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Purpose: To review the rising prevalence of osteopenia and osteoporosis in sub-Saharan Africa and the challenges this poses to governments and healthcare services. Using existing studies, we compare the prevalence of osteopenia and osteoporosis in men and women from sub-Saharan Africa to US and UK cohorts. Context-specific disparities in healthcare are discussed particularly the challenges in diagnosis and treatment of osteoporosis. Recent Findings: There are few epidemiological data describing the burden of osteoporosis in sub-Saharan Africa. In the studies and cohorts presented here, osteoporosis prevalence varies by sex, country and area of residence, but is generally higher in African populations, than has previously been appreciated. Risk factors contributing to poorer bone health include HIV, malnutrition and “inflammaging.” Summary: Reprioritization towards care of ageing populations is urgently required. Equitable access to implementable preventative strategies, diagnostic services, treatments and pathways of care for bone health (for example embedded within HIV services) need now to be recognized and addressed by policy makers.

Anabolic treatment options for osteoporosis remain limited. One approach to discovering novel anabolic drug targets is to identify genetic causes of extreme high bone mass (HBM). We investigated a pedigree with unexplained HBM within the UK HBM study, a national cohort of probands with HBM and their relatives. Whole exome sequencing (WES) in a family with HBM identified a rare heterozygous missense variant (NM_004482.4:c.1657C>T, p.Arg553Trp) in GALNT3, segregating appropriately. Interrogation of data from the UK HBM study and the Anglo-Australasian Osteoporosis Genetics Consortium (AOGC) revealed an unrelated individual with HBM with another rare heterozygous variant (NM_004482.4:c.831T>A, p.Asp277Glu) within the same gene. In silico protein modelling predicted that p.Arg553Trp would disrupt salt-bridge interactions, causing instability of GALNT3; and that p.Asp277Glu would disrupt manganese binding and consequently GALNT3 catalytic function. Bi-allelic loss-of-function GALNT3 mutations alter FGF23 metabolism, resulting in hyperphosphatemia and causing familial tumoral calcinosis (FTC). However, bone mineral density (BMD) in FTC cases, when reported, has been either normal or low. Common variants in the GALNT3 locus show genome-wide significant associations with lumbar, femoral neck, and total body BMD. However, no significant associations with BMD are observed at loci coding for FGF23, its receptor FGFR1, or co-receptor klotho. Mendelian randomization analysis, using expression quantitative trait loci (eQTL) data from primary human osteoblasts and GWAS data from UK Biobank, suggested increased expression of GALNT3 reduces total body, lumbar spine and femoral neck BMD but has no effect on phosphate concentrations. In conclusion, rare heterozygous loss-of-function variants in GALNT3 may cause HBM without altering phosphate concentration. These findings suggest that GALNT3 may affect BMD through pathways other than FGF23 regulation, identification of which may yield novel anabolic drug targets for osteoporosis.

HIV infection has multi-system adverse effects in children, including on the growing skeleton. We aimed to determine the association between chronic HIV infection and bone architecture (density, size, strength) in peripubertal children. We conducted a cross-sectional study of children aged 8 to 16 years with HIV (CWH) on antiretroviral therapy (ART) and children without HIV (CWOH) recruited from schools and frequency-matched for age strata and sex. Outcomes, measured by tibial peripheral quantitative computed tomography (pQCT), included 4% trabecular and 38% cortical volumetric bone mineral density (vBMD), 4% and 38% cross-sectional area (CSA), and 38% stress-strain index (SSI). Multivariable linear regression tested associations between HIV status and outcomes, stratified by sex and puberty (Tanner 1-2 versus 3-5), adjusting for age, height, fat mass, physical activity, and socioeconomic and orphanhood statuses. We recruited 303 CWH and 306 CWOH; 50% were female. Although CWH were similar in age to CWOH (overall mean ± SD 12.4 ± 2.5 years), more were prepubertal (ie, Tanner 1; 41% versus 23%). Median age at ART initiation was 4 (IQR 2-7) years, whereas median ART duration was 8 (IQR 6-10) years. CWH were more often stunted (height-for-age Z-score

Monogenic high bone mass (HBM) disorders are characterized by an increased amount of bone in general, or at specific sites in the skeleton. Here, we describe 59 HBM disorders with 50 known disease-causing genes from the literature, and we provide an overview of the signaling pathways and mechanisms involved in the pathogenesis of these disorders. Based on this, we classify the known HBM genes into HBM (sub)groups according to uniform Gene Ontology (GO) terminology. This classification system may aid in hypothesis generation, for both wet lab experimental design and clinical genetic screening strategies. We discuss how functional genomics can shape discovery of novel HBM genes and/or mechanisms in the future, through implementation of omics assessments in existing and future model systems. Finally, we address strategies to improve gene identification in unsolved HBM cases and highlight the importance for cross-laboratory collaborations encompassing multidisciplinary efforts to transfer knowledge generated at the bench to the clinic. (c) 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Hip fractures are a major cause of morbidity and mortality in the elderly, and incur high health and social care costs. Given projected population ageing, the number of incident hip fractures is predicted to increase globally. As fracture classification strongly determines the chosen surgical treatment, differences in fracture classification influence patient outcomes and treatment costs. We aimed to create a machine learning method for identifying and classifying hip fractures, and to compare its performance to experienced human observers. We used 3659 hip radiographs, classified by at least two expert clinicians. The machine learning method was able to classify hip fractures with 19% greater accuracy than humans, achieving overall accuracy of 92%.

Additional File Table 1: Different contraceptive methods by menopause status in women living with and without HIV

Additional File Table 2: Multivariate model for factors associated with moderate and/or severe menopausal symptoms in Zimbabwean women living in Harare

The UKRI Medical Research Council National Musculoskeletal Ageing Network (Director: Professor Cyrus Cooper and Deputy-Director: Professor Nicholas Harvey) brings together, over a 2-year period, key UKRI MRC investments in musculoskeletal research: the MRC Lifecourse Epidemiology Centre, MRC-Versus Arthritis Centre for Integrated Research in Musculoskeletal Ageing (CIMA), MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research (CMAR), MRC Epidemiology Unit, MRC Integrative Epidemiology Unit, and MRC Unit for Lifelong Health and Ageing. Together, these span the Universities of Southampton, Sheffield, Liverpool, Newcastle, Nottingham, Birmingham, Oxford, Bristol, Cambridge, and UCL, with further links to associated NIHR Biomedical Research Centres. This multidisciplinary collaboration will underpin a step change in musculoskeletal ageing research capacity and strategy (principally across the diseases osteoporosis, osteoarthritis, sarcopenia, and rheumatoid arthritis) by identifying key tractable research priorities; developing an integrated multidisciplinary and diversified technology partnership to address the identified research gaps; providing a platform to disseminate best practice; supporting early and mid-career researchers to build research capacity and develop technical expertise to ensure longevity to current UKRI investments; prosecuting an ongoing programme of innovative studies from discovery science to clinical impact.In this editorial, we briefly set out perspectives on the current landscape and identify research priorities fundamental to achieving healthy musculoskeletal ageing, as articulated and agreed at a scoping workshop of the Network held at the Academy of Medical Sciences, London, UK, on June 17, 2022.

Objectives Observational analyses suggest that high bone mineral density (BMD) is a risk factor for osteoarthritis (OA); it is unclear whether this represents a causal effect or shared aetiology and whether these relationships are body mass index (BMI)-independent. We performed bidirectional Mendelian randomization (MR) to uncover the causal pathways between BMD, BMI and OA. Methods One-sample (1S)MR estimates were generated by two-stage least-squares regression. Unweighted allele scores instrumented each exposure. Two-sample (2S)MR estimates were generated using inverse-variance weighted random-effects meta-analysis. Multivariable MR (MVMR), including BMD and BMI instruments in the same model, determined the BMI-independent causal pathway from BMD to OA. Latent causal variable (LCV) analysis, using weight-adjusted femoral neck (FN)–BMD and hip/knee OA summary statistics, determined whether genetic correlation explained the causal effect of BMD on OA. Results 1SMR provided strong evidence for a causal effect of BMD estimated from heel ultrasound (eBMD) on hip and knee OA {odds ratio [OR]hip = 1.28 [95% confidence interval (CI) = 1.05, 1.57], p = 0.02, ORknee = 1.40 [95% CI = 1.20, 1.63], p = 3 × 10–5, OR per standard deviation [SD] increase}. 2SMR effect sizes were consistent in direction. Results suggested that the causal pathways between eBMD and OA were bidirectional (βhip = 1.10 [95% CI = 0.36, 1.84], p = 0.003, βknee = 4.16 [95% CI = 2.74, 5.57], p = 8 × 10–9, β = SD increase per doubling in risk). MVMR identified a BMI-independent causal pathway between eBMD and hip/knee OA. LCV suggested that genetic correlation (i.e. shared genetic aetiology) did not fully explain the causal effects of BMD on hip/knee OA. Conclusions These results provide evidence for a BMI-independent causal effect of eBMD on OA. Despite evidence of bidirectional effects, the effect of BMD on OA did not appear to be fully explained by shared genetic aetiology, suggesting a direct action of bone on joint deterioration.

IntroductionHip fractures are devastating injuries which incur high healthcare costs. Despite national standards and guidelines, there is substantial variation in hospital delivery of hip fracture care and in patient outcomes. This study aimed to understand organisational processes that facilitate successful delivery of hip fracture services.Methods Forty qualitative interviews were conducted with healthcare professionals involved in delivering hip fracture care at four English hospitals. Interview data were supplemented with documentary analysis of 23 anonymised British Orthopaedic Association hospital-initiated peer-review reports of services. Data were analysed thematically, with themes transposed onto key components of the care pathway. ResultsWe identified multiple aspects of service organisation that facilitated good care delivery. At admission, standardisation of training in nerve block administration impacted care delivery. During hospital stays, service delivery was improved by integrated, shared-care between orthopaedics and orthogeriatrics, and by strategies to improve trauma list efficiency. Adequately staffed orthogeriatric services and the ‘right’ skills and seniority mix were important to holistic care provision. Placing patients on designated hip fracture wards concentrated staff expertise. Collaborative working was achieved through multi-disciplinary team (MDT) meetings between key staff, protocols and care pathways that defined roles and responsibilities, MDT documentation, ‘joined-up’ IT systems within hospitals and with primary care, and shared working spaces such as shared offices and on wards. Trauma and hip fracture coordinators organised care processes and provided a valuable central point of contact within teams. Nominated leads, representing diverse specialties, worked together in MDT planning meetings to develop joint protocols, establish audit priorities, and agree shared goals. Routine, comprehensive monitoring and evaluation of service delivery, with findings shared throughout the MDT, was beneficial. ConclusionsOur study has characterised potentially modifiable elements of successful hip fracture service delivery. Findings are intended to help services overcome organisational barriers towards delivery of high-quality hip fracture services.

IntroductionOlder adults who sustain a hip fracture require complex multidisciplinary care, which can challenge organisational structures within hospitals. Despite standards and guidelines, substantial variation remains in hip fracture care delivery across the UK. We aimed to determine which hospital-level organisational factors predict adverse patient outcomes in the post injury period.Methods A cohort of 178,757 patients aged 60+ years in England and Wales (2016-19) who sustained a hip fracture was examined. Patient-level Hospital Episodes Statistics, National Hip Fracture Database, and mortality data were linked to metrics from 18 hospital-level organisational audits/reports/series. Multilevel models determined the organisational factors, independent of patient case-mix, associated with three patient outcomes: length of hospital stay (LOS), 30-day all-cause mortality, and emergency 30-day readmission. ResultsOverall LOS was mean 21 days (standard deviation, 20); 13,126 (7.3%) died within 30-days; and 25,239 (15.3%) were readmitted. 25 organisational factors independently predicted LOS: for example, a hospital’s ability to promptly mobilise ≥90% of patients was associated with a 2-day (95%CI:1.3-2.7) shorter LOS, and hospitals where all patients received orthogeriatric assessment within 72 hours of admission had mean 1.5-day (95%CI:0.6-2.3) shorter LOS. Ten organisational factors independently predicted 30-day mortality: providing prompt surgery (≤36 hours from admission) to >80% patients was associated with the same 10% reduction in mortality (95%CI:4-15%), as was discussion of “patient experience” feedback at clinical governance meetings (95%CI:5-15%). Nine organisational factors independently predicted readmission: knowledge of time from discharge to start of community therapy was associated with 17% (95%CI:9-24%) lower readmission rates. Organisational delivery of clinical governance, surgery, and physiotherapy were associated with all outcomes.ConclusionsMultiple, potentially modifiable, organisational factors are associated with important patient outcomes post-hip fracture. These factors, if causal, indicate auditable components of hospital care where interventions can be targeted to reduce variability in hip fracture care delivery, to improve patient outcomes.

BACKGROUND: This trial aimed to determine the efficacy of leucine and/or perindopril in improving physical function in older people with sarcopenia. METHODS: Placebo-controlled, parallel group, double-blind, randomized two-by-two factorial trial. We recruited adults aged?70years with sarcopenia, defined as low gait speed (

BACKGROUND: Of the 2 million children living with HIV globally, 90% live in sub-Saharan Africa. Despite antiretroviral therapy, longstanding HIV infection is associated with several chronic complications in children including growth failure, particularly stunting and delayed puberty. Vitamin D deficiency, which is highly prevalent among children living with HIV in sub-Saharan Africa, has a further adverse impact on bone health. This trial aims to establish whether supplementation with vitamin D3 and calcium carbonate improves musculoskeletal health among peripubertal children living with HIV. METHODS/DESIGN: We will conduct an individually randomised, double-blinded, placebo-controlled trial of weekly high-dose vitamin D3 (20,000 IU) plus daily calcium carbonate (500mg) supplementation for 48 weeks. Eight hundred and forty children living with HIV aged 11-19 years taking ART for ≥6 months will be enrolled and followed up for 96 weeks. The primary outcome is total body less-head bone mineral content for lean mass adjusted for height (TBLH-BMCLBM) Z-score at 48 weeks, measured by dual-energy X-ray absorptiometry (DEXA). Secondary outcomes are DEXA-measured lumbar spine bone mineral apparent density Z-score, number of respiratory infections, lean muscle mass and grip strength at 48 and 96 weeks and TBLH-BMCLBM Z-scores at 96 weeks. Sub-studies will investigate the effect of the intervention on vitamin D3 pathway metabolites and markers of bone turnover, intestinal microbiota, and innate and acquired immune function. DISCUSSION: This is the largest trial to date of vitamin D supplementation in children living with HIV. Intervening to address deficits in bone accrual in childhood is critical for optimising adolescent and early adult bone health and prevention of later adult osteoporotic fractures. Trial results will draw attention to the need to screen for and treat long-term comorbidities in children living with HIV in resource-limited settings. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR20200989766029 . Registered on 3 September 2020.

Background: This trial aimed to determine the efficacy of leucine and/or perindopril in improving physical function in older people with sarcopenia. Methods: Placebo-controlled, parallel group, double-blind, randomized two-by-two factorial trial. We recruited adults aged ≥ 70 years with sarcopenia, defined as low gait speed (

The rollout of antiretroviral therapy globally has increased life expectancy across Southern Africa, where 20.6 million people now live with human immunodeficiency virus (HIV). We aimed to determine the prevalence of age-related osteoporosis and sarcopenia, and investigate the association between HIV, bone mineral density (BMD), muscle strength and lean mass, and gait speed. A cross-sectional community-based study of individuals aged 20-80 years in rural South Africa collected demographic and clinical data, including HIV status, grip strength, gait speed, body composition, and BMD. Sarcopenia was defined by the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) guidelines, and osteoporosis as BMD T-score ≤ -2.5 (if age ≥50 years). The mean ± standard deviation (SD) age of 805 black South African participants was 44.6 ± 14.8 years, 547 (68.2%) were female; 34 (13.2%) were men, and 129 (23.6%) women had HIV, with 88% overall taking anti-retroviral therapy. A femoral neck T-score ≤ -2.5, seen in four of 95 (4.2%) men and 39 of 201 (19.4%) women age ≥50 years, was more common in women with than without HIV (13/35 [37.1%] versus 26/166 [15.7%]; p = 0.003). Although no participant had confirmed sarcopenia, probable sarcopenia affected more men than women (30/258 [11.6%] versus 24/547 [4.4%]; p = .001]. Although appendicular lean mass (ALM)/height2 index was lower in both men and women with HIV, there were no differences in grip strength, gait speed, or probable sarcopenia by HIV status. Older age, female sex, lower ALM/height2 index, slower gait speed, and HIV infection were all independently associated with lower femoral neck BMD. In conclusion, osteoporosis rather than sarcopenia is the common musculoskeletal disease of aging in rural South Africa; older women with HIV may experience greater bone losses than women without HIV. Findings raise concerns over future fracture risk in Southern Africa, where HIV clinics should consider routine bone health assessment, particularly in aging women. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

BackgroundThe COVID-19 pandemic has impacted health, economies and the functioning of societies globally. In addition to direct health effects, it has indirectly impacted population health by limiting access to non-COVID treatments, including joint replacements. The pandemic has necessitated re-organisation of healthcare with the private-sector providing support to public hospitals in some areas. The full impact is therefore difficult to ascertain from public data sources alone.MethodsWe used a mandatory prospective national register of private and publicly funded hip, knee, shoulder, elbow and ankle replacements in England, Wales and Northern Ireland. Descriptive analysis of the provision of joint replacement comparing data from 2019 to 2020 and predicted deficit recovery.FindingsThere was a substantial deficit in the provision of joint replacement in 2020 compared to 2019 with 106,922(48.8%) fewer procedures performed; resulting in 45,116 (44%) fewer hip replacements, 57,115(52%) fewer knee replacements, 3,878(50%) fewer shoulder replacements, 280 (33%) fewer elbow replacements and 533(53%) fewer ankle replacements performed. Wales and Northern Ireland were disproportionately affected with an overall reduction of 8,001(67%) and 2,833(64%) respectively compared to 96,088(47%) in England.An immediate 5% expansion in provision from the 2019 baseline will eliminate the deficit over approximately 10 years (by 2031), whilst a 10% expansion will address the deficit by 2026. InterpretationThis large national analysis of both private and publicly funded joint replacements illustrates a substantial accumulated deficit of surgery, equivalent to six-months of normal activity across England, Wales and Northern Ireland, due to the indirect effects of COVID-19. As the pandemic evolves, further waves of infection are likely to restrict surgery and see the deficit increase, therefore projections of time taken to address the deficit must thus be regarded as the best-case scenario. A significant expansion of joint replacement services compared 2019 is urgently required to address this deficit. FundingThis study was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston National Health Service Foundation Trust and the University of Bristol. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This study was also supported by funding from the National Joint Registry. Posts of authors of this work are part funded by a grant from the National Joint Registry to conduct statistical analysis for the National Joint Registry. This study was supported by the NIHR Biomedical Research Centre at Oxford University Hospitals NHS Foundation Trust and the University of Oxford. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10-75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.

The discovery that sclerostin is the defective protein underlying the rare heritable bone mass disorder, sclerosteosis, ultimately led to development of anti-sclerostin antibodies as a new treatment for osteoporosis. In the era of large scale GWAS, many additional genetic signals associated with bone mass and related traits have since been reported. However, how best to interrogate these signals in order to identify the underlying gene responsible for these genetic associations, a prerequisite for identifying drug targets for further treatments, remains a challenge. The resources available for supporting functional genomics research continues to expand, exemplified by "multi-omics" database resources, with improved availability of datasets derived from bone tissues. These databases provide information about potential molecular mediators such as mRNA expression, protein expression, and DNA methylation levels, which can be interrogated to map genetic signals to specific genes based on identification of causal pathways between the genetic signal and the phenotype being studied. Functional evaluation of potential causative genes has been facilitated by characterization of the "osteocyte signature", by broad phenotyping of knockout mice with deletions of over 7,000 genes, in which more detailed skeletal phenotyping is currently being undertaken, and by development of zebrafish as a highly efficient additional in vivo model for functional studies of the skeleton. Looking to the future, this expanding repertoire of tools offers the hope of accurately defining the major genetic signals which contribute to osteoporosis. This may in turn lead to the identification of additional therapeutic targets, and ultimately new treatments for osteoporosis.

Novel anabolic drug targets are needed to treat osteoporosis. Having established a large national cohort with unexplained high bone mass (HBM), we aimed to identify a novel monogenic cause of HBM and provide insight into a regulatory pathway potentially amenable to therapeutic intervention. We investigated a pedigree with unexplained HBM in whom previous sequencing had excluded known causes of monogenic HBM. Whole exome sequencing identified a rare (minor allele frequency 0.0023), highly evolutionarily conserved missense mutation in SMAD9 (c.65T>C, p.Leu22Pro) segregating with HBM in this autosomal dominant family. The same mutation was identified in another two unrelated individuals both with HBM. In silico protein modeling predicts the mutation severely disrupts the MH1 DNA‐binding domain of SMAD9. Affected individuals have bone mineral density (BMD) Z‐scores +3 to +5, mandible enlargement, a broad frame, torus palatinus/mandibularis, pes planus, increased shoe size, and a tendency to sink when swimming. Peripheral quantitative computed tomography (pQCT) measurement demonstrates increased trabecular volumetric BMD and increased cortical thickness conferring greater predicted bone strength; bone turnover markers are low/normal. Notably, fractures and nerve compression are not found. Both genome‐wide and gene‐based association testing involving estimated BMD measured at the heel in 362,924 white British subjects from the UK Biobank Study showed strong associations with SMAD9 (PGWAS = 6 × 10−16; PGENE = 8 × 10−17). Furthermore, we found Smad9 to be highly expressed in both murine cortical bone–derived osteocytes and skeletal elements of zebrafish larvae. Our findings support SMAD9 as a novel HBM gene and a potential novel osteoanabolic target for osteoporosis therapeutics. SMAD9 is thought to inhibit bone morphogenetic protein (BMP)‐dependent target gene transcription to reduce osteoblast activity. Thus, we hypothesize SMAD9 c.65T>C is a loss‐of‐function mutation reducing BMP inhibition. Lowering SMAD9 as a potential novel anabolic mechanism for osteoporosis therapeutics warrants further investigation. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Objective: HIV-positive children, adolescents, and young adults are at increased risk poor musculoskeletal outcomes. Increased incidence of vitamin D deficiency in youth living with HIV may further adversely affect musculoskeletal health. We investigated the impact of vitamin D supplementation on a range of musculoskeletal outcomes among individuals aged 0-25 years living with HIV.Methods: A systematic review was conducted using databases: PubMed/Medline, CINAHL, Web of Knowledge, and EMBASE. Interventional randomised control trials, quasi-experimental trials, and previous systematic reviews/meta-analyses were included. Outcomes included: BMD, BMC, fracture incidence, muscle strength, linear growth (height-for-age Z-score [HAZ]), and biochemical/endocrine biomarkers including bone turnover markers. Results: Of 497 records, 20 studies met inclusion criteria. Thirteen studies were conducted in North America, one in Asia, two in Europe, and four in Sub-Saharan Africa. High-dose vitamin D supplementation regimens (1,000-7,000 IU/day) were successful in achieving serum 25-hydroxyvitamin-D (25OHD) concentrations above study-defined thresholds. No improvements were observed in BMD, BMC, or in muscle power, force and strength; however, improvements in neuromuscular motor skills were demonstrated. HAZ was unaffected by low-dose (200-400 IU/day) supplementation. A single study found positive effects on HAZ with high-dose supplementation (7,000 vs 4,000IU/day). Conclusions: Measured bone outcomes were unaffected by high-dose vitamin D supplementation, even when target 25OHD measurements were achieved. This may be due to: insufficient sample size, follow-up, intermittent dosing, non-standardised definitions of vitamin D deficiency, or heterogeneity of enrolment criteria pertaining to baseline vitamin D concentration. High-dose vitamin D may improve HAZ and neuromuscular motor skills. Adequately powered trials are needed in settings where HIV burden is greatest.

Objective:HIV-positive children, adolescents, and young adults are at increased risk poor musculoskeletal outcomes. Increased incidence of vitamin D deficiency in youth living with HIV may further adversely affect musculoskeletal health. We investigated the impact of vitamin D supplementation on a range of musculoskeletal outcomes among individuals aged 0–25 years living with HIV.Methods:A systematic review was conducted using databases: PubMed/Medline, CINAHL, Web of Knowledge, and EMBASE. Interventional randomised control trials, quasi-experimental trials, and previous systematic reviews/meta-analyses were included. Outcomes included: BMD, BMC, fracture incidence, muscle strength, linear growth (height-for-age Z-score [HAZ]), and biochemical/endocrine biomarkers including bone turnover markers.Results:Of 497 records, 20 studies met inclusion criteria. Thirteen studies were conducted in North America, one in Asia, two in Europe, and four in Sub-Saharan Africa. High-dose vitamin D supplementation regimens (1,000–7,000 IU/day) were successful in achieving serum 25-hydroxyvitamin-D (25OHD) concentrations above study-defined thresholds. No improvements were observed in BMD, BMC, or in muscle power, force and strength; however, improvements in neuromuscular motor skills were demonstrated. HAZ was unaffected by low-dose (200–400 IU/day) supplementation. A single study found positive effects on HAZ with high-dose supplementation (7,000 vs 4,000IU/day).Conclusions:Measured bone outcomes were unaffected by high-dose vitamin D supplementation, even when target 25OHD measurements were achieved. This may be due to: insufficient sample size, follow-up, intermittent dosing, non-standardised definitions of vitamin D deficiency, or heterogeneity of enrolment criteria pertaining to baseline vitamin D concentration. High-dose vitamin D may improve HAZ and neuromuscular motor skills. Adequately powered trials are needed in settings where HIV burden is greatest.

Background Generalised high bone mass (HBM), associated with features of a mild skeletal dysplasia, has a prevalence of 0.18% in a UK DXA-scanned adult population. We hypothesized that the genetic component of extreme HBM includes contributions from common variants of small effect and rarer variants of large effect, both enriched in an extreme phenotype cohort. Methods We performed a genome-wide association study (GWAS) of adults with either extreme high or low BMD. Adults included individuals with unexplained extreme HBM (n = 240) from the UK with BMD Z-scores ≥+3.2, high BMD females from the Anglo-Australasian Osteoporosis Genetics Consortium (AOGC) (n = 1055) with Z-scores +1.5 to +4.0 and low BMD females also part of AOGC (n = 900), with Z-scores −1.5 to −4.0. Following imputation, we tested association between 6,379,332 SNPs and total hip and lumbar spine BMD Z-scores. For potential target genes, we assessed expression in human osteoblasts and murine osteocytes. Results We observed significant enrichment for associations with established BMD-associated loci, particularly those known to regulate endochondral ossification and Wnt signalling, suggesting that part of the genetic contribution to unexplained HBM is polygenic. Further, we identified associations exceeding genome-wide significance between BMD and four loci: two established BMD-associated loci (5q14.3 containing MEF2C and 1p36.12 containing WNT4) and two novel loci: 5p13.3 containing NPR3 (rs9292469; minor allele frequency [MAF] = 0.33%) associated with lumbar spine BMD and 11p15.2 containing SPON1 (rs2697825; MAF = 0.17%) associated with total hip BMD. Mouse models with mutations in either Npr3 or Spon1 have been reported, both have altered skeletal phenotypes, providing in vivo validation that these genes are physiologically important in bone. NRP3 regulates endochondral ossification and skeletal growth, whilst SPON1 modulates TGF-β regulated BMP-driven osteoblast differentiation. Rs9292469 (downstream of NPR3) also showed some evidence for association with forearm BMD in the independent GEFOS sample (n = 32,965). We found Spon1 was highly expressed in murine osteocytes from the tibiae, femora, humeri and calvaria, whereas Npr3 expression was more variable. Conclusion We report the most extreme-truncate GWAS of BMD performed to date. Our findings, suggest potentially new anabolic bone regulatory pathways that warrant further study., Highlights • This GWAS found significant enrichment for associations with known BMD loci suggesting a polygenic contribution to high BMD • We identified a novel locus at: 5p13.3 containing NPR3 (lead SNP rs9292469) associated with lumbar spine BMD • We identified a novel locus at: 11p15.2 containing SPON1 (lead SNP rs2697825) associated with total hip BMD • Mouse models with mutations in either Npr3 or Spon1 have been reported, both have altered skeletal phenotypes • Our findings suggest potentially new anabolic bone regulatory pathways; however, further investigation is warranted

BackgroundSarcopenia has been associated with reduced physical activity (PA). We aimed to determine if sarcopenia, and specific components of muscle size, function and physical performance, are associated with high impacts achieved during habitual PA, as these are related to bone strength in community-dwelling older women.MethodsParticipants were older women from the Cohort of Skeletal Health in Bristol and Avon. We defined sarcopenia using the EWGSOP criteria. Lower limb peak muscle power and force were assessed using Jumping Mechanography (JM). High vertical impacts were assessed by tri-axial accelerometry (at least 1.5g above gravity). Cross-sectional associations were analysed by linear regression, adjusting for age, height and weight (or fat mass for models including appendicular lean mass index), comorbidities, smoking, alcohol and Index of Multiple Deprivation.ResultsOur analyses included 380 participants, with mean age 76.7 (SD 3.0) years; 242 (64%) also completed JM. In age-adjusted analysis, a negative relationship was observed between severity of sarcopenia and high, but not medium or low, impacts (p=0.03 for trend). Regarding components of sarcopenia underlying this relationship, multivariable analyses revealed that gait speed [β 1.47(95% CI 1.14,1.89), [β-1] reflects the proportionate increase in high impacts per SD increase in exposure] and peak force [1.40(1.07,1.84)] were independently associated with high impacts.ConclusionsOlder women with sarcopenia experienced fewer bone-strengthening high impacts than those with pre-sarcopenia or without sarcopenia. To increase bone strengthening activity in older women, interventions need to improve both lower limb muscle force and walking speed.

OBJECTIVE: Statistical shape modeling (SSM) of radiographs has been used to explore relationships between altered joint shape and hip osteoarthritis (OA). We aimed to apply SSM to Dual-energy X-ray Absorptiometry (DXA) hip scans, and examine associations between resultant hip shape modes (HSMs), radiographic hip OA (RHOA), and hip pain, in a large population based cohort.METHOD: SSM was performed on baseline hip DXA scans from the Osteoporotic Fractures in Men (MrOS) Study. Associations between the top ten HSMs, and prevalent RHOA from pelvic radiographs obtained 4.6 years later, were analysed in 4100 participants. RHOA was defined as Croft score ≥ 2. Hip pain was based on pain on walking, hip pain on examination, and Western Ontario and McMaster Universities Arthritis Index (WOMAC).RESULTS: The five HSMs associated with RHOA showed features of either pincer- or cam-type deformities. HSM 1 (increased pincer-type deformity) was positively associated with RHOA [1.23 (1.09,1.39)] [odds ratio and 95% CI]. HSM 8 (reduced pincer-type deformity) was inversely associated with RHOA [0.79 (0.70,0.89)]. HSM 10 (increased cam-type deformity) was positively associated with RHOA [1.21 (1.07,1.37)]. HSM 3 and HSM 4 (reduced cam-type deformity) were inversely associated with RHOA [0.73 (0.65,0.83) and 0.82 (0.73,0.93) respectively]. HSM 3 was inversely related to pain on examination [0.84 (0.76,0.92)] and walking [0.88, (0.81,0.95)], and to WOMAC score [0.87 (0.80,0.93)].CONCLUSIONS: DXA-derived measures of hip shape are associated with RHOA, and to a lesser extent hip pain, possibly reflecting their role in the pathogenesis of hip OA.

OBJECTIVE: Increasing numbers of children with HIV are surviving to adolescence and encountering multiple clinical and social consequences of longstanding HIV infection. We aimed to investigate the association between HIV and disability, social functioning and school inclusion among 6 to 16 year-olds in Zimbabwe.METHODS: HIV-infected children receiving antiretroviral therapy from a public sector HIV clinic, and HIV-uninfected children attending primary care clinics in the same catchment area were recruited. Standardised questionnaires were used to collect sociodemographic, social functioning and disability data. Multivariable logistic regression was used to assess the relationship between HIV status and disability and functioning.RESULTS: We recruited 202 HIV-infected and 285 HIV-uninfected children. There was no difference in age and gender between the two groups, but a higher proportion of HIV-infected children were orphaned. The prevalence of any disability was higher in HIV-infected than uninfected children (37.6% vs. 18.5%, pCONCLUSIONS: Children with HIV commonly experience disabilities and this is associated with social and educational exclusion. Rehabilitation and support services are needed to facilitate educational attainment and social participation in this group. This article is protected by copyright. All rights reserved.

Summary Common variants in WNT pathway genes have been associated with bone mass and fat distribution, the latter predicting diabetes and cardiovascular disease risk. Rare mutations in the WNT co-receptors LRP5 and LRP6 are similarly associated with bone and cardiometabolic disorders. We investigated the role of LRP5 in human adipose tissue. Subjects with gain-of-function LRP5 mutations and high bone mass had enhanced lower-body fat accumulation. Reciprocally, a low bone mineral density-associated common LRP5 allele correlated with increased abdominal adiposity. Ex vivo LRP5 expression was higher in abdominal versus gluteal adipocyte progenitors. Equivalent knockdown of LRP5 in both progenitor types dose-dependently impaired β-catenin signaling and led to distinct biological outcomes: diminished gluteal and enhanced abdominal adipogenesis. These data highlight how depot differences in WNT/β-catenin pathway activity modulate human fat distribution via effects on adipocyte progenitor biology. They also identify LRP5 as a potential pharmacologic target for the treatment of cardiometabolic disorders., Graphical Abstract, Highlights • Carriers of LRP5 variants display altered body fat distribution • LRP5 is more highly expressed in abdominal versus gluteal fat progenitor cells • LRP5 knockdown in both progenitor types leads to different biological responses • LRP5 modulates fat progenitor biology by controlling β-catenin signaling dosage, Loh et al. identify the WNT co-receptor LRP5 as a regulator of human body fat distribution, an independent predictor of diabetes and cardiovascular disease risk. Studying LRP5 gene variant carriers and human fat progenitors, they show that LRP5 differentially modulates regional adipose progenitor biology by titrating WNT/β-catenin signaling dosage.

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Osteoporosis and cardiovascular disease(CVD) are both common causes of morbidity and mortality. Previous studies, mainly of people over 60 years, suggest a relationship between these conditions. Our aim was to determine the association between bone characteristics and CVD markers in younger and middle-aged individuals. Women (n=3,366) and their adolescent offspring (n= 4,368) from the UK population-based cohort study, Avon Longitudinal Study of Parents and Children(ALSPAC), were investigated. We measured total body(TB) and hip BMD, TB bone area(BA) and bone mineral content(BMC) by DXA, and carotid intima-media thickness(cIMT) by high-resolution ultrasound. Arterial distensibility was calculated as the difference between systolic and diastolic arterial diameters. Linear regression determined associations between bone exposures and cIMT (in adolescents), and both cIMT and arterial distensibility (in women), generating partial correlation coefficients. Mean(SD) age of women was 48(4.2) years, BMI 26.2(5.0)kg/m2, 71% were premenopausal. In confounder-adjusted analyses (age, height, lean mass, fat mass, menopause, smoking, estrogen replacement, calcium/vitamin D supplementation and education) TB and hip BMD were both positively associated with cIMT (0.071 [0.030, 0.112], p=0.001; 0.063 [0.025, 0.101], p=0.001, respectively). Femoral neck BMD and TB BMD, BMC and BA were positively associated with arterial distensibility. Mean(SD) age of adolescents was 17(0.4) years, BMI 23(4.1)kg/m2 and 44.5% were male. Total hip and TB measurements were positively associated with cIMT, with similar magnitudes of association to those seen in their mothers. In contrast to most published findings we identified weak positive associations between BMD and cIMT in predominantly premenopausal women and their adolescent offspring. We found greater femoral neck BMD and TB DXA measurements to be associated with reduced arterial stiffness. Rather than a relationship with pre-clinical atherosclerosis, in these relatively young populations, we speculate our associations between BMD, cIMT and arterial distensibility may reflect a shared relationship between bone and vascular growth and development.

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

© 2015 Macmillan Publishers Limited. All rights reserved. The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10-14), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10-11; ncases = 98,742 and n controls = 409,511). Using an En1 cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10-11). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

Osteoporosis pseudoglioma syndrome (OPPG) is a rare autosomal recessive condition of congenital blindness and severe childhood osteoporosis with skeletal fragility, caused by loss-of-function mutations in the LRP5 (Low-density lipoprotein receptor-related protein 5) gene. We report the first case of atypical (subtrochanteric) femoral fracture (AFF) in OPPG, occurring in a 38 year old man within the context of relatively low bone turnover and trabecular osteoporosis on bone histology. We identify two novel LRP5 mutations: R752W is associated with low bone mass density (BMD), as demonstrated by the heterozygous carriage identified in his 57 year old mother; however, the combination of this R752W mutation with another novel W79R mutation, causes a severe case of compound heterozygous OPPG. We undertake three-dimensional homology modelling of the four extracellular YWTD β-propeller/EGF-like domains (E1-E4) of LRP5, and show that both novel mutations destabilise the β-propeller domains that are critical for protein and ligand binding to regulate Wnt signalling and osteoblast function. Whilst AFFs have been reported in other rare bone diseases, this is the first in a genetic condition of primary osteoblast dysfunction. The relatively low bone turnover observed, and knowledge of LRP5 function, implicates impaired bone remodelling in the pathogenesis of AFF. © 2014 American Society for Bone and Mineral Research.

Common variants in WNT pathway genes have been associated with bone mass and fat distribution, the latter predicting diabetes and cardiovascular disease risk. Rare mutations in the WNT co-receptors LRP5 and LRP6 are similarly associated with bone and cardiometabolic disorders. We investigated the role of LRP5 in human adipose tissue. Subjects with gain-of-function LRP5 mutations and high bone mass had enhanced lower-body fat accumulation. Reciprocally, a low bone mineral density-associated common LRP5 allele correlated with increased abdominal adiposity. Ex vivo LRP5 expression was higher in abdominal versus gluteal adipocyte progenitors. Equivalent knockdown of LRP5 in both progenitor types dose-dependently impaired beta-catenin signaling and led to distinct biological outcomes: diminished gluteal and enhanced abdominal adipogenesis. These data highlight how depot differences in WNT/beta-catenin pathway activity modulate human fat distribution via effects on adipocyte progenitor biology. They also identify LRP5 as a potential pharmacologic target for the treatment of cardiometabolic disorders.

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OBJECTIVES: To assess variation in access to and use of community rehabilitation services for patients with a hip fracture, and whether this affects length of stay in hospital. DESIGN: Cross-sectional study using administrative patient-level data from Hospital Episode Statistics (HES) and organisational survey data. SETTING: A regional health economy in South West England served by four acute National Health Service (NHS) hospital trusts and six former Primary Care Trusts (PCTs). POPULATION: 1230 hip fracture patients treated in an acute hospital between 1 April 2011 and 29 February 2012. MAIN OUTCOMES: Information about access to community rehabilitation services for each acute hospital and PCT, reported by organisational survey. Rates of patients transferred from acute hospital to community rehabilitation hospitals (CRH) across eight groups with varying access; determined by acute hospital and PCT. Median lengths of stay in the acute hospital, and in the acute hospital plus CRH combined. Associations between the rate of transfer to a CRH and median lengths of stay assessed using Spearman's rank correlation coefficient (rs). RESULTS: Access to community rehabilitation services varied, including the number of CRH inpatient beds, formal access criteria and waiting times. In one PCT, no home-based rehabilitation service was available. The percentage of patients transferred to a CRH ranged from 2.1% to 54.7%. A higher transfer rate was associated with a shorter median length of stay in the acute hospital (rs=-0.8; p=0.01), but a longer median combined length of stay in the acute hospital and CRH (rs=+0.7; p=0.04). CONCLUSIONS: Within one geographical area, there was wide variation in availability and use of community rehabilitation services for patients discharged from an acute hospital following a hip fracture. Reliance on transfers to community rehabilitation hospitals was associated with a longer length of stay in the NHS.

OBJECTIVE: Previous studies of skeletal remains have suggested that both enthesophytes and osteophytes are manifestations of an underlying bone-forming tendency. A greater prevalence of osteophytes has been observed among individuals with high bone mass (HBM) compared with controls. This study was undertaken to examine the possible interrelationships between bone mass, enthesophytes, and osteophytes in a population of individuals with extreme HBM.METHODS: Cases of HBM (defined according to bone mineral density [BMD] Z scores on dual x-ray absorptiometry) from the UK-based HBM study were compared with a control group comprising unaffected family members and general population controls from the Chingford and Hertfordshire cohort studies. Pelvic radiographs from cases and controls were pooled and evaluated, in a blinded manner, by a single observer, who performed semiquantitative grading of the radiographs for the presence and severity of osteophytes and enthesophytes (score range 0-3 for each). Logistic regression analysis was used to identify significant associations, with a priori adjustment for age, sex, and body mass index.RESULTS: In this study, 226 radiographs from HBM cases and 437 radiographs from control subjects were included. Enthesophytes (grade ?1) and moderate enthesophytes (grade ?2) were more prevalent in HBM cases compared with controls (adjusted odds ratio [OR] 3.00 [95% confidence interval (95% CI) 1.96-4.58], P < 0.001 for any enthesophyte; adjusted OR 4.33 [95% CI 2.67-7.02], P < 0.001 for moderate enthesophytes). In the combined population of cases and controls, the enthesophyte grade was positively associated with BMD at both the total hip and lumbar spine (adjusted P for trend < 0.001). In addition, a positive association between osteophytes and enthesophytes was observed; for each unit increase in enthesophyte grade, the odds of any osteophyte being present were increased >2-fold (P < 0.001).CONCLUSION: Strong interrelationships were observed between osteophytes, enthesophytes, and HBM, which may be helpful in defining a distinct subset of patients with osteoarthritis characterized by excess bone formation.

Context: Theroleandimportance of circulating sclerostin is poorly understood. Highbonemass(HBM) caused by activating LRP5 mutations has been reported to be associated with increased plasma sclerostin concentrations; whether the same applies to HBM due to other causes is unknown. Objective: Our objective was to determine circulating sclerostin concentrations in HBM. Design and Participants: In this case-control study, 406 HBM index cases were identified by screening dual-energy x-ray absorptiometry (DXA) databases from 4 United Kingdom centers (n = 219 088), excluding significant osteoarthritis/artifact. Controls comprised unaffected relatives and spouses. Main measures: Plasma sclerostin; lumbar spine L1, total hip, and total body DXA; and radial and tibial peripheral quantitative computed tomography (subgroup only) were evaluated. Results: Sclerostin concentrations were significantly higher in both LRP5 HBM and non-LRP5 HBM cases compared with controls: mean (SD) 130.1 (61.7) and 88.0 (39.3) vs 66.4 (32.3) pmol/L (both P < .001, which persisted after adjustment for a priori confounders). In combined adjusted analyses of cases and controls, sclerostin concentrations were positively related to all bone parameters found to be increased in HBM cases (ie, L1, total hip, and total body DXA bone mineral density and radial/tibial cortical area, cortical bone mineral density, and trabecular density). Although these relationships were broadly equivalent in HBM cases and controls, there was some evidence that associations between sclerostin and trabecular phenotypes were stronger in HBM cases, particularly for radial trabecular density (interaction P

Context: Little is known of the relationships between muscle function and bone, based on the recently developed technique of jumping mechanography. Objective: Our objective was to determine associations between peak ground reaction force and peak power during a 1-legged hopping test and a single 2-legged jump, respectively, and cortical bone parameters. Design and Setting: This was a cross-sectional observational study in participants from the high bone mass cohort. Participants: Participants included 70 males (mean age 58 years) and 119 females (mean age 56 years); high bone mass cases and controls were pooled. Main Outcome Measures: Total hip bone mineral density (BMD) (measured by dual-energy x-ray absorptiometry scanning) and mid-tibial peripheral quantitative computed tomography (Stratec XCT2000L). Results: Jump power was positively related to hip BMD (standardized β [95% confidence interval] = 0.29 [0.07, 0.51], P = .01), but hopping force was not (0.03 [-0.16, 0.22], P = .74) (linear regression analysis adjusted for age, gender, height, and weight). In 113 participants with force and peripheral quantitative computed tomography data, both jump power and hopping force were positively associated with tibial strength strain index (0.26 [0.09, 0.44], P < .01; and 0.24 [0.07, 0.42], P = .01 respectively). Although hopping force was positively associated with bone size (total bone area 0.22 [0.03, 0.42], P = .02), jump power was not (0.10 [-0.10, 0.30], P = .33). In contrast, jump power was inversely associated with endocortical circumference adjusted for periosteal circumference (-0.24 [-0.40, -0.08], P < .01) whereas no association was seen for hopping force (-0.10 [-0.26, 0.07], P = .24). Conclusions: Although power and force are both positively associated with cortical bone strength, distinct mechanisms appear to be involved because power was primarily associated with reduced endocortical expansion (reflected by endocortical circumference adjusted for periosteal circumference, and hip BMD), whereas force was associated with increased periosteal expansion (reflected by total bone area).

Additional file 1: Supplementary Table 1. Baseline characteristics for those with and without follow-up data, Supplementary Figure 1. associations between HBM and incident OA and incident and progressive OA sub-phenotypes in person-level analyses.

Additional file 1: Supplementary Table 1. Baseline characteristics for those with and without follow-up data, Supplementary Figure 1. associations between HBM and incident OA and incident and progressive OA sub-phenotypes in person-level analyses.

It is unclear if puberty timing influences future physical activity (PA). To investigate the association of puberty timing with PA across adolescence and adulthood. Data were from two British cohorts. Participants from an adolescent birth cohort (females = 2349, males = 1720) prospectively reported age at menarche and voice break and had PA recorded by Actigraph accelerometers at ages 14 years and 16 years. A cohort of middle-aged and older adults (40–70 years; females = 48,282; males = 36,112) recalled their age at puberty and had PA (mean acceleration; mg) measured by AxivityAX3 accelerometers. After adjustment for age, education, smoking and BMI, per 1-year older age at menarche was associated with higher mean counts/minute at age 14 years (0.07 SD counts/minute; 95% CI = 0.04–0.11) with associations attenuated at age 16 years (0.02; −0.03–0.07). Differences in mean acceleration per older year at menarche were close to the null in women aged 40–49 years (0.02 mg; 0.01–0.03), 50–59 years (0.01; 0.00–0.02) and 60–70 years (0.01; 0.00–0.01). Age at voice break and PA associations were close to the null in both cohorts. We found a positive association between puberty timing and PA in females which weakened at older ages and limited evidence of an association at any age in males.

It is unclear if puberty timing influences future physical activity (PA). To investigate the association of puberty timing with PA across adolescence and adulthood. Data were from two British cohorts. Participants from an adolescent birth cohort (females = 2349, males = 1720) prospectively reported age at menarche and voice break and had PA recorded by Actigraph accelerometers at ages 14 years and 16 years. A cohort of middle-aged and older adults (40–70 years; females = 48,282; males = 36,112) recalled their age at puberty and had PA (mean acceleration; mg) measured by AxivityAX3 accelerometers. After adjustment for age, education, smoking and BMI, per 1-year older age at menarche was associated with higher mean counts/minute at age 14 years (0.07 SD counts/minute; 95% CI = 0.04–0.11) with associations attenuated at age 16 years (0.02; −0.03–0.07). Differences in mean acceleration per older year at menarche were close to the null in women aged 40–49 years (0.02 mg; 0.01–0.03), 50–59 years (0.01; 0.00–0.02) and 60–70 years (0.01; 0.00–0.01). Age at voice break and PA associations were close to the null in both cohorts. We found a positive association between puberty timing and PA in females which weakened at older ages and limited evidence of an association at any age in males.