Showing papers by "Cyrus Cooper published in 2007"

The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women.

Abstract: BMD and clinical risk factors predict hip and other osteoporotic fractures. The combination of clinical risk factors and BMD provide higher specificity and sensitivity than either alone. To develop a risk assessment tool based on clinical risk factors (CRFs) with and without BMD. Nine population-based studies were studied in which BMD and CRFs were documented at baseline. Poisson regression models were developed for hip fracture and other osteoporotic fractures, with and without hip BMD. Fracture risk was expressed as gradient of risk (GR, risk ratio/SD change in risk score). CRFs alone predicted hip fracture with a GR of 2.1/SD at the age of 50 years and decreased with age. The use of BMD alone provided a higher GR (3.7/SD), and was improved further with the combined use of CRFs and BMD (4.2/SD). For other osteoporotic fractures, the GRs were lower than for hip fracture. The GR with CRFs alone was 1.4/SD at the age of 50 years, similar to that provided by BMD (GR = 1.4/SD) and was not markedly increased by the combination (GR = 1.4/SD). The performance characteristics of clinical risk factors with and without BMD were validated in eleven independent population-based cohorts. The models developed provide the basis for the integrated use of validated clinical risk factors in men and women to aid in fracture risk prediction.

Grip strength, body composition, and mortality

Abstract: BACKGROUND: Several studies in older people have shown that grip strength predicts all-cause mortality. The mechanisms are unclear. Muscle strength declines with age, accompanied by a loss of muscle mass and an increase in fat, but the role that body composition plays in the association between grip strength and mortality has been little explored. We investigated the relation between grip strength, body composition, and cause-specific and total mortality in 800 men and women aged 65 and over. METHODS: During 197374 the UK Department of Health and Social Security surveyed random samples of men and women aged 65 and over living in eight areas of Britain to assess the nutritional state of the elderly population. The survey included a clinical examination by a geriatrician who assessed grip strength and anthropometry. We used Cox proportional hazards models to examine mortality over 24 years of follow-up. RESULTS: Poorer grip strength was associated with increased mortality from all-causes, from cardiovascular disease, and from cancer in men, though not in women. After adjustment for potential confounding factors, including arm muscle area and BMI, the relative risk of death in men was 0.81 (95% CI 0.700.95) from all-causes, 0.73 (95% CI 0.600.89) from cardiovascular disease, and 0.81 (95% CI 0.660.98) from cancer per SD increase in grip strength. These associations remained statistically significant after further adjustment for fat-free mass or % body fat. CONCLUSION: Grip strength is a long-term predictor of mortality from all-causes, cardiovascular disease, and cancer in men. Muscle size and other indicators of body composition did not explain these associations.

Fracture risk with intermittent high-dose oral glucocorticoid therapy.

Abstract: Objective: To evaluate the risk of fracture in patients receiving intermittent therapy with high-dose oral glucocorticoids (GCs). Methods: The study group comprised 191,752 patients from the UK General Practice Database who were 40 years of age and older and received therapy with GCs. The followup time period was divided into the categories of current and no exposure. The daily dose and cumulative dose for each time period were determined. Relative risks were estimated using Cox proportional hazards models, adjusted for age, sex, body mass index, smoking, disease history, and drug history. Fractures of the radius/ulna, humerus, rib, femur/hip, pelvis, or vertebrae were included in the evaluation. Results: Patients who intermittently received high-dose GCs (daily dose 15 mg) and had no or little previous exposure to GCs (cumulative exposure 1 gm) had a small increased risk of osteoporotic (but not hip/femur) fracture; this risk increased substantially with increasing cumulative exposure. Among patients who received a daily dose 30 mg and whose cumulative exposure was >5 gm, the relative risk (RR) of osteoporotic fracture was 3.63 (95% confidence interval [95% CI] 2.54-5.20), the RR of fracture of the hip/femur was 3.13 (95% CI 1.49-6.59), and the RR of vertebral fracture was 14.42 (95% CI 8.29-25.08). Conclusion: Intermittent use of high-dose oral GCs (daily dose 15 mg and cumulative exposure 1 gm) may result in a small increased risk of osteoporotic fracture. Conversely, patients who receive several courses of high-dose GCs (daily dose 15 mg and cumulative exposure >1 gm) have a substantially increased risk of fracture.

Dietary patterns in infancy: the importance of maternal and family influences on feeding practice

Abstract: It is not known what constitutes an optimal diet in infancy. There are relatively few studies of weaning practice in the UK, and there is a need for prospective data on the effects of infant diet and nutrition on health in later life. We describe the dietary patterns, defined using principal components analysis of FFQ data, of 1434 infants aged 6 and 12 months, born between 1999 and 2003. The two most important dietary patterns identified at 6 and 12 months were very similar. The first pattern was characterised by high consumption of fruit, vegetables and home-prepared foods (‘infant guidelines’ pattern). The second pattern was characterised by high consumption of bread, savoury snacks, biscuits and chips (‘adult foods’ pattern). Dietary pattern scores were correlated at 6 and 12 months (r 0·46 ‘infant guidelines’; r 0·45 ‘adult foods’). These patterns, which reflect wide variations in weaning practice, are associated with maternal and family characteristics. A key influence on the infant diet is the quality of the maternal diet. Women who comply with dietary recommendations, and who have high intakes of fruit and vegetables, wholemeal bread and rice and pasta, are more likely to have infants who have comparable diets – with high ‘infant guidelines’ pattern scores. Conversely, women whose own diets are characterised by high intakes of chips, white bread, crisps and sweets are more likely to have infants who have high ‘adult foods’ pattern scores. The effects of these patterns on growth and development, and on long-term outcomes need to be investigated.

Grip strength and the metabolic syndrome: findings from the Hertfordshire Cohort Study

Abstract: INTRODUCTION: Sarcopenia, the loss of muscle mass and strength with age, is significantly associated with type 2 diabetes in older people. AIM: To determine whether there is a relationship between grip strength and features of the metabolic syndrome. DESIGN: Cross-sectional study. METHODS: Data were collected on grip strength, fasting glucose, triglycerides and HDL cholesterol, blood pressure, waist circumference and 2 h glucose after an oral glucose tolerance test, in a population-based sample of 2677 men and women aged 59-73 years. RESULTS: In men and women combined, a standard deviation (SD) decrease in grip strength was significantly associated with higher: fasting triglycerides (0.05 SD unit increase, 95%CI 0.02-0.09, p = 0.006); blood pressure (OR 1.13, 95%CI 1.04-1.24, p = 0.004); waist circumference (0.08 SD unit increase, 95%CI 0.06-0.10, p DISCUSSION: Our findings suggest that impaired grip strength is associated with the individual features, as well as with the overall summary definitions, of the metabolic syndrome. The potential for grip strength to be used in the clinical setting needs to be explored.

Maternal Size in Pregnancy and Body Composition in Children

Abstract: Context: Evidence suggests that babies’ fat mass at birth is greater if their mothers were themselves fatter during pregnancy, but it is unclear whether this association persists into childhood. Objective: Our objective was to examine the relation between maternal size in pregnancy, early growth and body composition in children. Design and Setting: We conducted a prospective cohort study in Southampton, United Kingdom. Participants: Participants included 216 9-yr-old children whose mothers had participated in a study of nutrition during pregnancy. Main Outcome Measures: Fat mass and lean mass were measured by dual-energy x-ray absorptiometry and adjusted for height (fat mass index and lean mass index). Results: Fat mass index at age 9 yr was greater in children whose mothers had a larger mid-upper arm circumference in late pregnancy or a higher prepregnant body mass index. For 1 sd increase in maternal mid-upper arm circumference in late pregnancy, fat mass index rose by 0.26 [95% confidence interval (CI)...

Non-compliance: the Achilles' heel of anti-fracture efficacy.

Abstract: About 50% of patients fail to comply or persist with anti-osteoporosis treatment regimens within 1 year. Poor compliance is associated with higher fracture rates. Causes of poor compliance are unknown. As it is not possible to predict poor compliance, close monitoring of compliance is needed. Despite evidence supporting the anti-fracture efficacy of several pharmacological agents, approximately 50% of patients do not follow their prescribed treatment regimen and/or discontinue treatment within 1 year. Poor compliance is associated with higher fracture rates and increased morbidity, mortality and cost. However, as poor compliance, even to placebo, is associated with adverse outcomes, the higher morbidity appears to be only partly the result of lack of treatment: as yet, undefined characteristics place poor compliers at higher risk of morbidity and mortality. Only a small proportion (e.g., 6%) of the variability in compliance is explained by putative causal factors such as older age, co-morbidity or greater number of medications. Regimens with longer dosing intervals, such as weekly dosing, improve compliance, persistence and outcomes, but only modestly. As it is not possible to predict poor compliance, close monitoring of compliance should be an obligatory duty in clinical care. How this is best achieved has yet to be established, but poor persistence occurs as early as 3 months of starting treatment, indicating the need for early monitoring.

Relationship of height, weight and body mass index to the risk of hip and knee replacements in middle-aged women.

Abstract: OBJECTIVES: To examine the effect of height, weight and body mass index (BMI) on the risk of hip and knee replacement in middle-aged women. METHODS: In a prospective cohort study 490 532 women aged 50-69 yrs who were recruited in the UK in 1996-2001 were followed over 2.9 yrs for incident primary hip and knee replacements. RESULTS: Height, weight and BMI were all associated with the risk of hip and knee replacement. Comparing the tallest group (>/=170 cm) with the shortest (/= 30 kg/m(2)) to women with a BMI < 22.5 kg/m(2), the relative risks for hip and knee replacement were 2.47 (95%CI 2.11-2.89) and 10.51 (95%CI 7.85-14.08), respectively. These effects did not vary according to age, education, alcohol and tobacco consumption, or with use of hormonal therapies. Currently, an estimated 27% of hip replacements and 69% of knee replacements in middle-aged women in the UK are attributable to obesity. CONCLUSION: In middle-aged women, the risk of having a hip or knee replacement increases with both increasing height and increasing BMI. From a clinical perspective, relatively small increases in average BMI among middle-aged women are likely to have a substantial impact on the already increasing rates of joint replacement in the UK.

Parental Determinants of Neonatal Body Composition

Abstract: 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 ...

How accurate are diagnoses for rheumatoid arthritis and juvenile idiopathic arthritis in the General Practice Research Database

Abstract: Objective. To identify characteristics that predict a valid rheumatoid arthritis (RA) or juvenile idiopathic arthritis (JIA) diagnosis among RA- and JIA-coded individuals in the General Practice Research Database (GPRD), and to assess limitations of this type of diagnostic validation. Methods. Four RA and 2 JIA diagnostic groups were created with differing strengths of evidence of RA/JIA (Group 1 = strongest evidence), based oil RA/JIA medical codes. Individuals were sampled from each group and clinical and 0 prescription data were extracted from anonymized hospital/practice correspondence and electronic records. American College of Rheumatology and International League of Associations for Rheumatology diagnostic criteria were, used to validate diagnoses. A data- derived diagnostic algorithm that maximized sensitivity and specificity was identified using logistic regression. Results. Among 223 RA-coded individuals. the diagnostic algorithm classified individuals as having RA if they had an appropriate GPRD disease-modifying antirheumatic drug prescription or 3 other GPRD characteristics: >1 RA code during followup, RA diagnostic Group 1 or 2, and no later alternative diagnostic code. This algorithm had >80% sensitivity and specificity when applied to a test data set. Among 101 JIA-coded individuals, the strongest predictor of a valid diagnosis was a Group 1 diagnostic code (>90% sensitivity and specificity). Conclusion. Validity of an RA diagnosis among RA-coded GPRD individuals appears high for patients with specific characteristics. The findings are important for both interpreting results Of Published GPRD studies and identifying RA/JIA patients for future GPRD-based research. However, several limitations were identified, and further debate is needed on how best to validate chronic disease diagnoses in the GPRD

Lipid profile, obesity and bone mineral density: the Hertfordshire Cohort Study

Abstract: BACKGROUND: Body mass index (BMI) and bone mineral density (BMD) are positively correlated in several studies, but few data relate bone density, lipid profile and anthropometric measures. AIM: To investigate these relationships in a large, well-characterized cohort of men and women (The Hertfordshire Cohort Study). METHODS: Men (n = 465) and women (n = 448) from Hertfordshire, UK were recruited. Information was available on demographic and lifestyle factors, anthropometric measurements, body fat percentage, fasting triglycerides, cholesterol (total, HDL, LDL), apolipoprotein (a) and apolipoprotein (b); bone mineral density (BMD) was recorded at the lumbar spine and total femur. RESULTS: BMD at the lumbar spine (males r = 0.15, p = 0.001; females r = 0.14, p = 0.003) and total femoral region (males r = 0.18, p = 0.0001; females r = 0.16, p = 0.0008) was related to serum triglyceride level, even after adjustment for waist-hip ratio, age, social class and lifestyle factors, but not if body fat percentage was substituted for waist-hip ratio in the regression model. Fasting HDL cholesterol level was related to lumbar spine BMD in women (r = -0.15, p = 0.001) and total femoral BMD in both sexes (males r = -0.15, p = 0.002; females r = -0.23, p DISCUSSION: In this cohort, relationships between lipid profile and BMD were robust to adjustment for one measure of central obesity (waist-hip ratio), but not total body fat. This broadly supports the idea that adiposity may confound the relationship between lipids and bone mass.

Long-term outcome following total hip arthroplasty: a controlled longitudinal study.

Abstract: Objective To assess long-term outcome and predictors of prognosis following total hip arthroplasty (THA) for osteoarthritis (OA). Methods We studied 282 patients from 2 English health districts ∼8 years after THA, along with 295 controls selected from the general population. Baseline data were collected by interview and examination, on sex, age, comorbidity, body mass index (BMI), and Short Form 36 (SF-36) functional status, and preoperative radiographic severity of OA was graded. Functional status was reassessed at followup by postal questionnaire. Predictors of change in physical functioning were analyzed by linear regression. Results Over followup, cases who had THA reported a median improvement of 10 points in SF-36 score for physical functioning, whereas in controls there was a median deterioration of 10 points (P < 0.0001). Mental health improved by a median of 12 points in both cases and controls. Change in physical functioning was significantly worse in women and at older ages among both cases and controls. In cases, Croft grade 5 OA was associated with a physical functioning score improvement 19.4 points (95% confidence interval 7.7, 31.2) greater than the improvement in grades 0–3, but BMI was unrelated to change in physical functioning. Conclusion Improvements in physical functioning following THA for OA are sustained in the long term and are more frequent in patients with more severe radiographic features preoperatively. We found no indication that patients who are overweight benefit less from THA, but further evidence is needed on the prognostic influence of more severe obesity.

Use of inhaled and oral glucocorticoids, severity of inflammatory disease and risk of hip/femur fracture: a population-based case-control study.

Abstract: BACKGROUND: Patients using higher dosages of inhaled or oral glucocorticoids (GCs) have an increased risk of hip/femur fractures. The role of the underlying disease in the aetiology of this increased risk has not been widely studied. OBJECTIVE: To evaluate the contribution of the underlying disease to the risk of hip/femur fracture in patients using inhaled or oral GCs. DESIGN AND SUBJECTS: A case-control study within the Dutch PHARMO-RLS database was conducted. Cases (n = 6763) were adult patients with a first hip/femur fracture during enrolment. Each case was matched to four controls by age, gender and region. RESULTS: The risk of hip/femur fracture increased with current use of inhaled GCs (crude OR 1.30, 95% CI:1.16-1.47) and with current use of oral GCs (crude OR 1.66, 95% CI: 1.46-1.90). After adjustment for disease severity, the risk of hip/femur fracture was no longer statistically significantly increased in inhaled GC users (adjusted OR 1.08, 95% CI: 0.91-1.27), whilst it remained elevated in oral GC users (adjusted OR 1.43, 95% CI: 1.22-1.67). Patients using inhaled GCs without any exposure to oral GCs had no increased risk of fracture (adjusted OR 0.98, 95% CI: 0.79-1.22). CONCLUSION: Inhaled GC users had no increased risk of femur/hip fracture after adjustment for underlying disease severity. Our data suggest that, even at higher dosages, inhaled GC use is not an independent risk factor for fracture. In contrast, oral GC use was associated with an increased risk of fracture, which was not fully explained by the underlying disease severity.

The importance of the disease process and disease-modifying antirheumatic drug treatment in the development of septic arthritis in patients with rheumatoid arthritis.

Abstract: Objective To evaluate the effect of disease-modifying antirheumatic drugs (DMARDs) on the likelihood of patients with rheumatoid arthritis (RA) developing septic arthritis (SA). Methods The United Kingdom General Practice Research Database (GPRD) was used to identify adults with RA, and age-, sex-, and practice-matched control subjects. Subjects were studied between 1987 and 2002. The risk of developing SA (excluding infected joint replacements) for individuals with RA was calculated and the effect of DMARD use determined. Results A total of 136,977 subjects (34,250 patients with RA, 102,747 controls) were identified. SA was identified in 345 subjects, of which 321 (236 in patients with RA, 85 in controls) cases occurred during the study period. The incidence rate of SA was 12.9 times higher in subjects with RA than in those without (95% confidence interval [95% CI] 10.1–16.5, P < 0.001). The incident rate ratios (IRRs) for developing SA while receiving DMARDs compared with receiving no DMARDs were different for different medications. Penicillamine (adjusted IRR 2.51, 95% CI 1.29–4.89, P = 0.004), sulfasalazine (adjusted IRR 1.74, 95% CI 1.04–2.91, P = 0.03), and prednisolone (adjusted IRR 2.94, 95% CI 1.93–4.46, P < 0.001) were associated with an increased incidence of SA when compared with not receiving any DMARD. The use of other DMARDs including methotrexate showed no such effect. Conclusion Individuals with RA have an increased risk of developing SA. This increased risk can be attributed to both the disease process and the use of DMARDs.

Use of beta-blockers and the Risk of Hip/Femur fracture in the United Kingdom and the Netherlands

Abstract: Data from in vivo studies have indicated a role for β-blockers in the prevention of bone loss. Some epidemiological studies have found protective effects of β-blockers on fracture risk. However, there is limited information on the association with cumulative dose and type of β-blockers used. We conducted two case-control studies using data from the UK General Practice Research Database (GPRD) and the Dutch PHARMO Record Linkage System (RLS). Cases were patients with a first hip or femur fracture; controls were individually matched on practice/region, gender, year of birth, and calendar time. Current use of β-blockers was defined as a prescription in 90 days before the index date. We adjusted for medical conditions and drugs associated with falling or bone mineral density. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression analysis. The study population included 22,247 cases and controls in the GPRD and 6,763 cases and 26,341 controls in the PHARMO RLS. Current use of β-blockers was associated with a reduced risk of hip/femur fracture in both the GPRD (adjusted OR = 0.82, 95% CI 0.74–0.91) and PHARMO RLS (adjusted OR = 0.87, 95% CI 0.80–0.95) study populations. However, this reduction of risk was not associated with cumulative dose, lipophilicity, or receptor selectivity of β-blockers. The protective effect of β-blockers was only present among patients with a history of use of other antihypertensive agents (GPRD adjusted OR = 0.72, 95% CI 0.64–0.83; PHARMO RLS adjusted OR = 0.76, 95% CI 0.67–0.86) but not in patients using β-blockers only (GPRD adjusted OR = 0.97, 95% CI 0.82–1.14; PHARMO RLS adjusted OR = 1.01, 95% CI 0.90–1.14). Also, in patients with a history of use of other antihypertensive agents, no dose-response relationship with β-blocker use was found. The effect was constant with cumulative dose and the OR was below 1.0 even among patients who just started treatment with β-blockers. As the mechanism by which β-blockers could influence bone mineral density is likely to need some time to exert a clinically relevant effect, all these finding suggests that the association between β-blockers and fracture risk is not causal.

Size at birth and its relation to muscle strength in young adult women

Abstract: Objective: to assess the relationship between development in utero, assessed by birth weight, and muscle strength in young adult women as assessed by grip strength. Methods: a total of 1563 participants aged 20– 40 years in the Southampton Women’s Survey had their grip strength measured during pregnancy. At recruitment to the survey the women had been asked to recall their birth weight or obtain it from their parents. For 536 women born in Southampton, birth weight was obtained from hospital records. Grip strength was related to birth weight using multiple linear regression analysis, adjusting for age, height, weight and reported physical activity. Results: grip strength increased with age, height, weight, physical activity and birth weight. In the mutually-adjusted model, grip strength increased by 1.10 kg per kilogram of birth weight (95% CI: 0.58–1.61 kg). In women with hospital birth weight data the relationship strengthened to 1.44 kg per kilogram of birth weight (95% CI: 0.50– 2.38 kg). Conclusions: grip strength in women in their twenties and thirties is at or approaching its peak. The association between grip strength and birth weight was remarkably similar to findings from other studies of women at younger and older ages. This indicates that in utero development has consequences for muscle strength throughout the life course, even allowing for the increase to peak muscle strength and then its decline as a woman ages.

Prevalence and functionality of paucimorphic and private MC4R mutations in a large, unselected European British population, scanned by meltMADGE.

Abstract: Identification of unknown mutations has remained laborious, expensive, and only viable for studies of selected cases. Population-based "reference ranges" of rarer sequence diversity are not available. However, the research and diagnostic interpretation of sequence variants depends on such information. Additionally, this is the only way to determine prevalence of severe, moderate, and silent mutations and is also relevant to the development of screening programs. We previously described a system, meltMADGE, suitable for mutation scanning at the population level. Here we describe its application to a population-based study of MC4R (melanocortin 4 receptor) mutations, which are associated with obesity. We developed nine assays representing MC4R and examined a population sample of 1,100 subjects. Two "paucimorphisms" were identified (c.307G>A/p.Val103Ile in 27 subjects and c.-178A>C in 22 subjects). Neither exhibited any anthropometric effects, whereas there would have been >90% power to detect a body mass index (BMI) effect of 0.5 kg/m(2) at P=0.01. Two "private" variants were also identified. c.335C>T/p.Thr112Met has been previously described and appears to be silent. A novel variant, c.260C>A/p.Ala87Asp, was observed in a subject with a BMI of 31.5 kg/m(2) (i.e., clinically obese) but not on direct assay of a further 3,525 subjects. This mutation was predicted to be deleterious and analysis using a cyclic AMP (cAMP) responsive luciferase reporter assay showed substantial loss of function of the mutant receptor. This population-based mutation scan of MC4R suggests that there is no severe MC4R mutation with high prevalence in the United Kingdom, but that obesity-causing MC4R mutation at 1 in 1,100 might represent one of the commonest autosomal dominant disorders in man.

The autoantibody rheumatoid factor may be an independent risk factor for ischaemic heart disease in men

Abstract: Background: Subjects with rheumatoid arthritis have an increased prevalence of ischaemic heart disease (IHD). This is most likely in those people with the autoantibody rheumatoid factor (RF). RF is strongly associated with rheumatoid arthritis (RA) but is also present in up to 15% of all adults. Objective: To determine whether RF might identify people in a general population who also share an increased likelihood of developing IHD. Methods: Subjects from the Hertfordshire Cohort Study were investigated for the presence of RF. Subjects completed a questionnaire and attended a clinic where a history of IHD was recorded (ECG, coronary artery bypass grafting, Rose chest pain). Associations between the presence of RF, antinuclear antibodies (ANA), anticardiolipin antibodies (ACA) and IHD in 567 men and 589 women were investigated and compared with traditional risk factors for IHD. Results: RF was associated with an increased likelihood of IHD in men (odds ratio (OR) = 3.1, 95% CI 1.7 to 5.4, p Conclusion: This work suggests that RF is an independent risk factor for IHD in the general population. It lends support to the importance of inflammation in atherosclerosis and suggests that autoimmune processes may be involved. In addition, it raises the intriguing possibility that RF may have a direct role in the pathogenesis of IHD in some subjects.

Use of beta-2 agonists and risk of hip/femur fracture: a population-based case-control study.

Abstract: INTRODUCTION: Administration of beta-2 agonists decreased bone mineral density in rats. But the association between bronchodilators and fracture risk has not been studied in humans. OBJECTIVES: To examine the association between use of beta-2 agonists and risk of hip/femur fracture. METHODS: We conducted a population-based case-control study (6763 cases) in the Dutch PHARMO database. Current beta-2 agonist use was compared to never use. We adjusted for severity of the underlying respiratory disease and disease and drug history. RESULTS: A hospitalisation for asthma/COPD in the year before index date increased risk of hip/femur fracture: crude OR 2.17 (95% CI, 1.41-3.34). Patients using higher doses of beta-2 agonists had increased risk of hip/femur fracture: crude OR 1.94 (95% CI, 1.41-2.66) for daily dosages of >or=1600 microg albuterol equivalent. The excess fracture risk reduced after adjustment for disease severity (1.46; 95% CI, 1.02-2.08) and after exclusion of oral glucocorticoid users (1.31; 95% CI, 0.80-2.15). Risk of hip/femur fracture was similar between users of beta-2 agonists, inhaled glucocorticoids and anticholinergics. CONCLUSION: We found increases in the risk of hip/femur fracture in patients using higher doses of beta-2 agonists. However, the excess risk of hip/femur fracture substantially reduced after exclusion of oral glucocorticoid users and after adjustment for the underlying disease. Risk of hip/femur fracture was similar between users of beta-2 agonists, inhaled glucocorticoids and anticholinergics. The severity of the underlying disease, rather than the use of beta-2 agonists, may play an important role in the aetiology of hip/femur fractures in patients using beta-2 agonists.

Individual fracture risk and the cost-effectiveness of bisphosphonates in patients using oral glucocorticoids

Abstract: OBJECTIVES: There are few data on the cost-effectiveness of bisphosphonates with oral glucocorticoids (GCs). An individual patient-based pharmaco-economic model was developed. METHODS: Data were obtained from a cohort of oral GC users aged 40+ (n = 190 000) in the UK General Practice Research Database. Individualized fracture and mortality risks were calculated specific for age, sex, daily and cumulative GC dose, indication and other clinical risk factors. UK costs of medication and direct costs of fracture were obtained from National Institute for Clinical Excellence and used to estimate costs per quality-adjusted life-year (QALY) gained and fracture prevented for bisphosphonates in patients treated for 5 yrs with GCs. RESULTS: With the use of 5 mg GCs daily, the cost per one QALY gained with bisphosphonates was 41k UK pounds (95% confidence intervals 22-72k) in women aged <60 [men 40k pounds (29-54k)], 17k pounds (13-24k) in women aged 60-79 [men 43k pounds (31-60k)], 5k pounds(3-6k) in women aged 80+ [men 35k pounds (25-46k)]. With 15 mg GC, these figures were 17k pounds (14-21k), 13k pounds (10-16k) and 15k pounds (9-26k) in women and 22k pounds (17-26k), 34 pounds (23-53k) and 33k pounds (27-42k) in men, respectively. When stratifying by overall fracture risk and life expectancy at the start of GC therapy, cost per QALY increased with decreasing life expectancy. Patients with rheumatoid arthritis had comparatively better cost-effectiveness, given higher fracture risk and better life expectancy. CONCLUSIONS: The cost-effectiveness of bisphosphonates varied substantially. Bisphosphonates can be considered cost-effective in patients with higher fracture risks, such as elderly patients (with a life expectancy over 5 yrs), and younger patients with a fracture history, low body mass index, rheumatoid arthritis or using high GC doses.

Specific associations of insulin resistance with impaired health-related quality of life in the Hertfordshire Cohort Study.

Abstract: Insulin resistance is a metabolic abnormality that underlies Type 2 diabetes, the metabolic syndrome and cardiovascular disease, but it may also be associated with more global health deficits. This study assessed associations of insulin resistance with health-related quality of life (HRQoL) in different domains of physical and mental health in a large elderly population study. Cross-sectional data of 1212 participants from the Hertfordshire Cohort Study were analysed. Insulin resistance was assessed by the homeostatic model assessment (HOMA-IR), and HRQoL was measured using the SF-36 health survey. Poor HRQoL was defined by a score lower than the sex-specific 10th percentile of each scale, and logistic regressions yielded odds ratios in relation to the HOMA-IR scores. Subsequent analyses adjusted for the influence of age, smoking, alcohol consumption, social class, BMI, coronary heart disease and depression. Results showed an increase in poor HRQoL with an increase in HOMA-IR scores for physical functioning (OR = 2.29; CI: 1.67-3.13), vitality (OR = 1.45; CI: 1.05-2.00), and general health (OR = 1.62; CI: 1.19-2.21). In men, but not in women, associations with physical functioning were independent of confounding variables. The results indicate that insulin resistance is associated with poor HRQoL in domains of physical health, but not in domains of mental health.

Variation in the matrix metalloproteinase-3, -7, -12 and -13 genes is associated with functional status in rheumatoid arthritis

Abstract: As matrix metalloproteinases (MMPs) play an important role in rheumatoid arthritis, we investigated whether variation in MMP genes was associated with functional disability in rheumatoid arthritis patients. A cohort of patients with seropositive rheumatoid arthritis were recruited and genotyped for the MMP1-1607 1G > 2G, MMP3-1612 5A > 6A, MMP7-153C > T, MMP7-181G > A, MMP12-82A > G and MMP13-77A > G polymorphisms. Genotypes were then analysed in relation to functional disability assessed by Steinbrocker index and Health Assessment Questionnaire (HAQ) score. We detected an association between the MMP13-77 A > G polymorphism and Steinbrocker index, with patients of the A/A genotype having higher score than patients of the A/G or G/G genotype (P = 0.005), and the association remained significant after adjusting for age, sex, erythrocyte sedimentation rate, presence of erosive disease, Ritchie score, prednisolone therapy and years of diagnosis (P = 0.003). We also observed a relationship of Steinbrocker index with the MMP3-1612 5A > 6A, MMP7-181 A > G and MMP12-82A > G polymorphisms (P = 0.082, P = 0.037 and P = 0.045). No association was detected between the MMP1-1607 1G > 2G and MMP7-153C > T polymorphisms and either Steinbrocker index or HAQ score. These results suggest that MMP3, MMP7, MMP12 and MMP13 genotypes may play a role in determining functional status of rheumatoid arthritis.

Serum fasting cortisol in relation to bone, and the role of genetic variations in the glucocorticoid receptor.

Abstract: Objective To examine the relationship between endogenous cortisol and bone, and the role of genetic variations in the glucocorticoid receptor (GR). Design and patients The Longitudinal Ageing Study Amsterdam (LASA), a population-based cohort study in older men and women. Measurements Serum fasting cortisol was assessed by competitive immunoassay (n = 1214); bone mineral density (BMD) by dual X-ray absorptiometry (DXA) (n = 502); broadband ultrasound attenuation (BUA) by ultrasound (n = 1209); fractures by self-report (n = 1211); and GR gene polymorphisms (ER22/23EK, N363S, 9beta, BclI) were genotyped by Taqman (n = 858). Results Higher serum fasting cortisol was significantly associated with lower BMD at all sites and BUA at the heel in women, although most relationships were attenuated by age and body mass index (BMI). The effect on femoral neck BMD remained statistically significant in the fully adjusted model (r = -0.135, P = 0.04). No significant associations in men were found. Female 9beta G-allele carriers had 50.2 nmol/l lower cortisol and 1.2 lower free cortisol levels than AA homozygotes [P = 0.01 for (free) cortisol]. Furthermore, female BclI GG homozygotes had 54.8 nmol/l higher cortisol levels than C-carriers (P = 0.03). In the total population, BclI GG homozygotes had 0.05 g/cm(2) lower trochanteric region BMD (P = 0.03). For the other GR gene polymorphisms, no significant associations were found. Conclusions Higher cortisol levels are associated with lower femoral neck BMD in elderly women. The G allele of the 9beta polymorphism was associated with lower serum cortisol levels in women. Female BclI GG homozygotes had higher serum cortisol levels, and BclI GG homozygotes had lower trochanteric region BMD in the total population.

PTHR1 Polymorphisms Influence BMD Variation through Effects on the Growing Skeleton

Abstract: We investigated whether polymorphisms in PTHR1 are associated with bone mineral density (BMD), to determine whether the association of this gene with BMD was due to effects on attainment of peak bone mass or effects on subsequent bone loss. The PTHR1 gene, including its 14 exons, their exon-intron boundaries, and 1,500 bp of its promoter region, was screened for polymorphisms by denaturing high-performance liquid chromatography (dHPLC) and sequencing in 36 osteoporotic cases. Eleven single-nucleotide polymorphisms (SNPs), one tetranucleotide repeat, and one tetranucleotide deletion were identified. A cohort of 634 families, including 1,236 men (39%) and 1,926 women (61%) ascertained with probands with low BMD (Z 5%) and the tetranucleotide repeat. In our osteoporosis families, association was noted between lumbar spine BMD and alleles of a known functional tetranucleotide repeat (U4) in the PTHR1 promoter region (P = 0.042) and between two and three marker haplotypes of PTHR1 polymorphisms with lumbar spine, femoral neck, and total hip BMD (P = 0.021-0.047). This association was restricted to the youngest tertile of the population (age 16-39 years, P = 0.013-0.048). A similar association was found for the ALSPAC cohort: two marker haplotypes of SNPs A48609T and C52813T were associated with height (P = 0.006) and total body less head BMD (P = 0.02), corrected for age and gender, confirming the family findings. These findings suggest a role for PTHR1 variation in determining peak BMD.

Readiness of elders to use assistive devices to maintain their independence in the home

Abstract: With an increasing proportion of the population surviving into old age, it is important that as many people as possible are enabled to maintain their health and independence. Assistive devices, a term that encompasses all products which ‘compensate, relieve or neutralise’ a person's impairments [1, p80], are known to improve independence. The actual number who could benefit from any particular device is difficult to determine, but the proportion increases with age. However, the degree to which elders become aware of assistive devices and their benefits, how they feel such devices fit with their lifestyle and image, and how ready they are to acquire and use them is not well known. The aims of this study were: To explore the current use and intention to use assistive devices in a cohort of 72-82 year olds. To gain information that will inform future research aimed at exploring ways to increase appropriate uptake of assistive devices.

Is Birth Weight Associated with Risk of Depressive Symptoms in Young Women? Evidence from the Southampton Women's Survey

Abstract: Although some studies have shown negative associations between birth weight and risk of depression, others have not. Studies also differ regarding the age and gender specificity of reported associations. In this paper, the authors report on a study of 5,830 women aged 20–34 years from the general population in Southampton, United Kingdom, interviewed in 2000–2002 that found no relation between birth weight and current depressive symptoms or past treatment for depression. Prevalence ratios for current symptoms and for past treatment, in relation to reported or recorded birth weights, were all remarkably close to 1.0, with narrow 95% confidence intervals. For example, the prevalence ratio from the fully adjusted model for current depressive symptoms in relation to a standard deviation increase in reported birth weight was 1.01 (95% confidence interval: 0.98, 1.05). Generally, the associations reported elsewhere are not strong. The authors found a weak, inverse association in exploratory analyses of duration of gestation at birth in relation to depressive symptoms, but this finding requires replication. Because birth weight and duration of gestation are relatively poor markers of fetal development, other markers of fetal and early development should be explored. However, data from this study do not support a major developmental contribution to the etiology of depression in women.