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Osteoporosis: HELP
Articles by Stephen K. Kaptoge
Based on 9 articles published since 2010
(Why 9 articles?)
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Between 2010 and 2020, S. Kaptoge wrote the following 9 articles about Osteoporosis.
 
+ Citations + Abstracts
1 Article An atlas of genetic influences on osteoporosis in humans and mice. 2019

Morris, John A / Kemp, John P / Youlten, Scott E / Laurent, Laetitia / Logan, John G / Chai, Ryan C / Vulpescu, Nicholas A / Forgetta, Vincenzo / Kleinman, Aaron / Mohanty, Sindhu T / Sergio, C Marcelo / Quinn, Julian / Nguyen-Yamamoto, Loan / Luco, Aimee-Lee / Vijay, Jinchu / Simon, Marie-Michelle / Pramatarova, Albena / Medina-Gomez, Carolina / Trajanoska, Katerina / Ghirardello, Elena J / Butterfield, Natalie C / Curry, Katharine F / Leitch, Victoria D / Sparkes, Penny C / Adoum, Anne-Tounsia / Mannan, Naila S / Komla-Ebri, Davide S K / Pollard, Andrea S / Dewhurst, Hannah F / Hassall, Thomas A D / Beltejar, Michael-John G / Anonymous2961133 / Adams, Douglas J / Vaillancourt, Suzanne M / Kaptoge, Stephen / Baldock, Paul / Cooper, Cyrus / Reeve, Jonathan / Ntzani, Evangelia E / Evangelou, Evangelos / Ohlsson, Claes / Karasik, David / Rivadeneira, Fernando / Kiel, Douglas P / Tobias, Jonathan H / Gregson, Celia L / Harvey, Nicholas C / Grundberg, Elin / Goltzman, David / Adams, David J / Lelliott, Christopher J / Hinds, David A / Ackert-Bicknell, Cheryl L / Hsu, Yi-Hsiang / Maurano, Matthew T / Croucher, Peter I / Williams, Graham R / Bassett, J H Duncan / Evans, David M / Richards, J Brent. ·Department of Human Genetics, McGill University, Montréal, Québec, Canada. · Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada. · University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia. · MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. · Garvan Institute of Medical Research, Sydney, New South Wales, Australia. · Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK. · Institute for Systems Genetics, New York University Langone Medical Center, New York, NY, USA. · Department of Research, 23andMe, Inc., Mountain View, CA, USA. · Research Institute of the McGill University Health Centre, Montréal, Québec, Canada. · McGill University and Genome Quebec Innovation Centre, Montréal, Québec, Canada. · Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Biomedical Genetics, University of Rochester, Rochester, NY, USA. · Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. · Department of Medicine, McGill University, Montréal, Québec, Canada. · Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. · MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK. · NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK. · NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK. · Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece. · Center for Evidence Synthesis in Health, Department of Health Services, Policy and Practice, School of Public Health, Brown University, Providence, RI, USA. · Department of Epidemiology and Biostatistics, Imperial College London, London, UK. · Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Gothenburg, Sweden. · Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA. · Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. · Department of Medicine, Harvard Medical School, Boston, MA, USA. · Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA, USA. · Musculoskeletal Research Unit, Department of Translational Health Sciences, University of Bristol, Bristol, UK. · Children's Mercy Hospitals and Clinics, Kansas City, MO, USA. · Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK. · Center for Musculoskeletal Research, Department of Orthopaedics, University of Rochester, Rochester, NY, USA. · University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia. d.evans1@uq.edu.au. · MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. d.evans1@uq.edu.au. · Department of Human Genetics, McGill University, Montréal, Québec, Canada. brent.richards@mcgill.ca. · Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada. brent.richards@mcgill.ca. · Department of Medicine, McGill University, Montréal, Québec, Canada. brent.richards@mcgill.ca. · Department of Epidemiology, Biostatistics & Occupational Health, McGill University, Montréal, Québec, Canada. brent.richards@mcgill.ca. · Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. brent.richards@mcgill.ca. ·Nat Genet · Pubmed #30598549.

ABSTRACT: Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10

2 Article Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density. 2018

Alonso, Nerea / Estrada, Karol / Albagha, Omar M E / Herrera, Lizbeth / Reppe, Sjur / Olstad, Ole K / Gautvik, Kaare M / Ryan, Niamh M / Evans, Kathryn L / Nielson, Carrie M / Hsu, Yi-Hsiang / Kiel, Douglas P / Markozannes, George / Ntzani, Evangelia E / Evangelou, Evangelos / Feenstra, Bjarke / Liu, Xueping / Melbye, Mads / Masi, Laura / Brandi, Maria Luisa / Riches, Philip / Daroszewska, Anna / Olmos, José Manuel / Valero, Carmen / Castillo, Jesús / Riancho, José A / Husted, Lise B / Langdahl, Bente L / Brown, Matthew A / Duncan, Emma L / Kaptoge, Stephen / Khaw, Kay-Tee / Usategui-Martín, Ricardo / Del Pino-Montes, Javier / González-Sarmiento, Rogelio / Lewis, Joshua R / Prince, Richard L / D'Amelio, Patrizia / García-Giralt, Natalia / Nogués, Xavier / Mencej-Bedrac, Simona / Marc, Janja / Wolstein, Orit / Eisman, John A / Oei, Ling / Medina-Gómez, Carolina / Schraut, Katharina E / Navarro, Pau / Wilson, James F / Davies, Gail / Starr, John / Deary, Ian / Tanaka, Toshiko / Ferrucci, Luigi / Gianfrancesco, Fernando / Gennari, Luigi / Lucas, Gavin / Elosua, Roberto / Uitterlinden, André G / Rivadeneira, Fernando / Ralston, Stuart H. ·Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. · Departments of Internal Medicine and Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands. · Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar. · Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway. · Department of Clinical Biochemistry, Lovisenberg Diakonale Hospital, Oslo, Norway. · Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. · Centre for Genomic and Experimental Medicine, IGMM, University of Edinburgh, Edinburgh, UK. · Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK. · Department of Public Health and Preventive Medicine, Oregon Health and Science University, Portland, Oregon, USA. · Department of Medicine Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA. · BROAD Institute of MIT and Harvard, Cambridge, Massachusetts, USA. · Musculoskeletal Research Center, Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts, USA. · Harvard Medical School, Boston, Massachusetts, USA. · Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece. · Centre for Evidence Synthesis in Health, Department of Health Services, Policy and Practice, School of Public Health, Brown University, Rhode Island, USA. · Department of Epidemiology and Biostatistics, Imperial College London, London, UK. · Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. · Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · Department of Medicine, Stanford School of Medicine, Stanford, California, USA. · Department of Surgery and Translational Medicine, University of Florence, Florence, Italy. · Institute of Ageing and Chronic Disease, The MRC-Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing, University of Liverpool, Liverpool, UK. · Department of Internal Medicine, Hospital UM Valdecilla, University of Cantabria, IDIVAL, RETICEF, Santander, Spain. · Department of Endocrinology and Internal Medicine THG, Aarhus University Hospital, Aarhus, Denmark. · Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia. · Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia. · Department of Endocrinology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia. · Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. · Department of Public Health and Primary Care, School of Medicine, University of Cambridge, Cambridge, UK. · Molecular Medicine Unit, Department of Medicine and Biomedical Research Institute of Salamanca (IBSAL), University Hospital of Salamanca, University of Salamanca - CSIC, Salamanca, Spain. · School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia. · Centre for Kidney Research, School of Public Health, University of Sydney, Sydney, New South Wales, Australia. · School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia. · Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia. · Gerontology and Bone Metabolic Diseases Unit, Department of Medical Science, University of Torino, Torino, Italy. · Department of Internal Medicine, Hospital del Mar-IMIM, RETICEF, Universitat Autonoma de Barcelona, Barcelona, Spain. · Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia. · Osteoporosis and Bone Biology Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. · Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK. · Edinburgh/British Heart Foundation Centre for Cardiovascular Science, QMRI, University of Edinburgh, Edinburgh, UK. · MRC Human Genetics Unit, MRC, IGMM, University of Edinburgh, Edinburgh, UK. · Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA. · Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council of Italy, Naples, Italy. · Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy. · Grup de Recerca en Genètica i Epidemiologia Cardiovascular, IMIM, Barcelona, Spain. ·Ann Rheum Dis · Pubmed #29170203.

ABSTRACT: OBJECTIVES: To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis. METHODS: Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies. RESULTS: A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10 CONCLUSION: We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism.

3 Article Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis. 2017

Kemp, John P / Morris, John A / Medina-Gomez, Carolina / Forgetta, Vincenzo / Warrington, Nicole M / Youlten, Scott E / Zheng, Jie / Gregson, Celia L / Grundberg, Elin / Trajanoska, Katerina / Logan, John G / Pollard, Andrea S / Sparkes, Penny C / Ghirardello, Elena J / Allen, Rebecca / Leitch, Victoria D / Butterfield, Natalie C / Komla-Ebri, Davide / Adoum, Anne-Tounsia / Curry, Katharine F / White, Jacqueline K / Kussy, Fiona / Greenlaw, Keelin M / Xu, Changjiang / Harvey, Nicholas C / Cooper, Cyrus / Adams, David J / Greenwood, Celia M T / Maurano, Matthew T / Kaptoge, Stephen / Rivadeneira, Fernando / Tobias, Jonathan H / Croucher, Peter I / Ackert-Bicknell, Cheryl L / Bassett, J H Duncan / Williams, Graham R / Richards, J Brent / Evans, David M. ·University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia. · MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. · Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada. · Department of Human Genetics, McGill University, Montréal, Québec, Canada. · Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands. · Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands. · Division of Obstetrics and Gynaecology, The University of Western Australia, Perth, Western Australia, Australia. · Garvan Institute of Medical Research, Sydney, New South Wales, Australia. · St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia. · Musculoskeletal Research Unit, Department of Translational Health Sciences, University of Bristol, Bristol, UK. · Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK. · Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK. · Donnelly Center for Cellular and Biomedical Research, University of Toronto, Toronto, Ontario, Canada. · MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK. · NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK. · NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK. · Gerald Bronfman Department of Oncology, McGill University, Montréal, Québec, Canada. · Department of Epidemiology, Biostatistics &Occupational Health, McGill University, Montréal, Québec, Canada. · Department of Pathology and Institute for Systems Genetics, New York University Langone Medical Center, New York, New York, USA. · Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. · Strangeways Research Laboratory, Cambridge, UK. · School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia. · Center for Musculoskeletal Research, Department of Orthopaedics, University of Rochester, Rochester, New York, USA. · Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. ·Nat Genet · Pubmed #28869591.

ABSTRACT: Osteoporosis is a common disease diagnosed primarily by measurement of bone mineral density (BMD). We undertook a genome-wide association study (GWAS) in 142,487 individuals from the UK Biobank to identify loci associated with BMD as estimated by quantitative ultrasound of the heel. We identified 307 conditionally independent single-nucleotide polymorphisms (SNPs) that attained genome-wide significance at 203 loci, explaining approximately 12% of the phenotypic variance. These included 153 previously unreported loci, and several rare variants with large effect sizes. To investigate the underlying mechanisms, we undertook (1) bioinformatic, functional genomic annotation and human osteoblast expression studies; (2) gene-function prediction; (3) skeletal phenotyping of 120 knockout mice with deletions of genes adjacent to lead independent SNPs; and (4) analysis of gene expression in mouse osteoblasts, osteocytes and osteoclasts. The results implicate GPC6 as a novel determinant of BMD, and also identify abnormal skeletal phenotypes in knockout mice associated with a further 100 prioritized genes.

4 Article Degenerative inter-vertebral disc disease osteochondrosis intervertebralis in Europe: prevalence, geographic variation and radiological correlates in men and women aged 50 and over. 2017

Armbrecht, Gabriele / Felsenberg, Dieter / Ganswindt, Melanie / Lunt, Mark / Kaptoge, Stephen K / Abendroth, Klaus / Aroso Dias, Antonio / Bhalla, Ashok K / Cannata Andia, Jorge / Dequeker, Jan / Eastell, Richard / Hoszowski, Krzysztof / Lyritis, George / Masaryk, Pavol / van Meurs, Joyce / Miazgowski, Tomasz / Nuti, Ranuccio / Poór, Gyula / Redlund-Johnell, Inga / Reid, David M / Schatz, Helmut / Todd, Christopher J / Woolf, Anthony D / Rivadeneira, Fernando / Javaid, Muhammad K / Cooper, Cyrus / Silman, Alan J / O'Neill, Terence W / Reeve, Jonathan / Anonymous5221111. ·Department of Radiology and Nuclear Medicine, Free University, Berlin, Germany. · NIHR Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, & Arthritis Research UK Centre for Epidemiology, Manchester, University of Manchester. · Department of Public Health and Primary Care, Strangeways Research Laboratory, Cambridge, UK. · Klinik fur Innere Medezin IV, Jena, Germany. · Rheumatology, Hospital de San Joao, Oporto, Portugal. · Rheumatology, Royal National Hospital for Rheumatic Diseases, Bath, UK. · Nephrology, Asturias General Hospital, Oviedo, Spain. · Rheumatology, University Hospital, Leuven, Belgium. · Mellanby Centre for Bone Research, University of Sheffield, Sheffield, UK. · Medicine, PKP Hospital, Warsaw, Poland. · Laboratory for the Research of Musculoskeletal System, University of Athens, Athens, Greece. · Rheumatology, Institute of Rheumatic Diseases, Piestany, Slovakia. · Department of Epidemiology and Department of Internal Medicine, Erasmus University, Rotterdam, Netherlands. · Department of Hypertension and Internal Medicine, Pomeranian Medical University, Szczecin, Poland. · Institute of Clinical Medicine, University of Siena, Siena, Italy. · 1st Department of Rheumatology and Metabolic Osteology, National Institute of Rheumatology and Physiotherapy, Budapest, Hungary. · Orthopaedics and Radiology, Malmö General Hospital, Malmö, Sweden. · School of Medicine, Medical Science and Nutrition, University of Aberdeen, Aberdeen, UK. · Rheumatology, Med Klinik & Polyklinik, Bochum, Germany. · School of Health Sciences, The University of Manchester, Oxford Road, Manchester. · Institute of Health Care Research, Peninsula College of Medicine and Dentistry, Universities of Exeter and Plymouth, Royal Cornwall Hospital, Truro. · Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, NIHR Musculo-skeletal Biomedical Research Unit, Botnar Research Centre, Oxford, UK. ·Rheumatology (Oxford) · Pubmed #28398504.

ABSTRACT: Objectives: To assess the prevalences across Europe of radiological indices of degenerative inter-vertebral disc disease (DDD); and to quantify their associations with, age, sex, physical anthropometry, areal BMD (aBMD) and change in aBMD with time. Methods: In the population-based European Prospective Osteoporosis Study, 27 age-stratified samples of men and women from across the continent aged 50+ years had standardized lateral radiographs of the lumbar and thoracic spine to evaluate the severity of DDD, using the Kellgren-Lawrence (KL) scale. Measurements of anterior, mid-body and posterior vertebral heights on all assessed vertebrae from T4 to L4 were used to generate indices of end-plate curvature. Results: Images from 10 132 participants (56% female, mean age 63.9 years) passed quality checks. Overall, 47% of men and women had DDD grade 3 or more in the lumbar spine and 36% in both thoracic and lumbar spine. Risk ratios for DDD grades 3 and 4, adjusted for age and anthropometric determinants, varied across a three-fold range between centres, yet prevalences were highly correlated in men and women. DDD was associated with flattened, non-ovoid inter-vertebral disc spaces. KL grade 4 and loss of inter-vertebral disc space were associated with higher spine aBMD. Conclusion: KL grades 3 and 4 are often used clinically to categorize radiological DDD. Highly variable European prevalences of radiologically defined DDD grades 3+ along with the large effects of age may have growing and geographically unequal health and economic impacts as the population ages. These data encourage further studies of potential genetic and environmental causes.

5 Article Vertebral Scheuermann's disease in Europe: prevalence, geographic variation and radiological correlates in men and women aged 50 and over. 2015

Armbrecht, G / Felsenberg, D / Ganswindt, M / Lunt, M / Kaptoge, S K / Abendroth, K / Aroso, A / Banzer, D / Bhalla, A K / Dequeker, J / Eastell, R / Hoszowski, K / Lyritis, G / Delmas, P D / Masaryk, P / Miazgowski, T / Cannata, J / Nuti, R / Oei, L / Poor, G / Redlund-Johnell, I / Reid, D M / Reisinger, W / Schatz, H / Todd, C J / Woolf, A D / Javaid, K / Rivadeneira, F / Silman, A J / Cooper, C / O'Neill, T W / Reeve, J / Anonymous5090831. ·Department of Radiology and Nuclear Medicine, Free University, Berlin, Germany. · ARC Epidemiology Unit, University of Manchester Musculoskeletal Biomedical Research Unit & Arthritis Research UK Centre for Epidemiology, Manchester, UK. · Department of Public Health and Primary Care, Strangeways Research Laboratory, Cambridge, UK. · Klinik fur Innere Medezin IV, Jena, Germany. · Hospital de San Joao, Oporto, Portugal. · Röntgen u Nuklearmed, Krankenhaus Behring, Berlin, Germany. · Royal National Hospital for Rheumatic Diseases, Bath, UK. · University Hospital, Leuven, Belgium. · Department of Human Metabolism, University of Sheffield, Sheffield, UK. · PKP Hospital, Warsaw, Poland. · Laboratory for Research on the Musculoskeletal System, University of Athens, Athens, Greece. · Centre de Médécine Specialisée Claude Gauthier, Montceau-les-Mines France & U Inserm 504, Lyon, France. · Institute of Rheumatic Diseases, Piestany, Slovakia. · Department of Hypertension, Pomeranian Medical University, Szczecin, Poland. · Asturias General Hospital, Oviedo, Spain. · Institute of Clinical Medicine, University of Siena, Siena, Italy. · Departments of Epidemiology and Internal Medicine, Erasmus University, Rotterdam, Netherlands. · National Institute of Rheumatology and Physiotherapy, Budapest, Hungary. · Orthopaedics and Radiology, Malmö General Hospital, Malmö, Sweden. · School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK. · Charité Inst fur Rontgendiagnostik, Berlin, Germany. · Med Klinik & Polyklinik Bochum, Bochum, Germany. · School of Nursing, Midwifery and Social Work, University of Manchester, Manchester, UK. · Royal Cornwall Hospital, Truro, UK. · NIHR Musculo-skeletal Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre & Institute of Musculoskeletal Sciences, Windmill Road, Oxford, OX3 7LD, UK. · Arthritis Research UK, Chesterfield, S41 7TD, UK. · NIHR Musculo-skeletal Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre & Institute of Musculoskeletal Sciences, Windmill Road, Oxford, OX3 7LD, UK. jonathan.reeve@ndorms.ox.ac.uk. ·Osteoporos Int · Pubmed #26021761.

ABSTRACT: INTRODUCTION: This study aims to assess the prevalence of Scheuermann's disease of the spine across Europe in men and women over 50 years of age, to quantitate its association with bone mineral density (BMD) and to assess its role as a confounder for the radiographic diagnosis of osteoporotic fracture. METHODS: In 27 centres participating in the population-based European Vertebral Osteoporosis Study (EVOS), standardised lateral radiographs of the lumbar and of the thoracic spine from T4 to L4 were assessed in all those of adequate quality. The presence of Scheuermann's disease, a confounder for prevalent fracture in later life, was defined by the presence of at least one Schmorl's node or irregular endplate together with kyphosis (sagittal Cobb angle >40° between T4 and T12) or a wedged-shaped vertebral body. Alternatively, the (rare) Edgren-Vaino sign was taken as diagnostic. The 6-point-per-vertebral-body (13 vertebrae) method was used to assess osteoporotic vertebral shape and fracture caseness. DXA BMD of the L2-L4 and femoral neck regions was measured in subsets. We also assessed the presence of Scheuermann's by alternative published algorithms when these used the radiographic signs we assessed. RESULTS: Vertebral radiographic images from 4486 men and 5655 women passed all quality checks. Prevalence of Scheuermann's varied considerably between centres, and based on random effect modelling, the overall European prevalence using our method was 8% with no significant difference between sexes. The highest prevalences were seen in Germany, Sweden, the UK and France and low prevalences were seen in Hungary, Poland and Slovakia. Centre-level prevalences in men and women were highly correlated. Scheuermann's was not associated with BMD of the spine or hip. CONCLUSIONS: Since most of the variation in population impact of Scheuermann's was unaccounted for by the radiological and anthropometric data, the search for new genetic and environmental determinants of this disease is encouraged.

6 Article Predictive ability of heel quantitative ultrasound for incident fractures: an individual-level meta-analysis. 2015

McCloskey, E V / Kanis, J A / Odén, A / Harvey, N C / Bauer, D / González-Macias, J / Hans, D / Kaptoge, S / Krieg, M A / Kwok, T / Marin, F / Moayyeri, A / Orwoll, E / Gluёr, C / Johansson, H. ·Academic Unit of Bone Metabolism and Mellanby Centre for Bone Research, University of Sheffield, Metabolic Bone Centre, Northern General Hospital, Herries Road, Sheffield, S5 7AU, UK, e.v.mccloskey@sheffield.ac.uk. ·Osteoporos Int · Pubmed #25690339.

ABSTRACT: INTRODUCTION: The aim of this meta-analysis was to investigate the association between parameters of QUS and risk of fracture. METHODS: In an individual-level analysis, we studied participants in nine prospective cohorts from Asia, Europe and North America. Heel broadband ultrasonic attenuation (BUA dB/MHz) and speed of sound (SOS m/s) were measured at baseline. Fractures during follow-up were collected by self-report and in some cohorts confirmed by radiography. An extension of Poisson regression was used to examine the gradient of risk (GR, hazard ratio per 1 SD decrease) between QUS and fracture risk adjusted for age and time since baseline in each cohort. Interactions between QUS and age and time since baseline were explored. RESULTS: Baseline measurements were available in 46,124 men and women, mean age 70 years (range 20-100). Three thousand and eighteen osteoporotic fractures (787 hip fractures) occurred during follow-up of 214,000 person-years. The summary GR for osteoporotic fracture was similar for both BUA (1.45, 95 % confidence intervals (CI) 1.40-1.51) and SOS (1.42, 95 % CI 1.36-1.47). For hip fracture, the respective GRs were 1.69 (95 % CI, 1.56-1.82) and 1.60 (95 % CI, 1.48-1.72). However, the GR was significantly higher for both fracture outcomes at lower baseline BUA and SOS (p < 0.001). The predictive value of QUS was the same for men and women and for all ages (p > 0.20), but the predictive value of both BUA and SOS for osteoporotic fracture decreased with time (p = 0.018 and p = 0.010, respectively). For example, the GR of BUA for osteoporotic fracture, adjusted for age, was 1.51 (95 % CI 1.42-1.61) at 1 year after baseline, but at 5 years, it was 1.36 (95 % CI 1.27-1.46). CONCLUSIONS: Our results confirm that quantitative ultrasound is an independent predictor of fracture for men and women particularly at low QUS values.

7 Article Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium. 2014

Moayyeri, Alireza / Hsu, Yi-Hsiang / Karasik, David / Estrada, Karol / Xiao, Su-Mei / Nielson, Carrie / Srikanth, Priya / Giroux, Sylvie / Wilson, Scott G / Zheng, Hou-Feng / Smith, Albert V / Pye, Stephen R / Leo, Paul J / Teumer, Alexander / Hwang, Joo-Yeon / Ohlsson, Claes / McGuigan, Fiona / Minster, Ryan L / Hayward, Caroline / Olmos, José M / Lyytikäinen, Leo-Pekka / Lewis, Joshua R / Swart, Karin M A / Masi, Laura / Oldmeadow, Chris / Holliday, Elizabeth G / Cheng, Sulin / van Schoor, Natasja M / Harvey, Nicholas C / Kruk, Marcin / del Greco M, Fabiola / Igl, Wilmar / Trummer, Olivia / Grigoriou, Efi / Luben, Robert / Liu, Ching-Ti / Zhou, Yanhua / Oei, Ling / Medina-Gomez, Carolina / Zmuda, Joseph / Tranah, Greg / Brown, Suzanne J / Williams, Frances M / Soranzo, Nicole / Jakobsdottir, Johanna / Siggeirsdottir, Kristin / Holliday, Kate L / Hannemann, Anke / Go, Min Jin / Garcia, Melissa / Polasek, Ozren / Laaksonen, Marika / Zhu, Kun / Enneman, Anke W / McEvoy, Mark / Peel, Roseanne / Sham, Pak Chung / Jaworski, Maciej / Johansson, Åsa / Hicks, Andrew A / Pludowski, Pawel / Scott, Rodney / Dhonukshe-Rutten, Rosalie A M / van der Velde, Nathalie / Kähönen, Mika / Viikari, Jorma S / Sievänen, Harri / Raitakari, Olli T / González-Macías, Jesús / Hernández, Jose L / Mellström, Dan / Ljunggren, Osten / Cho, Yoon Shin / Völker, Uwe / Nauck, Matthias / Homuth, Georg / Völzke, Henry / Haring, Robin / Brown, Matthew A / McCloskey, Eugene / Nicholson, Geoffrey C / Eastell, Richard / Eisman, John A / Jones, Graeme / Reid, Ian R / Dennison, Elaine M / Wark, John / Boonen, Steven / Vanderschueren, Dirk / Wu, Frederick C W / Aspelund, Thor / Richards, J Brent / Bauer, Doug / Hofman, Albert / Khaw, Kay-Tee / Dedoussis, George / Obermayer-Pietsch, Barbara / Gyllensten, Ulf / Pramstaller, Peter P / Lorenc, Roman S / Cooper, Cyrus / Kung, Annie Wai Chee / Lips, Paul / Alen, Markku / Attia, John / Brandi, Maria Luisa / de Groot, Lisette C P G M / Lehtimäki, Terho / Riancho, José A / Campbell, Harry / Liu, Yongmei / Harris, Tamara B / Akesson, Kristina / Karlsson, Magnus / Lee, Jong-Young / Wallaschofski, Henri / Duncan, Emma L / O'Neill, Terence W / Gudnason, Vilmundur / Spector, Timothy D / Rousseau, François / Orwoll, Eric / Cummings, Steven R / Wareham, Nick J / Rivadeneira, Fernando / Uitterlinden, Andre G / Prince, Richard L / Kiel, Douglas P / Reeve, Jonathan / Kaptoge, Stephen K. ·Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. ·Hum Mol Genet · Pubmed #24430505.

ABSTRACT: Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

8 Article A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus. 2014

Oei, Ling / Hsu, Yi-Hsiang / Styrkarsdottir, Unnur / Eussen, Bert H / de Klein, Annelies / Peters, Marjolein J / Halldorsson, Bjarni / Liu, Ching-Ti / Alonso, Nerea / Kaptoge, Stephen K / Thorleifsson, Gudmar / Hallmans, Göran / Hocking, Lynne J / Husted, Lise Bjerre / Jameson, Karen A / Kruk, Marcin / Lewis, Joshua R / Patel, Millan S / Scollen, Serena / Svensson, Olle / Trompet, Stella / van Schoor, Natasja M / Zhu, Kun / Buckley, Brendan M / Cooper, Cyrus / Ford, Ian / Goltzman, David / González-Macías, Jesús / Langdahl, Bente Lomholt / Leslie, William D / Lips, Paul / Lorenc, Roman S / Olmos, José M / Pettersson-Kymmer, Ulrika / Reid, David M / Riancho, José A / Slagboom, P Eline / Garcia-Ibarbia, Carmen / Ingvarsson, Thorvaldur / Johannsdottir, Hrefna / Luben, Robert / Medina-Gómez, Carolina / Arp, Pascal / Nandakumar, Kannabiran / Palsson, Stefan Th / Sigurdsson, Gunnar / van Meurs, Joyce B J / Zhou, Yanhua / Hofman, Albert / Jukema, J Wouter / Pols, Huibert A P / Prince, Richard L / Cupples, L Adrienne / Marshall, Christian R / Pinto, Dalila / Sato, Daisuke / Scherer, Stephen W / Reeve, Jonathan / Thorsteinsdottir, Unnur / Karasik, David / Richards, J Brent / Stefansson, Kari / Uitterlinden, André G / Ralston, Stuart H / Ioannidis, John P A / Kiel, Douglas P / Rivadeneira, Fernando / Estrada, Karol. ·Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. ·J Med Genet · Pubmed #24343915.

ABSTRACT: BACKGROUND: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk. AIM: To identify CNVs associated with osteoporotic bone fracture risk. METHOD: We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies. RESULTS: A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p = 8.69 × 10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p = 0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk. CONCLUSIONS: These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.

9 Article Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. 2012

Estrada, Karol / Styrkarsdottir, Unnur / Evangelou, Evangelos / Hsu, Yi-Hsiang / Duncan, Emma L / Ntzani, Evangelia E / Oei, Ling / Albagha, Omar M E / Amin, Najaf / Kemp, John P / Koller, Daniel L / Li, Guo / Liu, Ching-Ti / Minster, Ryan L / Moayyeri, Alireza / Vandenput, Liesbeth / Willner, Dana / Xiao, Su-Mei / Yerges-Armstrong, Laura M / Zheng, Hou-Feng / Alonso, Nerea / Eriksson, Joel / Kammerer, Candace M / Kaptoge, Stephen K / Leo, Paul J / Thorleifsson, Gudmar / Wilson, Scott G / Wilson, James F / Aalto, Ville / Alen, Markku / Aragaki, Aaron K / Aspelund, Thor / Center, Jacqueline R / Dailiana, Zoe / Duggan, David J / Garcia, Melissa / Garcia-Giralt, Natàlia / Giroux, Sylvie / Hallmans, Göran / Hocking, Lynne J / Husted, Lise Bjerre / Jameson, Karen A / Khusainova, Rita / Kim, Ghi Su / Kooperberg, Charles / Koromila, Theodora / Kruk, Marcin / Laaksonen, Marika / Lacroix, Andrea Z / Lee, Seung Hun / Leung, Ping C / Lewis, Joshua R / Masi, Laura / Mencej-Bedrac, Simona / Nguyen, Tuan V / Nogues, Xavier / Patel, Millan S / Prezelj, Janez / Rose, Lynda M / Scollen, Serena / Siggeirsdottir, Kristin / Smith, Albert V / Svensson, Olle / Trompet, Stella / Trummer, Olivia / van Schoor, Natasja M / Woo, Jean / Zhu, Kun / Balcells, Susana / Brandi, Maria Luisa / Buckley, Brendan M / Cheng, Sulin / Christiansen, Claus / Cooper, Cyrus / Dedoussis, George / Ford, Ian / Frost, Morten / Goltzman, David / González-Macías, Jesús / Kähönen, Mika / Karlsson, Magnus / Khusnutdinova, Elza / Koh, Jung-Min / Kollia, Panagoula / Langdahl, Bente Lomholt / Leslie, William D / Lips, Paul / Ljunggren, Östen / Lorenc, Roman S / Marc, Janja / Mellström, Dan / Obermayer-Pietsch, Barbara / Olmos, José M / Pettersson-Kymmer, Ulrika / Reid, David M / Riancho, José A / Ridker, Paul M / Rousseau, François / Slagboom, P Eline / Tang, Nelson L S / Urreizti, Roser / Van Hul, Wim / Viikari, Jorma / Zarrabeitia, María T / Aulchenko, Yurii S / Castano-Betancourt, Martha / Grundberg, Elin / Herrera, Lizbeth / Ingvarsson, Thorvaldur / Johannsdottir, Hrefna / Kwan, Tony / Li, Rui / Luben, Robert / Medina-Gómez, Carolina / Palsson, Stefan Th / Reppe, Sjur / Rotter, Jerome I / Sigurdsson, Gunnar / van Meurs, Joyce B J / Verlaan, Dominique / Williams, Frances M K / Wood, Andrew R / Zhou, Yanhua / Gautvik, Kaare M / Pastinen, Tomi / Raychaudhuri, Soumya / Cauley, Jane A / Chasman, Daniel I / Clark, Graeme R / Cummings, Steven R / Danoy, Patrick / Dennison, Elaine M / Eastell, Richard / Eisman, John A / Gudnason, Vilmundur / Hofman, Albert / Jackson, Rebecca D / Jones, Graeme / Jukema, J Wouter / Khaw, Kay-Tee / Lehtimäki, Terho / Liu, Yongmei / Lorentzon, Mattias / McCloskey, Eugene / Mitchell, Braxton D / Nandakumar, Kannabiran / Nicholson, Geoffrey C / Oostra, Ben A / Peacock, Munro / Pols, Huibert A P / Prince, Richard L / Raitakari, Olli / Reid, Ian R / Robbins, John / Sambrook, Philip N / Sham, Pak Chung / Shuldiner, Alan R / Tylavsky, Frances A / van Duijn, Cornelia M / Wareham, Nick J / Cupples, L Adrienne / Econs, Michael J / Evans, David M / Harris, Tamara B / Kung, Annie Wai Chee / Psaty, Bruce M / Reeve, Jonathan / Spector, Timothy D / Streeten, Elizabeth A / Zillikens, M Carola / Thorsteinsdottir, Unnur / Ohlsson, Claes / Karasik, David / Richards, J Brent / Brown, Matthew A / Stefansson, Kari / Uitterlinden, André G / Ralston, Stuart H / Ioannidis, John P A / Kiel, Douglas P / Rivadeneira, Fernando. ·Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. ·Nat Genet · Pubmed #22504420.

ABSTRACT: Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.