Visceral Adipose Tissue Is Associated With Bone Microarchitecture in the Framingham Osteoporosis Study

Obesity has been traditionally considered to protect the skeleton against osteoporosis and fracture. Recently, body fat, specifically visceral adipose tissue (VAT), has been associated with lower bone mineral density (BMD) and increased risk for some types of fractures. We studied VAT and bone microarchitecture in 710 participants (58% women, age 61.3 ± 7.7 years) from the Framingham Offspring cohort to determine whether cortical and trabecular BMD and microarchitecture differ according to the amount of VAT. VAT was measured from CT imaging of the abdomen. Cortical and trabecular BMD and microarchitecture were measured at the distal tibia and radius using high‐resolution peripheral quantitative computed tomography (HR‐pQCT). We focused on 10 bone parameters: cortical BMD (Ct.BMD), cortical tissue mineral density (Ct.TMD), cortical porosity (Ct.Po), cortical thickness (Ct.Th), cortical bone area fraction (Ct.A/Tt.A), trabecular density (Tb.BMD), trabecular number (Tb.N), trabecular thickness (Tb.Th), total area (Tt.Ar), and failure load (FL) from micro–finite element analysis. We assessed the association between sex‐specific quartiles of VAT and BMD, microarchitecture, and strength in all participants and stratified by sex. All analyses were adjusted for age, sex, and in women, menopausal status, then repeated adjusting for body mass index (BMI) or weight. At the radius and tibia, Ct.Th, Ct.A/Tt.A, Tb.BMD, Tb.N, and FL were positively associated with VAT (all p‐trend <0.05), but no other associations were statistically significant except for higher levels of cortical porosity with higher VAT in the radius. Most of these associations were only observed in women, and were no longer significant when adjusting for BMI or weight. Higher amounts of VAT are associated with greater BMD and better microstructure of the peripheral skeleton despite some suggestions of significant deleterious changes in cortical measures in the non–weight bearing radius. Associations were no longer significant after adjustment for BMI or weight, suggesting that the effects of VAT may not have a substantial effect on the skeleton independent of BMI or weight. © 2016 American Society for Bone and Mineral Research.     

Genetic and Environmental Variances of Bone Microarchitecture and Bone Remodeling Markers: A Twin Study

All genetic and environmental factors contributing to differences in bone structure between individuals mediate their effects through the final common cellular pathway of bone modeling and remodeling. We hypothesized that genetic factors account for most of the population variance of cortical and trabecular microstructure, in particular intracortical porosity and medullary size – void volumes (porosity), which establish the internal bone surface areas or interfaces upon which modeling and remodeling deposit or remove bone to configure bone microarchitecture. Microarchitecture of the distal tibia and distal radius and remodeling markers were measured for 95 monozygotic (MZ) and 66 dizygotic (DZ) white female twin pairs aged 40 to 61 years. Images obtained using high‐resolution peripheral quantitative computed tomography were analyzed using StrAx1.0, a nonthreshold‐based software that quantifies cortical matrix and porosity. Genetic and environmental components of variance were estimated under the assumptions of the classic twin model. The data were consistent with the proportion of variance accounted for by genetic factors being: 72% to 81% (standard errors ～18%) for the distal tibial total, cortical, and medullary cross‐sectional area (CSA); 67% and 61% for total cortical porosity, before and after adjusting for total CSA, respectively; 51% for trabecular volumetric bone mineral density (vBMD; all p < 0.001). For the corresponding distal radius traits, genetic factors accounted for 47% to 68% of the variance (all p ≤ 0.001). Cross‐twin cross‐trait correlations between tibial cortical porosity and medullary CSA were higher for MZ (r_MZ = 0.49) than DZ (r_DZ = 0.27) pairs before (p = 0.024), but not after (p = 0.258), adjusting for total CSA. For the remodeling markers, the data were consistent with genetic factors accounting for 55% to 62% of the variance. We infer that middle‐aged women differ in their bone microarchitecture and remodeling markers more because of differences in their genetic factors than differences in their environment. © 2014 American Society for Bone and Mineral Research.     

Heritability of Thoracic Spine Curvature and Genetic Correlations With Other Spine Traits: The Framingham Study

Hyperkyphosis is a common spinal disorder in older adults, characterized by excessive forward curvature of the thoracic spine and adverse health outcomes. The etiology of hyperkyphosis has not been firmly established, but may be related to changes that occur with aging in the vertebrae, discs, joints, and muscles, which function as a unit to support the spine. Determining the contribution of genetics to thoracic spine curvature and the degree of genetic sharing among co‐occurring measures of spine health may provide insight into the etiology of hyperkyphosis. The purpose of our study was to estimate heritability of thoracic spine curvature using T₄–T₁₂ kyphosis (Cobb) angle and genetic correlations between thoracic spine curvature and vertebral fracture, intervertebral disc height narrowing, facet joint osteoarthritis (OA), lumbar spine volumetric bone mineral density (vBMD), and paraspinal muscle area and density, which were all assessed from computed tomography (CT) images. Participants included 2063 women and men in the second and third generation offspring of the original cohort of the Framingham Study. Heritability of kyphosis angle, adjusted for age, sex, and weight, was 54% (95% confidence interval [CI], 43% to 64%). We found moderate genetic correlations between kyphosis angle and paraspinal muscle area (_G, –0.46; 95% CI, –0.67 to –0.26), vertebral fracture (_G, 0.39; 95% CI, 0.18 to 0.61), vBMD (_G, –0.23; 95% CI, –0.41 to –0.04), and paraspinal muscle density (_G, –0.22; 95% CI, –0.48 to 0.03). Genetic correlations between kyphosis angle and disc height narrowing (_G, 0.17; 95% CI, –0.05 to 0.38) and facet joint OA (_G, 0.05; 95% CI, –0.15 to 0.24) were low. Thoracic spine curvature may be heritable and share genetic factors with other age‐related spine traits including trunk muscle size, vertebral fracture, and bone mineral density. © 2016 American Society for Bone and Mineral Research.     

Diabetes and Deficits in Cortical Bone Density,Microarchitecture, and Bone Size: Framingham HR‐pQCT Study

Older adults with type 2 diabetes (T2D) tend to have normal or greater areal bone mineral density (aBMD), as measured by DXA, than those who do not have diabetes (non‐T2D). Yet risk of fracture is higher in T2D, including 40% to 50% increased hip fracture risk. We used HR‐pQCT to investigate structural mechanisms underlying skeletal fragility in T2D. We compared cortical and trabecular bone microarchitecture, density, bone area, and strength in T2D and non‐T2D. In secondary analyses we evaluated whether associations between T2D and bone measures differed according to prior fracture, sex, and obesity. Participants included 1069 members of the Framingham Study, who attended examinations in 2005 to 2008 and underwent HR‐pQCT scanning in 2012 to 2015. Mean age was 64 ± 8 years (range, 40 to 87 years), and 12% (n = 129) had T2D. After adjustment for age, sex, weight, and height, T2D had lower cortical volumetric BMD (vBMD) (p < 0.01), higher cortical porosity (p = 0.02), and smaller cross‐sectional area (p = 0.04) at the tibia, but not radius. Trabecular indices were similar or more favorable in T2D than non‐T2D. Associations between T2D and bone measures did not differ according to sex or obesity status (all interaction p > 0.05); however, associations did differ in those with a prior fracture and those with no history of fracture. Specifically, cortical vBMD at the tibia and cortical thickness at the radius were lower in T2D than non‐T2D, but only among those individuals with a prior fracture. Cortical porosity at the radius was higher in T2D than non‐T2D, but only among those who did not have a prior fracture. Findings from this large, community‐based study of older adults suggest that modest deterioration in cortical bone and reductions in bone area may characterize diabetic bone disease in older adults. Evaluation of these deficits as predictors of fracture in T2D is needed to develop prevention strategies in this rapidly increasing population of older adults. © 2017 American Society for Bone and Mineral Research.     

Ethnic Differences in Peripheral Skeletal Development Among Urban South African Adolescents: A Ten‐Year Longitudinal pQCT Study

There are no longitudinal pQCT data of bone growth and development from sub‐Saharan Africa, where rapid environmental, societal, and economic transitions are occurring, and where fracture rates are predicted to rise. The aim of this study was to compare skeletal development in black and white South African adolescents using longitudinal data from the Birth to Twenty study. The Birth to Twenty Bone Health subcohort consisted of 543 adolescents (261 [178 black] girls, 282 [201 black] boys). Annual pQCT measurements of the radial and tibial metaphysis and diaphysis were obtained between ages 12 and 22 years (distal metaphysis: cross‐sectional area [CSA] and trabecular bone mineral density [BMD]; diaphysis: total and cortical CSA, cortical BMD, and polar stress‐strain index [SSIp]). Age at peak height velocity (APHV) was calculated to account for differences in maturational timing between ethnic groups and sexes. Mixed‐effects models were used to describe trajectories for each pQCT outcome. Likelihood‐ratio tests were used to summarize the overall difference in trajectories between black and white participants within each sex. APHV (mean ± SD years) was similar in black (11.8 ± 0.8) and white (12.2 ± 1.0) girls, but delayed in black (14.2 ± 1.0) relative to white boys (13.3 ± 0.8). By 4 years post‐APHV, white adolescents had significantly greater cortical CSA and SSIp than black adolescents at the radius. There were no significant differences at the radial metaphysis but there was some divergence, such that black adolescents had greater radial trabecular BMD by the end of follow‐up. At the tibia, white adolescents had lower diaphyseal CSA and SSIp, and greater metaphyseal CSA. There was no ethnic difference in tibial trabecular BMD. There are ethnic differences in bone growth and development, independent of maturation, in South African adolescents. This work gives new insights into the possible etiology of childhood fractures, which occur most commonly as peripheral sites. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.     

The Relationship Between Greater Prepubertal Adiposity,Subsequent Age of Maturation,and Bone Strength During Adolescence

This longitudinal study investigated whether greater prepubertal adiposity was associated with subsequent timing of maturation and bone strength during adolescence in 135 girls and 123 boys participating in the Iowa Bone Development Study. Greater adiposity was defined using body mass index (BMI) data at age 8 years to classify participants as overweight (OW, ≥85th percentile for age and sex) or healthy weight (HW). Maturation was defined as the estimated age of peak height velocity (PHV) based on a series of cross‐sectional estimates. Measurements were taken at ages 11, 13, 15, and 17 years for estimates of body composition by dual‐energy X‐ray absorptiometry (DXA), bone compression (bone strength index), and torsion strength (polar strength‐strain index) at the radius and tibia by pQCT, and femoral neck bending strength (section modulus) by hip structural analysis. Bone strength in OW versus HW were evaluated by fitting sex‐specific linear mixed models that included centered age (visit age – grand mean age of cohort) as the time variable and adjusted for change in fat mass, and limb length in model 1. Analyses were repeated using biological age (visit age – age PHV) as the time variable for model 1 with additional adjustment for lean mass in model 2. BMI was negatively associated with age of maturation (p < 0.05). OW versus HW girls had significantly greater bone strength (p < 0.001) in model 1, whereas OW versus HW boys had significantly greater bone strength (p < 0.001) at the tibia and femoral neck but not radius (p > 0.05). Analyses were repeated using biological age, which yielded reduced parameter estimates for girls but similar results for boys (model 1.) Differences were no longer present after adjustment for lean mass (model 2) in girls (p > 0.05) whereas differences at the tibia were sustained in boys (p < 0.05). These findings demonstrate sex‐ and site‐specific differences in the associations between adiposity, maturation, and bone strength. © 2016 American Society for Bone and Mineral Research.     

Heterogeneity and Spatial Distribution of Intravertebral Trabecular Bone Mineral Density in the Lumbar Spine Is Associated With Prevalent Vertebral Fracture

The spatial heterogeneity in trabecular bone density within the vertebral centrum is associated with vertebral strength and could explain why volumetric bone mineral density (vBMD) exhibits low sensitivity in identifying fracture risk. This study evaluated whether the heterogeneity and spatial distribution of trabecular vBMD are associated with prevalent vertebral fracture. We examined the volumetric quantitative computed tomography (QCT) scans of the L₃ vertebra in 148 participants in the Framingham Heart Study Multidetector CT study. Of these individuals, 37 were identified as cases of prevalent fracture, and 111 were controls, matched on sex and age with three controls per case. vBMD was calculated within 5-mm contiguous cubic regions of the centrum. Two measures of heterogeneity were calculated: (i) interquartile range (IQR); and (ii) quartile coefficient of variation (QCV). Ratios in the spatial distributions of the trabecular vBMD were also calculated: anterior/posterior, central/outer, superior/mid-transverse, and inferior/mid-transverse. Heterogeneity and spatial distributions were compared between cases and controls using Wilcoxon rank sum tests and t tests and tested for association with prevalent fractures with conditional logistic regressions independent of integral vBMD. Prevalent fracture cases had lower mean ± SD integral vBMD (134 ± 38 versus165 ± 42 mg/cm³, p < .001), higher QCV (0.22 ± 0.13 versus 0.17 ± 0.09, p = .003), and lower anterior/posterior rBMD (0.65 ± 0.13 versus 0.78 ± 0.16, p < .001) than controls. QCV was positively associated with increased odds of prevalent fracture (OR 1.61; 95% CI, 1.04 to 2.49; p = .034), but this association was not independent of integral vBMD (p = .598). Increased anterior/posterior trabecular vBMD ratio was associated with decreased odds of prevalent fracture independent of integral vBMD (OR 0.38; 95% CI, 0.20 to 0.71; p = .003). In conclusion, increased trabecular vBMD in the anterior versus posterior centrum, but not trabecular vBMD heterogeneity, was associated with decreased risk of prevalent fracture independent of integral vBMD. Regional measurements of trabecular vBMD could aid in determining the risk and underlying mechanisms of vertebral fracture. © 2019 American Society for Bone and Mineral Research.     

The “Goldilocks Day” for Children's Skeletal Health: Compositional Data Analysis of 24-Hour Activity Behaviors

Optimization of children's activity behaviors for skeletal health is a key public health priority, yet it is unknown how many hours of moderate to vigorous physical activity (MVPA), light physical activity (LPA), sedentary behavior, or sleep constitute the best day—the “Goldilocks Day”—for children's bone structure and function. To describe the best day for children's skeletal health, we used data from the cross-sectional Child Health CheckPoint. Included participants (n = 804, aged 10.7 to 12.9 years, 50% male) underwent tibial peripheral quantitative CT to assesses cross-sectional area, trabecular and cortical density, periosteal and endosteal circumference, polar moment of inertia, and polar stress–strain index. Average daily time-use composition (MVPA, LPA, sedentary time, and sleep) was assessed through 8-day, 24-hour accelerometry. Skeletal outcomes were regressed against time-use compositions expressed as isometric log-ratios (with quadratic terms where indicated), adjusted for sex, age, pubertal status, and socioeconomic position. The models were used to estimate optimal time-use compositions (associated with best 5% of each skeletal outcome), which were plotted in three-dimensional quaternary figures. The center of the overlapping area was considered the Goldilocks Day for skeletal health. Children's time-use composition was associated with all skeletal measures (all p ≤ 0.001) except cross-sectional area (p = 0.72). Days with more sleep and MVPA, less sedentary time, and moderate LPA were beneficially associated with skeletal measures, except cortical density, which was adversely associated. The Goldilocks daily time-use composition for overall skeletal health was center (range): 10.9 (10.5 to 11.5) hours sleep; 8.2 (7.8 to 8.8) hours sedentary time; 3.4 (2.8 to 4.2) hours LPA, and 1.5 (1.3 to 1.5) hours MVPA. Estimated optimal sleep duration is consistent with current international guidelines (9 to 11 hours), while estimated optimal MVPA exceeds recommendations of at least 60 min/d. This first study to describe optimal durations of daily activities for children's skeletal health provides evidence to underpin guidelines. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Cross‐sectional Versus Longitudinal Change in a Prospective HR‐pQCT Study

Longitudinal studies assessing age‐related changes using high‐resolution peripheral quantitative computed tomography (HR‐pQCT) provide novel insight compared with cross‐sectional analyses. The purpose of this cohort study was 1) to determine individuals’ change in HR‐pQCT parameters over 5 years relative to least significant change (LSC), and 2) to evaluate if predicted rate of change from cross‐sectional data is comparable to actual change from longitudinal investigation. A cohort of 466 (162 male, 304 female) participants completed two HR‐pQCT scans with 5 years between assessments. After image registration, standard and cortical morphological analyses were conducted. Rate of bone microarchitectural change was compared between cross‐sectional models and actual change calculated from longitudinal analyses. At the young end of the life span, we observed gains in total bone density of +0.2% to +2.9% per year, whereas the older participants (aged >50 years) lost total bone density at a rate of –0.3% to –1.3% per year. Declines in total bone density begin at age 40 years in females and 60 years in males, and significant adaptation was found at both ends of the age spectrum with respect to the LSC. Models predicting rate of change from cross‐sectional data were similar to the actual change reported in this longitudinal study for total density and cortical thickness at the radius and cortical density at the tibia, but we found that changes in comparison to our 5‐year longitudinal results were often overestimated from cross‐sectional data. Studies aimed at observing age‐related changes in a normative cohort, especially in a follow‐up period of less than 5 years, are better to focus on the tibia rather than the radius because of the increased sensitivity to change at the tibia. © 2017 American Society for Bone and Mineral Research.     

Effects of Supplemental Vitamin D on Bone Health Outcomes in Women and Men in the VITamin D and OmegA-3 TriaL (VITAL)

Although supplemental vitamin D is used to promote bone health in the general population, data from randomized controlled trials (RCTs) have been inconsistent. We determined whether daily, vitamin D₃ supplementation improves bone mineral density (BMD) and/or structure. VITamin D and OmegA-3 TriaL (VITAL) is a double-blind, placebo-controlled RCT of supplemental vitamin D₃ (2000 IU/d) and/or omega-3 fatty acids (1 g/d) in 25,871 adults nationwide. This ancillary study included a subcohort of 771 participants (men ≥50 and women ≥55 years; not taking bone active medications) evaluated at baseline and at 2-year follow-up (89% retention). Total 25(OH)D levels were measured by liquid chromatography tandem mass spectrometry (Quest Diagnostics, San Juan Capistrano, CA, USA). Free 25(OH)D (FVD) levels were measured using the ELISA assay by Future Diagnostics Solutions BV (Wijchen, Netherlands). Primary endpoints were 2-year changes in areal (a) BMD at the spine, hip, and whole body determined by dual-energy X-ray absorptiometry (DXA). Secondary endpoints were 2-year changes in volumetric (v) BMD and cortical thickness at the radius and tibia assessed by peripheral quantitative computed tomography. Supplemental vitamin D₃ versus placebo had no effect on 2-year changes in aBMD at the spine (0.33% versus 0.17%; p = 0.55), femoral neck (−0.27% versus −0.68%; p = 0.16), total hip (−0.76% versus −0.95%; p = 0.23), or whole body (−0.22% versus −0.15%; p = 0.60), or on measures of bone structure. Effects did not vary by sex, race/ethnicity, body mass index, or 25(OH)D levels. Among participants with baseline FVD levels below the median (<14.2 pmol/L), there was a slight increase in spine aBMD (0.75% versus 0%; p = 0.043) and attenuation in loss of total hip aBMD (−0.42% versus −0.98%; p = 0.044) with vitamin D₃. Whether baseline FVD levels help to identify those more likely to benefit from supplementation warrants further study. Supplemental vitamin D₃ versus placebo for 2 years in general healthy adults not selected for vitamin D insufficiency did not improve BMD or structure. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

Pregnancy-Related Bone Mineral and Microarchitecture Changes in Women Aged 30 to 45 Years

At birth, the neonatal skeleton contains 20 to 30 g calcium (Ca). It is hypothesized maternal bone mineral may be mobilized to support fetal skeletal development, although evidence of pregnancy-induced mineral mobilization is limited. We recruited healthy pregnant (n = 53) and non-pregnant non-lactating (NPNL; n = 37) women aged 30 to 45 years (mean age 35.4 ± 3.8 years) and obtained peripheral quantitative computed tomography (pQCT) and high-resolution pQCT (HR-pQCT) scans from the tibia and radius at 14 to 16 and 34 to 36 weeks of pregnancy, with a similar scan interval for NPNL. Multiple linear regression models were used to assess group differences in change between baseline and follow-up; differences are expressed as standard deviation scores (SDS) ± SEM. Decreases in volumetric bone mineral density (vBMD) outcomes were found in both groups; however, pregnancy-related decreases for pQCT total and trabecular vBMD were −0.65 ± 0.22 SDS and −0.50 ± 0.23 SDS greater (p < .05). HR-pQCT total and cortical vBMD decreased compared with NPNL by −0.49 ± 0.24 SDS and −0.67 ± 0.23 SDS, respectively; trabecular vBMD decreased in both groups to a similar magnitude. Pregnancy-related changes in bone microarchitecture significantly exceeded NPNL change for trabecular number (0.47 ± 0.23 SDS), trabecular separation (−0.54 ± 0.24 SDS), cortical thickness (−1.01 ± 0.21 SDS), and cortical perimeter (0.78 ± 0.23 SDS). At the proximal radius, cortical vBMD and endosteal circumference increased by 0.50 ± 0.23 SDS and 0.46 ± 0.23 SDS, respectively, compared with NPNL, whereas cortical thickness decreased −0.50 ± 0.22 SDS. Pregnancy-related decreases in total and compartment-specific vBMD exceed age-related change at the distal tibia. Changes at the radius were only evident with pQCT at the cortical-rich proximal site and suggest endosteal resorption. Although the magnitude of these pregnancy-related changes in the appendicular skeleton are small, if they reflect global changes across the skeleton at large, they may contribute substantially to the Ca requirements of the fetus. © 2020 Crown copyright. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). This article is published with the permission of the Controller of HMSO and the Queen's Printer for Scotland.     

Pregnancy-Related Change in pQCT and Bone Biochemistry in a Population With a Habitually Low Calcium Intake

In pregnancy, changes in maternal calcium (Ca) economy occur to satisfy fetal Ca demand. It is unclear whether maternal mineral reserves facilitate these requirements and no data exist from sub-Saharan Africa. The aim was to determine skeletal changes with peripheral quantitative computed tomography (pQCT) and bone biochemistry between early second and third trimesters. Pregnant rural Gambians aged 18 to 45 years (n = 467) participating in a trial of antenatal nutritional supplements (ISRCTN49285450) had pQCT scans and blood collections at mean (SD) 14 (3) and 31 (1) weeks’ gestation. Outcomes were pQCT: radius/tibia 4% total volumetric bone mineral density (vBMD), trabecular vBMD, total cross-sectional area (CSA), 33%/38% radius/tibia cortical vBMD, bone mineral content (BMC), total CSA; biochemistry: collagen type 1 cross-linked β-C-telopeptide (β-CTX), type 1 procollagen N-terminal (P1NP), parathyroid hormone (PTH), and 1,25(OH)₂D. Independent t tests tested whether pooled or within-group changes differed from 0. Multiple regression was performed adjusting for age. Data for change are expressed as mean (confidence interval [CI] 2.5, 97.5%). Radius trabecular vBMD, cortical vBMD, and BMC increased by 1.15 (0.55, 1.75)%, 0.41 (0.24, 0.58)%, and 0.47 (0.25, 0.69)%. Tibia total and trabecular vBMD increased by 0.34 (0.15, 0.54)% and 0.46 (0.17, 0.74)%, while tibia cortical vBMD, BMC, and cortical CSA increased by 0.35 (0.26, 0.44)%, 0.55 (0.41, 0.68)% and 0.20 (0.09, 0.31)%, respectively. CTX, PTH, and 1,25(OH)₂D increased by 23.0 (15.09, 29.29)%, 13.2 (8.44, 19.34)%, and 21.0 (17.67, 24.29)%, while P1NP decreased by 32.4 (−37.19, −28.17)%. No evidence of mobilization was observed in the peripheral skeleton. Resorption, although higher in late versus early gestation, was lower throughout pregnancy compared with non-pregnant non-lactating (NPNL) in the same community. Formation was lower in late pregnancy than in early, and below NPNL levels. This suggests a shift in the ratio of resorption to formation. Despite some evidence of change in bone metabolism, in this population, with habitually low Ca intakes, the peripheral skeleton was not mobilized as a Ca source for the fetus. © 2021 crown copyright . Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). The article published with the permission of the Controller of HMSO and the Queen's Printer of Scotland..     

Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD,Reduced Vertebral Fracture Risk,and Increased Expression of SLC1A3 and EPHB2

Genome‐wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta‐analysis (n = 15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta‐analyses to determine associations with morphometric vertebral fracture (n = 21,701) and clinical vertebral fracture (n = 5893). Expression quantitative trait locus (eQTL) analyses of iliac crest biopsies were performed in 84 postmenopausal women, and murine osteoblast expression of genes implicated by eQTL or by proximity to vBMD‐associated SNPs was examined. We identified significant vBMD associations with five loci, including: 1p36.12, containing WNT4 and ZBTB40; 8q24, containing TNFRSF11B; and 13q14, containing AKAP11 and TNFSF11. Two loci (5p13 and 1p36.12) also contained associations with radiographic and clinical vertebral fracture, respectively. In 5p13, rs2468531 (minor allele frequency [MAF] = 3%) was associated with higher vBMD (β = 0.22, p = 1.9 × 10^–8) and decreased risk of radiographic vertebral fracture (odds ratio [OR] = 0.75; false discovery rate [FDR] p = 0.01). In 1p36.12, rs12742784 (MAF = 21%) was associated with higher vBMD (β = 0.09, p = 1.2 × 10^–10) and decreased risk of clinical vertebral fracture (OR = 0.82; FDR p = 7.4 × 10^–4). Both SNPs are noncoding and were associated with increased mRNA expression levels in human bone biopsies: rs2468531 with SLC1A3 (β = 0.28, FDR p = 0.01, involved in glutamate signaling and osteogenic response to mechanical loading) and rs12742784 with EPHB2 (β = 0.12, FDR p = 1.7 × 10^–3, functions in bone‐related ephrin signaling). Both genes are expressed in murine osteoblasts. This is the first study to link SLC1A3 and EPHB2 to clinically relevant vertebral osteoporosis phenotypes. These results may help elucidate vertebral bone biology and novel approaches to reducing vertebral fracture incidence. © 2016 American Society for Bone and Mineral Research.     

Sex-Specific Associations Between Cardiac Workload,Peripheral Vascular Calcification,and Bone Mineral Density: The Gambian Bone and Muscle Aging Study

Noncommunicable diseases (NCD) are rapidly rising in Africa, with multimorbidity increasing the burden on health and social care. Osteoporosis and cardiovascular disease (CVD) share common risk factors; both often remain undiagnosed until a major life-threatening event occurs. We investigated the associations between cardiac workload, peripheral vascular calcification (PVC), and bone parameters in Gambian adults. The Gambian Bone and Muscle Aging Study (GamBAS) recruited 249 women and 239 men aged 40 to 75+ years. Body composition and areal bone mineral density (aBMD) were measured using dual-energy X-ray absorptiometry; peripheral quantitative computed tomography (pQCT) scans were performed at the radius and tibia. Supine blood pressure and heart rate were measured and used to calculate rate pressure product and pulse pressure. Presence of PVC was determined from tibia pQCT scans. Sex interactions were tested (denoted as p-int); adjustments were made for residuals of appendicular lean mass (ALM) and fat mass (FM). There were negative associations between rate pressure product and aBMD in women only, all p-int < .05; after adjustment for ALM residuals, for every 10% increase in rate pressure product, aBMD was lower at the whole body (−0.6% [−1.2, −0.1]), femoral neck (−0.9% [−1.8, −0.05]), L₁ to L₄ (−0.6% [−1.7, 0.5]), and radius (−1.9% [−2.8, −0.9]); there were similar associations when adjusted for FM residuals. Similar negative associations were found between pulse pressure and aBMD in women only. PVC were found in 26.6% men and 22.5% women; women but not men with calcification had poorer cardiac health and negative associations with aBMD (all sites p-int < .001). There were consistent associations with cardiac parameters and pQCT outcomes at the radius and tibia in women only. Multiple markers of cardiac health are associated with poorer bone health in Gambian women. In the context of epidemiological transition and changing NCD burden, there is a need to identify preventative strategies to slow/prevent the rising burden in CVD and osteoporosis in Sub-Saharan Africa. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Genetics of Bone Mass in Childhood and Adolescence: Effects of Sex and Maturation Interactions

We aimed to determine if adult bone mineral density (BMD) susceptibility loci were associated with pediatric bone mass and density, and if sex and pubertal stage influenced any association. We analyzed prospective areal BMD (aBMD) and bone mineral content (BMC) data from the Bone Mineral Density in Childhood Study (n = 603, European ancestry, 54% female). Linear mixed models were used to assess if 77 single‐nucleotide polymorphisms (SNPs) near known adult BMD susceptibility loci interacted with sex and pubertal stage to influence the aBMD/BMC; adjusting for age, BMI, physical activity, and dietary calcium. The strongest main association was observed between an SNP near C7orf58 and distal radius aBMD. However, this association had a significant sex?SNP interaction, revealing a significant association only in females (b = –0.32, p = 1.8 × 10^–6). Furthermore, the C12orf23 locus had significant interactions with both sex and pubertal stage, revealing associations in females during Tanner stage I for total hip aBMD (b = 0.24, p = 0.001) and femoral neck aBMD (b = 0.27, p = 3.0 × 10^–5). In contrast, the sex?SNP interactions for loci near LRP5 and WNT16 uncovered associations that were only in males for total body less head BMC (b = 0.22, p = 4.4 × 10^–4) and distal radius aBMD (b = 0.27, p = 0.001), respectively. Furthermore, the LRP5 locus interacted with both sex and pubertal stage, demonstrating associations that were exclusively in males during Tanner V for total hip aBMD (b = 0.29, p = 0.003). In total, significant sex?SNP interactions were found at 15 loci; pubertal stage?SNP interactions at 23 loci and 19 loci interacted with both sex and pubertal stage. In conclusion, variants originally associated with adult BMD influence bone mass in children of European ancestry, highlighting the fact that many of these loci operate early in life. However, the direction and magnitude of associations for a large number of SNPs only became evident when accounting for sex and maturation. © 2015 American Society for Bone and Mineral Research.     

Associations of Breastfeeding,Maternal Smoking,and Birth Weight With Bone Density and Microarchitecture in Young Adulthood: a 25-Year Birth-Cohort Study

We have found that early-life exposures are associated with areal bone mineral density (aBMD) at ages 8 and 16 years. This study aimed to assess whether these associations persist into young adulthood when peak bone mass (PBM) is achieved and extend this analysis to microarchitecture. Participants were followed from perinatal period to 25 years old (n = 201). Outcomes were total body, spine, and hip aBMD (by dual-energy X-ray absorptiometry [DXA]), and cortical and trabecular bone measures at the distal radius and tibia (by high-resolution peripheral quantitative computed tomography [HRpQCT]). Early-life exposures including breastfeeding, maternal smoking during pregnancy, and birth weight. Sex, weight, height, vegetables, fruit and calcium intake at age 25 years were regarded as potential confounders in the analysis. There were significant interactions between period of gestation and early-life exposures for bone measures, so all analyses were stratified by period of gestation. Breastfeeding was beneficially associated with hip and total body aBMD, total, cortical and trabecular volumetric BMD (vBMD), cortical thickness, porosity, trabecular number (Tb.N), separation (Tb.Sp), and bone volume fraction (Tb.BV/TV) at radius and/or tibia at age 25 years in participants born prematurely (β ranged from −0.92 to 0.94), but there were no associations in those born at term. Maternal smoking had no association with any DXA/HRpQCT measures in those born prematurely but was detrimentally associated with inner transitional zone porosity and Tb.N (β = 0.40 and β = −0.37, respectively) in those full-term participants. Associations of birth weight with bone measures did not persist after adjustment for weight gain since birth. Breastfeeding was associated with a lower risk of lower limb fractures and maternal smoking had a deleterious association with upper limb fractures. In conclusion, breastfeeding and maternal smoking may have effects on peak bone microarchitecture whereas the association with birth weight is countered by subsequent growth. © 2020 American Society for Bone and Mineral Research.