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.

Opportunistically identifiable vertebral fractures on routine radiological imaging predict mortality: observational cohort study.

In men and women with opportunistically identifiable vertebral fractures (VFs) on routine CT scans including the chest and/or abdomen, the risk of death is 51% higher than in those with no VF on the CT scan, and 325% higher than an age- and sex-matched general population cohort. PURPOSE: There is little knowledge about the risk of death in patients with VFs present on routine radiological imaging. We evaluated the risk of death in men and women aged 50 years or older with opportunistically identifiable VFs on routine CT scans and not treated with osteoporosis medications. METHODS: Thoracic and lumbar VFs were identified through a blinded, two-step approach on CT scans performed as part of normal clinical care in a Danish hospital in 2010 or later. Subjects with VF were matched on age and sex against those with no VF (1:2-ratio) and a general population cohort (1:3-ratio), respectively, and followed for up to 7 years through the national Danish registers. Subjects treated with an osteoporosis medication in the year prior to baseline were excluded. RESULTS: Subjects with VF had a significantly higher risk of death during follow-up as compared to subjects with no VF on the CT scan (adjusted hazard ratio [HR] 1.51 [95% confidence interval 1.27-1.79; p < 0.001]) and even more so when compared to the general population cohort (HR 4.25 [3.53-5.12; p < 0.001]). In subjects with versus without VF on the CT scan, the risk was higher in those with moderate or severe VF, in those with no malignancy prior to baseline, and in those with a lower Charlson comorbidity index score. CONCLUSION: Subjects with VF available for identification on routine CT scans face a substantially increased risk of death. Opportunistic identification and reporting of VF is important to identify these patients to allow intervention if indicated.

IOF position on scientists and societies operating in conflict zones.

This position paper of the International Osteoporosis Foundation reports the findings of an IOF Commission to consider to recommend rules of partnership with scientists belonging to a country which is currently responsible for an armed conflict, anywhere in the world. The findings and recommendations have been adopted unanimously by the Board of IOF.

Race-specific FRAX models are evidence-based and support equitable care: a response to the ASBMR Task Force report on Clinical Algorithms for Fracture Risk.

Task Force on 'Clinical Algorithms for Fracture Risk' commissioned by the American Society for Bone and Mineral Research (ASBMR) Professional Practice Committee has recommended that FRAX® models in the US do not include adjustment for race and ethnicity. This position paper finds that an agnostic model would unfairly discriminate against the Black, Asian and Hispanic communities and recommends the retention of ethnic and race-specific FRAX models for the US, preferably with updated data on fracture and death hazards. In contrast, the use of intervention thresholds based on a fixed bone mineral density unfairly discriminates against the Black, Asian and Hispanic communities in the US. This position of the Working Group on Epidemiology and Quality of Life of the International Osteoporosis Foundation (IOF) is endorsed both by the IOF and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO).

A meta-analysis of previous falls and subsequent fracture risk in cohort studies.

The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm. INTRODUCTION: Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD). METHODS: The resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients. RESULTS: Falls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33-1.51) and men (HR 1.53, 95% CI 1.41-1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27-1.84) in men vs. HR 1.32 (95% CI 1.20-1.45) in women, P for interaction = 0.013). The HRs associated with previous falls decreased with age in women and with duration of follow-up in men and women for most fracture outcomes. There was no evidence of an interaction between falls and BMD for fracture risk. Subsequent risk for a major osteoporotic fracture increased with each additional previous fall in women and men. CONCLUSIONS: A previous self-reported fall confers an increased risk of fracture that is largely independent of BMD. Previous falls should be considered as an additional risk factor in future iterations of FRAX to improve fracture risk prediction.

Fracture Risk and Health Profiles Differ According to Relationship Status: Findings from the Hertfordshire Cohort Study.

Registry studies have suggested associations between relationship status and fracture risk. We considered associations between relationship status and incident fracture in the Hertfordshire Cohort Study, comprising community-dwelling older adults, and explored associations between socioeconomic and lifestyle factors with relationship status. 2997 participants completed a baseline questionnaire (1998-2004) and clinic visit. Participants were followed up until December 2018 using Hospital Episode Statistics, which report clinical outcomes using codes from the 10th revision of the International Classification of Diseases (ICD-10); these codes were used to ascertain incident fractures. Relationship status (not currently married/cohabiting vs currently married/cohabiting) at baseline was examined in relation to incident fracture using Cox regression. Associations between baseline characteristics and relationship status were examined using logistic regression. Mean baseline age was 66.2 years. 80% were married/cohabiting at baseline; 15% had an incident fracture (mean (SD) follow-up duration: 14.4 (4.5) years). The following were related to greater likelihood of not being married/cohabiting: older age (women only); higher BMI (women only); current smoking; high alcohol consumption (men only); poorer diet quality (men only); lower physical activity; leaving school before age 15 (women only); and not owning one's home. Those not married/cohabiting had greater risk of incident fracture compared to those who were (age-adjusted hazard ratios (95% CI) 1.58 (1.06, 2.38) among men, 1.35 (1.06, 1.72) among women); associations were attenuated after accounting for the above factors associated with relationship status in the corresponding sex. This suggests that differences in health profiles and lifestyle according to relationship status may explain the association between relationship status and fracture risk.

The Conceptual Definition of Sarcopenia: Delphi Consensus from the Global Leadership Initiative in Sarcopenia (GLIS).

IMPORTANCE: Sarcopenia, the age-related loss of muscle mass and strength/function, is an important clinical condition. However, no international consensus on the definition exists. OBJECTIVE: The Global Leadership Initiative in Sarcopenia (GLIS) aimed to address this by establishing the global conceptual definition of sarcopenia. DESIGN: The GLIS steering committee was formed in 2019-21 with representatives from all relevant scientific societies worldwide. During this time, the steering committee developed a set of statements on the topic and invited members from these societies to participate in a two-phase International Delphi Study. Between 2022 and 2023, participants ranked their agreement with a set of statements using an online survey tool (SurveyMonkey). Statements were categorised based on predefined thresholds: strong agreement (>80%), moderate agreement (70-80%) and low agreement (<70%). Statements with strong agreement were accepted, statements with low agreement were rejected and those with moderate agreement were reintroduced until consensus was reached. RESULTS: 107 participants (mean age: 54 ± 12 years [1 missing age], 64% men) from 29 countries across 7 continents/regions completed the Delphi survey. Twenty statements were found to have a strong agreement. These included; 6 statements on 'general aspects of sarcopenia' (strongest agreement: the prevalence of sarcopenia increases with age (98.3%)), 3 statements on 'components of sarcopenia' (muscle mass (89.4%), muscle strength (93.1%) and muscle-specific strength (80.8%) should all be a part of the conceptual definition of sarcopenia)) and 11 statements on 'outcomes of sarcopenia' (strongest agreement: sarcopenia increases the risk of impaired physical performance (97.9%)). A key finding of the Delphi survey was that muscle mass, muscle strength and muscle-specific strength were all accepted as 'components of sarcopenia', whereas impaired physical performance was accepted as an 'outcome' rather than a 'component' of sarcopenia. CONCLUSION AND RELEVANCE: The GLIS has created the first global conceptual definition of sarcopenia, which will now serve to develop an operational definition for clinical and research settings.

Radiofrequency echographic multi spectrometry (REMS) in the diagnosis and management of osteoporosis: state of the art.

Radiofrequency Echographic Multi Spectrometry (REMS) is a radiation-free, portable technology, which can be used for the assessment and monitoring of osteoporosis at the lumbar spine and femoral neck and may facilitate wider access to axial BMD measurement compared with standard dual-energy x-ray absorptiometry (DXA).There is a growing literature demonstrating a strong correlation between DXA and REMS measures of BMD and further work supporting 5-year prediction of fracture using the REMS Fragility Score, which provides a measure of bone quality (in addition to the quantitative measure of BMD).The non-ionising radiation emitted by REMS allows it to be used in previously underserved populations including pregnant women and children and may facilitate more frequent measurement of BMD.The portability of the device means that it can be deployed to measure BMD for frail patients at the bedside (avoiding the complications in transfer and positioning which can occur with DXA), in primary care, the emergency department, low-resource settings and even at home.The current evidence base supports the technology as a useful tool in the management of osteoporosis as an alternative to DXA.

Predictive value of sarcopenia components for all-cause mortality: findings from population-based cohorts.

BACKGROUND: Low grip strength and gait speed are associated with mortality. However, investigation of the additional mortality risk explained by these measures, over and above other factors, is limited. AIM: We examined whether grip strength and gait speed improve discriminative capacity for mortality over and above more readily obtainable clinical risk factors. METHODS: Participants from the Health, Aging and Body Composition Study, Osteoporotic Fractures in Men Study, and the Hertfordshire Cohort Study were analysed. Appendicular lean mass (ALM) was ascertained using DXA; muscle strength by grip dynamometry; and usual gait speed over 2.4-6 m. Verified deaths were recorded. Associations between sarcopenia components and mortality were examined using Cox regression with cohort as a random effect; discriminative capacity was assessed using Harrell's Concordance Index (C-index). RESULTS: Mean (SD) age of participants (n = 8362) was 73.8(5.1) years; 5231(62.6%) died during a median follow-up time of 13.3 years. Grip strength (hazard ratio (95% CI) per SD decrease: 1.14 (1.10,1.19)) and gait speed (1.21 (1.17,1.26)), but not ALM index (1.01 (0.95,1.06)), were associated with mortality in mutually-adjusted models after accounting for age, sex, BMI, smoking status, alcohol consumption, physical activity, ethnicity, education, history of fractures and falls, femoral neck bone mineral density (BMD), self-rated health, cognitive function and number of comorbidities. However, a model containing only age and sex as exposures gave a C-index (95% CI) of 0.65(0.64,0.66), which only increased to 0.67(0.67,0.68) after inclusion of grip strength and gait speed. CONCLUSIONS: Grip strength and gait speed may generate only modest adjunctive risk information for mortality compared with other more readily obtainable risk factors.

Recommendations for the optimal use of bone forming agents in osteoporosis.

Bone forming agents, also known as anabolic therapies, are essential in managing osteoporosis, particularly for patients at very high-risk of fractures. Identifying candidates who will benefit the most from these treatments is crucial. For example, this group might include individuals with severe osteoporosis, multiple vertebral fractures, a recent fragility fracture or those unresponsive to antiresorptive treatments. Definitions of patients with a very high fracture risk vary across nations, are often based on fracture history, bone mineral density (BMD), and/or fracture risk calculated by FRAX® or other algorithms. However, for very high-risk patients, anabolic agents such as teriparatide, abaloparatide, or romosozumab are commonly recommended as first-line therapies due to their ability to stimulate new bone formation and improve bone microarchitecture, offering significant benefits in rapid fracture reduction over antiresorptive therapies. The cost-effectiveness of these agents is a critical consideration for decision-makers. Despite their higher costs, their effectiveness in significantly reducing fracture risk and improving quality of life can justify the investment, especially when long-term savings from reduced fracture rates and associated healthcare costs are considered. Additionally, after completing a course of anabolic therapy, transitioning to antiresorptive agents like bisphosphonates or denosumab is crucial to maintain the gains in bone density and minimize subsequent fracture risks. This sequential treatment approach ensures sustained protection and optimal resource utilization. In summary, the effective use of bone forming agents in osteoporosis requires a comprehensive strategy that includes accurate patient identification, consideration of cost-effectiveness, and implementation of appropriate sequential treatments, ultimately maximizing patient outcomes and healthcare efficiency.

Intensive physical activity following total hip arthroplasty increased the revision risk after 15 years: a cohort study of 973 patients from the Geneva Arthroplasty Register.

BACKGROUND AND PURPOSE: Younger recipients of total hip arthroplasty (THA) highly prioritize returning to preoperative levels of physical activity (PA). Surgeons have tended to give cautious advice concerning high-impact sports participation, but there have been few long-term studies. The purpose of our study was to investigate the risk of revision arthroplasty in relation to postoperative PA levels. METHODS: Patients registered in the Geneva Arthroplasty Register (GAR) who had elective THA when they were aged < 65 years were studied. Postoperative PA was collected prospectively 5-yearly using the UCLA activity scale. Cox proportional hazards models were used to estimate associations between PA and risk of revision THA. RESULTS: Amongst 1,370 eligible subjects, median age at THA 58 years (interquartile range 51-61), UCLA scores were available for 973 (71%). During follow-up over 15 years, there were 79 revisions, giving a cumulative risk of 7.4% (95% confidence interval [CI] 5.8-9.4). After adjusting for covariates, we found an increased risk of revision for each unit increase in postoperative PA (HR 1.2, CI 1.1-1.4), and among people performing the most intensive PA (HR 2.7, CI 1.3-5.6) compared with those who were inactive. CONCLUSION: The overall risk of revision was small but intensive and moderate PA may be associated with an increased risk of revision.

The need to distinguish intervention thresholds and diagnostic thresholds in the management of osteoporosis.

This position paper of the International Osteoporosis Foundation (IOF) and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) addresses the rationale for separate diagnostic and intervention thresholds in osteoporosis. We conclude that the current BMD-based diagnostic criteria for osteoporosis be retained whilst clarity is brought to bear on the distinction between diagnostic and intervention thresholds.

The effect of pregnancy vitamin D supplementation on offspring bone mineral density in childhood: a systematic review and meta-analysis.

Systematic review and meta-analysis of the effect of moderate- to high-dose vitamin D supplementation in pregnancy on offspring bone mineralisation found a positive effect of vitamin D supplementation on offspring bone mineral density (BMD) at age 4-6 years, with a smaller effect on bone mineral content. PURPOSE: A systematic review and meta-analysis was performed to assess the effect of pregnancy vitamin D supplementation on offspring bone mineral density (BMD) in childhood. METHODS: A literature search was conducted for published RCTs of antenatal vitamin D supplementation with assessment of offspring BMD or bone mineral content (BMC) by dual-energy X-ray absorptiometry (DXA) using MEDLINE and EMBASE up to 13th July 2022. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Study findings were grouped in two age groups of offspring assessment: neonatal period and early childhood (3-6 years). Random-effects meta-analysis of the effect on BMC/BMD at 3-6 years was performed using RevMan 5.4.1, yielding standardised mean difference (SMD) (95% CI). RESULTS: Five RCTs were identified with offspring assessment of BMD or BMC; 3250 women were randomised within these studies. Risk of bias was low in 2 studies and "of concern" in 3. Supplementation regimes and the control used (3 studies used placebo and 2 used 400 IU/day cholecalciferol) varied, but in all studies the intervention increased maternal 25-hydroxvitamin D status compared to the control group. Two trials assessing BMD in the neonatal period (total n = 690) found no difference between groups, but meta-analysis was not performed as one trial represented 96.4% of those studied at this age. Three trials assessed offspring whole-body-less-head BMD at age 4-6 years. BMD was higher in children born to mothers supplemented with vitamin D [0.16 SD (95% confidence interval 0.05, 0.27), n = 1358] with a smaller effect on BMC [0.07 SD (95% CI - 0.04, 0.19), n = 1351]. CONCLUSIONS: There are few RCTs published to address this question, and these are inconsistent in methodology and findings. However, meta-analysis of three trials suggests moderate- to high-dose vitamin D supplementation in pregnancy might increase offspring BMD in early childhood, but further trials are required to confirm this finding. (Prospero CRD42021288682; no funding received).

Update on the clinical use of trabecular bone score (TBS) in the management of osteoporosis: results of an expert group meeting organized by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), and the International Osteoporosis Foundation (IOF) under the auspices of WHO Collaborating Center for Epidemiology of Musculoskeletal Health and Aging.

PURPOSE: Trabecular bone score (TBS) is a grey-level textural measurement acquired from dual-energy X-ray absorptiometry lumbar spine images and is a validated index of bone microarchitecture. In 2015, a Working Group of the European Society on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) published a review of the TBS literature, concluding that TBS predicts hip and major osteoporotic fracture, at least partly independent of bone mineral density (BMD) and clinical risk factors. It was also concluded that TBS is potentially amenable to change as a result of pharmacological therapy. Further evidence on the utility of TBS has since accumulated in both primary and secondary osteoporosis, and the introduction of FRAX and BMD T-score adjustment for TBS has accelerated adoption. This position paper therefore presents a review of the updated scientific literature and provides expert consensus statements and corresponding operational guidelines for the use of TBS. METHODS: An Expert Working Group was convened by the ESCEO and a systematic review of the evidence undertaken, with defined search strategies for four key topics with respect to the potential use of TBS: (1) fracture prediction in men and women; (2) initiating and monitoring treatment in postmenopausal osteoporosis; (3) fracture prediction in secondary osteoporosis; and (4) treatment monitoring in secondary osteoporosis. Statements to guide the clinical use of TBS were derived from the review and graded by consensus using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. RESULTS: A total of 96 articles were reviewed and included data on the use of TBS for fracture prediction in men and women, from over 20 countries. The updated evidence shows that TBS enhances fracture risk prediction in both primary and secondary osteoporosis, and can, when taken with BMD and clinical risk factors, inform treatment initiation and the choice of antiosteoporosis treatment. Evidence also indicates that TBS provides useful adjunctive information in monitoring treatment with long-term denosumab and anabolic agents. All expert consensus statements were voted as strongly recommended. CONCLUSION: The addition of TBS assessment to FRAX and/or BMD enhances fracture risk prediction in primary and secondary osteoporosis, adding useful information for treatment decision-making and monitoring. The expert consensus statements provided in this paper can be used to guide the integration of TBS in clinical practice for the assessment and management of osteoporosis. An example of an operational approach is provided in the appendix. This position paper presents an up-to-date review of the evidence base, synthesised through expert consensus statements, which informs the implementation of Trabecular Bone Score in clinical practice.

Real-world evidence: new opportunities for osteoporosis research. Recommendations from a Working Group from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO).

This narrative review summarises the recommendations of a Working Group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) for the conduct and reporting of real-world evidence studies with a focus on osteoporosis research. PURPOSE: Vast amounts of data are routinely generated at every healthcare contact and activity, and there is increasing recognition that these real-world data can be analysed to generate scientific evidence. Real-world evidence (RWE) is increasingly used to delineate the natural history of disease, assess real-life drug effectiveness, understand adverse events and in health economic analysis. The aim of this work was to understand the benefits and limitations of this type of data and outline approaches to ensure that transparent and high-quality evidence is generated. METHODS: A ESCEO Working Group was convened in December 2022 to discuss the applicability of RWE to osteoporosis research and approaches to best practice. RESULTS: This narrative review summarises the agreed recommendations for the conduct and reporting of RWE studies with a focus on osteoporosis research. CONCLUSIONS: It is imperative that research using real-world data is conducted to the highest standards with close attention to limitations and biases of these data, and with transparency at all stages of study design, data acquisition and curation, analysis and reporting to increase the trustworthiness of RWE study findings.

Biochemical Markers of Musculoskeletal Health and Aging to be Assessed in Clinical Trials of Drugs Aiming at the Treatment of Sarcopenia: Consensus Paper from an Expert Group Meeting Organized by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the Centre Académique de Recherche et d'Expérimentation en Santé (CARES SPRL), Under the Auspices of the World Health Organization Collaborating Center for the Epidemiology of Musculoskeletal Conditions and Aging.

In clinical trials, biochemical markers provide useful information on the drug's mode of action, therapeutic response and side effect monitoring and can act as surrogate endpoints. In pharmacological intervention development for sarcopenia management, there is an urgent need to identify biomarkers to measure in clinical trials and that could be used in the future in clinical practice. The objective of the current consensus paper is to provide a clear list of biochemical markers of musculoskeletal health and aging that can be recommended to be measured in Phase II and Phase III clinical trials evaluating new chemical entities for sarcopenia treatment. A working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) proposed classifying biochemical markers into 2 series: biochemical markers evaluating musculoskeletal status and biochemical markers evaluating causal factors. For series 1, the group agreed on 4 biochemical markers that should be assessed in Phase II or Phase III trials (i.e., Myostatin-Follistatin, Brain Derived Neurotrophic Factor, N-terminal Type III Procollagen and Serum Creatinine to Serum Cystatin C Ratio - or the Sarcopenia Index). For series 2, the group agreed on 6 biochemical markers that should be assessed in Phase II trials (i.e., the hormones insulin-like growth factor-1 (IGF-I), dehydroepiandrosterone sulphate, and cortisol, and the inflammatory markers C-reactive protein (CRP), interleukin-6 and tumor necrosis factor-α), and 2 in Phase III trials (i.e., IGF-I and CRP). The group also proposed optional biochemical markers that may provide insights into the mode of action of pharmacological therapies. Further research and development of new methods for biochemical marker assays may lead to the evolution of these recommendations.

Evaluation and interpretation of latent class modelling strategies to characterise dietary trajectories across early life: a longitudinal study from the Southampton Women's Survey.

There is increasing interest in modelling longitudinal dietary data and classifying individuals into subgroups (latent classes) who follow similar trajectories over time. These trajectories could identify population groups and time points amenable to dietary interventions. This paper aimed to provide a comparison and overview of two latent class methods: group-based trajectory modelling (GBTM) and growth mixture modelling (GMM). Data from 2963 mother-child dyads from the longitudinal Southampton Women's Survey were analysed. Continuous diet quality indices (DQI) were derived using principal component analysis from interviewer-administered FFQ collected in mothers pre-pregnancy, at 11- and 34-week gestation, and in offspring at 6 and 12 months and 3, 6-7 and 8-9 years. A forward modelling approach from 1 to 6 classes was used to identify the optimal number of DQI latent classes. Models were assessed using the Akaike and Bayesian information criteria, probability of class assignment, ratio of the odds of correct classification, group membership and entropy. Both methods suggested that five classes were optimal, with a strong correlation (Spearman's = 0·98) between class assignment for the two methods. The dietary trajectories were categorised as stable with horizontal lines and were defined as poor (GMM = 4 % and GBTM = 5 %), poor-medium (23 %, 23 %), medium (39 %, 39 %), medium-better (27 %, 28 %) and best (7 %, 6 %). Both GBTM and GMM are suitable for identifying dietary trajectories. GBTM is recommended as it is computationally less intensive, but results could be confirmed using GMM. The stability of the diet quality trajectories from pre-pregnancy underlines the importance of promotion of dietary improvements from preconception onwards.

Measures of attributes of locomotor capacity in older people: a systematic literature review following the COSMIN methodology.

BACKGROUND: Locomotor capacity (LC) is an important domain of intrinsic capacity and key determinant of functional ability and well-being in older age. The United Nations Decade of Healthy Ageing (2021-2030) calls for strengthening data and research on healthy ageing, including the measurement of older persons' LC. To advance the measurement and monitoring of LC, there is pressing need to identify valid and reliable measures. OBJECTIVE: To identify all the available tools that were validated for measurement of LC or of its specific attributes in older people and to assess the methodological quality of the studies and measurement properties of the tools. DESIGN: Systematic review. SETTING: Anywhere (Community-dwelling; long-term care facility; etc.). SUBJECTS: Older people. METHODS: We used highly sensitive search strategies to search the following databases: Medline, Embase, Scopus, CINAHL and PsycINFO. The study was conducted following the COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) methodology for systematic review of outcome measurement instruments. RESULTS: A total of 125 studies were included, which assessed tools for balance (n = 84), muscle power (n = 12), muscle strength (n = 32, including four studies about tools for balance and muscle power) and endurance (n = 1). No studies on tools for muscle function, joint function, or locomotor capacity overall, were retrieved. We identified 69 clinician-report or objective assessment tools for balance, 30 for muscle strength, 12 for muscle power and 1 endurance assessment tool. The GRADE assessment of quality of evidence showed that only a few tools have high quality evidence for both sufficient validity and reliability: The Balance Evaluation Systems Test (BESTest), the Mini-Balance Evaluation Systems Test (Mini-BESTest), the Berg Balance Scale (BBS) and the Timed Up and Go (TUG) test. CONCLUSIONS: A few tools with high quality evidence for sufficient validity and reliability are currently available for balance assessment in older people that may be recommended for use in clinical and research settings. Further validation studies are required for muscle strength, muscle power and endurance assessment tools.

Does antenatal cholecalciferol supplementation affect the mode or timing of delivery? Post hoc analyses of the MAVIDOS randomized controlled trial.

BACKGROUND: Observational studies relating maternal 25-hydroxyvitamin D status to timing and mode of delivery have reported inconsistent results. We assessed the effect of antenatal cholecalciferol supplementation on the incidence of preterm birth, delivery mode and post-partum haemorrhage (PPH). METHODS: MAVIDOS was a randomized, double-blind, placebo-controlled trial of 1000 IU/day cholecalciferol from 14 weeks' gestation until delivery. Gestational age, mode of delivery [categorized as spontaneous vaginal delivery (SVD), instrumental (including forceps and vacuum extraction) or Caesarean section] and PPH (>500 ml estimated blood loss) were determined from medical records. RESULTS: A total of 965 women participated in the study until delivery. Gestation at birth and incidence of preterm birth (cholecalciferol 5.7%, placebo 4.5%, P = 0.43) were similar between the two treatment groups. SVD (versus instrumental or Caesarean delivery) was more likely in women randomized to cholecalciferol [Relative Risk (RR) 1.13, 95% confidence interval (CI) 1.02,1.25] due to lower instrumental (RR 0.68, 95%CI 0.51,0.91) but similar risk of Caesarean delivery (RR 0.94, 95%CI 0.74,1.19). PPH was less common in women randomized to cholecalciferol [32.1% compared with placebo (38.1%, P = 0.054) overall], but similar when stratified by delivery mode. CONCLUSIONS: Antenatal cholecalciferol supplementation did not alter timing of birth or prevalence of preterm birth but demonstrated a possible effect on the likelihood of SVD.

Investigating the relationship between self-perception of fracture risk and prior fracture: findings from the Hertfordshire Cohort Study.

BACKGROUND: Self-perceived risk of fracture (SPR) is associated with fracture independent of FRAX calculated risk. To understand this better we considered whether lifestyle factors not included in the FRAX algorithm and psychosocial factors (social isolation, self-efficacy, or mental health status) explain the relationship between SPR and fracture. METHODS: We studied 146 UK community-dwelling older adults from the Hertfordshire Cohort Study. SPR ranked as 'lower', 'similar' and 'higher' relative to others of the same age, was assessed by questionnaire. Social isolation was assessed using the six-item Lubben Social Network Scale; self-efficacy was assessed using a shortened General Self-Efficacy Scale (GSE); mental health status was assessed using the anxiety/depression item from the EuroQoL questionnaire. SPR in relation to previous self-reported fracture was examined using logistic regression. RESULTS: Among participants of median age 83.4 (IQR 81.5-85.5) years, SPR was lower for 54.1% of participants, similar for 30.8%, and higher for 15.1%; 74.7% reported no previous fractures. Greater SPR was associated with increased odds of previous fractures when adjusting for sex and age only (OR 1.72, 95% CI 1.03-2.87, per higher band of SPR). While further individual adjustment for social isolation (1.73, 1.04-2.89), self-efficacy (1.71, 1.02-2.85), or mental health (1.77, 1.06-2.97) did not attenuate the relationship, individual adjustment for diet quality and number of comorbidities did. CONCLUSIONS: Adjustment for social isolation, self-efficacy or mental health status did not attenuate the relationship between SPR and fracture. By contrast, lifestyle factors not included in FRAX, such as diet quality, did attenuate relationships, suggesting a possible future area of investigation.