SynthesisArthritis & rheumatology (Hoboken, N.J.)2023
Lowering of Circulating Sclerostin May Increase Risk of Atherosclerosis and Its Risk Factors: Evidence From a Genome-Wide Association Meta-Analysis Followed by Mendelian Randomization.
Open access · hybridAbstract readMeta-Analysis
In one paragraph
Synthesis in Arthritis & rheumatology (Hoboken, N.J.), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
0numbers the graph read from it
0cells of the map it votes in
28citing papers in PubMed, 1 pooled it
10.6field-weighted citation impact, top 1% of its field
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it, 34 citations in OpenAlex.
- Pooled it
- Multi-cohort proteogenomic analyses reveal genetic effects across the proteome and diseasome.Cell · 2026Article
- PHEWAS, TWAS, Mendelian Randomization in Osteoporosis Research: the good, the bad, and the ugly.Current osteoporosis reports · 2026Review
- A new age of osteoanabolic therapy? A real-world, two-centre study comparing effects of romosozumab, teriparatide, and antiresorptive therapies for osteoporosis.Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA · 2026Article
- Comprehensive bioinformatics analysis and experimental validation reveal the role of circadian rhythm-related genes in the crosstalk between osteoporosis and atherosclerosis.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Article
- Effect of genetically proxied plasma sclerostin levels on the risk of ischemic stroke: A drug-target Mendelian randomization study.Medicine · 2026Article
- Macrophagic Sclerostin Loop2-ApoER2 Interaction Required by Sclerostin for Cardiovascular Protective Action.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Interorgan Communications in Skeletal Pathophysiology: From Molecular Pathways to Multidisciplinary Therapies.Research (Washington, D.C.) · 2026Review
- Cardiovascular Outcomes Following Therapeutic Sclerostin Inhibition Compared With Alternative Anabolic Therapies: A Real-World Propensity Score-Matched Analysis.Journal of osteoporosis · 2026Article
- The role of bone in whole-body energy metabolism.Nature reviews. Endocrinology · 2025Review
- Reply.Arthritis & rheumatology (Hoboken, N.J.) · 2025Article
- Genetic data do not provide evidence that lower sclerostin is associated with increased risk of atherosclerosis: comment on the article by Zheng et al.Arthritis & rheumatology (Hoboken, N.J.) · 2025Article
- Dusp1 in osteolytic diseases-mechanisms and therapeutic potential.Scientific reports · 2025Article
- A flexible machine learning Mendelian randomization estimator applied to predict the safety and efficacy of sclerostin inhibition.American journal of human genetics · 2025Article
- Role of Sclerostin in Cardiovascular System.International journal of molecular sciences · 2025Review
- Treatment Considerations for Severe Osteoporosis in Older Adults.Drugs & aging · 2025Review
- Τhe story of sclerostin inhibition: the past, the present, and the future.Hormones (Athens, Greece) · 2025Review
- Research Progress on the Influence of Novel Targeted Drugs for Osteoporosis on Glucose Metabolism.Biomolecules · 2025Review
- Comparative effectiveness and cardiovascular safety of romosozumab versus teriparatide in patients with osteoporosis: a population-based cohort study.Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA · 2024Article
- Effect of genetically predicted sclerostin on cardiovascular biomarkers, risk factors, and disease outcomes.Nature communications · 2024Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
37 authors at 20 institutions in 11 countries.
Jie ZhengDepartment of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, and Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the People's Republic of China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China, and MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Bristol, UK.ORCID 0000-0002-6623-6839
Eleanor WheelerMRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
Maik PietznerMRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK, and Computational Medicine, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany.
Till F M AndlauerDepartment of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
Michelle S YauMarcus Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, Massachusetts.ORCID 0000-0002-0445-6334
April E HartleyMRC IEU, Bristol Medical School, University of Bristol, Bristol, UK.ORCID 0000-0003-4932-1588
Ben Michael BrumptonK.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, and HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway.
Humaira RasheedMRC IEU, Bristol Medical School, University of Bristol, Bristol, UK, and HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway, and Division of Medicine and Laboratory Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.
John P KempMRC IEU, Bristol Medical School, University of Bristol, Bristol, UK, and Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia, and The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Queensland, Australia.
Monika FryszMRC IEU, Bristol Medical School, University of Bristol, and Musculoskeletal Research Unit, University of Bristol, Bristol, UK.ORCID 0000-0001-5729-778X
Jamie RobinsonMRC IEU, Bristol Medical School, University of Bristol, Bristol, UK.
Sjur ReppeUnger-Vetlesen Institute, Lovisenberg Diaconal Hospital and Department of Plastic and Reconstructive Surgery, Oslo University Hospital and Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway.
Vid PrijateljDepartment of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands.ORCID 0000-0002-9463-3962
Kaare M GautvikUnger-Vetlesen Institute, Lovisenberg Diaconal Hospital, Oslo, Norway.
Louise FalkMRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK, and Computational Medicine, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany.
Winfried MaerzClinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria, and SYNLAB Academy, SYNLAB Holding Deutschland GmbH and Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Ingrid GergeiVth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim, and Therapeutic Area Cardiovascular Medicine, Boehringer Ingelheim International GmbH, Ingelheim, Germany.
Patricia A PeyserDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor.
Maryam KavousiDepartment of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
Paul S de VriesHuman Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston.
Clint L MillerCenter for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville.
Maxime BosDepartment of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
Sander W van der LaanCentral Diagnostics Laboratory, Division of Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Rajeev MalhotraCardiology Division, Department of Medicine, Massachusetts General Hospital, Boston.
Markus HerrmannClinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
Hubert ScharnaglClinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.ORCID 0000-0002-2750-006X
Marcus KleberSYNLAB Academy, SYNLAB Holding Deutschland GmbH, Mannheim, Germany.
George DedoussisDepartment of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.
Eleftheria ZegginiInstitute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, and Technical University of Munich (TUM) and Klinikum Rechts der Isar, TUM School of Medicine, Munich, Germany.ORCID 0000-0003-4238-659X
Maria NethanderSahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg and Bioinformatics and Data Centre, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Claes OhlssonSahlgrenska Osteoporosis Centre, Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
Mattias LorentzonSahlgrenska Osteoporosis Centre, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden, and Region Västra Götaland, Geriatric Medicine, Sahlgrenska University Hospital, Mölndal, Sweden, and Mary McKillop Institute for Health Research, Australian Catholic University, Melbourne, Victoria, Australia.
Nick WarehamMRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
Claudia LangenbergMRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK, and Computational Medicine, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany.
Michael V HolmesMRC IEU, Bristol Medical School, University of Bristol, and Medical Research Council Population Health Research Unit, University of Oxford, and Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, and National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospital, Oxford, UK.
George Davey SmithMRC IEU, Bristol Medical School, University of Bristol, Bristol, UK.
Jonathan H TobiasMRC IEU, Bristol Medical School, University of Bristol, and Musculoskeletal Research Unit, University of Bristol, Bristol, UK.
University of Bristol · GBUniversity of Cambridge · GBErasmus MC · NLSahlgrenska University Hospital · SEMedical University of Graz · ATTUM Klinikum · DEBoehringer Ingelheim (Germany) · DEHarokopio University of Athens · GRHarvard University · USLovisenberg Diakonale Sykehus · NOMassachusetts General Hospital · USNational Institute for Health Research · GBNorwegian University of Science and Technology · NOOffice of Public Health Genomics · USOslo University Hospital · NOShanghai Jiao Tong University · CNSynlab Czech (Czechia) · CZSynlab (Germany) · DEThe University of Queensland · AUThe University of Texas Health Science Center at Houston · US
Funding
Research BaseP30DK072488 · NIDDK · UNIVERSITY OF MARYLAND BALTIMORE · PI MITCHELL, BRAXTON D, TAYLOR, SIMEON I. · 2005 to 2019
$17.3MCHARGE Consortium: Omics Discovery for CVD and Aging PhenotypesR01HL105756 · NHLBI · UNIVERSITY OF WASHINGTON · PI Bruce M Psaty, NICHOLAS L SMITH · 2011 to 2026
$9.5MResearch and Evaluation Support Core Unit (RESCU Core)P30AR072571 · NIAMS · BOSTON UNIVERSITY MEDICAL CAMPUS · PI TUHINA NEOGI · 2019 to 2026
$6.9MMultimodal genetic regulatory architecture of coronary artery diseaseR01HL148239 · NHLBI · UNIVERSITY OF VIRGINIA · PI Clint L Miller · 2019 to 2026
$4.2MThe Role of Histone Deacetylase 9 in Vascular CalcificationR01HL142809 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI MALHOTRA, RAJEEV · 2018 to 2022
$4.0MWhole-genome sequencing analysis of coronary atherosclerosis and related traitsR01HL146860 · NHLBI · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI DE VRIES, PAUL STEFAN · 2020 to 2024
$3.9MThe Role of Arylsulfatase in Vascular CalcificationR01HL162928 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI PAUL STEFAN DE VRIES, Rajeev Malhotra · 2023 to 2026
$2.6MCharacterization of Functional Iron Deficiency and Repletion in Heart Failure with Preserved Ejection FractionR01HL159514 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI LEWIS, GREGORY DYER, MALHOTRA, RAJEEV · 2021 to 2024
$2.5MSystemic contribution of age-associated epigenetic mechanisms to osteoarthritisR01AR075356 · NIAMS · HEBREW REHABILITATION CENTER FOR AGED · PI YAU, MICHELLE SZU-HUEI · 2019 to 2022
$1.7MMedical Research Council G9815508Medical Research Council MC_PC_15018Medical Research Council MC_PC_19009Medical Research Council MC_UU_00006/1Medical Research Council MC_UU_00011/1Medical Research Council MC_UU_00032/1NHLBI NIH HHS R01 HL105756NHLBI NIH HHS R01 HL142809NHLBI NIH HHS R01 HL146860NHLBI NIH HHS R01 HL148239NHLBI NIH HHS R01 HL159514NHLBI NIH HHS R01 HL162928NIAMS NIH HHS P30 AR072571NIAMS NIH HHS R01 AR075356NIDDK NIH HHS P30 DK072488NIH HHS N01-AR-2-2258NIH HHS N01-AR-2-2259NIH HHS N01-AR-2-2260NIH HHS N01-AR-2-2261NIH HHS N01-AR-2-2262Wellcome TrustWellcome Trust 20378/Z/16/ZWellcome Trust WT088806Wellcome Trust WT092830MWellcome Trust WT102215/2/13/2
Abstract
objectiveIn this study, we aimed to establish the causal effects of lowering sclerostin, target of the antiosteoporosis drug romosozumab, on atherosclerosis and its risk factors.
methodsA genome-wide association study meta-analysis was performed of circulating sclerostin levels in 33,961 European individuals. Mendelian randomization (MR) was used to predict the causal effects of sclerostin lowering on 15 atherosclerosis-related diseases and risk factors.
resultsWe found that 18 conditionally independent variants were associated with circulating sclerostin. Of these, 1 cis signal in SOST and 3 trans signals in B4GALNT3, RIN3, and SERPINA1 regions showed directionally opposite signals for sclerostin levels and estimated bone mineral density. Variants with these 4 regions were selected as genetic instruments. MR using 5 correlated cis-SNPs suggested that lower sclerostin increased the risk of type 2 diabetes mellitus (DM) (odds ratio [OR] 1.32 [95% confidence interval (95% CI) 1.03-1.69]) and myocardial infarction (MI) (OR 1.35 [95% CI 1.01-1.79]); sclerostin lowering was also suggested to increase the extent of coronary artery calcification (CAC) (β = 0.24 [95% CI 0.02-0.45]). MR using both cis and trans instruments suggested that lower sclerostin increased hypertension risk (OR 1.09 [95% CI 1.04-1.15]), but otherwise had attenuated effects.
conclusionThis study provides genetic evidence to suggest that lower levels of sclerostin may increase the risk of hypertension, type 2 DM, MI, and the extent of CAC. Taken together, these findings underscore the requirement for strategies to mitigate potential adverse effects of romosozumab treatment on atherosclerosis and its related risk factors.
Indexed as
AtherosclerosisDiabetes Mellitus, Type 2HypertensionMyocardial InfarctionGenome-Wide Association StudyHumansMendelian Randomization AnalysisPolymorphism, Single NucleotideRisk Factors
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