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1.  Maternal gestational vitamin D supplementation and offspring bone health: a multicentre randomised, double-blind, placebo-controlled trial (MAVIDOS) 
Background
Maternal vitamin D status has been associated with lower bone mass of the offspring in many, but not all, observational studies. However, proof that maternal vitamin D repletion during pregnancy improves offspring bone mass is lacking.
Methods
Between 06/10/2008 and 11/02/2014, we randomly assigned pregnant women with a serum 25-hydroxyvitamin D [25(OH)D] 25-100nmol/l at 12 weeks’ gestation to either 1000IU/day cholecalciferol or matched placebo from 14 weeks’ gestation until delivery. Serum 25(OH)D was measured at 14 and 34 weeks’ gestation. Neonatal whole body bone mineral, assessed within 2 weeks after birth (n=665) by dual-energy X-ray absorptiometry (DXA), was the primary outcome. Secondary pre-specified analyses explored interactions with study centre, maternal ethnicity, parity, compliance, protocol completion, baseline BMI, baseline 25(OH)D and change in 25(OH)D from 14 to 34 weeks; and offspring sex and season of birth.
Findings
We found no difference in neonatal whole body bone mineral content (BMC) of infants born to mothers randomised to 1000IU/day cholecalciferol compared with infants born to mothers randomised to placebo [61.6g (95%CI: 60.3, 62.8g) vs 60.5g (95%CI: 59.3, 61.7g) respectively, p=0.21].
Interpretation
Supplementation of mothers with 1000IU/day cholecalciferol during pregnancy did not lead to increased offspring whole body BMC compared with placebo.
doi:10.1016/S2213-8587(16)00044-9
PMCID: PMC4843969  PMID: 26944421
Vitamin D; cholecalciferol; supplementation; trial; osteoporosis; epidemiology; DXA; pregnancy; neonate
2.  Determinants of the Maternal 25-Hydroxyvitamin D Response to Vitamin D Supplementation During Pregnancy 
Context:
Current approaches to antenatal vitamin D supplementation do not account for interindividual differences in 25-hydroxyvitamin D (25(OH)D) response.
Objective:
We assessed which maternal and environmental characteristics were associated with 25(OH)D after supplementation with cholecalciferol.
Design:
Within-randomization-group analysis of participants in the Maternal Vitamin D Osteoporosis Study trial of vitamin D supplementation in pregnancy.
Setting:
Hospital antenatal clinics.
Participants:
A total of 829 pregnant women (422 placebo, 407 cholecalciferol). At 14 and 34 weeks of gestation, maternal anthropometry, health, and lifestyle were assessed and 25(OH)D measured. Compliance was determined using pill counts at 19 and 34 weeks.
Interventions:
1000 IU/d of cholecalciferol or matched placebo from 14 weeks of gestation until delivery.
Main Outcome Measure:
25(OH)D at 34 weeks, measured in a single batch (Diasorin Liaison).
Results:
25(OH)D at 34 weeks of gestation was higher in the women randomized to vitamin D (mean [SD], 67.7 [21.3] nmol/L) compared with placebo (43.1 [22.5] nmol/L; P < .001). In women randomized to cholecalciferol, higher pregnancy weight gain from 14 to 34 weeks of gestation (kg) (β = −0.81 [95% confidence interval −1.39, −0.22]), lower compliance with study medication (%) (β = −0.28 [−0.072, −0.48]), lower early pregnancy 25(OH)D (nmol/L) (β = 0.28 [0.16, 0.40]), and delivery in the winter vs the summer (β = −10.5 [−6.4, −14.6]) were independently associated with lower 25(OH)D at 34 weeks of gestation.
Conclusions:
Women who gained more weight during pregnancy had lower 25(OH)D in early pregnancy and delivered in winter achieved a lower 25(OH)D in late pregnancy when supplemented with 1000 IU/d cholecalciferol. Future studies should aim to determine appropriate doses to enable consistent repletion of 25(OH)D during pregnancy.
Within the treatment arm of the MAVIDOS RCT, poorer 25(OH)D response to 1000IU/d cholecalciferol was associated with lower initial 25(OH)D, greater pregnancy weight gain and delivery in winter.
doi:10.1210/jc.2016-2869
PMCID: PMC5155676  PMID: 27788053
3.  Maternal serum retinol and β-carotene concentrations and neonatal bone mineralization: results from the Southampton Women’s Survey cohort1 
Background: Studies in older adults and animals have suggested contrasting relations between bone health and different vitamin A compounds. To our knowledge, the associations between maternal vitamin A status and offspring bone development have not previously been elucidated.
Objective: We examined the associations between maternal serum retinol and β-carotene concentrations during late pregnancy and offspring bone mineralization assessed at birth with the use of dual-energy X-ray absorptiometry.
Design: In the Southampton Women’s Survey mother-offspring birth cohort, maternal health, lifestyle, and diet were assessed prepregnancy and at 11 and 34 wk of gestation. In late pregnancy, maternal serum retinol and β-carotene concentrations were measured. Offspring total body bone mineral density (BMD), bone mineral content (BMC), and bone area (BA) were measured within 2 wk after birth.
Results: In total, 520 and 446 mother-offspring pairs had measurements of maternal serum retinol and β-carotene, respectively. Higher maternal serum retinol in late pregnancy was associated with lower offspring total body BMC (β = −0.10 SD/SD; 95% CI: −0.19, −0.02; P = 0.020) and BA (β = −0.12 SD/SD; 95% CI: −0.20, −0.03; P = 0.009) but not BMD. Conversely, higher maternal serum β-carotene concentrations in late pregnancy were associated with greater total body BMC (β = 0.12 SD/SD; 95% CI: 0.02, 0.21; P = 0.016) and BA (β = 0.12 SD/SD; 95% CI: 0.03, 0.22; P = 0.010) but not BMD.
Conclusions: Maternal serum retinol and β-carotene concentrations had differing associations with offspring bone size and growth at birth: retinol was negatively associated with these measurements, whereas β-carotene was positively associated. These findings highlight the need for further investigation of the effects of maternal retinol and carotenoid status on offspring bone development.
doi:10.3945/ajcn.116.130146
PMCID: PMC5039809  PMID: 27629051
bone development; epidemiology; pregnancy; vitamin A; retinol; β-carotene
4.  The neighbourhood environment and use of neighbourhood resources in older adults with and without lower limb osteoarthritis: results from the Hertfordshire Cohort Study 
Clinical Rheumatology  2016;35(11):2797-2805.
This study aimed to examine the associations of perceptions of neighbourhood cohesion and neighbourhood problems and objectively measured neighbourhood deprivation with the use of neighbourhood resources by older adults with and without lower limb osteoarthritis (LLOA), and to assess whether these relationships are stronger in older persons with LLOA than in those without the condition. Data from the Hertfordshire Cohort Study were used. American College of Rheumatology classification criteria were used to diagnose clinical LLOA (knee and/or hip osteoarthritis). Use of neighbourhood resources was assessed using the Home and Community Environment instrument. Participants were asked about their perceptions of neighbourhood cohesion and neighbourhood problems. Objective neighbourhood deprivation was assessed using the Index of Multiple Deprivation score based on 2010 census data. Of the 401 participants (71–80 years), 74 (18.5 %) had LLOA. The neighbourhood measures were not significantly associated with use of resources in the full sample. A trend for a negative association between use of public transport and perceived neighbourhood problems was observed in participants with LLOA (OR = 0.77, 99 % CI = 0.53–1.12), whereas a trend for a positive association between perceived neighbourhood problems and use of public transport was found in participants without LLOA (OR = 1.18, 99 % CI = 1.00–1.39). The perception of more neighbourhood problems seems only to hinder older adults with LLOA to make use of public transport. Older adults with LLOA may be less able to deal with neighbourhood problems and more challenging environments than those without the condition.
doi:10.1007/s10067-016-3388-5
PMCID: PMC5063902  PMID: 27567628
Neighbourhood environment; Older population; Osteoarthritis
5.  Clustering of lifestyle risk factors and poor physical function in older adults: The Hertfordshire Cohort Study 
OBJECTIVES
To examine the relationship between number of lifestyle risk factors (out of: low physical activity, poor diet, obesity and smoking) and physical function in older community-dwelling men and women.
DESIGN
Cross-sectional study, Hertfordshire, UK
PARTICIPANTS
1682 men and 1540 women aged 59-73 years
MEASUREMENTS
Physical activity was assessed by administered questionnaire and a score derived (0-100); low activity was defined as a score ≤50. Diet was assessed by food frequency questionnaire; diet quality was assessed according to a score for a principal component analysis-defined ‘healthy’ dietary pattern. Poor diet was categorised as a dietary pattern score in the lowest quarter of the distribution. Obesity was defined as BMI ≥30kg/m2. Physical function was assessed by self-report (SF-36 PF); poor function was defined as a score in lowest quarter of the distribution. A sub-group of participants had objective assessments of physical function (timed up-and-go, timed 3-m walk, chair rises, one-legged standing balance).
RESULTS
There were graded positive increases in prevalence of poor self-reported physical function in both men and women, in parallel with increasing number of risk factors (men: adjusted odds ratio for 3 or 4 risk factors in comparison with none: 3.79 (95% CI 2.31 to 6.21); women: adjusted odds ratio 5.37 (95% CI 2.66 to10.84). With the exception of balance, the objective assessments also showed graded relationships with increasing number of risk factors, such that a greater number of risk factors was associated with poorer physical function.
CONCLUSION
These modifiable lifestyle risk factors are linked to marked differences in risk of poorer physical function in older adults. Efforts to encourage healthy lifestyles have the potential to improve physical function and to promote healthier ageing.
doi:10.1111/jgs.12457
PMCID: PMC4930137  PMID: 24083502
older adults; SF-36; physical function; lifestyle; risk factor
6.  Exome-wide analysis of rare coding variation identifies novel associations with COPD and airflow limitation in MOCS3, IFIT3 and SERPINA12 
Thorax  2016;71(6):501-509.
Background
Several regions of the genome have shown to be associated with COPD in genome-wide association studies of common variants.
Objective
To determine rare and potentially functional single nucleotide polymorphisms (SNPs) associated with the risk of COPD and severity of airflow limitation.
Methods
3226 current or former smokers of European ancestry with lung function measures indicative of Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 COPD or worse were genotyped using an exome array. An analysis of risk of COPD was carried out using ever smoking controls (n=4784). Associations with %predicted FEV1 were tested in cases. We followed-up signals of interest (p<10−5) in independent samples from a subset of the UK Biobank population and also undertook a more powerful discovery study by meta-analysing the exome array data and UK Biobank data for variants represented on both arrays.
Results
Among the associated variants were two in regions previously unreported for COPD; a low frequency non-synonymous SNP in MOCS3 (rs7269297, pdiscovery=3.08×10−6, preplication=0.019) and a rare SNP in IFIT3, which emerged in the meta-analysis (rs140549288, pmeta=8.56×10−6). In the meta-analysis of % predicted FEV1 in cases, the strongest association was shown for a splice variant in a previously unreported region, SERPINA12 (rs140198372, pmeta=5.72×10−6). We also confirmed previously reported associations with COPD risk at MMP12, HHIP, GPR126 and CHRNA5. No associations in novel regions reached a stringent exome-wide significance threshold (p<3.7×10−7).
Conclusions
This study identified several associations with the risk of COPD and severity of airflow limitation, including novel regions MOCS3, IFIT3 and SERPINA12, which warrant further study.
doi:10.1136/thoraxjnl-2015-207876
PMCID: PMC4893124  PMID: 26917578
COPD epidemiology; Tobacco and the lung
7.  Lean mass and fat mass have differing associations with bone microarchitecture assessed by high resolution peripheral quantitative computed tomography in men and women from the Hertfordshire Cohort Study 
Bone  2015;81:145-151.
Understanding the effects of muscle and fat on bone is increasingly important in the optimisation of bone health. We explored relationships between bone microarchitecture and body composition in older men and women from the Hertfordshire Cohort Study. 175 men and 167 women aged 72-81 years were studied. High resolution peripheral quantitative computed tomography (HRpQCT) images (voxel size 82μm) were acquired from the non-dominant distal radius and tibia with a Scanco XtremeCT scanner. Standard morphological analysis was performed for assessment of macrostructure, densitometry, cortical porosity and trabecular microarchitecture. Body composition was assessed using dual energy x-ray absorptiometry (DXA) (Lunar Prodigy Advanced). Lean mass index (LMI) was calculated as lean mass divided by height squared and fat mass index (FMI) as fat mass divided by height squared. The mean (standard deviation) age in men and women was 76 (3) years. In univariate analyses, tibial cortical area (p<0.01), cortical thickness (p<0.05) and trabecular number (p<0.01) were positively associated with LMI and FMI in both men and women. After mutual adjustment, relationships between cortical area and thickness were only maintained with LMI [tibial cortical area, β(95% confidence interval (CI)): men 6.99 (3.97,10.01), women 3.59 (1.81,5.38)] whereas trabecular number and density were associated with FMI. Interactions by sex were found, including for the relationships of LMI with cortical area and FMI with trabecular area in both the radius and tibia (p<0.05). In conclusion, LMI and FMI appeared to show independent relationships with bone microarchitecture. Further studies are required to confirm the direction of causality and explore the mechanisms underlying these tissue-specific associations.
doi:10.1016/j.bone.2015.07.013
PMCID: PMC4641321  PMID: 26187195
muscle; bone microarchitecture; fat; HRpQCT; mechanostat; epidemiology
9.  Effect of co-morbidities on fracture risk: Findings from the Global Longitudinal Study of Osteoporosis in Women (GLOW) 
Bone  2012;50(6):1288-1293.
Introduction
Greater awareness of the relationship between co-morbidities and fracture risk may improve fracture-prediction algorithms such as FRAX.
Materials and methods
We used a large, multinational cohort study (GLOW) to investigate the effect of co-morbidities on fracture risk. Women completed a baseline questionnaire detailing past medical history, including co-morbidity history and fracture. They were re-contacted annually to determine incident clinical fractures. A co-morbidity index, defined as number of baseline co-morbidities, was derived. The effect of adding the co-morbidity index to FRAX risk factors on fracture prevention was examined using chi-squared tests, the May-Hosmer test, c index and comparison of predicted versus observed fracture rates.
Results
Of 52,960 women with follow-up data, enrolled between October 2006 and February 2008, 3224 (6.1%) sustained an incident fracture over 2 years. All recorded co-morbidities were significantly associated with fracture, except for high cholesterol, hypertension, celiac disease, and cancer. The strongest association was seen with Parkinson’s disease (age-adjusted hazard ratio [HR]: 2.2; 95% CI: 1.6–3.1; P<0.001). Co-morbidities that contributed most to fracture prediction in a Cox regression model with FRAX risk factors as additional predictors were: Parkinson’s disease, multiple sclerosis, chronic obstructive pulmonary disease, osteoarthritis, and heart disease.
Conclusion
Co-morbidities, as captured in a co-morbidity index, contributed significantly to fracture risk in this study population. Parkinson’s disease carried a particularly high risk of fracture; and increasing co-morbidity index was associated with increasing fracture risk. Addition of co-morbidity index to FRAX risk factors improved fracture prediction.
doi:10.1016/j.bone.2012.02.639
PMCID: PMC4886309  PMID: 22426498
Fracture risk; Co-morbidities; Parkinson’s disease; Multiple sclerosis; FRAX
10.  Quantifying Habitual Levels of Physical Activity According to Impact in Older People: Accelerometry Protocol for the VIBE Study 
Physical activity (PA) may need to produce high impacts to be osteogenic. The aim of this study was to identify threshold(s) for defining high impact PA for future analyses in the VIBE (Vertical Impact and Bone in the Elderly) study, based on home recordings with triaxial accelerometers. Recordings were obtained from 19 Master Athlete Cohort (MAC; mean 67.6 years) and 15 Hertfordshire Cohort Study (HCS; mean 77.7 years) participants. Data cleaning protocols were developed to exclude artifacts. Accelerations expressed in g units were categorized into three bands selected from the distribution of positive Y-axis peak accelerations. Data were available for 6.6 and 4.4 days from MAC and HCS participants respectively, with approximately 14 hr recording daily. Three-fold more 0.5–1.0g impacts were observed in MAC versus HCS, 20-fold more 1.0–1.5g impacts, and 140-fold more impacts ≥ 1.5g. Our analysis protocol successfully distinguishes PA levels in active and sedentary older individuals.
doi:10.1123/japa.2015-0066
PMCID: PMC4856876  PMID: 26372670
peak g; accelerometry; VIBE
11.  Tracking of 25-hydroxyvitamin D status during pregnancy: the importance of vitamin D supplementation 
Background
The role of maternal 25-hydroxyvitamin D [25(OH)D] in fetal development is uncertain and findings of observational studies are inconsistent. Most studies have assessed 25(OH)D only once in pregnancy, but the tracking of an individual’s 25(OH)D during pregnancy is unknown.
Objective
We determined the tracking of serum 25(OH)D from early to late pregnancy, and factors which influence this.
Design
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 weeks gestation. A Fourier transformation was used to model seasonal variation in 25(OH)D for early and late pregnancy, separately, and the difference between measured and seasonally modelled 25(OH)D calculated to generate a season-corrected 25(OH)D. Tracking was assessed using Pearson’s correlation coefficient, and multivariate linear regression used to determine factors associated with change in season-corrected 25(OH)D.
Results
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 weeks gestation (r=0.53, p<0.0001, n=1753). Vitamin D supplementation was the strongest predictor of tracking: compared with women who never used supplements, discontinuing supplementation after 11 weeks was associated with reduction in season-corrected 25(OH)D (β=−7.3nmol/l, p<0.001), whereas commencing (β=12.6nmol/l, p<0.001) or continuing (β=6.6nmol/l, p<0.001) supplementation were associated with increases. Higher pregnancy weight gain was associated with reduction in season-corrected 25(OH)D (β=−0.4nmol/l per kg, p=0.015), whereas greater physical activity (β=0.4nmol/l per hour/week, p=0.011) was associated with increases.
Conclusions
There is 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 design and analysis and approaches to intervention studies and clinical care.
doi:10.3945/ajcn.115.115295
PMCID: PMC4634223  PMID: 26399867
Moon; Crozier; Dennison; Davies; Robinson; Inskip; Godfrey; Cooper; Harvey
12.  Differences in childhood adiposity influence upper limb fracture site 
Bone  2015;79:88-93.
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 and SFT z-scores than those with UA fractures (p<0.05 for all). SFT z-scores were also higher in children with forearm fractures compared to hand fractures, but children withor 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. The differences in anthropometry and overweight/obesity were similar for 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.
doi:10.1016/j.bone.2015.05.031
PMCID: PMC4521307  PMID: 26027507
fracture; adiposity; obesity; children
14.  Accumulation of risk factors associated with poor bone health in older adults 
Summary
Clustering of factors linked with poor bone health is common in older adults and is associated with lower bone density and increased fracture risk in women.
Purpose
Many factors are associated with bone mineral density, which in turn is strongly linked with risk of fragility fracture. We assessed how commonly clustering of risk factors occurs and related such clustering to bone mineral density in a population of older community-dwelling men and women.
Method
This is a cross-sectional study with 498 men and 498 women aged 59 to 72 years, who were participants in the Hertfordshire Cohort Study, in whom incident fracture was recorded. Physical activity, diet quality, history of prior fracture, family history of fracture, cigarette and alcohol consumption and comorbidities were obtained through baseline questionnaire. Measurements of grip strength and bone mineral density of the lumbar spine and total femur were also taken.
Results
Clustering of risk factors was common, with over 30 % having two or more. In women, a graded association between the number of risk factors and low bone density was seen, and strong relationships were also seen between the number of risk factors and incident fracture; women with three or more risk factors had an adjusted hazard ratio (HR) of incident fracture of 5.98 (1.67, 21.43; p = 0.006) compared to women with no risk factors; women with two risk factors had an adjusted HR of 2.97 (1.14, 7.74; p = 0.03) and those with one, 2.28 (0.90, 5.75; p = 0.08).
Conclusion
Clustering of risk factors for poor bone health is common in community-dwelling older adults and is associated with increased risk of fracture and adverse bone health in women.
doi:10.1007/s11657-015-0250-3
PMCID: PMC4688304  PMID: 26693939
Clustering; Lifestyle; Bone mineral density; Smoking; Alcohol
15.  Longitudinal changes in lean mass predict pQCT measures of tibial geometry and mineralisation at 6-7 years 
Bone  2015;75:105-110.
Background
Studies in childhood suggest that both body composition and early postnatal growth are associated with bone mineral density (BMD). However, little is known of the relationships between longitudinal changes in fat (FM) and lean mass (LM), and bone development in pre-pubertal children. We therefore investigated these associations in a population-based mother-offspring cohort, the Southampton Women’s Survey.
Methods
Total FM and LM were assessed at birth and 6-7 years of age by Dual-Energy X-ray Absorptiometry (DXA). At 6-7y, total cross-sectional area (CSA) and trabecular volumetric BMD (vBMD) at the 4% site (metaphysis) of the tibia was assessed using peripheral quantitative computed tomography [pQCT (Stratec XCT-2000)]. Total CSA, cortical CSA, cortical vBMD and strength-strain index (SSI) were measured at the 38% site (diaphysis). FM, LM and bone parameters were adjusted for age and sex and standardised to create within-cohort z-scores. Change in LM (ΔLM) or FM (ΔFM) was represented by change in z-score from birth to 7y and conditioned on the birth measurement. Linear regression was used to explore the associations between ΔLM or ΔFM and standardised pQCT outcomes, before and after mutual adjustment and for linear growth. The β-coefficient represents SD change in outcome per unit SD change in predictor.
Results
DXA at birth, in addition to both DXA and pQCT scans at 6-7y, were available for 200 children (48.5% male). ΔLM adjusted for ΔFM was positively associated with tibial total CSA at both the 4% (β=0.57SD/SD, p<0.001) and 38% sites (β=0.53SD/SD, p<0.001), cortical CSA (β=0.48SD/SD, p<0.001) and trabecular vBMD (β=0.30SD/SD, p<0.001), but not with cortical vBMD. These relationships persisted after adjustment for linear growth. In contrast, ΔFM adjusted for ΔLM was only associated with 38% total and cortical CSA, which became non-significant after adjustment for linear growth.
Conclusion
In this study, gain in childhood LM was positively associated with bone size and trabecular vBMD at 6-7 years of age. In contrast, no relationships between change in FM and bone were observed, suggesting that muscle growth, rather than accrual of fat mass, may be a more important determinant of childhood bone development.
doi:10.1016/j.bone.2015.02.015
PMCID: PMC4556067  PMID: 25703480
Osteoporosis; epidemiology; body composition; pQCT; growth; childhood
16.  Osteoarthritis and frailty in elderly individuals across six European countries: results from the European Project on OSteoArthritis (EPOSA) 
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.
doi:10.1186/s12891-015-0807-8
PMCID: PMC4650343  PMID: 26578262
European; Older people; Osteoarthritis; Frailty; Prevalence
17.  Does the frequency and intensity of physical activity in adolescence have an impact on bone? The Tromsø Study, Fit Futures 
Background
Optimization of the genetic potential for bone accrual in early life may prevent future fractures. Possible modification factors include lifestyle factors such as nutrition and physical activity. Measured levels of bone mineral density (BMD) and bone mass content (BMC) are indicators of bone strength, and are correlated with fracture risk. This study explored the impact of self-reported physical activity frequencies and intensity on BMD and BMC in Norwegian adolescents.
Methods
In 2010–2011 school students in two North-Norwegian municipalities were invited to a health survey, the Fit Future study. 508 girls and 530 boys aged 15–18 years attended. BMD and BMC were measured by dual X-ray absorptiometry. Physical activity and other lifestyle-factors were reported by questionnaires and clinical interviews. Statistical analyses were performed sex stratified, using ANOVA for comparison of means and linear regression models adjusting for factors known to affect bone.
Results
Approximately 2/3 of girls and boys reported themselves as physically active outside school hours. Active participants had a significantly higher BMD and BMC at all sites (p < 0.001), except for BMC total body in girls, compared to inactive participants. In multiple linear regression analyses, increased physical activity measured as days a week, categorized into seldom, moderate and highly, was positively associated with BMD (g/cm2) at all sites in girls. Girls reporting themselves as highly active had BMD levels 0.093 g/cm2, 0.090 g/cm2 and 0.046 g/cm2 higher (p < 0.001) than their more seldom active peers at femoral neck, total hip and total body respectively. Corresponding values for boys were 0.125 g/cm2, 0.133 g/cm2 and 0.66 g/cm2. BMC measures showed similar trends at femoral neck and total hip.
Conclusions
Increased level of physical activity is associated with higher BMD and BMC levels in adolescents. For both sexes high activity frequency seems to be essential, whilst boys reporting quite hard intensity has an additional impact. The differential effects of physical activity on bone strength in adolescence have clinical implications, especially in preventive strategies.
doi:10.1186/s13102-015-0020-y
PMCID: PMC4641333  PMID: 26561526
Population-based study; Physical activity; Adolescents; Bone mineral density; DXA
18.  Further evidence of the developmental origins of osteoarthritis: results from the Hertfordshire Cohort Study 
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 (HCS).
Data were available for 222 men and 222 women. Clinical OA was defined based on American College of Rheumatology (ACR) 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.
doi:10.1017/S2040174414000373
PMCID: PMC4521289  PMID: 25154411
Osteoarthritis; Bone; Programming; Birth weight
19.  Can We Identify Patients with High Risk of Osteoarthritis Progression Who Will Respond to Treatment? A Focus on Biomarkers and Frailty 
Drugs & Aging  2015;32(7):525-535.
Osteoarthritis (OA), a disease affecting different patient phenotypes, appears as an optimal candidate for personalized healthcare. The aim of the discussions of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) working group was to explore the value of markers of different sources in defining different phenotypes of patients with OA. The ESCEO organized a series of meetings to explore the possibility of identifying patients who would most benefit from treatment for OA, on the basis of recent data and expert opinion. In the first meeting, patient phenotypes were identified according to the number of affected joints, biomechanical factors, and the presence of lesions in the subchondral bone. In the second meeting, summarized in the present article, the working group explored other markers involved in OA. Profiles of patients may be defined according to their level of pain, functional limitation, and presence of coexistent chronic conditions including frailty status. A considerable amount of data suggests that magnetic resonance imaging may also assist in delineating different phenotypes of patients with OA. Among multiple biochemical biomarkers identified, none is sufficiently validated and recognized to identify patients who should be treated. Considerable efforts are also being made to identify genetic and epigenetic factors involved in OA, but results are still limited. The many potential biomarkers that could be used as potential stratifiers are promising, but more research is needed to characterize and qualify the existing biomarkers and to identify new candidates.
doi:10.1007/s40266-015-0276-7
PMCID: PMC4516900  PMID: 26085027
20.  Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium 
Moayyeri, Alireza | Hsu, Yi-Hsiang | Karasik, David | Estrada, Karol | Xiao, Su-Mei | Nielson, Carrie | Srikanth, Priya | Giroux, Sylvie | Wilson, Scott G. | Zheng, Hou-Feng | Smith, Albert V. | Pye, Stephen R. | Leo, Paul J. | Teumer, Alexander | Hwang, Joo-Yeon | Ohlsson, Claes | McGuigan, Fiona | Minster, Ryan L. | Hayward, Caroline | Olmos, José M. | Lyytikäinen, Leo-Pekka | Lewis, Joshua R. | Swart, Karin M.A. | Masi, Laura | Oldmeadow, Chris | Holliday, Elizabeth G. | Cheng, Sulin | van Schoor, Natasja M. | Harvey, Nicholas C. | Kruk, Marcin | del Greco M, Fabiola | Igl, Wilmar | Trummer, Olivia | Grigoriou, Efi | Luben, Robert | Liu, Ching-Ti | Zhou, Yanhua | Oei, Ling | Medina-Gomez, Carolina | Zmuda, Joseph | Tranah, Greg | Brown, Suzanne J. | Williams, Frances M. | Soranzo, Nicole | Jakobsdottir, Johanna | Siggeirsdottir, Kristin | Holliday, Kate L. | Hannemann, Anke | Go, Min Jin | Garcia, Melissa | Polasek, Ozren | Laaksonen, Marika | Zhu, Kun | Enneman, Anke W. | McEvoy, Mark | Peel, Roseanne | Sham, Pak Chung | Jaworski, Maciej | Johansson, Åsa | Hicks, Andrew A. | Pludowski, Pawel | Scott, Rodney | Dhonukshe-Rutten, Rosalie A.M. | van der Velde, Nathalie | Kähönen, Mika | Viikari, Jorma S. | Sievänen, Harri | Raitakari, Olli T. | González-Macías, Jesús | Hernández, Jose L. | Mellström, Dan | Ljunggren, Östen | Cho, Yoon Shin | Völker, Uwe | Nauck, Matthias | Homuth, Georg | Völzke, Henry | Haring, Robin | Brown, Matthew A. | McCloskey, Eugene | Nicholson, Geoffrey C. | Eastell, Richard | Eisman, John A. | Jones, Graeme | Reid, Ian R. | Dennison, Elaine M. | Wark, John | Boonen, Steven | Vanderschueren, Dirk | Wu, Frederick C.W. | Aspelund, Thor | Richards, J. Brent | Bauer, Doug | Hofman, Albert | Khaw, Kay-Tee | Dedoussis, George | Obermayer-Pietsch, Barbara | Gyllensten, Ulf | Pramstaller, Peter P. | Lorenc, Roman S. | Cooper, Cyrus | Kung, Annie Wai Chee | Lips, Paul | Alen, Markku | Attia, John | Brandi, Maria Luisa | de Groot, Lisette C.P.G.M. | Lehtimäki, Terho | Riancho, José A. | Campbell, Harry | Liu, Yongmei | Harris, Tamara B. | Akesson, Kristina | Karlsson, Magnus | Lee, Jong-Young | Wallaschofski, Henri | Duncan, Emma L. | O'Neill, Terence W. | Gudnason, Vilmundur | Spector, Timothy D. | Rousseau, François | Orwoll, Eric | Cummings, Steven R. | Wareham, Nick J. | Rivadeneira, Fernando | Uitterlinden, Andre G. | Prince, Richard L. | Kiel, Douglas P. | Reeve, Jonathan | Kaptoge, Stephen K.
Human Molecular Genetics  2014;23(11):3054-3068.
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 × 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 × 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 × 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.
doi:10.1093/hmg/ddt675
PMCID: PMC4038791  PMID: 24430505
21.  Leisure time computer use and adolescent bone health—findings from the Tromsø Study, Fit Futures: a cross-sectional study 
BMJ Open  2015;5(6):e006665.
Objectives
Low levels of physical activity may have considerable negative effects on bone health in adolescence, and increasing screen time in place of sporting activity during growth is worrying. This study explored the associations between self-reported screen time at weekends and bone mineral density (BMD).
Design
In 2010/2011, 1038 (93%) of the region’s first-year upper-secondary school students (15–18 years) attended the Tromsø Study, Fit Futures 1 (FF1). A follow-up survey (FF2) took place in 2012/2013. BMD at total hip, femoral neck and total body was measured as g/cm² by dual X-ray absorptiometry (GE Lunar prodigy). Lifestyle variables were self-reported, including questions on hours per day spent in front of television/computer during weekends and hours spent on leisure time physical activities. Complete data sets for 388/312 girls and 359/231 boys at FF1/FF2, respectively, were used in analyses. Sex stratified multiple regression analyses were performed.
Results
Many adolescents balanced 2–4 h screen time with moderate or high physical activity levels. Screen time was positively related to body mass index (BMI) in boys (p=0.002), who spent more time in front of the computer than girls did (p<0.001). In boys, screen time was adversely associated with BMDFF1 at all sites, and these associations remained robust to adjustments for age, puberty, height, BMI, physical activity, vitamin D levels, smoking, alcohol, calcium and carbonated drink consumption (p<0.05). Screen time was also negatively associated with total hip BMDFF2 (p=0.031). In contrast, girls who spent 4–6 h in front of the computer had higher BMD than the reference (<2 h).
Conclusions
In Norwegian boys, time spent on screen-based sedentary activity was negatively associated with BMD levels; this relationship persisted 2 years later. Such negative associations were not present among girls. Whether this surprising result is explained by biological differences remains unclear.
doi:10.1136/bmjopen-2014-006665
PMCID: PMC4486947  PMID: 26063563
EPIDEMIOLOGY; PUBLIC HEALTH
22.  How well do radiographic, clinical and self-reported diagnoses of knee osteoarthritis agree? Findings from the Hertfordshire cohort study 
SpringerPlus  2015;4:177.
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.
doi:10.1186/s40064-015-0949-z
PMCID: PMC4408304  PMID: 25932366
Osteoarthritis; Epidemiology; Agreement; Radiographic; Definition
23.  Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region 
Annals of the Rheumatic Diseases  2012;72(3):427-436.
Background and objectives
Chronic widespread pain (CWP) is a common disorder affecting ∼10% of the general population and has an estimated heritability of 48–52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP.
Methods
We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain.
Results
The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2×10−8). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7×10−7) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4×10−8, I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7×10−4).
Conclusions
We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.
doi:10.1136/annrheumdis-2012-201742
PMCID: PMC3691951  PMID: 22956598
Gene Polymorphism; Fibromyalgis/Pain Syndromes; Epidemiology
24.  Multistage genome-wide association meta-analyses identified two new loci for bone mineral density 
Human Molecular Genetics  2013;23(7):1923-1933.
Aiming to identify novel genetic variants and to confirm previously identified genetic variants associated with bone mineral density (BMD), we conducted a three-stage genome-wide association (GWA) meta-analysis in 27 061 study subjects. Stage 1 meta-analyzed seven GWA samples and 11 140 subjects for BMDs at the lumbar spine, hip and femoral neck, followed by a Stage 2 in silico replication of 33 SNPs in 9258 subjects, and by a Stage 3 de novo validation of three SNPs in 6663 subjects. Combining evidence from all the stages, we have identified two novel loci that have not been reported previously at the genome-wide significance (GWS; 5.0 × 10−8) level: 14q24.2 (rs227425, P-value 3.98 × 10−13, SMOC1) in the combined sample of males and females and 21q22.13 (rs170183, P-value 4.15 × 10−9, CLDN14) in the female-specific sample. The two newly identified SNPs were also significant in the GEnetic Factors for OSteoporosis consortium (GEFOS, n = 32 960) summary results. We have also independently confirmed 13 previously reported loci at the GWS level: 1p36.12 (ZBTB40), 1p31.3 (GPR177), 4p16.3 (FGFRL1), 4q22.1 (MEPE), 5q14.3 (MEF2C), 6q25.1 (C6orf97, ESR1), 7q21.3 (FLJ42280, SHFM1), 7q31.31 (FAM3C, WNT16), 8q24.12 (TNFRSF11B), 11p15.3 (SOX6), 11q13.4 (LRP5), 13q14.11 (AKAP11) and 16q24 (FOXL1). Gene expression analysis in osteogenic cells implied potential functional association of the two candidate genes (SMOC1 and CLDN14) in bone metabolism. Our findings independently confirm previously identified biological pathways underlying bone metabolism and contribute to the discovery of novel pathways, thus providing valuable insights into the intervention and treatment of osteoporosis.
doi:10.1093/hmg/ddt575
PMCID: PMC3943521  PMID: 24249740
25.  Understanding NHS hospital admissions in England: linkage of Hospital Episode Statistics to the Hertfordshire Cohort Study 
Age and ageing  2014;43(5):653-660.
Background
Concern over the sustainability of the National Health Service 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
2997 community-dwelling men and women aged 59-73 years completed a baseline HCS assessment between 1998 and 2004; HES and mortality data to 31/03/2010 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 8741 admissions; rates were 391 per 1000 person-years among men (95%CI 380, 402) and 327 among women (95%CI 316,338), p<0.0001 for gender difference. 1187 men (75%) and 981 women (69%) were admitted to hospital at least once; among these, median numbers of admissions were 3 in men (IQR 1,6) and 2 in women (IQR 1,5). 48% 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 National Health Service.
doi:10.1093/ageing/afu020
PMCID: PMC4151283  PMID: 24598084
hospital admissions; older people; hospital episode statistics; data linkage; healthcare burden

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