Circulating sclerostin levels are positively related to coronary artery disease severity and related risk factors

Romosozumab is a newly available treatment for osteoporosis acting by sclerostin inhibition. Its cardiovascular safety has been questioned after finding excess cardiovascular disease (CVD)‐related events in a pivotal phase 3 trial. Previous studies of relationships between circulating sclerostin levels and CVD and associated risk factors have yielded conflicting findings, likely reflecting small numbers and selected patient groups. We aimed to characterize relationships between sclerostin and CVD and related risk factors in more detail by examining these in two large cohorts, Ludwigshafen Risk and Cardiovascular Health study (LURIC; 34% female, mean age 63.0 years) and Avon Longitudinal Study of Parents and Children study (ALSPAC) mothers (mean age 48.1 years). Together these provided 5069 participants with complete data. Relationships between sclerostin and CVD risk factors were meta‐analyzed, adjusted for age, sex (LURIC), body mass index, smoking, social deprivation, and ethnicity (ALSPAC). Higher sclerostin levels were associated with higher risk of diabetes mellitus (DM) (odds ratio [OR] = 1.25; 95% confidence interval [CI] 1.12, 1.37), risk of elevated fasting glucose (OR 1.15; CI 1.04, 1.26), and triglyceride levels (β 0.03; CI 0.00, 0.06). Conversely, higher sclerostin was associated with lower estimated glomerular filtration rate (eGFR) (β −0.20; CI −0.38, −0.02), HDL cholesterol (β −0.05; CI −0.10, −0.01), and apolipoprotein A‐I (β −0.05; CI −0.08, −0.02) (difference in mean SD per SD increase in sclerostin, with 95% CI). In LURIC, higher sclerostin was associated with an increased risk of death from cardiac disease during follow‐up (hazard ratio [HR] = 1.13; 1.03, 1.23) and with severity of coronary artery disease on angiogram as reflected by Friesinger score (0.05; 0.01, 0.09). Associations with cardiac mortality and coronary artery severity were partially attenuated after adjustment for risk factors potentially related to sclerostin, namely LDL and HDL cholesterol, log triglycerides, DM, hypertension, eGFR, and apolipoprotein A‐I. Contrary to trial evidence suggesting sclerostin inhibition leads to an increased risk of CVD, sclerostin levels appear to be positively associated with coronary artery disease severity and mortality, partly explained by a relationship between higher sclerostin levels and major CVD risk factors. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)

Cam morphology but neither acetabular dysplasia nor pincer morphology is associated with osteophytosis throughout the hip: findings from a cross-sectional study in UK Biobank

Objectives: to examine whether acetabular dysplasia (AD), cam and/or pincer morphology are associated with radiographic hip osteoarthritis (rHOA) and hip pain in UK Biobank (UKB) and, if so, what distribution of osteophytes is observed.Design: participants from UKB with a left hip dual-energy X-ray absorptiometry (DXA) scan had alpha angle (AA), lateral centre-edge angle (LCEA) and joint space narrowing (JSN) derived automatically. Cam and pincer morphology, and AD were defined using AA and LCEA. Osteophytes were measured manually and rHOA grades were calculated from JSN and osteophyte measures. Logistic regression was used to examine the relationships between these hip morphologies and rHOA, osteophytes, JSN, and hip pain.Results: 6,807 individuals were selected (mean age: 62.7; 3382/3425 males/females). Cam morphology was more prevalent in males than females (15.4% and 1.8% respectively). In males, cam morphology was associated with rHOA [OR 3.20 (95% CI 2.41–4.25)], JSN [1.53 (1.24–1.88)], and acetabular [1.87 (1.48–2.36)], superior [1.94 (1.45–2.57)] and inferior [4.75 (3.44–6.57)] femoral osteophytes, and hip pain [1.48 (1.05–2.09)]. Broadly similar associations were seen in females, but with weaker statistical evidence. Neither pincer morphology nor AD showed any associations with rHOA or hip pain.Conclusions: cam morphology was predominantly seen in males in whom it was associated with rHOA and hip pain. In males and females, cam morphology was associated with inferior femoral head osteophytes more strongly than those at the superior femoral head and acetabulum. Further studies are justified to characterise the biomechanical disturbances associated with cam morphology, underlying the observed osteophyte distribution

Machine-learning derived acetabular dysplasia and cam morphology are features of severe hip osteoarthritis : findings from UK Biobank

Acknowledgements and disclosures The authors would like to thank Dr Martin Williams, Consultant Musculoskeletal Radiologist North Bristol NHS Trust, who provided substantial training and expertise in osteophyte assessment on DXA images. This research has been conducted using the UK Biobank Resource (application number 17295). Financial Support: RE, MF, FS are supported, and this work is funded by a Wellcome Trust collaborative award (reference number 209233). BGF is supported by a Medical Research Council (MRC) clinical research training fellowship (MR/S021280/1). CL was funded by the MRC, UK (MR/S00405X/1) as well as a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (223267/Z/21/Z). NCH acknowledges support from the MRC and NIHR Southampton Biomedical Research Centre, University of Southampton, and University Hospital Southampton. This research was funded in whole, or in part, by the Wellcome Trust [Grant number 223267/Z/21/Z]. NCH has received consultancy, lecture fees and honoraria from Alliance for Better Bone Health, AMGEN, MSD, Eli Lilly, Servier, UCB, Shire, Consilient Healthcare, Kyowa Kirin and Internis Pharma. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.Peer reviewedPublisher PD

Regenerating zebrafish scales express a subset of evolutionary conserved genes involved in human skeletal disease

BACKGROUND: Scales are mineralised exoskeletal structures that are part of the dermal skeleton. Scales have been mostly lost during evolution of terrestrial vertebrates whilst bony fish have retained a mineralised dermal skeleton in the form of fin rays and scales. Each scale is a mineralised collagen plate that is decorated with both matrix-building and resorbing cells. When removed, an ontogenetic scale is quickly replaced following differentiation of the scale pocket-lining cells that regenerate a scale. Processes promoting de novo matrix formation and mineralisation initiated during scale regeneration are poorly understood. Therefore, we performed transcriptomic analysis to determine gene networks and their pathways involved in dermal scale regeneration. RESULTS: We defined the transcriptomic profiles of ontogenetic and regenerating scales of zebrafish and identified 604 differentially expressed genes (DEGs). These were enriched for extracellular matrix, ossification, and cell adhesion pathways, but not in enamel or dentin formation processes indicating that scales are reminiscent to bone. Hypergeometric tests involving monogenetic skeletal disorders showed that DEGs were strongly enriched for human orthologues that are mutated in low bone mass and abnormal bone mineralisation diseases (P< 2× 10(−3)). The DEGs were also enriched for human orthologues associated with polygenetic skeletal traits, including height (P< 6× 10(−4)), and estimated bone mineral density (eBMD, P< 2× 10(−5)). Zebrafish mutants of two human orthologues that were robustly associated with height (COL11A2, P=6× 10(−24)) or eBMD (SPP1, P=6× 10(−20)) showed both exo- and endo- skeletal abnormalities as predicted by our genetic association analyses; col11a2(Y228X/Y228X) mutants showed exoskeletal and endoskeletal features consistent with abnormal growth, whereas spp1(P160X/P160X) mutants predominantly showed mineralisation defects. CONCLUSION: We show that scales have a strong osteogenic expression profile comparable to other elements of the dermal skeleton, enriched in genes that favour collagen matrix growth. Despite the many differences between scale and endoskeletal developmental processes, we also show that zebrafish scales express an evolutionarily conserved sub-population of genes that are relevant to human skeletal disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12915-021-01209-8

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 β = 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

Automatic Segmentation of Hip Osteophytes in DXA Scans using U-Nets

Osteophytes are distinctive radiographic features of osteo-arthritis (OA) in the form of small bone spurs protruding from joints that contribute significantly to symptoms. Identifying the genetic determinants of osteophytes would improve the understanding of their biological pathways and contributions to OA. To date, this has not been possible due to the costs and challenges associated with manually outlining osteophytes in sufficiently large datasets. Automatic systems that can segment osteophytes would pave the way for this research and also have potential clinical applications. We propose, to the best of our knowledge, the first work on automating pixel-wise segmentation of osteophytes in hip dual-energy x-ray absorptiometry scans (DXAs). Based on U-Nets, we developed an automatic system to detect and segment osteophytes at the superior and the inferior femoral head, and the lateral acetabulum. The system achieved sensitivity, specificity, and average Dice scores (±std) of (0.98, 0.92, 0.71±0.19) for the superior femoral head [793 DXAs], (0.96, 0.85, 0.66±0.24) for the inferior femoral head [409 DXAs], and (0.94, 0.73, 0.64±0.24) for the lateral acetabulum [760 DXAs]. This work enables large-scale genetic analyses of the role of osteophytes in OA, and opens doors to using low-radiation DXAs for screening for radiographic hip OA

Causal relationships between anthropometric traits, bone mineral density, osteoarthritis and spinal stenosis: A Mendelian randomisation investigation

ObjectiveSpinal stenosis is a common condition among older individuals, with significant morbidity attached. Little is known about its risk factors but degenerative conditions, such as osteoarthritis (OA) have been identified for their mechanistic role. This study aims to explore causal relationships between anthropometric risk factors, OA, and spinal stenosis using Mendelian randomisation (MR) techniques.DesignWe applied two-sample MR to investigate the causal relationships between genetic liability for select risk factors and spinal stenosis. Next, we examined the genetic relationship between OA and spinal stenosis with linkage disequilibrium score regression and Causal Analysis Using Summary Effect estimates MR method. Finally, we used multivariable MR (MVMR) to explore whether OA and body mass index (BMI) mediate the causal pathways identified.ResultsOur analysis revealed strong evidence for the effect of higher BMI (odds ratio [OR] = 1.54, 95%CI: 1.41-1.69, p-value = 2.7 × 10−21), waist (OR = 1.43, 95%CI: 1.15-1.79, p-value = 1.5 × 10−3) and hip (OR = 1.50, 95%CI: 1.27-1.78, p-value = 3.3 × 10−6) circumference on spinal stenosis. Strong evidence of causality was also observed for higher bone mineral density (BMD): total body (OR = 1.21, 95%CI: 1.12-1.29, p-value = 1.6 × 10−7), femoral neck (OR = 1.35, 95%CI: 1.09-1.37, p-value = 7.5×10−7), and lumbar spine (OR = 1.38, 95%CI: 1.25-1.52, p-value = 4.4 × 10−11). We detected high genetic correlations between spinal stenosis and OA (rg range: 0.47-0.66), with Causal Analysis Using Summary Effect estimates results supporting a causal effect of OA on spinal stenosis (ORallOA = 1.6, 95%CI: 1.41-1.79). Direct effects of BMI, BMD on spinal stenosis remained after adjusting for OA in the MVMR.ConclusionsGenetic susceptibility to anthropometric risk factors, particularly higher BMI and BMD can increase the risk of spinal stenosis, independent of OA status. These results may inform preventative strategies and treatments

Automatic segmentation of hip osteophytes in DXA scans sing U-nets

Osteophytes are distinctive radiographic features of osteo-arthritis (OA) in the form of small bone spurs protruding from joints that contribute significantly to symptoms. Identifying the genetic determinants of osteophytes would improve the understanding of their biological pathways and contributions to OA. To date, this has not been possible due to the costs and challenges associated with manually outlining osteophytes in sufficiently large datasets. Automatic systems that can segment osteophytes would pave the way for this research and also have potential clinical applications. We propose, to the best of our knowledge, the first work on automating pixel-wise segmentation of osteophytes in hip dual-energy x-ray absorptiometry scans (DXAs). Based on U-Nets, we developed an automatic system to detect and segment osteophytes at the superior and the inferior femoral head, and the lateral acetabulum. The system achieved sensitivity, specificity, and average Dice scores (±std) of (0.98, 0.92, 0.71±0.19) for the superior femoral head [793 DXAs], (0.96, 0.85, 0.66±0.24) for the inferior femoral head [409 DXAs], and (0.94, 0.73, 0.64±0.24) for the lateral acetabulum [760 DXAs]. This work enables large-scale genetic analyses of the role of osteophytes in OA, and opens doors to using low-radiation DXAs for screening for radiographic hip OA