CT (LOD = 2.51), TBLM x CSA (LOD = 2.51), TBLM x BR (LOD = 2.64), and TBLM x Z (LOD = 2.55) in women. In this study, we identified several genomic regions (e.g., 3q12 and 20q13) that seem to be linked to both FNCS-GPs and TBLM. These regions are of interesting because they may harbor genes that may contribute to variation in both FNCS-GPs and TBLM.

Gender differences in the ratio between humerus width and length are established prior to puberty

SummaryOn a sample of 1,317 children aged 9.9 years we developed a novel method of measuring humeral dimensions from total body dual-energy X-ray absorptiometry (DXA) scans and showed that gender differences in the ratio between humeral width and length are established prior to puberty.IntroductionIt is recognised that long bone cross-sectional area is greater in males compared to females, which is thought to reflect more rapid periosteal bone growth in boys. However, it is currently unclear whether these findings reflect gender differences in bone size or shape. In the present study, we investigated whether gender differences exist in the balance between longitudinal and periosteal long bone growth in children, leading to gender differences in bone shape, based on a novel method for evaluating shape of the humerus. We also examined whether these differences are established prior to puberty.MethodsLength, area and width of the humerus were estimated from total body DXA scans in 1,317 children aged 9.9 ± 0.33 years, who had participated in a nested case-control study of fractures within the Avon Longitudinal Study of Parents and Children (ALSPAC) (a geographically based birth cohort based in South West England). No differences were observed with respect to parameters of humeral geometry according to fracture history, and so both groups were pooled for further analysis. Aspect ratio (AR) of the humerus was calculated as humeral width divided by length. Total body height and weight were measured at the same time as the DXA scan. Puberty was assessed using self-completion questionnaires.ResultsHumeral width and length were positively associated with age and height in boys and girls combined (P < 0.001), and with Tanner stage in girls (P < 0.002). In contrast, age, height and Tanner stage were not related to humeral AR. We then examined gender differences in humeral shape according to pubertal stage. In prepubertal children (i.e. Tanner stage 1), humeral length was similar in boys and girls, but width (1.92 vs 1.88 cm, P < 0.001) and area (47.7 vs 46.9 cm2, P < 0.001) were greater in boys, resulting in a greater AR (7.78 vs 7.53, P < 0.001). Similar gender differences were observed in early pubertal children (i.e. Tanner stage 2).ConclusionWe conclude that the greater periosteal diameter of boys compared to girls reflects differences in the balance between longitudinal and periosteal bone growth. Interestingly, resulting gender differences in humeral AR are established in prepubertal children.

Interactions between microstructural and geometrical adaptation in human cortical bone

With aging and in disease, the changes in bone microstructure and geometry influence the mechanical properties of cortical bone, however, the level of interaction between the two is not known. Here, we investigate the interaction between the changes in microstructural and geometrical properties of the aging male tibia in proximal and distal middiaphysis. The microstructural measurements include variables related to the size and density of osteons and intracortical porosity. The macroscopic geometrical properties include variables related to bone surfaces (periosteal and endosteal) and cross section (area, moment of inertia). Site-specific correlations were found between the microstructural and geometrical properties along the bone length and at different bone surfaces. In contrast to the proximal middiaphysis of male tibia, where no correlation existed, significant (p<0.05) correlations were found in the distal middiaphysis of tibia. The changes in parameters partially related to bone formation in the cortex, including the osteonal area, showed positive correlations with an increase in the periosteal diameter. Similarly, parameters related to bone resorption and/or failed formation in the cortex, including porosity and pore size, showed significant correlations with cortical thinning. These findings support the concept that, with aging, anabolic and catabolic responses in the human tibia at microstructural and macrostructural levels are spatially related and site specific.

Varying contributions of growth and ageing to racial and sex differences in femoral neck structure and strength in old age

The structural basis of racial and sex differences in femoral neck (FN) fragility in old age was assessed in a cross-sectional study of 829 healthy Chinese and 1181 healthy Caucasian subjects aged 18 to 93 years in Melbourne, Australia. We measured FN bone mineral density (BMD), periosteal diameter, and estimated endocortical diameter, cortical thickness, volumetric BMD (vBMD), section modulus, and buckling ratio using dual X-ray absorptiometry. Racial and sex differences in structural and strength indices were adjusted for age, bone length and body weight and were expressed in standard deviation (SD) unit. In young adulthood, Chinese women had a 0.85 SD narrower FN, a 0.47 SD thinner cortex and a 0.79 SD shorter FN axis length (FNAL) than Caucasian women. Across age, Chinese and Caucasian women had similar increments in endocortical and periosteal diameters and similar decrements in cortical thickness and vBMD (both ∼20%). In young adult males, FN periosteal diameter did not differ by race, but cortical thickness was 0.35 SD lower in Chinese than Caucasians. Across age, increments in periosteal and endocortical diameters were less in Chinese than Caucasian men so cortical thickness and vBMD diminished less in Chinese than in Caucasian men. In both races, young adult women had narrower FN than men. As Chinese women had a greater increment in periosteal diameter than Chinese men across age, the sex difference in FN periosteal diameter established in young adulthood diminished in old age. As Caucasian men had a greater increment in periosteal diameter than Caucasian women, the sex difference in FN periosteal diameter established in young adulthood increased with age. In old age, for both sexes, Chinese had a higher fracture risk in bending than Caucasians, but a lower fracture risk by buckling. For both races, women had a higher fracture risk in bending than men. Racial and sexual dimorphism in the absolute and relative behavior of the periosteal and endocortical surfaces throughout life produce race- and sex-specific differences in FN size, cortical thickness, and indices of bone strength in old age.