Publications by authors named "Nicholas C Harvey"

218 Publications

Estimation of biological heart age using cardiovascular magnetic resonance radiomics.

Sci Rep 2022 Jul 27;12(1):12805. Epub 2022 Jul 27.

William Harvey Research Institute, NIHR Barts Biomedical Research Centre, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.

We developed a novel interpretable biological heart age estimation model using cardiovascular magnetic resonance radiomics measures of ventricular shape and myocardial character. We included 29,996 UK Biobank participants without cardiovascular disease. Images were segmented using an automated analysis pipeline. We extracted 254 radiomics features from the left ventricle, right ventricle, and myocardium of each study. We then used Bayesian ridge regression with tenfold cross-validation to develop a heart age estimation model using the radiomics features as the model input and chronological age as the model output. We examined associations of radiomics features with heart age in men and women, observing sex-differential patterns. We subtracted actual age from model estimated heart age to calculate a "heart age delta", which we considered as a measure of heart aging. We performed a phenome-wide association study of 701 exposures with heart age delta. The strongest correlates of heart aging were measures of obesity, adverse serum lipid markers, hypertension, diabetes, heart rate, income, multimorbidity, musculoskeletal health, and respiratory health. This technique provides a new method for phenotypic assessment relating to cardiovascular aging; further studies are required to assess whether it provides incremental risk information over current approaches.
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http://dx.doi.org/10.1038/s41598-022-16639-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9329281PMC
July 2022

Activity Behaviors in British 6-Year-Olds: Cross-Sectional Associations and Longitudinal Change During the School Transition.

J Phys Act Health 2022 Jul 21:1-8. Epub 2022 Jul 21.

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge,United Kingdom.

Background: To explore activity behaviors at school entry, we describe temporal/demographic associations with accelerometer-measured physical activity in a population-based sample of British 6-year-olds, and examine change from ages 4 to 6.

Methods: A total of 712 six-year-olds (308 at both ages) wore Actiheart accelerometers for ≥3 (mean 6.0) days. We derived minutes per day sedentary (<20 cpm) and moderate to vigorous physical activity (MVPA, ≥460 cpm), also segmented across mornings (06:00 AM to 09:00 AM), school (09:00 AM to 3:00 PM), and evenings (3:00 PM to 11:00 PM). Using mixed effects linear regression, we analyzed associations between temporal/demographic factors and children's activity intensities at age 6, and change between ages 4 and 6.

Results: Six-year-old children engaged in MVPA (mean [SD]): 64.9 (25.7) minutes per day (53% met UK guidelines). Girls did less MVPA than boys, particularly during school hours. Children were less active on weekends (vs weekdays) and more active on spring/summer evenings (vs winter). Longitudinally, 6-year-old children did less light physical activity (-44.7; 95% confidence interval, -49.9 to -39.6 min/d) but were more sedentary (30.0; 24.5 to 35.5), and engaged in greater MVPA (7.6; 5.6 to 9.7) compared to when they were aged 4.

Conclusion: Half of 6-year-old children met current activity guidelines; MVPA levels were lower in girls and at weekends. UK children became more sedentary but did more MVPA as they entered formal schooling. Physical activity promotion efforts should capitalize on these changes in MVPA, to maintain positive habits.
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http://dx.doi.org/10.1123/jpah.2021-0718DOI Listing
July 2022

Telomere length and risk of incident fracture and arthroplasty: findings from UK Biobank.

J Bone Miner Res 2022 Jul 25. Epub 2022 Jul 25.

MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK.

We investigated independent associations between telomere length and risk of fracture and arthroplasty in UK Biobank participants. Leucocyte telomere length (LTL) was measured in baseline samples using a validated PCR method. We used, in men and women separately, Cox proportional hazards models to calculate the hazard ratio for incident fracture (any, osteoporotic) or arthroplasty (hip or knee) over 1,186,410 person-years of follow-up. Covariates included age, white cell count, ethnicity, smoking, alcohol, physical activity and menopause (women). In further analyses we adjusted for either estimated bone mineral density from heel quantitative ultrasound, handgrip strength, gait speed, total fat mass (bioimpedance) or blood biomarkers, all measured at baseline (2006-2010). We studied 59,500 women and 51,895 men, mean(SD) age 56.4(8.0) and 57.0(8.3) years respectively. During follow-up there were 5,619 fractures; 5,285 hip and 4,261 knee arthroplasties. In confounder-adjusted models, longer LTL was associated with reduced risk of incident knee arthroplasty in both men [hazard ratio/SD (95%CI): 0.93 (0.88,0.97)] and women [0.92 (0.88,0.96)] and hip arthroplasty in men [0.91 (0.87,0.95)] but not women [0.98 (0.94,1.01)]. Longer LTL was weakly associated with reduced risk of any incident fracture in women [hazard ratio/SD (95% CI): 0.96 (0.93,1.00)] with less evidence in men [0.98 (0.93,1.02)]. Associations with incident outcomes were not materially altered by adjustment for heel estimated bone mineral density, grip strength, gait speed, fat mass or blood biomarker measures. In this, the largest study to date, longer LTL was associated with lower risk of incident knee or hip arthroplasty, but only weakly associated with lower risk of fracture. The relative risks were low at a population level, but our findings suggest that common factors acting on the myeloid and musculoskeleletal systems might influence later life musculoskeletal outcomes. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/jbmr.4664DOI Listing
July 2022

Pregnancy Vitamin D Supplementation and Childhood Bone Mass at Age 4 Years: Findings From the Maternal Vitamin D Osteoporosis Study (MAVIDOS) Randomized Controlled Trial.

JBMR Plus 2022 Jul 11;6(7):e10651. Epub 2022 Jun 11.

Medical Research Council (MRC) Lifecourse Epidemiology Centre University of Southampton Southampton UK.

In the Maternal Vitamin D Osteoporosis Study (MAVIDOS) randomized trial, vitamin D supplementation in pregnancy did not lead to greater neonatal bone mass across the trial as a whole, but, in a prespecified secondary analysis by season of birth, led to greater neonatal bone mass among winter-born babies. Demonstrating persistence of this effect into childhood would increase confidence in a long-term benefit of this intervention. We investigated whether antenatal vitamin D supplementation increases offspring bone mineralization in early childhood in a prespecified, single-center follow-up of a double-blinded, multicenter, randomized controlled clinical trial based in the UK (MAVIDOS). A total of 1123 women in early pregnancy with a baseline 25-hydroxyvitamin D level 25-100 nmol/L from three research centers (2008-2014) were randomized to 1000 IU/d cholecalciferol or matched placebo from 14 weeks of gestation to delivery. Offspring born at the Southampton, UK research center were assessed at age 4 years (2013-2018). Anthropometry and dual-energy X-ray absorptiometry (DXA) were performed (yielding whole body less head [WBLH] bone mineral content [BMC], areal bone mineral density [aBMD], bone area [BA], and body composition). Of 723 children, 564 (78.0%) children attended the 4-year visit, 452 of whom had a useable DXA. Maternal vitamin D supplementation led to greater WBLH aBMD in the children compared with placebo (mean [95% confidence interval {CI}]: supplemented group: 0.477 (95% CI, 0.472-0.481) g/cm; placebo group: 0.470 (95% CI, 0.466-0.475) g/cm,  = 0.048). Associations were consistent for BMC and lean mass, and in age- and sex-adjusted models. Effects were observed across the whole cohort irrespective of season of birth. Maternal-child interactions were observed, with a greater effect size among children with low milk intake and low levels of physical activity. Child weight, height, and body mass index (BMI) were similar by maternal randomization group. These findings suggest a sustained beneficial effect of maternal vitamin D supplementation in pregnancy on offspring aBMD at age 4 years, but will require replication in other trials. © 2022 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9289979PMC
July 2022

Menopausal hormone therapy reduces the risk of fracture regardless of falls risk or baseline FRAX probability-results from the Women's Health Initiative hormone therapy trials.

Osteoporos Int 2022 Jul 14. Epub 2022 Jul 14.

Mary McKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia.

In a combined analysis of 25,389 postmenopausal women aged 50-79 years, enrolled in the two Women's Health Initiative hormone therapy trials, menopausal hormone therapy vs. placebo reduced the risk of fracture regardless of baseline FRAX fracture probability and falls history.

Introduction: The aim of this study was to determine if the anti-fracture efficacy of menopausal hormone therapy (MHT) differed by baseline falls history or fracture risk probability as estimated by FRAX, in a combined analysis of the two Women's Health Initiative (WHI) hormone therapy trials.

Methods: A total of 25,389 postmenopausal women aged 50-79 years were randomized to receive MHT (n = 12,739) or matching placebo (n = 12,650). At baseline, questionnaires were used to collect information on falls history, within the last 12 months, and clinical risk factors. FRAX 10-year probability of major osteoporotic fracture (MOF) was calculated without BMD. Incident clinical fractures were verified using medical records. An extension of Poisson regression was used to investigate the relationship between treatment and fractures in (1) the whole cohort; (2) those with prior falls; and (3) those without prior falls. The effect of baseline FRAX probability on efficacy was investigated in the whole cohort.

Results: Over 4.3 ± 2.1 years (mean ± SD), MHT (vs. placebo) significantly reduced the risk of any clinical fracture (hazard ratio [HR] 0.72 [95% CI, 0.65-0.78]), MOF (HR 0.60 [95% CI, 0.53-0.69]), and hip fracture (0.66 [95% CI, 0.45-0.96]). Treatment was effective in reducing the risk of any clinical fracture, MOF, and hip fracture in women regardless of baseline FRAX MOF probability, with no evidence of an interaction between MHT and FRAX (p > 0.30). Similarly, there was no interaction (p > 0.30) between MHT and prior falls.

Conclusion: In the combined WHI trials, compared to placebo, MHT reduces fracture risk regardless of FRAX probability and falls history in postmenopausal women.
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http://dx.doi.org/10.1007/s00198-022-06483-yDOI Listing
July 2022

Machine Learning-Derived Acetabular Dysplasia and Cam Morphology Are Features of Severe Hip Osteoarthritis: Findings From UK Biobank.

J Bone Miner Res 2022 Jul 10. Epub 2022 Jul 10.

Musculoskeletal Research Unit, University of Bristol, Bristol, UK.

The contribution of shape changes to hip osteoarthritis (HOA) remains unclear, as is the extent to which these vary according to HOA severity. In the present study, we used statistical shape modeling (SSM) to evaluate relationships between hip shape and HOA of different severities using UK Biobank DXA images. We performed a cross-sectional study in individuals with left hip dual-energy X-ray absorptiometry (DXA) scans. Statistical shape modeling (SSM) was used to quantify hip shape. Radiographic HOA (rHOA) was classified using osteophyte size and number and joint space narrowing. HOA outcomes ranged in severity from moderate (grade 2) to severe (grade ≥3) rHOA, hospital-diagnosed HOA, and subsequent total hip replacement (THR). Confounder-adjusted logistic regression between the top 10 hip shape modes (HSMs) and OA outcomes was performed. Further models adjusted for alpha angle (AA) and lateral center-edge angle (LCEA), reflecting acetabular dysplasia and cam morphology, respectively. Composite HSM figures were produced combining HSMs associated with separate OA outcomes. A total of 40,311 individuals were included (mean 63.7 years, 47.8% male), of whom 5.7% had grade 2 rHOA, 1.7% grade ≥3 rHOA, 1.3% hospital-diagnosed HOA, and 0.6% underwent THR. Composite HSM figures for grade 2 rHOA revealed femoral neck widening, increased acetabular coverage, and enlarged lesser and greater trochanters. In contrast, grade ≥3 rHOA, hospital-diagnosed HOA, and THR were suggestive of cam morphology and reduced acetabular coverage. Associations between HSMs depicting cam morphology and reduced acetabular coverage and more severe HOA were attenuated by AA and LCEA adjustment, respectively. Relationships between hip shape and HOA differed according to severity. Notably, cam morphology and acetabular dysplasia were features of severe HOA, but unrelated to moderate disease, suggesting possible prognostic utility. © 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).
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http://dx.doi.org/10.1002/jbmr.4649DOI Listing
July 2022

Maternal antenatal vitamin D supplementation and offspring risk of atopic eczema in the first 4 years of life: evidence from a randomized controlled trial.

Br J Dermatol 2022 Jun 28. Epub 2022 Jun 28.

Medical Research Council Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK.

Background: Evidence linking prenatal maternal vitamin D supplementation with the offspring's risk of atopic eczema is inconsistent, with most data coming from observational studies.

Objectives: To examine the influence of maternal cholecalciferol supplementation during pregnancy on the risk of atopic eczema in the offspring at ages 12, 24 and 48 months.

Methods: Within the UK Maternal Vitamin D Osteoporosis Study (MAVIDOS) double-blind, randomized placebo-controlled trial, we examined the relationship of maternal vitamin D supplementation during pregnancy with offspring atopic eczema at ages 12, 24 and 48 months. In MAVIDOS, pregnant women were allocated to either cholecalciferol 1000 IU per day or matched placebo, taken from around 14 weeks' gestation until delivery, with the primary outcome of neonatal whole-body bone mineral content. The prevalence of atopic eczema in the offspring was ascertained at ages 12 (n = 635), 24 (n = 610) and 48 (n = 449) months, based on the UK Working Party criteria for the definition of atopic dermatitis. The trial was registered with ISRCTN (82927713) and EudraCT (2007-001716-23).

Results: The characteristics of mothers and offspring were similar between the intervention and placebo groups, apart from longer breastfeeding duration in the intervention group. Adjusting for breastfeeding duration, offspring of mothers who received cholecalciferol 1000 IU daily had a lower odds ratio (OR) of atopic eczema at age 12 months [OR 0·55, 95% confidence interval (CI) 0·32-0·97, P = 0·04]; this effect weakened and was not statistically significant at ages 24 months (OR 0·76, 95% CI 0·47-1·23) or 48 months (OR 0·75, 95% CI 0·37-1·52). The statistical interaction of intervention and breastfeeding duration in relation to eczema at age 12 months was not significant (P = 0·41), but stratification showed reduced infantile eczema risk in the intervention group for infants breastfed for ≥ 1 month (OR 0·48, 95% CI 0·24-0·94, P = 0·03) but not in those breastfed for < 1 month (OR 0·80, 95% CI 0·29-2·17, P = 0·66).

Conclusions: Our data provide the first randomized controlled trial evidence of a protective effect of antenatal cholecalciferol supplementation on the risk of infantile atopic eczema, with the effect potentially being via increased breast milk cholecalciferol levels. The findings support a developmental influence on atopic eczema, and point to a potentially modifiable perinatal influence on atopic eczema. What is already known about this topic? There are currently no antenatal interventions proven to reduce the incidence of infantile atopic eczema in the general population. However, observational studies have led to speculation that antenatal vitamin D supplementation may be beneficial.
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http://dx.doi.org/10.1111/bjd.21721DOI Listing
June 2022

Quantitating Age-Related BMD Textural Variation from DXA Region-Free-Analysis: A Study of Hip Fracture Prediction in Three Cohorts.

J Bone Miner Res 2022 Jun 24. Epub 2022 Jun 24.

Department of Oncology and Metabolism, The University of Sheffield, Sheffield, UK.

The risk of osteoporotic fracture is inversely related to bone mineral density (BMD), but how spatial BMD pattern influences fracture risk remains incompletely understood. This study used a pixel-level spatiotemporal atlas of proximal femoral BMD in 13,338 white European women (age 20-97 years) to quantitate age-related texture variation in BMD maps and generate a "reference" map of bone aging. We introduce a new index, called Densitometric Bone Age (DBA), as the age at which an individual site-specific BMD map (the proximal femur is studied here) best matches the median aging trajectory at that site in terms of the root mean squared error (RMSE). The ability of DBA to predict incident hip fracture and hip fracture pattern over 5 years following baseline BMD was compared against conventional region-based BMD analysis in a subset of 11,899 women (age 45-97 years), for which follow-up fracture records exist. There were 208 subsequent incident hip fractures in the study populations (138 femoral necks [FNs], 52 trochanteric [TR], 18 sites unspecified). DBA had modestly better performance compared to the conventional FN-BMD, TR-BMD, and total hip (TOT)-BMD in identifying hip fractures measured as the area under the curve (AUC) using receiver operating characteristics (ROC) curve analysis by 2% (95% confidence interval [CI], -0.5% to 3.5%), 3% (95% CI, 1.0% to 4.0%), and 1% (95% CI, 0.4% to 1.6%), respectively. Compared to FN-BMD T-score, DBA improved the ROC-AUC for predicting TR fractures by ~5% (95% CI, 1.1% to 9.8%) with similar performance in identifying FN fractures. Compared to TR-BMD T-score, DBA improved the ROC-AUC for the prediction of FN fractures by ~3% (95% CI, 1.1% to 4.9%), with similar performance in identifying TR fractures. Our findings suggest that DBA may provide a spatially sensitive measure of proximal femoral fragility that is not captured by FN-BMD or TR-BMD alone. © 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).
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http://dx.doi.org/10.1002/jbmr.4638DOI Listing
June 2022

Osteoporosis in 2022: Care gaps to screening and personalised medicine.

Best Pract Res Clin Rheumatol 2022 Jun 9:101754. Epub 2022 Jun 9.

MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton General Hospital, Southampton, UK; NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospitals Southampton NHS Foundation Trust, Southampton, UK. Electronic address:

Osteoporosis care has evolved markedly over the last 50 years, such that there are now an established clinical definition, validated methods of fracture risk assessment, and a range of effective pharmacological agents. However, it is apparent that both in the context of primary and secondary fracture prevention, there is a considerable gap between the population at high fracture risk and those actually receiving appropriate antiosteoporosis treatment. In this narrative review article, we document recent work describing the burden of disease, approaches to management, and service provision across Europe, emerging data on gaps in care, and existing/new ways in which these gaps may be addressed at the level of healthcare systems and policy. We conclude that although the field has come a long way in recent decades, there is still a long way to go, and a concerted, integrated effort is now required from all of us involved in this field to address these urgent issues to ensure the best possible outcomes for our patients.
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http://dx.doi.org/10.1016/j.berh.2022.101754DOI Listing
June 2022

Associations Between Late Pregnancy Dietary Inflammatory Index (DII) and Offspring Bone Mass: A Meta-Analysis of the Southampton Women's Survey (SWS) and the Avon Longitudinal Study of Parents and Children (ALSPAC).

J Bone Miner Res 2022 Jun 10. Epub 2022 Jun 10.

MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK.

Systemic inflammation is associated with reduced bone mineral density and may be influenced by pro-inflammatory diets. We undertook an observational analysis of associations between late pregnancy energy-adjusted dietary inflammatory index (E-DII) scores and offspring bone outcomes in childhood. E-DII scores (higher scores indicating pro-inflammatory diets) were derived from food frequency questionnaires in late pregnancy in two prospective mother-offspring cohorts: the Southampton Women's Survey (SWS) and the Avon Longitudinal Study of Parents and Children (ALSPAC). The mean (SD) offspring age at dual-energy X-ray absorptiometry (DXA) scanning was 9.2 (0.2) years. Linear regression was used to assess associations between E-DII and bone outcomes, adjusting for offspring sex and age at DXA and maternal age at childbirth, educational level, pre-pregnancy body mass index (BMI), parity, physical activity level, and smoking in pregnancy. Associations were synthesized using fixed-effect meta-analysis. Beta coefficients represent the association per unit E-DII increment. In fully adjusted models (total n = 5910) late pregnancy E-DII was negatively associated with offspring whole body minus head bone area (BA: β = -3.68 [95% confidence interval -6.09, -1.27] cm /unit), bone mineral content (BMC: β = -4.16 [95% CI -6.70, -1.62] g/unit), and areal bone mineral density (aBMD: β = -0.0012 [95% CI -0.0020, -0.0004] g.cm /unit), but there was only a weak association with BMC adjusted for BA (β = -0.48 [95% CI -1.11, 0.15] g/unit) at 9 years. Adjustment for child height partly or, for weight, fully attenuated the associations. Higher late pregnancy E-DII scores (representing a more pro-inflammatory diet) are negatively associated with offspring bone measures, supporting the importance of maternal and childhood diet on longitudinal offspring bone health. © 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).
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http://dx.doi.org/10.1002/jbmr.4623DOI Listing
June 2022

The Impact of Maternal Obesity on Offspring Cardiovascular Health: A Systematic Literature Review.

Front Endocrinol (Lausanne) 2022 20;13:868441. Epub 2022 May 20.

William Harvey Research Institute, NIHR Barts Biomedical Research Centre, Queen Mary University of London, London, United Kingdom.

Objective: Obesity and cardiovascular disease are major global public health problems. Maternal obesity has been linked to multiple adverse health consequences for both mother and baby. Obesity during pregnancy may adversely alter the intrauterine environment, which has been hypothesised to predispose the offspring to poorer cardiovascular health throughout life. In this paper, we systematically review current literature examining the links between maternal obesity and offspring cardiovascular health.

Methods: This study is registered with PROSPERO (CRD42021278567) and was conducted in accordance with the PRISMA guidelines. A comprehensive systematic literature search was conducted, including two electronic databases (Ovid Medline, Embase), cross-referencing, author searching, and grey literature searches. We selected studies exploring the relationship between maternal obesity and offspring cardiovascular health, using pre-defined eligibility criteria. Studies were critically appraised using the ROBINS-I tool.

Results: From 1,214 results, 27 articles met the eligibility criteria. Multiple cardiovascular outcomes were considered, including congenital heart disease, cardiometabolic parameters, and cardiovascular diseases in neonates, children, and adults. In these studies, maternal obesity was consistently associated with congenital heart disease, several adverse cardiometabolic parameters throughout life including higher body mass index and insulin levels, and greater risk of cardiovascular disease in adulthood. Hypothesized underlying mechanisms are complex and multifactorial comprising genetic, environmental, and socioeconomic components, which can be difficult to quantify. Heterogeneity in study designs, highly selected study samples, and high risk of bias in some studies limit conclusions regarding causality.

Conclusions: We identified consistent evidence of links between maternal obesity and poorer offspring cardiovascular health throughout the lifecourse, extending from the neonatal period into adulthood. Although underlying mechanisms are unclear, our findings support consideration of targeted maternal obesity prevention for promotion of offspring cardiovascular health. This all-encompassing systematic review provides critical appraisal of the latest evidence, defines gaps and biases of existing literature, and may inform potential new public health strategies for cardiovascular disease prevention.

Systematic Review Registration: [https://www.crd.york.ac.uk/prospero], identifier PROSPERO (CRD42021278567).
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http://dx.doi.org/10.3389/fendo.2022.868441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164814PMC
May 2022

Analysis of Comorbidities, Clinical Outcomes, and Parathyroidectomy in Adults With Primary Hyperparathyroidism.

JAMA Netw Open 2022 06 1;5(6):e2215396. Epub 2022 Jun 1.

Sahlgrenska Osteoporosis Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.

Importance: Patients with primary hyperparathyroidism (pHPT) appear to have an increased risk of fractures and other comorbidities, such as cardiovascular disease, although results from previous studies have been inconsistent. Evidence of the association of parathyroidectomy (PTX) with these outcomes is also limited because of the lack of large well-controlled trials.

Objective: To investigate whether untreated pHPT was associated with an increased risk of incident fractures and cardiovascular events (CVEs) and whether PTX was associated with a reduced risk of these outcomes.

Design, Setting, And Participants: This cohort study included all patients who were diagnosed with pHPT at hospitals in Sweden between July 1, 2006, and December 31, 2017. Each patient was matched with 10 control individuals from the general population by sex, birth year, and county of residence. The patients were followed up until December 31, 2017. Data analyses were performed from October 2021 to April 2022.

Main Outcomes And Measures: The primary outcomes were fractures, CVEs, and death. Cumulative incidence of events was estimated using the 1-minus Kaplan-Meier estimator of corresponding survival function. Cox proportional hazards regression models were used to calculate hazard ratios (HRs).

Results: A total of 16 374 patients with pHPT were identified (mean [SD] age, 67.5 [12.9] years; 12 806 women [78.2%]), with 163 740 control individuals. The follow-up time was 42 310 person-years for the pHPT group and 803 522 person-years for the control group. Compared with the control group, the pHPT group had a higher risk of any fracture (unadjusted HR, 1.39; 95% CI, 1.31-1.48), hip fracture (unadjusted HR, 1.51; 95% CI, 1.35-1.70), CVEs (unadjusted HR, 1.45; 95% CI, 1.34-1.57), and death (unadjusted HR, 1.72; 95% CI, 1.65-1.80). In a time-dependent Poisson regression model, PTX was associated with a reduced risk of any fracture (HR, 0.83; 95% CI, 0.75-0.93), hip fracture (HR, 0.78; 95% CI, 0.61-0.98), CVEs (HR, 0.84; 95% CI, 0.73-0.97), and death (HR, 0.59; 95% CI, 0.53-0.65).

Conclusions And Relevance: Results of this study suggest that pHPT is associated with increased risk of fractures, CVEs, and death, highlighting the importance of identifying patients with this condition to prevent serious unfavorable outcomes. The reduced risk of these outcomes associated with PTX suggests a clinical benefit of surgery.
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http://dx.doi.org/10.1001/jamanetworkopen.2022.15396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9166253PMC
June 2022

Pericardial adiposity is independently linked to adverse cardiovascular phenotypes: a CMR study of 42 598 UK Biobank participants.

Eur Heart J Cardiovasc Imaging 2022 May 31. Epub 2022 May 31.

William Harvey Research Institute, NIHR Barts Biomedical Research Centre, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.

Aims: We evaluated independent associations of cardiovascular magnetic resonance (CMR)-measured pericardial adipose tissue (PAT) with cardiovascular structure and function and considered underlying mechanism in 42 598 UK Biobank participants.

Methods And Results: We extracted PAT and selected CMR metrics using automated pipelines. We estimated associations of PAT with each CMR metric using linear regression adjusting for age, sex, ethnicity, deprivation, smoking, exercise, processed food intake, body mass index, diabetes, hypertension, height cholesterol, waist-to-hip ratio, impedance fat measures, and magnetic resonance imaging abdominal visceral adiposity measures. Higher PAT was independently associated with unhealthy left ventricular (LV) structure (greater wall thickness, higher LV mass, more concentric pattern of LV hypertrophy), poorer LV function (lower LV global function index, lower LV stroke volume), lower left atrial ejection fraction, and lower aortic distensibility. We used multiple mediation analysis to examine the potential mediating effect of cardiometabolic diseases and blood biomarkers (lipid profile, glycaemic control, inflammation) in the PAT-CMR relationships. Higher PAT was associated with cardiometabolic disease (hypertension, diabetes, high cholesterol), adverse serum lipids, poorer glycaemic control, and greater systemic inflammation. We identified potential mediation pathways via hypertension, adverse lipids, and inflammation markers, which overall only partially explained the PAT-CMR relationships.

Conclusion: We demonstrate association of PAT with unhealthy cardiovascular structure and function, independent of baseline comorbidities, vascular risk factors, inflammatory markers, and multiple non-invasive and imaging measures of obesity. Our findings support an independent role of PAT in adversely impacting cardiovascular health and highlight CMR-measured PAT as a potential novel imaging biomarker of cardiovascular risk.
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http://dx.doi.org/10.1093/ehjci/jeac101DOI Listing
May 2022

Trabecular Bone Score Adjustment for the Fracture Risk Assessment Tool (FRAX®).

Calcif Tissue Int 2022 08 20;111(2):226-227. Epub 2022 May 20.

Centre for Metabolic Bone Diseases, University of Sheffield, Sheffield, UK.

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http://dx.doi.org/10.1007/s00223-022-00994-wDOI Listing
August 2022

Interdisciplinary management of FGF23-related phosphate wasting syndromes: a Consensus Statement on the evaluation, diagnosis and care of patients with X-linked hypophosphataemia.

Nat Rev Endocrinol 2022 06 28;18(6):366-384. Epub 2022 Apr 28.

Division of Bone Diseases, Department of Medicine, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.

X-linked hypophosphataemia (XLH) is the most frequent cause of hypophosphataemia-associated rickets of genetic origin and is associated with high levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23). In addition to rickets and osteomalacia, patients with XLH have a heavy disease burden with enthesopathies, osteoarthritis, pseudofractures and dental complications, all of which contribute to reduced quality of life. This Consensus Statement presents the outcomes of a working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, and provides robust clinical evidence on management in XLH, with an emphasis on patients' experiences and needs. During growth, conventional treatment with phosphate supplements and active vitamin D metabolites (such as calcitriol) improves growth, ameliorates leg deformities and dental manifestations, and reduces pain. The continuation of conventional treatment in symptom-free adults is still debated. A novel therapeutic approach is the monoclonal anti-FGF23 antibody burosumab. Although promising, further studies are required to clarify its long-term efficacy, particularly in adults. Given the diversity of symptoms and complications, an interdisciplinary approach to management is of paramount importance. The focus of treatment should be not only on the physical manifestations and challenges associated with XLH and other FGF23-mediated hypophosphataemia syndromes, but also on the major psychological and social impact of the disease.
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http://dx.doi.org/10.1038/s41574-022-00662-xDOI Listing
June 2022

Maternal and Fetal Genetic Variation in Vitamin D Metabolism and Umbilical Cord Blood 25-Hydroxyvitamin D.

J Clin Endocrinol Metab 2022 07;107(8):e3403-e3410

MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton,UK.

Context: Single nucleotide polymorphisms (SNPs) in vitamin D metabolism pathway genes are associated with circulating 25-hydroxyvitamin D (25(OH)D) in adults. Less is known about the relationships between mother and offspring SNPs and umbilical cord blood 25(OH)D.

Objective: (1) To undertake a meta-analysis of the relationships of maternal and offspring SNPs in the vitamin D metabolism pathway and cord blood 25(OH)D in pregnant women including novel data; and (2) to examine these relationships in women who received antenatal cholecalciferol supplementation in a clinical trial.

Methods: Novel data analysis from an observational mother-offspring cohort study (Southampton Women's Survey) and the MAVIDOS double-blind, randomized, placebo-controlled trial of 1000 IU/day cholecalciferol supplementation in pregnancy, and an electronic literature search of published studies in PubMed up to 31 July 2021. Studies reporting associations between rs12785878 (DHCR7), rs10741657 (CYP2R1), rs6013897 (CYP24A1), or rs2282679 (GC) and cord blood 25(OH)D. One published study was included in addition to the novel data analysis. Associations between both maternal and offspring SNPs at rs2282679 (GC) and rs12785878 (DHCR7), and cord blood 25(OH)D were identified. When maternal genotype was adjusted for offspring genotype, and vice versa, there was persisting evidence for associations with maternal rs12785878 (β [95% CI] 1.6 nmol/L [0.3, 2.8] per common allele), and offspring rs2282679 (β 3.1 nmol/L ]2.0, 4.4] per common allele). Maternal and offspring SNPs at rs1074657 and rs613897 were not associated with cord blood 25(OH)D.

Result: Associations between both maternal and offspring SNPs at rs2282679 (GC) and rs12785878 (DHCR7), and cord blood 25(OH)D were identified. When maternal genotype was adjusted for offspring genotype, and vice versa, there was persisting evidence for associations with maternal rs12785878 (β [95% CI] 1.6 nmol/L [0.3, 2.8] per common allele), and offspring rs2282679 (β 3.1 nmol/L ]2.0, 4.4] per common allele). Maternal and offspring SNPs at rs1074657 and rs613897 were not associated with cord blood 25(OH)D.

Conclusion: Common genetic variation in the vitamin D metabolism pathway is associated with umbilical cord blood 25(OH)D.
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http://dx.doi.org/10.1210/clinem/dgac263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9282354PMC
July 2022

Potential Adverse Effect of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) on Bisphosphonate Efficacy: An Exploratory Post Hoc Analysis From a Randomized Controlled Trial of Clodronate.

J Bone Miner Res 2022 06 20;37(6):1117-1124. Epub 2022 Apr 20.

Mellanby Centre for Musculoskeletal Research, Medical Research Council (MRC) Versus Arthritis Centre for Integrated Research in Musculoskeletal Ageing, Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to have weak but beneficial effects on bone health, including fracture risk, but many epidemiological studies are likely confounded. We explored the relationship between NSAIDs and fracture risk in a post hoc analysis of a well-documented, randomized, placebo-controlled study of the bisphosphonate, clodronate, in which treatment reduced osteoporotic fracture risk by 23%. Concurrent medication use at baseline was used to identify those prescribed oral NSAIDs. Only verified, incident fractures were included in the analysis. A total of 1082 (20.8%) women reported use of NSAIDs at baseline. They were slightly, but significantly, younger (mean 79 versus 80 years, p = 0.004), heavier (mean 66.7 versus 64.7 kg, p < 0.001) than nonusers, with slightly higher femoral neck bone mineral density (FN-BMD, 0.66 versus 0.64 g/cm , p < 0.001). In an adjusted model, NSAID use was associated with a significant increase in osteoporotic fracture risk over the 3-year study period (hazard ratio [HR] 1.27; 95% confidence interval [CI], 1.01-1.62; p = 0.039). However, this increase in risk was not statistically significant in the placebo group (HR 1.11; 95% CI, 0.81-1.52). In women receiving clodronate, the effect of the bisphosphonate to reduce osteoporotic fracture risk was not observed in those receiving NSAIDs (HR 0.95; 95% CI, 0.65-1.41; p = 0.81) in contrast to those not using NSAIDs (HR 0.71; 95% CI, 0.58-0.89; p = 0.002). In a subset with hip BMD repeated at 3 years, BMD loss during clodronate therapy was greater in those women receiving NSAIDs than in nonusers (eg, total hip -2.75% versus -1.27%, p = 0.078; femoral neck -3.06% versus -1.12%, p = 0.028), and was not significantly different from that observed in women receiving placebo. The efficacy of the bisphosphonate, clodronate, to reduce fracture risk was largely negated in those receiving NSAIDs. Although the mechanism is unclear, this clinically significant observation requires exploration in studies of commonly used bisphosphonates. © 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).
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http://dx.doi.org/10.1002/jbmr.4548DOI Listing
June 2022

Is the skull responsive to bone mineralisation stimuli in children?

Bone 2022 07 8;160:116415. Epub 2022 Apr 8.

MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK; NIHR Southampton Nutrition Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK. Electronic address:

Background: Whole-body-less-head (WBLH) is the recommended skeletal region of interest (ROI) for dual-energy X-ray absorptiometry (DXA) assessment of bone mineral density (BMD) in children. Historically it has been suggested that the skull is less responsive than the rest of the skeleton to stimuli that affect BMD but there are few published data to support this notion. We compared the associations of BMD with anthropometric, body composition, diet, and activity variables across various ROI.

Methods: Children from the Southampton Women's Survey (SWS) mother-offspring cohort participated at age 6-7 years, including measurement of height, weight, and whole-body and lumbar spine (LS) BMD by DXA (Hologic Discovery). Physical activity was assessed by accelerometry (Actiheart) and diet by interviewer-led questionnaire. BMD was measured in the following skeletal ROI: whole-body, skull, WBLH and lower limbs (all derived from the whole-body scan) and LS.

Results: 1218 children participated. Height z-score, weight z-score, lean mass and milk intake were associated with skull BMD, but associations were weaker than observed for other ROI; for example, the association between lean mass and skull BMD was β (95% CI) 0.11 (0.08, 0.14) SD/kg, compared with 0.32 (0.30, 0.34), 0.38 (0.37, 0.40) and 0.23 (0.21, 0.25) SD/kg for whole body, WBLH and lumbar spine, respectively. Relationships with whole-body BMD were attenuated compared with WBLH.

Conclusion: Associations between skull BMD and anthropometry, body composition and dietary variables were weaker than for other DXA sites. These findings support, and importantly provide a quantitative basis for, the recommendation that the skull should be excluded from whole-body DXA analyses in children.
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http://dx.doi.org/10.1016/j.bone.2022.116415DOI Listing
July 2022

Digital health interventions for osteoporosis and post-fragility fracture care.

Ther Adv Musculoskelet Dis 2022 28;14:1759720X221083523. Epub 2022 Mar 28.

University of Cambridge School of Clinical Medicine, CB2 0QQ Cambridge, UK.

The growing burden from osteoporosis and fragility fractures highlights a need to improve osteoporosis management across healthcare systems. Sub-optimal management of osteoporosis is an area suitable for digital health interventions. While fracture liaison services (FLSs) are proven to greatly improve care for people with osteoporosis, such services might benefit from technologies that enhance automation. The term 'Digital Health' covers a variety of different tools including clinical decision support systems, electronic medical record tools, patient decision aids, patient apps, education tools, and novel artificial intelligence (AI) algorithms. Within the scope of this review are AI solutions that use algorithms within health system registries to target interventions. Clinician-targeted, patient-targeted, or system-targeted digital health interventions could be used to improve management and prevent fragility fractures. This review was commissioned by The Royal Osteoporosis Society and Bone Research Academy during the production of the 2020 Research Roadmap (https://theros.org.uk), with the intention of identifying gaps where targeted research funding could lead to improved patient health. We explore potential uses of digital technology in the general management of osteoporosis. Evidence suggests that digital technologies can support multidisciplinary teams to provide the best possible patient care based on current evidence and to support patients in self-management. However, robust randomised controlled studies are still needed to assess the effectiveness and cost-effectiveness of these technologies.
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http://dx.doi.org/10.1177/1759720X221083523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8966117PMC
March 2022

Incidence of hip fracture in Saudi Arabia and the development of a FRAX model.

Arch Osteoporos 2022 04 2;17(1):56. Epub 2022 Apr 2.

Mary McKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia.

A prospective hospital-based survey in representative regions of Saudi Arabia determined the incidence of fractures at the hip. The hip fracture rates were used to create a FRAX® model to facilitate fracture risk assessment in Saudi Arabia.

Objective: This paper describes the incidence of hip fracture in the Kingdom of Saudi Arabia that was used to characterize the current and future burden of hip fracture, to develop a country-specific FRAX® tool for fracture prediction and to compare fracture probabilities with neighbouring countries.

Methods: During a 2-year (2017/2018) prospective survey in 15 hospitals with a defined catchment population, hip fractures in Saudi citizens were prospectively identified from hospital registers. The number of hip fractures and future burden was determined from national demography. Age- and sex-specific incidence of hip fracture and national mortality rates were incorporated into a FRAX model for Saudi Arabia. Fracture probabilities were compared with those from Kuwait and Abu Dhabi.

Results: The incidence of hip fracture applied nationally suggested that the estimated number of hip fractures nationwide in persons over the age of 50 years for 2015 was 2,949 and is predicted to increase nearly sevenfold to 20,328 in 2050. Hip fracture rates were comparable with estimates from Abu Dhabi and Kuwait. By contrast, probabilities of a major osteoporotic fracture or hip fracture from the age of 70 years were much lower than those seen in Abu Dhabi and Kuwait due to higher mortality estimates for Saudi Arabia.

Conclusion: A country-specific FRAX tool for fracture prediction has been developed for Saudi Arabia which is expected to help guide decisions about treatment.
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http://dx.doi.org/10.1007/s11657-022-01085-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8976798PMC
April 2022

Management of patients at very high risk of osteoporotic fractures through sequential treatments.

Aging Clin Exp Res 2022 Apr 24;34(4):695-714. Epub 2022 Mar 24.

MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK.

Osteoporosis care has evolved markedly over the last 50 years, such that there are now an established clinical definition, validated methods of fracture risk assessment and a range of effective pharmacological agents. Currently, bone-forming (anabolic) agents, in many countries, are used in those patients who have continued to lose bone mineral density (BMD), patients with multiple subsequent fractures or those who have fractured despite treatment with antiresorptive agents. However, head-to-head data suggest that anabolic agents have greater rapidity and efficacy for fracture risk reduction than do antiresorptive therapies. The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) convened an expert working group to discuss the tools available to identify patients at high risk of fracture, review the evidence for the use of anabolic agents as the initial intervention in patients at highest risk of fracture and consider the sequence of therapy following their use. This position paper sets out the findings of the group and the consequent recommendations. The key conclusion is that the current evidence base supports an "anabolic first" approach in patients found to be at very high risk of fracture, followed by maintenance therapy using an antiresorptive agent, and with the subsequent need for antiosteoporosis therapy addressed over a lifetime horizon.
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http://dx.doi.org/10.1007/s40520-022-02100-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9076733PMC
April 2022

Epidemiology of hip fracture in Qatar and development of a country specific FRAX model.

Arch Osteoporos 2022 03 18;17(1):49. Epub 2022 Mar 18.

Mary McKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia.

Hip fracture data were retrieved from electronical medical records for the years 2017-2019 in the State of Qatar and used to create a FRAX® model to facilitate fracture risk assessment. Hip fracture rates were comparable with estimates from Saudi Arabia, Abu Dhabi, and Kuwait but fracture probabilities varied due to differences in mortality.

Objective: This paper describes the epidemiology of osteoporotic fractures in the State of Qatar that was used to develop the country-specific fracture prediction FRAX® tool.

Methods: Hip fracture data were retrieved from electronic medical records for the years 2017-2019 in the State of Qatar. The age and sex specific incidence of hip fracture in Qatari residents and national mortality rates were used to create a FRAX® model. Fracture probabilities were compared with those from neighboring countries having FRAX models.

Results: Hip fracture rates were comparable with estimates from Saudi Arabia, Abu Dhabi and Kuwait. In contrast, probabilities of a major osteoporotic fracture or hip fracture were lower in Qatar than in Kuwait but higher than those in Abu Dhabi and Saudi Arabia due to differences in mortality.

Conclusion: The FRAX model should enhance accuracy of determining fracture probability among the Qatari population and help guide decisions about treatment.
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http://dx.doi.org/10.1007/s11657-022-01083-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8933304PMC
March 2022

Association of shorter leucocyte telomere length with risk of frailty.

J Cachexia Sarcopenia Muscle 2022 06 17;13(3):1741-1751. Epub 2022 Mar 17.

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

Background: Frailty is a multidimensional syndrome of decline that affects multiple systems and predisposes to adverse health outcomes. Although chronological age is the major risk factor, inter-individual variation in risk is not fully understood. Leucocyte telomere length (LTL), a proposed marker of biological age, has been associated with risk of many diseases. We sought to determine whether LTL is associated with risk of frailty.

Methods: We utilized cross-sectional data from 441 781 UK Biobank participants (aged 40-69 years), with complete data on frailty indicators and LTL. Frailty was defined as the presence of at least three of five indicators: weaker grip strength, slower walking pace, weight loss in the past year, lower physical activity, and exhaustion in the past 2 weeks. LTL was measured using a validated qPCR method and reported as a ratio of the telomere repeat number (T) to a single-copy gene (S) (T/S ratio). Association of LTL with frailty was evaluated using adjusted (chronological age, sex, deprivation, smoking, alcohol intake, body mass index, and multimorbidity) multinomial and ordinal regression models, and results are presented as relative risk (RRR) or odds ratios (OR), respectively, alongside the 95% confidence interval (CI). Mendelian randomization (MR), using 131 genetic variants associated with LTL, was used to assess if the association of LTL with frailty was causal.

Results: Frail participants (4.6%) were older (median age difference (95% CI): 3 (2.5; 3.5) years, P = 2.73 × 10 ), more likely to be female (61%, P = 1.97 × 10 ), and had shorter LTL (-0.13SD vs. 0.03SD, P = 5.43 × 10 ) than non-frail. In adjusted analyses, both age and LTL were associated with frailty (RRR = 1.03 (95% CI: 1.02; 1.04) per year of older chronological age, P = 3.99 × 10 ; 1.10 (1.08; 1.11) per SD shorter LTL, P = 1.46 × 10 ). Within each age group (40-49, 50-59, 60-69 years), the prevalence of frailty was about 33% higher in participants with shorter (-2SD) versus longer telomeres (+2SD). MR analysis showed an association of LTL with frailty that was directionally consistent with the observational association, but not statistically significant (MR-Median: OR (95% CI): 1.08 (0.98; 1.19) per SD shorter LTL, P = 0.13).

Conclusions: Inter-individual variation in LTL is associated with the risk of frailty independently of chronological age and other risk factors. Our findings provide evidence for an additional biological determinant of frailty.
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http://dx.doi.org/10.1002/jcsm.12971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9178164PMC
June 2022

Placental uptake and metabolism of 25(OH)vitamin D determine its activity within the fetoplacental unit.

Elife 2022 03 8;11. Epub 2022 Mar 8.

The Institute of Developmental Sciences, Human Development and Health, Faculty of Medicine University of Southampton, Southampton, United Kingdom.

Pregnancy 25-hydroxyvitamin D [25(OH)D] concentrations are associated with maternal and fetal health outcomes. Using physiological human placental perfusion and villous explants, we investigate the role of the placenta in regulating the relationships between maternal 25(OH)D and fetal physiology. We demonstrate active placental uptake of 25(OH)D by endocytosis, placental metabolism of 25(OH)D into 24,25-dihydroxyvitamin D and active 1,25-dihydroxyvitamin D [1,25(OH)D], with subsequent release of these metabolites into both the maternal and fetal circulations. Active placental transport of 25(OH)D and synthesis of 1,25(OH)D demonstrate that fetal supply is dependent on placental function rather than simply the availability of maternal 25(OH)D. We demonstrate that 25(OH)D exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta, with widespread effects on the placenta itself. These data demonstrate a complex interplay between vitamin D and the placenta and will inform future interventions using vitamin D to support fetal development and maternal adaptations to pregnancy.
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http://dx.doi.org/10.7554/eLife.71094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8903835PMC
March 2022

FREM predicts 10-year incident fracture risk independent of FRAX® probability: a registry-based cohort study.

Osteoporos Int 2022 Jul 17;33(7):1457-1463. Epub 2022 Feb 17.

Research Unit OPEN, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.

The Danish Fracture Risk Evaluation Model (FREM) was found to predict fracture risk independent of 10-year fracture probability derived with the FRAX® tool including bone mineral density from DXA.

Introduction: FREM was developed from Danish public health registers without DXA information to identify high imminent risk of major osteoporotic fracture (MOF) and hip fracture (HF), while FRAX® estimates 10-year fracture probability from clinical risk factors and femoral neck bone mineral density (BMD) from DXA. The FREM algorithm showed significant 1- and 2-year fracture risk stratification when applied to a clinical population from Manitoba, Canada. We examined whether FREM predicts 10-year fracture risk independent of 10-year FRAX probability computed with BMD.

Methods: Using the Manitoba BMD Program registry, we identified women and men aged ≥ 45 years undergoing baseline BMD assessment. We calculated FREM and FRAX scores, and identified incident fractures over 10 years. Hazard ratios (HRs) for incident fracture were estimated according to FREM quintile, adjusted for FRAX probability. We compared predicted with observed 10-year cumulative fracture probability estimated with competing mortality.

Results: The study population comprised 74,446 women, mean age 65.2 years; 7945 men, mean age 67.5 years. There were 7957 and 646 incident MOF and 2554 and 294 incident HF in women and men, respectively. Higher FREM scores were associated with increased risk for MOF (highest vs middle quintile HRs 1.49 women, 2.06 men) and HF (highest vs middle quintile HRs 2.15 women, 2.20 men) even when adjusted for FRAX. Greater mortality with higher FREM scores attenuated its effect on 10-year fracture probability. In the highest FREM quintile, observed slightly exceeded predicted 10-year probability for MOF (ratios 1.05 in women, 1.49 in men) and HF (ratios 1.29 in women, 1.34 in men).

Conclusions: Higher FREM scores identified women and men at increased fracture risk even when adjusted for FRAX probability that included BMD; hence, FREM provides additional predictive information to FRAX. FRAX slightly underestimated 10-year fracture probability in those falling within the highest FREM quintile.
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http://dx.doi.org/10.1007/s00198-022-06349-3DOI Listing
July 2022

The Effect of Fracture Recency on Observed 10-Year Fracture Probability: A Registry-Based Cohort Study.

J Bone Miner Res 2022 05 22;37(5):848-855. Epub 2022 Feb 22.

Centre for Metabolic Bone Diseases, University of Sheffield Medical School, Sheffield, UK.

FRAX estimates 10-year fracture major osteoporotic fracture (MOF) and hip fracture probability from multiple risk factors. FRAX does not consider prior fracture site or time since fracture. Fracture risk is greater in the initial 2-year post-fracture period (imminent risk), implying that FRAX may underestimate risk in this setting. We used the population-based Manitoba Bone Mineral Density (BMD) Program registry to examine the effect of fracture recency and site on incident fracture risk predictions using FRAX. We identified women aged 40 years or older with baseline BMD and FRAX scores. Observed fracture outcomes to 10 years were compared with predicted 10-year fracture probability stratified by prior fracture status: none, recent (<2 years [median 0.3 years]), and remote (≥2 years [median 10.6 years]). For women with recent fractures, we also examined proposed multipliers to adjust FRAX for the effect of fracture recency and site. The cohort comprised 33,465 women aged 40 to 64 years (1897 recent fracture, 2120 remote fracture) and 33,806 women aged ≥65 years (2365 fracture, 4135 remote fracture). Observed fracture probability was consistent with predicted probability in most analyses. In women aged 40 to 64 years, there was a significant effect of recent vertebral and humerus fracture on MOF (observed to predicted 1.61 and 1.48, respectively), but these effects were still lower than the proposed multipliers (2.32 and 1.67, respectively). No significant effect of fracture recency was found after hip or forearm fracture in either age group. Our findings contribute to accumulating evidence of the importance of recent fracture. The effect of fracture recency was not consistent across fracture sites and with a lower magnitude than previously reported. Further quantification of effect size and specificity in additional independent cohorts is warranted to validate and refine recent-fracture multipliers in fracture risk assessment. © 2022 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4526DOI Listing
May 2022

Epigenetic regulation of bone mass.

Best Pract Res Clin Endocrinol Metab 2022 03 4;36(2):101612. Epub 2022 Jan 4.

MRC Lifecourse Epidemiology Centre, University of Southampton, UK; NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK. Electronic address:

Osteoporosis, characterised by low bone mass, poor bone structure, and an increased risk of fracture, is a major public health problem. There is increasing evidence that the influence of the environment on gene expression, through epigenetic processes, contributes to variation in BMD and fracture risk across the lifecourse. Such epigenetic processes include DNA methylation, histone and chromatin modifications and non-coding RNAs. Examples of associations with phenotype include DNA methylation in utero linked to maternal vitamin D status, and to methylation of target genes such as OPG and RANKL being associated with osteoporosis in later life. Epigenome-wide association studies and multi-omics technologies have further revealed susceptibility loci, and histone acetyltransferases, deacetylases and methylases are being considered as therapeutic targets. This review encompasses recent advances in our understanding of epigenetic mechanisms in the regulation of bone mass and osteoporosis development, and outlines possible diagnostic and prognostic biomarker applications.
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http://dx.doi.org/10.1016/j.beem.2021.101612DOI Listing
March 2022

Potential influences on optimizing long-term musculoskeletal health in children and adolescents with X-linked hypophosphatemia (XLH).

Orphanet J Rare Dis 2022 01 31;17(1):30. Epub 2022 Jan 31.

Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA.

In recent years, much progress has been made in understanding the mechanisms of bone growth and development over a lifespan, including the crosstalk between muscle and bone, to achieve optimal structure and function. While there have been significant advances in understanding how to help improve and maintain bone health in normal individuals, there is limited knowledge on whether these mechanisms apply or are compromised in pathological states. X-linked hypophosphatemia (XLH) (ORPHA:89936) is a rare, heritable, renal phosphate-wasting disorder. The resultant chronic hypophosphatemia leads to progressive deterioration in musculoskeletal function, including impaired growth, rickets, and limb deformities in children, as well as lifelong osteomalacia with reduced bone quality and impaired muscle structure and function. The clinical manifestations of the disease vary both in presentation and severity in affected individuals, and many of the consequences of childhood defects persist into adulthood, causing significant morbidity that impacts physical function and quality of life. Intervention to restore phosphate levels early in life during the critical stages of skeletal development in children with XLH could optimize growth and may prevent or reduce bone deformities in childhood. A healthier bone structure, together with improved muscle function, can lead to physical activity enhancing musculoskeletal health throughout life. In adults, continued management may help to maintain the positive effects acquired from childhood treatment, thereby slowing or halting disease progression. In this review, we summarize the opinions from members of a working group with expertise in pediatrics, epidemiology, and bone, joint and muscle biology, on potential outcomes for people with XLH, who have been optimally treated from an early age and continue treatment throughout life.
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http://dx.doi.org/10.1186/s13023-021-02156-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8802511PMC
January 2022

Osteoporosis in Europe: a compendium of country-specific reports.

Arch Osteoporos 2022 01 26;17(1):23. Epub 2022 Jan 26.

Mary McKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia.

This report describes epidemiology, burden, and treatment of osteoporosis in each of the 27 countries of the European Union plus Switzerland and the UK (EU 27+2).

Introduction: The aim of this report was to characterize the burden of osteoporosis in each of the countries of the European Union plus Switzerland and the UK in 2019 and beyond.

Methods: The data on fracture incidence and costs of fractures in the EU27+2 was taken from a concurrent publication in this journal (SCOPE 2021: a new scorecard for osteoporosis in Europe) and country-specific information extracted. The information extracted covered four domains: burden of osteoporosis and fractures; policy framework; service provision; and service uptake.

Results: The clinical and economic burden of osteoporotic fractures in 2019 is given for each of the 27 countries of the EU plus Switzerland and the UK. Each domain was ranked and the country performance set against the scorecard for all nations studied. Data were also compared with the first SCOPE undertaken in 2010. Fifteen of the 16 score card metrics on healthcare provision were used in the two surveys. Scores had improved or markedly improved in 15 countries, remained constant in 8 countries and worsened in 3 countries. The average treatment gap increased from 55% in 2010 to 71% in 2019. Overall, 10.6 million women who were eligible for treatment were untreated in 2010. In 2019, this number had risen to 14.0 million.

Conclusions: In spite of the high cost of osteoporosis, a substantial treatment gap and projected increase of the economic burden driven by aging populations, the use of pharmacological prevention of osteoporosis has decreased in recent years, suggesting that a change in healthcare policy concerning the disease is warranted.
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http://dx.doi.org/10.1007/s11657-021-00969-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8789736PMC
January 2022
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