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Hip fractures are a major cause of morbidity and mortality in the elderly, and incur high health and social care costs. Given projected population ageing, the number of incident hip fractures is predicted to increase globally. As fracture classification strongly determines the chosen surgical treatment, differences in fracture classification influence patient outcomes and treatment costs. We aimed to create a machine learning method for identifying and classifying hip fractures, and to compare its performance to experienced human observers. We used 3659 hip radiographs, classified by at least two expert clinicians. The machine learning method was able to classify hip fractures with 19% greater accuracy than humans, achieving overall accuracy of 92%.

Objectives: To examine the genetic architecture of cam morphology, using alpha angle (AA) as a proxy measure, we conducted an AA genome wide association study (GWAS), followed by Mendelian randomisation (MR) to evaluate its causal relationship with hip osteoarthritis (HOA).Methods: Observational analyses examined associations between AA derived from hip DXA scans in UK Biobank (UKB), and radiographic HOA (rHOA) and subsequent total hip replacement (THR). Afterwards, an AA GWAS meta-analysis was performed (n=44,214), using AA previously derived in the Rotterdam Study (RS). Linkage disequilibrium score regression assessed the genetic correlation between AA and HOA. Genetic associations with PResults: DXA-derived AA showed expected associations between AA and rHOA (OR 1.63 [95% CI 1.58-1.67]) and THR (HR 1.45 [1.33-1.59]) in UKB. The heritability of AA was 10% and AA had a moderate genetic correlation with HOA (rg =0.26 [0.10-0.43]). Eight independent genetic signals were associated with AA. Two-sample MR provided weak evidence of causal effects of AA on HOA risk (inverse variance weighted (IVW): OR=1.84 [1.14-2.96], P 0.01). In contrast, genetic predisposition for HOA had stronger evidence of a causal effect on increased AA (IVW: β=0.09 [0.04-0.13], P 4.58 x 10-05 ).Conclusions: Expected observational associations between AA and related clinical outcomes provided face-validity for the DXA-derived AA measures. Evidence of bidirectional associations between AA and HOA, particularly in the reverse direction, suggests that hip shape modelling secondary to a genetic predisposition to HOA contributes to the well-established relationship between HOA and cam morphology in older adults.

Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (ORIDD = 0.92, P = 1.6 × 10−39; ORdorsalgia = 0.92, P = 7.2 × 10−15) is with a 3’UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 − 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10−11); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes.

Extended data for 'Metabolic profiling of adolescent non-alcoholic fatty liver disease'

Objectives Observational analyses suggest that high bone mineral density (BMD) is a risk factor for osteoarthritis (OA); it is unclear whether this represents a causal effect or shared aetiology and whether these relationships are body mass index (BMI)-independent. We performed bidirectional Mendelian randomization (MR) to uncover the causal pathways between BMD, BMI and OA. Methods One-sample (1S)MR estimates were generated by two-stage least-squares regression. Unweighted allele scores instrumented each exposure. Two-sample (2S)MR estimates were generated using inverse-variance weighted random-effects meta-analysis. Multivariable MR (MVMR), including BMD and BMI instruments in the same model, determined the BMI-independent causal pathway from BMD to OA. Latent causal variable (LCV) analysis, using weight-adjusted femoral neck (FN)–BMD and hip/knee OA summary statistics, determined whether genetic correlation explained the causal effect of BMD on OA. Results 1SMR provided strong evidence for a causal effect of BMD estimated from heel ultrasound (eBMD) on hip and knee OA {odds ratio [OR]hip = 1.28 [95% confidence interval (CI) = 1.05, 1.57], p = 0.02, ORknee = 1.40 [95% CI = 1.20, 1.63], p = 3 × 10–5, OR per standard deviation [SD] increase}. 2SMR effect sizes were consistent in direction. Results suggested that the causal pathways between eBMD and OA were bidirectional (βhip = 1.10 [95% CI = 0.36, 1.84], p = 0.003, βknee = 4.16 [95% CI = 2.74, 5.57], p = 8 × 10–9, β = SD increase per doubling in risk). MVMR identified a BMI-independent causal pathway between eBMD and hip/knee OA. LCV suggested that genetic correlation (i.e. shared genetic aetiology) did not fully explain the causal effects of BMD on hip/knee OA. Conclusions These results provide evidence for a BMI-independent causal effect of eBMD on OA. Despite evidence of bidirectional effects, the effect of BMD on OA did not appear to be fully explained by shared genetic aetiology, suggesting a direct action of bone on joint deterioration.

Additional file 3. Review history.

Additional file 2: Supplementary Figures. Fig. S1. SITAR modeled mean curves for aBMD and BMC by sex and ancestry. Fig. S2. Phenotypic and genetic correlation plots. Fig. S3. Manhattan and QQ plots. Fig. S4. Overlap of signals (A) among skeletal sites and (B) SITAR parameters. Fig. S5. TET2 locus. Fig. S6. Flow chart showing choice of loci for functional follow-up. Fig. S7. Locus zoom regional plots, ancestry and sex-specific association results, and SITAR curves by genotype for (A) signal 17 and (B) signal S6, and (C) Locuszoom plots with African American LD background for the three signals.. Fig. S8. Gene expression after siRNA knockdown before and after BMP2 treatment. Fig. S9. Staining results in hFOBs. Fig. S10. Gene expression of BMP2 signaling markers and osteoblast markers. Fig. S11. Gene expression of chondrogenic and adipogenic markers in hMSC-osteoblasts. Fig. S12. CRISPR-Cas9 deletion of sentinel SNP at PRPF38A locus. Fig. S13. rs34455069 is predicted to disrupt two transcription factor binding sites.. Fig. S14. SITAR mean curves in ALSPAC.

Novel anabolic drug targets are needed to treat osteoporosis. Having established a large national cohort with unexplained high bone mass (HBM), we aimed to identify a novel monogenic cause of HBM and provide insight into a regulatory pathway potentially amenable to therapeutic intervention. We investigated a pedigree with unexplained HBM in whom previous sequencing had excluded known causes of monogenic HBM. Whole exome sequencing identified a rare (minor allele frequency 0.0023), highly evolutionarily conserved missense mutation in SMAD9 (c.65T>C, p.Leu22Pro) segregating with HBM in this autosomal dominant family. The same mutation was identified in another two unrelated individuals both with HBM. In silico protein modeling predicts the mutation severely disrupts the MH1 DNA‐binding domain of SMAD9. Affected individuals have bone mineral density (BMD) Z‐scores +3 to +5, mandible enlargement, a broad frame, torus palatinus/mandibularis, pes planus, increased shoe size, and a tendency to sink when swimming. Peripheral quantitative computed tomography (pQCT) measurement demonstrates increased trabecular volumetric BMD and increased cortical thickness conferring greater predicted bone strength; bone turnover markers are low/normal. Notably, fractures and nerve compression are not found. Both genome‐wide and gene‐based association testing involving estimated BMD measured at the heel in 362,924 white British subjects from the UK Biobank Study showed strong associations with SMAD9 (PGWAS = 6 × 10−16; PGENE = 8 × 10−17). Furthermore, we found Smad9 to be highly expressed in both murine cortical bone–derived osteocytes and skeletal elements of zebrafish larvae. Our findings support SMAD9 as a novel HBM gene and a potential novel osteoanabolic target for osteoporosis therapeutics. SMAD9 is thought to inhibit bone morphogenetic protein (BMP)‐dependent target gene transcription to reduce osteoblast activity. Thus, we hypothesize SMAD9 c.65T>C is a loss‐of‐function mutation reducing BMP inhibition. Lowering SMAD9 as a potential novel anabolic mechanism for osteoporosis therapeutics warrants further investigation. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

In a population-based sample of British women aged over 70 years old, lean mass and peak lower limb muscle force were both independently associated with hip strength and fracture risk indices, thereby suggesting a potential benefit of promoting leg muscle strengthening exercise for the prevention of hip fractures in postmenopausal women.INTRODUCTION: To investigate cross-sectional associations of lean mass and physical performance, including lower limb muscle function, with hip strength, geometry and fracture risk indices (FRIs) in postmenopausal women.METHODS: Data were from the Cohort of Skeletal Health in Bristol and Avon. Total hip (TH) and femoral neck (FN) bone mineral density (BMD), hip geometry and total body lean mass (TBLM) were assessed by dual x-ray absorptiometry (DXA). Finite element analysis of hip DXA was used to derive FN, intertrochanteric and subtrochanteric FRIs. Grip strength, gait speed and chair rise time were measured objectively. Lower limb peak muscle force and muscle power were assessed by jumping mechanography.RESULTS: In total, 241 women were included (age = 76.4; SD = 2.6 years). After adjustment for age, height, weight/fat mass and comorbidities, TBLM was positively associated with hip BMD (β TH BMD = 0.36, P ≤ 0.001; β FN BMD = 0.26, P = 0.01) and cross-section moment of inertia (0.24, P ≤ 0.001) and inversely associated with FN FRI (- 0.21, P = 0.03) and intertrochanteric FRI (- 0.11, P = 0.05) (estimates represent SD difference in bone measures per SD difference in TBLM). Lower limb peak muscle force was positively associated with hip BMD (β TH BMD = 0.28, P ≤ 0.001; β FN BMD = 0.23, P = 0.008) and inversely associated with FN FRI (- 0.17, P = 0.04) and subtrochanteric FRI (- 0.18, P = 0.04). Associations of grip strength, gait speed, chair rise time and peak muscle power with hip parameters were close to the null. CONCLUSIONS: Lean mass and lower limb peak muscle force were associated with hip BMD and geometrical FRIs in postmenopausal women. Leg muscle strengthening exercises may therefore help prevent hip fractures in older women.

BackgroundSarcopenia has been associated with reduced physical activity (PA). We aimed to determine if sarcopenia, and specific components of muscle size, function and physical performance, are associated with high impacts achieved during habitual PA, as these are related to bone strength in community-dwelling older women.MethodsParticipants were older women from the Cohort of Skeletal Health in Bristol and Avon. We defined sarcopenia using the EWGSOP criteria. Lower limb peak muscle power and force were assessed using Jumping Mechanography (JM). High vertical impacts were assessed by tri-axial accelerometry (at least 1.5g above gravity). Cross-sectional associations were analysed by linear regression, adjusting for age, height and weight (or fat mass for models including appendicular lean mass index), comorbidities, smoking, alcohol and Index of Multiple Deprivation.ResultsOur analyses included 380 participants, with mean age 76.7 (SD 3.0) years; 242 (64%) also completed JM. In age-adjusted analysis, a negative relationship was observed between severity of sarcopenia and high, but not medium or low, impacts (p=0.03 for trend). Regarding components of sarcopenia underlying this relationship, multivariable analyses revealed that gait speed [β 1.47(95% CI 1.14,1.89), [β-1] reflects the proportionate increase in high impacts per SD increase in exposure] and peak force [1.40(1.07,1.84)] were independently associated with high impacts.ConclusionsOlder women with sarcopenia experienced fewer bone-strengthening high impacts than those with pre-sarcopenia or without sarcopenia. To increase bone strengthening activity in older women, interventions need to improve both lower limb muscle force and walking speed.

The purpose of this study was to establish the feasibility of using an aerobics class to producepotentially bone protective vertical impacts of ≥ 4g in older adults and to determine whetherimpacts can be predicted by physical function. Participants recruited from older adult exerciseclasses completed an SF-12 questionnaire, short physical performance battery, and an aerobicsclass with seven different components, performed at low and high intensity. Maximum g and jerkvalues 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. Inmultivariate analyses, age (–0.53; –0.77, –0.28) (standardized beta coefficient; 95% CI) and 4-mwalk time (–0.39; –0.63, –0.16) were inversely related to maximum g. Aerobics classes can beused to produce relatively high vertical accelerations in older individuals, although the outcome isstrongly dependent on age and physical function.

Additional file 1: Supplementary Table 1. Baseline characteristics for those with and without follow-up data, Supplementary Figure 1. associations between HBM and incident OA and incident and progressive OA sub-phenotypes in person-level analyses.

Additional file 1: Supplementary Table 1. Baseline characteristics for those with and without follow-up data, Supplementary Figure 1. associations between HBM and incident OA and incident and progressive OA sub-phenotypes in person-level analyses.

Sclerostin inhibition is a new therapeutic approach for increasing bone mineral density (BMD) but its cardiovascular safety is unclear. We conducted a genome-wide association study (GWAS) meta-analysis of circulating sclerostin in 33,961 Europeans followed by Mendelian randomization (MR) to estimate the causal effects of sclerostin on 15 atherosclerosis-related diseases and risk factors. GWAS meta-analysis identified 18 variants independently associated with sclerostin, which including a novel cis signal in the SOST region and three trans signals in B4GALNT3, RIN3 and SERPINA1 regions that were associated with opposite effects on circulating sclerostin and eBMD. MR combining these four SNPs suggested lower sclerostin increased hypertension risk (odds ratio [OR]=1.09, 95%CI=1.04 to 1.15), whereas bi-directional analyses revealed little evidence for an effect of genetic liability to hypertension on sclerostin levels. MR restricted to cis (SOST) SNPs additionally suggested sclerostin inhibition increased risk of type 2 diabetes (T2DM) (OR=1.26; 95%CI=1.08 to 1.48) and myocardial infarction (MI) (OR=1.31, 95% CI=1.183 to 1.45). Furthermore, these analyses suggested sclerostin inhibition increased coronary artery calcification (CAC) (β=0.74, 95%CI=0.33 to 1.15), levels of apoB (β=0.07; 95%CI=0.04 to 0.10; this result was driven by rs4793023) and triglycerides (β=0.18; 95%CI=0.13 to 0.24), and reduced HDL-C (β=-0.14; 95%CI=-0.17 to -0.10). This study provides genetic evidence to support a causal effect of sclerostin inhibition on increased hypertension risk. Cis-only analyses suggested that sclerostin inhibition additionally increases the risk of T2DM, MI, CAC, and an atherogenic lipid profile. Together, our findings reinforce the requirement for strategies to mitigate against adverse effects of sclerostin inhibitors like romosozumab on atherosclerosis and its related risk factors.

BackgroundIndividuals with high bone mass (HBM) have a greater odds of prevalent radiographic hip osteoarthritis (OA), reflecting an association with bone-forming OA sub-phenotypes (e.g. osteophytosis, subchondral sclerosis). As the role of bone mineral density (BMD) in hip OA progression is unclear, we aimed to determine if individuals with HBM have increased incidence and/or progression of bone-forming OA sub-phenotypes.MethodsWe analysed an adult cohort with and without HBM (L1 and/or total hip BMDZ-score > + 3.2) with pelvic radiographs collected at baseline and 8-year follow-up. Sub-phenotypes were graded using the OARSI atlas. Superior/inferior acetabular/femoral osteophyte and medial/superior joint space narrowing (JSN) grades were summed and Δosteophyte and ΔJSN derived. Pain and functional limitations were quantified using the WOMAC questionnaire. Associations between HBM status and change in OA sub-phenotypes were determined using multivariable linear/logistic regression, adjusting for age, sex, height, total body fat mass, follow-up time and baseline sub-phenotype grade. Generalised estimating equations accounted for individual-level clustering.ResultsOf 136 individuals, 62% had HBM at baseline, 72% were female and mean (SD) age was 59 (10) years. HBM was positively associated with both Δosteophytes and ΔJSN (adjusted mean grade differences between individuals with and without HBMβosteophyte = 0.30 [0.01, 0.58],p = 0.019 andβJSN = 0.10 [0.01, 0.18],p = 0.019). Incident subchondral sclerosis was rare. HBM individuals had higher WOMAC hip functional limitation scores (β = 8.3 [0.7, 15.98],p = 0.032).ConclusionsHBM is associated with the worsening of hip osteophytes and JSN over an average of 8 years, as well as increased hip pain and functional limitation.