Sex differences in proximal femur shape : findings from a population-based study in adolescents

We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. The UK Medical Research Council and the Wellcome Trust (ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. MF was supported by a Wellcome Trust PhD studentship (ref: 105504/Z/14/Z). LP works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council and the University of Bristol (MC_UU_00011/1). Arthritis Research UK project grant (ref: 20244) supported the generation of adult reference statistical shape model. This publication is the work of the authors and MF will serve as guarantor for the contents of this paper. None of the funders had any influence on data collection, analysis, interpretation of the results, or writing of the paper.Peer reviewedPublisher PD

Using statistical shape modelling of DXA images to quantify the shape of the proximal femur at ages 14 and 18 years in the Avon Longitudinal Study of Parents and Children [version 1; referees: 1 approved with reservations]

This work was supported by the Wellcome Trust through a PhD Studentship to MF [105504] and the ALSPAC core programme grant [102215]. The UK Medical Research Council and Wellcome [102215] and the University of Bristol provide core support for ALSPAC. LP works in a unit that receives support from the UK Medical Research Council and the University of Bristol [ MC_ UU_12013/4 & MC_UU_12013/5]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Circulating sclerostin levels are positively related to coronary artery disease severity and related risk factors

Romosozumab is a newly available treatment for osteoporosis acting by sclerostin inhibition. Its cardiovascular safety has been questioned after finding excess cardiovascular disease (CVD)‐related events in a pivotal phase 3 trial. Previous studies of relationships between circulating sclerostin levels and CVD and associated risk factors have yielded conflicting findings, likely reflecting small numbers and selected patient groups. We aimed to characterize relationships between sclerostin and CVD and related risk factors in more detail by examining these in two large cohorts, Ludwigshafen Risk and Cardiovascular Health study (LURIC; 34% female, mean age 63.0 years) and Avon Longitudinal Study of Parents and Children study (ALSPAC) mothers (mean age 48.1 years). Together these provided 5069 participants with complete data. Relationships between sclerostin and CVD risk factors were meta‐analyzed, adjusted for age, sex (LURIC), body mass index, smoking, social deprivation, and ethnicity (ALSPAC). Higher sclerostin levels were associated with higher risk of diabetes mellitus (DM) (odds ratio [OR] = 1.25; 95% confidence interval [CI] 1.12, 1.37), risk of elevated fasting glucose (OR 1.15; CI 1.04, 1.26), and triglyceride levels (β 0.03; CI 0.00, 0.06). Conversely, higher sclerostin was associated with lower estimated glomerular filtration rate (eGFR) (β −0.20; CI −0.38, −0.02), HDL cholesterol (β −0.05; CI −0.10, −0.01), and apolipoprotein A‐I (β −0.05; CI −0.08, −0.02) (difference in mean SD per SD increase in sclerostin, with 95% CI). In LURIC, higher sclerostin was associated with an increased risk of death from cardiac disease during follow‐up (hazard ratio [HR] = 1.13; 1.03, 1.23) and with severity of coronary artery disease on angiogram as reflected by Friesinger score (0.05; 0.01, 0.09). Associations with cardiac mortality and coronary artery severity were partially attenuated after adjustment for risk factors potentially related to sclerostin, namely LDL and HDL cholesterol, log triglycerides, DM, hypertension, eGFR, and apolipoprotein A‐I. Contrary to trial evidence suggesting sclerostin inhibition leads to an increased risk of CVD, sclerostin levels appear to be positively associated with coronary artery disease severity and mortality, partly explained by a relationship between higher sclerostin levels and major CVD risk factors. © 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)

The effect of pubertal timing, as reflected by height tempo, on proximal femur shape:findings from a population-based study in adolescents

Funding The UK Medical Research Council and the Wellcome Trust (ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. MF was supported by a Wellcome Trust PhD studentship (ref: 105504/Z/14/Z). LP works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council and the University of Bristol (MC_UU_00011/1). A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). Age 17 clinical assessment was specifically funded by Wellcome Trust (084632/Z/08/Z). This publication is the work of the authors and MF will serve as guarantor for the contents of this paper. None of the funders had any influence on data collection, analysis, interpretation of the results, or writing of the paper. Acknowledgements We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses.Peer reviewedPublisher PD

The influence of adult hip shape genetic variants on adolescent hip shape : Findings from a population-based DXA study

Acknowledgments: We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. The UK Medical Research Council and the Wellcome Trust (ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents /grant-acknowledgements.pdf). GWAS data was generated at Laboratory Corporation of America (LabCorp Holdings, Burlington, NC, USA) by 23andMe and small subset was also performed at Wellcome Sanger Institute to check data quality. MF was supported by a Wellcome Trust PhD studentship (ref: 105504/Z/14/Z). LP works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol which is supported by the Medical Research Council and the University of Bristol (MC_UU_00011/1). This publication is the work of the authors and MF will serve as guarantor for the contents of this paper. None of the funders had any influence on data collection, analysis, interpretation of the results, or writing of the paper.Peer reviewedPublisher PD

Machine-learning derived acetabular dysplasia and cam morphology are features of severe hip osteoarthritis : findings from UK Biobank

Acknowledgements and disclosures The authors would like to thank Dr Martin Williams, Consultant Musculoskeletal Radiologist North Bristol NHS Trust, who provided substantial training and expertise in osteophyte assessment on DXA images. This research has been conducted using the UK Biobank Resource (application number 17295). Financial Support: RE, MF, FS are supported, and this work is funded by a Wellcome Trust collaborative award (reference number 209233). BGF is supported by a Medical Research Council (MRC) clinical research training fellowship (MR/S021280/1). CL was funded by the MRC, UK (MR/S00405X/1) as well as a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (223267/Z/21/Z). NCH acknowledges support from the MRC and NIHR Southampton Biomedical Research Centre, University of Southampton, and University Hospital Southampton. This research was funded in whole, or in part, by the Wellcome Trust [Grant number 223267/Z/21/Z]. NCH has received consultancy, lecture fees and honoraria from Alliance for Better Bone Health, AMGEN, MSD, Eli Lilly, Servier, UCB, Shire, Consilient Healthcare, Kyowa Kirin and Internis Pharma. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.Peer reviewedPublisher PD

Cam morphology but neither acetabular dysplasia nor pincer morphology is associated with osteophytosis throughout the hip: findings from a cross-sectional study in UK Biobank

Objectives: to examine whether acetabular dysplasia (AD), cam and/or pincer morphology are associated with radiographic hip osteoarthritis (rHOA) and hip pain in UK Biobank (UKB) and, if so, what distribution of osteophytes is observed.Design: participants from UKB with a left hip dual-energy X-ray absorptiometry (DXA) scan had alpha angle (AA), lateral centre-edge angle (LCEA) and joint space narrowing (JSN) derived automatically. Cam and pincer morphology, and AD were defined using AA and LCEA. Osteophytes were measured manually and rHOA grades were calculated from JSN and osteophyte measures. Logistic regression was used to examine the relationships between these hip morphologies and rHOA, osteophytes, JSN, and hip pain.Results: 6,807 individuals were selected (mean age: 62.7; 3382/3425 males/females). Cam morphology was more prevalent in males than females (15.4% and 1.8% respectively). In males, cam morphology was associated with rHOA [OR 3.20 (95% CI 2.41–4.25)], JSN [1.53 (1.24–1.88)], and acetabular [1.87 (1.48–2.36)], superior [1.94 (1.45–2.57)] and inferior [4.75 (3.44–6.57)] femoral osteophytes, and hip pain [1.48 (1.05–2.09)]. Broadly similar associations were seen in females, but with weaker statistical evidence. Neither pincer morphology nor AD showed any associations with rHOA or hip pain.Conclusions: cam morphology was predominantly seen in males in whom it was associated with rHOA and hip pain. In males and females, cam morphology was associated with inferior femoral head osteophytes more strongly than those at the superior femoral head and acetabulum. Further studies are justified to characterise the biomechanical disturbances associated with cam morphology, underlying the observed osteophyte distribution

Associations between prenatal indicators of mechanical loading and proximal femur shape: findings from a population-based study in ALSPAC offspring

Objectives: Hip development is influenced by mechanical loading, but associations between prenatal loading and hip shape in later life remain unexplored. Methods: We examined associations between prenatal loading indicators (gestation length, oligohydramnios (OH) and breech) obtained from obstetric records and hip shape modes (HSMs) generated using dual-energy X-ray absorptiometry images taken at age 14- and 18-years in participants from the UK Avon Longitudinal Study of Parents and Children (ALSPAC). These associations were examined in 2453 (30 OH, 105 breech) and 2330 (27 OH, 95 breech) participants with complete data at age 14- and 18-years respectively using confounder-adjusted models. Results: At 14 years HSM2 was 0.59SD lower in OH males, and HSM5 (-0.31SD) and HSM9 (-0.32SD) were lower in OH in both sexes. At 18 years HSM1 (-0.44SD) and HSM2 (-0.71SD) were lower and HSM6 (0.61SD) and HSM8 (1.06SD) were higher in OH males, whilst HSM5 was lower in OH in both sexes. OH appeared to be associated with a wider femoral neck and head, and larger lesser/greater trochanters. Only weak associations were observed between gestation length/breech and HSMs. Conclusions: These results suggest that prenatal skeletal loading, in particular oligohydramnios, may influence adolescent joint shape with associations generally stronger in males

Associations of Body Mass and Fat Indexes With Cardiometabolic Traits

Background Body mass index (BMI) is criticized for not distinguishing fat from lean mass and ignoring fat distribution, leaving its ability to detect health effects unclear. Objectives The aim of this study was to compare BMI with total and regional fat indexes from dual-energy x-ray absorptiometry in their associations with cardiometabolic traits. Duration of exposure to and change in each index across adolescence were examined in relation to detailed traits in young adulthood. Methods BMI was examined alongside total, trunk, arm, and leg fat indexes (each in kilograms per square meter) from dual-energy x-ray absorptiometry at ages 10 and 18 years in relation to 230 traits from targeted metabolomics at age 18 years in 2,840 offspring from the Avon Longitudinal Study of Parents and Children. Results Higher total fat mass index and BMI at age 10 years were similarly associated with cardiometabolic traits at age 18 years, including higher systolic and diastolic blood pressure, higher very low-density lipoprotein and low-density lipoprotein cholesterol, lower high-density lipoprotein cholesterol, higher triglycerides, and higher insulin and glycoprotein acetyls. Associations were stronger for both indexes measured at age 18 years and for gains in each index from age 10 to 18 years (e.g., 0.45 SDs [95% confidence interval: 0.38 to 0.53] in glycoprotein acetyls per SD unit gain in fat mass index vs. 0.38 SDs [95% confidence interval: 0.27 to 0.48] per SD unit gain in BMI). Associations resembled those for trunk fat index. Higher lean mass index was weakly associated with traits and was not protective against higher fat mass index. Conclusions The results of this study support abdominal fatness as a primary driver of cardiometabolic dysfunction and BMI as a useful tool for detecting its effects