Associations between life course longitudinal growth and hip shapes at ages 60-64 years: evidence from the MRC National Survey of Health and Development.

OBJECTIVE: We sought to examine associations between height gain across childhood and adolescence with hip shape in individuals aged 60-64 years from the Medical Research Council National Survey of Health and Development, a nationally representative British birth cohort. METHODS: Height was measured at ages 2, 4, 6, 7, 11 and 15 years, and self-reported at age 20 years. 10 modes of variation in hip shape (HM1-10), described by statistical shape models, were previously ascertained from DXA images taken at ages 60-64 years. Associations between (1) height at each age; (2) Super-Imposition by Translation And Rotation (SITAR) growth curve variables of height size, tempo and velocity; and (3) height gain during specific periods of childhood and adolescence, and HM1-10 were tested. RESULTS: Faster growth velocity was associated with a wider, flatter femoral head and neck, as described by positive scores for HM6 (regression coefficient 0.014; 95% CI 0.08 to 0.019; p<0.001) and HM7 (regression coefficient 0.07; 95% CI 0.002 to 0.013; p=0.009), and negative scores for HM10 (regression coefficient -0.006; 95% CI -0.011 to 0.00, p=0.04) and HM2 (males only, regression coefficient -0.017; 95% CI -0.026 to -0.09; p<0.001). Similar associations were observed with greater height size and later height tempo. Examination of height gains during specific periods of childhood and adolescence identified those during the adolescence period as being most consistently associated. CONCLUSION: Our analyses suggest that individual growth patterns, particularly in the adolescent period, are associated with modest variations in hip shape at 60-64 years, which are consistent with features seen in osteoarthritis.

Dual-energy X-ray absorptiometry derived knee shape may provide a useful imaging biomarker for predicting total knee replacement: Findings from a study of 37,843 people in UK Biobank.

Objective: We aimed to create an imaging biomarker for knee shape using knee dual-energy x-ray absorptiometry (DXA) scans and investigate its potential association with subsequent total knee replacement (TKR), independently of radiographic features of knee osteoarthritis and established risk factors. Methods: Using a 129-point statistical shape model, knee shape (expressed as a B-score) and minimum joint space width (mJSW) of the medial joint compartment (binarized as above or below the first quartile) were derived. Osteophytes were manually graded in a subset of images and an overall score was assigned. Cox proportional hazards models were used to examine the associations of B-score, mJSW and osteophyte score with TKR risk, adjusting for age, sex, height and weight. Results: The analysis included 37,843 individuals (mean age 63.7 years). In adjusted models, B-score was associated with TKR: each unit increase in B-score, reflecting one standard deviation from the mean healthy shape, corresponded to a hazard ratio (HR) of 2.25 (2.08, 2.43), while a lower mJSW had a HR of 2.28 (1.88, 2.77). Among the 6719 images scored for osteophytes, mJSW was replaced by osteophyte score in the most strongly predictive model for TKR. In ROC analyses, a model combining B-score, osteophyte score, and demographics outperformed a model including demographics alone (AUC â€‹= â€‹0.87 vs 0.73). Conclusions: Using statistical shape modelling, we derived a DXA-based imaging biomarker for knee shape that was associated with kOA progression. When combined with osteophytes and demographic data, this biomarker may help identify individuals at high risk of TKR, facilitating targeted interventions.

Comparison between UK Biobank and Shanghai Changfeng suggests distinct hip morphology may contribute to ethnic differences in the prevalence of hip osteoarthritis.

OBJECTS: Joint morphology is a risk factor for hip osteoarthritis (HOA) and could explain ethnic differences in HOA prevalence. Therefore, we aimed to compare the prevalence of radiographic HOA (rHOA) and hip morphology between the predominantly White UK Biobank (UKB) and exclusively Chinese Shanghai Changfeng (SC) cohorts. METHODS: Left hip iDXA scans were used to quantify rHOA, from a combination of osteophytes (grade ≥1) and joint space narrowing (grade ≥1), and hip morphology. Using an 85-point Statistical Shape Model (SSM) we evaluated cam (alpha angle ≥60°) and pincer (lateral centre-edge angle (LCEA) ≥45°) morphology and acetabular dysplasia (LCEA <25°). Diameter of femoral head (DFH), femoral neck width (FNW), and hip axis length (HAL) were also obtained from these points. Results were adjusted for differences in age, height, and weight and stratified by sex. RESULTS: Complete data were available for 5924 SC and 39,020 White UKB participants with mean ages of 63.4 and 63.7 years old. rHOA prevalence was considerably lower in female (2.2% versus 13.1%) and male (12.0% and 25.1%) SC compared to UKB participants. Cam morphology, rarely seen in females, was less common in SC compared with UKB males (6.3% versus 16.5%). Composite SSM modes, scaled to the same overall size, revealed SC participants to have a wider femoral head compared to UKB participants. FNW and HAL were smaller in SC compared to UKB, whereas DFH/FNW ratio was higher in SC. CONCLUSIONS: rHOA prevalence is lower in Chinese compared with White individuals. Several differences in hip shape were observed, including frequency of cam morphology, FNW, and DFH/FNW ratio. These characteristics have previously been identified as risk factors for HOA and may contribute to observed ethnic differences in HOA prevalence.

The identification of distinct protective and susceptibility mechanisms for hip osteoarthritis: findings from a genome-wide association study meta-analysis of minimum joint space width and Mendelian randomisation cluster analyses.

BACKGROUND: Hip minimum joint space width (mJSW) provides a proxy for cartilage thickness. This study aimed to conduct a genome-wide association study (GWAS) of mJSW to (i) identify new genetic determinants of mJSW and (ii) identify which mJSW loci convey hip osteoarthritis (HOA) risk and would therefore be of therapeutic interest. METHODS: GWAS meta-analysis of hip mJSW derived from plain X-rays and DXA was performed, stratified by sex and adjusted for age and ancestry principal components. Mendelian randomisation (MR) and cluster analyses were used to examine causal effect of mJSW on HOA. FINDINGS: 50,745 individuals were included in the meta-analysis. 42 SNPs, which mapped to 39 loci, were identified. Mendelian randomisation (MR) revealed little evidence of a causal effect of mJSW on HOA (ORIVW 0.98 [95% CI 0.82-1.18]). However, MR-Clust analysis suggested the null MR estimates reflected the net effect of two distinct causal mechanisms cancelling each other out, one of which was protective, whereas the other increased HOA susceptibility. For the latter mechanism, all loci were positively associated with height, suggesting mechanisms leading to greater height and mJSW increase the risk of HOA in later life. INTERPRETATIONS: One group of mJSW loci reduce HOA risk via increased mJSW, suggesting possible utility as targets for chondroprotective therapies. The second group of mJSW loci increased HOA risk, despite increasing mJSW, but were also positively related to height, suggesting they contribute to HOA risk via a growth-related mechanism. FUNDING: Primarily funded by the Medical Research Council and Wellcome Trust.

A Genome-Wide Association Study Meta-Analysis of Alpha Angle Suggests Cam-Type Morphology May Be a Specific Feature of Hip Osteoarthritis in Older Adults.

OBJECTIVE: To examine the genetic architecture of cam morphology using alpha angle (AA) as a proxy measure and conduct an AA genome-wide association study (GWAS) followed by Mendelian randomization (MR) to evaluate its causal relationship with hip osteoarthritis (OA). METHODS: Observational analyses examined associations between AA measurements derived from hip dual x-ray absorptiometry (DXA) scans from the UK Biobank study and radiographic hip OA outcomes and subsequent total hip replacement. Following these analyses, an AA GWAS meta-analysis was performed (N = 44,214) using AA measurements previously derived in the Rotterdam Study. Linkage disequilibrium score regression assessed the genetic correlation between AA and hip OA. Genetic associations considered significant (P < 5 × 10-8 ) were used as AA genetic instrument for 2-sample MR analysis. RESULTS: DXA-derived AA showed expected associations between AA and radiographic hip OA (adjusted odds ratio [OR] 1.63 [95% confidence interval (95% CI) 1.58, 1.67]) and between AA and total hip replacement (adjusted hazard ratio 1.45 [95% CI 1.33, 1.59]) in the UK Biobank study cohort. The heritability of AA was 10%, and AA had a moderate genetic correlation with hip OA (rg  = 0.26 [95% CI 0.10, 0.43]). Eight independent genetic signals were associated with AA. Two-sample MR provided weak evidence of causal effects of AA on hip OA risk (inverse variance weighted OR 1.84 [95% CI 1.14, 2.96], P = 0.01). In contrast, genetic predisposition for hip OA had stronger evidence of a causal effect on increased AA (inverse variance weighted ß = 0.09 [95% CI 0.04, 0.13], P = 4.58 × 10-5 ). CONCLUSION: Expected observational associations between AA and related clinical outcomes provided face validity for the DXA-derived AA measurements. Evidence of bidirectional associations between AA and hip OA, particularly for risk of hip OA on AA, suggests that hip shape modeling secondary to a genetic predisposition to hip OA contributes to the well-established relationship between hip OA and cam morphology in older adults.

Machine Learning-Derived Acetabular Dysplasia and Cam Morphology Are Features of Severe Hip Osteoarthritis: Findings From UK Biobank.

The contribution of shape changes to hip osteoarthritis (HOA) remains unclear, as is the extent to which these vary according to HOA severity. In the present study, we used statistical shape modeling (SSM) to evaluate relationships between hip shape and HOA of different severities using UK Biobank DXA images. We performed a cross-sectional study in individuals with left hip dual-energy X-ray absorptiometry (DXA) scans. Statistical shape modeling (SSM) was used to quantify hip shape. Radiographic HOA (rHOA) was classified using osteophyte size and number and joint space narrowing. HOA outcomes ranged in severity from moderate (grade 2) to severe (grade ≥3) rHOA, hospital-diagnosed HOA, and subsequent total hip replacement (THR). Confounder-adjusted logistic regression between the top 10 hip shape modes (HSMs) and OA outcomes was performed. Further models adjusted for alpha angle (AA) and lateral center-edge angle (LCEA), reflecting acetabular dysplasia and cam morphology, respectively. Composite HSM figures were produced combining HSMs associated with separate OA outcomes. A total of 40,311 individuals were included (mean 63.7 years, 47.8% male), of whom 5.7% had grade 2 rHOA, 1.7% grade ≥3 rHOA, 1.3% hospital-diagnosed HOA, and 0.6% underwent THR. Composite HSM figures for grade 2 rHOA revealed femoral neck widening, increased acetabular coverage, and enlarged lesser and greater trochanters. In contrast, grade ≥3 rHOA, hospital-diagnosed HOA, and THR were suggestive of cam morphology and reduced acetabular coverage. Associations between HSMs depicting cam morphology and reduced acetabular coverage and more severe HOA were attenuated by AA and LCEA adjustment, respectively. Relationships between hip shape and HOA differed according to severity. Notably, cam morphology and acetabular dysplasia were features of severe HOA, but unrelated to moderate disease, suggesting possible prognostic utility. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Digital health interventions for osteoporosis and post-fragility fracture care.

The growing burden from osteoporosis and fragility fractures highlights a need to improve osteoporosis management across healthcare systems. Sub-optimal management of osteoporosis is an area suitable for digital health interventions. While fracture liaison services (FLSs) are proven to greatly improve care for people with osteoporosis, such services might benefit from technologies that enhance automation. The term 'Digital Health' covers a variety of different tools including clinical decision support systems, electronic medical record tools, patient decision aids, patient apps, education tools, and novel artificial intelligence (AI) algorithms. Within the scope of this review are AI solutions that use algorithms within health system registries to target interventions. Clinician-targeted, patient-targeted, or system-targeted digital health interventions could be used to improve management and prevent fragility fractures. This review was commissioned by The Royal Osteoporosis Society and Bone Research Academy during the production of the 2020 Research Roadmap (https://theros.org.uk), with the intention of identifying gaps where targeted research funding could lead to improved patient health. We explore potential uses of digital technology in the general management of osteoporosis. Evidence suggests that digital technologies can support multidisciplinary teams to provide the best possible patient care based on current evidence and to support patients in self-management. However, robust randomised controlled studies are still needed to assess the effectiveness and cost-effectiveness of these technologies.

A novel semi-automated classifier of hip osteoarthritis on DXA images shows expected relationships with clinical outcomes in UK Biobank.

OBJECTIVE: Conventional scoring methods for radiographic hip OA (rHOA) are subjective and show inconsistent relationships with clinical outcomes. To provide a more objective rHOA scoring method, we aimed to develop a semi-automated classifier based on DXA images and confirm its relationships with clinical outcomes. METHODS: Hip DXAs in UK Biobank (UKB) were marked up for osteophyte area from which acetabular, superior and inferior femoral head osteophyte grades were derived. Joint space narrowing (JSN) grade was obtained automatically from minimum joint space width (mJSW) measures. Clinical outcomes related to rHOA comprised hip pain, hospital diagnosed OA (HES OA) and total hip replacement. Logistic regression and Cox proportional hazard modelling were used to examine associations between overall rHOA grade (0-4; derived from combining osteophyte and JSN grades) and the clinical outcomes. RESULTS: A toal of 40 340 individuals were included in the study (mean age 63.7), of whom 81.2% had no evidence of rHOA, while 18.8% had grade ≥1 rHOA. Grade ≥1 osteophytes at each location and JSN were associated with hip pain, HES OA and total hip replacement. Associations with all three clinical outcomes increased progressively according to rHOA grade, with grade 4 rHOA and total hip replacement showing the strongest association [57.70 (38.08-87.44)]. CONCLUSIONS: Our novel semi-automated tool provides a useful means for classifying rHOA on hip DXAs, given its strong and progressive relationships with clinical outcomes. These findings suggest DXA scanning can be used to classify rHOA in large DXA-based cohort studies supporting further research, with the future potential for population-based screening.

Osteophyte size and location on hip DXA scans are associated with hip pain: Findings from a cross sectional study in UK Biobank.

OBJECTIVE: It remains unclear how the different features of radiographic hip osteoarthritis (rHOA) contribute to hip pain. We examined the relationship between rHOA, including its individual components, and hip pain using a novel dual-energy x-ray absorptiometry (DXA)-based method. METHODS: Hip DXAs were obtained from UK Biobank. A novel automated method obtained minimum joint space width (mJSW) from points placed around the femoral head and acetabulum. Osteophyte areas at the lateral acetabulum, superior and inferior femoral head were derived manually. Semi-quantitative measures of osteophytes and joint space narrowing (JSN) were combined to define rHOA. Logistic regression was used to examine the relationships between these variables and hip pain, obtained via questionnaires. RESULTS: 6807 hip DXAs were examined. rHOA was present in 353 (5.2%) individuals and was associated with hip pain [OR 2.42 (1.78-3.29)] and hospital diagnosed OA [6.01 (2.98-12.16)]. Total osteophyte area but not mJSW was associated with hip pain in mutually adjusted models [1.31 (1.23-1.39), 0.95 (0.87-1.04) respectively]. On the other hand, JSN as a categorical variable showed weak associations between grade ≥ 1 and grade ≥ 2 JSN with hip pain [1.30 (1.06-1.60), 1.80 (1.34-2.42) respectively]. Acetabular, superior and inferior femoral osteophyte areas were all independently associated with hip pain [1.13 (1.06-1.20), 1.13 (1.05-1.24), 1.10 (1.03-1.17) respectively]. CONCLUSION: In this cohort, the relationship between rHOA and prevalent hip pain was explained by 2-dimensional osteophyte area, but not by the apparent mJSW. Osteophytes at different locations showed important, potentially independent, associations with hip pain, possibly reflecting the contribution of distinct biomechanical pathways.

Opportunistic diagnosis of osteoporosis, fragile bone strength and vertebral fractures from routine CT scans; a review of approved technology systems and pathways to implementation.

Osteoporosis causes bones to become weak, porous and fracture more easily. While a vertebral fracture is the archetypal fracture of osteoporosis, it is also the most difficult to diagnose clinically. Patients often suffer further spine or other fractures, deformity, height loss and pain before diagnosis. There were an estimated 520,000 fragility fractures in the United Kingdom (UK) in 2017 (costing £4.5 billion), a figure set to increase 30% by 2030. One way to improve both vertebral fracture identification and the diagnosis of osteoporosis is to assess a patient's spine or hips during routine computed tomography (CT) scans. Patients attend routine CT for diagnosis and monitoring of various medical conditions, but the skeleton can be overlooked as radiologists concentrate on the primary reason for scanning. More than half a million CT scans done each year in the National Health Service (NHS) could potentially be screened for osteoporosis (increasing 5% annually). If CT-based screening became embedded in practice, then the technique could have a positive clinical impact in the identification of fragility fracture and/or low bone density. Several companies have developed software methods to diagnose osteoporosis/fragile bone strength and/or identify vertebral fractures in CT datasets, using various methods that include image processing, computational modelling, artificial intelligence and biomechanical engineering concepts. Technology to evaluate Hounsfield units is used to calculate bone density, but not necessarily bone strength. In this rapid evidence review, we summarise the current literature underpinning approved technologies for opportunistic screening of routine CT images to identify fractures, bone density or strength information. We highlight how other new software technologies have become embedded in NHS clinical practice (having overcome barriers to implementation) and highlight how the novel osteoporosis technologies could follow suit. We define the key unanswered questions where further research is needed to enable the adoption of these technologies for maximal patient benefit.

Associations between prenatal indicators of mechanical loading and proximal femur shape: findings from a population-based study in ALSPAC offspring.

OBJECTIVES: Hip development is influenced by mechanical loading, but associations between prenatal loading and hip shape in later life remain unexplored. METHODS: We examined associations between prenatal loading indicators (gestation length, oligohydramnios (OH) and breech) obtained from obstetric records and hip shape modes (HSMs) generated using dual-energy X-ray absorptiometry images taken at age 14- and 18-years in participants from the UK Avon Longitudinal Study of Parents and Children (ALSPAC). These associations were examined in 2453 (30 OH, 105 breech) and 2330 (27 OH, 95 breech) participants with complete data at age 14- and 18-years respectively using confounder-adjusted models. RESULTS: At 14 years HSM2 was 0.59SD lower in OH males, and HSM5 (-0.31SD) and HSM9 (-0.32SD) were lower in OH in both sexes. At 18 years HSM1 (-0.44SD) and HSM2 (-0.71SD) were lower and HSM6 (0.61SD) and HSM8 (1.06SD) were higher in OH males, whilst HSM5 was lower in OH in both sexes. OH appeared to be associated with a wider femoral neck and head, and larger lesser/greater trochanters. Only weak associations were observed between gestation length/breech and HSMs. CONCLUSIONS: These results suggest that prenatal skeletal loading, in particular oligohydramnios, may influence adolescent joint shape with associations generally stronger in males.

Is intrinsic lumbar spine shape associated with lumbar disc degeneration? An exploratory study.

BACKGROUND: Lumbar disc degeneration (LDD) is a condition associated with recurrent low back pain (LBP). Knowledge regarding effective management is limited. As a step towards the identification of risk, prognostic or potentially modifiable factors in LDD patients, the aim of this study was to explore the hypothesis that intrinsic lumbar spine shape is associated with LDD and clinical outcomes in symptomatic adults. METHODS: 3 T MRI was used to acquire T2-weighted sagittal images (L1-S1) from 70 healthy controls and LDD patients (mean age 49 years, SD 11, range 31-71 years). Statistical Shape Modelling (SSM) was used to describe lumbar spine shape. SSM identified variations in lumbar shape as 'modes' of variation and quantified deviation from the mean. Intrinsic shape differences were determined between LDD groups using analysis of variance with post-hoc comparisons. The relationship between intrinsic shape and self-reported function, mental health and quality of life were also examined. RESULTS: The first 7 modes of variation explained 91% of variance in lumbar shape. Higher LDD sum scores correlated with a larger lumbar lordosis (Mode 1 (55% variance), P = 0.02), even lumbar curve distribution (Mode 2 (12% variance), P = 0.05), larger anterior-posterior (A-P) vertebral diameter (Mode 3 (10% variance), P = 0.007) and smaller L4-S1 disc spaces (Mode 7 (2% variance), P ≤ 0.001). In the presence of recurrent LBP, LDD was associated with a larger A-P vertebral diameter (Mode 3) and a more even lumbar curvature with smaller L5/S1 disc spaces (Mode 4), which was significantly associated with patient quality of life (P = 0.002-0.04, rp = 0.43-0.61)). CONCLUSIONS: This exploratory study provides new evidence that intrinsic shape phenotypes are associated with LDD and quality of life in patients. Longitudinal studies are required to establish the potential role of these risk or prognostic shape phenotypes.

Motor development in infancy and spine shape in early old age: Findings from a British birth cohort study.

Spine shape changes dramatically in early life, influenced by attainment of developmental milestones such as independent walking. Whether these associations persist across life is unknown. Therefore, we investigated associations between developmental milestones and spine shape, as determined using statistical shape models (SSMs) of lumbar spine from dual-energy X-ray absorptiometry scans in 1327 individuals (688 female) at 60 to 64 years in the MRC National Survey of Health and Development. Lumbar lordosis angle (L4 inferior endplate to T12 superior endplate) was measured using the two-line Cobb method. In analyses adjusted for sex, height, lean and fat mass, socioeconomic position, and birthweight, later walking age was associated with greater lordosis described by SSM1 (regression coefficient, 0.023; 95% CI, 0.000-0.047; P = .05) and direct angle measurement. Modest associations between walking age and less variation in anterior-posterior vertebral size caudally (SSM6) were also observed (0.021; 95% CI, -0.002 to 0.044; P = .07). Sex interactions showed that later walking was associated with larger relative vertebral anterior-posterior dimensions in men (SSM3; -0.043; 95% CI, -0.075 to 0.01; P = .01) but not women (0.018; 95% CI, -0.0007 to 0.043; P = .17). Similar associations were observed between age at independent standing and SSMs but there was little evidence of association between sitting age and spine shape. Unadjusted associations between walking age and SSMs 1 and 6 remained similar after adjustment for potential confounders and mediators. This suggests that these associations may be explained by altered mechanical loading of the spine during childhood growth, although other factors could contribute. Early life motor development, particularly walking, may have a lasting effect on the features of spine morphology with clinical significance.

Statistical shape modelling provides a responsive measure of morphological change in knee osteoarthritis over 12 months.

OBJECTIVES: Responsive biomarkers are needed to assess the progression of OA and their lack has hampered previous clinical trials. Statistical shape modelling (SSM) from radiographic images identifies those at greatest risk of fast-progression or joint replacement, but its sensitivity to change has not previously been measured. This study evaluates the responsiveness of SSM in knee OA in a 12-month observational study. METHODS: A total of 109 people were recruited who had undergone knee radiographs in the previous 12 months, and were grouped based on severity of radiographic OA (Kellgren-Lawrence grading). An SSM was built from three dual-energy X-ray absorptiometry scans at 6-month intervals. Change-over-time and OA were assessed using generalized estimating equations, standardized response means (SRM) and reliable change indices. RESULTS: Mode 1 showed typical features of radiographic OA and had a strong link with Kellgren-Lawrence grading but did not change significantly during the study. Mode 3 showed asymmetrical changes consistent with medial cartilage loss, osteophytes and joint malalignment, and was responsive to change, with a 12-month SRM of 0.63. The greatest change was observed in the moderate radiographic OA group (SRM 0.92) compared with the controls (SRM 0.21), and the reliable change index identified 14% of this group whose progression was clinically significant. CONCLUSION: Shape changes linked the progression of osteophytosis with increasing malalignment within the joint. Modelling of the whole joint enabled quantification of change beyond the point where bone-to-bone contact has been made. The knee SSM is, therefore, a responsive biomarker for radiographic change in knees over 12 months.

The effect of pubertal timing, as reflected by height tempo, on proximal femur shape: Findings from a population-based study in adolescents.

OBJECTIVE: To examine the relationship between pubertal timing (using measures of height tempo) and proximal femur shape in a large adolescent cohort. METHODS: Hip DXA scans were obtained in offspring from the Avon Longitudinal Study of Parents and Children. To quantify hip morphology, the images were analyzed using Shape software based on a 53-point statistical shape model and independent modes of variation (hip shape mode (HSM) scores) for each image were generated. Height tempo (which corresponds to age at peak height velocity (aPHV)) was estimated from serial height measurements collected between age 5-20 years. Multivariable linear regression was used to examine cross-sectional associations between height tempo and the top ten HSMs at age 14 and 18, adjusting for sex and fat mass index (FMI). RESULTS: Complete outcome and covariate data were available from 3827 and 3507 participants at age 14 and 18 years, respectively. Mean aPHV was 13.5 and 11.8 years for males and females, respectively. At age 14, height tempo was associated with a majority of modes, except for HSM4 and there was strong evidence of interaction by sex. In males, all modes showed evidence of an association with tempo, independent of FMI, with the strongest observed for HSM8 (adjusted ß 0.38 (0.33, 0.43) p = 4.1 × 10-50). Compared with males, the associations were generally weaker in females, with the strongest effect observed for HSM8 (adjusted ß 0.10 (0.05, 0.14) p = 1.6 × 10-5). The overall effect of later pubertal timing on proximal femur shape in males was a narrower femoral neck and larger superolateral head, whereas in females these changes were hard to discern. When assessed at age 18, there was little relationship between tempo and proximal femur shape in either sex. CONCLUSION: Our results indicate that significant changes in hip shape occur during puberty, including aspects of shape which may be related to future risk of hip OA and/or fracture. However, puberty timing per se does not appear to exert long lasting effects on proximal femur shape.

Genome-wide Associations Reveal Human-Mouse Genetic Convergence and Modifiers of Myogenesis, CPNE1 and STC2.

Muscle bulk in adult healthy humans is highly variable even after height, age, and sex are accounted for. Low muscle mass, due to fewer and/or smaller constituent muscle fibers, would exacerbate the impact of muscle loss occurring in aging or disease. Genetic variability substantially influences muscle mass differences, but causative genes remain largely unknown. In a genome-wide association study (GWAS) on appendicular lean mass (ALM) in a population of 85,750 middle-aged (aged 38-49 years) individuals from the UK Biobank (UKB), we found 182 loci associated with ALM (p < 5 × 10-8). We replicated associations for 78% of these loci (p < 5 × 10-8) with ALM in a population of 181,862 elderly (aged 60-74 years) individuals from UKB. We also conducted a GWAS on hindlimb skeletal muscle mass of 1,867 mice from an advanced intercross between two inbred strains (LG/J and SM/J); this GWAS identified 23 quantitative trait loci. Thirty-eight positional candidates distributed across five loci overlapped between the two species. In vitro studies of positional candidates confirmed CPNE1 and STC2 as modifiers of myogenesis. Collectively, these findings shed light on the genetics of muscle mass variability in humans and identify targets for the development of interventions for treatment of muscle loss. The overlapping results between humans and the mouse model GWAS point to shared genetic mechanisms across species.

Age at Onset of Walking in Infancy Is Associated With Hip Shape in Early Old Age.

Bones' shapes and structures adapt to the muscle and reaction forces they experience during everyday movements. Onset of independent walking, at approximately 12 months, represents the first postnatal exposure of the lower limbs to the large forces associated with bipedal movements; accordingly, earlier walking is associated with greater bone strength. However, associations between early life loading and joint shape have not been explored. We therefore examined associations between walking age and hip shape at age 60 to 64 years in 1423 individuals (740 women) from the MRC National Survey of Health and Development, a nationally representative British birth cohort. Walking age in months was obtained from maternal interview at age 2 years. Ten modes of variation in hip shape (HM1 to HM10), described by statistical shape models, were ascertained from DXA images. In sex-adjusted analyses, earlier walking age was associated with higher HM1 and HM7 scores; these associations were maintained after further adjustment for height, body composition, and socioeconomic position. Earlier walking was also associated with lower HM2 scores in women only, and lower HM4 scores in men only. Taken together, this suggests that earlier walkers have proportionately larger (HM4) and flatter (HM1, HM4) femoral heads, wider (HM1, HM4, HM7) and flatter (HM1, HM7) femoral necks, a smaller neck-shaft angle (HM1, HM4), anteversion (HM2, HM7), and early development of osteophytes (HM1). These results suggest that age at onset of walking in infancy is associated with variations in hip shape in older age. Early walkers have a larger femoral head and neck and smaller neck-shaft angle; these features are associated with reduced hip fracture risk, but also represent an osteoarthritic-like phenotype. Unlike results of previous studies of walking age and bone mass, associations in this study were not affected by adjustment for lean mass, suggesting that associations may relate directly to skeletal loading in early life when joint shape changes rapidly. © 2018 American Society for Bone and Mineral Research.

Identification of Novel Loci Associated With Hip Shape: A Meta-Analysis of Genomewide Association Studies.

We aimed to report the first genomewide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p < 5 × 10-9 , adjusted for 10 independent outcomes) single-nucleotide polymorphisms (SNPs) were associated with HSM1, and three SNPs with HSM2. One SNP, in high linkage disequilibrium with rs2158915 associated with HSM1, was associated with HSM5 at genomewide significance. In a look-up of previous GWASs, three of the identified SNPs were associated with hip osteoarthritis, one with hip fracture, and five with height. Seven SNPs were within 200 kb of genes involved in endochondral bone formation, namely SOX9, PTHrP, RUNX1, NKX3-2, FGFR4, DICER1, and HHIP. The SNP adjacent to DICER1 also showed osteoblast cis-regulatory activity of GSC, in which mutations have previously been reported to cause hip dysplasia. For three of the lead SNPs, SNPs in high LD (r2 > 0.5) were identified, which intersected with open chromatin sites as detected by ATAC-seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

Genome wide association analysis in a mouse advanced intercross line.

The LG/J x SM/J advanced intercross line of mice (LG x SM AIL) is a multigenerational outbred population. High minor allele frequencies, a simple genetic background, and the fully sequenced LG and SM genomes make it a powerful population for genome-wide association studies. Here we use 1,063 AIL mice to identify 126 significant associations for 50 traits relevant to human health and disease. We also identify thousands of cis- and trans-eQTLs in the hippocampus, striatum, and prefrontal cortex of ~200 mice. We replicate an association between locomotor activity and Csmd1, which we identified in an earlier generation of this AIL, and show that Csmd1 mutant mice recapitulate the locomotor phenotype. Our results demonstrate the utility of the LG x SM AIL as a mapping population, identify numerous novel associations, and shed light on the genetic architecture of mammalian behavior.