Dual-energy X-ray absorptiometry derived knee shape may provide a useful imaging biomarker for predicting total knee replacement: Findings from a study of 37,843 people in UK Biobank.

Objective: We aimed to create an imaging biomarker for knee shape using knee dual-energy x-ray absorptiometry (DXA) scans and investigate its potential association with subsequent total knee replacement (TKR), independently of radiographic features of knee osteoarthritis and established risk factors. Methods: Using a 129-point statistical shape model, knee shape (expressed as a B-score) and minimum joint space width (mJSW) of the medial joint compartment (binarized as above or below the first quartile) were derived. Osteophytes were manually graded in a subset of images and an overall score was assigned. Cox proportional hazards models were used to examine the associations of B-score, mJSW and osteophyte score with TKR risk, adjusting for age, sex, height and weight. Results: The analysis included 37,843 individuals (mean age 63.7 years). In adjusted models, B-score was associated with TKR: each unit increase in B-score, reflecting one standard deviation from the mean healthy shape, corresponded to a hazard ratio (HR) of 2.25 (2.08, 2.43), while a lower mJSW had a HR of 2.28 (1.88, 2.77). Among the 6719 images scored for osteophytes, mJSW was replaced by osteophyte score in the most strongly predictive model for TKR. In ROC analyses, a model combining B-score, osteophyte score, and demographics outperformed a model including demographics alone (AUC â€‹= â€‹0.87 vs 0.73). Conclusions: Using statistical shape modelling, we derived a DXA-based imaging biomarker for knee shape that was associated with kOA progression. When combined with osteophytes and demographic data, this biomarker may help identify individuals at high risk of TKR, facilitating targeted interventions.

Lifecourse correlates of self-rated health and associations with subsequent mortality: findings from the Hertfordshire Cohort Study.

Background: Poor self-rated health (SRH) has been shown to predict adverse health outcomes among older people, however these associations have traditionally only been considered at one point in the lifecourse, usually midlife or later. Here we examined lifecourse correlates of SRH in early, mid and later life, relating these to subsequent risk of mortality in a community-dwelling cohort. Methods: 2989 men and women from the Hertfordshire Cohort Study (HCS) were included in this study. The HCS was initially retrospective and linked contemporary health outcome data to early life data available from health ledgers but investigations from baseline (1998-2004, aged 59-73) onwards have been prospective. At baseline, participants completed an initial clinic visit, which included questionnaire assessment of SRH, reported as 'excellent', 'very good', 'good', 'fair', or 'poor'. Socioeconomic, lifestyle, mental health and demographic information was also collected. Deaths were recorded from baseline to 31/12/2018. Baseline characteristics in relation to SRH were examined using sex-stratified ordinal logistic regression; these factors were examined in relation to mortality using sex-stratified Cox regression. Statistically significant exposures were then included in sex-stratified mutually-adjusted models. Results: In mutually-adjusted analysis, numerous contemporaneous correlates of poorer SRH in the seventh decade were identified and included obesity, lower physical activity, greater comorbidity and higher levels of depression among men and women. For example, odds ratios for being in a lower category of SRH were as follows: obese (BMI≥30) vs underweight/healthy (BMI<25) (men 1.60 (1.21, 2.11), women 1.65 (1.25, 2.17)) and per additional system medicated (men 1.62 (1.47, 1.77), women 1.53 (1.41, 1.66)). By contrast, factors earlier in the lifecourse (early growth, age left full-time education) were not associated with SRH in late adulthood. 36% of men and 26% of women died during follow-up. Hazard ratios (95% CI) for mortality per lower category of SRH were 1.22 (1.10,1.36) among men and 1.17 (1.01,1.35) among women after adjustment for age, BMI, smoking, physical activity, diet quality, education, home ownership status, comorbidity level and depression levels, suggesting residual confounding by other unrecorded factors that are related to SRH. Conclusions: Poorer SRH in the seventh decade was a risk factor for mortality. Importantly modifiable adverse health behaviours in the seventh decade, such as low physical activity, were associated with poorer SRH and later mortality after adjustment for socioeconomic factors and comorbidity level. By contrast early growth and education were not related to later SRH. These data suggest that attention to lifestyle in late midlife may be associated with better SRH and subsequent health outcomes, highlighting the value of intervention at this stage of the lifecourse.

Influence of vitamin D supplementation on growth, body composition, pubertal development and spirometry in South African schoolchildren: a randomised controlled trial (ViDiKids).

OBJECTIVE: To determine whether weekly oral vitamin D supplementation influences growth, body composition, pubertal development or spirometric outcomes in South African schoolchildren. DESIGN: Phase 3 double-blind randomised placebo-controlled trial. SETTING: Socioeconomically disadvantaged peri-urban district of Cape Town, South Africa. PARTICIPANTS: 1682 children of black African ancestry attending government primary schools and aged 6-11 years at baseline. INTERVENTIONS: Oral vitamin D3 (10 000 IU/week) versus placebo for 3 years. MAIN OUTCOME MEASURES: Height-for-age and body mass index-for-age, measured in all participants; Tanner scores for pubertal development, spirometric lung volumes and body composition, measured in a subset of 450 children who additionally took part in a nested substudy. RESULTS: Mean serum 25-hydroxyvitamin D3 concentration at 3-year follow-up was higher among children randomised to receive vitamin D versus placebo (104.3 vs 64.7 nmol/L, respectively; mean difference (MD) 39.7 nmol/L, 95% CI 37.6 to 41.9 nmol/L). No statistically significant differences in height-for-age z-score (adjusted MD (aMD) -0.08, 95% CI -0.19 to 0.03) or body mass index-for-age z-score (aMD -0.04, 95% CI -0.16 to 0.07) were seen between vitamin D versus placebo groups at follow-up. Among substudy participants, allocation to vitamin D versus placebo did not influence pubertal development scores, % predicted forced expiratory volume in 1 s (FEV1), % predicted forced vital capacity (FVC), % predicted FEV1/FVC, fat mass or fat-free mass. CONCLUSIONS: Weekly oral administration of 10 000 IU vitamin D3 boosted vitamin D status but did not influence growth, body composition, pubertal development or spirometric outcomes in South African schoolchildren. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov NCT02880982, South African National Clinical Trials Register DOH-27-0916-5527.

FRAX predicts cardiovascular risk in women undergoing osteoporosis screening: the Manitoba bone mineral density registry.

Osteoporosis and cardiovascular disease (CVD) are highly prevalent in older women, with increasing evidence for shared risk factors and pathogenesis. Although FRAX was developed for the assessment of fracture risk, we hypothesized that it might also provide information on CVD risk. To test the ability of the FRAX tool and FRAX-defined risk factors to predict incident CVD in women undergoing osteoporosis screening with DXA, we performed a retrospective prognostic cohort study which included women aged 50 yr or older with a baseline DXA scan in the Manitoba Bone Mineral Density Registry between March 31, 1999 and March 31, 2018. FRAX scores for major osteoporotic fracture (MOF) were calculated on all participants. Incident MOF and major adverse CV events (MACE; hospitalized acute myocardial infarction [AMI], hospitalized non-hemorrhagic cerebrovascular disease [CVA], or all-cause death) were ascertained from linkage to population-based healthcare data. The study population comprised 59 696 women (mean age 65.7 ± 9.4 yr). Over mean 8.7 yr of observation, 6021 (10.1%) had MOF, 12 277 women (20.6%) had MACE, 2274 (3.8%) had AMI, 2061 (3.5%) had CVA, and 10 253 (17.2%) died. MACE rates per 1000 person-years by FRAX risk categories low (10-yr predicted MOF <10%), moderate (10%-19.9%) and high (≥20%) were 13.5, 34.0, and 64.6, respectively. Although weaker than the association with incident MOF, increasing FRAX quintile was associated with increasing risk for MACE (all P-trend <.001), even after excluding prior CVD and adjusting for age. HR for MACE per SD increase in FRAX was 1.99 (95%CI, 1.96-2.02). All FRAX-defined risk factors (except parental hip fracture and lower BMI) were independently associated with higher non-death CV events. Although FRAX is intended for fracture risk prediction, it has predictive value for cardiovascular risk.

Cardiovascular Magnetic Resonance Reference Ranges From the Healthy Hearts Consortium.

BACKGROUND: The absence of population-stratified cardiovascular magnetic resonance (CMR) reference ranges from large cohorts is a major shortcoming for clinical care. OBJECTIVES: This paper provides age-, sex-, and ethnicity-specific CMR reference ranges for atrial and ventricular metrics from the Healthy Hearts Consortium, an international collaborative comprising 9,088 CMR studies from verified healthy individuals, covering the complete adult age spectrum across both sexes, and with the highest ethnic diversity reported to date. METHODS: CMR studies were analyzed using certified software with batch processing capability (cvi42, version 5.14 prototype, Circle Cardiovascular Imaging) by 2 expert readers. Three segmentation methods (smooth, papillary, anatomic) were used to contour the endocardial and epicardial borders of the ventricles and atria from long- and short-axis cine series. Clinically established ventricular and atrial metrics were extracted and stratified by age, sex, and ethnicity. Variations by segmentation method, scanner vendor, and magnet strength were examined. Reference ranges are reported as 95% prediction intervals. RESULTS: The sample included 4,452 (49.0%) men and 4,636 (51.0%) women with average age of 61.1 ± 12.9 years (range: 18-83 years). Among these, 7,424 (81.7%) were from White, 510 (5.6%) South Asian, 478 (5.3%) mixed/other, 341 (3.7%) Black, and 335 (3.7%) Chinese ethnicities. Images were acquired using 1.5-T (n = 8,779; 96.6%) and 3.0-T (n = 309; 3.4%) scanners from Siemens (n = 8,299; 91.3%), Philips (n = 498; 5.5%), and GE (n = 291, 3.2%). CONCLUSIONS: This work represents a resource with healthy CMR-derived volumetric reference ranges ready for clinical implementation.

Cognitive function and skeletal size and mineral density at age 6-7 years: Findings from the Southampton Women's Survey.

INTRODUCTION: Poor cognitive function and osteoporosis commonly co-exist in later life. In women, this is often attributed to post-menopausal estrogen loss. However, a common early life origin for these conditions and the associations between cognitive function and bone mineral density (BMD) in childhood have not previously been explored. We examined these relationships at age 6-7 years in the Southampton Women's Survey (SWS) mother-offspring cohort. METHODS: Child occipitofrontal circumference (OFC), a proxy for brain volume, intelligence quotient (IQ) [Wechsler Abbreviated Scale of Intelligence] and visual recognition and working memory [CANTAB® Delayed Matching to Sample (DMS) and Spatial Span Length (SSP), respectively] were assessed. Whole-body-less-head (WBLH) and lumbar spine dual-energy X-ray absorptiometry [Hologic Discovery] (DXA) were performed to measure bone area (BA), bone mineral content (BMC), BMD and bone mineral apparent density (BMAD). Linear regression was used to examine associations between age and sex standardized variables (ß represent standard deviation (SD) difference per SD of cognitive function). RESULTS: DXA was performed in 1331 children (mean (SD) age 6.8 (0.33) years, 51.5 % male), with OFC, IQ, DMS and SSP assessed in 1250, 551, 490 and 460, respectively. OFC (ß = 0.25 SD/SD, 95%CI 0.20,0.30), IQ (ß = 0.11 SD/SD, 95%CI 0.02,0.19), and DMS (ß = 0.11, SD/SD, 95%CI 0.01,0.20) were positively associated with WBLH BA, with similar associations for lumbar spine BA. OFC and DMS were also positively associated with WBLH BMC, but only OFC was associated with BMD (WBLH: ß = 0.38 SD/SD, 95%CI 0.33,0.43; LS: ß = 0.19 SD/SD, 95%CI 0.13,0.24). CONCLUSION: Childhood brain volume was positively associated with measures of skeletal size and BMD, whereas IQ and memory were associated only with skeletal size. These findings suggest that common early life determinants for skeletal growth and BMD and cognitive function should be explored to identify potential early-life approaches to preventing osteoporosis and cognitive decline.

Influence of vitamin D supplementation on bone mineral content, bone turnover markers, and fracture risk in South African schoolchildren: multicenter double-blind randomized placebo-controlled trial (ViDiKids).

Randomized controlled trials (RCTs) to determine the influence of vitamin D on BMC and fracture risk in children of Black African ancestry are lacking. We conducted a sub-study (n = 450) nested within a phase 3 RCT of weekly oral supplementation with 10 000 IU vitamin D3 vs placebo for 3 yr in HIV-uninfected Cape Town schoolchildren aged 6-11 yr. Outcomes were BMC at the whole body less head (WBLH) and LS and serum 25-hydroxyvitamin D3 (25(OH)D3), PTH, alkaline phosphatase, C-terminal telopeptide, and PINP. Incidence of fractures was a secondary outcome of the main trial (n = 1682). At baseline, mean serum 25(OH)D3 concentration was 70.0 nmol/L (SD 13.5), and 5.8% of participants had serum 25(OH)D3 concentrations <50 nmol/L. Among sub-study participants, end-trial serum 25(OH)D3 concentrations were higher for participants allocated to vitamin D vs placebo (adjusted mean difference [aMD] 39.9 nmol/L, 95% CI, 36.1 to 43.6) and serum PTH concentrations were lower (aMD -0.55 pmol/L, 95% CI, -0.94 to -0.17). However, no interarm differences were seen for WBLH BMC (aMD -8.0 g, 95% CI, -30.7 to 14.7) or LS BMC (aMD -0.3 g, 95% CI, -1.3 to 0.8) or serum concentrations of bone turnover markers. Fractures were rare among participants in the main trial randomized to vitamin D vs placebo (7/755 vs 10/758 attending at least 1 follow-up; adjusted odds ratio 0.70, 95% CI, 0.27 to 1.85). In conclusion, a 3-yr course of weekly oral vitamin D supplementation elevated serum 25(OH)D3 concentrations and suppressed serum PTH concentrations in HIV-uninfected South African schoolchildren of Black African ancestry but did not influence BMC or serum concentrations of bone turnover markers. Fracture incidence was low, limiting power to detect an effect of vitamin D on this outcome.

Vitamin D­the "sunshine vitamin"­is essential for helping the body to absorb calcium from the diet, which is laid down in bone to improve its strength. There is a lack of clinical trials testing whether vitamin D supplements can improve bone content of calcium and other minerals, or reduce risk of bone fractures (broken bones) in children of Black African ancestry. We therefore conducted such a study, recruiting 1682 schoolchildren aged 6­11 yr living in Cape Town, South Africa. We found that a weekly dose of 10 000 international units (250 micrograms) of vitamin D3, given by mouth for 3 yr, was effective in boosting vitamin D levels in trial participants who received it. However, this did not have any effect on bone content of calcium and other minerals. Relatively few children experienced a broken bone during the study, so we were unable to say with confidence whether or not vitamin D supplements might affect this outcome.

Femoral neck width genetic risk score is a novel independent risk factor for hip fractures.

Femoral neck width (FNW) derived from DXA scans may provide a useful adjunct to hip fracture prediction. Therefore, we investigated whether FNW is related to hip fracture risk independently of femoral neck bone mineral density (FN-BMD), using a genetic approach. FNW was derived from points automatically placed on the proximal femur using hip DXA scans from 38 150 individuals (mean age 63.8 yr, 48.0% males) in UK Biobank (UKB). Genome-wide association study (GWAS) identified 71 independent genome-wide significant FNW SNPs, comprising genes involved in cartilage differentiation, hedgehog, skeletal development, in contrast to SNPs identified by FN-BMD GWAS which primarily comprised runx1/Wnt signaling genes (MAGMA gene set analyses). FNW and FN-BMD SNPs were used to generate genetic instruments for multivariable Mendelian randomization. Greater genetically determined FNW increased risk of all hip fractures (odds ratio [OR] 1.53; 95% CI, 1.29-1.82 per SD increase) and femoral neck fractures (OR 1.58;1.30-1.92), but not trochanteric or forearm fractures. In contrast, greater genetically determined FN-BMD decreased fracture risk at all 4 sites. FNW and FN-BMD SNPs were also used to generate genetic risk scores (GRSs), which were examined in relation to incident hip fracture in UKB (excluding the FNW GWAS population; n = 338 742, 3222 cases) using a Cox proportional hazards model. FNW GRS was associated with increased risk of all incident hip fractures (HR 1.08;1.05-1.12) and femoral neck fractures (hazard ratio [HR] 1.10;1.06-1.15), but not trochanteric fractures, whereas FN-BMD GRS was associated with reduced risk of all hip fracture types. We conclude that the underlying biology regulating FNW and FN-BMD differs, and that DXA-derived FNW is causally related to hip fractures independently of FN-BMD, adding information beyond FN-BMD for hip fracture prediction. Hence, FNW derived from DXA analyses or a FNW GRS may contribute clinically useful information beyond FN-BMD for hip fracture prediction.

Femoral neck width (FNW) derived from DXA scans may provide useful information about hip fracture prediction, over and above that provided by BMD measurements. Therefore, we investigated whether FNW is related to hip fracture risk independently of BMD, using a genetic approach. FNW was derived from points automatically placed on the hip in DXA scans obtained from 38 150 individuals (mean age 63.8 yr, 48.0% males) in UK Biobank. Seventy-one distinct genetic factors were found to be associated with FNW. Individuals who were predicted by their genes to have greater FNW had a higher risk of hip but not forearm fractures. In contrast, those with greater genetically determined BMD of the femoral neck had a lower risk of both hip and forearm fractures. We conclude that the underlying biology regulating FNW and BMD of the femoral neck differs, and that FNW derived from DXA analyses may contribute clinically useful information beyond BMD for hip fracture prediction.

Evidence-Based Guideline for the management of osteoporosis in men.

Historically, osteoporosis has been viewed as a disease of women, with research, trials of interventions and guidelines predominantly focused as such. It is apparent, however, that this condition causes a substantial health burden in men also, and that its assessment and management must ultimately be addressed across both sexes. In this article, an international multidisciplinary working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases presents GRADE-assessed recommendations for the diagnosis, monitoring and treatment of osteoporosis in men. The recommendations are based on a comprehensive review of the latest research related to diagnostic and screening approaches for osteoporosis and its associated high fracture risk in men, covering disease burden, appropriate interpretation of bone densitometry (including the use of a female reference database for densitometric diagnosis in men) and absolute fracture risk, thresholds for treatment, and interventions that can be used therapeutically and their health economic evaluation. Future work should specifically address the efficacy of anti-osteoporosis medications, including denosumab and bone-forming therapies.

Sarcopenia definitions and their association with fracture risk in older Swedish women.

The purpose of this study was to investigate the prevalence of three sarcopenia definitions and their associations with fracture risk in older Swedish women when adjusted for fracture risk assessment (FRAX)-based risk factors; 2,883 women with a mean age of 77.8 years were included. Sarcopenia was defined based on the Sarcopenia Definitions and Outcomes Consortium (SDOC; low handgrip strength [kg] and gait speed (m/s)), revised European Working Group on Sarcopenia in Older People (EWGSOP2; low appendicular lean mass index, appendicular lean mass [ALM]/height; kg/m2], and hand grip strength [kg]), and Asian Working Group for Sarcopenia (AWGS; low ALM (kg), and hand grip strength [kg]) definitions. Femoral neck T-score was obtained from dual-energy X-ray absorptiometry. All fractures, confirmed by X-ray or medical record review, were subsequently categorized as major osteoporotic fractures (MOFs) and hip fractures. Deaths were verified through regional registers. The total follow-up time was 6.4 ± 1.3 (mean ± SD) yr. Cox regression (hazard ratios [HR] and 95% CIs) analyses were performed with adjustment for age, FRAX variables, and femoral neck T-score. Sarcopenia prevalence was 4.5% (n = 129) according to SDOC, 12.5% (n = 360) for EWGSOP2, and 10.3% (n = 296) defined by AWGS. Individuals with sarcopenia defined by SDOC had a higher mortality risk than individuals without sarcopenia (HR: 3.41; 95% CI: 2.51, 4.62) after adjusting for age and FRAX variables. Sarcopenia according to EWGSOP2 and AWGS was not associated with an increased fracture risk after adjusting for age and FRAX variables. Individuals with sarcopenia defined by SDOC had a higher risk for any fractures (HR: 1.48; 95% CI: 1.10, 1.99) and MOF (HR: 1.42; 95% CI: 1.03, 1.98) compared with individuals without sarcopenia after adjusting for clinical risk factors used in FRAX. In conclusion, sarcopenia defined by SDOC, incorporating muscle function/strength, was the only sarcopenia definition associated with fracture risk in older women.

This study aimed to investigate the risk of sarcopenia on fracture risk in older Swedish women. Data were utilized from 2,883 women aged 75­80 yr in the Swedish Sahlgrenska University Hospital Prospective Evaluation of Risk of Bone Fractures cohort. Sarcopenia was defined using three different definitions, including the Sarcopenia Definitions and Outcomes Consortium (SDOC), which includes grip strength and gait speed, while the revised European Working Group on Sarcopenia in Older People (EWGSOP2) and the Asian Working Group for Sarcopenia (AWGS) definitions include appendicular lean mass measured by dual-energy X-ray absorptiometry and grip strength. The results demonstrated that SDOC-defined sarcopenia was associated with a higher mortality risk, with increased risk of any fractures, and major osteoporotic fractures, whereas the EWGSOP2 and AWGS definitions were not associated with fracture risk. In summary, the study demonstrates that sarcopenia defined by SDOC, considering muscle function and strength, rather than lean mass, was the only investigated sarcopenia definition associated with fracture risk.

The serum small non-coding RNA (SncRNA) landscape as a molecular biomarker of age associated muscle dysregulation and insulin resistance in older adults.

Small noncoding RNAs (sncRNAs) are implicated in age-associated pathologies, including sarcopenia and insulin resistance (IR). As potential circulating biomarkers, most studies have focussed on microRNAs (miRNAs), one class of sncRNA. This study characterized the wider circulating sncRNA transcriptome of older individuals and associations with sarcopenia and IR. sncRNA expression including miRNAs, transfer RNAs (tRNAs), tRNA-associated fragments (tRFs), and piwi-interacting RNAs (piRNAs) was measured in serum from 21 healthy and 21 sarcopenic Hertfordshire Sarcopenia Study extension women matched for age (mean 78.9 years) and HOMA2-IR. Associations with age, sarcopenia and HOMA2-IR were examined and predicted gene targets and biological pathways characterized. Of the total sncRNA among healthy controls, piRNAs were most abundant (85.3%), followed by tRNAs (4.1%), miRNAs (2.7%), and tRFs (0.5%). Age was associated (FDR < 0.05) with 2 miRNAs, 58 tRNAs, and 14 tRFs, with chromatin organization, WNT signaling, and response to stress enriched among gene targets. Sarcopenia was nominally associated (p < .05) with 12 tRNAs, 3 tRFs, and 6 piRNAs, with target genes linked to cell proliferation and differentiation such as Notch Receptor 1 (NOTCH1), DISC1 scaffold protein (DISC1), and GLI family zinc finger-2 (GLI2). HOMA2-IR was nominally associated (p<0.05) with 6 miRNAs, 9 tRNAs, 1 tRF, and 19 piRNAs, linked with lysine degradation, circadian rhythm, and fatty acid biosynthesis pathways. These findings identify changes in circulating sncRNA expression in human serum associated with chronological age, sarcopenia, and IR. These may have clinical utility as circulating biomarkers of ageing and age-associated pathologies and provide novel targets for therapeutic intervention.

Muscle parameters in fragility fracture risk prediction in older adults: A scoping review.

Half of osteoporotic fractures occur in patients with normal/osteopenic bone density or at intermediate or low estimated risk. Muscle measures have been shown to contribute to fracture risk independently of bone mineral density. The objectives were to review the measurements of muscle health (muscle mass/quantity/quality, strength and function) and their association with incident fragility fractures and to summarize their use in clinical practice. This scoping review follows the PRISMA-ScR guidelines for reporting. Our search strategy covered the three overreaching concepts of 'fragility fractures', 'muscle health assessment' and 'risk'. We retrieved 14 745 references from Medline Ovid SP, EMBASE, Web of Science Core Collection and Google Scholar. We included original and prospective studies on community-dwelling adults aged over 50 years that analysed an association between at least one muscle parameter and incident fragility fractures. We systematically extracted 17 items from each study, including methodology, general characteristics and results. Data were summarized in tables and graphically presented in adjusted forest plots. Sixty-seven articles fulfilled the inclusion criteria. In total, we studied 60 muscle parameters or indexes and 322 fracture risk ratios over 2.8 million person-years (MPY). The median (interquartile range) sample size was 1642 (921-5756), age 69.2 (63.5-73.6) years, follow-up 10.0 (4.4-12.0) years and number of incident fragility fractures 166 (88-277). A lower muscle mass was positively/not/negatively associated with incident fragility fracture in 28 (2.0), 64 (2.5) and 10 (0.2 MPY) analyses. A lower muscle strength was positively/not/negatively associated with fractures in 53 (1.3), 57 (1.7 MPY) and 0 analyses. A lower muscle function was positively/not/negatively associated in 63 (1.9), 45 (1.0 MPY) and 0 analyses. An in-depth analysis shows how each single muscle parameter was associated with each fragility fractures subtype. This review summarizes markers of muscle health and their association with fragility fractures. Measures of muscle strength and function appeared to perform better for fracture risk prediction. Of these, hand grip strength and gait speed are likely to be the most practical measures for inclusion in clinical practice, as in the evaluation of sarcopenia or in further fracture risk assessment scores. Measures of muscle mass did not appear to predict fragility fractures and might benefit from further research, on D3-creatine dilution test, lean mass indexes and artificial intelligence methods.

Musculoskeletal health and life-space mobility in older adults: Findings from the Hertfordshire Cohort Study.

This study explores the relationship between musculoskeletal conditions of ageing and life-space mobility (LSM) in 1110 community-dwelling older adults from the Hertfordshire Cohort Study. LSM is a novel measure which captures ability to mobilise within the home, locally and more widely. Among men, older age, care receipt, not driving a car, lower wellbeing, and reduced physical function were associated with lower LSM, while in women only driving status and physical function were associated with LSM. Osteoporosis, arthritis, and fractures had no significant associations with LSM in either gender. These findings provide support for sex-specificity in the determinants of LSM and inform novel approaches to improving mobility and health in older age.

Sex-based differences in risk factors for incident myocardial infarction and stroke in the UK Biobank.

AIM: This study examined sex-based differences in associations of vascular risk factors with incident cardiovascular events in the UK Biobank. METHODS: Baseline participant demographic, clinical, laboratory, anthropometric, and imaging characteristics were collected. Multivariable Cox regression was used to estimate independent associations of vascular risk factors with incident myocardial infarction (MI) and ischaemic stroke for men and women. Women-to-men ratios of hazard ratios (RHRs), and related 95% confidence intervals, represent the relative effect-size magnitude by sex. RESULTS: Among the 363 313 participants (53.5% women), 8470 experienced MI (29.9% women) and 7705 experienced stroke (40.1% women) over 12.66 [11.93, 13.38] years of prospective follow-up. Men had greater risk factor burden and higher arterial stiffness index at baseline. Women had greater age-related decline in aortic distensibility. Older age [RHR: 1.02 (1.01-1.03)], greater deprivation [RHR: 1.02 (1.00-1.03)], hypertension [RHR: 1.14 (1.02-1.27)], and current smoking [RHR: 1.45 (1.27-1.66)] were associated with a greater excess risk of MI in women than men. Low-density lipoprotein cholesterol was associated with excess MI risk in men [RHR: 0.90 (0.84-0.95)] and apolipoprotein A (ApoA) was less protective for MI in women [RHR: 1.65 (1.01-2.71)]. Older age was associated with excess risk of stroke [RHR: 1.01 (1.00-1.02)] and ApoA was less protective for stroke in women [RHR: 2.55 (1.58-4.14)]. CONCLUSION: Older age, hypertension, and smoking appeared stronger drivers of cardiovascular disease in women, whereas lipid metrics appeared stronger risk determinants for men. These findings highlight the importance of sex-specific preventive strategies and suggest priority targets for intervention in men and women.

Patients' preferences for fracture risk communication: the Risk Communication in Osteoporosis (RICO) study.

The RICO study indicated that most patients would like to receive information regarding their fracture risk but that only a small majority have actually received it. Patients globally preferred a visual presentation of fracture risk and were interested in an online tool showing the risk. PURPOSE: The aim of the Risk Communication in Osteoporosis (RICO) study was to assess patients' preferences regarding fracture risk communication. METHODS: To assess patients' preferences for fracture risk communication, structured interviews with women with osteoporosis or who were at risk for fracture were conducted in 11 sites around the world, namely in Argentina, Belgium, Canada at Hamilton and with participants from the Osteoporosis Canada Canadian Osteoporosis Patient Network (COPN), Japan, Mexico, Spain, the Netherlands, the UK, and the USA in California and Washington state. The interviews used to collect data were designed on the basis of a systematic review and a qualitative pilot study involving 26 participants at risk of fracture. RESULTS: A total of 332 women (mean age 67.5 ± 8.0 years, 48% with a history of fracture) were included in the study. Although the participants considered it important to receive information about their fracture risk (mean importance of 6.2 ± 1.4 on a 7-point Likert scale), only 56% (i.e. 185/332) had already received such information. Globally, participants preferred a visual presentation with a traffic-light type of coloured graph of their FRAX® fracture risk probability, compared to a verbal or written presentation. Almost all participants considered it important to discuss their fracture risk and the consequences of fractures with their healthcare professionals in addition to receiving information in a printed format or access to an online website showing their fracture risk. CONCLUSIONS: There is a significant communication gap between healthcare professionals and patients when discussing osteoporosis fracture risk. The RICO study provides insight into preferred approaches to rectify this communication gap.

Fracture prediction in rheumatoid arthritis: validation of FRAX with bone mineral density for incident major osteoporotic fractures.

OBJECTIVES: FRAX® uses clinical risk factors, with or without bone mineral density (BMD), to calculate 10-year fracture risk. Rheumatoid arthritis (RA) is a risk factor for osteoporotic fracture and a FRAX input variable. FRAX predates the current era of RA treatment. We examined how well FRAX predicts fracture in contemporary RA patients. METHODS: Administrative data from patients receiving BMD testing were linked to the Manitoba Population Health Research Data Repository. Observed cumulative 10-year Major Osteoporotic Fracture (MOF) probability was compared with FRAX-predicted 10-year MOF probability with BMD for assessing calibration. MOF risk stratification was assessed using Cox regression. RESULTS: RA patients (N = 2,099, 208 with incident MOF) and non-RA patients (N = 2,099, with 165 incident MOF) were identified. For RA patients, FRAX predicted 10-year risk was 13.2% and observed 10-year MOF risk was 13.2% (95% CI 11.6% to 15.1%). The slope of the calibration plot was 0.67 (95% CI 0.53-0. 81) in those with RA vs 0.98 (95% CI 0.61-1.34) in non-RA patients. Risk was overestimated in RA patients with high FRAX scores (>20%), but FRAX was well-calibrated in other groups. FRAX stratified risk in those with and without RA (hazard ratios 1.52, 95% 1.25-1.72 vs 2.00, 95% 1.73-2.31), with slightly better performance in the latter (p-interaction = 0.004). CONCLUSIONS: FRAX predicts fracture risk in contemporary RA patients but may slightly overestimate risk in those already at high predicted risk. Thus, the current FRAX tool continues to be appropriate for fracture risk assessment in RA patients.

Comparison between UK Biobank and Shanghai Changfeng suggests distinct hip morphology may contribute to ethnic differences in the prevalence of hip osteoarthritis.

OBJECTS: Joint morphology is a risk factor for hip osteoarthritis (HOA) and could explain ethnic differences in HOA prevalence. Therefore, we aimed to compare the prevalence of radiographic HOA (rHOA) and hip morphology between the predominantly White UK Biobank (UKB) and exclusively Chinese Shanghai Changfeng (SC) cohorts. METHODS: Left hip iDXA scans were used to quantify rHOA, from a combination of osteophytes (grade ≥1) and joint space narrowing (grade ≥1), and hip morphology. Using an 85-point Statistical Shape Model (SSM) we evaluated cam (alpha angle ≥60°) and pincer (lateral centre-edge angle (LCEA) ≥45°) morphology and acetabular dysplasia (LCEA <25°). Diameter of femoral head (DFH), femoral neck width (FNW), and hip axis length (HAL) were also obtained from these points. Results were adjusted for differences in age, height, and weight and stratified by sex. RESULTS: Complete data were available for 5924 SC and 39,020 White UKB participants with mean ages of 63.4 and 63.7 years old. rHOA prevalence was considerably lower in female (2.2% versus 13.1%) and male (12.0% and 25.1%) SC compared to UKB participants. Cam morphology, rarely seen in females, was less common in SC compared with UKB males (6.3% versus 16.5%). Composite SSM modes, scaled to the same overall size, revealed SC participants to have a wider femoral head compared to UKB participants. FNW and HAL were smaller in SC compared to UKB, whereas DFH/FNW ratio was higher in SC. CONCLUSIONS: rHOA prevalence is lower in Chinese compared with White individuals. Several differences in hip shape were observed, including frequency of cam morphology, FNW, and DFH/FNW ratio. These characteristics have previously been identified as risk factors for HOA and may contribute to observed ethnic differences in HOA prevalence.

Association between subclinical atherosclerosis and cardiac structure and function-results from the UK Biobank Study.

Aims: Heart failure (HF) is a major health problem and early diagnosis is important. Atherosclerosis is the main cause of HF and carotid intima-media thickness (IMT) is a recognized early measure of atherosclerosis. This study aimed to investigate whether increased carotid IMT is associated with changes in cardiac structure and function in middle-aged participants of the UK Biobank Study without overt cardiovascular disease. Methods and results: Participants of the UK Biobank who underwent CMR and carotid ultrasound examinations were included in this study. Patients with heart failure, angina, atrial fibrillation, and history of myocardial infarction or stroke were excluded. We used multivariable linear regression models adjusted for age, sex, physical activity, body mass index, body surface area, hypertension, diabetes, smoking, ethnicity, socioeconomic status, alcohol intake, and laboratory parameters. In total, 4301 individuals (61.6 ± 7.5 years, 45.9% male) were included. Multivariable linear regression analyses showed that increasing quartiles of IMT was associated with increased left and right ventricular (LV and RV) and left atrial volumes and greater LV mass. Moreover, increased IMT was related to lower LV end-systolic circumferential strain, torsion, and both left and right atrial ejection fractions (all P < 0.05). Conclusion: Increased IMT showed an independent association over traditional risk factors with enlargement of all four cardiac chambers, decreased function in both atria, greater LV mass, and subclinical LV dysfunction. There may be additional risk stratification that can be derived from the IMT to identify those most likely to have early cardiac structural/functional changes.

DNA methylation of insulin signaling pathways is associated with HOMA2-IR in primary myoblasts from older adults.

BACKGROUND: While ageing is associated with increased insulin resistance (IR), the molecular mechanisms underlying increased IR in the muscle, the primary organ for glucose clearance, have yet to be elucidated in older individuals. As epigenetic processes are suggested to contribute to the development of ageing-associated diseases, we investigated whether differential DNA methylation was associated with IR in human primary muscle stem cells (myoblasts) from community-dwelling older individuals. METHODS: We measured DNA methylation (Infinium HumanMethylationEPIC BeadChip) in myoblast cultures from vastus lateralis biopsies (119 males/females, mean age 78.24 years) from the Hertfordshire Sarcopenia Study extension (HSSe) and examined differentially methylated cytosine phosphate guanine (CpG) sites (dmCpG), regions (DMRs) and gene pathways associated with HOMA2-IR, an index for the assessment of insulin resistance, and levels of glycated hemoglobin HbA1c. RESULTS: Thirty-eight dmCpGs (false discovery rate (FDR) < 0.05) were associated with HOMA2-IR, with dmCpGs enriched in genes linked with JNK, AMPK and insulin signaling. The methylation signal associated with HOMA2-IR was attenuated after the addition of either BMI (6 dmCpGs), appendicular lean mass index (ALMi) (7 dmCpGs), grip strength (15 dmCpGs) or gait speed (23 dmCpGs) as covariates in the model. There were 8 DMRs (Stouffer < 0.05) associated with HOMA2-IR, including DMRs within T-box transcription factor (TBX1) and nuclear receptor subfamily-2 group F member-2 (NR2F2); the DMRs within TBX1 and NR2F2 remained associated with HOMA2-IR after adjustment for BMI, ALMi, grip strength or gait speed. Forty-nine dmCpGs and 21 DMRs were associated with HbA1c, with cg13451048, located within exoribonuclease family member 3 (ERI3) associated with both HOMA2-IR and HbA1c. HOMA2-IR and HbA1c were not associated with accelerated epigenetic ageing. CONCLUSIONS: These findings suggest that insulin resistance is associated with differential DNA methylation in human primary myoblasts with both muscle mass and body composition making a significant contribution to the methylation changes associated with IR.