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Introduction: although it has been suggested that overweight and obese children have an increased risk of fracture, recent studies in post-menopausal women have shown that the relationship between obesity and fracture risk varies by fracture site. We therefore assessed whether adiposity and overweight/obesity prevalence differed by upper limb fracture site in children.Methods: height, weight, BMI, triceps and subscapular skinfold thickness (SFT) were measured in children aged 3–18 years with an acute upper limb fracture. Data was compared across three fracture sites (hand, forearm and upper arm/shoulder [UA]), and to published reference data.Results: 401 children (67.1% male, median age 11.71 years, range 3.54–17.27 years) participated. 34.2%, 50.6% and 15.2% had fractures of the hand, forearm and UA, respectively. Children with forearm fractures had higher weight, BMI, subscapular SFT and fat percentage z-scores than those with UA fractures (p < 0.05 for all). SFT and fat percentage z-scores were also higher in children with forearm fractures compared to hand fractures, but children with hand and UA fractures did not differ. Overweight and obesity prevalence was higher in children with forearm fractures (37.6%) than those with UA fractures (19.0%, p = 0.009). This prevalence was also higher than the published United Kingdom population prevalence (27.9%, p = 0.003), whereas that of children with either UA (p = 0.13) or hand fractures (29.1%, p = 0.76) did not differ. These differences in anthropometry and overweight/obesity prevalence by fracture site were evident in boys, but not present in girls.Conclusion: measurements of adiposity and the prevalence of overweight/obesity differ by fracture site in children, and in particular boys, with upper limb fractures

The role of maternal 25-hydroxyvitamin D [25(OH)D] in fetal development is uncertain, and findings of observational studies have been inconsistent. Most studies have assessed 25(OH)D only one time during pregnancy, but to our knowledge, the tracking of an individual's 25(OH)D during pregnancy has not been assessed previously.We determined the tracking of serum 25(OH)D from early to late pregnancy and factors that influence this.The Southampton Women's Survey is a prospective mother-offspring birth-cohort study. Lifestyle, diet, and 25(OH)D status were assessed at 11 and 34 wk of gestation. A Fourier transformation was used to model the seasonal variation in 25(OH)D for early and late pregnancy separately, and the difference between the measured and seasonally modeled 25(OH)D was calculated to generate a season-corrected 25(OH)D. Tracking was assessed with the use of the Pearson correlation coefficient, and multivariate linear regression was used to determine factors associated with the change in season-corrected 25(OH)D.A total of 1753 women had 25(OH)D measured in both early and late pregnancy. There was a moderate correlation between season-corrected 25(OH)D measurements at 11 and 34 wk of gestation (r = 0.53, P0.0001; n = 1753). Vitamin D supplementation was the strongest predictor of tracking; in comparison with women who never used supplements, the discontinuation of supplementation after 11 wk was associated with a reduction in season-corrected 25(OH)D (β = -7.3 nmol/L; P0.001), whereas the commencement (β = 12.6 nmol/L; P0.001) or continuation (β = 6.6 nmol/L; P0.001) of supplementation was associated with increases in season-corrected 25(OH)D. Higher pregnancy weight gain was associated with a reduction in season-corrected 25(OH)D (β = -0.4 nmol · L(-1) · kg(-1); P = 0.015), whereas greater physical activity (β = 0.4 nmol/L per h/wk; P = 0.011) was associated with increases.There is a moderate tracking of 25(OH)D status through pregnancy; factors such as vitamin D supplementation, weight gain, and physical activity are associated with changes in season-corrected 25(OH)D from early to late gestation. These findings have implications for study designs and analyses and approaches to intervention studies and clinical care.

PurposeChronic heavy alcohol consumption is associated with bone density loss and increased fracture risk, while low levels of alcohol consumption have been reported as beneficial in some studies. However, studies relating alcohol consumption to bone geometry, volumetric bone mineral density (vBMD) and bone microarchitecture, as assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), are lacking.MethodsHere we report an analysis from the Hertfordshire Cohort Study, in which we studied associations between HR-pQCT measures at the distal radius and tibia and alcohol consumption in 376 participants (198 men and 178 women) aged 72.1–81.4 years.ResultsA total of 30 (15.2%), 90 (45.5%) and 78 (39.4%) men drank minimal/none (< 1 unit/week), low (? 1 unit/week and < 11 units/week) and moderate/high (? 11 units/week) amounts of alcohol respectively. These figures were 74 (41.8%), 80 (45.2%) and 23 (13.0%) respectively in women for minimal/none (< 1 unit/week), low (? 1 unit/week and < 8 units/week) and moderate/high (? 8 units/week). At the distal radius, after adjustment for confounding factors (age, BMI, smoking status, dietary calcium intake, physical activity and socioeconomic status and years since menopause and HRT use for women), men that drank low alcohol had lower cortical thickness (p = 0.038), cortical vBMD (p = 0.033), and trabecular vBMD (p = 0.028) and higher trabecular separation (p = 0.043) than those that drank none/minimal alcohol. Similar differences were shown between minimal/none and moderate/high alcohol although these only reached statistical significance for the cortical parameters. Interestingly, after similar adjustment, women showed similar differences in the trabecular compartment between none/minimal alcohol and low alcohol at the distal tibia. However, women that drank moderate/high alcohol had significantly higher trabecular vBMD (p = 0.007), trabecular thickness (p = 0.026), and trabecular number (p = 0.042) and higher trabecular separation (p = 0.026) at the distal radius than those that drank low alcohol.ConclusionsOur results suggest that alcohol consumption (low and moderate/high) may have a detrimental impact on bone health in men in both the cortical and trabecular compartments at the distal radius with similar results in women in the trabecular compartment between none/minimal alcohol and low alcohol at the distal tibia suggesting that avoidance of alcohol may be beneficial for bone health.AbbreviationsaBMD, areal bone mineral density; BMI, body mass index; Ct. area, cortical area; Ct.vBMD, cortical density; Ct.Po, cortical porosity; Ct.Th, cortical thickness; DXA, dual energy X-ray absorptiometry; HCS, Hertfordshire Cohort Study; HRpQCT, high-resolution peripheral quantitative computed tomography; pQCT, peripheral quantitative computed tomography; Tt.area, total cross-sectional area; Tb.vBMD, trabecular BMD; Tb.N, trabecular number; Tb.Th, trabecular thickness; Tb.Sp, trabecular separation; vBMD, volumetric bone mineral density.

Symptomatic knee osteoarthritis (OA) can be viewed as the end result of a molecular cascade which ensues after certain triggers occur and ultimately results in irreversible damage to the articular cartilage. The clinical phenotype that knee OA can produce is variable and often difficult to accurately predict. This is further complicated by the often poor relationship between radiographic OA and knee pain. As a consequence, it can be difficult to compare studies that use different definitions of OA. However, the literature suggests that while there are multiple causes of knee OA, two have attracted particular attention over recent years; occupation related knee OA and OA subsequent to previous knee injury. The evidence of a relationship, and the strength of this association, is discussed in this chapter.

Osteoporosis and sarcopenia are common in older age and associated with significant morbidity and mortality. Consequently, they are both attended by a considerable socioeconomic burden. Osteoporosis was defined by the World Health Organisation (WHO) in 1994 as a bone mineral density of less than 2.5 standard deviations below the sex-specific young adult mean and this characterisation has been adopted globally. Subsequently, a further step forward was taken when bone mineral density was incorporated into fracture risk prediction algorithms, such as the Fracture Risk Assessment Tool (FRAX®) also developed by the WHO. In contrast, for sarcopenia there have been several diagnostic criteria suggested, initially relating to low muscle mass alone and more recently low muscle mass and muscle function. However, none of these have been universally accepted. This has led to difficulties in accurately delineating the burden of disease, exploring geographic differences, and recruiting appropriate subjects to clinical trials. There is also uncertainty about how improvement in sarcopenia should be measured in pharmaceutical trials. Reasons for these difficulties include the number of facets of muscle health available, e.g. mass, strength, function, and performance, and the various clinical outcomes to which sarcopenia can be related such as falls, fracture, disability and premature mortality. It is imperative that a universal definition of sarcopenia is reached soon to facilitate greater progress in research into this debilitating condition. This article is part of a Special Issue entitled "Muscle Bone Interactions".

Osteoarthritis is a syndrome affecting a variety of patient profiles. A European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis and the European Union Geriatric Medicine Society working meeting explored the possibility of identifying different patient profiles in osteoarthritis. The risk factors for the development of osteoarthritis include systemic factors (e.g., age, sex, obesity, genetics, race, and bone density) and local biomechanical factors (e.g., obesity, sport, joint injury, and muscle weakness); most also predict disease progression, particularly joint injury, malalignment, and synovitis/effusion. The characterization of patient profiles should help to better orientate research, facilitate trial design, and define which patients are the most likely to benefit from treatment. There are a number of profile candidates. Generalized, polyarticular osteoarthritis and local, monoarticular osteoarthritis appear to be two different profiles; the former is a feature of osteoarthritis co-morbid with inflammation or the metabolic syndrome, while the latter is more typical of post-trauma osteoarthritis, especially in cases with severe malalignment. Other biomechanical factors may also define profiles, such as joint malalignment, loss of meniscal function, and ligament injury. Early- and late-stage osteoarthritis appear as separate profiles, notably in terms of treatment response. Finally, there is evidence that there are two separate profiles related to lesions in the subchondral bone, which may determine benefit from bone-active treatments. Decisions on appropriate therapy should be made considering clinical presentation, underlying pathophysiology, and stage of disease. Identification of patient profiles may lead to more personalized healthcare, with more targeted treatment for osteoarthritis.

Objective Epidemiological studies of knee osteoarthritis (OA) have often used a radiographic definition. However, the clinical syndrome of OA is influenced by a broad range of factors in addition to the structural changes required for radiographic OA. Hence more recently several studies have adopted a clinical or self-reported approach to OA diagnosis rather than a radiographic approach. The aim of this study was to investigate agreement between radiographic OA and the clinical and self-reported diagnoses of OA. Design Data were available for 199 men and 196 women in the Hertfordshire Cohort Study (HCS), UK. Participants completed a questionnaire detailing self-reported OA. Clinical OA was defined based on American College of Rheumatology (ACR) criteria. Knee radiographs were taken and graded for overall Kellgren and Lawrence (K&L) score. Results The mean (standard deviation (SD)) age of study participants was 75.2 (2.6) years and almost identical proportions of men and women. The prevalence of knee OA differed depending on the method employed for diagnosis; 21% of the study participants self-reported knee OA, 18% of the participants had clinical knee OA and 42% of the participants had radiographic OA. Of those 72 study participants with a self-reported diagnosis of knee OA 52 (72%) had a radiographic diagnosis of knee OA, while 66% (39 out of 59) of study participants with clinical knee OA had a diagnosis of radiographic knee OA. However 58% of those participants diagnosed with radiographic OA did not have either self-reported knee OA or a diagnosis of clinical OA. Therefore in comparison with the radiographic definition of OA, both the clinical and self-report definitions had high specificity (91.5% & 91.5% respectively) and low sensitivity (24.5% and 32.7% respectively). Conclusion There is modest agreement between the radiographic, clinical and self-report methods of diagnosis of knee OA.

Aims: Evidence suggests that intrauterine bone mineral accrual predicts osteoporosis risk in later life, and that maternal 25(OH)- vitamin D status in pregnancy is a determinant of neonatal bone mass. We aimed to explore the relationship between intrauterine bone mineral accrual in the offspring, and 1) maternal 25(OH)- vitamin D status during late pregnancy, and 2) expression of calcium transporters in the placenta. Methods: Pregnancies were recruited from the Southampton Women’s Survey, a unique, ongoing, well established cohort of women, aged 20–34 years, assessed before and during pregnancy. Maternal 25(OH)-vitamin D status was measured by radioimmunoassay in late pregnancy (34 weeks); the healthy, term, neonates underwent whole body (WB) DXA within 20 days of birth, using a Lunar DPX instrument. Placental samples, snap frozen in liquid nitrogen within 30 minutes of birth, were available for 70 of the pregnancies. A quantitative real time polymerase chain reaction was used to measure the mRNA expression of PMCA isoforms 1, 3 and 4 in the placenta, using beta-actin as a control gene. Results: 556 (286 males) neonates were studied. Offspring of mothers who were deficient ( late pregnancy had lower bone mass than those of replete mothers. Thus the mean WB bone area (BA) of the female offspring of 25(OH)-vitamin D deficient mothers was 110cm2 vs 119cm2 in offspring of replete mothers (p=0.04). The mean WB bone mineral content (BMC) for offspring of deficient vs replete mothers was 58g vs 63g (p=0.04), respectively. The relationships in the boys did not reach statistical significance. There was no association with maternal alkaline phosphatase. After controlling for beta-actin expression, PMCA3 mRNA expression predicted neonatal WB BA (r=0.28,p=0.02), WB BMC (r=0.25,p=0.04), placental weight (r=0.26,p=0.03), and birth weight (r=0.33,p=0.006). Conclusions: These data are consistent with previous findings that mothers deficient in 25(OH)-vitamin D in pregnancy have children with reduced bone mass. The mechanism underlying this process may be explained, in part, by the demonstrated association between expression of the placental calcium transporter PMCA3 and neonatal whole body bone mineral content. Further elucidation of this process may allow development of novel therapeutic strategies to optimise childhood bone mineral accrual and thus reduce osteoporotic fractures in future generations.

Investigators have suggested a link between birth weight and both hand and lumbar spine osteoarthritis (OA). In this study, we sought to extend these observations by investigating relationships between growth in early life, and clinical and radiological diagnoses of OA at the hand, knee and hip, among participants from the Hertfordshire Cohort Study. Data were available for 222 men and 222 women. Clinical OA was defined based on American College of Rheumatology criteria. Radiographs were taken of the knees and hips, and graded for the presence of osteophytes and overall Kellgren and Lawrence (KL) score. Lower weight at year one was associated with higher rates of clinical hand OA (OR 1.396, 95% CI 1.05, 1.85, P=0.021). Individuals with lower birth weights were more likely to have hip osteophytes (OR 1.512, 95% CI 1.14, 2.00, P=0.004) and this remained robust after adjustment for confounders. Furthermore, a low weight at one year was also associated with a higher osteophyte number in the lateral compartment of the knee, after adjustment for confounders (OR 1.388, 95% CI 1.01, 1.91, P=0.043). We have found further evidence of a relationship between early life factors and adult OA. These findings accord with previous studies.

Summary: Despite the proven predictive ability of bone mineral density, Fracture Risk Assessment Tool ( FRAX® ), bone turnover markers, and fracture for osteoporotic fracture, their use as targets for treatment of osteoporosis is limited. Introduction: Treat-to-target is a strategy applied in several fields of medicine and has recently become an area of interest in the management of osteoporosis. Its role in this setting remains controversial. This article was prepared following a European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis ( ESCEO ) working group meeting convened under the auspices of the International Osteoporosis Foundation ( IOF ) to discuss the feasibility of applying such a strategy in osteoporosis in Europe. Methods: Potential targets range from the absence of an incident fracture to fixed levels of bone mineral density ( BMD ), a desired FRAX® score, a specified level of bone turnover markers or indeed changes in any one or a combination of these parameters. Results: Despite the proven predictive ability of all of these variables for fracture ( particularly BMD and FRAX ), their use as targets remains limited due to low sensitivity, the influence of confounders and current lack of evidence that targets can be consistently reached. Conclusion: ESCEO considers that it is not currently feasible to apply a treat-to-target strategy in osteoporosis, though it did identify a need to continue to improve the targeting of treatment to those at higher risk ( target-to-treat strategy ) and a number of issues for the research agenda. These include international consensus on intervention thresholds and definition of treatment failure, further exploration of the relationship between fracture and BMD, and FRAX and treatment efficacy and investigation of the potential of short-term targets to improve adherence.

To investigate patterns of physical activity in older adults with knee osteoarthritis (OA) compared to older adults without knee OA across 6 European countries. We expect country-specific differences in the physical activity levels between persons with knee OA compared to persons without knee OA. A varying degree of physical activity levels across countries would express a facilitating or impeding influence of the social, environmental, and other contextual factors on a physically active lifestyle.Baseline cross-sectional data from the European Project on Osteoarthritis were analyzed. In total, 2,551 participants from 6 European countries (Germany, Italy, The Netherlands, Spain, Sweden, and the UK) were included.Participants with knee OA were less likely to follow physical activity recommendations and had poorer overall physical activity profiles than those without knee OA (mean 62.9 versus 81.5 minutes/day, respectively; P = 0.015). The magnitude of this difference varied across countries. Detailed analysis showed that low physical activity levels in persons with knee OA could be attributed to less everyday walking time (odds ratio 1.31, 95% confidence interval 1.07-1.62).This study highlighted the fact that having knee OA is associated with a varying degree of physical activity patterns in different countries. This national variation implies that low levels of physical activity among persons with knee OA cannot be explained exclusively by individual or disease-specific factors, but that social, environmental, and other contextual factors should also be taken into account.

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 relationship between early growth and adult femoral geometry has not been studied previously. In 333 adults, we were able to show that infant weight predicts femoral width and cross-sectional moment of inertia but not femoral neck length. These results support the hypothesis that growth in early life leads to persisting differences in proximal femoral geometry. Introduction: Both femoral geometry and bone mass have been shown independently to predict both hip strength and fracture risk. Whereas growth during intrauterine and early postnatal life has been shown to influence adult bone mass, the relationship between growth in early life and adult femoral geometry has not been described previously. Materials and Methods: We studied the relationship between growth during early life, adult hip geometry, and proximal femur bone mass in a sample of 333 men and women (60–75 years of age), for whom birth weight and weight at 1 year of age were recorded. Hip geometry was derived using Hip Structure Analysis software from proximal femur DXA scans (Hologic QDR 1000). Results: There were significant (p < 0.002) relationships between weight at age 1 year and measures of femoral width as well as intertrochanteric (IT) cross-sectional moment of inertia (CSMI), but not with femoral neck length. The relationships with measures of femoral width but not CSMI remained after adjusting for adult body weight and were independent of proximal femoral BMC. Conclusions: These results support the hypothesis that different patterns of growth in utero and during the first year of life lead to persisting differences in proximal femoral geometry, thereby mediating in part the effects of early growth on risk of hip fracture in adulthood.

Osteoporosis is a major cause of morbidity and mortality through its association with age-related fractures. Although most effort in fracture prevention has been directed at retarding the rate of age-related bone loss and reducing the frequency and severity of trauma among elderly people, evidence is growing that peak bone mass is an important contributor to bone strength during later life. The normal patterns of skeletal growth have been well characterised in cross-sectional and longitudinal studies. It has been confirmed that boys have higher bone mineral content (BMC), but not volumetric bone density, than girls. Furthermore, there is a dissociation between the peak velocities for height gain and bone mineral accrual in both genders. Puberty is the period during which volumetric density appears to increase in both axial and appendicular sites. Many factors influence the accumulation of bone mineral during childhood and adolescence, including heredity, gender, diet, physical activity, endocrine status, and sporadic risk factors such as cigarette smoking. In addition to these modifiable factors during childhood, evidence has also accrued that fracture risk might be programmed during intrauterine life. Epidemiological studies have demonstrated a relationship between birth weight, weight in infancy, and adult bone mass. This appears to be mediated through modulation of the set-point for basal activity of pituitary-dependent endocrine systems such as the HPA and GH/IGF-1 axes. Maternal smoking, diet (particularly vitamin D deficiency), and physical activity also appear to modulate bone mineral acquisition during intrauterine life; furthermore, both low birth size and poor childhood growth are directly linked to the later risk of hip fracture. The optimisation of maternal nutrition and intrauterine growth should also be included within preventive strategies against osteoporotic fracture, albeit for future generations.

The Hertfordshire Cohort Study based in the U.K. was the first to report associations between fetal or infant growth and the prevalence of adult glucose intolerance and diabetes. Many studies have replicated the findings with respect to birth weight, but there have been fewer observations in relationship to infant growth, because this is infrequently recorded in routine datasets. Recently, we carried out glucose tolerance tests in a more recently born group of men and women from the Hertfordshire Cohort Study. The objective was to determine whether the associations with weights at birth and 1 year of age reported in the original study of people born between 1920 and 1930 were observed in people born between 1931 and 1939. Birth weight was inversely related to the overall prevalence of diabetes (comprising newly diagnosed as well as existing cases) in men and women. However, weight at 1 year of age was not associated with diabetes in either sex. Analysis of data from the glucose tolerance tests showed that both sexes had evidence of higher insulin and glucose concentrations in people who were small at birth or during infancy. Finally, direct comparison of 2-h plasma glucose concentrations in the previous and current Hertfordshire study suggested that both surveys showed broad similarity of the trends in glucose tolerance with birth or infant weights; most differences arose at the extremes of the birth weight, possibly because of the small numbers of subjects studied in these groups.

PURPOSE OF REVIEW: Osteoporosis remains a major public health problem through its association with fragility fractures. Recent data suggest that the annual cost in Europe is 13 billion euros, mainly accounted for by hospitalisation after fracture. Understanding the epidemiology of osteoporosis is an essential step in developing strategies to reduce the burden of osteoporotic fracture in the population. RECENT FINDINGS: This article will review recent advances surrounding the epidemiology of osteoporosis, the burden of fracture in children and adults in this country and abroad, morbidity associated with such fractures, associations of disease and medication with fragility fracture, and advances in diagnostic techniques and identification of at-risk groups. SUMMARY: The papers studied highlight the wealth of high-quality research in this field, and they help in the visualisation of strategies to identify individuals at high risk of fragility fracture and to quantify fracture risk by measurement of bone density, bone quality, and risk factor algorithms.

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.

Evidence is accumulating that the risk of osteoporosis in later life may be determined in part by environmental influences on bone development during intrauterine and early postnatal life. A potential role for fetal leptin in mediating these effects is suggested by animal studies showing that leptin influences prenatal osteoblast growth and development, and that fetal leptin concentrations are altered by changes in maternal nutrition. In a group of term human infants we reported previously that maternal birthweight, smoking, fat mass, and exercise during late pregnancy independently predict neonatal bone mass. To investigate the potential role of leptin in mediating these effects, we now relate leptin concentrations in umbilical venous serum to neonatal bone mass and body composition in 117 infants. There were strong positive associations between umbilical venous leptin concentration and each of whole body bone mineral contents (BMC) (r = 0.42, P < or = 0.001) and estimated volumetric bone density (r = 0.21, P = 0.02); whole body lean mass (r = 0.21, P < or = 0.024); and whole body fat mass (r = 0.60, P < 0.001). The associations with neonatal BMC and fat mass, but not with lean mass, were independent of associations that we have reported previously between cord serum insulin-like growth factor 1 (IGF-1) concentrations and neonatal body composition. Among the maternal determinants of neonatal bone mass, cord leptin explained the relationship with maternal fat stores, but not those with the mother's own birthweight, smoking, or physical activity. We conclude that umbilical venous leptin predicts both the size of the neonatal skeleton and its estimated volumetric mineral density. In addition, among previously documented maternal determinants of neonatal bone mass in healthy pregnancies, maternal fat stores may mediate their effect on fetal bone accrual through variation in fetal leptin concentrations.

There is increasing evidence to support the role of the intrauterine and early postnatal environment in determining adult bone mass and risk of fracture. The mechanisms by which this occurs are uncertain but include perturbations in several endocrine axes. Vitamin D is integrally involved in bone metabolism and is therefore an ideal candidate. This study assesses whether birthweight and weight at 1 year of age are associated with the calcium vitamin D axis in elderly women. Vitamin D metabolites, parathyroid hormone, bone mineral density and biochemical markers of bone turnover were measured in 129 healthy women (mean age 65.5 years) from the MRC Hertfordshire Cohort Study whose birthweight and weight at 1 year were available from records. Serum 1,25 (OH)2 vitamin D concentrations were reduced with increasing weight at 1 year (19.1% reduction between the lowest and highest tertiles, P < 0.01). A similar, but weaker trend was seen for birthweight. These associations were not explained by serum levels of serum calcium, phosphate, PTH, creatinine or sex hormones. The association of serum calcium with 1,25 (OH)2 vitamin D was greatest in the lowest tertile with little association in the highest tertile suggesting an increased sensitivity of renal 1-? hydroxylase in the lowest tertile. Highest levels of 1,25 (OH)2 vitamin D were associated with low BMD and high levels of urinary N-telopeptide suggesting that vitamin D metabolism may mediate the intrauterine and early postnatal environmental effects on adult BMD.

AIMS/HYPOTHESIS: Previous studies have suggested that the high bone density often observed in type 2 diabetic patients may be explained by insulin resistance. We explored this hypothesis in the Hertfordshire Cohort Study. METHODS: A total of 465 men and 444 women aged 59 to 71 years and with no prior diagnosis of diabetes attended a clinic where a glucose tolerance test was performed and bone density measured at the femoral neck and lumbar spine. Biochemical markers of bone turnover (serum osteocalcin and urinary mean c-terminal cross-linking telopeptide of type II collagen) were measured in 163 men. RESULTS: According to WHO criteria, 83 men and 134 women were diagnosed with impaired glucose tolerance and a further 33 men and 32 women were diagnosed as having type 2 diabetes. Bone density was higher in newly diagnosed diabetic subjects, with relationships stronger in women (p

A number of studies have suggested that the metabolic syndrome (principally, the combination of hypertension, glucose intolerance, and dyslipidemia) is associated with subtle dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis leading to raised circulating cortisol concentrations. The mechanisms underlying these observations are not known. We assessed the salivary cortisol response to awakening and pituitary-adrenal responses during a 100-microg human corticotrophin-releasing hormone (CRH) test and a dexamethasone-suppressed CRH test in a well-characterized group of 65-year-old men (n = 122). In the cohort from which this subgroup was drawn, there were associations between the components of the metabolic syndrome and 9 am cortisol concentration in line with previous studies. However, there were no significant associations between blood pressure, glucose tolerance, and lipid concentrations and the dynamic tests of HPA activity. We therefore found no evidence to suggest that exaggerated pituitary responsiveness or increased central drive to the pituitary, as determined by CRH testing, plays a part in the development of the metabolic syndrome.

Summary Background Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency. Methods We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z -score-weighted meta-analysis. Genotype scores were constructed for confirmed variants. Findings Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1·9×10 −109 for rs2282679, in GC ); 11q12 (p=2·1×10 −27 for rs12785878, near DHCR7 ); and 11p15 (p=3·3×10 −20 for rs10741657, near CYP2R1 ). Variants at an additional locus (20q13, CYP24A1 ) were genome-wide significant in the pooled sample (p=6·0×10 −10 for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2·47, 95% CI 2·20–2·78, p=2·3×10 −48 ) or lower than 50 nmol/L (1·92, 1·70–2·16, p=1·0×10 −26 ) compared with those in the lowest quartile. Interpretation Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency. Funding Full funding sources listed at end of paper (see Acknowledgments).

In several areas of investigation, the results of a bumper year in osteoporosis research are set to stoke rather than settle debate. From the origins of bone health to the use of established and experimental therapies, the new findings will be discussed into 2011 and beyond.

Background: Osteoarthritis (OA) is the most common cause of disability in the elderly. Clinical frailty is associated with high mortality, but few studies have explored the relationship between OA and frailty. The objective of this study was to consider the association between OA and frailty/pre-frailty in an elderly population comprised of six European cohorts participating in the EPOSA project. Methods: Longitudinal study using baseline data and first follow-up waves, from EPOSA; 2,455 individuals aged 65-85 years were recruited from pre-existing population-based cohorts in Germany, Italy, the Netherlands, Spain, Sweden and the United Kingdom. Data were collected on clinical OA at any site (hand, knee or hip), based on the clinical classification criteria developed by the American College of Rheumatology (ACR). Frailty was defined according to Fried's criteria. The covariates considered were age, gender, educational level, obesity and country. We used multinomial logistic regression to analyse the associations between OA, frailty/pre-frailty and other covariates. Results: The overall prevalence of clinical OA at any site was 30.4 % (95 % CI:28.6-32.2); frailty was present in 10.2 % (95 % CI:9.0-11.4) and pre-frailty in 51.0 % (95 % CI:49.0-53.0). The odds of frailty was 2.96 (95 % CI:2.11-4.16) and pre-frailty 1.54 (95 % CI:1.24-1.91) as high among OA individuals than those without OA. The association remained when Knee OA, hip OA or hand OA were considered separately, and was stronger in those with increasing number of joints. Conclusions: Clinical OA is associated with frailty and pre-frailty in older adults in European countries. This association might be considered when designing appropriate intervention strategies for OA management, The study was supported by a non-commercial private funder. The Indicators for Monitoring COPD and Asthma - Activity and Function in the Elderly in Ulm study (IMCA - ActiFE) was supported by the European Union (No.: 2005121) and the Ministry of Science, Baden-Württemberg. The Italian cohort study is part of the National Research Council Project on Aging (PNR). The Longitudinal Aging Study Amsterdam (LASA) is financially supported by the Dutch Ministry of Health, Welfare and Sports. The Peñagrande study was partially supported by the National Fund for Health Research (Fondo de Investigaciones en Salud) of Spain (project numbers FIS PI 05/1898; FIS RETICEF RD06/0013/1013 and FIS PS09/02143). The Swedish Twin Registry is supported in part by the Swedish Ministry of Higher Education. The Hertfordshire Cohort Study is funded by the Medical Research Council of Great Britain, Arthritis Research UK, the British Heart Foundation and the International Osteoporosis Foundation.

Background: concern over the sustainability of the National Health Service (NHS) is often focussed on rising numbers of hospital admissions, particularly among older people. Hospital admissions are enumerated routinely by the Hospital Episode Statistics (HES) Service, but published data do not allow individual-level service use to be explored. This study linked information on Hertfordshire Cohort Study (HCS) participants with HES inpatient data, with the objective of describing patterns and predictors of admissions among individuals. Methods: 2,997 community-dwelling men and women aged 59–73 years completed a baseline HCS assessment between 1998 and 2004; HES and mortality data to 31 March 2010 were linked with the HCS database. This paper describes patterns of hospital use among the cohort at both the admission and individual person level. Results: the cohort experienced 8,741 admissions; rates were 391 per 1,000 person-years among men (95% CI: 380, 402) and 327 among women (95% CI: 316, 338), P < 0.0001 for gender difference. A total of 1,187 men (75%) and 981 women (69%) were admitted to hospital at least once; among these, median numbers of admissions were 3 in men (inter-quartile range, (IQR): 1, 6) and 2 in women (IQR: 1, 5). Forty-eight percent of those ever admitted had experienced an emergency admission and 70% had been admitted overnight. Discussion: It is possible to link routinely collected HES data with detailed information from a cohort study. Hospital admission is common among community-dwelling ‘young-old’ men and women. These linked datasets will facilitate research into lifecourse determinants of hospital admission and inform strategies to manage demand on the NHS.

Peripheral quantitative computed tomography (pQCT) captures novel aspects of bone geometry that may contribute to fracture risk and offers the ability to measure both volumetric bone mineral density (vBMD) and a separation of trabecular and cortical compartments of bone, but longitudinal data relating measures obtained from this technique to incident fractures are lacking. Here we report an analysis from the Hertfordshire Cohort Study, where we were able to study associations between measures obtained from pQCT and DXA in 182 men and 202 women aged 60-75 years at baseline with incident fractures over 6 years later. Among women, radial cortical thickness (HR 1.72, 95% CI 1.16, 2.54, p=0.007) and cortical area (HR 1.91, 95% CI 1.27, 2.85, p=0.002) at the 66% slice were both associated with incident fractures; these results remained significant after adjustment for confounders (age, BMI, social class, cigarette smoking and alcohol consumption, physical activity, dietary calcium, HRT and years since menopause). Further adjustment for aBMD made a little difference to the results. At the tibia, cortical area (HR 1.58, 95% CI 1.10, 2.28, p=0.01), thickness (HR 1.49, 95% CI 1.08, 2.07, p=0.02) and density (HR 1.64, 95% CI 1.18, 2.26, p=0.003) at the 38% site were all associated with incident fractures with the cortical area and density relationships remaining robust to adjustment for the confounders listed above. Further adjustment for aBMD at this site did lead to attenuation of relationships. Among men, tibial stress-strain index (SSI) was predictive of incident fractures (HR 2.30, 95% CI 1.28, 4.13, p=0.005). Adjustment for confounding variables and aBMD did not render this association non-significant. In conclusion, we have demonstrated relationships between measures of bone size, density and strength obtained by pQCT and incident fracture. These relationships were attenuated but in some cases remained significant after adjustment for BMD measures obtained by DXA, suggesting that some additional information may be conferred by this assessment.

BACKGROUND: It is unclear whether or not the current evidence base allows definite conclusions to be made regarding the optimal maternal circulating concentration of 25-hydroxyvitamin D [25(OH)D] during pregnancy, and how this might best be achieved. OBJECTIVES: To answer the following questions: (1) What are the clinical criteria for vitamin D deficiency in pregnant women? (2) What adverse maternal and neonatal health outcomes are associated with low maternal circulating 25(OH)D? (3) Does maternal supplementation with vitamin D in pregnancy lead to an improvement in these outcomes (including assessment of compliance and effectiveness)? (4) What is the optimal type (D2 or D3), dose, regimen and route for vitamin D supplementation in pregnancy? (5) Is supplementation with vitamin D in pregnancy likely to be cost-effective? METHODS: We performed a systematic review and where possible combined study results using meta-analysis to estimate the combined effect size. Major electronic databases [including Database of Abstracts of Reviews of Effects (DARE), Centre for Reviews and Dissemination (CRD), Cochrane Database of Systematic Reviews (CDSR) and the Health Technology Assessment (HTA) database] were searched from inception up to June 2012 covering both published and grey literature. Bibliographies of selected papers were hand-searched for additional references. Relevant authors were contacted for any unpublished findings and additional data if necessary. Abstracts were reviewed by two reviewers. INCLUSION AND EXCLUSION CRITERIA: SUBJECTS: pregnant women or pregnant women and their offspring. EXPOSURE: either assessment of vitamin D status [dietary intake, sunlight exposure, circulating 25(OH)D concentration] or supplementation of participants with vitamin D or food containing vitamin D (e.g. oily fish). OUTCOMES: offspring - birthweight, birth length, head circumference, bone mass, anthropometry and body composition, risk of asthma and atopy, small for gestational dates, preterm birth, type 1 diabetes mellitus, low birthweight, serum calcium concentration, blood pressure and rickets; mother - pre-eclampsia, gestational diabetes mellitus, risk of caesarean section and bacterial vaginosis. RESULTS: Seventy-six studies were included. There was considerable heterogeneity between the studies and for most outcomes there was conflicting evidence. The evidence base was insufficient to reliably answer question 1 in relation to biochemical or disease outcomes. For questions 2 and 3, modest positive relationships were identified between maternal 25(OH)D and (1) offspring birthweight in meta-analysis of three observational studies using log-transformed 25(OH)D concentrations after adjustment for potential confounding factors [pooled regression coefficient 5.63 g/10% change maternal 25(OH)D, 95% confidence interval (CI) 1.11 to 10.16 g], but not in those four studies using natural units, or across intervention studies; (2) offspring cord blood or postnatal calcium concentrations in a meta-analysis of six intervention studies (all found to be at high risk of bias; mean difference 0.05 mmol/l, 95% CI 0.02 to 0.05 mmol/l); and (3) offspring bone mass in observational studies judged to be of good quality, but which did not permit meta-analysis. The evidence base was insufficient to reliably answer questions 4 and 5. LIMITATIONS: Study methodology varied widely in terms of study design, population used, vitamin D status assessment, exposure measured and outcome definition. CONCLUSIONS: The evidence base is currently insufficient to support definite clinical recommendations regarding vitamin D supplementation in pregnancy. Although there is modest evidence to support a relationship between maternal 25(OH)D status and offspring birthweight, bone mass and serum calcium concentrations, these findings were limited by their observational nature (birthweight, bone mass) or risk of bias and low quality (calcium concentrations). High-quality randomised trials are now required. STUDY REGISTRATION: This study is registered as PROSPERO CRD42011001426. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The aging population will result in an increasing burden of osteoporotic fractures, necessitating the identification of novel strategies for prevention. There is increasing recognition that factors in utero may influence bone mineral accrual, and, thus, osteoporosis risk. The role of calcium and vitamin D has received much attention in recent years, and in this review, we will survey available studies relating maternal calcium and vitamin D status during pregnancy to offspring bone development. The evidence base supporting a positive influence on intrauterine skeletal growth appears somewhat stronger for maternal 25(OH)-vitamin D concentration than for calcium intake, and the available data point toward the need for high-quality randomized controlled trials in order to inform public health policy. It is only with such a rigorous approach that it will be possible to delineate the optimal strategy for vitamin D supplementation in pregnancy in relation to offspring bone health.

s / Osteoarthritis and Cartilage 22 (2014) S57–S489 S343 601 THE PREVALENCE OF RADIOGRAPHIC HIP OSTEOARTHRITIS IS INCREASED IN HIGH BONE MASS; A CASE-CONTROL STUDY S.A. Hardcastle y, P. Dieppe yz, C.L. Gregson y, D. Hunter x, G. Thomas x, N.K. Arden kx, T.D. Spector{, D.J. Hart{, M.J. Laugharne#, G.A. Clague yy, M.H. Edwards k, E. Dennison k, C. Cooper kx, M. Williams zz, G. Davey Smith xx, J.H. Tobias y. yMusculoskeletal Res. Unit, Univ. of Bristol, Bristol, UNITED KINGDOM; zUniv. of Exeter Med. Sch., Exeter, UNITED KINGDOM; xNIHR Musculoskeletal BioMed. Res. Unit, Univ. of Oxford, Oxford, United Kingdom; kMRC Lifecourse Epidemiology Unit, Univ. of Southampton, Southampton, United Kingdom; {Dept. of Twin Res. and Genetic Epidemiology, King’s Coll. London, London, United Kingdom; Dept. of Radiology, Royal United Hosp., Bath, United Kingdom; yyDept. of Radiology, Royal Glamorgan Hosp., Llantrisant, United Kingdom; zzDept. of Radiology, North Bristol NHS Trust, Bristol, United Kingdom; xxMRC Integrative Epidemiology Unit, Univ. of Bristol, Bristol, United Kingdom Purpose: Numerous epidemiological studies have reported an association between increased bone mineral density (BMD) and osteoarthritis (OA), but whether this represents cause or effect remains unclear. To establish whether higher BMD predisposes to OA, we aimed to determine whether individuals with High Bone Mass (HBM) have a higher prevalence of radiographic hip OA compared with controls. Methods: HBM cases were recruited from 15 UK centres by systematically screening DXA databases. HBM was defined in index cases as a total hip Z-score þ3.2 and L1 Z-score þ1.2, or vice-versa, and in firstdegree relatives of index cases as total hip Z-score plus L1 Z-score þ3.2; unaffected relatives were recruited as controls. AP pelvic X-rays were performed in participants aged 40 years. Age-stratified random sampling was used to select further population controls from the Chingford 1000-women and Hertfordshire cohort studies. All radiographs were assessed for features of OA (Croft score, osteophytes, joint space narrowing (JSN), cysts, sclerosis) by a single observer blinded to case-control status using an atlas. Minimum joint space width (JSW) was measured using a computer-aided method. Intra-observer repeatability for most features was good. Analyses used logistic regression, with generalised estimating equations to account for within-person clustering (right/left), adjusted a priori for age, gender and body mass index (BMI). Results: Analyses included 530 HBM hips in 272 cases (mean age 62.9 years, 74% female) and 1702 control hips in 863 controls (mean age 64.8 years, 84% female), after excluding poor quality films and hip replacements (n1⁄4109). The prevalence of radiographic hip OA, defined as Croft score 3, was increased in cases compared with controls (20.0% vs. 13.6%). Results of logistic regression analyses for the binary radiographic OA variables in HBM cases vs. controls are shown in the table below, adjusted for age, gender and BMI. Cases had an increased odds of hip OA compared with controls after adjustment (OR 1.52 [1.09, 2.11], p1⁄40.013). In analyses of individual radiographic features, osteophytes (both any osteophyte, and moderate ( grade 2) osteophytes) and subchondral sclerosis were also more prevalent in cases compared with controls. However, the prevalence of JSN was not increased in HBM cases, and measured JSW did not differ between the groups (mean difference 0.04mm [-0.05, 0.13], p1⁄40.39). Analyses were repeated in the different control groups separately, and stratified by gender, with broadly similar findings. Logistic regression analysis of radiographic hip OA variables in HBM cases vs. all

Unhealthy dietary patterns are associated with poor lung function. It is not known whether this is due to low consumption of antioxidant-rich fruit and vegetables, or is a consequence of higher intakes of harmful dietary constituents, such as processed meat. We examined the individual and combined associations of processed meat, fruit and vegetable consumption and dietary total antioxidant capacity (TAC) with lung function among 1551 males and 1391 females in the UK in the Hertfordshire Cohort Study. Diet was assessed using a food frequency questionnaire. After controlling for confounders, processed meat consumption was negatively associated with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio in males and females, while fruit and vegetable consumption and dietary TAC were positively associated with FEV1 and FVC, but not FEV1/FVC ratio. In males, the negative association between processed meat consumption and FEV1 was more marked in those who had low fruit and vegetable consumption (p=0.035 for interaction), and low dietary TAC (p=0.025 for interaction). The deficit in FEV1/FVC associated with processed meat consumption was larger in males who smoked (p=0.022 for interaction). Higher processed meat consumption is associated with poorer lung function, especially in males who have lower fruit and vegetable consumption or dietary TAC, and among current smokers.

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.

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

Osteoporosis is a systemic disorder characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture. It has a significant impact on public health through the increased morbidity, mortality, and economic costs associated with fractures. The most common fracture sites are hip, spine and distal forearm. Among the different types of, the clinical and economic impact of hip and vertebral fractures have received most attention. There has been growing evidence, however, to suggest that the personal and public burden of fractures at other sites, including distal radius fracture, may have been underrecognized. This review will focus on the consequences of the Cinderella of the osteoporotic fractures – the distal radius fracture.

This is the accepted manuscript version. Published version is available at http://dx.doi.org/10.1007/s11657-014-0185-0 Summary: Bone mass achievement predicts later fracture risk. This population-based study describes bone mineral density levels (BMD) and associated factors in Norwegian adolescents. Compared with international reference ranges, BMD levels appear higher and physical activity levels are positively associated with BMD. Purpose: Norway has one of the highest reported incidences of osteoporotic fractures. Maximization of peak bone mass may prevent later fractures. This population-based study compared BMD levels of Norwegian adolescents with international reference ranges and explored associated factors. Methods: All first year upper secondary school students, aged 15-19 years in the Tromsø region were invited to the Fit Futures study in 2010-2011. Over 90% of the invited participants attended, 508 girls and 530 boys. BMD was measured at total hip, femoral neck and total body by dual x-ray absorptiometry. Lifestyle variables were collected by self-administered questionnaires and interviews. All analyses were performed sex stratified, using linear regression models. Results: In girls mean BMD (SD) was 1.060 (0.124), 1.066 (0.123) and 1.142 (0.077) g/cm² at the total hip, femoral neck and total body respectively. In boys corresponding values were 1.116 (0.147), 1.103 (0.150) and 1.182 (0.097), with significant higher values than the Lunar pediatric reference at 16 years of age In girls, height and self-reported intensive physical activity of more than four hours a week and early sexual maturation were positively associated with BMD at both femoral sites (pConclusions: Despite the heavy fracture burden, Norwegian adolescents´ BMD levels are higher than agematched Caucasians. Physical activity is associated with 1 SD increased BMD levels in those involved in competition or hard training.

People with osteoarthritis (OA) frequently report that their joint pain is influenced by weather conditions. This study aimed to examine whether there are differences in perceived joint pain between older people with OA who reported to be weather-sensitive versus those who did not in six European countries with different climates and to identify characteristics of older persons with OA that are most predictive of perceived weather sensitivity. Methods Baseline data from the European Project on OSteoArthritis (EPOSA) were used. ACR classification criteria were used to determine OA. Participants with OA were asked about their perception of weather as influencing their pain. Using a two-week follow-up pain calendar, average self-reported joint pain was assessed (range: 0 (no pain)-10 (greatest pain intensity)). Linear regression analyses, logistic regression analyses and an independent t-test were used. Analyses were adjusted for several confounders. Results The majority of participants with OA (67.2%) perceived the weather as affecting their pain. Weather-sensitive participants reported more pain than non-weather-sensitive participants (M = 4.1, SD = 2.4 versus M = 3.1, SD = 2.4; p, The Indicators for Monitoring COPD and Asthma - Activity and Function in the Elderly in Ulm study (IMCA - ActiFE) is supported by the European Union (No.: 2005121) and the Ministry of Science, Baden-Württemberg. The Italian cohort study is part of the National Research Council Project on Aging (PNR). The Longitudinal Aging Study Amsterdam (LASA) is financially supported by the Dutch Ministry of Health, Welfare and Sports. The Peñagrande study was partially supported by the National Fund for Health Research (Fondo de Investigaciones en Salud) of Spain (project numbers FIS PI 05/1898; FIS RETICEF RD06/0013/1013 and FIS PS09/02143). The Swedish Twin Registry is supported in part by the Swedish Ministry of Higher Education. The Hertfordshire Cohort Study was supported by the Medical Research Council, UK.

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 5 0.009), whereas mean 24-h serum total cortisol concentrations were higher in males (mean, 9.0 mg/dL; SD, 1.4) than in females (mean, 7.3 mg/dL; SD, 1.4; P 5 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 5 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 5 0.14; P 5 0.01), whereas cross-ApEn values of paired GH-cortisol were best predicted by FSH concentrations (r 2 5 0.37; P 5 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 5 0.30; P , 0.0001) and 4.3 h in females (r 5 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 5 20.21; P , 0.0001) and 6.3 h in females (r 52 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 GHcortisol 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. (J Clin Endocrinol Metab 86: 3393‐3399, 2001)