Year: 2019
Type: preprint
Abstract: Background Inhibition of sclerostin is a novel therapeutic approach to lowering fracture risk. However, phase III randomised controlled trials (RCTs) of romosozumab, a monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events. Methods We used two independent genetic variants (rs7209826 and rs188810925) in SOST (encoding sclerostin) associated with bone mineral density (BMD) as proxies for therapeutic inhibition of sclerostin. We estimated the effects on risk of osteoporosis, fracture, coronary heart disease (CHD) and a further 22 cardiometabolic risk factors and diseases, by combining data from up to 478,967 participants of European ancestry from three prospective cohorts and up to 1,030,836 participants from nine GWAS consortia. In addition, we performed meta-analyses of cardiovascular outcome data from phase III RCTs of romosozumab. Results Meta-analysis of RCTs identified a higher risk of cardiac ischemic events in patients randomised to romosozumab (25 events among 4,298 individuals; odds ratio [OR] 2·98; 95% confidence interval [CI], 1·18 to 7·55; P=0·017). Scaled to the equivalent dose of romosozumab (210mg/month; 0·09 g/cm 2 higher BMD), the SOST variants associated with lower risk of fracture (OR, 0·59; 95% CI, 0·54-0·66; P= 1·4×10 −24 ), and osteoporosis (OR, 0·43; 95% CI, 0·36-0·52; P=2·4×10 −18 ). The SOST variants associated with higher risk of myocardial infarction and/or coronary revascularisation (69,649 cases; OR, 1·18; 95% CI, 1·06-1·32; P=0·003) and type 2 diabetes (OR 1·15; 95% CI, 1·05-1·27; P=0·003), higher systolic blood pressure (1·3mmHg; 95% CI 0·8-1·9; P=5·9×10 −6 ) and waist-to-hip-ratio adjusted for BMI (0·05 SDs; 95% CI, 0·02 to 0·08; P=8·5×10 −4 ). Conclusions Genetically and therapeutically lowered sclerostin leads to higher risk of cardiovascular events. Rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors is warranted.
DOI: 10.1101/531004
Authors: Jonas Bovijn, Kristi Krebs, Chia-Yen Chen, Ruth Boxall, Jenny C. Censin, Teresa Ferreira, Sara L. Pulit, Craig A. Glastonbury, Samantha Laber, Iona Y. Millwood, Kuang Lin, Liming Li, Zhengming Chen, Lili Milani, Robin G. Walters, Reedik Mägi, Benjamin M. Neale, Cecilia M. Lindgren, Michael V. Holmes
Institutions: Centre for Human Genetics, University of Oxford, University of Tartu, Broad Institute, Massachusetts General Hospital, Stanley Center for Psychiatric Research, MRC Population Health Research Unit, University Medical Center Utrecht, Peking University, John Radcliffe Hospital, National Institute for Health and Care Research
Language: English
Subfield: Orthopedics and Sports Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: GlaxoSmithKline, Li Ka Shing Foundation, Wellcome Trust, Cancer Research UK, National Institute for Health and Care Research, British Heart Foundation, University of Oxford, National Natural Science Foundation of China, ZonMw, Eesti Teadusagentuur, Ministry of Science and Technology of the People's Republic of China, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, BHF Centre of Research Excellence, Oxford, National Institutes of Health, Centers for Disease Control and Prevention, Medical Research Council, NIHR Oxford Biomedical Research Centre, Clarendon Fund
Awards: High Throughput Science - Genomic and metabolmic analysis of haemorrhagic in the China Kadoorie Biobank, G1215279462, G1260843, G1300722292, Omics for health: an integrated approach to understand and predict human disease, G1395603813, China Kadoorie Biobank (CKB) prospective study of 0.5 million adults, G1630586902, G1649993721, China Kadoorie Biobank (CKB) of 0.5 million adults., G1673798266, G1881568983, G1905341482, G1912839387, G2093189309, G211934369, G2196673094, G2212417510, G2243627235, China Kadoorie Biobank (CKB) prospective study of 0.5 million adults, G2462784243, Harvard Reproductive Endocrine Sciences Center, G2579291025, G2800483660, G297046553, G3165331058, G3217496469, G3319528975, G3731018732, The Kadoorie Biobank study., Research Excellence (renewal), G4042561528, G4051821870, Role of Rare and Common Genetic Variants in Adverse Drug Reactions, G4231664761, G4393287264, G4420358607, G4592251203, G4617978461, G4665801985, G4869591214, G5158796881, G5248341131, China Kadoorie Biobank (CKB) of 0.5 million adults., The Kadoorie Biobank study., G6195916859, G6215260116, G7086945402, G7146276943, Data Science Methods and Applications (DSMA), Estonian Centre for Genomics, G7606975397, G7813753016, G7855137468, Methods for faster and more reliable analysis of genome sequences, G815574155, China kadoorie biobank - University of Oxford, G8233656547, G8368010179, G8406115503, G8509280843, Novel diagnostic markers of nervous system diseases and factors predicting treatment outcome, G8643922336, Drug target validation and risk prediction for coronary heart disease using targeted blood-based metabolomics and proteomics, G8809076263, G948687719
OpenAlex ID: W3020568216