{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T19:40:44Z","timestamp":1768678844047,"version":"3.49.0"},"reference-count":26,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T00:00:00Z","timestamp":1768435200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: The vitamin K epoxide reductase complex subunit 1 (VKORC1) plays a central role in the vitamin K cycle, which is essential for \u03b3-carboxylation of multiple bone-related proteins. Genetic variants in VKORC1 may influence bone mineral density (BMD) and osteoporosis risk. Materials and Methods: A systematic review and meta-analysis were conducted to evaluate the association between VKORC1 polymorphisms and osteopenia and osteoporosis. Relevant studies were identified through PubMed, Scopus, and Web of Science databases. Data on study characteristics, genotypes, BMD measurement, ethnicity, sex, and menopausal status were extracted. Results: Six studies comprising 7335 participants were included. All studies assessed BMD using dual-energy X-ray absorptiometry (DXA). The mean participant age ranged from 41.9 to 63.7 years. The VKORC1 variants most frequently studied, which were included in the meta-analysis, were rs9923231 and rs9934438. The overall effect of VKORC1 risk alleles on osteopenia\/osteoporosis was significant with a p = 0.041 (fixed effects OR = 1.16, 95% CI = 1.01\u20131.35). Heterogeneity among studies was insignificant (I2 = 0%, p = 0.893). Conclusions: A modest association was observed for the VKORC1 variants. The current body of evidence requires further studies to elucidate whether VKORC1 polymorphisms have a clinically meaningful role in bone health.<\/jats:p>","DOI":"10.3390\/medicina62010180","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T14:35:38Z","timestamp":1768487738000},"page":"180","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Association Between VKORC1 Gene Polymorphisms and Osteopenia and Osteoporosis: A Systematic Review and Meta-Analysis"],"prefix":"10.3390","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4549-3526","authenticated-orcid":false,"given":"\u015etefan Cristian","family":"Vesa","sequence":"first","affiliation":[{"name":"Division of Pharmacology, Toxicology and Clinical Pharmacology, Department of Morpho-Functional Sciences, University of Medicine and Pharmacy \u201cIuliu Ha\u021bieganu\u201d, 8 Victor Babe\u015f Street, 400347 Cluj-Napoca, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vlad-Mihai","family":"Ichim","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Medicine and Pharmacy \u201cIuliu Ha\u021bieganu\u201d, 8 Victor Babe\u015f Street, 400347 Cluj-Napoca, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvina","family":"Ilu\u021b","sequence":"additional","affiliation":[{"name":"Department of Medical Disciplines, Faculty of Nursing and Health Sciences, University of Medicine and Pharmacy \u201cIuliu Ha\u021bieganu\u201d, 8 Victor Babe\u015f Street, 400347 Cluj-Napoca, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7755-2028","authenticated-orcid":false,"given":"Stefano","family":"Miglietta","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnologies and Environment, University of Bari, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0687-7180","authenticated-orcid":false,"given":"Mihai","family":"Lupu","sequence":"additional","affiliation":[{"name":"Division of Physiology, Department of Morpho-Functional Sciences, University of Medicine and Pharmacy \u201cIuliu Ha\u021bieganu\u201d, 8 Victor Babe\u015f Street, 400347 Cluj-Napoca, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8362-6639","authenticated-orcid":false,"given":"Camelia Alexandra","family":"Coada","sequence":"additional","affiliation":[{"name":"Division of Physiology, Department of Morpho-Functional Sciences, University of Medicine and Pharmacy \u201cIuliu Ha\u021bieganu\u201d, 8 Victor Babe\u015f Street, 400347 Cluj-Napoca, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonia Eugenia","family":"Macarie","sequence":"additional","affiliation":[{"name":"Division of Geriatrics and Gerontology, Department of Medical Specialties, University of Medicine and Pharmacy \u201cIuliu Ha\u021bieganu\u201d, 8 Victor Babe\u015f Street, 400347 Cluj-Napoca, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ovidiu","family":"Chiroban","sequence":"additional","affiliation":[{"name":"Division of Forensic Medicine, Department of Community Medicine, University of Medicine and Pharmacy \u201cIuliu Ha\u021bieganu\u201d, 8 Victor Babe\u015f Street, 400347 Cluj-Napoca, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3511-2788","authenticated-orcid":false,"given":"Anca Dana","family":"Buzoianu","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, Toxicology and Clinical Pharmacology, Department of Morpho-Functional Sciences, University of Medicine and Pharmacy \u201cIuliu Ha\u021bieganu\u201d, 8 Victor Babe\u015f Street, 400347 Cluj-Napoca, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4457-8456","authenticated-orcid":false,"given":"Octavia","family":"Sabin","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, Toxicology and Clinical Pharmacology, Department of Morpho-Functional Sciences, University of Medicine and Pharmacy \u201cIuliu Ha\u021bieganu\u201d, 8 Victor Babe\u015f Street, 400347 Cluj-Napoca, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s43465-023-01012-3","article-title":"Epidemiology of Osteoporosis","volume":"57","author":"Agrawal","year":"2023","journal-title":"JOIO"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1007\/s12603-023-1971-4","article-title":"Sex Specific Global Burden of Osteoporosis in 204 Countries and Territories, from 1990 to 2030: An Age-Period-Cohort Modeling Study","volume":"27","author":"Zhu","year":"2023","journal-title":"J. Nutr. Health Aging"},{"key":"ref_3","first-page":"46","article-title":"An Overview and Management of Osteoporosis","volume":"4","year":"2017","journal-title":"Eur. J. Rheumatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/s41574-019-0282-7","article-title":"A Road Map for Understanding Molecular and Genetic Determinants of Osteoporosis","volume":"16","author":"Yang","year":"2020","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/s41588-018-0302-x","article-title":"An Atlas of Genetic Influences on Osteoporosis in Humans and Mice","volume":"51","author":"Morris","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Tsugawa, N., and Shiraki, M. (2020). Vitamin K Nutrition and Bone Health. Nutrients, 12.","DOI":"10.3390\/nu12071909"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Aaseth, J.O., Finnes, T.E., Askim, M., and Alexander, J. (2024). The Importance of Vitamin K and the Combination of Vitamins K and D for Calcium Metabolism and Bone Health: A Review. Nutrients, 16.","DOI":"10.20944\/preprints202406.0766.v1"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1002\/cpt.668","article-title":"Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update","volume":"102","author":"Johnson","year":"2017","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Abdullah-Koolmees, H., van Keulen, A.M., Nijenhuis, M., and Deneer, V.H.M. (2021). Pharmacogenetics Guidelines: Overview and Comparison of the DPWG, CPIC, CPNDS, and RNPGx Guidelines. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.595219"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1016\/j.jmoldx.2020.04.204","article-title":"Recommendations for Clinical Warfarin Genotyping Allele Selection: A Report of the Association for Molecular Pathology and the College of American Pathologists","volume":"22","author":"Pratt","year":"2020","journal-title":"J. Mol. Diagn."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 Statement: An Updated Guideline for Reporting Systematic Reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Lo, C.K.-L., Mertz, D., and Loeb, M. (2014). Newcastle-Ottawa Scale: Comparing Reviewers\u2019 to Authors\u2019 Assessments. BMC Med. Res. Methodol., 14.","DOI":"10.1186\/1471-2288-14-45"},{"key":"ref_13","unstructured":"R Core Team (2021). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing."},{"key":"ref_14","first-page":"153","article-title":"How to Perform a Meta-Analysis with R: A Practical Tutorial","volume":"22","author":"Balduzzi","year":"2019","journal-title":"BMJ Ment. Health"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ciubean, A.D., Ungur, R.A., Irsay, L., Ciortea, V.M., Borda, I.M., Dogaru, G.B., Trifa, A.P., Vesa, S.C., and Buzoianu, A.D. (2019). Polymorphisms of FDPS, LRP5, SOST and VKORC1 Genes and Their Relation with Osteoporosis in Postmenopausal Romanian Women. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0225776"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Crawford, D.C., Brown-Gentry, K., and Rieder, M.J. (2010). VKORC1 Common Variation and Bone Mineral Density in the Third National Health and Nutrition Examination Survey. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0015088"},{"key":"ref_17","first-page":"734","article-title":"Relationship between VKORC1 Single Nucleotide Polymorphism 1173C>T, Bone Mineral Density & Carotid Intima-Media Thickness","volume":"137","author":"Fodor","year":"2013","journal-title":"Indian J. Med. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.arcmed.2020.10.008","article-title":"Genetic Variation in VKORC1 and Risk for Osteoporosis","volume":"52","author":"He","year":"2021","journal-title":"Arch. Med. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"281","DOI":"10.2174\/1871530318666180212100119","article-title":"Association between Vitamin K Epoxide Reductase (VKORC1)-1639G>A Polymorphism and Osteoporosis in Postmenopausal Women","volume":"18","author":"Kutluturk","year":"2018","journal-title":"Endocr. Metab. Immune Disord.-Drug Targets"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"101","DOI":"10.14715\/cmb\/2023.69.6.16","article-title":"The Association Between Bone Remodeling Markers, Genes Polymorphisms with Incidence of Osteopenia Among Young Saudi Female","volume":"69","author":"Taha","year":"2023","journal-title":"Cell. Mol. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1097\/FPC.0b013e32833433b6","article-title":"VKORC1 Pharmacogenomics Summary","volume":"20","author":"Owen","year":"2010","journal-title":"Pharmacogenet. Genom."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The Mutational Constraint Spectrum Quantified from Variation in 141,456 Humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1002\/cpt.2350","article-title":"An Evidence-Based Framework for Evaluating Pharmacogenomics Knowledge for Personalized Medicine","volume":"110","author":"Huddart","year":"2021","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e739","DOI":"10.6061\/clinics\/2019\/e739","article-title":"Is There Any Association between Osteoporotic Vertebral Fracture and Vitamin K Epoxide Reductase Complex Subunit-1 Polymorphism in Turkish Society? A Pilot Study","volume":"74","author":"Ozgen","year":"2019","journal-title":"Clinics"},{"key":"ref_25","unstructured":"(2025, October 18). Genetic Polymorphisms and Their Influence on Therapeutic Response to Alendronate\u2014A Pilot Study. Available online: https:\/\/scispace.com\/papers\/genetic-polymorphisms-and-their-influence-on-therapeutic-3reqjv8f7h."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.trsl.2010.05.005","article-title":"Vitamin K Epoxide Reductase (VKORC1) Gene Mutations in Osteoporosis: A Pilot Study","volume":"156","author":"Holzer","year":"2010","journal-title":"Transl. Res."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/62\/1\/180\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T15:17:37Z","timestamp":1768490257000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/62\/1\/180"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,15]]},"references-count":26,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["medicina62010180"],"URL":"https:\/\/doi.org\/10.3390\/medicina62010180","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,15]]}}}