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Background: Vitamin D supplements are widely used for improving bone health in children and adolescents, but their effects in vitamin D-deficient children are unclear., Objectives: This study aimed to examine whether the effect of vitamin D supplementation on bone mineral density (BMD) in children and adolescents differs by baseline vitamin D status and estimate the effect in vitamin D-deficient individuals., Methods: This is a systematic review and individual participant data (IPD) meta-analysis. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, MBASE, CINAHL, AMED, and ISI Web of Science (until May 27, 2020) for randomized controlled trials (RCTs) of vitamin D supplementation reporting bone density outcomes after ≥6 mo in healthy individuals aged 1-19 y. We used two-stage IPD meta-analysis to determine treatment effects on total body bone mineral content and BMD at the hip, femoral neck, lumbar spine, and proximal and distal forearm after 1 y; examine whether effects varied by baseline serum 25-hydroxyvitamin D [25(OH)D] concentration, and estimate treatment effects for each 25(OH)D subgroup., Results: Eleven RCTs were included. Nine comprising 1439 participants provided IPD (86% females, mean baseline 25(OH)D = 36.3 nmol/L). Vitamin D supplementation had a small overall effect on total hip areal BMD (weighted mean difference = 6.8; 95% confidence interval: 0.7, 12.9 mg/cm 2 ; I 2 = 7.2%), but no effects on other outcomes. There was no clear evidence of linear or nonlinear interactions between baseline 25(OH)D and treatment; effects were similar in baseline 25(OH)D subgroups (cutoff of 35 or 50 nmol/L). The evidence was of high certainty., Conclusions: Clinically important benefits for bone density from 1-y vitamin D supplementation in healthy children and adolescents, regardless of baseline vitamin D status, are unlikely. However, our findings are mostly generalizable to White postpubertal girls and do not apply to those with baseline 25(OH)D outside the studied range or with symptomatic vitamin D deficiency (e.g., rickets). This study was preregistered at PROSPERO as CRD42017068772. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42017068772., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background: Lateral spine images for vertebral fracture assessment can be easily obtained on modern bone density machines. Abdominal aortic calcification (AAC) can be scored on these images by trained imaging specialists to assess cardiovascular disease risk. However, this process is laborious and requires careful training., Methods: Training and testing of model performance of the convolutional neural network (CNN) algorithm for automated AAC-24 scoring utilised 5012 lateral spine images (2 manufacturers, 4 models of bone density machines), with trained imaging specialist AAC scores. Validation occurred in a registry-based cohort study of 8565 older men and women with images captured as part of routine clinical practice for fracture risk assessment. Cox proportional hazards models were used to estimate the association between machine-learning AAC (ML-AAC-24) scores with future incident Major Adverse Cardiovascular Events (MACE) that including death, hospitalised acute myocardial infarction or ischemic cerebrovascular disease ascertained from linked healthcare data., Findings: The average intraclass correlation coefficient between imaging specialist and ML-AAC-24 scores for 5012 images was 0.84 (95% CI 0.83, 0.84) with classification accuracy of 80% for established AAC groups. During a mean follow-up 4 years in the registry-based cohort, MACE outcomes were reported in 1177 people (13.7%). With increasing ML-AAC-24 scores there was an increasing proportion of people with MACE (low 7.9%, moderate 14.5%, high 21.2%), as well as individual MACE components (all p-trend <0.001). After multivariable adjustment, moderate and high ML-AAC-24 groups remained significantly associated with MACE (HR 1.54, 95% CI 1.31-1.80 & HR 2.06, 95% CI 1.75-2.42, respectively), compared to those with low ML-AAC-24., Interpretation: The ML-AAC-24 scores had substantial levels of agreement with trained imaging specialists, and was associated with a substantial gradient of risk for cardiovascular events in a real-world setting. This approach could be readily implemented into these clinical settings to improve identification of people at high CVD risk., Funding: The study was supported by a National Health and Medical Research Council of Australia Ideas grant and the Rady Innovation Fund, Rady Faculty of Health Sciences, University of Manitoba., Competing Interests: Declaration of interests DPK has received a grant from Solarea Bio and royalties from Wolters Kluwer. DPK sits on the Scientific Advisory Boards of Solarea Bio, Pfizer and Reneo and has participated on the Data Safety Monitoring Board for the AgNovos Healthcare osteoporosis treatment trial. All other authors have no disclosures to declare., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Skull bone mineral density (SK-BMD) provides a suitable trait for the discovery of key genes in bone biology, particularly to intramembranous ossification, not captured at other skeletal sites. We perform a genome-wide association meta-analysis (n ~ 43,800) of SK-BMD, identifying 59 loci, collectively explaining 12.5% of the trait variance. Association signals cluster within gene-sets involved in skeletal development and osteoporosis. Among the four novel loci (ZIC1, PRKAR1A, AZIN1/ATP6V1C1, GLRX3), there are factors implicated in intramembranous ossification and as we show, inherent to craniosynostosis processes. Functional follow-up in zebrafish confirms the importance of ZIC1 on cranial suture patterning. Likewise, we observe abnormal cranial bone initiation that culminates in ectopic sutures and reduced BMD in mosaic atp6v1c1 knockouts. Mosaic prkar1a knockouts present asymmetric bone growth and, conversely, elevated BMD. In light of this evidence linking SK-BMD loci to craniofacial abnormalities, our study provides new insight into the pathophysiology, diagnosis and treatment of skeletal diseases., (© 2023. The Author(s).)

Objective: To explore the impact of virtual reality (VR) training on anti-fall ability and bone mineral density (BMD) among elderly patients admitted to a healthcare institution., Methods: People (aged 50) with osteoporosis in an elderly care institution in Anhui Province June 2020 to October 2021 were selected and randomly divided into VR group (n = 25) and control group (n = 25). In VR group, the virtual reality rehabilitation training system was used for training, while control group was treated with traditional fall prevention exercise intervention. The changes of Berg Balance Scale (BBS), timed up and go test (TUGT), functional gait assessment (FGA), bone mineral density (BMD) and falls during 12 months of training were compared between the two groups., Results: BBS and FGA were positively correlated with BMD of the lumbar vertebrae and femoral neck, and TUGT was negatively correlated with BMD of the lumbar vertebrae and femoral neck. After 12 months of training, the BBS score, TUGT evaluation and FGA evaluation of the two groups were significantly improved compared with those prior to training (P < 0.05). However, there was no significant difference in the lumbar spine and femoral neck BMD between the two groups 6 months after the intervention. The femoral neck and lumbar spine BMD of the VR group improved, and it was significantly higher than that of the control group 12 months after the intervention. Nevertheless, there was no significant difference in terms of the incidence of adverse events between the two groups., Conclusion: VR training can improve anti-fall ability and increase femoral neck and lumbar spine BMD and can effectively prevent and reduce the risk of injury among elderly people with osteoporosis., (© 2023. The Author(s).)

Although suboptimal bone health has been reported in children and adolescents with low motor competence (LMC), it is not known whether such deficits are present at the time of peak bone mass. We examined the impact of LMC on bone mineral density (BMD) in 1043 participants (484 females) from the Raine Cohort Study. Participants had motor competence assessed using the McCarron Assessment of Neuromuscular Development at 10, 14, and 17 years, and a whole-body dual-energy X-ray absorptiometry (DXA) scan at 20 years. Bone loading from physical activity was estimated from the International Physical Activity Questionnaire at the age of 17 years. The association between LMC and BMD was determined using general linear models that controlled for sex, age, body mass index, vitamin D status, and prior bone loading. Results indicated LMC status (present in 29.6% males and 21.9% females) was associated with a 1.8% to 2.6% decrease in BMD at all load-bearing bone sites. Assessment by sex showed that the association was mainly in males. Osteogenic potential of physical activity was associated with increased BMD dependent on sex and LMC status, with males with LMC showing a reduced effect from increasing bone loading. As such, although engagement in osteogenic physical activity is associated with BMD, other factors involved in physical activity, eg, diversity, movement quality, may also contribute to BMD differences based upon LMC status. The finding of lower peak bone mass for individuals with LMC may reflect a higher risk of osteoporosis, especially for males; however, further research is required. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

We have previously shown that abdominal aortic calcification (AAC), a marker of advanced atherosclerotic disease, is weakly associated with reduced hip areal bone mineral density (aBMD). To better understand the vascular-bone health relationship, we explored this association with other key determinants of whole-bone strength and fracture risk at peripheral skeletal sites. This study examined associations of AAC with peripheral quantitative computed tomography (pQCT)-assessed total, cortical and trabecular volumetric BMD (vBMD), bone structure and strength of the radius and tibia among 648 community-dwelling older women (mean ± SD age 79.7 ± 2.5 years). We assessed associations between cross-sectional (2003) and longitudinal (progression from 1998/1999-2003) AAC assessed on lateral dual-energy X-ray absorptiometry (DXA) images with cross-sectional (2003) and longitudinal (change from 2003 to 2005) pQCT bone measures at the 4% radius and tibia, and 15% radius. Partial Spearman correlations (adjusted for age, BMI, calcium treatment) revealed no cross-sectional associations between AAC and any pQCT bone measures. AAC progression was not associated with any bone measure after adjusting for multiple comparisons, despite trends for inverse correlations with total bone area at the 4% radius (r s  =  - 0.088, p = 0.044), 4% tibia (r s  =  - 0.085, p = 0.052) and 15% radius (r s  =  - 0.101, p = 0.059). Neither AAC in 2003 nor AAC progression were associated with subsequent 2-year pQCT bone changes. ANCOVA showed no differences in bone measures between women with and without AAC or AAC progression, nor across categories of AAC extent. Collectively, these finding suggest that peripheral bone density and structure, or its changes with age, are not associated with central vascular calcification in older women., (© 2022. The Author(s).)

Bone mineral density (BMD) of the hip is routinely measured unilaterally, but can differ between left and right. This study aimed to establish total hip T-score thresholds for measuring contralateral hip BMD, to avoid missing the diagnosis of osteoporosis. In 4914 participants (2709 females) in the Busselton Healthy Ageing Study, BMD of both hips and lumbar spine (L1-L4) was measured by dual-energy x-ray absorptiometry (DXA) using a GE Lunar Prodigy Pro densitometer. Least significant change (LSC) was calculated according to International Society for Clinical Densitometry recommendations. For participants whose left-right total hip BMD difference exceeded LSC, the 95th percentile of the difference in T-score was calculated, then added to -2.5 (the cut-off for osteoporosis) to derive T-score thresholds for measuring contralateral hip to avoid a missed diagnosis in 95% of individuals. Participant mean age (±SD) was 57.4 ± 5.8 years; total hip T-score was 0.7 ± 0.1 in males and -0.2 ± 1.1 in females. Left and right total hip BMD were highly correlated (r = 0.943 for males, 0.959 for females), but in 56.2% of males and 50.0% of females, the left-right difference exceeded the LSC of 0.026 g/cm 2 . In these participants, the 95th percentile of difference in T-score between two hips was 0.872 in males and 0.742 in females. This gave T-score thresholds for measuring contralateral total hip BMD of -1.6 (males) and -1.8 (females). When total hip T-score is between -1.6 and -2.5 (males), or between -1.8 and -2.5 (females), measuring contralateral hip BMD could avoid a missed diagnosis of osteoporosis., (Copyright © 2022 The International Society for Clinical Densitometry. All rights reserved.)

Ground impacts during physical activity may be important for peak bone mass. We found differences in how energy expenditure and impact scores estimated from a physical activity questionnaire related to bone health in young adults. Using both estimate types can improve our understanding of the skeletal benefits of physical activity., Purpose: It is unclear whether mechanical loading during physical activity, estimated from physical activity questionnaires which assess metabolic equivalents of task (METs), is associated with skeletal health. This longitudinal study investigated how physical activity loading scores, assessed at ages 17 and 20 years, (a) compares with physical activity measured in METs, and (b) is associated with bone mass at age 20 years., Methods: A total of 826 participants from the Raine Study Gen2 were assessed for physical activity energy expenditure via the International Physical Activity Questionnaire (IPAQ) at age 17 and 20 years. Loading scores (the product of peak force and application rate) per week were subsequently estimated from the IPAQ. Whole-body and appendicular bone mineral density (BMD) at age 20 years were assessed by dual-energy X-ray absorptiometry., Results: Bland-Altman minimal detectable difference for physical activity Z- scores at age 17 and 20 years were 1.59 standard deviations (SDs) and 1.33 SDs, respectively, greater than the a priori minimal clinically important change of 0.5 SDs. Loading score, but not IPAQ score, had significant positive associations with whole-body and leg BMD after adjustment for covariates (β = 0.008 and 0.012 g/cm 2 , respectively, for age 17 and 20 years loading scores). IPAQ score at age 20 years, but not loading score, had a significant positive association with arm BMD (β = 0.007 g/cm 2 )., Conclusion: This study revealed disagreement in associations of self-reported METs and loading score estimates with bone health in young adults. Coupling traditional energy expenditure questionnaire outcomes with bone-loading estimates may improve understanding of the location-specific skeletal benefits of physical activity in young adults., (© 2022. The Author(s).)

Although a relationship between vascular disease and osteoporosis has been recognized, its clinical importance for fracture risk evaluation remains uncertain. Abdominal aortic calcification (AAC), a recognized measure of vascular disease detected on single-energy images performed for vertebral fracture assessment, may also identify increased osteoporosis risk. In a prospective 10-year study of 1024 older predominantly white women (mean age 75.0 ± 2.6 years) from the Perth Longitudinal Study of Aging cohort, we evaluated the association between AAC, skeletal structure, and fractures. AAC and spine fracture were assessed at the time of hip densitometry and heel quantitative ultrasound. AAC was scored 0 to 24 (AAC24) and categorized into low AAC (score 0 and 1, n = 459), moderate AAC (score 2 to 5, n = 373), and severe AAC (score >6, n = 192). Prevalent vertebral fractures were calculated using the Genant semiquantitative method. AAC24 scores were inversely related to hip BMD ( r s = -0.077, p = 0.013), heel broadband ultrasound attenuation ( r s = -0.074, p = 0.020), and the Stiffness Index ( r s = -0.073, p = 0.022). In cross-sectional analyses, women with moderate to severe AAC were more likely to have prevalent fracture and lumbar spine imaging-detected lumbar spine fractures, but not thoracic spine fractures (Mantel-Haenszel test of trend p < 0.05). For 10-year incident clinical fractures and fracture-related hospitalizations, women with moderate to severe AAC (AAC24 score >1) had increased fracture risk (HR 1.48; 95% CI, 1.15 to 1.91; p = 0.002; HR 1.46; 95% CI, 1.07 to 1.99; p = 0.019, respectively) compared with women with low AAC. This relationship remained significant after adjusting for age and hip BMD for clinical fractures (HR 1.40; 95% CI, 1.08 to 1.81; p = 0.010), but was attenuated for fracture-related hospitalizations (HR 1.33; 95% CI, 0.98 to 1.83; p = 0.073). In conclusion, older women with more marked AAC are at higher risk of fracture, not completely captured by bone structural predictors. These findings further support the concept that vascular calcification and bone pathology may share similar mechanisms of causation that remain to be fully elucidated © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

The vitamin D debate relates in part to ideal public health population levels of circulating 25-hydroxyvitamin D (25OHD) to maintain bone structure and reduce fracture. In a secondary analysis of 1348 women aged 70 to 85 years at baseline (1998) from the Perth Longitudinal Study of Aging in Women (a 5-year calcium supplementation trial followed by two 5-year extensions), we examined the dose-response relations of baseline plasma 25OHD with hip DXA BMD at year 1, lumbar spine BMD, and trabecular bone score (TBS) at year 5, and fracture-related hospitalizations over 14.5 years obtained by health record linkage. Mean baseline plasma 25OHD was 66.9 ± 28.2 nmol/L and 28.5%, 36.4%, and 35.1% of women had levels <50, 50 to 74.9, and ≥75 nmol/L, respectively. Generalized additive models showed that total hip and femoral neck BMD and TBS, but not spine BMD, were higher with increasing plasma 25OHD up to 100 nmol/L. Compared with those with 25OHD <50 nmol/L, women with 25OHD ≥75 nmol/L had significantly higher total hip and femoral neck BMD at year 1 (3.3% to 3.9%) and TBS at year 5 (2.0%), all P < 0.05. During the follow-up, 27.6% of women experienced any fracture-related hospitalization and 10.6% hip fracture-related hospitalization. Penalized spline regression models showed a decrease in risk with increased 25OHD levels up to 65 nmol/L and 75 nmol/L for hip fracture and any fracture-related hospitalization, respectively. Cox regression grouped analyses showed that compared with women with 25OHD <50 nmol/L, those with 25OHD levels 50 to 74.9 and ≥75 nmol/L had significantly lower risk for hip fracture [HR 0.60 (95% CI, 0.40 to 0.91) and 0.61 (95% CI, 0.40 to 0.92), respectively], and any fracture-related hospitalization [HR 0.77 (95% CI, 0.59 to 0.99) and 0.70 (95% CI, 0.54 to 0.91), respectively]. In older white women, 25OHD levels >50 nmol/L are a minimum public health target and 25OHD levels beyond 75 nmol/L may not have additional benefit to reduce fracture risk. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

There is a critical need for longitudinal cohort studies to consider the association of the cumulative exposure of physical activity during childhood and adolescence and bone mass. The aim of this study was to investigate the relationship between organized sports trajectories (that capture distinct and potentially meaningful patterns over critical developmental periods) and bone mass at age 20 years. Participation in organized sport was recorded by parental report at ages 5, 8, 10, 14, and 17 years in 984 offspring (48% female) of a pregnancy cohort (Raine Study). Latent class analysis identified three trajectory classes in each sex. In females, these were "consistent sport participators" (48%), "dropouts" (34%), and "non-participators" (18%); in males, "consistent sport participators" (55%), "dropouts" (37%), and "sport joiners" (8%). Whole-body bone mineral content (BMC) at age 20 years was assessed by dual-energy X-ray absorptiometry (DXA). At age 20 years, after adjustment for covariates measured at age 20 years, including height, lean mass, physical activity, calcium intake, serum 25-hydroxyvitamin D, alcohol, and smoking, males who were "consistent sport participators" had significantly greater whole-body and leg BMC than those who dropped out of sport (p < 0.001), whereas males who joined sports had significantly greater leg BMC than those who dropped out of sport (p = 0.002). Females in the "consistent sport participator" trajectory had significantly greater leg BMC than those who dropped out (all p = 0.004). Participation in organized sport during childhood and adolescence is associated with bone mass at age 20 years. Because attainment of optimal peak bone mass in young adulthood is protective against osteoporosis in later life, this may have long-term skeletal benefits. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

Context: In a previous community-based, cross-sectional study, males with type 1 diabetes (T1D) had lower bone mineral density (BMD) than did matched people without diabetes but females with T1D had normal BMD., Objective: To determine whether BMD in the males continued to decline, the neutral effect of T1D on BMD in females persisted, and whether temporal BMD changes reflected changes in bone turnover markers., Design: Longitudinal observational study., Setting: Urban community., Patients: Forty-eight of the original 102 original cross-sectional study participants (20 males, 28 females) of mean age 42.0 years and median diabetes duration 14.6 years at baseline who were restudied a mean of 10.3 years later., Main Outcome Measures: BMD at total hip, femoral neck, lumbar spine (L1 to L4), and distal forearm. Biochemical bone turnover markers., Results: After adjustment for age, body mass index (BMI), and renal function, there was no temporal change in BMD at the hip or forearm in the males (P ≥ 0.12), but lumbar spine BMD increased (P = 0.009). Females exhibited no statistically significant change in BMD in similar multivariable models that also included postmenopausal status, except a mild increase at the forearm (P = 0.046). Age- and sex-related changes in bone turnover markers paralleled those in general population studies., Conclusions: There is a reduction in BMD in males with T1D that occurs early in the course of the disease but then stabilizes. BMD in females with T1D remains similar to that expected for age, BMI, and postmenopausal status.

Lateral spine images are captured using bone densitometers for vertebral fracture assessment (VFA) in older women. Abdominal aortic calcification (AAC) is commonly seen on these images; however, the long-term prognosis in women with AAC remains uncertain. In a prospective study of 1052 community-dwelling ambulant white women over 70 years old abdominal aortic calcification 24 scale (AAC24) scores were calculated from digital lateral spine images captured during bone density testing in 1998 or 1999. Cardiovascular risk factors were assessed in 1998, whereas 14.5-year atherosclerotic vascular disease (ASVD)-related hospitalizations and deaths (events) were available through linked health records. Using established cut points for AAC 471 women (45%) had low AAC (AAC24 score 0 or 1), 387 (37%) moderate AAC (AAC24 score 2-5), and 197 (19%) had high AAC (AAC24 score ≥6). Over 14.5 years, 420 women experienced an ASVD event. Increasing severity of AAC was associated with increased absolute risk of ASVD events (37%, 39%, and 49%, respectively, p = 0.008 for trend), ASVD deaths (15%, 21%, and 27%, respectively, p < 0.001 for trend), and all-cause mortality (30%, 38%, and 44%, respectively, p < 0.001 for trend). After adjusting for Framingham risk scores, women with high AAC had increased relative hazard for ASVD events, HR 1.37 (95% CI, 1.07 to 1.77; p = 0.013) compared to women with low AAC. Similarly, women with moderate AAC and high AAC had increased relative hazards for ASVD deaths HR 1.41 (95% CI, 1.03 to 1.94; p = 0.034) and HR 1.80 (95% CI, 1.26 to 2.57; p = 0.001), or any deaths HR 1.30 (95% CI, 1.03 to 1.64; p = 0.026) and HR 1.53 (95% CI, 1.17 to 2.00; p = 0.002), compared to women with low AAC. In conclusion, more advanced AAC on images captured for VFA is associated with long-term ASVD hospitalizations and deaths before and after adjusting for Framingham risk scores. AAC assessment could be considered in addition to VFA to identify individuals who may benefit for more aggressive cardiovascular primary prevention strategies. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

Osteoporosis is a complex disease with a strong genetic component. Genomewide association studies (GWAS) have been very successful at identifying common genetic variants associated with bone parameters. A recently published study documented the results of the largest GWAS for bone mineral density (BMD) performed to date (n = 142,487), identifying 307 conditionally independent single-nucleotide polymorphisms (SNPs) as associated with estimated BMD (eBMD) at the genomewide significance level. The vast majority of these variants are non-coding SNPs. Expression quantitative trait locus (eQTL) studies using disease-specific cell types have increasingly been integrated with the results from GWAS to identify genes through which the observed GWAS associations are likely mediated. We generated a unique human osteoclast-specific eQTL data set using cells differentiated in vitro from 158 participants. We then used this resource to characterize the 307 recently identified BMD GWAS SNPs for association with nearby genes (±500 kb). After correction for multiple testing, 24 variants were found to be significantly associated with the expression of 32 genes in the osteoclast-like cells. Bioinformatics analysis suggested that these variants and those in strong linkage disequilibrium with them are enriched in regulatory regions. Several of the eQTL associations identified are relevant to genes that present strongly as having a role in bone, particularly IQGAP1, CYP19A1, CTNNB1, and COL6A3. Supporting evidence for many of the associations was obtained from publicly available eQTL data sets. We have also generated strong evidence for the presence of a regulatory region on chromosome 15q21.2 relevant to both the GLDN and CYP19A1 genes. In conclusion, we have generated a unique osteoclast-specific eQTL resource and have used this to identify 32 eQTL associations for recently identified BMD GWAS loci, which should inform functional studies of osteoclast biology. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

Introduction: Our previous study-level (aggregate data) meta-analysis suggested that vitamin D supplements may be beneficial for bone density specifically in children with vitamin D deficiency. However, the misclassification of vitamin D status inherent in study-level data means that the results are not definitive and cannot provide an accurate assessment of the size of any effect. Therefore, we propose to undertake an individual patient data (IPD) meta-analysis to determine whether the effect of vitamin D supplementation on bone density in children differs according to baseline vitamin D status, and to specifically estimate the effect of vitamin D in children who are vitamin D deficient., Methods and Analysis: This study has been designed to adhere to the Preferred Reporting Items for Systematic Review and Meta-Analyses of IPD statement. We will include randomised placebo-controlled trials of vitamin D supplementation reporting bone density outcomes at least 6 months after the study commenced in children and adolescents (aged <20 years) without coexistent medical conditions or treatments causing osteoporosis. We will update the search of the original review to cover the period 2009-2017, using the same methods as the original review. Fully anonymised data on all randomised patients will be requested. Outcomes will be femoral neck, total hip, lumbar spine and proximal and distal forearm bone mineral density, and total body bone mineral content. A two-stage IPD meta-analysis will be used to examine the effect of baseline serum 25-hydroxyvitamin D (25(OH)D) on treatment effect for each bone density outcome. Restricted maximum likelihood will be used to estimate the random-effects meta-analysis models, with 95% CI for summary effects. Heterogeneity will be assessed by I 2 and potential publication bias (small-study effects) and availability bias by funnel plots, Egger's test and Peter's test., Ethics and Dissemination: Ethics approval will not be required as the data are to be used for the primary purpose for which they were collected and all original individual studies had ethics approval. Results of the IPD meta-analysis will be submitted for publication in a peer-reviewed journal., Prospero Registration Number: CRD42017068772., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: To our knowledge, there are few longitudinal studies of vitamin D status from childhood to early adulthood, and it is uncertain whether vitamin D predicts peak bone mass in young adults. Objectives: The purpose of this longitudinal study was to evaluate the long-term stability of vitamin D status from ages 6 to 20 y in healthy individuals and to study associations between serum 25-hydroxyvitamin D [25(OH)D] at different developmental stages and bone mass measured at age 20 y. Design: Participants were offspring of the Western Australian Pregnancy Cohort (Raine) study. Serum 25(OH)D was assessed at ages 6, 14, 17, and 20 y, and whole-body bone mineral content (BMC) and bone mineral density (BMD) were measured at age 20 y through the use of dual-energy X-ray absorptiometry (DXA). Our analysis included 821 participants (385 females) who had ≥3 serum 25(OH)D measures and DXA data. We used latent class growth analysis and identified 4 vitamin D status trajectories: consistently lower ( n = 259), decreasing ( n = 125), increasing ( n = 138), and consistently higher ( n = 299). Results: There were significant correlations between serum 25(OH)D concentrations at different time points in both sexes ( r = 0.346-0.560, P < 0.001), with stronger correlations at adjacent time points. In males, but not in females, serum 25(OH)D at ages 6, 17, and 20 y was positively associated with total-body BMC and BMD at age 20 y [covariate-adjusted increments of 40.7-53.9 g and 14.7-18.6 mg/cm 2 , respectively, per 25 nmol/L 25(OH)D]; when 25(OH)D at all 4 ages was included in the same model, the concentration at age 6 y remained significant. Males in the "consistently higher" trajectory had 3.2-3.4% higher total body BMC and BMD than those who were in the "consistently lower" trajectory, accounting for age and anthropometric and lifestyle factors. Conclusions: Within both sexes, there are moderate associations between vitamin D status measured in prepuberty, adolescence, and early adulthood. Vitamin D status in childhood is a significant predictor of peak bone mass in male but not female subjects., (© 2017 American Society for Nutrition.)

Low BMI is a risk factor for osteoporosis, but it is not clear if relationships between BMI, lean mass (LM), fat mass (FM) and BMD are consistent across different levels of BMI. We studied 1929 Caucasian participants (1014 females) aged 45-66years in the Busselton Healthy Ageing Study in Western Australia. Body composition and BMD of total body, lumbar spine, total hip and femoral neck were measured using DXA. From generalized additive models, the positive relationships between BMI and BMD were weaker at high BMI, particularly at the spine and in males. In the entire cohort, adjusting for relevant covariates, LM and FM were significant predictors of all BMD measures in both genders. In men, analysis by tertiles of BMI showed that LM and FM (in kg) were positively associated with BMD (in mg/cm(2)) in tertile 1 except for LM and spine BMD (LM β: 5.18-6.80, FM β: 3.38-9.24, all P<0.05), but not in the middle or upper tertiles (LM β: -3.12-3.07, FM β: -4.75-1.82, P>0.05). In women, LM was positively associated with BMD in each tertile of BMI, except for spine BMD in the upper tertile, with regression coefficients lower in the upper tertile (β: 5.16-9.95, 5.76-9.56 and 2.80-5.78, respectively, all P<0.05). FM was positively associated with total body, spine and total hip BMD in women in BMI tertile 1 (β: 2.86-6.68, P<0.05); these associations were weaker or absent in the middle and upper tertiles. In conclusion, in middle-aged adults the positive relationships between lean or fat mass with BMD among those with higher BMI are absent in males and weaker in females., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged > 55 years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey–Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey–Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han–Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p < 5 × 10− 8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p = 4.6 × 10− 8. However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% CI: 0.98–1.14; p = 0.17), displaying high degree of heterogeneity (I2 = 57%; Qhet p = 0.0006). Under Han–Eskin alternative random effects model the summary effect was significant (p = 0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size > 1.25) may still be consistent with an effect size < 1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.

It is uncertain whether the vitamin D status of pregnant women influences bone mass of their children. Cohort studies have yielded conflicting results; none have examined offspring at skeletal maturity. This longitudinal, prospective study investigated the association between maternal vitamin D status and peak bone mass of offspring in 341 mother and offspring pairs in the Western Australian Pregnancy Cohort (Raine) Study. Maternal serum samples collected at 18 weeks gestation were assayed for 25-hydroxyvitamin D (25OHD). Outcomes were total body bone mineral content (BMC) and bone mineral density (BMD) measured by dual-energy X-ray absorptiometry in offspring at 20 years of age. The mean (± SD) maternal serum 25OHD concentration was 57.2 ± 19.2 nmol/L; 132 women (38.7%) were vitamin D-deficient (25OHD <50 nmol/L). After adjustment for season of sample collection, maternal factors, and offspring factors (sex, birth weight, and age, height, lean mass, and fat mass at 20 years), maternal 25OHD concentration was positively associated with total body BMC and BMD in offspring, with a mean difference of 19.2 (95% confidence interval [CI], 5.6-32.7) g for BMC and 4.6 (95% CI, 0.1-9.1) mg/cm(2) for BMD per 10.0 nmol/L of maternal 25OHD. Maternal vitamin D deficiency was associated with 2.7% lower total body BMC (mean ± SE) (2846 ± 20 versus 2924 ± 16 g, p = 0.004) and 1.7% lower total body BMD (1053 ± 7 versus 1071 ± 5 mg/cm(2) , p = 0.043) in the offspring. We conclude that vitamin D deficiency in pregnant women is associated with lower peak bone mass in their children. This may increase fracture risk in the offspring in later life., (© 2014 American Society for Bone and Mineral Research.)

Objective: To observe the influence on adjacent lumbar bone density after strengthening of T12, L1 segment vertebral osteoporotic compression fracture by percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP) in postmenopausal female., Methods: Between January 2008 and June 2011, 59 patients with T12, L1 segment thoracolumbar osteoporotic compression fracture were treated with PVP in 29 cases (PVP group) and PKP in 30 cases (PKP group), who were in accordance with the inclusion and exclusion criteria. No significant difference was found in gender, duration of menopause, disease druation, causes of injury, fractured vertebral body, and vertebral fracture classification between 2 groups (P > 0.05). The kyphosis Cobb angle of surgical area was measured at preoperation, 1 week after operation, and last follow-up; the lower three lumbar spine bone mineral density (BMD) of the surgical area, the femoral neck BMD, and body mass index (BMI) of patients were measured at perioperative period and last follow-up to find out the statement of anti-osteoporosis; FRAX online tools were used to evaluate the probability of major osteoporotic fracture and hip fracture of the next 10 years., Results: The average follow-up was 25.5 months (range, 12-48 months) in 2 groups. There was significant difference in kyphosis Cobb angle of T12, L1 between preoperation and last follow-up in 2 groups (P < 0.05); the Cobb angle of PKP group was significantly less than that of PVP group at 1 week after operation and last follow-up (P < 0.05). No significant difference was found in BMI between 2 groups, and between perioperative period and last follow-up in the same group (P > 0.05). The lower three lumbar spine BMD of the surgical area and its T value at last follow-up was improved significantly when compared with BMD at perioperative period (P < 0.05); there was no significant difference in the lower three lumbar spine BMD and its T value between 2 groups at perioperative period (P > 0.05), but significant difference was found between two groups at last follow-up (P < 0.05). Difference was not significant in the femoral neck BMD and its T value between 2 groups, and between perioperative period and last follow-up in the same group (P > 0.05). The probability of major osteoporotic fracture and hip fracture of the next 10 years was not significantly different between 2 groups and between perioperative period and last follow-up in the same group (P > 0.05)., Conclusion: The increased BMD of adjacent lumbar spine can improve the strength of the vertebral body and reduce the incidence of adjacent vertebral fracture in patients with T12, L1 segment vertebral osteoporotic compression fracture after PVP/PKP, and PKP is superior to PVP increasing BMD of adjacent lumbar spine.

Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10(-5) ; female effect = -0.007 and p = 3.3 × 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. © 2012 American Society for Bone and Mineral Research., (Copyright © 2012 American Society for Bone and Mineral Research.)

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

Background: Two major factors associated with skeletal fracture in older persons are intrinsic bone strength and risk of falling. This study examined the role of Timed Up and Go (TUG) test performance, a validated predictor of falling, and hip areal bone mineral density (BMD), a validated predictor of bone strength in fracture prediction in a 10-year longitudinal study., Methods: The study participants were 1126 women (mean [SD] age at baseline, 75.0 [2.6] years) living in Perth, Western Australia. Assessments included TUG test at baseline and dual-energy x-ray absorptiometry total hip areal BMD measurement at year 1. Incident clinical osteoporotic fracture over 10 years was confirmed by radiographic records. Complete incident hip fracture data were obtained from a hospital morbidity database., Results: One-third (32.7%) of participants had slow TUG test performance (>10.2 seconds), and 54.2% of participants had low hip areal BMD (T-score of less than -1). Relative to risks among participants having normal TUG test performance and normal BMD, risks of nonvertebral fracture and hip fracture were significantly higher among participants who had slow TUG test performance and normal hip BMD (nonvertebral fracture hazard ratio [HR], 1.84; hip fracture HR, 2.48) or both slow TUG test performance and low hip BMD (nonvertebral fracture HR, 2.51; hip fracture HR, 4.68). For nonvertebral fracture and hip fracture, the population-attributable risks of slow TUG test performance with normal hip BMD were 19.3% and 32.3%, of normal TUG test performance with low hip BMD were 31.3% and 50.3%, and of both slow TUG test performance and low hip BMD were 30.1% and 55.9%, respectively., Conclusion: TUG test performance is an independent risk factor for incident nonvertebral fracture and a feasible inexpensive physical performance assessment for use in clinical practice to screen patients with increased risk of fracture.

To assess the association between protein intakes and bone mass accrual in girls, data were analysed for 757 pre-pubertal girls (mean age 10.1 years) in urban Beijing, China, who participated in a 5-year study including 2 years of milk supplementation (intervention groups only) and 3 years of follow-up study. At 0, 12, 24, 48 and 60 months from the baseline, bone mass of the proximal or distal forearm (PF or DF) and total body (TB) was measured with dual energy X-ray absorptiometry; dietary intakes were assessed by a 3-d food record (including two weekdays and one weekend day). Linear mixed models were used and continuous variables were logarithm transformed. The mean longitudinal Ca intake (432-675 mg/d on average) positively influenced bone mineral content (BMC) at TB, PF and DF after controlling for baseline bone mass and other possible confounders. However, negative associations were observed between protein intake (55.9-61.0 g/d on average) and BMC accrual at TB, PF or DF (beta = - 1.92, - 10.2 or - 4.82, respectively, P < 0.01) after adjustment. When protein intake was considered according to animal or plant food sources, protein from animal foods, particularly meat, had significant negative effects on BMC accrual at DF or PF after adjustment. It was concluded that higher protein intake, especially from animal foods, appeared to have a negative effect on bone mass accrual in Chinese pubertal girls with low Ca intakes.

Long-term effects of high dietary protein intake on muscle and bone structure in the elderly are not clear. The aim of this study was to investigate the relationship between baseline protein intake and lean mass and BMC 5 yr later in a cohort of elderly postmenopausal women. A total of 862 community-dwelling women 75 +/- 3 yr of age provided baseline data including nutrient intake assessed by a food frequency questionnaire. At 5 yr, upper arm muscle area (UAMA) and body composition using DXA were measured. Baseline protein intake was 81 +/- 28 g/d (1.2 +/- 0.4 g/kg/d), contributing 19 +/- 3% of total energy intake. There were positive correlations between baseline protein intake and whole body and appendicular bone-free lean mass and BMC (r = 0.14-0.18, p < 0.001) and UAMA (r = 0.08, p < 0.05). Compared with those in the lowest tertile of protein intake (<66 g/d), women in the top tertile (>87 g/d) had 5.4-6.0% higher whole body and appendicular lean mass and UAMA and 5.3-6.0% higher whole body and appendicular BMC. These effects remained after adjusting for potential confounders. However, the effect on BMC disappeared after further adjustment for lean mass. This study shows that high protein intake is associated with long-term beneficial effects on muscle mass and size and bone mass in elderly women. The protein effect on bone may be partly mediated by its effects on muscle.

Our goal in this cross-sectional study was to investigate the influence of low-vitamin D status on bone mass, bone turnover, and muscle strength in 301 healthy Chinese adolescent girls. Blood plasma 25-hydroxyvitamin D [25(OH)D] was measured by RIA and plasma and urine biomarkers of bone turnover were measured. Bone mineral content (BMC) and density and bone area for the whole body and the distal and proximal forearm were measured by dual energy X-ray absorptiometry. When vitamin D deficiency was defined as a serum 25(OH)D concentration of < or =50 nmol/L and severe deficiency as <25 nmol/L, 57.8% of subjects were vitamin D deficient and 31.2% were severely deficient. Multivariate analysis shows that girls with adequate vitamin D status had higher size-adjusted BMC for the whole body (P < 0.001), distal forearm (P < 0.001), and proximal forearm (P < 0.01) than those with poorer vitamin D status after adjusting for body size, handgrip strength, physical activity, and dietary intakes of calcium and vitamin D. Similar results were also found for handgrip muscle strength. Participants with adequate vitamin D status had significantly lower concentrations of bone alkaline phosphatase in plasma and deoxypyridinoline:creatinine ratio in urine compared with those of the vitamin D-deficient girls. Adolescent girls with adequate vitamin D status had significantly higher bone mass and muscle strength compared with those with poor vitamin D status. This may be attributed in part to a lower rate of bone remodeling with adequate vitamin D status. These findings suggest that adequate vitamin D status during adolescence is important for optimizing bone mass, which may lead to higher peak bone mass at maturity. Poor vitamin D status also compromises forearm muscle strength.

Unlabelled: There are few longitudinal data on bone development during puberty in children with low calcium intake. This 5-yr longitudinal study showed that, in Chinese girls, the mean apparent calcium retention efficiency during puberty was 40.9%, PHV occurred at 3-0 yr before menarche, and peak bone mineral accretion occurred 1 yr later than PHV. Chinese girls have high calcium retention efficiency during puberty., Introduction: There are few longitudinal data on bone development during puberty in children with low dietary calcium intake. The aim of this study was to examine the rate of growth and bone mineral accretion and study the predictors of total body BMC during puberty in a 5-yr longitudinal study with Chinese girls., Materials and Methods: Ninety-two girls, 9.5-10.5 yr of age at baseline, from the unsupplemented control group of a school milk intervention trial were included in this analysis. Data on anthropometric measurements, total body BMC as assessed by DXA, and calcium intake as assessed by a 3-day food record were obtained at baseline and 1, 2, 4, and 5 yr., Results: The mean age of menarche was 12.1 +/- 1.0 yr. The mean annual rate of bone mineral accretion was 197.4 g/yr during the follow-up period, representing a calcium accretion rate of 162.3 mg/d. This calcium retention rate and the average dietary calcium intake of 444.1 mg/d gave an apparent calcium retention efficiency of 40.9%. Peak height velocity (PHV) occurred at 3-0 yr before menarche. Peak bone mineral accretion occurred 1 yr later than PHV. There was a decrease in size-corrected BMD in the year before menarche. In the linear mixed-effects model analysis containing body size and lifestyle factors, we found that height, body weight, and calcium intake were significant independent predictors of total body BMC., Conclusions: Chinese girls with low habitual dietary calcium intake have high calcium retention efficiency during puberty. Because calcium intake is a significant predictor of total body BMC, increasing dietary calcium intake may have beneficial effects on bone mineral accretion in these girls.

Much existing data on the effects of calcium or milk products on bone mineral accretion are based on bone mineral content (BMC) or areal bone mineral density (aBMD), neither of which accounts for changing bone size during the growing period. The aim of this study was to investigate the effects of 2-year milk supplementation on total body size-corrected BMD in Chinese girls with low habitual dietary calcium intake. Chinese girls aged 10 years were randomised, according to their school, to receive calcium fortified milk (Ca milk), or calcium and vitamin D fortified milk (CaD milk) for two years or act as unsupplemented controls. Dual-energy X-ray absorptiometry total body bone measures were obtained from 345 girls at baseline and 2 years. Size-corrected total body and regional BMD was calculated as: BMDsc = BMC/BApc, where pc was the regression coefficient of the natural logarithm transformed total body BMC and bone area. After 2 years, both supplemented groups had significantly greater gain in BMDsc of total body (3.5-5.8%, p < 0.05) and legs (3.0-5.9%, p < 0.05) than did the control group. Milk supplementation showed positive effects on bone mineral accretion when accounting for the changing skeletal size during growth. The effects were mainly on the lower limbs.

The aim of the present study was to determine association between body composition, muscle strength, diet and physical exercise with bone mineral content (BMC) and bone area (BA) in 283 Chinese adolescent girls aged 15 years in Beijing, China. Body composition, pubertal stage, physical activity and dietary intakes were assessed using standard validated protocols. Total body and forearm bone, lean body mass (LBM) and fat body mass (FBM) were determined by dual X-ray absorptiometry. Multivariate linear regression analyses were carried out to examine the predictors of BMC and BA, after controlling for potential confounders. The subjects had a mean age of 15.0 (sd 0.9) years and 99.6 % of them had reached menarche. Multivariate analyses showed that LBM, FBM, handgrip muscle strength and milk intake were significant independent determinants of BMC and BA of the total body and/or forearm sites. LBM was found to be a stronger independent determinant than FBM of BMC and BA, whereas handgrip muscle strength was only found as significant determinant of BMC and BA at the forearm sites than in total body BMC and BA. Further, total physical activity level had a significant positive association with handgrip and LBM. This suggested that greater muscle strength and higher LBM may reflect higher levels of physical activity. Therefore, continuous healthy lifestyle practices such as adequate intake of milk and continuous participation in physical activity should be encouraged throughout adolescence to optimise bone growth during this period.

Background: A 2-y school milk intervention trial showed that 330 mL of a dietary milk supplement (fortified with calcium alone or with both calcium and vitamin D) enhanced the growth and bone mineral accretion of Chinese girls aged 10 y at baseline. Girls who received milk fortified with both calcium and vitamin D also had better vitamin D status than did girls who received nothing or girls who received milk fortified only with calcium., Objective: The aim was to evaluate whether these effects were sustained 3 y after supplement withdrawal., Design: Anthropometric measures and dietary intake were reassessed in 501 of the 698 girls whose data had been studied at the end of the intervention. As in the intervention phase, total-body bone mineral content and bone mineral density and serum 25-hydroxyvitamin D concentrations were measured in half of these subjects., Results: At follow-up, 99% of girls had reached menarche, at a mean (+/-SD) menarcheal age of 12.1 +/- 1.1 y. No significant differences in the timing of menarche were observed between the 3 groups (P = 0.6). No significant differences in the changes of total-body bone mineral content and bone mineral density since baseline were observed between the groups. The group receiving calcium-fortified milk had significantly greater gains in sitting height (0.9 +/- 0.3%; P = 0.02) than did the control group. The group that received calcium- and vitamin D-fortified milk had 17.1 +/- 6.7% lower serum 25-hydroxyvitamin D concentrations than did the control group (P = 0.04), but the difference was attenuated by additional adjustment for physical activity level (14.2 +/- 6.7%; P = 0.08)., Conclusion: Milk supplementation during early puberty does not have long-lasting effects on bone mineral accretion.

A 2-year milk intervention trial was carried out with 757 girls, aged 10 years, from nine primary schools in Beijing (April 1999 - March 2001). Schools were randomised into three groups: group 1, 238 girls consumed a carton of 330 ml milk fortified with Ca on school days over the study period; group 2, 260 girls received the same quantity of milk additionally fortified with 5 or 8 microg cholecalciferol; group 3, 259 control girls. Anthropometric and bone mineralisation measurements, as well as dietary, health and physical-activity data, were collected at baseline and after 12 and 24 months of the trial. Over the 2-year period the consumption of this milk, with or without added cholecalciferol, led to significant increases in the changes in height (> or =0.6 %), sitting height (> or =0.8 %), body weight (> or 2.9 %), and (size-adjusted) total-body bone mineral content (> or =1.2 %) and bone mineral density (> or =3.2 %). Those subjects receiving additional cholecalciferol compared with those receiving the milk without added 25-hydoxycholecalciferol had significantly greater increases in the change in (size-adjusted) total-body bone mineral content (2.4 v. 1.2 %) and bone mineral density (5.5 v. 3.2 %). The milk fortified with cholecalciferol significantly improved vitamin D status at the end of the trial compared with the milk alone or control groups. It is concluded that an increase in milk consumption, e.g. by means of school milk programmes, would improve bone growth during adolescence, particularly when Ca intake and vitamin D status are low.

Apolipoprotein ɛ4 (APOE ɛ4) may be a genetic risk factor for reduced bone mineral density (BMD) and muscle function, which could have implications for fall and fracture risk. We examined the association between APOE ɛ4 status and long-term fall- and fracture-related hospitalization risk in older women. A total of 1 276 community-dwelling women from the Perth Longitudinal Study of Aging Women (mean age ±  SD  = 75.2 ± 2.7 years) were included. At baseline, women underwent APOE genotyping and detailed phenotyping for covariates including prevalent falls and fractures, as well as health and lifestyle factors. The association between APOE ɛ4 and fall-, any fracture-, and hip fracture-related hospitalizations, obtained over 14.5 years from linked health records, was examined using multivariable-adjusted Cox-proportional hazard models. Over 14.5 years, 507 (39.7%) women experienced a fall-related hospitalization and 360 (28.2%) women experienced a fracture-related hospitalization, including 143 (11.2%) attributed to a hip fracture. In multivariable-adjusted models, compared to noncarriers, APOE ɛ4 carriers (n  = 297, 23.3%) had greater risk for a fall- (hazard ratio [HR] 1.48, 95% CI: 1.22–1.81), fracture- (HR 1.28, 95% CI: 1.01–1.63), or hip fracture-related hospitalization (HR 1.83, 95% CI: 1.29–2.61). The estimates remained similar when specific fall and fracture risk factors (fear of falling, plasma 25-hydroxyvitamin D, grip strength, timed up-and-go, hip BMD, vitamin K status, prevalent diabetes, HbA1c, cholesterol, and abbreviated mental test score) were added to the multivariable model. In conclusion, APOE ɛ4 is a potential risk factor for fall- and fracture-related hospitalization in community-dwelling older women. Screening for APOE ɛ4 could provide clinicians an opportunity to direct higher-risk individuals to appropriate intervention strategies. [ABSTRACT FROM AUTHOR]

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

Osteoporosis is a disease that is characterised by reduced bone mineral density (BMD) and can be exacerbated by the excessive bone resorption of osteoclasts (OCs). Bioinformatic methods, including functional enrichment and network analysis, can provide information about the underlying molecular mechanisms that participate in the progression of osteoporosis. In this study, we harvested human OC-like cells differentiated in culture and their precursor peripheral blood mononuclear cells (PBMCs) and characterised the transcriptome of the two cell types using RNA-sequencing in order to identify differentially expressed genes. Differential gene expression analysis was performed in RStudio using the edgeR package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to identify enriched GO terms and signalling pathways, with inter-connected regions characterised using protein–protein interaction analysis. In this study, we identified 3201 differentially expressed genes using a 5% false discovery rate; 1834 genes were upregulated, whereas 1367 genes were downregulated. We confirmed a significant upregulation of several well-established OC genes including CTSK, DCSTAMP, ACP5, MMP9, ITGB3, and ATP6V0D2. The GO analysis suggested that upregulated genes are involved in cell division, cell migration, and cell adhesion, while the KEGG pathway analysis highlighted oxidative phosphorylation, glycolysis and gluconeogenesis, lysosome, and focal adhesion pathways. This study provides new information about changes in gene expression and highlights key biological pathways involved in osteoclastogenesis. [ABSTRACT FROM AUTHOR]

Context The skeletal effects of vitamin D remain controversial and it is uncertain whether variation in serum 25-hydroxyvitamin D (25OHD) levels over time influences bone mineral density (BMD). Objective We evaluated longitudinal stability of serum 25OHD and associations with changes in BMD in participants aged 46-70 years at baseline. Methods We studied 3698 Busselton Healthy Ageing Study participants (2040 female) with serum 25OHD and dual-energy x-ray absorptiometry (DXA) BMD assessments at baseline and at ∼6 years follow-up. Restricted cubic splines were used to evaluate associations between changes in 25OHD and BMD. Results Mean season-corrected serum 25OHD was 81.3 ± 22.7 and 78.8 ± 23.1 nmol/L at baseline and 6 years, respectively, and showed moderate correlation (intraclass correlation coefficient: 0.724). Significant predictors of change in 25OHD concentration (Δ25OHD) included baseline 25OHD, change in body mass index and vitamin D supplementation at follow-up. Greater decline in serum 25OHD over time was associated with significantly greater reduction in BMD at total hip and femoral neck, but the magnitude of the differences was small (estimated differences 0.004 g/cm2 and 0.005-0.007 g/cm2, respectively, for lowest quartile of Δ25OHD compared with higher quartiles, adjusted for sex, baseline BMD, 25OHD, and demographics). No significant associations between Δ25OHD and lumbar spine BMD were observed. Increase in 25OHD levels was not associated with change in BMD. Conclusions In this predominantly vitamin D–replete middle-aged cohort, serum 25OHD showed moderate longitudinal stability. Declining serum 25OHD over time was associated with greater reduction in BMD at the total hip and femoral neck. [ABSTRACT FROM AUTHOR]

This study aimed to examine metabolites in the plasma derived from postmenopausal women by untargeted metabolomics along with possible diagnostic markers for osteoporosis. From March 2020 through June 2020, 30 postmenopausal women with normal bone mineral density (BMD) were recruited in the N group, 30 postmenopausal women with postmenopausal osteoporosis were recruited in the postmenopausal osteoporosis (PMO) group, and 30 postmenopausal women with rheumatoid arthritis osteoporosis were recruited in the rheumatoid arthritis osteoporosis (RAOP) group. The height, weight, body mass index (BMI), total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), lumbar BMD, hip BMD, femoral neck BMD, and plasma metabolite levels were measured. Seven differential metabolites were observed between the PMO and N groups and recorded as metabolite set 1, and 38 differential metabolites were found between the RAOP and N groups and recorded as metabolite set 2. Six same metabolites were found between these two metabolite sets. The area under the curve (AUC) of the combined receiver operating characteristic (ROC) curves for the six metabolites was 0.900. In this study, six metabolites with a diagnostic value for osteoporosis were found in the plasma of postmenopausal women, and the combined diagnosis efficiency of these six metabolites was high. [ABSTRACT FROM AUTHOR]

Background: Adolescents have a higher consumption of sugar-sweetened beverages (SSBs) than other age groups, but little is known of the impact of SSB intake during adolescence on body composition and bone mass in early adulthood.Objectives: Associations of SSB intake from 14 to 20 y with fat, lean, and bone mass at 20 y of age were evaluated.Methods: Study participants were 1137 offspring (562 females) from the Raine Study. Food intake, including SSB consumption in servings/d (1 serving = 250 mL), was estimated using FFQs at 14, 17, and 20 y of age. DXA scanning at 20 y measured whole body fat mass, lean mass, and bone mineral content (BMC). Using latent class growth analysis, 4 SSB intake trajectory classes were identified: consistently low (n = 540, intakes mostly <0.5 serving/d), increasing (n = 65), decreasing (n = 258), and consistently high (n = 274, intakes mostly >1.3 servings/d).Results: Median total SSB intake was 0.8, 0.7, and 0.5 serving/d, and median carbonated SSB intake was 0.3, 0.3, and 0.4 serving/d at 14, 17, and 20 y, respectively. Mean ± SD BMI (in kg/m2) was 23.9 ± 4.2 at 20 y. After adjustment for covariates including sex, demographic, energy intake, and maternal factors, individuals with "consistently high" SSB consumption had significantly higher total body fat mass at 20 y than those with "consistently low" consumption (23.3 ± 0.6 compared with 21.2 ± 0.4 kg, P = 0.004), which remained significant after further adjustment for "Healthy" and "Western" dietary patterns (23.2 ± 0.6 compared with 21.2 ± 0.4 kg, P = 0.011). No significant associations were observed between SSB intake trajectory classes and lean body mass or BMC at 20 y.Conclusions: In this cohort, consistently higher consumption of SSBs in adolescence and early adulthood are associated with increased fat mass but not with bone mass at 20 y of age. [ABSTRACT FROM AUTHOR]

In older adults, high-normal circulating cortisol levels are associated with lower bone mass, but relationships between hypothalamic–pituitary–adrenal axis function and peak bone mass in young adults have not been examined. We studied 411 male and 390 female participants in the Western Australia Pregnancy Cohort (Raine) Study. At 18 years of age, participants underwent a Trier Social Stress Test (TSST) with measurement of plasma and salivary cortisol at baseline and at multiple time points after stress. Cortisol responses were classified as anticipatory responder (significant fall in cortisol during the test), reactive responder (significant increase) or non-responder. At 20 years, total body bone mineral content (BMC) and density (BMD) were measured by DXA. In males, after adjustment for weight, height (for BMC and bone area only), alcohol and smoking, there was a significant inverse relationship between both plasma and salivary cortisol measured at baseline in the TSST and each of BMC and BMD, such that each additional 10% of salivary cortisol was associated with reductions of 6.9 g (95% CI − 11.7, − 2.2) in BMC, and 1.8 mg/cm 2 (95% CI − 3.3, − 0.4) in BMD. Males classified as anticipatory responders in the TSST had 3.2% lower BMC (adjusted mean ± SE: 3131 ± 28 vs. 3233 ± 18 g, P = 0.006) and 2.5% lower BMD (1108 ± 9 vs. 1136 ± 6 mg/cm 2 , P = 0.022) than reactive responders. In females, there were no significant relationships between baseline cortisol or TSST responses and BMC or BMD in covariate-adjusted analyses. We conclude that in young males (but not females), higher circulating cortisol at the baseline of the stress test and an anticipatory responder pattern on the TSST are associated with lower total body bone mass. [ABSTRACT FROM AUTHOR]