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1.  Placental Size Is Associated Differentially With Postnatal Bone Size and Density 
Journal of Bone and Mineral Research  2016;31(10):1855-1864.
ABSTRACT
We investigated relationships between placental size and offspring adolescent bone indices using a population‐based, mother–offspring cohort. The Avon Longitudinal Study of Parents and Children (ALSPAC) recruited pregnant women from the southwest of England between 1991 and 1993. There were 12,942 singleton babies born at term who survived at least the first 12 months. From these, 8933 placentas were preserved in formaldehyde, with maternal permission for their use in research studies. At the approximate age of 15.5 years, the children underwent a dual‐energy X‐ray absorptiometry (DXA) scan (measurements taken of the whole body minus head bone area [BA], bone mineral content [BMC], and areal bone mineral density [aBMD]). A peripheral quantitative computed tomography (pQCT) scan (Stratec XCT2000L; Stratec, Pforzheim, Germany) at the 50% tibial site was performed at this visit and at approximately age 17.7 years. In 2010 a sample of 1680 placentas were measured and photographed. To enable comparison of effect size across different variables, predictor and outcome variables were standardized to Z‐scores and therefore results may be interpreted as partial correlation coefficients. Complete placental, DXA, and pQCT data were available for 518 children at age 15.5 years. After adjustment for gender, gestational age at birth, and age at time of pQCT, the placental area was positively associated with endosteal circumference (β [95% CI]: 0.21 [0.13, 0.30], p < 0.001), periosteal circumference (β [95% CI]: 0.19 [0.10, 0.27], p < 0.001), and cortical area (β [95% CI]: 0.10 [0.01, 0.18], p = 0.03), and was negatively associated with cortical density (β [95% CI]: –0.11 [–0.20, –0.03], p = 0.01) at age 15.5 years. Similar relationships were observed for placental volume, and after adjustment for additional maternal and offspring covariates. These results suggest that previously observed associations between placental size and offspring bone development persist into older childhood, even during puberty, and that placental size is differentially related to bone size and volumetric density. © 2016 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).
doi:10.1002/jbmr.2840
PMCID: PMC5010780  PMID: 26999363
OSTEOPOROSIS; EPIDEMIOLOGY; PLACENTA; BONE MASS; DXA; pQCT; ASLPAC
2.  Maternal preeclampsia is associated with reduced adolescent off-spring hip bone mineral density in a UK population based birth cohort 
Introduction
A suboptimal intrauterine environment has been postulated to have adverse long-term health effects, including an increased risk of osteoporosis. Since preeclampsia (PE) and to a lesser extent gestational hypertension (GH) are associated with impaired placental function we postulated that these represent hitherto unrecognised risk factors for reduced bone mineral density (BMD) of the offspring.
Objective
To investigate if exposure to PE or GH in utero is associated with BMD of the offspring as measured in late adolescence.
Methods
Mother-offspring pairs from the UK population based cohort study ALSPAC were investigated (N=3088 with relevant data). Multivariable linear regression was used to examine associations between PE/GH and total body, spine and total hip BMD at age 17.
Results
Of the 3088 mother-offspring pairs, 2% (n=60) of the mothers fulfilled criteria for PE and 14% (n=416) for GH. In confounder-adjusted analyses (ie age of scan, gender, maternal factors, including BMI, offspring height, fat and lean mass), PE was negatively associated with BMD at the hip (-0.30SD (-0.50, -0.10)) (SD difference (95% confidence interval)). This association was not attenuated by further adjustment for gestational age and birthweight, which were hypothesized to be on the causal pathway. There was also weak evidence for a negative association between PE and total body BMD (-0.17SD (-0.36, 0.02)), whereas no relationship was evident at the spine (-0.11SD (-0.30, 0.09)). In contrast, a positive association of GH with offspring total body, hip and spine BMD attenuated to the null with adjustment for confounders, in particular confounding via the maternal and offspring adiposity/size and the link between the two.
Conclusion
Modest negative associations from exposure to PE, but not GH may represent a hitherto unrecognised risk factor for low BMD. Further exploration of the causal relationship of the in utero environment on subsequent offspring bone health is required.
doi:10.1002/jbmr.2506
PMCID: PMC4540657  PMID: 25761963
Gestational hypertension; DXA; ALSPAC
3.  The Impact of Small Spinal Curves in Adolescents Who Have Not Presented to Secondary Care 
Spine  2016;41(10):E611-E617.
Study Design.
A prospective, population-based, birth cohort study.
Objective.
The aim of this study was to identify whether there is any hidden burden of disease associated with smaller spinal curves.
Summary of Background Data.
Adolescent idiopathic scoliosis is present in 3% to 5% of the general population. Large curves are associated with increased pain and reduced quality of life. However, no information is available on the impact of smaller curves, many of which do not reach secondary care.
Methods.
The Avon Longitudinal Study of Parents and Children (ALSPAC) recruited over 14,000 pregnant women from the Bristol area of South-West England between 1991 and 1992 and has followed up their offspring regularly. At age 15, presence or absence of spinal curvature ≥6 degrees in the offspring was identified using the validated dual-energy X-ray absorptiometry Scoliosis Measure on 5299 participants. At age 18, a structured pain questionnaire was administered to 4083 participants. Logistic regression was used to investigate any association between presence of a spinal curve at age 15 and self-reported outcomes at age 18 years.
Results.
Full data were available for 3184 participants. Two hundred two (6.3%) had a spinal curve ≥6 degrees and 125 (3.9%) had a curve ≥10 degrees (median curve size of 11 degrees). About 46.3% reported aches and pains that lasted for a day or longer in the previous month. About 16.3% reported back pain. Those with spinal curves were 42% more likely to report back pain than those without (odds ratio 1.42, 95% confidence interval 1.00–2.02, P = 0.047). Those with spinal curves had more days off school and were more likely to avoid activities that caused their pain.
Conclusion.
Our results highlight that small scoliotic curves may be less benign than previously thought. Teenagers with small curves may not present to secondary care, but are nonetheless reporting increased pain, more days off school, and avoidance of activities. These data suggest that we should reconsider current scoliosis screening and treatment practices.
Level of Evidence: 2
doi:10.1097/BRS.0000000000001330
PMCID: PMC4959823  PMID: 26583476
ALSPAC; cohort; days of school; DSM; DXA; epidemiology; impact; pain; scoliosis; small curves
4.  Motor Competence in Early Childhood Is Positively Associated With Bone Strength in Late Adolescence 
Journal of Bone and Mineral Research  2016;31(5):1089-1098.
ABSTRACT
The onset of walking in early childhood results in exposure of the lower limb to substantial forces from weight bearing activity that ultimately contribute to adult bone strength. Relationships between gross motor score (GMS), at 18 months and bone outcomes measured at age 17 years were examined in 2327 participants in the Avon Longitudinal Study of Parents and Children (ALSPAC). Higher GMS indicated greater motor competence in weight‐bearing activities. Total hip bone mineral density (BMD) and hip cross‐sectional moment of inertia (CSMI) were assessed from dual‐energy X‐ray absorptiometry (DXA). Bone measures including cortical bone mineral content (BMC), periosteal circumference (PC), cortical thickness (CT), cortical bone area (CBA), cortical BMD (BMDC) and cross‐sectional moment of inertia (CSMI) were assessed by peripheral quantitative computed tomography (pQCT) at 50% distal‐proximal length. Before adjustment, GMS was associated with hip BMD, CSMI, and tibia BMC, PC, CT, CBA and CSMI (all p < 0.001) but not BMDC (p > 0.25). Strongest associations (standardized regression coefficients with 95% CI) were between GMS and hip BMD (0.086; 95% CI, 0.067 to 0.105) and tibia BMC (0.105; 95% CI, 0.089 to 0.121). With the exception of hip BMD, larger regression coefficients were observed in males (gender interactions all p < 0.05). Adjustment for lean mass resulted in substantial attenuation of regression coefficients, suggesting associations between impaired motor competence and subsequent bone development are partly mediated by alterations in body composition. In conclusion, impaired motor competence in childhood is associated with lower adolescent bone strength, and may represent a risk factor for subsequent osteoporosis. © 2015 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).
doi:10.1002/jbmr.2775
PMCID: PMC4864944  PMID: 26713753
ALSPAC; MOTOR CONTROL; BODY COMPOSITION; BONE MINERAL DENSITY
5.  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
6.  Characterization of Vertical Accelerations Experienced by Older People Attending an Aerobics Class Designed to Produce High Impacts 
The purpose of this study was to establish the feasibility of using an aerobics class to produce potentially bone protective vertical impacts of ≥ 4g in older adults and to determine whether impacts can be predicted by physical function. Participants recruited from older adult exercise classes completed an SF-12 questionnaire, short physical performance battery, and an aerobics class with seven different components, performed at low and high intensity. Maximum g and jerk values were identified for each activity. Forty-one participants (mean 69 years) were included. Mean maximal values approached or exceeded the 4g threshold for four of the seven exercises. In multivariate analyses, age (–0.53; –0.77, –0.28) (standardized beta coefficient; 95% CI) and 4-m walk time (–0.39; –0.63, –0.16) were inversely related to maximum g. Aerobics classes can be used to produce relatively high vertical accelerations in older individuals, although the outcome is strongly dependent on age and physical function.
doi:10.1123/japa.2016-0060
PMCID: PMC4857800  PMID: 26421605
accelerometry; exercise; older adults
7.  Mutations in Known Monogenic High Bone Mass Loci Only Explain a Small Proportion of High Bone Mass Cases 
ABSTRACT
High bone mass (HBM) can be an incidental clinical finding; however, monogenic HBM disorders (eg, LRP5 or SOST mutations) are rare. We aimed to determine to what extent HBM is explained by mutations in known HBM genes. A total of 258 unrelated HBM cases were identified from a review of 335,115 DXA scans from 13 UK centers. Cases were assessed clinically and underwent sequencing of known anabolic HBM loci: LRP5 (exons 2, 3, 4), LRP4 (exons 25, 26), SOST (exons 1, 2, and the van Buchem's disease [VBD] 52‐kb intronic deletion 3′). Family members were assessed for HBM segregation with identified variants. Three‐dimensional protein models were constructed for identified variants. Two novel missense LRP5 HBM mutations ([c.518C>T; p.Thr173Met], [c.796C>T; p.Arg266Cys]) were identified, plus three previously reported missense LRP5 mutations ([c.593A>G; p.Asn198Ser], [c.724G>A; p.Ala242Thr], [c.266A>G; p.Gln89Arg]), associated with HBM in 11 adults from seven families. Individuals with LRP5 HBM (∼prevalence 5/100,000) displayed a variable phenotype of skeletal dysplasia with increased trabecular BMD and cortical thickness on HRpQCT, and gynoid fat mass accumulation on DXA, compared with both non‐LRP5 HBM and controls. One mostly asymptomatic woman carried a novel heterozygous nonsense SOST mutation (c.530C>A; p.Ser177X) predicted to prematurely truncate sclerostin. Protein modeling suggests the severity of the LRP5‐HBM phenotype corresponds to the degree of protein disruption and the consequent effect on SOST‐LRP5 binding. We predict p.Asn198Ser and p.Ala242Thr directly disrupt SOST binding; both correspond to severe HBM phenotypes (BMD Z‐scores +3.1 to +12.2, inability to float). Less disruptive structural alterations predicted from p.Arg266Cys, p.Thr173Met, and p.Gln89Arg were associated with less severe phenotypes (Z‐scores +2.4 to +6.2, ability to float). In conclusion, although mutations in known HBM loci may be asymptomatic, they only account for a very small proportion (∼3%) of HBM individuals, suggesting the great majority are explained by either unknown monogenic causes or polygenic inheritance. © 2015 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).
doi:10.1002/jbmr.2706
PMCID: PMC4832273  PMID: 26348019
LRP5; SOST; ANABOLIC; SEQUENCING; PROTEIN MODELING
8.  Osteoarthritis and bone mineral density: are strong bones bad for joints? 
BoneKEy Reports  2015;4:624.
Osteoarthritis (OA) is a common and disabling joint disorder affecting millions of people worldwide. In OA, pathological changes are seen in all of the joint tissues including bone. Although both cross-sectional and longitudinal epidemiological studies have consistently demonstrated an association between higher bone mineral density (BMD) and OA, suggesting that increased BMD is a risk factor for OA, the mechanisms underlying this observation remain unclear. Recently, novel approaches to examining the BMD-OA relationship have included studying the disease in individuals with extreme high bone mass, and analyses searching for genetic variants associated with both BMD variation and OA, suggesting possible pleiotropic effects on bone mass and OA risk. These studies have yielded valuable insights into potentially relevant pathways that might one day be exploited therapeutically. Although animal models have suggested that drugs reducing bone turnover (antiresorptives) may retard OA progression, it remains to be seen whether this approach will prove to be useful in human OA. Identifying individuals with a phenotype of OA predominantly driven by increased bone formation could help improve the overall response to these treatments. This review aims to summarise current knowledge regarding the complex relationship between BMD and OA.
doi:10.1038/bonekey.2014.119
PMCID: PMC4303262  PMID: 25628884
9.  Maternal Preeclampsia Is Associated With Reduced Adolescent Offspring Hip BMD in a UK Population‐Based Birth Cohort 
Journal of Bone and Mineral Research  2015;30(9):1684-1691.
ABSTRACT
A suboptimal intrauterine environment has been postulated to have adverse long‐term health effects, including an increased risk of osteoporosis. Because preeclampsia (PE) and to a lesser extent gestational hypertension (GH) are associated with impaired placental function, we postulated that these represent hitherto unrecognized risk factors for reduced bone mineral density (BMD) of the offspring. The objective of this study was to investigate if exposure to PE or GH in utero is associated with BMD of the offspring as measured in late adolescence. Mother‐offspring pairs from the UK population‐based cohort study, Avon Longitudinal Study of Parents and Children (ALSPAC), were investigated (n = 3088 with relevant data). Multivariable linear regression was used to examine associations between PE/GH and total body, spine, and total hip BMD at age 17 years. Of the 3088 mother‐offspring pairs, 2% (n = 60) of the mothers fulfilled criteria for PE and 14% (n = 416) for GH. In confounder‐adjusted analyses (ie, age of scan, gender, maternal factors, including BMI, offspring height, fat mass, and lean mass), PE was negatively associated with BMD at the hip (SD difference –0.30; 95%CI, –0.50 to –0.10). This association was not attenuated by further adjustment for gestational age and birth weight, which were hypothesized to be on the causal pathway. There was also weak evidence for a negative association between PE and total body BMD (SD difference –0.17; 95% CI, –0.36 to 0.02), whereas no relationship was evident at the spine (SD difference –0.11; 95% CI, –0.30 to 0.09). In contrast, a positive association of GH with offspring total body, hip, and spine BMD attenuated to the null with adjustment for confounders, in particular confounding via the maternal and offspring adiposity/size and the link between the two. Modest negative associations from exposure to PE, but not GH may represent a hitherto unrecognized risk factor for low BMD. Further exploration of the causal relationship of the in utero environment on subsequent offspring bone health is required. © 2015 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.
doi:10.1002/jbmr.2506
PMCID: PMC4540657  PMID: 25761963
GESTATIONAL HYPERTENSION; DXA; ALSPAC
10.  Urban-Rural Differences in Bone Mineral Density: A Cross Sectional Analysis Based on the Hyderabad Indian Migration Study 
PLoS ONE  2015;10(10):e0140787.
Background
Fracture risk is rising in countries undergoing rapid rural to urban migration, but whether this reflects an adverse effect of urbanization on intrinsic bone strength, as reflected by bone mineral density (BMD), is currently unknown.
Methods
Lumbar spine (LS) and total hip (TH) BMD, and total body fat and lean mass, were obtained from DXA scans performed in the Hyderabad arm of the Indian Migration Study (54% male, mean age 49 years). Sib-pair comparisons were performed between rural-urban migrants (RUM) and rural non-migrated (RNM) siblings (N = 185 sib-pairs).
Results
In analyses adjusted for height, gender, age and occupation, rural to urban migration was associated with higher lumbar and hip BMD and greater predicted hip strength; ΔLS BMD 0.030 (0.005, 0.055) g/cm2, ΔTH BMD 0.044 (0.024; 0.064) g/cm2, Δcross-sectional moment of inertia 0.162 (0.036, 0.289) cm4. These differences were largely attenuated after adjusting for body composition, insulin levels and current lifestyle factors ie. years of smoking, alcohol consumption and moderate to vigorous physical activity. Further analyses suggested that differences in lean mass, and to a lesser extent fat mass, largely explained the BMD differences which we observed.
Conclusions
Rural to urban migration as an adult is associated with higher BMD and greater predicted hip strength, reflecting associated alterations in body composition. It remains to be seen how differences in BMD between migration groups will translate into fracture risk in becoming years.
doi:10.1371/journal.pone.0140787
PMCID: PMC4618924  PMID: 26484878
11.  Does Bone Resorption Stimulate Periosteal Expansion? A Cross‐Sectional Analysis of β‐C‐telopeptides of Type I Collagen (CTX), Genetic Markers of the RANKL Pathway, and Periosteal Circumference as Measured by pQCT 
Journal of Bone and Mineral Research  2014;29(4):1015-1024.
ABSTRACT
We hypothesized that bone resorption acts to increase bone strength through stimulation of periosteal expansion. Hence, we examined whether bone resorption, as reflected by serum β‐C‐telopeptides of type I collagen (CTX), is positively associated with periosteal circumference (PC), in contrast to inverse associations with parameters related to bone remodeling such as cortical bone mineral density (BMDC). CTX and mid‐tibial peripheral quantitative computed tomography (pQCT) scans were available in 1130 adolescents (mean age 15.5 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC). Analyses were adjusted for age, gender, time of sampling, tanner stage, lean mass, fat mass, and height. CTX was positively related to PC (β = 0.19 [0.13, 0.24]) (coefficient = SD change per SD increase in CTX, 95% confidence interval)] but inversely associated with BMDC (β = –0.46 [–0.52,–0.40]) and cortical thickness [β = –0.11 (–0.18, –0.03)]. CTX was positively related to bone strength as reflected by the strength‐strain index (SSI) (β = 0.09 [0.03, 0.14]). To examine the causal nature of this relationship, we then analyzed whether single‐nucleotide polymorphisms (SNPs) within key osteoclast regulatory genes, known to reduce areal/cortical BMD, conversely increase PC. Fifteen such genetic variants within or proximal to genes encoding receptor activator of NF‐κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) were identified by literature search. Six of the 15 alleles that were inversely related to BMD were positively related to CTX (p < 0.05 cut‐off) (n = 2379). Subsequently, we performed a meta‐analysis of associations between these SNPs and PC in ALSPAC (n = 3382), Gothenburg Osteoporosis and Obesity Determinants (GOOD) (n = 938), and the Young Finns Study (YFS) (n = 1558). Five of the 15 alleles that were inversely related to BMD were positively related to PC (p < 0.05 cut‐off). We conclude that despite having lower BMD, individuals with a genetic predisposition to higher bone resorption have greater bone size, suggesting that higher bone resorption is permissive for greater periosteal expansion. © 2014 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
doi:10.1002/jbmr.2093
PMCID: PMC4138988  PMID: 24014423
CTX; BONE RESORPTION; PERIOSTEAL EXPANSION; pQCT
12.  Birth weight is positively related to bone size in adolescents but inversely related to cortical bone mineral density: Findings from a large prospective cohort study 
Bone  2014;65(100):77-82.
To examine the influence of intrauterine environment on subsequent bone development, we investigated the relationship between birth weight and cortical bone parameters, and the role of puberty, bone resorption and insulin as possible mediators. Bone outcomes were obtained from mid-tibial pQCT scans performed at age 15.5 years in 1960 males and 2192 females from the ALSPAC birth cohort. Birth weight was positively related to periosteal circumference (PC) [beta = 0.40 (0.34, 0.46)], which was largely but not completely attenuated after adjustment for height and weight [beta = 0.07 (0.02, 0.12)] (SD change in outcome per 1 kg increase in birth weight with 95% CI). Based on our height and weight adjusted model, the association was stronger in females compared to males (P = 0.02 for gender interaction), and persisted in 2842 participants with equivalent results at age 17.7 years. Conversely, birth weight was inversely related to cortical bone mineral density (BMDC) at age 15.5 years after adjusting for height and weight [beta = − 0.18 (− 0.23, − 0.13)], with a stronger association in males compared to females (P = 0.01 for gender interaction), but an equivalent association was not seen at 17.7 years. In further analyses performed on data from age 15.5 years, the association between birth weight and PC was unaffected by adjustment for puberty (Tanner stage at age 13.5 years), bone resorption (fasting beta-carboxyterminal cross linking telopeptide (βCTX) at age 15.5 years) or insulin (fasting insulin at age 15.5 years). In contrast, the association with BMDC was attenuated by approximately 30% after adjustment for puberty or bone resorption, and by 50% after adjustment for both factors combined. We conclude that the inverse relationship between birth weight and BMDC is in part mediated by effects of puberty and bone resorption, which may help to explain the transitory nature of this association, in contrast to the more persisting relationship with PC.
Highlights
•Birth weight (BW) was positively related to periosteal circumference (PC) at age 15, even after height and weight adjustment.•The association of BW with PC was stronger in females, and was also seen at age 17.7 years.•BW was inversely related to cortical bone mineral density (BMDC) at age 15.5 years after height and weight adjustment.•The inverse association of BW with BMDC was stronger in males, but there was no association at 17.7 years.•The association of BW with BMDC was attenuated by approximately 50% after adjustment for puberty and bone resorption.
doi:10.1016/j.bone.2014.05.008
PMCID: PMC4073227  PMID: 24840816
pQCT; Periosteal circumference; Tibia; Puberty; Bone resorption
13.  Life-course determinants of bone mass in young adults from a transitional rural community in India: the Andhra Pradesh Children and Parents Study (APCAPS)123 
Background: Undernutrition and physical inactivity are both associated with lower bone mass.
Objective: This study aimed to investigate the combined effects of early-life undernutrition and urbanized lifestyles in later life on bone mass accrual in young adults from a rural community in India that is undergoing rapid socioeconomic development.
Design: This was a prospective cohort study of participants of the Hyderabad Nutrition Trial (1987–1990), which offered balanced protein-calorie supplementation to pregnant women and preschool children younger than 6 y in the intervention villages. The 2009–2010 follow-up study collected data on current anthropometric measures, bone mineral density (BMD) measured by dual-energy X-ray absorptiometry, blood samples, diet, physical activity, and living standards of the trial participants (n = 1446, aged 18–23 y).
Results: Participants were generally lean and had low BMD [mean hip BMD: 0.83 (women), 0.95 (men) g/cm2; lumbar spine: 0.86 (women), 0.93 (men) g/cm2]. In models adjusted for current risk factors, no strong evidence of a positive association was found between BMD and early-life supplementation. On the other hand, current lean mass and weight-bearing physical activity were positively associated with BMD. No strong evidence of an association was found between BMD and current serum 25-hydroxyvitamin D or dietary intake of calcium, protein, or calories.
Conclusions: Current lean mass and weight-bearing physical activity were more important determinants of bone mass than was early-life undernutrition in this population. In transitional rural communities from low-income countries, promotion of physical activity may help to mitigate any potential adverse effects of early nutritional disadvantage.
doi:10.3945/ajcn.113.068791
PMCID: PMC4021785  PMID: 24695898
14.  META-ANALYSIS OF GENOME-WIDE STUDIES IDENTIFIES WNT16 AND ESR1 SNPS ASSOCIATED WITH BONE MINERAL DENSITY IN PREMENOPAUSAL WOMEN 
Previous genome-wide association studies (GWAS) have identified common variants in genes associated with variation in bone mineral density (BMD), although most have been carried out in combined samples of older women and men. Meta-analyses of these results have identified numerous SNPs of modest effect at genome-wide significance levels in genes involved in both bone formation and resorption, as well as other pathways. We performed a meta-analysis restricted to premenopausal white women from four cohorts (n= 4,061 women, ages 20 to 45) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. Following imputation, age- and weight-adjusted BMD values were tested for association with each SNP. Association of a SNP in the WNT16 gene (rs3801387; p=1.7 × 10−9) and multiple SNPs in the ESR1/C6orf97 (rs4870044; p=1.3 × 10−8) achieved genome-wide significance levels for lumbar spine BMD. These SNPs, along with others demonstrating suggestive evidence of association, were then tested for association in seven Replication cohorts that included premenopausal women of European, Hispanic-American, and African-American descent (combined n=5,597 for femoral neck; 4,744 for lumbar spine). When the data from the Discovery and Replication cohorts were analyzed jointly, the evidence was more significant (WNT16 joint p=1.3 × 10−11; ESR1/C6orf97 joint p= 1.4 × 10−10). Multiple independent association signals were observed with spine BMD at the ESR1 region after conditioning on the primary signal. Analyses of femoral neck BMD also supported association with SNPs in WNT16 and ESR1/C6orf97 (p< 1 × 10−5). Our results confirm that several of the genes contributing to BMD variation across a broad age range in both sexes have effects of similar magnitude on BMD of the spine in premenopausal women. These data support the hypothesis that variants in these genes of known skeletal function also affect BMD during the premenopausal period.
doi:10.1002/jbmr.1796
PMCID: PMC3691010  PMID: 23074152
Bone mineral density; GWAS; premenopausal; meta-analysis; genetics
15.  Jump Power and Force Have Distinct Associations With Cortical Bone Parameters: Findings From a Population Enriched by Individuals With High Bone Mass 
Context:
Little is known of the relationships between muscle function and bone, based on the recently developed technique of jumping mechanography.
Objective:
Our objective was to determine associations between peak ground reaction force and peak power during a 1-legged hopping test and a single 2-legged jump, respectively, and cortical bone parameters.
Design and Setting:
This was a cross-sectional observational study in participants from the high bone mass cohort.
Participants:
Participants included 70 males (mean age 58 years) and 119 females (mean age 56 years); high bone mass cases and controls were pooled.
Main Outcome Measures:
Total hip bone mineral density (BMD) (measured by dual-energy x-ray absorptiometry scanning) and mid-tibial peripheral quantitative computed tomography (Stratec XCT2000L).
Results:
Jump power was positively related to hip BMD (standardized β [95% confidence interval] = 0.29 [0.07, 0.51], P = .01), but hopping force was not (0.03 [−0.16, 0.22], P = .74) (linear regression analysis adjusted for age, gender, height, and weight). In 113 participants with force and peripheral quantitative computed tomography data, both jump power and hopping force were positively associated with tibial strength strain index (0.26 [0.09, 0.44], P < .01; and 0.24 [0.07, 0.42], P = .01 respectively). Although hopping force was positively associated with bone size (total bone area 0.22 [0.03, 0.42], P = .02), jump power was not (0.10 [−0.10, 0.30], P = .33). In contrast, jump power was inversely associated with endocortical circumference adjusted for periosteal circumference (−0.24 [−0.40, −0.08], P < .01) whereas no association was seen for hopping force (−0.10 [−0.26, 0.07], P = .24).
Conclusions:
Although power and force are both positively associated with cortical bone strength, distinct mechanisms appear to be involved because power was primarily associated with reduced endocortical expansion (reflected by endocortical circumference adjusted for periosteal circumference, and hip BMD), whereas force was associated with increased periosteal expansion (reflected by total bone area).
doi:10.1210/jc.2013-2837
PMCID: PMC3952022  PMID: 24203064
16.  Genome-wide association study of primary tooth eruption identifies pleiotropic loci associated with height and craniofacial distances 
Human Molecular Genetics  2013;22(18):3807-3817.
Twin and family studies indicate that the timing of primary tooth eruption is highly heritable, with estimates typically exceeding 80%. To identify variants involved in primary tooth eruption, we performed a population-based genome-wide association study of ‘age at first tooth’ and ‘number of teeth’ using 5998 and 6609 individuals, respectively, from the Avon Longitudinal Study of Parents and Children (ALSPAC) and 5403 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966). We tested 2 446 724 SNPs imputed in both studies. Analyses were controlled for the effect of gestational age, sex and age of measurement. Results from the two studies were combined using fixed effects inverse variance meta-analysis. We identified a total of 15 independent loci, with 10 loci reaching genome-wide significance (P < 5 × 10−8) for ‘age at first tooth’ and 11 loci for ‘number of teeth’. Together, these associations explain 6.06% of the variation in ‘age of first tooth’ and 4.76% of the variation in ‘number of teeth’. The identified loci included eight previously unidentified loci, some containing genes known to play a role in tooth and other developmental pathways, including an SNP in the protein-coding region of BMP4 (rs17563, P = 9.080 × 10−17). Three of these loci, containing the genes HMGA2, AJUBA and ADK, also showed evidence of association with craniofacial distances, particularly those indexing facial width. Our results suggest that the genome-wide association approach is a powerful strategy for detecting variants involved in tooth eruption, and potentially craniofacial growth and more generally organ development.
doi:10.1093/hmg/ddt231
PMCID: PMC3749866  PMID: 23704328
17.  Analysis of Body Composition in Individuals With High Bone Mass Reveals a Marked Increase in Fat Mass in Women But Not Men 
Context
High bone mass (HBM), detected in 0.2% of dual-energy x-ray absorptiometry (DXA) scans, is characterized by raised body mass index, the basis for which is unclear.
Objective
To investigate why body mass index is elevated in individuals with HBM, we characterized body composition and examined whether differences could be explained by bone phenotypes, eg, bone mass and/or bone turnover.
Design, Setting, and Participants
We conducted a case-control study of 153 cases with unexplained HBM recruited from 4 UK centers by screening 219 088 DXA scans. A total of 138 first-degree relatives (of whom 51 had HBM) and 39 spouses were also recruited. Unaffected individuals served as controls.
Main Outcome Measures
We measured fat mass, by DXA, and bone turnover markers.
Results
Among women, fat mass was inversely related to age in controls (P=.01), but not in HBM cases (P=.96) in whom mean fat mass was 8.9 [95% CI 4.7, 13.0] kg higher compared with controls (fully adjusted mean difference, P<.001). Increased fat mass in male HBM cases was less marked (gender interaction P=.03). Compared with controls, lean mass was also increased in female HBM cases (by 3.3 [1.2,5.4] kg; P<.002); however, lean mass increases were less marked than fat mass increases, resulting in 4.5% lower percentage lean mass in HBM cases (P<.001). Osteocalcin was also lower in female HBM cases compared with controls (by 2.8 [0.1, 5.5] μg/L; P=.04). Differences in fat mass were fully attenuated after hip bone mineral density (BMD) adjustment (P = .52) but unchanged after adjustment for bone turnover (P < .001), whereas the greater hip BMD in female HBM cases was minimally attenuated by fat mass adjustment (P<.001).
Conclusions
HBM is characterized by a marked increase in fat mass in females, statistically explained by their greater BMD, but not by markers of bone turnover.
doi:10.1210/jc.2012-3342
PMCID: PMC3589712  PMID: 23337721
18.  Genetic Determinants of Trabecular and Cortical Volumetric Bone Mineral Densities and Bone Microstructure 
PLoS Genetics  2013;9(2):e1003247.
Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n = 5,878) followed by replication (n = 1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p = 3.6×10−14; LOC285735, rs271170, p = 2.7×10−12; OPG, rs7839059, p = 1.2×10−10; and ESR1/C6orf97, rs6909279, p = 1.1×10−9). The trabecular vBMD GWA meta-analysis (n = 2,500) followed by replication (n = 1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p = 1.9×10−9). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n = 729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60–0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk.
Author Summary
Osteoporosis is a common highly heritable skeletal disease characterized by reduced bone mineral density (BMD) and deteriorated bone microstructure, resulting in an increased risk of fracture. Most previous genetic epidemiology studies have focused on the genetics of the complex trait BMD, not being able to separate genetic determinants of the trabecular and cortical bone compartments and bone microstructure. The trabecular and cortical BMDs can be analysed separately by computed tomography. Therefore, we performed separate genome-wide association studies for trabecular and cortical BMDs, demonstrating that the genetic determinants of cortical and trabecular BMDs differ. Genetic variants in the RANKL, LOC285735, OPG, and ESR1 loci were associated with cortical BMD, while a genetic variant in the FMN2/GREM2 locus was associated with trabecular BMD. Two of these are novel bone-related loci. Follow-up analyses of bone microstructure demonstrated that a genetic variant in the RANKL locus is associated with cortical porosity and that the FMN2/GREM2 locus is associated with trabecular number and thickness. We propose that a genetic variant in the RANKL locus influences cortical BMD via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences trabecular BMD and fracture risk via effects on both trabecular number and thickness.
doi:10.1371/journal.pgen.1003247
PMCID: PMC3578773  PMID: 23437003
19.  High bone mass is associated with an increased prevalence of joint replacement: a case–control study 
Rheumatology (Oxford, England)  2013;52(6):1042-1051.
Objective. Epidemiological studies have shown an association between OA and increased BMD. To explore the nature of this relationship, we examined whether the risk of OA is increased in individuals with high bone mass (HBM), in whom BMD is assumed to be elevated due to a primary genetic cause.
Methods. A total of 335 115 DXA scans were screened to identify HBM index cases (defined by DXA scan as an L1 Z-score of ≥+3.2 and total hip Z-score ≥+1.2, or total hip Z-score ≥+3.2 and L1 Z-score ≥+1.2). In relatives, the definition of HBM was L1 Z-score plus total hip Z-score ≥+3.2. Controls comprised unaffected relatives and spouses. Clinical indicators of OA were determined by structured assessment. Analyses used logistic regression adjusting for age, gender, BMI and social deprivation.
Results. A total of 353 HBM cases (mean age 61.7 years, 77% female) and 197 controls (mean age 54.1 years, 47% female) were included. Adjusted NSAID use was more prevalent in HBM cases versus controls [odds ratio (OR) 2.17 (95% CI 1.10, 4.28); P = 0.03]. The prevalence of joint replacement was higher in HBM cases (13.0%) than controls (4.1%), with an adjusted OR of 2.42 (95% CI 1.06, 5.56); P = 0.04. Adjusted prevalence of joint pain and knee crepitus did not differ between cases and controls.
Conclusion. HBM is associated with increased prevalence of joint replacement surgery and NSAID use compared with unaffected controls.
doi:10.1093/rheumatology/kes411
PMCID: PMC3651613  PMID: 23362220
osteoarthritis; high bone mass; bone mineral density; DXA; joint replacement
20.  Analysis of Body Composition in Individuals With High Bone Mass Reveals a Marked Increase in Fat Mass in Women But Not Men 
Context:
High bone mass (HBM), detected in 0.2% of dual-energy x-ray absorptiometry (DXA) scans, is characterized by raised body mass index, the basis for which is unclear.
Objective:
To investigate why body mass index is elevated in individuals with HBM, we characterized body composition and examined whether differences could be explained by bone phenotypes, eg, bone mass and/or bone turnover.
Design, Setting, and Participants:
We conducted a case-control study of 153 cases with unexplained HBM recruited from 4 UK centers by screening 219 088 DXA scans. A total of 138 first-degree relatives (of whom 51 had HBM) and 39 spouses were also recruited. Unaffected individuals served as controls.
Main Outcome Measures:
We measured fat mass, by DXA, and bone turnover markers.
Results:
Among women, fat mass was inversely related to age in controls (P = .01), but not in HBM cases (P = .96) in whom mean fat mass was 8.9 [95% CI 4.7, 13.0] kg higher compared with controls (fully adjusted mean difference, P < .001). Increased fat mass in male HBM cases was less marked (gender interaction P = .03). Compared with controls, lean mass was also increased in female HBM cases (by 3.3 [1.2, 5.4] kg; P < .002); however, lean mass increases were less marked than fat mass increases, resulting in 4.5% lower percentage lean mass in HBM cases (P < .001). Osteocalcin was also lower in female HBM cases compared with controls (by 2.8 [0.1, 5.5] μg/L; P = .04). Differences in fat mass were fully attenuated after hip bone mineral density (BMD) adjustment (P = .52) but unchanged after adjustment for bone turnover (P < .001), whereas the greater hip BMD in female HBM cases was minimally attenuated by fat mass adjustment (P < .001).
Conclusions:
HBM is characterized by a marked increase in fat mass in females, statistically explained by their greater BMD, but not by markers of bone turnover.
doi:10.1210/jc.2012-3342
PMCID: PMC3589712  PMID: 23337721
21.  The high bone mass phenotype is characterised by a combined cortical and trabecular bone phenotype: Findings from a pQCT case–control study☆ 
Bone  2013;52(1):380-388.
High bone mass (HBM), detected in 0.2% of DXA scans, is characterised by a mild skeletal dysplasia largely unexplained by known genetic mutations. We conducted the first systematic assessment of the skeletal phenotype in unexplained HBM using pQCT in our unique HBM population identified from screening routine UK NHS DXA scans.
pQCT measurements from the mid and distal tibia and radius in 98 HBM cases were compared with (i) 65 family controls (constituting unaffected relatives and spouses), and (ii) 692 general population controls.
HBM cases had substantially greater trabecular density at the distal tibia (340 [320, 359] mg/cm3), compared to both family (294 [276, 312]) and population controls (290 [281, 299]) (p < 0.001 for both, adjusted for age, gender, weight, height, alcohol, smoking, malignancy, menopause, steroid and estrogen replacement use). Similar results were obtained at the distal radius. Greater cortical bone mineral density (cBMD) was observed in HBM cases, both at the midtibia and radius (adjusted p < 0.001). Total bone area (TBA) was higher in HBM cases, at the distal and mid tibia and radius (adjusted p < 0.05 versus family controls), suggesting greater periosteal apposition. Cortical thickness was increased at the mid tibia and radius (adjusted p < 0.001), implying reduced endosteal expansion. Together, these changes resulted in greater predicted cortical strength (strength strain index [SSI]) in both tibia and radius (p < 0.001). We then examined relationships with age; tibial cBMD remained constant with increasing age amongst HBM cases (adjusted β − 0.01 [− 0.02, 0.01], p = 0.41), but declined in family controls (− 0.05 [− 0.03, − 0.07], p < 0.001) interaction p = 0.002; age-related changes in tibial trabecular BMD, CBA and SSI were also divergent. In contrast, at the radius HBM cases and controls showed parallel age-related declines in cBMD and trabecular BMD.
HBM is characterised by increased trabecular BMD and by alterations in cortical bone density and structure, leading to substantial increments in predicted cortical bone strength. In contrast to the radius, neither trabecular nor cortical BMD declined with age in the tibia of HBM cases, suggesting attenuation of age-related bone loss in weight-bearing limbs contributes to the observed bone phenotype.
Highlights
► High Bone Mass (HBM) is characterised by increased bone size, cortical BMD, cortical thickness and increased strength strain index. ► In HBM, trabecular density is also increased at both the distal radius and tibia. ► Tibial cortical and trabecular BMD decline with age in controls, but not in HBM implying attenuation of age-related loss. ► Similar differences in age-related bone loss are not seen at the radius, suggesting a possible interaction with weight-bearing.
doi:10.1016/j.bone.2012.10.021
PMCID: PMC3526774  PMID: 23103330
HBM, high bone mass; NHS, National Health Service; pQCT, peripheral quantitative computed tomography; OA, osteoarthritis; L1, 1st lumbar vertebra; cBMD, cortical bone mineral density; tBMD, trabecular bone mineral density; TBA, total bone area; CBA, cortical bone area; SSI, strength strain index; SD, standard deviation; PVE, partial volume effect; High bone mass; pQCT; Cortical; Trabecular; Age; BMD
22.  WNT16 Influences Bone Mineral Density, Cortical Bone Thickness, Bone Strength, and Osteoporotic Fracture Risk 
PLoS Genetics  2012;8(7):e1002745.
We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ∼2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of −0.11 standard deviations [SD] per C allele, P = 6.2×10−9). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (−0.14 SD per C allele, P = 2.3×10−12, and −0.16 SD per G allele, P = 1.2×10−15, respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3×10−9), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9×10−6 and rs2707466: OR = 1.22, P = 7.2×10−6). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16−/− mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%–61% (6.5×10−13
Author Summary
Bone traits are highly dependent on genetic factors. To date, numerous genetic loci for bone mineral density (BMD) and only one locus for osteoporotic fracture have been previously identified to be genome-wide significant. Cortical bone has been reported to be an important determinant of bone strength; so far, no genome-wide association studies (GWAS) have been performed for cortical bone thickness (CBT) of the tibial and radial diaphysis or BMD at forearm, a skeletal site rich in cortical bone. Therefore, we performed two separated meta-analyses of GWAS for cortical thickness of the tibia in 3 independent cohorts of 5,878 men and women, and for forearm BMD in 5 cohorts of 5,672 individuals. We identified the 7q31 locus, which contains WNT16, to be associated with CBT and BMD. Four SNPs from this locus were then tested in 2,023 osteoporotic fracture cases and 3,740 controls. One of these SNPs was genome-wide significant, and two were genome-wide suggestive, for forearm fracture. Generating a mouse with targeted disruption of Wnt16, we also demonstrated that mice lacking this protein had substantially thinner bone cortices and reduced bone strength than their wild-type littermates. These findings highlight WNT16 as a clinically relevant member of the Wnt signaling pathway and increase our understanding of the etiology of osteoporosis-related phenotypes and fracture.
doi:10.1371/journal.pgen.1002745
PMCID: PMC3390364  PMID: 22792071
Background Objective measures of physical activity calibrated against energy expenditure may have limited utility in studying relationships with musculoskeletal phenotypes. We wished to assess an alternative approach using an accelerometer calibrated according to impact loading.
Methods Of the 17-year olds from the Avon Longitudinal Study of Parents and Children (ALSPAC), 732 wore Newtest accelerometers while performing day-to-day activities for a mean of 5.8 days. Outputs were categorized as light, moderate, high and very high impact, based on the thresholds identified in 22 adolescents during graded activities. In subsequent regression analyses, activity data and fat mass were normalized by log transformation.
Results The number of counts relating to high impact activity was ∼2% that of light impact activity, and 33% greater in boys when compared with girls. High impact activity was more strongly related to lean mass [light: 0.033 (95% CI −0.023 to 0.089), moderate: 0.035 (95% CI −0.010 to 0.080) and high: 0.044 (95% CI 0.010 to 0.078)] (β = SD change in outcome per doubling in activity, height adjusted, boys and girls combined). In contrast, lower impact activity was more strongly related to fat mass [light: −0.069 (95% CI −0.127 to −0.011), moderate: −0.060 (95% CI −0.107 to −0.014) and high: −0.033 (95% CI −0.069 to 0.003)]. In a more fully adjusted model including other activity types and fat/lean mass, lean mass was related to only high activity (boys and girls combined), whereas fat mass was related to only moderate activity (girls only).
Conclusions Using an accelerometer calibrated according to impact loading revealed that high impact activity is related to lean but not fat mass.
doi:10.1093/ije/dys073
PMCID: PMC3429873  PMID: 22576953
Accelerometer; fat mass; lean mass; ALSPAC; impact loading
PLoS ONE  2012;7(3):e31821.
Background
Epigenetic markings acquired in early life may have phenotypic consequences later in development through their role in transcriptional regulation with relevance to the developmental origins of diseases including obesity. The goal of this study was to investigate whether DNA methylation levels at birth are associated with body size later in childhood.
Principal Findings
A study design involving two birth cohorts was used to conduct transcription profiling followed by DNA methylation analysis in peripheral blood. Gene expression analysis was undertaken in 24 individuals whose biological samples and clinical data were collected at a mean ± standard deviation (SD) age of 12.35 (0.95) years, the upper and lower tertiles of body mass index (BMI) were compared with a mean (SD) BMI difference of 9.86 (2.37) kg/m2. This generated a panel of differentially expressed genes for DNA methylation analysis which was then undertaken in cord blood DNA in 178 individuals with body composition data prospectively collected at a mean (SD) age of 9.83 (0.23) years. Twenty-nine differentially expressed genes (>1.2-fold and p<10−4) were analysed to determine DNA methylation levels at 1–3 sites per gene. Five genes were unmethylated and DNA methylation in the remaining 24 genes was analysed using linear regression with bootstrapping. Methylation in 9 of the 24 (37.5%) genes studied was associated with at least one index of body composition (BMI, fat mass, lean mass, height) at age 9 years, although only one of these associations remained after correction for multiple testing (ALPL with height, pCorrected = 0.017).
Conclusions
DNA methylation patterns in cord blood show some association with altered gene expression, body size and composition in childhood. The observed relationship is correlative and despite suggestion of a mechanistic epigenetic link between in utero life and later phenotype, further investigation is required to establish causality.
doi:10.1371/journal.pone.0031821
PMCID: PMC3303769  PMID: 22431966
Age and Ageing  2011;41(1):46-52.
Background: identification of individuals with high fracture risk from within primary care is complex. It is likely that the true contribution of falls to fracture risk is underestimated.
Methods: cross-sectional analysis of a population-based cohort of 3,200 post-menopausal women aged 73 ± 4 years. Self-reported data were collected on fracture, osteoporosis clinical risk factors and falls/mobility risk factors. Self-reported falls were compared with recorded falls on GP computerised records. Multivariable logistic regression was used to identify independent risk factors for fracture.
Results: a total of 838 (26.2%) reported a fracture after aged 50; 441 reported falling more than once per year, but 69% of these had no mention of falls on their computerised GP records. Only age [odds ratios (OR): 1.37 per 5 year increase, 95% confidence interval (CI): 1.23–1.53], height (1.02 per cm increase, 95% CI: 1.01–1.04), weight (OR: 0.99 per kg increase, 95% CI: 0.98–0.99) and falls (OR: 1.49 for more than once per year compared with less, 95% CI: 1.13–1.94) were independent risk factors for fracture. Falls had the strongest association.
Conclusion: when identifying individuals with high fracture risk we estimate that more than one fall per year is at least twice as important as height and weight. Furthermore, using self-reported falls data is essential as computerised GP records underestimate falls prevalence.
doi:10.1093/ageing/afr132
PMCID: PMC3234077  PMID: 22107913
fractures; falls; COSHIBA; FRAX; cohort study; elderly

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