Article Text

Vitamin K antagonist anticoagulant usage is associated with increased incidence and progression of osteoarthritis
  1. Cindy G Boer1,
  2. Ingrid Szilagyi1,2,
  3. N Long Nguyen1,
  4. Tuhina Neogi3,
  5. Ingrid Meulenbelt4,
  6. M Arfan Ikram5,
  7. André G Uitterlinden1,5,
  8. Sita Bierma-Zeinstra2,
  9. Bruno H Stricker5,
  10. Joyce B van Meurs1
  1. 1 Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
  2. 2 Department of General Practice, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
  3. 3 Section of Rheumatology, Department of Medicine, Boston University Medical Campus, Boston, Massachusetts, USA
  4. 4 Section Molecular Epidemiology, Department Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
  5. 5 Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
  1. Correspondence to Dr Joyce B van Meurs, Internal Medicine, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands; j.vanmeurs{at}erasmusmc.nl

Abstract

Objectives Vitamin K is hypothesised to play a role in osteoarthritis (OA) pathogenesis through effects on vitamin K-dependent bone and cartilage proteins, and therefore may represent a modifiable risk factor. A genetic variant in a vitamin K-dependent protein that is an essential inhibitor for cartilage calcification, matrix Gla protein (MGP), was associated with an increased risk for OA. Vitamin K antagonist anticoagulants (VKAs), such as warfarin and acenocoumarol, act as anticoagulants through inhibition of vitamin K-dependent blood coagulation proteins. VKAs likely also affect the functioning of other vitamin K-dependent proteins such as MGP.

Methods We investigated the effect of acenocoumarol usage on progression and incidence of radiographic OA in 3494 participants of the Rotterdam Study cohort. We also examined the effect of MGP and VKORC1 single nucleotide variants on this association.

Results Acenocoumarol usage was associated with an increased risk of OA incidence and progression (OR=2.50, 95% CI=1.94–3.20), both for knee (OR=2.34, 95% CI=1.67–3.22) and hip OA (OR=2.74, 95% CI=1.82–4.11). Among acenocoumarol users, carriers of the high VKORC1(BB) expression haplotype together with the MGP OA risk allele (rs1800801-T) had an increased risk of OA incidence and progression (OR=4.18, 95% CI=2.69–6.50), while this relationship was not present in non-users of that group (OR=1.01, 95% CI=0.78–1.33).

Conclusions These findings support the importance of vitamin K and vitamin K-dependent proteins, as MGP, in the pathogenesis of OA. Additionally, these results may have direct implications for the clinical prevention of OA, supporting the consideration of direct oral anticoagulants in favour of VKAs.

  • osteoarthritis
  • epidemiology
  • pharmacogenetics

Data availability statement

Data are available upon reasonable request. All relevant data supporting the key findings of this study are available within the article and its supplementary data. Due to ethical and legal restrictions, individual-level data of the Rotterdam Study (RS) cannot be made publicly available. Data are available upon request to the data manager of the Rotterdam Study Frank van Rooij (f.vanrooij@erasmusmc.nl) and subject to local rules and regulations. This includes submitting a proposal to the management team of RS, where upon approval, analysis needs to be done on a local server with protected access, complying with GDPR regulations.

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Data availability statement

Data are available upon reasonable request. All relevant data supporting the key findings of this study are available within the article and its supplementary data. Due to ethical and legal restrictions, individual-level data of the Rotterdam Study (RS) cannot be made publicly available. Data are available upon request to the data manager of the Rotterdam Study Frank van Rooij (f.vanrooij@erasmusmc.nl) and subject to local rules and regulations. This includes submitting a proposal to the management team of RS, where upon approval, analysis needs to be done on a local server with protected access, complying with GDPR regulations.

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Footnotes

  • Handling editor Josef S Smolen

  • Twitter @CurlyGeneticist

  • Contributors CGB designed the study, performed the analyses, made the figures and tables, and wrote the manuscript. IS contributed to study design. NLN performed analysis. TN and IM contributed to study design. AGU and MAI provided access to the Rotterdam study dataset. SB-Z contributed to study design. BS provided pharmacological data, contributed to study design and analysis. JBvM designed the study and supervised this work. All authors critically assessed the manuscript.

  • Funding This research was funded by the Dutch Arthritis Society (ReumaNederland). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. The Rotterdam Study GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (numbers 175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project number 050-060-810. TN was supported by NIH K24 AR070892.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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