Measurement and initial characterization of leukocyte telomere length in 474,074 participants in UK Biobank.

Leukocyte telomere length (LTL) is a proposed marker of biological age. Here we report the measurement and initial characterization of LTL in 474,074 participants in UK Biobank. We confirm that older age and male sex associate with shorter LTL, with women on average ~7 years younger in 'biological age' than men. Compared to white Europeans, LTL is markedly longer in African and Chinese ancestries. Older paternal age at birth is associated with longer individual LTL. Higher white cell count is associated with shorter LTL, but proportions of white cell subtypes show weaker associations. Age, ethnicity, sex and white cell count explain ~5.5% of LTL variance. Using paired samples from 1,351 participants taken ~5 years apart, we estimate the within-individual variability in LTL and provide a correction factor for this. This resource provides opportunities to investigate determinants and biomedical consequences of variation in LTL.

Vertebral Scheuermann's disease in Europe: prevalence, geographic variation and radiological correlates in men and women aged 50 and over.

UNLABELLED: In 27 centres across Europe, the prevalence of deforming spinal Scheuermann's disease in age-stratified population-based samples of over 10,000 men and women aged 50+ averaged 8% in each sex, but was highly variable between centres. Low DXA BMD was un-associated with Scheuermann's, helping the differential diagnosis from osteoporosis. INTRODUCTION: This study aims to assess the prevalence of Scheuermann's disease of the spine across Europe in men and women over 50 years of age, to quantitate its association with bone mineral density (BMD) and to assess its role as a confounder for the radiographic diagnosis of osteoporotic fracture. METHODS: In 27 centres participating in the population-based European Vertebral Osteoporosis Study (EVOS), standardised lateral radiographs of the lumbar and of the thoracic spine from T4 to L4 were assessed in all those of adequate quality. The presence of Scheuermann's disease, a confounder for prevalent fracture in later life, was defined by the presence of at least one Schmorl's node or irregular endplate together with kyphosis (sagittal Cobb angle >40° between T4 and T12) or a wedged-shaped vertebral body. Alternatively, the (rare) Edgren-Vaino sign was taken as diagnostic. The 6-point-per-vertebral-body (13 vertebrae) method was used to assess osteoporotic vertebral shape and fracture caseness. DXA BMD of the L2-L4 and femoral neck regions was measured in subsets. We also assessed the presence of Scheuermann's by alternative published algorithms when these used the radiographic signs we assessed. RESULTS: Vertebral radiographic images from 4486 men and 5655 women passed all quality checks. Prevalence of Scheuermann's varied considerably between centres, and based on random effect modelling, the overall European prevalence using our method was 8% with no significant difference between sexes. The highest prevalences were seen in Germany, Sweden, the UK and France and low prevalences were seen in Hungary, Poland and Slovakia. Centre-level prevalences in men and women were highly correlated. Scheuermann's was not associated with BMD of the spine or hip. CONCLUSIONS: Since most of the variation in population impact of Scheuermann's was unaccounted for by the radiological and anthropometric data, the search for new genetic and environmental determinants of this disease is encouraged.

Predictive ability of heel quantitative ultrasound for incident fractures: an individual-level meta-analysis.

UNLABELLED: The relationship between bone quantitative ultrasound (QUS) and fracture risk was estimated in an individual level data meta-analysis of 9 prospective studies of 46,124 individuals and 3018 incident fractures. Low QUS is associated with an increase in fracture risk, including hip fracture. The association with osteoporotic fracture decreases with time. INTRODUCTION: The aim of this meta-analysis was to investigate the association between parameters of QUS and risk of fracture. METHODS: In an individual-level analysis, we studied participants in nine prospective cohorts from Asia, Europe and North America. Heel broadband ultrasonic attenuation (BUA dB/MHz) and speed of sound (SOS m/s) were measured at baseline. Fractures during follow-up were collected by self-report and in some cohorts confirmed by radiography. An extension of Poisson regression was used to examine the gradient of risk (GR, hazard ratio per 1 SD decrease) between QUS and fracture risk adjusted for age and time since baseline in each cohort. Interactions between QUS and age and time since baseline were explored. RESULTS: Baseline measurements were available in 46,124 men and women, mean age 70 years (range 20-100). Three thousand and eighteen osteoporotic fractures (787 hip fractures) occurred during follow-up of 214,000 person-years. The summary GR for osteoporotic fracture was similar for both BUA (1.45, 95 % confidence intervals (CI) 1.40-1.51) and SOS (1.42, 95 % CI 1.36-1.47). For hip fracture, the respective GRs were 1.69 (95 % CI, 1.56-1.82) and 1.60 (95 % CI, 1.48-1.72). However, the GR was significantly higher for both fracture outcomes at lower baseline BUA and SOS (p < 0.001). The predictive value of QUS was the same for men and women and for all ages (p > 0.20), but the predictive value of both BUA and SOS for osteoporotic fracture decreased with time (p = 0.018 and p = 0.010, respectively). For example, the GR of BUA for osteoporotic fracture, adjusted for age, was 1.51 (95 % CI 1.42-1.61) at 1 year after baseline, but at 5 years, it was 1.36 (95 % CI 1.27-1.46). CONCLUSIONS: Our results confirm that quantitative ultrasound is an independent predictor of fracture for men and women particularly at low QUS values.

Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.

BACKGROUND: Uncertainties persist about the magnitude of associations of diabetes mellitus and fasting glucose concentration with risk of coronary heart disease and major stroke subtypes. We aimed to quantify these associations for a wide range of circumstances. METHODS: We undertook a meta-analysis of individual records of diabetes, fasting blood glucose concentration, and other risk factors in people without initial vascular disease from studies in the Emerging Risk Factors Collaboration. We combined within-study regressions that were adjusted for age, sex, smoking, systolic blood pressure, and body-mass index to calculate hazard ratios (HRs) for vascular disease. FINDINGS: Analyses included data for 698 782 people (52 765 non-fatal or fatal vascular outcomes; 8.49 million person-years at risk) from 102 prospective studies. Adjusted HRs with diabetes were: 2.00 (95% CI 1.83-2.19) for coronary heart disease; 2.27 (1.95-2.65) for ischaemic stroke; 1.56 (1.19-2.05) for haemorrhagic stroke; 1.84 (1.59-2.13) for unclassified stroke; and 1.73 (1.51-1.98) for the aggregate of other vascular deaths. HRs did not change appreciably after further adjustment for lipid, inflammatory, or renal markers. HRs for coronary heart disease were higher in women than in men, at 40-59 years than at 70 years and older, and with fatal than with non-fatal disease. At an adult population-wide prevalence of 10%, diabetes was estimated to account for 11% (10-12%) of vascular deaths. Fasting blood glucose concentration was non-linearly related to vascular risk, with no significant associations between 3.90 mmol/L and 5.59 mmol/L. Compared with fasting blood glucose concentrations of 3.90-5.59 mmol/L, HRs for coronary heart disease were: 1.07 (0.97-1.18) for lower than 3.90 mmol/L; 1.11 (1.04-1.18) for 5.60-6.09 mmol/L; and 1.17 (1.08-1.26) for 6.10-6.99 mmol/L. In people without a history of diabetes, information about fasting blood glucose concentration or impaired fasting glucose status did not significantly improve metrics of vascular disease prediction when added to information about several conventional risk factors. INTERPRETATION: Diabetes confers about a two-fold excess risk for a wide range of vascular diseases, independently from other conventional risk factors. In people without diabetes, fasting blood glucose concentration is modestly and non-linearly associated with risk of vascular disease. FUNDING: British Heart Foundation, UK Medical Research Council, and Pfizer.

Bone micro-architecture and determinants of strength in the radius and tibia: age-related changes in a population-based study of normal adults measured with high-resolution pQCT.

SUMMARY: We recruited a population-based sample of 58 males and 74 females aged 20-79 from a primary care medical practice to provide normative and descriptive data for high-resolution peripheral quantitative computed tomography (pQCT) parameters. Important effects of ageing and contrasts in the effects of sex on the micro-architecture and strength of upper and lower limb bones were revealed. INTRODUCTION: The advent of high-resolution pQCT scanners has permitted non-invasive assessment of structural data on cortical and trabecular bone. METHODS: We investigated age-related changes in pQCT and finite element (FE) modelling parameters at the distal radius and distal tibia in a population-based cross-sectional study of 58 males and 74 females aged 20-79 years. Linear regression models including quadratic terms for age were used for inference. RESULTS: Age-related changes and sex differences were generally similar for pQCT parameters at the radius and tibia. At each site, mean values for bone density, cortical thickness and trabecular micro-architecture (number, separation and thickness) were lower (trabecular separation higher) in women than men. Changes with age were most apparent for bone density and cortical thickness, which declined with age, in contrast to trabecular micro-architecture parameters which were not significantly associated with age (p > 0.05) in either sex. Cortical bone density and thickness declined faster in women than men after age 50 and trabecular bone density was consistently lower in women. FE-analysis predicted failure load decreased with age and percentage of load carried by trabecular bone increased (p < 0.05). CONCLUSIONS: These data show contrasts in the effects of sex on the micro-architecture and strength of upper and lower limb bones with ageing. The faster decline in cortical bone thickness and density in women than men after age 50 and consistently lower trabecular bone density in women have implications for the excess risks of wrist and hip fractures in women.

Associations of plasma fibrinogen levels with established cardiovascular disease risk factors, inflammatory markers, and other characteristics: individual participant meta-analysis of 154,211 adults in 31 prospective studies: the fibrinogen studies collaboration.

Long-term increases in plasma fibrinogen levels of 1 g/liter are associated with an approximate doubling of risk of major cardiovascular disease outcomes, but causality remains uncertain. To quantify cross-sectional associations of fibrinogen levels with established risk factors and other characteristics, the investigators combined individual data on 154,211 apparently healthy adults from 31 prospective studies conducted between 1967 and 2003, using a linear mixed model that included random effects at the cohort level. Fibrinogen levels increased with age and showed continuous, approximately linear relations with several risk markers and slightly curvilinear associations with log triglycerides, albumin, and tobacco and alcohol consumption. Female sex, Black ethnicity, lower socioeconomic status, and alcohol abstinence were each associated with modestly higher fibrinogen levels. Approximately one third of the variation in fibrinogen levels was explained by cohort, age, and sex. An additional 7% was explained by established risk factors (notably, positive associations with smoking and body mass index and an inverse association with high density lipoprotein cholesterol), and a further 10% was explained by inflammatory markers (notably, a positive association with C-reactive protein). The association with body mass index was twice as strong in women as in men, whereas the association with smoking was much stronger in men. These findings substantially advance understanding of the correlates and possible determinants of fibrinogen levels.

Risks of relapse in patients with acute anterior uveitis.

AIM: To quantify the rate of recurrence of acute anterior uveitis (AAU), and evaluate the influence of associated risk factors. METHODS: We retrospectively reviewed the case notes of 185 patients with acute anterior uveitis, from their time of presentation to August 2001. The time to the first three recurrences of AAU from the onset of the disease was recorded, as well as the site of recurrence. Information regarding risk factors (for example (HLA-B27) status, spondyloarthropathy (SpA), family history of AAU/SpA and history of non-specific joint pain) were also collected. RESULTS: Patients were followed up until their third relapse, or up to the censoring date (August 2001) if less than three relapses had occurred. The median length of follow-up was 35 months. One hundred and twenty-two patients (66%) developed at least one relapse and 67 (36%) had three or more relapses. Kaplan-Meier estimate of median interval between disease onset and the first relapse was 24 months 95% CI (16 to 34) and between the first and second relapse was 14 months 95% CI (9 to 22), and was 15 months 95% CI (10 to 25) months between the second and third relapse. Using Cox regression only the number of previous relapses was significantly associated with the risk of AAU recurrence. There was no significant association between other reported risk factors and the risk of relapse, and neither did any risk factor significantly modify the association between previous relapses and AAU recurrence (p>0.066 for all interactions). There was a borderline significant difference in survival according to the laterality pattern of recurrences (ipsilateral, alternate, or bilateral) with a slightly greater than expected number of events in those with bilateral recurrence (p = 0.048). CONCLUSION: Patients with previous relapse(s) of AAU have a greater risk of AAU recurrence compared to those at disease onset but the risk of recurrence appears not to increase in a dose-response manner with increasing number of previous relapses. Demographic and extraocular features do not appear to influence the rate, or risk of recurrence of AAU.

Effects of physical activity on evolution of proximal femur structure in a younger elderly population.

INTRODUCTION: For a fixed weight, a wider bone of standardised length is stiffer. But moving the cortices away from the centre of mass risks creating structural (elastic) instability, and hip fractures have been postulated to occur as a consequence of buckling of the thinned supero-lateral femoral neck cortex during a fall. We hypothesised that stereotyped physical activity (e.g., walking) may help conserve bending resistance (section modulus, Z) through redistribution of bone tissue, but it might be at the expense of supero-lateral cortical stability. METHODS: Hip structural analysis (HSA) software applied to DXA scans was used to derive measurements of section modulus and distances of a cross-section's centre of mass from the supero-lateral cortical margin (lateral distance, in cm). DXA scans were obtained on 1361 men and women in the EPIC-Norfolk population-based prospective cohort study. Up to 4 repeat DXA scans were done in 8 years of follow-up. Weight, height and activities of daily living were assessed on each occasion. A detailed physical activity and lifestyle questionnaire was administered at baseline. The lateral distance was measured on three narrow cross-sections with good precision: narrow neck (NN, coefficient of variation 2.6%), intertrochanter (IT) and shaft (S). A linear mixed model was used to assess associations with predictors. RESULTS: Ageing was associated with medial shifting of the centre of mass, so that lateral distance increased. Both greater weight and height were associated with greater lateral distance (P<0.0001). Among physical activity-related variables, walking/cycling for >1 h/day (P=0.025), weekly time spent on moderate impact activity (P=0.003), forced expiratory volume in 1 s (NN and IT, P<0.026) and lifetime physical activity (IT, P<0.0001) were associated with higher lateral distance. However, after adjusting for these variables, activities of daily living scores (NN, P<0.0001) and weekly time spent on low impact hip flexing activities were associated with shorter lateral distance (P=0.001). Greater baseline lateral distance was significantly associated with increased risk of subsequent hip fracture (n=26) in females (P<0.05, all regions) independently of age, height and bone mineral content. CONCLUSION: The age-related shift medially of the centre of mass of the femoral neck and trochanter may have adverse effects on fracture resistance in the event of a fall, so compromising the beneficial effects of walking on fitness, strength and risk of falling. The role of more diverse physical activity patterns in old age that impose loading on the supero-lateral cortex of the femur, involving for example hip flexion and stretching, needs investigation for their ability to correct this medial shifting of the centre of mass.

Geographic and other determinants of BMD change in European men and women at the hip and spine. a population-based study from the Network in Europe for Male Osteoporosis (NEMO).

INTRODUCTION: While the determinants of BMD change have been studied in women, there have been few longitudinal studies in men. As part of the Network in Europe for Male Osteoporosis (NEMO) study, data were analysed from 1337 men and 1722 women aged 50-86y (mean=67 years) from 13 centres across Europe to assess determinants of BMD change and between-gender contrasts. METHODS: BMD was measured at the femoral neck, trochanter and/or L2-L4 spine on 2 occasions 0.8-8 years apart (mean=3.5 years) using DXA densitometers manufactured by Hologic (n=6), Lunar (n=5) and Norland (n=2). Each was cross-calibrated using the European Spine Phantom and annual rates of BMD change (g/cm(2)/year) were calculated from the standardised paired BMD values. The EPOS risk factor questionnaire was administered at baseline. RESULTS: In multivariate linear regression models, there were large between centre differences in the mean rates of BMD change in all 3 sites for both genders (P<0.0001) with the standard deviation of the between centre heterogeneity in the adjusted means being 0.005 g/cm(2)/year at the femoral neck. The overall adjusted mean annual rates of BMD change in g/cm(2)/year (95% CI) pooled across centres by random effects meta-analysis in men were: femoral neck -0.005 (-0.009, -0.001); trochanter -0.003 (-0.006, -0.001); and spine 0.000 (-0.004, 0.004). In women the respective estimates were: -0.007 (-0.009, -0.005); -0.004 (-0.006, -0.003); and -0.005 (-0.008, -0.001). The I(2) statistic for heterogeneity was between 81% and 94%, indicating strong evidence of between centre heterogeneity. Higher baseline BMD value was associated with subsequent greater decline in BMD (P<0.001). Preserved BMD was associated with higher baseline body weight in all 3 sites in men (P<0.012) but not in women. Weight gain preserved BMD (P<0.039) in all 3 sites for both genders, except the male spine. Increasing age was associated with faster BMD decline at the trochanter in both genders (P<0.026) and with a slower rate of decline at the female spine (P=0.002). Effects of lifestyle, physical activity, medications, and reproductive factors were not consistent across sites or between genders. CONCLUSION: These results show major geographic variations in rates of BMD change in men and women over 50 years of age across diverse European populations and demonstrate that body weight and weight gain are key determinants of BMD change in men.

Sex hormone status may modulate rate of expansion of proximal femur diameter in older women alongside other skeletal regulators.

CONTEXT: Little is known of associations between hip geometry and skeletal regulators. This is important because geometry is a determinant of both hip function and resistance to fracture. OBJECTIVE: We aimed to determine the effects of sex hormone status and other candidate regulators on hip geometry and strength. SUBJECTS AND METHODS: A random sample of 351 women aged 67-79 had two to four hip dual-energy x-ray absorptiometry scans performed over 8 yr of follow-up. Hip structural analysis software was used to measure subperiosteal diameter (PD) and the distance from the center of mass to the lateral cortical margin (d-lat) on three 5-mm-thick cross-sectional regions: narrow neck, intertrochanter, and shaft. Section modulus (Z), bone mineral density (grams per centimeter squared), and an index of bone mineral content (cross-sectional area) were calculated as estimators of bone strength. Serum analytes measured at baseline included SHBG, estradiol, PTH, creatinine, albumin, vitamin D metabolites, and glutamate- and gamma-carboxyglutamate-osteocalcin (OC). A linear mixed model was used to model associations with predictor variables, including testing whether the predictors significantly modified the effect of aging. RESULTS: Aging was associated with increasing PD and d-lat, and higher baseline SHBG significantly modified this effect, in the case of PD, increasing the rates of change at the narrow neck region by 19% for SHBG level 2 sd higher than population mean (P = 0.026). Higher baseline creatinine was independently associated with faster increases in PD and d-lat with aging (P < 0.041). Z declined faster with aging if baseline PTH was higher, and higher albumin had a contrary effect. Z was positively associated with free estradiol and inversely associated with SHBG and glutamate-OC. CONCLUSION: These results show large effects of SHBG on the regulation of proximal femur expansion and bending resistance, probably acting as a surrogate for low bioavailable estrogen. Potentially important effects for fracture resistance in old age were also revealed for PTH, markers related to renal function and the nutritional markers albumin and undercarboxylated OC.

Whom to treat? The contribution of vertebral X-rays to risk-based algorithms for fracture prediction. Results from the European Prospective Osteoporosis Study.

INTRODUCTION: Vertebral fracture is a strong risk factor for future spine and hip fractures; yet recent data suggest that only 5-20% of subjects with a spine fracture are identified in primary care. We aimed to develop easily applicable algorithms predicting a high risk of future spine fracture in men and women over 50 years of age. METHODS: Data was analysed from 5,561 men and women aged 50+ years participating in the European Prospective Osteoporosis Study (EPOS). Lateral thoracic and lumbar spine radiographs were taken at baseline and at an average of 3.8 years later. These were evaluated by an experienced radiologist. The risk of a new (incident) vertebral fracture was modelled as a function of age, number of prevalent vertebral fractures, height loss, sex and other fracture history reported by the subject, including limb fractures occurring between X-rays. Receiver Operating Characteristic (ROC) curves were used to compare the predictive ability of models. RESULTS: In a negative binomial regression model without baseline X-ray data, the risk of incident vertebral fracture significantly increased with age [RR 1.74, 95% CI (1.44, 2.10) per decade], height loss [1.08 (1.04, 1.12) per cm decrease], female sex [1.48 (1.05, 2.09)], and recalled fracture history; [1.65 (1.15, 2.38) to 3.03 (1.66, 5.54)] according to fracture site. Baseline radiological assessment of prevalent vertebral fracture significantly improved the areas subtended by ROC curves from 0.71 (0.67, 0.74) to 0.74 (0.70, 0.77) P=0.013 for predicting 1+ incident fracture; and from 0.74 (0.67, 0.81) to 0.83 (0.76, 0.90) P=0.001 for 2+ incident fractures. Age, sex and height loss remained independently predictive. The relative risk of a new vertebral fracture increased with the number of prevalent vertebral fractures present from 3.08 (2.10, 4.52) for 1 fracture to 9.36 (5.72, 15.32) for 3+. At a specificity of 90%, the model including X-ray data improved the sensitivity for predicting 2+ and 1+ incident fractures by 6 and 4 fold respectively compared with random guessing. At 75% specificity the improvements were 3.2 and 2.4 fold respectively. With the modelling restricted to the subjects who had BMD measurements (n=2,409), the AUC for predicting 1+ vs. 0 incident vertebral fractures improved from 0.72 (0.66, 0.79) to 0.76 (0.71, 0.82) upon adding femoral neck BMD (P=0.010). CONCLUSION: We conclude that for those with existing vertebral fractures, an accurately read spine X-ray will form a central component in future algorithms for targeting treatment, especially to the most vulnerable. The sensitivity of this approach to identifying vertebral fracture cases requiring anti-osteoporosis treatment, even when X-rays are ordered highly selectively, exceeds by a large margin the current standard of practice as recorded anywhere in the world.

Data collection from very low birthweight infants in a geographical region: methods, costs, and trends in mortality, admission rates, and resource utilisation over a five-year period.

AIMS: 1. To determine the survival and morbidity of infants at discharge with a birthweight of less than 1500 g in the geographically defined population of East Anglia. 2. To demonstrate a cost-effective method of regional data collection. 3. To determine whether there were any changes in the demand for neonatal care. STUDY DESIGN AND SUBJECTS: A prospective cohort analysis using a single database to collect data on 1244 very low birthweight infants from eight neonatal units in one Region from 1993 to 1997. RESULTS: Estimated ascertainment of VLBW infants to the study was 96%. Over the 5 years survival rates were stable (75-79%). 52% of deaths in infants admitted for neonatal care occurred on day 1, with just 15% of deaths occurring after 28 days of life. Mortality risk significantly decreased with increasing gestational age at birth. Compared to 22-25-week old infants, the mortality risk decreased by 65% for 26-27-week old infants (OR 0.35 95% CI (0.21, 0.59)) and by 92% for 32-39-week old infants (OR 0.08 95% CI (0.03, 0.21)) with intermediate odds ratios of 0.22 (0.12, 0.42) and 0.13 (0.06, 0.28) for the 28-29 and 30-39 weeks gestation, respectively. Higher birthweight, after adjusting for gestation also decreased the mortality risk (OR 0.78 per 100 g difference, 95% CI (0.71, 0.86)). No change was seen in the number of extremely preterm infants admitted for intensive care or resource utilisation, although a significant increase was seen in the number of infants dying in delivery rooms. There was a reduction in the reported incidence of pulmonary interstitial emphysema (10-4%) but no change in the number of ventilation days or the rate of chronic lung disease. The mean maternal age increased from 27.7 years to 28.9 years during the study. Maternal steroid administration increased (30% to 59%) and was associated with a decreased risk of mortality (OR 0.44, 95% CI: 0.31-0.62). CONCLUSIONS: It is possible to collect useful data from the neonatal period at a reasonable cost from a geographically defined population. This information was used for informing clinicians, counselling parents and in the era of managed clinical networks will be useful in guiding the provision of effective health care resources.

Rib fractures predict incident limb fractures: results from the European prospective osteoporosis study.

Population studies suggest that rib fractures are associated with a reduction in bone mass. While much is known about the predictive risk of hip, spine and distal forearm fracture on the risk of future fracture, little is known about the impact of rib fracture. The aim of this study was to determine whether a recalled history of rib fracture was associated with an increased risk of future limb fracture. Men and women aged 50 years and over were recruited from population registers in 31 European centres for participation in a screening survey of osteoporosis (European Prospective Osteoporosis Study). Subjects were invited to complete an interviewer-administered questionnaire that included questions about previous fractures including rib fracture, the age of their first fracture and also the level of trauma. Lateral spine radiographs were performed and the presence of vertebral deformity was determined morphometrically. Following the baseline survey, subjects were followed prospectively by annual postal questionnaire to determine the occurrence of clinical fractures. The subjects included 6,344 men, with a mean age of 64.2 years, and 6,788 women, with a mean age of 63.6 years, who were followed for a median of 3 years (range 0.4-5.9 years), of whom 135 men (2.3%) and 101 women (1.6%) reported a previous low trauma rib fracture. In total, 138 men and 391 women sustained a limb fracture during follow-up. In women, after age adjustment, those with a recalled history of low trauma rib fracture had an increased risk of sustaining 'any' limb fracture [relative hazard (RH)=2.3; 95% CI 1.3, 4.0]. When stratified by fracture type the predictive risk was more marked for hip (RH=7.7; 95% CI 2.3, 25.9) and humerus fracture (RH=4.5; 95% CI 1.4, 14.6) than other sites (RH=1.6; 95% CI 0.6, 4.3). Additional adjustment for prevalent vertebral deformity and previous (non-rib) low trauma fractures at other sites slightly reduced the strength of the association between rib fracture and subsequent limb fracture. In men, after age adjustment, there was a small though non-significant association between recalled history of rib fracture and future limb fracture. Our data highlight the importance of rib fracture as a marker of bone fragility in women.

Outcome at 2 years for very low birthweight infants in a geographical population: risk factors, cost, and impact of congenital anomalies.

AIM: To determine the type and rate of disability at 2 years of age in infants born in the geographically defined population of East Anglia with a birthweight less than 1500 g and to assess the risk factors for disability. STUDY DESIGN: A prospective cohort analysis from all eight neonatal units in East Anglia from 1993-1997 using a single database. METHODS: Local paediatricians assessed children at 2 years using the Health Status Questionnaire and data collection was centrally coordinated. RESULTS: Outcomes for 947 children, 99% of survivors, were available, 74 (7.8%) had severe disability and this was significantly associated with gestational age (p<0.0005), birthweight (p<0.0005) and sex (p=0.046). Major congenital abnormality contributed 27% of all severe disability. The overall cerebral palsy rate was 6.2%, nine children were blind and five had sensorineural hearing loss requiring aids. These children had a high level of use of community services with 19% of the cohort being referred to one or more community service. ELBW infants or those born <30 weeks gestation were 1.5 times and twice as likely to have moderate or severe disability and 2.3 and 5.4 times as likely to have cerebral palsy as those weighing 1000 to 1500 g or >30 weeks gestation. Boys were at higher risk of adverse outcome. CONCLUSIONS: The study was able to define the increased risk associated with being born at lower gestational age or lower birthweight and demonstrates successful ascertainment of outcomes for large local populations at a reasonable cost.

Changes in bone mineral density, body composition and biochemical markers of bone turnover during weight gain in adolescents with severe anorexia nervosa: a 1-year prospective study.

Osteoporosis is a serious complication of anorexia nervosa and in affected adolescents may result in a permanent deficit in bone mass. The pathophysiology of this bone disease has not been clearly defined. In this prospective study of 26 young women with anorexia nervosa aged 13-20 years (mean 16.5) we have measured changes in bone mineral density, total body composition and biochemical indices of bone turnover over 1 year. Over this period there was a mean weight gain of 10 kg and significant height gain with baseline and final values for body mass index of 14.2+/-1.7 and 17.6+/-2.3 kg/m2 (P<0.001). However, no significant changes were seen in bone mineral density in the spine or proximal femur during the study; total body bone mineral content was significantly higher than baseline at 3 months and 12 months (P=0.001 and P<0.0001), but total body bone mineral density at 3 months was significantly lower than baseline (P=0.003). Serum osteocalcin and bone-specific alkaline phosphatase values increased significantly and remained higher than baseline at all time points whereas urinary NTX/creatinine excretion showed a non-significant increase over the first 6 months of the study, but at 12 months, the mean value was significantly lower than baseline. Mean serum 25-hydroxyvitamin D levels showed a significant decrease at 6 months (P<0.05), but returned towards baseline thereafter. There was a significant increase in serum parathyroid hormone levels at all time points compared to baseline, these occurring within the normal range. These results indicate that although weight gain in young anorexics is associated with linear growth, bone mineral density does not increase. Whether this deficit can be corrected subsequently requires longer-term prospective studies.

Low BMD is less predictive than reported falls for future limb fractures in women across Europe: results from the European Prospective Osteoporosis Study.

We have previously shown that center- and sex-specific fall rates explained one-third of between-center variation in upper limb fractures across Europe. In this current analysis, our aim was to determine how much of the between-center variation in fractures could be attributed to repeated falling, bone mineral density (BMD), and other risk factors in individuals, and to compare the relative contributions of center-specific BMD vs. center-specific fall rates. A clinical history of fracture was assessed prospectively in 2451 men and 2919 women aged 50-80 from 20 centers participating in the European Prospective Osteoporosis Study (EPOS) using standardized questionnaires (mean follow-up = 3 years). Bone mineral density (BMD, femoral neck, trochanter, and/or spine) was measured in 2103 men and 2565 women at these centers. Cox regression was used to model the risk of incident fracture as a function of the person-specific covariates: age, BMD, personal fracture history (PFH), family hip fracture history (FAMHIP), time spent walking/cycling, number of 'all falls' and falls not causing fracture ('fracture-free') during follow-up, alcohol consumption, and body mass index. Center effects were modeled by inclusion of multiplicative gamma-distributed random effects, termed center-shared frailty (CSF), with mean 1 and finite variance theta (theta) acting on the hazard rate. The relative contributions of center-specific fall risk and center-specific BMD on the incidence of limb fractures were evaluated as components of CSF. In women, the risk of any incident nonspine fracture (n = 190) increased with age, PFH, FAMHIP, > or =1 h/day walking/cycling, and number of 'all falls' during follow-up (all P < 0.074). 'Fracture-free' falls (P = 0.726) and femoral neck BMD did not have a significant effect at the individual level, but there was a significant center-shared frailty effect (theta = 0.271, P = 0.001) that was reduced by 4% after adjusting for mean center BMD and reduced by 19% when adjusted for mean center fall rate. Femoral trochanter BMD was a significant determinant of lower limb fractures (n = 53, P = 0.014) and the center-shared frailty effect was significant for upper limb fractures (theta = 0.271, P = 0.011). This upper limb fracture center effect was unchanged after adjusting for mean center BMD but was reduced by 36% after adjusting for center mean fall rates. In men, risk of any nonspine fracture (n = 75) increased with PFH, fall during follow-up (P < 0.026), and with a decrease in trochanteric BMD [RR 1.38 (1.08, 1.79) per 1 SD decrease]. There was no center effect evident (theta = 0.081, P = 0.096). We conclude that BMD alone cannot be validly used to discriminate between the risk of upper limb fractures across populations without taking account of population-specific variations in fall risk and other factors. These variations might reflect shared environmental or possibly genetic factors that contribute quite substantially to the risk of upper limb fractures in women.

Discrimination between cases of hip fracture and controls is improved by hip structural analysis compared to areal bone mineral density. An ex vivo study of the femoral neck.

In vivo bone densitometry is affected by measurement inaccuracies arising from the assumptions made about soft tissue and marrow composition. This study tested the hypothesis that section modulus (SM, a measure of bending resistance) when measured ex vivo, would discriminate cases of hip fracture from controls better than areal bone mineral density (aBMD). The biopsies were from (n = 22, female) subjects that had suffered an intracapsular hip fracture. The control material (n = 24, female) was from post-mortem subjects. Serial peripheral quantitative computed tomography (pQCT) 1-mm thick cross-sectional images of femoral neck previously embedded in methacrylate were obtained with the Densiscan 1000 pQCT densitometer and matched for lateral location. The image voxels were converted to units of bone mass, which were then used to derive the section modulus. The data were used to derive means from which receiver operating characteristic (ROC) curves could be generated. The area under the curves (AUC) showed that discrimination between the fracture cases and controls was better for SM than aBMD [SM: AUC = 0.83 (95% confidence interval: 0.71, 0.96), aBMD: AUC = 0.70 (0.54, 0.85); P = 0.034]. To simulate the forces experienced during a sideways fall, the model's neutral axis was rotated by 210 degrees. The results for section modulus were predictable from those at 0 degrees (r(2) = 0.97). We conclude that biomechanical analysis of the distribution of bone within the femoral neck may offer a marked improvement in the ability to discriminate patients with an increased risk of intracapsular fracture. Progress towards implementing this form of analysis in clinical densitometry should improve its diagnostic value, but may depend in part on better image resolution and more accurate corrections for the variability between subjects in regional soft tissue composition.

Hip section modulus, a measure of bending resistance, is more strongly related to reported physical activity than BMD.

We hypothesized that measures of physical activity would have a closer relationship with section modulus (SM), an indicator of bending resistance, than with bone mineral density (BMD) because physical activity might expand the bony envelope, which tends to reduce BMD for a constant bone mineral content. Four hundred twenty-three men and 436 women (mean age 72 years, SD =3) were recruited from a prospective population-based cohort study to a study of hip bone loss. Hip BMD was measured on two occasions 2-5 years apart (mean 2.7, DXA-Hologic 1,000 W). Hip structural analysis (HSA) software was used to calculate SM and BMD from the DXA scans on three narrow regions: the narrow neck (NN), intertrochanter (IT) and shaft (S). A physical activity and lifestyle questionnaire was administered at baseline. Multivariate repeated measures analysis of variance was used to model the associations between personal attributes (weight, height, age), physical activity and lifestyle variables with SM, cross-sectional area (CSA), sub-periosteal diameter (PD) and BMD. Men and women were analysed together after tests for interactions with gender, which were found not to be significant. In all regions female gender was associated with having lower values of all outcomes, and body weight was positively associated with all outcomes, i.e., SM, CSA, PD and BMD ( P<0.0001). Sub-periosteal diameter was positively associated with reported lifetime physical activity (IT and S, P<0.0001). There was a significant decline of BMD with age at the NN and S regions ( P<0.026), and the PD increased with age (NN and S, P<0.019). Previous fracture history was associated with having lower values of BMD, SM and CSA (except for S; P<0.022). Both section modulus and CSA were positively associated with heavy physical activity after age 50 years in all regions ( P<0.019), whereas NN BMD was the only BMD associate of heavy physical activity after 50 ( P=0.036). Time spent per week on recreational activities classified as no impact activity was positively associated with BMD, CSA and SM (multivariate P<0.016). In conclusion, proximal femur diameter is associated positively with reported life-long physical activity. If this is mediated through a loading related effect on sub-periosteal expansion, BMD would be an unsatisfactory outcome measure in physical activity studies since it is inversely related to projected bone area. SM in contrast was associated with several measures of recent physical activity and relates more directly to the bending experienced by the proximal femur in response to a given load. These data are consistent with an effect of mechanical loading to regulate bone strength through an anabolic effect maximal in the subperiosteal cortex, where the highest loading-related strains are experienced.

Effects of dietary nutrients and food groups on bone loss from the proximal femur in men and women in the 7th and 8th decades of age.

We measured the impact of diet, anthropometry, physical activity and lifestyle variables on rates of hip bone mineral density (BMD) loss in 470 white men and 474 white women aged 67-79 years at recruitment dwelling in the community. The subjects were recruited from a prospective population-based diet and cancer study (EPIC-Norfolk) in Eastern England. Dietary intake was measured at baseline using 7-day food diaries and used to calculate intakes of some 31 nutrients and 22 food groups. Standardised questionnaires were used to collect data on anthropometry, physical activity and lifestyle variables. BMD loss (percent per annum; % p.a.) was measured using dual-energy X-ray absorptiometry performed on two occasions an average of 3 years apart (range 2-5 years). The mean rate of BMD change at the total hip region was -0.17% p.a. (SD 1.3% p.a.) in men and -0.41% p.a. (SD 1.2% p.a.) in women. In both men and women, weight gain protected against (and weight loss promoted) BMD loss ( P<0.0001). Markers of current physical activity were protective. In men, an increase of 1 l/s in FEV(1) was associated with an increase in BMD at an average rate of 0.25% p.a. ( P=0.013). In women, for every ten trips made per day climbing a flight of stairs, BMD increased at a rate of 0.22% p.a. ( P=0.005) and additionally a 10% increase in activities of daily living score was associated with BMD increasing at a rate of 0.12% p.a. ( P=0.011) in women. Nutritional variation appeared to have less impact on BMD loss. In men there was no evidence of an effect of any of the nutrients evaluated. However, in women, low intake of vitamin C was associated with faster rate of BMD loss. Women in the lowest tertile (7-57 mg/day) of vitamin C intake lost BMD at an average rate of -0.65% p.a., which was significantly faster compared to loss rates in the middle (58-98 mg/day) and upper (99-363 mg/day) tertiles of intake, which were -0.31% p.a. and -0.30% p.a., respectively ( P=0.016). There was no effect of fruits and vegetables, combined or separately, on rate of BMD loss. The results confirm that weight maintenance (or gain) and commonly practiced forms of physical activity appear to protect against BMD loss in this age group. Measures such as ensuring good general nutrition to guard against weight loss in the non-overweight elderly and maintenance of physical fitness could be valuable in protecting against BMD loss. The protective effect of vitamin C in women needs to be further investigated in other prospective cohort or intervention studies.

Is the predictive power of previous fractures for new spine and non-spine fractures associated with biochemical evidence of altered bone remodelling? The EPOS study. European Prospective Osteoporosis Study.

BACKGROUND: In the European Prospective Osteoporosis Study (EPOS), a past spine fracture increased risk of an incident fracture 3.6 - 12-fold even after adjusting for BMD. We examined the possibility that biochemical marker levels were associated with this unexplained BMD-independent element of fracture risk. METHODS: Each of 182 cases in EPOS of spine or non-spine fracture that occurred in 3.8 years of follow-up was matched by age, sex and study centre with two randomly assigned never-fractured controls and one case of past fracture. Analytes measured blind were: osteocalcin, bone-specific alkaline phosphatase, total alkaline phosphatase, serum creatinine, calcium, phosphate and albumin, together with the collagen cross-links degradation products serum CTS and urine CTX. Most subjects also had bone density measured by DXA. RESULTS: Cases who had recent fractures did not differ in marker levels from cases who had their last fracture more than 3 years previously. No statistically significant effect of recent fracture was found for any marker except osteocalcin, which was 17.6% lower in recent peripheral cases compared to unfractured controls (p<0.05) and this was independent of BMD. CONCLUSION: Past fracture as a risk indicator for future fracture is not strongly mediated through increased bone turnover.