Search

Aims: The 2021 European Society of Cardiology prevention guidelines recommend the use of (lifetime) risk prediction models to aid decisions regarding initiation of prevention. We aimed to update and systematically recalibrate the LIFEtime-perspective CardioVascular Disease (LIFE-CVD) model to four European risk regions for the estimation of lifetime CVD risk for apparently healthy individuals., Methods and Results: The updated LIFE-CVD (i.e. LIFE-CVD2) models were derived using individual participant data from 44 cohorts in 13 countries (687 135 individuals without established CVD, 30 939 CVD events in median 10.7 years of follow-up). LIFE-CVD2 uses sex-specific functions to estimate the lifetime risk of fatal and non-fatal CVD events with adjustment for the competing risk of non-CVD death and is systematically recalibrated to four distinct European risk regions. The updated models showed good discrimination in external validation among 1 657 707 individuals (61 311 CVD events) from eight additional European cohorts in seven countries, with a pooled C-index of 0.795 (95% confidence interval 0.767-0.822). Predicted and observed CVD event risks were well calibrated in population-wide electronic health records data in the UK (Clinical Practice Research Datalink) and the Netherlands (Extramural LUMC Academic Network). When using LIFE-CVD2 to estimate potential gain in CVD-free life expectancy from preventive therapy, projections varied by risk region reflecting important regional differences in absolute lifetime risk. For example, a 50-year-old smoking woman with a systolic blood pressure (SBP) of 140 mmHg was estimated to gain 0.9 years in the low-risk region vs. 1.6 years in the very high-risk region from lifelong 10 mmHg SBP reduction. The benefit of smoking cessation for this individual ranged from 3.6 years in the low-risk region to 4.8 years in the very high-risk region., Conclusion: By taking into account geographical differences in CVD incidence using contemporary representative data sources, the recalibrated LIFE-CVD2 model provides a more accurate tool for the prediction of lifetime risk and CVD-free life expectancy for individuals without previous CVD, facilitating shared decision-making for cardiovascular prevention as recommended by 2021 European guidelines., Competing Interests: Conflict of interest: Due to the very long author list, these will be provided per author using ICMJE forms at the revision stage, if applicable., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: To describe selected baseline characteristics, continuation with baricitinib and disease activity over time in patients initiating treatment with baricitinib in a UK real-world rheumatology setting., Methods: Baseline and follow-up data were analysed from baricitinib-treated patients newly recruited to the British Society for Rheumatology Biologics Registry-RA (BSRBR-RA) baricitinib cohort between 1 January 2018 and 31 March 2020. The primary objective was to evaluate continuation of baricitinib treatment in patients with at least one follow-up. Analyses were performed using the full baricitinib cohort, overall and by patient subgroup: biologic DMARD (bDMARD)/targeted synthetic (ts)DMARD-naive vs -experienced, baricitinib 4 vs 2 mg, age ≥65 vs <65 years, monotherapy vs combination therapy and male vs female., Results: At baseline, the study cohort (n = 561) was 76.5% female, mean age 60.0 years, had longstanding (mean 13.1 years) and severe RA, and 54.0% had previously received a bDMARD/tsDMARD. Of 265 and 110 patients completing the 6- and 12-month follow-ups with available data, 77.7 and 69.1% remained on baricitinib at each time, respectively. In all Kaplan-Meier analyses, >60% of patients remained on baricitinib at 540 days. Continuation of baricitinib therapy differed between some subgroup pairs (bDMARD/tsDMARD naive/experienced, baricitinib 2 mg/4 mg). Disease activity was lower at both follow-ups than at baseline, overall and in all subgroups., Conclusion: In the early years of real-world baricitinib use in the UK, a high proportion of patients continued with treatment at both 6 and 12 months, at which times disease activity was lower than at baseline., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To evaluate drug survival with monotherapy compared with combination therapy with MTX in RA older adults., Methods: Patients from the British Society for Rheumatology Biologics Register, a prospective observational cohort, who were biologic naïve and commencing their first TNF inhibitors (TNFi) were included. The cohort was stratified according to age: <75 and ≥75. Cox-proportional hazards models compared the risk of TNFi discontinuation from (i) any-cause, (ii) inefficacy and (iii) adverse events, between patients prescribed TNFi-monotherapy compared with TNFi MTX combination., Results: The analysis included 15 700 patients. Ninety-five percent were <75 years old. Comorbidity burden and disease activity were higher in the ≥75 cohort. Fifty-two percent of patients discontinued TNFi therapy during the follow-up period. Persistence with therapy was higher in the <75 cohort. Patients receiving TNFi monotherapy were more likely to discontinue compared with patients receiving concomitant MTX [hazard rate 1.12 (1.06-1.18) P <0.001]. This finding only held true in patients <75 [hazard rate (HR) 1.11 (1.05-1.17) vs ≥75 [HR 1.13 (0.90-1.41)]. Examining TNFi discontinuation by cause revealed patients ≥75 receiving TNFi monotherapy were less likely to discontinue TNFi due to inefficacy [HR 0.66 (0.43-0.99) P=0.04] and more likely to discontinue therapy from adverse events [HR 1.41(1.02-1.96) P =0.04]. These results were supported by the multivariate adjustment in complete case and imputed analyses., Conclusion: TNFi monotherapy is associated with increased treatment failure. In older adults, the disadvantage of TNFi monotherapy on drug survival is no longer seen. Patients ≥75 have fewer discontinuations due to inefficacy than adverse events compared with younger patients. This likely reflects greater disposition to toxicity but perhaps also a decline in immunogenicity associated with immunosenescence., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Job demand-control (DC) and effort-reward imbalance (ERI) are two commonly used measures of work stress which are independently associated with health., Aims: To test the hypothesis that DC and ERI have different and cumulative effects on health., Methods: DC and ERI were assessed in the Hertfordshire Cohort Study. The characteristics and occupations of men and women reporting either or both work stresses were compared and the interaction of these with health status were explored., Results: Complete data were available for 1021 men and 753 women, reporting on their most recent or current job. A total of 647 (63%) men and 444 (59%) women reported neither work stress, while 103 (10%) men and 78 (10%) women reported both. Patterns of ERI and DC, alone and in combination, were different by type of occupation and by gender. Men reporting both work stresses (as compared with neither) were more likely to be single. Reported ERI with DC in the most recent or current job was associated with: poorer SF-36 physical function scores (OR 2.3 [95% CI 1.5-3.7] for men; OR 2.0 [95% CI 1.2-3.6] for women) and mental health scores (OR 2.8 [95% CI 1.8-4.4] for men; OR 3.1 [95% CI 1.8-5.3] for women). Moreover, average grip strength was 1.7 kg (95% CI 0.2-3.3) lower among men who described both work stresses., Conclusion: DC and ERI are two models of the psychosocial workplace environment which offer different but cumulative insight into the impacts of work on an individual's psychological and physical health, particularly in a population sample.

Background: Exposure to higher magnitude vertical impacts is thought to benefit bone health. The correlates of this high-impact physical activity (PA) in later life are unknown., Methods: Participants were from the Cohort for Skeletal Health in Bristol and Avon, Hertfordshire Cohort Study and MRC National Survey of Health and Development. Associations of demographic, behavioural, physiological and psychological factors with vertical acceleration peaks ≥1.5 g (i.e. high-impact PA) from 7-day hip-worn accelerometer recordings were examined using linear regression., Results: A total of 1187 participants (mean age = 72.7 years, 66.6% females) were included. Age, sex, education, active transport, self-reported higher impact PA, walking speed and self-rated health were independently associated with high-impact PA whereas BMI and sleep quality showed borderline independent associations. For example, differences in log-high-impact counts were 0.50 (P < 0.001) for men versus women and -0.56 (P < 0.001) for worst versus best self-rated health. Our final model explained 23% of between-participant variance in high impacts. Other correlates were not associated with high-impact activity after adjustment., Conclusions: Besides age and sex, several factors were associated with higher impact PA in later life. Our findings help identify characteristics of older people that might benefit from interventions designed to promote osteogenic PA.

Background: multi-morbidity is an increasing challenge in western medicine and has the potential to impact patients' quality of life, treatment options and compliance with medications. The aim of this study was to identify the early-life predictors of long-term multi-morbidity in an historical cohort, the Hertfordshire Cohort Study (HCS)., Methods: perinatal and infant health records were kept on all children born in Hertfordshire between 1931 and 1939. Participants who were still alive in 1998 were recruited to the HCS and data collected on major chronic diseases. They were subsequently followed up in the Clinical Outcomes Study (COS), and data recorded on all major illnesses since HCS, as well as current medications. Ordinal logistic regression analysed the association between early-life factors and the number of morbidities in these two surveys as well as medication count., Results: a total of 2299 participants had data in COS, 1131 (49%) were female, median age (interquartile range) at recruitment to HCS was 66 (64-68) years. Higher rates of childhood illnesses were significantly associated with future multi-morbidity (multivariate odds ratio (OR) (95% confidence interval (CI)) 1.15 (1.06, 1.25)) and higher medication counts at COS (multivariate OR (95%CI) 1.14 (1.06, 1.23))., Conclusions: children who experience more illnesses at a young age may be prone to develop multi-morbidity in later life.

Background: weak hand grip strength in later life is a risk factor for disability, morbidity and mortality and is central to definitions of sarcopenia and frailty. It is unclear whether rate of change in grip strength adds to level of grip strength as a risk factor for poor ageing outcomes., Methods: study participants were 292 community-dwelling men and women whose grip strength was measured during the 1994/5 (average age 67) and 2003/5 (average age 76) phases of the Hertfordshire Ageing Study, UK. Individual rate of change in grip strength was estimated using a residual change method. Mortality was followed-up to 2011 (42 men and 21 women died)., Results: average grip strengths in 2003/5 were 38.4 kg (standard deviation [SD] = 8.1) and 23.7 kg (SD = 6.6) for men and women respectively. Average annualised rates of change in grip strength (2003/5 minus 1994/5) were modest owing to a healthy-participant effect (men: -0.12 kg/y, SD = 0.71; women: 0.08 kg/y, SD = 0.54) but varied widely. Mortality risk varied according to level and rate of change in grip strength (P = 0.03); death rates per 100 person years of follow-up were 6.7 (95% CI: 4.6, 9.6) among participants who lost grip over time and had low grip in 2003/5, in contrast with 0.8 (95% CI: 0.1, 5.8) among participants whose grip changed little over time and remained high in 2003/5., Conclusions: levels of grip strength in later life should be considered in conjunction with estimates of change in grip strength identified by repeat measurement over time. Normative data for longitudinal change in grip strength are required., (© The Author 2016. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Background: poor diet quality is common among older people, but little is known about influences on food choice, including the role of psychosocial factors at this age., Objective: to identify psychosocial correlates of diet quality in a community-dwelling population of men and women aged 59-73 years; to describe relationships with change in diet quality over 10 years., Design: Longitudinal cohort, Hertfordshire Cohort Study (HCS)., Subjects: HCS participants assessed at baseline (1998-2003: 1,048 men, 862 women); 183 men and 189 women re-assessed in 2011., Methods: diet was assessed by administered food frequency questionnaire; diet scores were calculated to describe diet quality at baseline and follow-up. A range of psychosocial factors (social support, social network, participation in leisure activities, depression and anxiety, sense of control) were assessed by questionnaire., Results: at baseline, better diet quality was related to a range of social factors, including increased confiding/emotional social support (men and women), practical support (men) and a larger social network (women) (all P < 0.05). For both men and women, greater participation in social and cognitive leisure activities was related to better diet quality (P < 0.005). There were few associations between measured psychosocial factors at baseline and change in diet score over 10 years, in the follow-up sub-group. However, greater participation in leisure activities, especially cognitive activities, at baseline was associated with smaller declines in diet quality over the 10-year follow-up period for both men (P = 0.017) and women (P = 0.014)., Conclusions: in community-dwelling older adults, a range of social factors, that includes greater participation in leisure activities, were associated with diets of better quality., (© The Author 2016. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Background: the first quality of life questionnaire specific to sarcopenia, the SarQoL®, has recently been developed and validated in French. To extend the availability and utilisation of this questionnaire, its translation and validation in other languages is necessary., Objective: the purpose of this study was therefore to translate the SarQoL® into English and validate the psychometric properties of this new version., Design: cross-sectional., Setting: Hertfordshire, UK., Subjects: in total, 404 participants of the Hertfordshire Cohort Study, UK., Methods: the translation part was articulated in five stages: (i) two initial translations from French to English; (ii) synthesis of the two translations; (iii) backward translations; (iv) expert committee to compare the backward translations with the original questionnaire and (v) pre-test. To validate the English SarQoL®, we assessed its validity (discriminative power, construct validity), reliability (internal consistency, test-retest reliability) and floor/ceiling effects., Results: the SarQoL® questionnaire was translated without any major difficulties. Results indicated a good discriminative power (lower score of quality of life for sarcopenic subjects, P = 0.01), high internal consistency (Cronbach's alpha of 0.88), consistent construct validity (high correlations found with domains related to mobility, usual activities, vitality, physical function and low correlations with domains related to anxiety, self-care, mental health and social problems) and excellent test-retest reliability (intraclass coefficient correlation of 0.95, 95%CI 0.92-0.97). Moreover, no floor/ceiling has been found., Conclusions: a valid SarQoL® English questionnaire is now available and can be used with confidence to better assess the disease burden associated with sarcopenia. It could also be used as a treatment outcome indicator in research., (© The Author 2016. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Objective: To determine feasibility of TNF inhibitor (TNFi) dose reduction for severe AS and PsA patients., Methods: A retrospective study in a real-world setting. Criteria for dose reduction of TNFi included BASDAI < 4 for ⩾6 months in AS; or DAS28-ESR ⩽ 3.2 for ⩾6 months in PsA. TNFi dose was reduced by one-third. Patients who flared (BASDAI > 4 in AS or DAS28-ESR > 3.2 in PsA) were re-escalated to standard treatment dose., Results: Twenty-six per cent (33/125) of AS and 18% (15/83) of PsA patients fulfilled criteria and underwent TNFi dose reduction. Fifty-eight per cent (19/33) of AS and 60% (9/15) of PsA patients maintained TNFi dose reduction for mean (s.d) of 1.0 (0.8) years. Reinstating standard dose of TNFi recaptured low disease activity in all patients who failed dose reduction within 24 weeks, with no statistically significant difference in mean BASDAI compared with those maintaining TNFi dose reduction in AS at 24 weeks [mean (s.d) BASDAI 2.4 (1.1) vs 1.9 (1.5), respectively (P = 0.229)]; however in PsA, those who failed dose reduction had higher disease activity compared with patients maintained on TNFi dose reduction at 24 weeks [mean (s.d) DAS28-ESR 2.7 (0.6) vs 1.3 (0.5), respectively (P ⩽ 0.001)]. In PsA, a lower DAS28-ESR prior to dose reduction of TNFi was associated with more successful dose reduction., Conclusions: In a real-world setting, 60% of individuals with severe AS and PsA who achieve low disease activity can successfully reduce the dose of TNFi therapy by a third for a mean of 1 year., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction: Osteoporosis is a significant public health issue affecting over half of women aged over 50. With an aging population, its importance is set to increase further over time. Prevention of fragility fractures avoids significant mortality and morbidity as well as saving significant direct and indirect costs to the economy. In this review, we discuss existing treatments to contextualize the treatment landscape, and demonstrate how our understanding of bone pathophysiology has led to novel therapies-in the form of combinations and altered durations of existing treatments, as well as newer drug therapies., Sources of Data: PubMed and Embase were searched for randomized controlled trials of new therapies for osteoporosis. These searches were supplemented with material presented in abstract form at international meetings., Areas of Agreement: New drugs that appear promising in the treatment of osteoporosis include the cathepsin K inhibitor, monoclonal antibodies against sclerostin and parathyroid hormone-related protein analog., Areas of Controversy: Separate to the development of novel drug therapies is the issue of how best to use agents that are currently available to us; specifically which agent to choose, alone or in combination; duration of therapy; how best to identify patients at highest risk of fracture, and to ensure the highest possible adherence to medication. Many of these issues have been addressed in other excellent review papers, and will not be considered in detail here., Growing Points: As with all new treatments, we await results of long-term use and experience in 'real life' patient populations., Areas Timely for Developing Research: As alluded to above, data are urgently required regarding the optimal duration of therapy; use of combination therapy; ordering of therapies for best therapeutic effect. As stratified medicine becomes more strongly considered in all areas of therapy, its merits in osteoporosis as in other musculoskeletal conditions, is timely and valuable., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Rheumatoid arthritis (RA) is characterized by local and systemic bone loss caused by increased bone resorption. We describe the current utilization of high-resolution peripheral quantitative computed tomography (HR-pQCT) in the evaluation of bone and joint in RA., Sources of Data: PubMed was searched for publications using keywords that included 'bone microarchitecture', 'high-resolution peripheral quantitative computed tomography' and 'rheumatoid arthritis'., Areas of Agreement: HR-pQCT may simultaneously allow assessment of trabecular and cortical bone parameters and be a useful method for depicting bone erosions., Areas of Controversy: HR-pQCT only assesses bone microarchitecture at the distal radius and tibia. Controversy exists regarding the optimal way to differentiate cortical and trabecular regions., Growing Points: Although HR-pQCT is currently a research tool, there is potential for its use in the clinical diagnosis and management in RA. Further research is required to evaluate the clinical relevance of imaging abnormalities identified in RA patients., (© The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: poor physical performance (PP) is known to be associated with disability, lower quality of life and higher mortality rates. Knee and hip osteoarthritis (OA) might be expected to contribute to poor PP, through joint pain and restricted range of movement. Both clinical and self-reported OA are often used for large-scale community and epidemiological studies., Objective: to examine the relationships between hip and knee OA and PP in a large data set comprising cohorts from six European countries., Methods: a total of 2,942 men and women aged 65-85 years from the Germany, Italy, Netherlands, Spain, Sweden and the UK were recruited. Assessment included an interview and clinical assessment for OA. PP was determined from walking speed, chair rises and balance (range 0-12); low PP was defined as a score of ≤9., Results: the mean (SD) age was 74.2 (5.1) years. Rates of self-reported OA were much higher than clinical OA. Advanced age, female gender, lower educational attainment, abstinence from alcohol and higher body mass index were independently associated with low PP. Clinical knee OA, hip OA or both were associated with a higher risk of low PP; OR (95% CI) 2.93 (2.36, 3.64), 3.79 (2.49, 5.76) and 7.22 (3.63, 14.38), respectively, with relationships robust to adjustment for the confounders above as well as pain., Conclusion: lower limb OA at the hip and knee is associated with low PP, and for clinical diagnosis relationships are robust to adjustment for pain. Those at highest risk have clinical OA at both sites., (© The Author 2014. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: vascular disease has been postulated to contribute to muscle dysfunction in old age. Previous studies examining the effects of cardiovascular drugs on muscle function have shown conflicting results. We therefore examined the association of angiotensin converting enzyme (ACE) inhibitor, thiazide and statin use with decline in grip strength in a well-characterised cohort., Methods: we analysed prospectively collected data from the Hertfordshire Cohort Study (HCS). For each medication, participants were divided into no baseline use/no use at follow-up, baseline use/no use at follow-up, no baseline use but use at follow-up and use at baseline and follow-up. For each group, annualised decline in grip strength (kg per year) was calculated, then adjusted for baseline age, height, weight, baseline grip strength, indices of ischaemic heart disease and hypertension. Analyses were conducted separately for males and females., Results: 639 participants were included in the analysis, mean age 65 years. 321 (50%) were male; mean follow-up time was 4.4 years. There were no differences in baseline grip between baseline users and non-users of any drug class. Adjusted grip strength change per year was similar for each group of ACE inhibitor use (P > 0.05). Similar analyses revealed no significant between-group differences for statin or thiazide use. Analysis of dropout rates by medication use revealed no evidence of selection bias., Conclusion: use of ACE inhibitors, statins or thiazides was not associated with differences in grip strength decline in healthy older people in the HCS., (© The Author 2014. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction: sarcopenia is associated with adverse health outcomes. The aim of this study was to describe the prevalence of sarcopenia in community-dwelling older people in the UK using the European Working Group on Sarcopenia in Older People (EWGSOP) consensus definition., Methods: we applied the EWGSOP definition to 103 community-dwelling men participating in the Hertfordshire Sarcopenia Study (HSS) using both the lowest third of dual-energy X-ray absorptiometry (DXA) lean mass (LM) and the lowest third of skin-fold-based fat-free mass (FFM) as markers of low muscle mass. We also used the FFM approach among 765 male and 1,022 female participants in the Hertfordshire Cohort Study (HCS). Body size, physical performance and self-reported health were compared in participants with and without sarcopenia., Results: the prevalence of sarcopenia in HSS men (mean age 73 years) was 6.8% and 7.8% when using the lowest third of DXA LM and FFM, respectively. DXA LM and FFM were highly correlated (0.91, P < 0.001). The prevalence of sarcopenia among the HCS men and women (mean age 67 years) was 4.6% and 7.9%, respectively. HSS and HCS participants with sarcopenia were shorter, weighed less and had worse physical performance. HCS men and women with sarcopenia had poorer self-reported general health and physical functioning scores., Conclusions: this is one of the first studies to describe the prevalence of sarcopenia in UK community-dwelling older people. The EWGSOP consensus definition was of practical use for sarcopenia case finding. The next step is to use this consensus definition in other ageing cohorts and among older people in a range of health-care settings.

Context: Maternal diet during pregnancy has been linked to offspring adiposity, but it is unclear whether maternal polyunsaturated fatty acid (PUFA) status during pregnancy affects offspring body composition., Objective: We investigated the associations between maternal plasma n-3 and n-6 PUFA status at 34 wk gestation and offspring body composition., Design and Setting: A prospective United Kingdom population-based mother-offspring cohort, the Southampton Women's Survey (SWS), was studied., Participants: A total of 12,583 nonpregnant women were recruited into the SWS, among whom 1987 delivered a baby before December 31, 2003; 293 mother-child pairs had complete measurements of maternal plasma PUFA concentrations in late pregnancy and offspring body composition at both ages 4 and 6 yr., Main Outcomes Measured: We measured offspring body composition by dual-energy x-ray absorptiometry, yielding fat mass, lean mass, percentage fat mass, and percentage lean mass. Results are presented as β-coefficients for standardized variables, therefore reflecting the sd change of the outcome for every 1 sd of the predictor., Results: After adjustment for maternal factors and child factors including height and duration of breast-feeding, maternal plasma n-6 PUFA concentration positively predicted offspring fat mass at 4 yr (β = 0.14 SD/SD; P = 0.01) and 6 yr (β = 0.11 SD/SD; P = 0.04), but there was no association with offspring lean mass at either age (β = 0.005 SD/SD, P = 0.89; and β = 0.008 SD/SD, P = 0.81, respectively). Maternal plasma n-3 PUFA concentration was not associated with offspring fat mass at 4 yr (β = 0.057 SD/SD; P = 0.34) or 6 yr (β = 0.069 SD/SD; P = 0.21). Maternal plasma n-3 PUFA status was positively associated with offspring lean mass on univariate analysis (4 yr, β = 0.11, P = 0.06; 6 yr, β = 0.14; P = 0.02); however, this was confounded by a positive association with offspring height., Conclusions: This observational study suggests that maternal n-6 PUFA status during pregnancy might influence offspring adiposity in childhood.

Background: reduced grip strength is associated with adverse health consequences, and there is interest in identifying modifiable influences. Cardiovascular drugs are commonly used by older people, but their effect on muscle strength is unclear., Methods: we investigated associations between cardiovascular drug use and grip strength among 1,572 men and 1,415 women, aged 59-73, who participated in the Hertfordshire Cohort Study., Results: Forty-five percent of participants were taking a cardiovascular drug. Furosemide was associated with average decreases in grip strength of 3.15 kg (95% confidence interval [CI] 0.90, 5.39, P < 0.01) among men and 2.35 kg (95% CI 0.93, 3.77, P < 0.01) among women after adjustment for age and height. Corresponding differences for nitrates were 1.84 kg (95% CI 0.29, 3.39, P = 0.02) among men and 3.66 kg (95% CI 1.99, 5.33, P < 0.01) among women. Calcium channel blockers and fibrates were associated with reduced grip among women. Statins were not associated with grip. The associations between grip strength and nitrate use in men and nitrate and fibrate use in women were robust to additional adjustment for co-morbidity., Conclusions: use of some cardiovascular drugs is associated with reduced grip strength in older people. These findings have potential implications for the functional ability of older people treated with these drugs.

Background: We have previously demonstrated that maternal body build and lifestyle factors predict neonatal bone mineral accrual. However, the paternal determinants of neonatal bone mass are not known. In this study we explored the relationship between a father's bone mass and that of his offspring., Methods: A total of 278 pregnancies (142 male and 136 female neonates) were recruited from the Southampton Women's Survey, a unique, well-established cohort of women, aged 20-34 yr, who had been assessed before and during pregnancy. The neonates and their fathers underwent whole body dual-x-ray absorptiometry (DXA) within 2 wk of birth using a Lunar DPX (General Electric Corp., Madison, WI) and Hologic Discovery instrument (Hologic Inc., Bedford, MA), respectively; correlation and regression methods were used to explore the parental determinants of neonatal bone mass., Results: After adjusting the paternal DXA indices for father's age and the neonatal for baby's gestational age and age at DXA scan, there were highly significant positive associations between baby's whole body bone area, bone mineral content, and bone mineral density and the corresponding indices in the father (P = 0.003, 0.0002, 0.046, respectively) among female infants. These relationships were independent of maternal height and fat stores. The associations for male infants with paternal DXA indices did not achieve statistical significance., Conclusions: The father's skeletal size predicts skeletal size more strongly in female than male offspring, independently of the mother's body build. These data point toward the importance of considering paternal genotype in studies exploring the developmental origins of osteoporotic fracture and raise intriguing mechanistic questions about the gender specificity of influences on intrauterine bone mineral accrual.

Background: Osteoporosis has a huge impact on public health, through the increased morbidity, mortality and economic costs associated with resultant fractures. The goal is to evaluate and identify those that are at risk of osteoporotic fracture in order to start preventative and therapeutic measures to reduce their risk of fracture., Sources of Data: This article reviews the data from randomized controlled trials for the current therapeutic agents available in the UK. It also reviews new trial data for promising osteoporosis therapies, in particular Denosumab, a monoclonal antibody against RANK ligand., Areas of Agreement: Bisphosphonates are the current recommended first-line treatments for patients with osteoporosis. AREAS OF CONTROVERSY/GROWING POINTS: There are a number of patients where bisphosphonates are contraindicated. Under these circumstances, it is important that clinicians have access to alternative treatments. The long-awaited National Institute for Health and Clinical Excellence (NICE) technology appraisals for both primary and secondary prevention and the clinical guidelines will clarify this. Treatment decisions should be based on risk factors and pharmaceutical intervention given to those with the highest risks., Areas Timely for Developing Research: Future studies are required to look at these agents in combination to see whether anti-fracture efficacy can be improved.

Background: There is a suggestion that acute dehydration in childhood may lead to elevated blood pressure. We examined if episodes of diarrhoea in childhood, a recognized proxy for acute dehydration, were related to measured blood pressure and coronary heart disease in older adults., Methods: Data were pooled from two prospective UK cohort studies (participants born 1920-39) in which episodes of diarrhoea were ascertained from health visitor records from birth until 5 years of age. Blood pressure and coronary heart disease were assessed during medical examination in men and women over 64 years of age. In total, 5203 men and women had data on diarrhoea in early life, adult blood pressure and a range of covariates; 4181 of these also had data on coronary heart disease status., Results: The prevalence of diarrhoea in infancy (3.3%) and between 1 and 5 years (1.1%) was low. There was no relation of diarrhoea from either period (age- and sex-adjusted results for diarrhoea in infancy presented here) with measured blood pressure [coefficient for systolic; 95% CI (confidence interval): 0.44; -2.88-3.76] or coronary heart disease (Odds ratio, OR; 95% CI: 0.91; 0.54-1.54) in adulthood. There was a similar lack of association when hypertension was the outcome of interest. These observations were unchanged after adjustment for a range of covariates., Conclusions: In the largest study to date to examine the relation, there was no evidence that diarrhoea in early life had an influence on measured blood pressure, hypertension or coronary heart disease in older adults.

Background: The prevalence of both childhood and adult obesity is rising in the developed world, and there is increasing interest in its underlying causes. A number of studies suggest a positive relationship between birth weight and childhood body mass index, but less is known about specific prenatal environmental influences on more direct measures of obesity. We used data from the Southampton Women's Survey to investigate parental influences on neonatal body composition ascertained by dual x-ray absorptiometry., Methods: Participating mothers were characterized in detail (anthropometry, lifestyle, diet) before and during pregnancy; information was also obtained on their partners. The offspring underwent assessment of fat and lean body mass by dual x-ray absorptiometry within 2 wk of birth. Linear regression methods were used to explore the parental determinants of neonatal body composition., Results: Complete data were available for 448 mother-offspring pairs. Taller women and those with higher parity had offspring with increased birth weight, fat, and lean mass (P < 0.05). Mothers who were taller, of greater parity, had greater fat stores, or walked more slowly also had offspring with greater proportionate body fat at birth (all P < 0.05). There was a weaker trend toward lower percentage fat and greater percentage lean in the offspring of mothers who smoked during pregnancy., Conclusion: Maternal size, parity, smoking history, walking speed, and fat stores are independent determinants of neonatal body composition. If these influences are shown to have persisting effects on body composition through to adulthood, they point to novel public health interventions early in life to prevent later obesity.

Low birth weight, a marker of adverse intrauterine circumstances, is known to be associated with a range of disease outcomes in later life, including coronary heart disease, hypertension, type 2 diabetes, and osteoporosis. However, it may also decrease the risk of other common conditions, most notably neoplastic disease. The authors describe the associations between birth weight, infant weight gain, and a range of mortality outcomes in the Hertfordshire Cohort. This study included 37,615 men and women born in Hertfordshire, United Kingdom, in 1911-1939; 7,916 had died by the end of 1999. For men, lower birth weight was associated with increased risk of mortality from circulatory disease (hazard ratio per standard deviation decrease in birth weight = 1.08, 95% confidence interval: 1.04, 1.11) and from accidental falls but with decreased risk of mortality from cancer (hazard ratio per standard deviation decrease in birth weight = 0.94, 95% confidence interval: 0.90, 0.98). For women, lower birth weight was associated with a significantly (p < 0.05) increased risk of mortality from circulatory and musculoskeletal disease, pneumonia, injury, and diabetes. Overall, a one-standard-deviation increase in birth weight reduced all-cause mortality risk by age 75 years by 0.86% for both men and women.

Epidemiological studies point to the importance of gene-environment interactions during early life as determinants of later osteoporosis and fracture. We examined associations between common single nucleotide polymorphisms in the human GH (GH1) gene and weight in infancy, adult bone mass and bone loss rates, and circulating GH profiles. Two hundred and five men and 132 women, aged 61-73 yr, in the Hertfordshire Cohort Study were included; bone mineral density was measured by dual energy x-ray absorptiometry over 4 yr. Twenty-four-hour circulating GH profiles were constructed in a subset of 71 men and women. Genomic DNA was examined for two single nucleotide polymorphisms in the GH gene (one in the promoter region and one in intron 4). Homozygotes at loci GH1 A5157G and T6331A displayed low baseline bone density and accelerated bone loss; there was also a significant (P = 0.04) interaction among weight at 1 yr, GH1 genotype, and bone loss rate. There was a graded association between alleles and circulating GH concentration among men. This study suggests that common diversity in the GH1 region predisposes to osteoporosis via effects on the level of GH expression. The interaction with infant weight suggests that early environment may influence the effect of GH1 genotype on bone loss.

Low birth weight and weight in infancy are associated with adult insulin resistance and type 2 diabetes. A proposed mechanism is programming of the hypothalamic-pituitary-adrenal axis by intrauterine undernutrition, leading to persistently elevated cortisol concentrations. We examined 24-h serum cortisol profiles (samples every 20 min) in 83 healthy elderly men and women whose birth weight and infant weight were recorded. Variables derived from these profiles included trough, peak, and area under the curve concentrations; the time of onset, rate of rise, duration, and peak of the early morning cortisol rise; postprandial secretion; and regularity of secretion (approximate entropy). None of these parameters was related to birth weight, weight at 1 yr, or change in weight SD score between birth and 1 yr. Consistent with other studies, 0730-0900 h cortisol concentrations were higher in men and women of lower birth weight, although this was not statistically significant (P = 0.08). Our findings do not support the hypothesis that reduced intrauterine and infant growth are associated with continuously raised cortisol concentrations in old age. Programmed effects on the hypothalamic-pituitary-adrenal axis may influence reactivity rather than resting secretion.

In humans, cortisol and GH are secreted in a pulsatile manner, and an interaction between GH and the hypothalamic-pituitary-adrenal axis has been established. In view of the sexually dimorphic pattern in GH secretion, we investigated the GH-cortisol bihormonal secretory dynamics in male and female healthy older individuals. We studied the GH and cortisol secretory patterns in 83 healthy subjects (45 men and 38 women; age range, 59.4-73.0 yr) by determining serum GH and cortisol concentrations at 20-min intervals for 24 h. The irregularity of GH and cortisol secretion was assessed using approximate entropy (ApEn), a scale- and model-independent statistic. The synchrony of joint GH-cortisol spontaneous secretion was quantified using the cross-ApEn statistic. Cross-correlation analysis of GH and cortisol patterns was computed at various time lags covering the 24-h period. Mean 24-h serum GH concentrations were significantly higher in females (mean, 1.31 mU/L; SD, 0.87) than in males (mean, 0.88 mU/L; SD, 0.42; P = 0.009), whereas mean 24-h serum total cortisol concentrations were higher in males (mean, 9.0 microg/dL; SD, 1.4) than in females (mean, 7.3 microg/dL; SD, 1.4; P = 0.0001). GH secretion was more irregular in females (mean ApEn, 0.81; SD, 0.23) than in males (mean ApEn, 0.60; SD, 0.20; P < 0.001). No significant difference in the regularity of cortisol secretion was noted between sexes. Cross-ApEn values of paired GH-cortisol were higher in females (mean, 1.15; SD, 0.18) than in males (mean, 1.01; SD, 0.16; P = 0.0003). Stepwise multiple linear regression analysis indicated that estradiol and insulin-like growth factor-binding protein-3 concentrations were independently related to GH ApEn values (r(2) = 0.14; P = 0.01), whereas cross-ApEn values of paired GH-cortisol were best predicted by FSH concentrations (r(2) = 0.37; P = 0.003). Cross-correlation analysis revealed a significant positive correlation between GH and cortisol, peaking at lag time of 4.7 h in males (r = 0.30; P < 0.0001) and 4.3 h in females (r = 0.14; P < 0.0001), with GH leading cortisol by these time intervals. In addition, a significant negative correlation between the two hormones was noted over time, peaking at 4.7 h in males (r = -0.21; P < 0.0001) and 6.3 h in females (r = -0.25; P < 0.0001), with cortisol leading GH by these time intervals. The above results indicate that in the elderly, females have a more disordered GH secretory pattern and a more asynchronous joint GH-cortisol secretion than their male counterparts. These observations most likely reflect bidirectional interactions between the GH and hypothalamic-pituitary-adrenal axis in humans as well as diminution of subsystem integrity and synchronous control of interconnected hormonal systems with advancing age.

Exogenous glucocorticoids are known to increase the risk of osteoporosis. However, the contribution made by endogenous circulating cortisol concentrations to adult skeletal status remains unknown. We examined this issue in a sample of 34 healthy men, aged 61-72 yr. Venous blood samples were obtained under standard conditions every 20 min over a 24-h period. Measurements were made of serum cortisol and cortisol-binding globulin. Bone mineral density was measured at the lumbar spine and proximal femur using dual energy x-ray absorptiometry. Measurements were made at baseline and 4 yr later. There was a weak negative association between integrated cortisol concentration and lumbar spine bone density (r = -0.37; P < 0.05); similar relationships (P < 0.05) existed at three of five proximal femoral sites. There were also statistically significant positive associations between the trough cortisol concentration and bone loss rate at the lumbar spine (r = 0.38; P < 0.05), femoral neck (r = 0.47; P < 0.001), and the trochanteric region (r = 0.41; P = 0.02) over the 4-yr follow-up period. The cross-sectional relationships between cortisol concentration and bone density were removed by adjustment for body mass index, but the influence on bone loss rate remained significant after adjusting for adiposity, cigarette smoking, alcohol consumption, dietary calcium intake, physical activity, and serum testosterone and estradiol levels. These observations suggest that the endogenous cortisol profile of healthy elderly men is a determinant of their bone mineral density and their rate of involutional bone loss.

In rodents, the sexually dimorphic pattern of pulsatile GH secretion is an important determinant of growth, liver enzyme function and insulin-like growth factor I (IGF-I) expression. Whether this difference is present in humans at different ages is unclear. We studied GH secretory patterns in the elderly by constructing 24-h serum GH profiles in 45 male and 38 female (age, 59.4-73.0 yr) volunteers and related patterns to IGF-I, IGF-binding protein-3 (IGFBP-3), and GH-binding protein levels; body mass index; and waist/hip ratio. Serum GH concentrations were measured in samples drawn at 20-min intervals and analyzed using a sensitive chemiluminescent assay (Nichols Institute Diagnostics: sensitivity, 0.036 mU/L). The 24-h serum GH profiles were analyzed using a concentration distribution method to determine GH peak and trough levels, spectral analysis, and assessment of serial irregularity by approximate entropy (ApEn). There was a highly significant difference in mean 24-h serum GH concentrations in females compared to males (males, 0.88 mU/L; females, 1.31 mU/L; P = 0.009) as a result of significantly higher trough GH levels (males, 0.04 mU/L; females, 0.16 mU/L; P < 0.001). Peak values were not significantly different. Serum IGF-I levels were significantly higher in males (males, 162.4 ng/mL; females, 87.8 ng/ mL; P < 0.001). Peak GH values were related to serum IGF-I levels (males: r = 0.39; P = 0.009; females: r = 0.5; P = 0.002), whereas trough GH levels were not. IGFBP-3 levels were similar and related to GH peaks only in males (r = 0.32; P = 0.03). GH was secreted with a dominant periodicity of 200 min in males and 280 min in females (P < 0.025). The proportion of time taken up by regular oscillatory activity was less in females (females, 11.1%; males, 14.7%; P = 0.01). GH secretion assessed by ApEn was more disordered in females (males, 0.60; females, 0.81; P < 0.001), and increasing disorder was associated with lower IGF-I levels. Body mass index was negatively related to GH in both sexes. In males, trough values were the major determinant (r = -0.31; P = 0.04), whereas in females, the peak value was the major determinant (r = 0.35; P = 0.04). Trough GH levels were inversely related in both sexes to waist/hip ratio (males: r = -0.40; P = 0.006; females: r = -0.44; P = 0.006) and to increasing secretory disorder (ApEn; r = -0.46; P < 0.001). These data demonstrate a sexually dimorphic pattern of GH secretion in the elderly.

Background: Recent epidemiological studies suggest that post-menopausal hormone replacement therapy might reduce the risk of hip osteoarthritis (OA) in women. However, the association of the disorder with other reproductive variables is controversial. We addressed this issue in a population-based case control study among 413 female cases and 413 age- and sex-matched controls., Methods: A total of 413 women listed for hip replacement because of primary OA over an 18 month period were compared with an equal number of controls selected from the general population and individually matched for age and general practice. Information about reproductive variables was obtained by questionnaire administered at interview., Results: The risk of hip OA was significantly elevated among women who had had an oophorectomy (OR = 1.9, 95% CI 1.0-3.7). After adjustment for body mass index, the presence of Heberden's nodes, previous hip injury and past leisure sporting activity (all independent risk factors for hip OA), and for other reproductive variables, there was a non-significant, protective effect of long-term hormone replacement therapy, such that > or =5 yr of use was associated with a 40% reduction in risk (OR = 0.6, 95% CI 0.2-1.8). Paradoxically, short-term HRT use (up to 5 yr duration) was associated with an excess risk of hip OA (OR = 1.7, 95% CI 0.9-3.3). There was no association between the risk of hip OA and use of oral contraceptives, parity or hysterectomy., Conclusions: These data are consistent with previous studies suggesting a protective effect of long-term hormone replacement therapy on the risk of hip OA. By contrast, an elevation of risk in short-term users was demonstrated. Our results also suggest that risk is increased among women who have undergone unilateral or bilateral oophorectomy. Studies are required to investigate the mechanisms underlying these associations.

Epidemiological studies suggest that retarded growth in infancy is associated with low adult bone mass. The mechanism underlying this association is unknown, but the programming of GH secretion or sensitivity by environmental influences during early development may play a role. We examined this issue in a sample of 37 healthy men, aged 63-73 yr, whose weight gain in infancy had been recorded. Venous blood samples were obtained under standard conditions every 20 min over a 24-h period. Measurements were made of the GH secretory profile, insulin-like growth factor I (IGF-I), IGF-binding protein-1 and -3, and GH-binding protein. Bone mineral density was measured at the lumbar spine and femoral neck using dual energy x-ray absortiometry. There was a statistically significant association between peak GH concentration (r = 0.46; P < 0.01) and fasting IGF-I concentration (r = 0.46; P < 0.01) with femoral neck bone density. After allowing for the peak GH concentration, median GH was negatively (P < 0.05) associated with bone mineral density. Weight at 1 yr was not related to peak GH, but was strongly related to the median GH concentration (r = 0.42; P = 0.01). These observations are consistent with a dual effect of GH secretion on bone density. High peak GH values drive IGF-I production and maintain bone mineralization in adult life. However, integrated GH secretion, after adjusting for the effect of pulse amplitude, is negatively associated with bone density in adult life. This particular characteristic of the GH secretory profile correlates with growth during infancy and might be programmed by environmental factors during intrauterine or early postnatal life.