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Background erectile dysfunction is associated with mortality, whereas the association between low testosterone (T) and higher mortality remains controversial. Sexual dysfunction and low T often coexist, but the relative importance of sexual symptoms versus low T in predicting mortality is not known. We studied the interrelationships between sex steroids and sexual symptoms with all-cause mortality in a large prospective cohort of European men. Design survival status was assessed in 1,788 community-dwelling men, aged 40–79, who participated in the European Male Ageing Study (EMAS). Sexual symptoms were evaluated via a validated questionnaire (EMAS-SFQ). Sex steroids were measured by mass spectrometry. Cox proportional hazard models were used to study the association between hormones, sexual symptoms and mortality. Results about 420 (25.3%) men died during a mean follow-up of 12.6 ± 3.1 years. Total T levels were similar in both groups, but free T was lower in those who died. Men with three sexual symptoms (erectile dysfunction, reduced morning erections and lower libido) had a higher mortality risk compared with men with none of these symptoms (adjusted hazard ratio (HR) and 95% confidence intervals: 1.75 (1.28–2.40, P = 0.001)). Particularly, erectile dysfunction and poor morning erections, but not lower libido, were associated with increased mortality (HR 1.40 (1.13–1.74, P = 0.002), 1.28 (1.04–1.59, P = 0.023) and 1.12 (0.90–1.39, P = 0.312), respectively). Further adjusting for total T, free T or oestradiol did not influence the observed risk. Conclusions sexual symptoms, in particular erectile dysfunction, predict all-cause mortality independently of sex steroids and can be an early warning sign of a poor health status.

Objectives To characterize the incidence of clinically diagnosed Paget’s disease of bone in the UK during 1999–2015 and to determine variations in the incidence of disease by age, sex, geography and level of deprivation. Methods Incident cases of Paget’s disease occurring between 1999 and 2015 were identified from primary care records. Overall crude incidence and incidence stratified by age and sex was calculated each year from 1999 to 2015. Direct age- and sex-standardized incidence was also calculated. We used Poisson regression to look at variations in incidence by deprivation and UK region. Results A total of 3592 incident cases of Paget’s disease were identified between 1999 and 2015. Incidence increased with age and at all ages was greater in men than women. In women and men, respectively, crude incidence increased from 0.037 and 0.074/10 000 population per year among those 45–49 years of age to 3.7 and 6.3/10 000 population per year among those ≥85 years. The overall standardized incidence decreased from 0.75/10 000 person-years in 1999 to 0.20/10 000 person-years in 2015. After adjustment for age and sex, incidence was >30% higher in the most- compared with least-deprived quintile of deprivation. There was evidence of geographic variation, with the highest incidence in the North West of England, which persisted after adjustment for age, sex and level of deprivation. Conclusion The incidence of clinically diagnosed Paget’s disease has continued to decrease since 1999. The reason for the decline in incidence remains unknown, although the rapidity of change points to an alteration in one or more environmental determinants.

Background/Aims Evidence from the UK suggest that the incidence of Paget's disease of bone declined during the latter half of the last century with a decline also in the incidence of clinically apparent disease. We aimed to characterise the recent incidence of clinically diagnosed Paget’s disease of bone in the UK by age and sex among those aged >18 years and, to determine whether the incidence has changed from 1999-2015. Methods Incident cases of Paget’s disease during 1999-2015 were identified from the first recorded diagnostic code for Paget’s disease in the UK Clinical Practice Research Datalink (CPRD) database. Crude incidence was calculated for each year from 1999 to 2015 and, to account for changes in the distribution of age and sex over time within the CPRD, direct age- and sex-standardised incidence rates were calculated for each year. This was done by multiplying the crude incidence in each age-sex stratum by the age-sex stratum weight of the 1999 population of those at risk of developing Paget’s disease. We looked also at the incidence of disease by quintile of index of multiple deprivation and geographic region. Using Poisson regression, we looked at the influence of deprivation and geography on occurrence of the disease after adjustment for age and sex. Results In total 3,592 incident cases of Paget’s disease were identified between 1999 and 2015. Overall the incidence increased with age and at all ages was greater in men than women. In men, and women, respectively, incidence increased from 0.074 and 0.037 per 10,000 per year at the age of 45-49 years to 6.3 and 3.7 per 10,000 per year at age of 85 years and older. When stratified by year, the age- and sex-standardised incidence fell from 0.75/10,000 person years in 1999 to 0.20/10,000 person years in 2015. Crude incidence (1999-2015) was slightly higher in those living in the most deprived areas (0.53/10,000 person years) compared to those in least deprived areas (0.43/10,000 person years). After adjustment for age and sex, compared to those in the highest quintile of index of multiple deprivation, those in the lowest quintile of index of multiple deprivation had over a 30% increased risk of disease. There was evidence also of geographic variation in the occurrence of disease with the highest incidence in the North West of England. Conclusion The incidence of clinically diagnosed Paget’s disease has continued to decrease since 1999. The reason for the decline remains unknown, though the rapidity of change points to an alteration in one or more environmental determinants. Disclosure M.J. Cook: None. S.R. Pye: None. W.G. Dixon: None. T.W. O'Neill: None.

Background: The association between low testosterone (T) and higher mortality in men remains controversial. Most studies focus only on the association between total T (TT) and mortality. While TT declines with age, free T (FT) shows a greater fall, due to the rise in SHBG. Moreover, higher LH as well as sexual dysfunction, often co-existing with low T, have also been associated with mortality in ageing men. Objective: To study the interrelationships between sex steroids, gonadotrophins and sexual symptoms with all-cause mortality in a large prospective cohort of European men. Methods: 1913 community-dwelling men, aged 40-79, participated in the European Male Ageing Study (EMAS) between 2003-2005. Sexual symptoms were assessed via a validated questionnaire (EMAS-SFQ). Sex steroids were measured by mass spectrometry. In 5 of 8 EMAS centres, survival status was available until 1 April 2018. Cox proportional hazard models were used to study the association between hormones, sexual symptoms and mortality. Because of the wide age range at study entry, age was used as time-scale, instead of years since inclusion adjusting for age. Results were expressed as hazard ratios (HR) with 95% confidence intervals, adjusted for centre, BMI and smoking. Results: 483 (25.3%) men died during a mean follow-up of 12.4±3.3 years. Men who died had a higher BMI (p=0.002), but smoking status did not differ. TT levels were similar in both groups, but FT was lower in those who died (mean±SD: 312±86 pmol/L vs 270±84, p12 nmol/L), the presence of sexual symptoms increased mortality risk (HR 1.51 (1.15-1.97); p=0.003). Finally, men with TT Conclusions: Men with the lowest FT and highest FSH levels have an increased mortality risk. Sexual symptoms, in particular erectile dysfunction, predict all-cause mortality independently of T levels. As both vascular disease and low T can influence erectile function, sexual symptoms can be an early sign for increased cardiovascular risk and mortality, as well as a sequela of low T.

Summary Background Psoriasis is associated with an increased risk of cardiovascular disease. Despite recommendation that exercise is important for cardiorespiratory fitness, patients with psoriasis avoid participation in physical activities for reasons that are, as yet, unclear. Objectives This study investigated the relationship between psoriasis‐specific experiences and self‐reported patterns of exercise, hypothesizing that individuals with psoriasis are less likely to engage in physical activity for reasons that are related to their psoriasis. Methods In total 404 patients with chronic plaque psoriasis were recruited. History, examination and physical activity were assessed for each participant. Results Overall, 52·8% (n = 188) of patients with psoriasis aged 18–65 years and 66% (n = 37) of those aged > 65 years engaged in less than the recommended amount of physical activity for cardiorespiratory fitness. As the severity and psychosocial impact of psoriasis increased, the participation in exercise (of all intensities) decreased. There was a significant negative correlation between Psoriasis Area and Severity Index and total activity in women aged 18–65 years (r = −0·19, 95% confidence interval −0·36 to 0; P = 0·04) and a significant negative correlation between physical activity and Dermatology Life Quality Index (DLQI) in all participants (r = −0·11, 95% confidence interval −0·21 to 0; P = 0·04). Individual components of the DLQI identified barriers to physical activity including skin sensitivity and reluctance to participate in leisure activities. Conclusions Psoriasis‐specific factors – severity, skin sensitivity, clothing choice, participation in social/leisure activities, and treatments – contribute to exercise avoidance and may augment the increased risk of cardiovascular disease in patients with psoriasis., What is already known about this topic? Psoriasis is associated with an increased prevalence of risk factors for cardiovascular disease.Despite recommendation that exercise is important for cardiorespiratory fitness, patients with moderate‐to-severe psoriasis participate in very little physical exercise for reasons that are, as yet, unclear. What does this study add? This study quantifies the significant lack of engagement with exercise in the population of people with psoriasis.Physical activity in those with psoriasis is significantly influenced by psoriasis severity, quality of life and a number of previously unrecognized psoriasis‐specific barriers. What is the translational message? Supporting patients with psoriasis to undertake regular physical activity could directly benefit weight management, cardiovascular disease and risk of metabolic syndrome, and increase wellbeing and psychosocial functioning. Linked Comment: Jarrett.Br J Dermatol 2020; 183:988–989. Plain language summary available online

Background Ageing is associated with sarcopenia, osteoporosis, and increased fall risk, all of which contribute to increased fracture risk. Mechanically, bone strength adapts in response to forces created by muscle contractions. Adaptations can be through changes in bone size, geometry, and bending strength. Muscle mass is often used as a surrogate for muscle force; however, force can be increased without changes in muscle mass. Increased fall risk with ageing has been associated with a decline in muscle power—which is a measure of mobility. The aims of this study were as follows: (i) to investigate the relationship between muscle parameters in the upper and lower limbs with age in UK men and the influence of ethnicity on these relationships; (ii) to examine the relationships between jump force/grip strength/cross-sectional muscle area (CSMA) with bone outcomes at the radius and tibia. Methods White European, Black Afro-Caribbean, and South Asian men aged 40–79 years were recruited from Manchester, UK. Cortical bone mineral content, cross-sectional area, cortical area, cross-sectional moment of inertia, and CSMA were measured at the diaphysis of the radius and tibia using peripheral quantitative computed tomography. Lower limb jump force and power were measured from a single two-legged jump performed on a ground-reaction force platform. Grip strength was measured using a dynamometer. Associations between muscle and bone outcomes was determined using linear regression with adjustments for age, height, weight, and ethnicity. Results Three hundred and one men were recruited. Jump force was negatively associated with age; for every 10 year increase in age, there was a 4% reduction in jump force (P

Context: During ageing, total testosterone (TT) declines and SHBG increases, resulting in a greater decrease in calculated free testosterone (cFT). Currently, guidelines suggest using TT to diagnose androgen deficiency and to reserve cFT only for men with borderline TT. Objective: To investigate if either low cFT or low TT is more strongly associated with androgen-related clinical endpoints. Methods: 3334 community-dwelling men, aged 40-79, were included. Differences in clinical variables between the referent group of men with both normal TT (≥10.5 nmol/L) and normal cFT (≥220 pmol/L) with those who had normal TT/low cFT, low TT/normal cFT and low TT/low cFT, were assessed by regression models adjusted for age, centre, BMI and comorbidities. Results: 2641 men had normal TT [18.4±5.5 (mean±SD) nmol/L]/normal cFT (326±74 pmol/L), 277 men had normal TT (14.2±3.7)/low cFT (194±23), 96 men had low TT (9.6±0.7)/normal cFT (247±20) and 320 men had low TT (7.8±2.5)/low cFT (160±55). Men with normal TT/low cFT were older and in poorer health. They had higher SHBG and LH, and reported more sexual and physical symptoms, while haemoglobin and bone ultrasound parameters were lower compared to the referent group. Men with low TT/normal cFT were younger and more obese. They had lower SHBG, but LH was normal, while features of androgen deficiency were lacking. Conclusions: Low cFT, even in the presence of normal TT, is associated with androgen deficiency-related symptoms. Normal cFT, despite low TT, is not associated with cognate symptoms. Therefore cFT levels should be assessed in men with suspected hypogonadal symptoms. ispartof: Journal of Clinical Endocrinology & Metabolism vol:101 issue:7 pages:2647-2657 ispartof: location:United States status: published

Summary Objective Elevated luteinizing hormone (LH) with normal testosterone (T) suggests compensated dysregulation of the gonadal axis. We describe the natural history, risk factors and clinical parameters associated with the development of high LH (HLH, LH >9.4 U/L) in ageing men with normal T (T ≥ 10.5 nmol/L). Design, Patients and Measurements We conducted a 4.3‐year prospective observational study of 3369 community‐dwelling European men aged 40‐79 years. Participants were classified as follows: incident (i) HLH (n = 101, 5.2%); persistent (p) HLH (n = 128, 6.6%); reverted (r) HLH (n = 46, 2.4%); or persistent normal LH (pNLH, n = 1667, 85.8%). Potential predictors and changes in clinical features associated with iHLH and rHLH were analysed using regression models. Results Age >70 years (OR = 4.12 [2.07‐8.20]), diabetes (OR = 2.86 [1.42‐5.77]), chronic pain (OR = 2.53 [1.34‐4.77]), predegree education (OR = 1.79 [1.01‐3.20]) and low physical activity (PASE ≤ 78, OR = 2.37 [1.24‐4.50]) predicted development of HLH. Younger age (40‐49 years, OR = 8.14 [1.35‐49.13]) and nonsmoking (OR = 5.39 [1.48‐19.65]) predicted recovery from HLH. Men with iHLH developed erectile dysfunction, poor health, cardiovascular disease (CVD) and cancer more frequently than pNLH men. In pHLH men, comorbidities, including CVD, developed more frequently, and cognitive and physical function deteriorated more, than in pNLH men. Men with HLH developed primary hypogonadism more frequently (OR = 15.97 [5.85‐43.60]) than NLH men. Men with rHLH experienced a small rise in BMI. Conclusions Elevation of LH with normal T is predicted by multiple factors, reverts frequently and is not associated with unequivocal evidence of androgen deficiency. High LH is a biomarker for deteriorating health in aged men who tend to develop primary hypogonadism.

Background In men, the long-term consequences of low serum levels of sex steroids, vitamin D metabolites, and insulin-like growth factor 1 (IGF-1) on the evolution of muscle mass, muscle strength, or physical performance are unclear. Moreover, there are no data about the relationship between these hormones and incident sarcopenia defined as low muscle mass and function. The aim of this study was to determine whether the baseline levels of sex hormones, vitamin D metabolites, and IGF-1 predict changes in muscle mass, muscle strength, physical performance, and incident sarcopenia. Methods In 518 men aged 40–79 years, recruited for participation in the European Male Ageing Study, total, free, and bioavailable testosterone (T), oestradiol (E), sex hormone-binding globulin, IGF-1, 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D (1,25(OH)2D), and parathyroid hormone were assessed at baseline. Appendicular lean mass (aLM), gait speed, and grip strength were measured at baseline and after a mean follow-up of 4.3 years. Sarcopenia was defined by the definition of Baumgartner (relative aLM ≤7.26 kg/m2), the International Working Group on Sarcopenia (IWGS), and the European Working Group on Sarcopenia in Older People (EWGSOP). Results aLM significantly decreased from age 50 years, while gait speed and grip strength significantly decreased from age 70 years. The incidence of sarcopenia by the definitions of Baumgartner, IWGS, and EWGSOP was 8.1%, 3.0%, and 1.6%, respectively. After adjustment for age, centre, body mass index, smoking, and number of comorbidities at baseline, baseline levels of T and vitamin D metabolites were not associated with change in aLM, gait speed, and/or grip strength, while a high baseline level of total E2 was associated with a greater decrease in aLM. In men aged ≥70 years, low IGF-1 was associated with a greater decrease in gait speed. Baseline endocrine variables were not independently associated with an increased risk of incident sarcopenia by any definition. Conclusions Low levels of T and 25OHD do not predict loss of muscle mass, gait speed, or grip strength in middle-aged and elderly community-dwelling European men. Low IGF-1 predicts change in gait speed in men aged ≥70 years.

Purpose Real‐world data for observational research commonly require formatting and cleaning prior to analysis. Data preparation steps are rarely reported adequately and are likely to vary between research groups. Variation in methodology could potentially affect study outcomes. This study aimed to develop a framework to define and document drug data preparation and to examine the impact of different assumptions on results. Methods An algorithm for processing prescription data was developed and tested using data from the Clinical Practice Research Datalink (CPRD). The impact of varying assumptions was examined by estimating the association between 2 exemplar medications (oral hypoglycaemic drugs and glucocorticoids) and cardiovascular events after preparing multiple datasets derived from the same source prescription data. Each dataset was analysed using Cox proportional hazards modelling. Results The algorithm included 10 decision nodes and 54 possible unique assumptions. Over 11 000 possible pathways through the algorithm were identified. In both exemplar studies, similar hazard ratios and standard errors were found for the majority of pathways; however, certain assumptions had a greater influence on results. For example, in the hypoglycaemic analysis, choosing a different variable to define prescription end date altered the hazard ratios (95% confidence intervals) from 1.77 (1.56‐2.00) to 2.83 (1.59‐5.04). Conclusions The framework offers a transparent and efficient way to perform and report drug data preparation steps. Assumptions made during data preparation can impact the results of analyses. Improving transparency regarding drug data preparation would increase the repeatability, reproducibility, and comparability of published results.

ObjectivesAutoantibodies directed against cytosolic 5′-nucleotidase 1A have been identified in many patients with inclusion body myositis. This retrospective study investigated the association between anticytosolic 5′-nucleotidase 1A antibody status and clinical, serological and histopathological features to explore the utility of this antibody to identify inclusion body myositis subgroups and to predict prognosis.Materials and methodsData from various European inclusion body myositis registries were pooled. Anticytosolic 5′-nucleotidase 1A status was determined by an established ELISA technique. Cases were stratified according to antibody status and comparisons made. Survival and mobility aid requirement analyses were performed using Kaplan-Meier curves and Cox proportional hazards regression.ResultsData from 311 patients were available for analysis; 102 (33%) had anticytosolic 5′-nucleotidase 1A antibodies. Antibody-positive patients had a higher adjusted mortality risk (HR 1.89, 95% CI 1.11 to 3.21, p=0.019), lower frequency of proximal upper limb weakness at disease onset (8% vs 23%, adjusted OR 0.29, 95% CI 0.12 to 0.68, p=0.005) and an increased prevalence of excess of cytochrome oxidase deficient fibres on muscle biopsy analysis (87% vs 72%, adjusted OR 2.80, 95% CI 1.17 to 6.66, p=0.020), compared with antibody-negative patients.InterpretationDifferences were observed in clinical and histopathological features between anticytosolic 5′-nucleotidase 1A antibody positive and negative patients with inclusion body myositis, and antibody-positive patients had a higher adjusted mortality risk. Stratification of inclusion body myositis by anticytosolic 5′-nucleotidase 1A antibody status may be useful, potentially highlighting a distinct inclusion body myositis subtype with a more severe phenotype.

The aim of this study was to determine whether bone turnover markers (BTMs) predict changes in areal bone mineral density (aBMD) in middle-aged and elderly European men. Older men with high bone turnover are at a higher risk of accelerated hip bone loss, but the clinical utility of BTMs in individuals is limited. Prospective studies on the value of BTMs to predict changes in aBMD in men are few and conflicting. The aim of this study was to determine whether BTMs predict changes in aBMD in middle-aged and elderly European men. In 487 men aged 40–79 years from the European Male Ageing Study (EMAS), BTMs were assessed at baseline and dual-energy X-ray absorptiometry (DXA) at the lumbar spine (LS), femoral neck (FN) and total hip (TH) was performed at baseline and after a mean follow-up of 4.3 years. The mean aBMD decreased by 0.32 %/year at FN and 0.22 %/year at TH and increased by 0.32 %/year at LS. Higher baseline levels of β C-terminal cross-linked telopeptide (β-CTX) and N-terminal propeptide of type I procollagen (PINP) were significantly associated with higher loss of hip aBMD in the whole cohort and men aged 60–79 years. These associations remained significant after adjustment for age, centre and body mass index (BMI). Men aged 60–79 years with β-CTX in the upper quintile were more likely of being in the upper quintile of annual percentage (%) aBMD loss at FN (OR = 4.27; 95% CI = 2.09–8.73) and TH (OR = 3.73; 95% CI = 1.84–7.57). The positive predictive value (PPV) was 46 % at both hip sites. Older men with high bone turnover have a higher risk of accelerated hip bone loss, but the PPV is low. BTMs are therefore unlikely to be of clinical utility in predicting accelerated hip bone loss in individual subjects.

Context The androgen receptor (AR) gene exon 1 CAG repeat length has been proposed to be a determinant of between-individual variations in androgen action in target tissues, which might regulate phenotypic differences of human ageing. However, findings on its phenotypic effects are inconclusive. Objective To assess whether the AR CAG repeat length is associated with longitudinal changes in endpoints that are influenced by testosterone (T) levels in middle-aged and elderly European men. Design Multinational European observational prospective cohort study. Participants A total of 1887 men (mean ± s.d. age: 63 ± 11 years; median follow up: 4.3 years) from centres of eight European countries comprised the analysis sample after exclusion of those with diagnosed diseases of the hypothalamic–pituitary–testicular (HPT) axis. Main outcome measures Longitudinal associations between the AR CAG repeat and changes in androgen-sensitive endpoints (ASEs) and medical conditions were assessed using regression analysis adjusting for age and centre. The AR CAG repeat length was treated as both a continuous and a categorical (6–20; 21–23; 24–39 repeats) predictor. Additional analysis investigated whether results were independent of baseline T or oestradiol (E2) levels. Results The AR CAG repeat, when used as a continuous or a categorical predictor, was not associated with longitudinal changes in ASEs or medical conditions after adjustments. These results were independent of T and E2 levels. Conclusion Within a 4-year time frame, variations in the AR CAG repeat do not contribute to the rate of phenotypic ageing, over and above, which might be associated with the age-related decline in T levels.

Objective:\ud In ageing men, the incidence and clinical significance of testosterone (T) decline accompanied by elevated luteinizing hormone (LH) are unclear. We describe the natural history, risk factors and clinical features associated with the development of biochemical primary hypogonadism (PHG, T < 10·5 nmol/l and LH>9·4U/l) in ageing men.\ud \ud Design, Patients and Measurements:\ud A prospective observational cohort survey of 3,369 community‐dwelling men aged 40‐79 years, followed up for 4·3 years. Men were classified as incident (i) PHG (eugonadal [EUG, T ≥ 10·5 nmol/l] at baseline, PHG at follow‐up), persistent (p) PHG (PHG at baseline and follow‐up), pEUG (EUG at baseline and follow‐up) and reversed (r) PHG (PHG at baseline, EUG at follow‐up). Predictors and changes in clinical features associated with the development of PHG were analysed by regression models.\ud \ud Results:\ud Of 1,991 men comprising the analytical sample, 97·5% had pEUG, 1·1% iPHG, 1·1% pPHG and 0·3% rPHG. The incidence of PHG was 0·2%/year. Higher age (>70 years) [OR 12·48 (1·27–122·13), P = 0·030] and chronic illnesses [OR 4·24 (1·08–16·56); P = 0·038] predicted iPHG. Upon transition from EUG to PHG, erectile function, physical vigour and haemoglobin worsened significantly. Men with pPHG had decreased morning erections, sexual thoughts and haemoglobin with increased insulin resistance.\ud \ud Conclusions:\ud Primary testicular failure in men is uncommon and predicted by old age and chronic illness. Some clinical features attributable to androgen deficiency, but not others, accompanied the T decline in men who developed biochemical PHG. Whether androgen replacement can improve sexual and/or physical function in elderly men with PHG merits further study.

Few studies have directly compared the ability of the most commonly used models of frailty to predict mortality among community-dwelling individuals. Here, we used a frailty index (FI), frailty phenotype (FP), and FRAIL scale (FS) to predict mortality in the EMAS. Participants were aged 40-79 years (n=2929) at baseline and 6.6% (n=193) died over a median 4.3 years of follow-up. The FI was generated from 39 deficits, including self-reported health, morbidities, functional performance and psychological assessments. The FP and FS consisted of five phenotypic criteria and both categorized individuals as robust when they had 0 criteria, prefrail as 1-2 criteria and frail as 3+ criteria. The mean FI increased linearly with age (r(2)=0.21) and in Cox regression models adjusted for age, center, smoking and partner status the hazard ratio (HR) for death for each unit increase of the FI was 1.49. Men who were prefrail or frail by either the FP or FS definitions, had a significantly increased risk of death compared to their robust counterparts. Compared to robust men, those who were FP frail at baseline had a HR for death of 3.84, while those who were FS frail had a HR of 3.87. All three frailty models significantly predicted future mortality among community-dwelling, middle-aged and older European men after adjusting for potential confounders. Our data suggest that the choice of frailty model may not be of paramount importance when predicting future risk of death, enabling flexibility in the approach used.

Previous studies of glucocorticoid (GC) therapy and mortality have had inconsistent results and have not considered possible perimortal bias—a type of protopathic bias where illness in the latter stages of life influences GC exposure, and might affect the observed relationship between GC use and death. This study aimed to investigate all-cause and cause-specific mortality in association with GC therapy in patients with rheumatoid arthritis (RA), and explore possible perimortal bias. A retrospective cohort study using the primary care electronic medical records. Oral GC exposure was identified from prescriptions. Mortality data were obtained from the UK Office for National Statistics. Multivariable Cox proportional hazards regression models assessed the association between GC use models and death. Several methods to explore perimortal bias were examined. The cohort included 16,762 patients. For ever GC use there was an adjusted hazard ratio for all-cause mortality of 1.97 (95 % CI 1.81–2.15). Current GC dose of below 5 mg per day (prednisolone equivalent dose) was not associated with an increased risk of death, but a dose–response association was seen for higher dose categories. The association between ever GC use and all-cause mortality was partly explained by perimortal bias. GC therapy was associated with an increased risk of mortality for all specific causes considered, albeit to a lesser extent for cardiovascular causes. GC use was associated with an increased risk of death in RA, at least partially explained by perimortal bias. Importantly, GC doses below 5 mg were not associated with an increased risk of death. Electronic supplementary material The online version of this article (doi:10.1007/s10654-016-0167-1) contains supplementary material, which is available to authorized users.

RJAHE is supported by a Biotechnology and Biological Sciences Research Council – Doctoral Training Partnership (BBSRC-DTP) PhD-fellowship, and is grateful for receiving support from the Fundatie van de Vrijvrouwe van Renswoude and Scholten-Cordes scholarship foundations. All authors would like to thank the men who participated in the HUSERMET-project (10) and are grateful for funding of the HUSERMET project by the U.K. BBSRC (Grant number: BB/C519038/1) and U.K. Medical Research Council, with contributions from Astra-Zeneca and GlaxoSmithKline. Objectives: To assess ethnic differences in male reproductive hormone levels and to determine if any differences are explained by adiposity, insulin resistance (IR), or comorbidities in older men. Design: Multi-ethnic cross-sectional observational study. Participants: Community dwelling middle-aged and elderly men residing in the U.K. aged 40-84 years of South Asian (SA; n=180), White European (WE; n=328) or African Caribbean (AC; n=166) origin. Observations: Measured testosterone (T), calculated free T (cFT), SHBG, and LH in SA, WE and AC men along with an assessment of body composition, IR, life-style factors and medical conditions. Results: Age-adjusted mean T and cFT levels were lower in SA men when compared to WE and AC men (mean (SEM) T: SA: 14·0 ± 0·4; WE: 17·1 ± 0·3; AC: 17·2 ± 0·5 nmol/l, P < 0·001; cFT: SA: 283 ± 7; WE: 313 ± 5; AC: 314 ± 8 pmol/l, P < 0·006). Compared to WE and AC men, SA men had higher levels of body fat, IR, comorbidities and diabetes. After adjusting for body fat, IR and other confounders, T levels in SA men remained lower than in WE men (P = 0·04) but ethnic differences in cFT became nonsignificant. LH levels were higher in SA than WE men in age-adjusted and fully adjusted models. Conclusions: T and cFT are lower in SA men than in WE and AC men. Whether ethnic-specific reference ranges for T and cFT might be appropriate in clinical practice requires further investigation. Ethnic differences in cFT, but not T, appear to be, more readily, explained by ethnic differences in adiposity, thus providing insights into potential pathophysiological mechanisms. Postprint

Background Ageing is associated with sarcopenia, osteoporosis, and increased fall risk, all of which contribute to increased fracture risk. Mechanically, bone strength adapts in response to forces created by muscle contractions. Adaptations can be through changes in bone size, geometry, and bending strength. Muscle mass is often used as a surrogate for muscle force; however, force can be increased without changes in muscle mass. Increased fall risk with ageing has been associated with a decline in muscle power—which is a measure of mobility. The aims of this study were as follows: (i) to investigate the relationship between muscle parameters in the upper and lower limbs with age in UK men and the influence of ethnicity on these relationships; (ii) to examine the relationships between jump force/grip strength/cross‐sectional muscle area (CSMA) with bone outcomes at the radius and tibia. Methods White European, Black Afro‐Caribbean, and South Asian men aged 40–79 years were recruited from Manchester, UK. Cortical bone mineral content, cross‐sectional area, cortical area, cross‐sectional moment of inertia, and CSMA were measured at the diaphysis of the radius and tibia using peripheral quantitative computed tomography. Lower limb jump force and power were measured from a single two‐legged jump performed on a ground‐reaction force platform. Grip strength was measured using a dynamometer. Associations between muscle and bone outcomes was determined using linear regression with adjustments for age, height, weight, and ethnicity. Results Three hundred and one men were recruited. Jump force was negatively associated with age; for every 10 year increase in age, there was a 4% reduction in jump force (P

Relatively little is known about the bone health of ethnic groups within the UK and data are largely restricted to women. The aim of this study was to investigate ethnic differences in areal bone mineral density (aBMD), volumetric bone mineral density (vBMD), bone geometry and strength in UK men. White European, Black Afro-Caribbean and South Asian men aged over 40 years were recruited from Greater Manchester, UK. aBMD at the spine, hip, femoral neck and whole body were measured by DXA. Bone geometry, strength and vBMD were measured at the radius and tibia using pQCT at the metaphysis (4%) and diaphysis (50% radius; 38% tibia) sites. Adjustments were made for age, weight and height. Black men had higher aBMD at the whole body, total hip and femoral neck compared to White and South Asian men independent of body size adjustments, with no differences between the latter two groups. White men had longer hip axis lengths than both Black and South Asian men. There were fewer differences in vBMD but White men had significantly lower cortical vBMD at the tibial diaphysis than Black and South Asian men (p, Highlights • Ethnic differences in bone health were investigated in UK men using DXA and pQCT • Areal BMD was highest in Black Afro-Caribbean compared to White and South Asian men • Black Afro-Caribbean men had the most advantageous geometry and bone distribution • No differences in areal BMD between South Asian and White men • At the tibia, South Asians had thinner cortices and lower strength than White men

ObjectiveTo assess the influence of sex hormones on markers of bone turnover and to explore the association between these markers and bone health in middle-aged and elderly European men.DesignA cross-sectional population-based survey.MethodsMen aged 40–79 years were recruited from population registers in eight European centres. Subjects completed a postal questionnaire which included questions concerning lifestyle and were invited to undergo quantitative ultrasound (QUS) of the calcaneus and to provide a fasting blood sample from which the bone markers serum N-terminal propeptide of type 1 procollagen (P1NP) and crosslinks (β C-terminal cross-linked telopeptide (β-cTX)), total testosterone, total oestradiol (E2), sex hormone-binding globulin (SHBG) and insulin-like growth factor 1 (IGF1) were measured. Dual-energy X-ray absorptiometry (DXA) of the hip and lumbar spine was performed in two centres.ResultsA total of 3120, mean age 59.9 years (s.d.=11.0) were included. After adjustment for centre, age, height, weight, lifestyle factors, season and other hormones, total and free E2were negatively associated with β-cTX but not P1NP while SHBG, IGF1 and parathyroid hormone (PTH) were positively associated with both β-cTX and P1NP. Total or free testosterone was not independently associated with either bone marker. After the same adjustments, higher levels of both bone markers were significantly associated with lower QUS parameters and lower DXA-assessed bone density at the total hip and lumbar spine.ConclusionsE2, SHBG, IGF1 and PTH contribute significantly to the regulation/rate of bone turnover in middle-aged and older European men. Higher rates of bone remodelling are negatively associated with male bone health.

Health care systems worldwide are having to adapt to ageing populations and increasing numbers of older people with frailty with complex health and social needs, and in the UK primary care is at the frontline of policy attempts to meet this challenge, but achieving the goal of making frailty an integral part of primary care practice is not without considerable challenges

BACKGROUND The association between aging-related testosterone deficiency and late-onset hypogonadism in men remains a controversial concept. We sought evidence-based criteria for identifying late-onset hypogonadism in the general population on the basis of an association between symptoms and a low testosterone level. METHODS We surveyed a random population sample of 3369 men between the ages of 40 and 79 years at eight European centers. Using questionnaires, we collected data with regard to the subjects' general, sexual, physical, and psychological health. Levels of total testosterone were measured in morning blood samples by mass spectrometry, and free testosterone levels were calculated with the use of Vermeulen's formula. Data were randomly split into separate training and validation sets for confirmatory analyses. RESULTS In the training set, symptoms of poor morning erection, low sexual desire, erectile dysfunction, inability to perform vigorous activity, depression, and fatigue were significantly related to the testosterone level. Increased probabilities of the three sexual symptoms and limited physical vigor were discernible with decreased testosterone levels (ranges, 8.0 to 13.0 nmol per liter [2.3 to 3.7 ng per milliliter] for total testosterone and 160 to 280 pmol per liter [46 to 81 pg per milliliter] for free testosterone). However, only the three sexual symptoms had a syndromic association with decreased testosterone levels. An inverse relationship between an increasing number of sexual symptoms and a decreasing testosterone level was observed. These relationships were independently confirmed in the validation set, in which the strengths of the association between symptoms and low testosterone levels determined the minimum criteria necessary to identify late-onset hypogonadism. CONCLUSIONS Late-onset hypogonadism can be defined by the presence of at least three sexual symptoms associated with a total testosterone level of less than 11 nmol per liter (3.2 ng per milliliter) and a free testosterone level of less than 220 pmol per liter (64 pg per milliliter).

Objectives. To determine the influence of disease-related variables on hand cortical bone loss in women with early inflammatory arthritis (IA), and whether hand cortical bone mass predicts subsequent joint damage. Method. Adults aged >/=16 years with recent onset of IA were recruited to the Norfolk Arthritis Register between 1990 and 1998, and followed prospectively. At baseline, patients had their joints examined for swelling and tenderness and had CRP and disease activity 28-joint assessment score (DAS-28) measured. Radiographs of the hands were performed in a subgroup of patients at Year 1 and at follow-up, which were assessed using digital X-ray radiogrammetry (DXR). They were also evaluated for the presence of erosions using Larsen's method. Linear mixed models were used to investigate whether disease-related factors predicted change in DXR-areal bone mineral density (BMD(a)). We also evaluated whether DXR-BMD(a) predicted the subsequent occurrence of erosive disease. Results. Two hundred and four women, mean (s.d.) age 55.1 (14.0) years, were included. Median follow-up between radiographs was 4 years. The mean within-subject change in BMD(a) was 0.024 g/cm(2) equivalent to 1% decline per year. After adjustment for age, height and weight, compared with those within the lower tertile for CRP, those in the upper tertile had greater subsequent loss of bone. This was true also for DAS-28 and Larsen score. Among those without erosions on the initial radiograph (121), DXR-BMD(a) at baseline did not predict the new occurrence of erosions. Conclusion. Increased disease activity and severity are associated with accelerated bone loss. However, lower BMD(a) did not predict the new occurrence of erosive disease

The influence of sex steroids on calcaneal quantitative ultrasound (QUS) parameters was assessed in a population sample of middle-aged and elderly European men. Higher free and total E(2) though not testosterone, were independently associated with higher QUS parameters.The aim of this study was to investigate the association between QUS parameters and sex steroids in middle-aged and elderly European men.Three thousand one hundred forty-one men aged between 40 and 79 years were recruited from eight European centres for participation in a study of male ageing: the European Male Ageing Study. Subjects were invited by letter to attend for an interviewer-administered questionnaire, blood sample and QUS of the calcaneus (Hologic-SAHARA). Blood was assessed for sex steroids including oestradiol (E(2)), testosterone (T), free and bio-available E(2) and T and sex hormone binding globulin (SHBG).Serum total T was not associated with any of the QUS parameters. Free T and both free and total E(2) were positively related to all QUS readings, while SHBG concentrations were negatively associated. These relationships were observed in both older and younger (60 years) men. In a multivariate model, after adjustment for age, centre, height, weight, physical activity levels and smoking, free E(2) and SHBG, though not free T, remained independently associated with the QUS parameters. After further adjustment for IGF-1, however, the association with SHBG became non-significant.Higher free and total E(2) are associated with bone health not only among the elderly but also middle-aged European men.

Objective.To determine whether perturbations of insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) were associated with the presence of chronic widespread pain (CWP) in men.Methods.The European Male Ageing Study (EMAS) is an 8-center population-based study of men aged 40–79 years recruited from population registers. A questionnaire asked about the presence and duration of musculoskeletal pain, from which subjects reporting CWP were identified. Subjects also had an interviewer-assisted questionnaire: levels of physical activity and mood were assessed, and height and weight were measured. IGF-1 and IGFBP-3 were assayed from a fasting blood sample. Logistic regression models were used to determine the association between IGF measures and CWP. Results were expressed as odds ratios or relative risk ratios.Results.A total of 3206 subjects provided full data. Of those, 1314 (39.0%) reported no pain in the past month and 278 (8.3%) reported pain that satisfied criteria for CWP. IGF-1 concentrations were similar among subjects who reported no pain and those with CWP: 131.5 mg/l and 128.4 mg/l, respectively. This was true also for IGFBP-3 (4.3 and 4.3 mg/l). Obesity was associated with low IGF-1 and a high IGFBP-3/IGF-1 ratio, indicating less bioavailable IGF-1, irrespective of pain status. This relationship persisted after adjustment for comorbidities, depression, smoking, alcohol consumption, and quality of life.Conclusion.Overall CWP was not associated with perturbations in IGF-1 and IGFBP-3 concentrations. Hypofunctioning of the axis was noted among subjects who were obese and this was not specific to CWP. These data suggest that IGF-1 is unlikely to be etiologically important in relation to CWP, although the relationship with growth hormone remains to be elucidated.

Genes involved in sex hormone pathways are candidates for influencing bone strength. Polymorphisms in these genes were tested for association with heel quantitative ultrasound (QUS) parameters in middle-aged and elderly European men. Men 40-79 yr of age were recruited from population registers in eight European centers for the European Male Aging Study (EMAS). Polymorphisms were genotyped in AR, ESR1, ESR2, CYP19A1, CYP17A1, SHBG, SRD5A2, LHB, and LHCGR. QUS parameters broadband ultrasound attenuation (BUA) and speed of sound (SOS) were measured in the heel and used to derive BMD. The relationships between QUS parameters and polymorphisms were assessed using linear regression adjusting for age and center. A total of 2693 men, with a mean age of 60.1 +/- 11.1 (SD) yr were included in the analysis. Their mean BUA was 80.0 +/- 18.9 dB/Mhz, SOS was 1550.2 +/- 34.1 m/s, and BMD was 0.542 +/- 0.141 g/cm(2). Significant associations were observed between multiple SNPs in a linkage disequilibrium (LD) block within CYP19A1, peaking at the TCT indel with the deletion allele associating with reduced ultrasound BMD in heterozygotes (beta =-0.016, p = -0.005) and homozygotes (beta = -0.029, p = 0.001). The results for BUA and SOS were similar. Significant associations with QUS parameters were also observed for the CAG repeat in AR and SNPs in CYP17A1, LHCGR, and ESR1. Our data confirm evidence of association between bone QUS parameters and polymorphisms in CYP19A1, as well as modest associations with polymorphisms in CYP17A1, ESR1, LHCGR, and AR in a population sample of European men; this supports a role for genetically determined sex hormone actions in influencing male bone health.

The individual variability in the waning androgenic-anabolic functions of aging men may be influenced by the CAG repeat polymorphism in exon 1 of the androgen receptor (AR), affecting androgen sensitivity. However, findings on its phenotypic effects are inconclusive.The aim was to investigate the relationships between health status, various reproductive hormones, and the AR CAG repeat length.We conducted a multinational prospective cohort observational study with cross-sectional baseline data.This was a population survey of community-dwelling men.Men (40-79 yr old; n = 3369) were randomly recruited from centers in eight European countries; CAG repeat analysis was performed in 2878 men.We measured the correlations of the CAG repeat length with selected endocrine, metabolic, and phenotypic parameters related to aging and sex hormone action.Only minor differences were found in CAG repeat lengths between the eight European countries. They showed significant positive association with total, free, and bioavailable levels of testosterone (T) and estradiol. FSH but not LH correlated inversely with CAG repeat length. Significant associations were found with bone ultrasound parameters at the calcaneus. Negative correlation was found with triglycerides, but not with other blood lipids or with anthropometry, blood pressure, hemoglobin, insulin sensitivity, or sexual and prostatic functions.The AR CAG repeat length correlates significantly with serum T and estradiol of aging men. Weaker transcriptional activity of the AR with longer CAG-encoded polyglutamine repeats appears to be totally or nearly totally compensated for by higher T levels. The residual phenotypic correlations may reflect differences in estrogen levels/actions after aromatization of the higher T levels.

Background: Lumbar disc degeneration is characterised radiologically by the presence of osteophytes, end-plate sclerosis and disc space narrowing. Aim: To determine the strength of the association between increasing severity of combinations of these features in a population sample of men and women. Methods: Men and women aged ⩾50 years were recruited from a primary care-based community health index in Aberdeen, UK. Participants had lateral spinal radiographs performed according to a standard protocol. The intervertebral disc spaces (L1/2–L4/5) were evaluated for the presence of anterior osteophytes, end-plate sclerosis and disc space narrowing using a graded semiquantitative score (grade 0–3). Log linear modelling was used to determine the associations (pairwise) between increasing severity of these features, with the results expressed as β coefficients and 95% confidence intervals (CIs). Results: There were 286 men (mean age 65.3 years) and 299 women (mean age 65.2 years) with spinal radiographs, yielding a total of 2340 assessable lumbar vertebral levels. In all, 73% of vertebral levels had evidence of osteophytes, 26% of sclerosis and 37% of disc space narrowing. Increasing severity of osteophyte grade was associated with an increasing severity both of sclerosis and of disc space narrowing, whereas the severity of sclerosis was associated with the severity of narrowing. This was true at all vertebral levels. The strongest association, however, was between osteophytes and sclerosis (β coefficient = 2.7, 95% CI 2.4 to 3.1). For sclerosis and narrowing the β coefficient was 1.9 (95% CI 1.7 to 2.1), whereas for osteophytes and narrowing the β coefficient was much weaker at 1.2 (95% CI 1.1 to 1.3). There was no important influence of vertebral level on any of these associations. Conclusion: The association between increasing severity of osteophytes and end-plate sclerosis is stronger than for other combinations of radiographic features of lumbar disc degeneration.

Introduction Guidelines for the management of rheumatoid arthritis (RA) recommend using influenza and pneumococcal vaccinations to mitigate infection risk. The level of adherence to these guidelines is not well known in the UK. The aims of this study were to describe the uptake of influenza and pneumococcal vaccinations in patients with RA in the UK, to compare the characteristics of those vaccinated to those not vaccinated and to compare vaccination rates across regions of the UK. Methods A retrospective cohort study of adults diagnosed with incident RA and treated with non-biologic immunosuppressive therapy, using data from a large primary care database. For the influenza vaccination, patients were considered unvaccinated on 1st September each year and upon vaccination their status changed to vaccinated. For pneumococcal vaccination, patients were considered vaccinated after their first vaccination until the end of follow-up. Patients were stratified by age 65 at the start of follow-up, given differences in vaccination guidelines for the general population. Results Overall (N = 15,724), 80% patients received at least one influenza vaccination, and 50% patients received a pneumococcal vaccination, during follow-up (mean 5.3 years). Of those aged below 65 years (N = 9,969), 73% patients had received at least one influenza vaccination, and 43% patients received at least one pneumococcal vaccination. Of those aged over 65 years (N = 5,755), 91% patients received at least one influenza vaccination, and 61% patients had received at least one pneumococcal vaccination. Those vaccinated were older, had more comorbidity and visited the GP more often. Regional differences in vaccination rates were seen with the highest rates in Northern Ireland, and the lowest rates in London. Conclusions One in five patients received no influenza vaccinations and one in two patients received no pneumonia vaccine over five years of follow-up. There remains significant scope to improve uptake of vaccinations in patients with RA.

Background The association between low levels of vitamin D and the occurrence of chronic widespread pain (CWP) remains unclear. The aim of our analysis was to determine the relationship between low vitamin D levels and the risk of developing CWP in a population sample of middle age and elderly men. Methods Three thousand three hundred sixty nine men aged 40–79 were recruited from 8 European centres for a longitudinal study of male ageing, the European Male Ageing Study. At baseline participants underwent assessment of lifestyle, health factors, physical characteristics and gave a fasting blood sample. The occurrence of pain was assessed at baseline and follow up (a mean of 4.3 years later) by shading painful sites on a body manikin. The presence of CWP was determined using the ACR criteria for fibromyalgia. Serum 25-hydroxyvitamin D (25-(OH) D) was assessed by radioimmunoassay. Logistic regression was used to determine the relationship between baseline vitamin D levels and the new occurrence of CWP. Results Two thousand three hundred thirteen men, mean age 58.8 years (SD = 10.6), had complete pain and vitamin data available and contributed to this analysis. 151 (6.5 %) developed new CWP at follow up and 577 (24.9 %) were pain free at both time points, the comparator group. After adjustment for age and centre, physical performance and number of comorbidities, compared to those in upper quintile of 25-(OH) D ( ≥36.3 ng/mL), those in the lowest quintile (

Background: we hypothesised that chronic widespread pain (CWP), by acting as a potential stressor, may predispose to the development of, or worsening, frailty. Setting: longitudinal analysis within the European Male Ageing Study (EMAS). Participants: a total of 2,736 community-dwelling men aged 40–79. Methods: subjects completed a pain questionnaire and shaded a manikin, with the presence of CWP defined using the American College of Rheumatology criteria. Physical activity, smoking, alcohol consumption and depression were measured. Repeat assessments took place a median of 4.3 years later. A frailty index (FI) was used, with frail defined as an FI >0.35. The association between CWP at baseline and the new occurrence of frailty was examined using logistic regression; the association between CWP at baseline and change in FI was examined using negative binomial regression. Results: at baseline, 218 (8.3%) men reported CWP. Of the 2,631 men who were defined as non-frail at baseline, 112 (4.3%) were frail at follow-up; their mean FI was 0.12 (SD 0.1) at baseline and 0.15 (SD 0.1) at follow-up, with a mean change of 0.03 (SD 0.08) P ≤ 0.001. Among men who were non-frail at baseline, those with CWP were significantly more likely to develop frailty. After adjustment for age and centre, compared with those with no pain, those with CWP at baseline had a 70% higher FI at follow-up; these associations remained significant after further adjustment for smoking, body mass index, depression, physical activity and FI at baseline. Conclusion: the presence of CWP is associated with an increased risk of frailty in older European men.

Context: Low testosterone (T) has been associated with incident metabolic syndrome (MetS), but it remains unclear if this association is independent of sex hormone binding globulin (SHBG). Estradiol (E2) may also be associated with MetS, but few studies have investigated this. Objective: To study the association between baseline sex steroids and the development of incident MetS and to investigate the influence of SHBG, body mass index (BMI) and insulin resistance on this risk. Methods: Three thousand three hundred sixty nine community-dwelling men aged 40–79 years were recruited for participation in EMAS. MetS was defined by the updated NCEP ATP III criteria. Testosterone and E2 levels were measured by liquid and gas chromatography/mass spectrometry, respectively. Logistic regression was used to assess the association between sex steroids and incident MetS. Results: One thousand six hundred fifty one men without MetS at baseline were identified. During follow-up, 289 men developed incident MetS, while 1362 men did not develop MetS. Men with lower baseline total T levels were at higher risk for developing MetS [odds ratio (OR) = 1.72, P < .001), even after adjustment for SHBG (OR = 1.43, P = .001), BMI (OR = 1.44, P < .001) or homeostasis model assessment of insulin resistance (HOMA-IR) (OR = 1.64, P < .001). E2 was not associated with development of MetS (OR = 1.04; P = .56). However, a lower E2/T ratio was associated with a lower risk of incident MetS (OR = 0.38; P < .001), even after adjustment for SHBG (OR = 0.48; P < .001), BMI (OR = 0.60; P = .001) or HOMA-IR (OR = 0.41; P < .001). Conclusions: In men, lower T levels, but not E2, are linked with an increased risk of developing MetS, independent of SHBG, BMI or insulin resistance. A lower E2/T ratio may be protective against developing MetS.

There are few data concerning the occurrence of peak bone mass in women of South Asian origin. The aim of this study was to determine the level of peak bone mass in South Asian women in the UK and to determine whether any observed differences could be explained by differences in body size. Two groups of South Asian women, those of (1) Pakistani Muslim and (2) Gujarati Hindu origin, together with a European group aged 18 to 36 years, were recruited from primary-care population age-sex registers in the Greater Manchester area. They were invited to attend for a detailed interview-assisted lifestyle questionnaire and assessment of height and weight. Bone mass density (BMD) at the hip and lumbar spine was measured by dual energy X-ray absorptiometry (DEXA) scan (Hologic QDR 4500). Volumetric bone density was measured at the distal radius using pQCT (Norland Stratec XCT 2000). Linear regression was used to determine whether any observed differences in the level of bone mass could be explained by differences in body size. A total of 119 European women with a mean age of 30.4 years, 98 Pakistani Muslim women with a mean age of 29.2 years and 20 Gujarati Hindu women with a mean age of 29.2 years had bone density measurements performed. The Europeans were taller and heavier than either South Asian group. Peak BMD was greater among the European than the Pakistani women at all three measuring sites, with the Gujarati women having intermediate values at the hip and lumbar spine. Observed differences disappeared, however, after adjusting for height and weight. There were no differences in volumetric density at the lumbar spine or distal radius between the groups. In summary, there are differences in the level of bone mass between European and South Asian women, though these can be explained by differences in bone size, height or weight.

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 x 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 x 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 x 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

Objectives: To determine the one year period prevalence of falls by age and sex in patients with rheumatoid arthritis and the influence of concurrent medical treatment and disability on the occurrence of falls in this group. Methods: A consecutive series of rheumatoid patients aged 35 years and over, attending hospital outpatient clinics at Hope hospital, Salford, were asked to complete an interview assisted questionnaire which asked about the occurrence and number of falls in the previous 12 months. Subjects who took part were asked about current treatment with antihypertensive agents, diuretics, sedatives or hypnotics, antidepressants, and a history of previous hip/knee surgery. They also completed the health assessment questionnaire (HAQ). Logistic regression was used to determine the association between these variables and falls in the previous 12 months. Results: 253 men and women, mean age 62 years, were studied, and 84 (33%) reported falling in the previous year (36% of women and 26% of men). Of these, 52% had fallen on more than one occasion. There was no important increase in the frequency of falls with age. After adjusting for age and sex, those who had fallen in the previous year were more likely to report taking antidepressant treatment (odds ratio (OR) = 2.09) and to have impairment in both walking (OR = 1.37) and rising (OR = 1.41). The HAQ score was higher in those who reported a fall than those who did not, though the difference was not statistically significant. Conclusions: In this hospital based survey, one in three patients with rheumatoid arthritis reported falling in the previous 12 months. Falls were associated with self reported impairment in lower limb function.

Context: There is little information on the potential impact of serum 1,25-dihydroxyvitamin D [1,25(OH)2D] on bone health including turnover.\ud \ud Objective: The objective of the study was to determine the influence of 1,25(OH)2D and 25-hydroxyvitamin D [25(OH)D] on bone health in middle-aged and older European men.\ud \ud Design, Setting, and Participants: Men aged 40–79 years were recruited from population registers in 8 European centers. Subjects completed questionnaires that included questions concerning lifestyle and were invited to attend for quantitative ultrasound (QUS) of the heel, assessment of height and weight, and a fasting blood sample from which 1,25(OH)2D, 25(OH)D, and PTH were measured. 1,25(OH)2D was measured using liquid chromatography tandem mass spectrometry. Bone markers serum N-terminal propeptide of type 1 procollagen (P1NP) and crosslinks (β-cTX) were also measured. Dual-energy x-ray absorptiometry (DXA) of the hip and lumbar spine was performed in 2 centers.\ud \ud Main Outcome Measure(s): QUS of the heel, bone markers P1NP and β-cTX, and DXA of the hip and lumbar spine were measured.\ud \ud Results: A total of 2783 men, mean age 60.0 years (SD 11.0) were included in the analysis. After adjustment for age and center, 1,25(OH)2D was positively associated with 25(OH)D but not with PTH. 25(OH)D was negatively associated with PTH. After adjustment for age, center, height, weight, lifestyle factors, and season, 1,25(OH)2D was associated negatively with QUS and DXA parameters and associated positively with β-cTX. 1,25(OH)2D was not correlated with P1NP. 25(OH)D was positively associated with the QUS and DXA parameters but not related to either bone turnover marker. Subjects with both high 1,25(OH)2D (upper tertile) and low 25(OH)D (lower tertile) had the lowest QUS and DXA parameters and the highest β-cTX levels.\ud \ud Conclusions: Serum 1,25(OH)2D is associated with higher bone turnover and poorer bone health despite being positively related to 25(OH)D. A combination of high 1,25(OH)2D and low 25(OH)D is associated with the poorest bone health.

vitamin D deficiency has been associated with an increased risk of mortality, but whether this relationship is causal or linked to co-existent comorbidity and adverse life factors remains uncertain. Our objective was to determine whether endogenous 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D) and parathyroid hormone (PTH) levels predicted all-cause, cardiovascular and cancer mortality independently of health and lifestyle factors.: prospective cohort analysis within the European Male Ageing Study.: 2,816 community-dwelling men aged 40-79 years at baseline.: Cox regression was used to examine the association of all-cause mortality with 25(OH)D, 1,25(OH)2D and PTH; cardiovascular and cancer mortality were modelled using competing-risks regression. Results were expressed as hazard ratios (HR) and 95% confidence intervals (CIs) for Cox models; sub-hazard ratios (SHR) and 95% CIs for competing-risks models.: a total of 187 men died during a median of 4.3 years of follow-up. Serum levels of 25(OH)D (per 1 SD decrease: HR = 1.45; 95% CI = 1.16, 1.81) and 1,25(OH)2D (per 1 SD decrease: HR = 1.20; 95% CI = 1.00, 1.44) were associated with an increased risk of all-cause mortality after adjusting for age, centre, smoking, self-reported morbidities, physical activity and functional performance. Only levels of 25(OH)D25 nmol/l predicted cancer mortality (SHR = 3.33; 95% CI = 1.38, 8.04).: lower 25(OH)D and 1,25(OH)2D levels independently predicted all-cause mortality in middle-aged and older European men. Associations with cancer mortality were only observed among men with very low levels of 25(OH)D. These associations were only partially explained by the range of adverse health and lifestyle factors measured here.