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1.  Jump Power and Force Have Distinct Associations With Cortical Bone Parameters: Findings From a Population Enriched by Individuals With High Bone Mass 
Little is known of the relationships between muscle function and bone, based on the recently developed technique of jumping mechanography.
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 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).
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).
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).
PMCID: PMC3952022  PMID: 24203064
2.  Bone Fragility Contributes to the Risk of Fracture in Children, Even After Moderate and Severe Trauma 
We prospectively examined whether the relationship between skeletal fragility and fracture risk in children 9.9 ± 0.3 (SD) yr is affected by trauma level. Bone size relative to body size and humeral vBMD showed similar inverse relationships with fracture risk, irrespective of whether fractures followed slight or moderate/severe trauma.
Fracture risk in childhood is related to underlying skeletal fragility. However, whether this relationship is confined to low-trauma fractures or whether skeletal fragility also contributes to the risk of fracture caused by higher levels of trauma is currently unknown.
Materials and Methods
Total body DXA scan results obtained at 9.9 yr of age were linked to reported fractures over the following 2 yr in children from the Avon Longitudinal Study of Parents and Children. DXA scan results that were subsequently derived included total body less head (TBLH) bone size relative to body size (calculated from TBLH area adjusted for height and weight) and humeral volumetric BMD (vBMD; derived from subregional analysis at this site). Trauma level was assigned using the Landin classification based on a questionnaire asking about precipitating causes.
Of the 6204 children with available data, 549 (8.9%) reported at least one fracture over the follow-up period, and trauma level was assigned in 280 as follows: slight trauma, 56.1%; moderate trauma, 41.0%; severe trauma, 2.9%. Compared with children without fractures, after adjustment for age, sex, socioeconomic status, and ethnicity, children with fractures from both slight and moderate/severe trauma had a reduced bone size relative to body size (1133 cm2 in nonfractured children versus 1112 cm2 for slight trauma fractures, p < 0.001; 1112 cm2 for moderate/severe trauma fractures, p = 0.001) and reduced humeral vBMD (0.494 g/cm3 in nonfractured children versus 0.484 g/cm3 for slight trauma fractures, p = 0.036; and 0.482g/cm3 for moderate/severe trauma fractures, p = 0.016).
Skeletal fragility contributes to fracture risk in children, not only in fractures caused by slight trauma but also in those that result from moderate or severe trauma.
PMCID: PMC2742712  PMID: 17922615
fractures; children; trauma levels; epidemiology; BMD; Avon Longitudinal Study of Parents and Children
3.  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.
PMCID: PMC3749866  PMID: 23704328
4.  Analysis of Body Composition in Individuals With High Bone Mass Reveals a Marked Increase in Fat Mass in Women But Not Men 
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.
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.
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).
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.
PMCID: PMC3589712  PMID: 23337721
5.  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.
PMCID: PMC3651613  PMID: 23362220
osteoarthritis; high bone mass; bone mineral density; DXA; joint replacement
6.  Analysis of Body Composition in Individuals With High Bone Mass Reveals a Marked Increase in Fat Mass in Women But Not Men 
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.
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.
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).
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.
PMCID: PMC3589712  PMID: 23337721
7.  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.
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.
PMCID: PMC3429873  PMID: 22576953
Accelerometer; fat mass; lean mass; ALSPAC; impact loading
PLoS ONE  2012;7(3):e31821.
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).
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.
PMCID: PMC3303769  PMID: 22431966
Bone  2010;48(3):654-658.
Fibrodysplasia Ossificans Progressiva (FOP) is a rare, autosomal dominant condition, classically characterised by heterotopic ossification beginning in childhood and congenital great toe malformations; occurring in response to a c.617 G>A ACVR1 mutation in the functionally important glycine/serine-rich domain of exon 6. Here we describe a novel c.587 T>C mutation in the glycine/serine-rich domain of ACVR1, associated with delayed onset of heterotopic ossification and an exceptionally mild clinical course. Absence of great toe malformations, the presence of early ossification of the cervical spine facets joints, plus mild bilateral camptodactyly of the 5th fingers, together with a novel ACVR1 mutation, are consistent with the ‘FOP-variant’ syndrome. The c.587 T>C mutation replaces a conserved leucine with proline at residue 196. Modelling of the mutant protein reveals a steric clash with the kinase domain that will weaken interactions with FKBP12 and induce exposure of the glycine/serine-rich repeat. The mutant receptor is predicted to be hypersensitive to ligand stimulation rather than being constitutively active, consistent with the mild clinical phenotype. This case extends our understanding of the ‘FOP-variant’ syndrome.
PMCID: PMC3160462  PMID: 21044902
Fibrodysplasia ossificans progressiva; FOP; ACVR1; Heterotopic ossification; Mutation
Background: Evidence indicates that intrauterine skeletal development has implications for bone mass in later life and that maternal fat stores in pregnancy are important for fetal bone mineral accrual.
Objective: We investigated whether childhood bone mass is influenced by maternal body mass index (BMI) via an intrauterine mechanism by comparing parental associations.
Design: We conducted a multivariable regression analysis of 7121 children in the Avon Longitudinal Study of Parents and Children. Total body less head (TBLH) and spine bone measures were derived from dual-energy X-ray absorptiometry scans at a mean age of 9.9 y. Maternal and paternal BMI values were derived from self-reported weight and height during pregnancy.
Results: Maternal prepregnancy BMI (SD score) was positively associated with offspring TBLH bone mineral content and bone mineral density (SD scores) [mean difference (95% CI): boys, 0.19 (0.16, 0.23) and 0.15 (0.12, 0.19), respectively; girls, 0.23 (0.19, 0.26) and 0.19 (0.16, 0.23), respectively] and spine bone mineral content and bone mineral density [boys, 0.20 (0.16, 0.24) and 0.18 (0.14, 0.22), respectively; girls, 0.22 (0.18, 0.26) and 0.21 (0.17, 0.25), respectively] and with TBLH and spine bone area–and spine area–adjusted bone mineral content. Associations of paternal BMI with these outcomes were similar, with no statistical evidence of a difference between maternal and paternal effects. Maternal associations were partly explained by offspring birth weight and gestational age and attenuated to the null after adjustment for offspring height and weight.
Conclusion: The positive relation between maternal prepregnancy BMI and offspring bone mass is likely due to shared familial, genetic, and environmental characteristics rather than to an intrauterine mechanism.
PMCID: PMC2937586  PMID: 20668048
Rheumatology (Oxford, England)  2009;49(3):505-512.
Vertebral fractures (VFs) are frequently under-recognized, reflecting their lack of diagnostic clinical features. For example, although VFs are associated with back pain, this is also common in the general population. To establish whether back pain can be used to recognize patients with VF, we investigated the site of pain in people with and without VFs using a simple tool.
A cohort of 504 post-menopausal women was recruited from primary care in South West UK. Back pain was assessed by self-completion of the Margolis pain diagram, and analysis was modified to assess whether pain was mid-line or lateral. VFs were diagnosed by the algorithm-based qualitative method on radiographs. A cross-sectional analysis was carried out to assess the association between back pain and VFs.
Three hundred and twenty-two women (64.1%) reported back pain over the last 12 months. Thirty seven (7.3%) had one or more VFs. In women with back pain, the presence of lateral waist area pain was associated with a 4.5-fold increased risk of VFs [odds ratio (OR) 4.48; 95% CI 2.02, 9.94; P<0.001].
In post-menopausal women with back pain, the presence of lateral waist pain, as shown on the Margolis pain diagram, may identify women at higher risk of prevalent VF.
PMCID: PMC2895162  PMID: 20015975
Back pain; Margolis pain diagram; Vertebral fractures
Maternal vitamin D status in pregnancy has been postulated to have important effects on intrauterine development. UVB radiation is not commonly measured but is the prime determinant of circulating 25-hydroxyvitamin-D [25-(OH)D] and is highly dependent on regional weather including cloud cover, ozone and sunshine hours.
Using linear regression we described the relationship between estimated ambient-erythemal ultraviolet (eUV) exposure in Oxford (1990–95) and total hours of sunshine and month in order to forecast eUV in nearby regions, whilst adjusting for regional variations in weather. The forecast was validated with empirical data collected from Cornwall and then predicted for the Avon region. Total 98-day prenatal ambient-eUV was then predicted in 355 expectant mothers in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort and its relationship with maternal vitamin D status was determined.
Estimated ambient-eUV was strongly associated with measured ambient-eUV (r2=0.989) with a near 1:1 prediction for the validation data set [β=0.99, 95% confidence interval (CI) 0.913, 1.067 r2=0.980]; strong seasonal associations were observed between eUV in the last trimester of pregnancy and maternal serum 25-(OH)D concentrations (r2=0.40).
This technique of prediction could be applied to existing cohorts allowing the relationship between maternal vitamin D status and the health of the offspring to be studied via instrumental variable analysis.
PMCID: PMC2788530  PMID: 19564248
Epidemiology; maternal exposure; pregnancy; prenatal exposure delayed effects; seasons; ultraviolet rays; vitamin D; instrumental variable; ALSPAC
The C677T MTHFR polymorphism has been associated with lumbar spine and hip BMD. In older adults, the genetic effect has been reported in women only. However, in younger adults, this influence may only be present in men. This study is the first to investigate associations between the C677T MTHFR polymorphism and bone phenotypes in children. Regression analyses were used to study the relationship between MTHFR genotype and bone phenotypes derived from total body DXA scans in children 9.9 yr of age from the Avon Longitudinal Study of Parents and Children (ALSPAC). A total of 5816 children had both genetic and DXA data for the total body less head region (TBLH) and 3196 for the spine. A strong association was observed between the C677T MTHFR genotype and spine BMD (p < 0.001; 0.10 SD decrease per T allele). There was some evidence that this genetic effect was stronger in boys compared with girls (p = 0.04 for sex interaction). In contrast, there was no association between the C677T MTHFR genotype and TBLH BMD. The association between MTHFR genotype and spine BMD was attenuated particularly in girls by high maternal dietary intakes of vitamin B6 and folate during pregnancy but not by child dietary intakes at 7 yr. To the extent that these findings reflect known influences of C677T MTHFR genotype on plasma homocysteine levels, our results suggest that the latter is an important regulator of spinal BMD in childhood.
PMCID: PMC2742728  PMID: 18715139
ALSPAC; DXA; MTHFR; genetic polymorphism
We examined the influence of habitual levels of physical activity on bone mass in childhood by studying the relationship between accelerometer recordings and DXA parameters in 4457 11-year-old children. Physical activity was positively related to both BMD and bone size in fully adjusted models. However, further exploration revealed that this effect on bone size was modified by fat mass.
Exercise interventions have been reported to increase bone mass in children, but it is unclear whether levels of habitual physical activity also influence skeletal development.
Materials and Methods
We used multivariable linear regression to analyze associations between amount of moderate and vigorous physical activity (MVPA), derived from accelerometer recordings for a minimum of 3 days, and parameters obtained from total body DXA scans in 4457 11-year-old boys and girls from the Avon Longitudinal Study of Parents and Children. The influence of different activity intensities was also studied by stratification based on lower and higher accelerometer cut-points for moderate (3600 counts/minute) and vigorous (6200 counts/minute) activity, respectively.
MVPA was positively associated with lower limb BMD and BMC adjusted for bone area (aBMC; p < 0.001, adjusted for age, sex, socio-economic factors, and height, with or without additional adjustment for lean and fat mass). MVPA was inversely related to lower limb bone area after adjusting for height and lean mass (p = 0.01), whereas a positive association was observed when fat mass was also adjusted for (p < 0.001). Lower limb BMC was positively related to MVPA after adjusting for height and lean and fat mass (p < 0.001), whereas little relationship was observed after adjusting for height and lean mass alone (p = 0.1). On multivariable regression analysis using the fully adjusted model, moderate activity exerted a stronger influence on lower limb BMC compared with light activity (light activity: 2.9 [1.2–4.7, p = 0.001]; moderate activity: 13.1 [10.6–15.5, p < 0.001]; regression coefficients with 95% confidence intervals and p values).
Habitual levels of physical activity in 11-year-old children are related to bone size and BMD, with moderate activity exerting the strongest influence. The effect on bone size (as reflected by DXA-based measures of bone area) was modified by adjustment for fat mass, such that decreased fat mass, which is associated with higher levels of physical activity, acts to reduce bone size and thereby counteract the tendency for physical activity to increase bone mass.
PMCID: PMC2742715  PMID: 17014381
DXA; accelerometer; bone size; fat mass
This is the first prospective cohort study of the association between bone mass and fracture risk in childhood. A total of 6213 children 9.9 years of age were followed for 24 months. Results showed an 89% increased risk of fracture per SD decrease in size-adjusted BMC.
Although previous case-control studies have reported that fracture risk in childhood is inversely related to bone mass, this has not been confirmed in prospective studies. Additionally, it remains unclear which constituent(s) of bone mass underlie this association. We carried out a prospective cohort study to examine the relationship between DXA measures in children 9.9 years of age and risk of fracture over the following 2 years.
Materials and Methods
Total body DXA scan results obtained at 9.9 years of age were linked to reported fractures over the following 2 years in children from a large birth cohort in southwest England. DXA measures consisted of total body less head (TBLH) BMD, bone area, and BMC, and results of subregional analysis of the humerus. Analyses were adjusted for age, sex, ethnicity, and social position.
Complete data were available on 6213 children. There was a weak inverse relationship between BMD at 9.9 years and subsequent fracture risk (OR per SD decrease = 1.12; 95% CI, 1.02–1.25). In analyses examining the relationship between fracture risk and volumetric BMD, fracture risk was inversely related to BMC adjusted for bone area, height, and weight (OR = 1.89; 95% CI, 1.18–3.04) and to estimated volumetric BMD of the humerus (OR = 1.29; 95% CI, 1.14–1.45). Fracture risk was unrelated to both TBLH and humeral bone area. However, in analyses of the relationship between fracture risk and bone size relative to body size, an inverse association was observed between fracture risk and TBLH area adjusted for height and weight (OR = 1.51; 95% CI, 1.17–1.95).
Fracture risk in childhood is related to volumetric BMD, reflecting an influence of determinants of volumetric BMD such as cortical thickness on skeletal fragility. Although bone size per se was not related to fracture risk, we found that children who fracture tend to have a smaller skeleton relative to their overall body size.
PMCID: PMC2742714  PMID: 16939408
population studies; bone densitometry; clinical/pediatrics; fractures; epidemiology
Low bone mass is a determinant of fractures in healthy children. Small studies provide limited evidence on the association between ethnicity, birth weight, family size, socioeconomic status, dietary calcium intake, or physical activity and fracture incidence. No studies have investigated whether these determinants of fracture risk act through affecting bone mass or through other mechanisms. The aim of this study was to use a population-based birth cohort to confirm which variables are determinants of fracture risk and to further study which of these risk factors act independently of bone mass. Children from the Avon Longitudinal Study of Parents and Children have been followed up from birth to 11 yr of age. Maternal self-reported data have been collected contemporaneously on early life factors, diet, puberty, and physical activity. These were linked to reported fractures between 9 and 11 yr of age. Multivariable logistic regression techniques were used to assess whether these potential determinants were independent of, or worked through, estimated volumetric BMD or estimated bone size relative to body size measured by total body DXA scan at 9.9 yr of age. A total of 2692 children had full data. One hundred ninety-three (7.2%) reported at least one fracture over the 2-yr follow-up period. Children who reported daily or more episodes of vigorous physical activity had double the fracture risk compared with those children who reported less than four episodes per week (OR, 2.06; 95% CI, 1.21–1.76). No other independent determinants of fracture risk in healthy children were found. In conclusion, reported vigorous physical activity is an independent risk factor for childhood fracture risk. However, the interrelationship between physical activity, bone mass, and childhood fracture risk suggests that the higher bone mass associated with increased physical activity does not compensate for the risk caused by increased exposure to injuries.
PMCID: PMC2742075  PMID: 18570539
fractures; children; physical activity; epidemiology; BMD; ALSPAC
Human Molecular Genetics  2009;18(8):1510-1517.
Peak bone mass achieved in adolescence is a determinant of bone mass in later life. In order to identify genetic variants affecting bone mineral density (BMD), we performed a genome-wide association study of BMD and related traits in 1518 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). We compared results with a scan of 134 adults with high or low hip BMD. We identified associations with BMD in an area of chromosome 12 containing the Osterix (SP7) locus, a transcription factor responsible for regulating osteoblast differentiation (ALSPAC: P = 5.8 × 10−4; Australia: P = 3.7 × 10−4). This region has previously shown evidence of association with adult hip and lumbar spine BMD in an Icelandic population, as well as nominal association in a UK population. A meta-analysis of these existing studies revealed strong association between SNPs in the Osterix region and adult lumbar spine BMD (P = 9.9 × 10−11). In light of these findings, we genotyped a further 3692 individuals from ALSPAC who had whole body BMD and confirmed the association in children as well (P = 5.4 × 10−5). Moreover, all SNPs were related to height in ALSPAC children, but not weight or body mass index, and when height was included as a covariate in the regression equation, the association with total body BMD was attenuated. We conclude that genetic variants in the region of Osterix are associated with BMD in children and adults probably through primary effects on growth.
PMCID: PMC2664147  PMID: 19181680
Approximately 12% of postmenopausal women have osteoporotic vertebral fractures (VFs); these are associated with excess morbidity and mortality and a high risk of future osteoporotic fractures. Despite this, less than one-third come to clinical attention, partly due to lack of clear clinical triggers for referral for spinal radiographs. The aim of this study was to investigate whether a novel primary care–based screening tool could be used to identify postmenopausal women with osteoporotic VFs and increase appropriate management of osteoporosis. A randomized controlled trial was undertaken in 15 general practices within the Bristol area of the UK. A total of 3200 women aged 65 to 80 years were enrolled, with no exclusion criteria. A simple screening tool was carried out by a nurse in primary care to identify women at high risk of osteoporotic VFs. All identified high-risk women were offered a diagnostic thoracolumbar radiograph. Radiographs were reported using standard National Health Service (NHS) reporting, with results sent back to each participant's general practitioner (GP). Participants in the control arm did not receive the screening tool or radiographs. The main outcome measure was self-reported prescription of medication for osteoporosis at 6 months with a random 5% subsample verified against electronic GP records. Secondary outcome was self-reported incidence of new fractures. Results showed that allocation to screening increased prescription of osteoporosis medications by 124% (odds ratio [OR] for prescription 2.24 at 6 months; 95% confidence interval [CI], 1.16 to 4.33). Allocation to screening also reduced fracture incidence at 12-month follow-up (OR for new fracture 0.60; 95% CI, 0.35–1.03; p = 0.063), although this did not reach statistical significance. This study supports the use of a simple screening tool administered in primary care to increase appropriate prescription of medications for osteoporosis in postmenopausal women in the UK. © 2012 American Society for Bone and Mineral Research
PMCID: PMC3378696  PMID: 22113935
Recent studies suggest that patients with type 2 diabetes mellitus are at increased risk of fracture, possibly because hyperinsulinemia is a risk factor for low bone mineral density, which may in turn be a consequence of a lipotoxic effect of visceral and/or intramuscular fat on bone. In the current study, we investigated whether insulin plays a role in cortical bone development by performing a cross-sectional study based on the Avon Longitudinal Study of Parents and Children (ALSPAC), where we examined associations between fasting insulin levels and peripheral quantitative computed tomography (pQCT) parameters as assessed at the mid-tibia in 2784 boys and girls with a mean age 15.5 years. In particular, we wished to examine whether associations that we observed were independent of body composition, including intramuscular fat. We found that insulin was inversely related to cortical bone mineral density (BMDC) after adjustment for age and after further adjustment for height, muscle cross-sectional area (MCSA), subcutaneous fat (SAT), and muscle density (MD), which is inversely related to intramuscular fat (−0.018, 95% confidence interval [CI] −0.030, −0.006, p < 0.0001). Insulin was positively related to periosteal circumference (PC) after adjusting for age (0.015, 95% CI 0.003, 0.027, p = 0.015; beta = change per 50% increase in insulin), but this changed to an inverse association after additional adjustment for height and body composition (−0.013, 95% CI −0.022, −0.003, p = 0.008). Path analyses revealed inverse associations between insulin and PC via a direct pathway (−0.012, 95% CI −0.022, −0.003, p = 0.01) and via MD (−0.002, 95% CI −0.004, −0.001, p = 0.0004), and positive associations between insulin and PC via SAT (0.013, 95% CI 0.009, 0.016, p < 0.0001) and MCSA (0.015, 95% CI 0.010, 0.020, p < 0.0001). In conclusion, we found an inverse relationship between insulin and PC via intramuscular fat, suggesting a lipotoxic effect on bone. However, an inverse association between insulin and both PC and BMDC persisted after adjusting for all body composition variables, suggesting insulin also acts to inhibit bone development via additional pathways yet to be elucidated. © 2012 American Society for Bone and Mineral Research
PMCID: PMC3378703  PMID: 22095452
Journal of Bone and Mineral Research  2012;27(9):1887-1895.
Whether a certain level of impact needs to be exceeded for physical activity (PA) to benefit bone accrual is currently unclear. To examine this question, we performed a cross-sectional analysis between PA and hip BMD in 724 adolescents (292 boys, mean 17.7 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC), partitioning outputs from a Newtest accelerometer into six different impact bands. Counts within 2.1 to 3.1g, 3.1 to 4.2g, 4.2 to 5.1g, and >5.1g bands were positively related to femoral neck (FN) BMD, in boys and girls combined, in our minimally adjusted model including age, height, and sex (0.5–1.1g: beta = −0.007, p = 0.8; 1.1–2.1g: beta = 0.003, p = 0.9; 2.1–3.1g: beta = 0.042, p = 0.08; 3.1–4.2g: beta = 0.058, p = 0.009; 4.2–5.1g: beta = 0.070, p = 0.001; >5.1g: beta = 0.080, p < 0.001) (beta = SD change per doubling in activity). Similar positive relationships were observed between high-impact bands and BMD at other hip sites (ward's triangle, total hip), hip structure indices derived by hip structural analysis of dual-energy X-ray absorptiometry (DXA) scans (FN width, cross-sectional area, cortical thickness), and predicted strength (cross-sectional moment of inertia). In analyses where adjacent bands were combined and then adjusted for other impacts, high impacts (>4.2g) were positively related to FN BMD, whereas, if anything, moderate (2.1–4.2g) and low impacts (0.5–2.1g) were inversely related (low: beta = −0.052, p = 0.2; medium: beta = −0.058, p = 0.2; high: beta = 0.137, p < 0.001). Though slightly attenuated, the positive association between PA and FN BMD, confined to high impacts, was still observed after adjustment for fat mass, lean mass, and socioeconomic position (high: beta = 0.096, p = 0.016). These results suggest that PA associated with impacts >4.2g, such as jumping and running (which further studies suggested requires speeds >10 km/h) is positively related to hip BMD and structure in adolescents, whereas moderate impact activity (eg, jogging) is of little benefit. Hence, PA may only strengthen lower limb bones in adolescents, and possibly adults, if this comprises high-impact activity. © 2012 American Society for Bone and Mineral Research.
PMCID: PMC3465797  PMID: 22492557
Mendelian randomisation analyses use genetic variants as instrumental variables (IVs) to estimate causal effects of modifiable risk factors on disease outcomes. Genetic variants typically explain a small proportion of the variability in risk factors; hence Mendelian randomisation analyses can require large sample sizes. However, an increasing number of genetic variants have been found to be robustly associated with disease-related outcomes in genome-wide association studies. Use of multiple instruments can improve the precision of IV estimates, and also permit examination of underlying IV assumptions. We discuss the use of multiple genetic variants in Mendelian randomisation analyses with continuous outcome variables where all relationships are assumed to be linear. We describe possible violations of IV assumptions, and how multiple instrument analyses can be used to identify them. We present an example using four adiposity-associated genetic variants as IVs for the causal effect of fat mass on bone density, using data on 5509 children enrolled in the ALSPAC birth cohort study. We also use simulation studies to examine the effect of different sets of IVs on precision and bias. When each instrument independently explains variability in the risk factor, use of multiple instruments increases the precision of IV estimates. However, inclusion of weak instruments could increase finite sample bias. Missing data on multiple genetic variants can diminish the available sample size, compared with single instrument analyses. In simulations with additive genotype-risk factor effects, IV estimates using a weighted allele score had similar properties to estimates using multiple instruments. Under the correct conditions, multiple instrument analyses are a promising approach for Mendelian randomisation studies. Further research is required into multiple imputation methods to address missing data issues in IV estimation.
PMCID: PMC3917707  PMID: 21216802
causal inference; econometrics; epidemiology; genetics; instrumental variables; Mendelian randomisation
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.
PMCID: PMC3691010  PMID: 23074152
Bone mineral density; GWAS; premenopausal; meta-analysis; genetics
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.
PMCID: PMC3578773  PMID: 23437003
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.
► 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.
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

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