Osteoarthritis Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-219483 on 12 April 2021. Downloaded from EPIDEMIOLOGICAL SCIENCE Vitamin K antagonist anticoagulant usage is associated with increased incidence and progression of osteoarthritis Cindy G Boer ,1 Ingrid Szilagyi,1,2 N Long Nguyen,1 Tuhina Neogi ,3 Ingrid Meulenbelt,4 M Arfan Ikram,5 André G Uitterlinden,1,5 Sita Bierma- Zeinstra,2 Bruno H Stricker,5 Joyce B van Meurs1 Handling editor Josef S ABSTRACT Key messages Smolen Objectives Vitamin K is hypothesised to play a role in osteoarthritis (OA) pathogenesis through effects ► Additional material is What is already known about this subject? published online only. To view on vitamin K- dependent bone and cartilage proteins, ► Osteoarthritis (OA) is the most common form please visit the journal online and therefore may represent a modifiable risk factor. A of arthritis worldwide, affecting 320 million (http:// dx. doi. org/ 10. 1136/ genetic variant in a vitamin K- dependent protein that is people, and is a leading cause of disability. To annrheumdis- 2020- 219483). an essential inhibitor for cartilage calcification, matrix date, there are no disease- modifying therapies Gla protein (MGP), was associated with an increased risk For numbered affiliations see available, and treatment development has been for OA. Vitamin K antagonist anticoagulants (VKAs), such end of article. hampered by existence of only few recognised as warfarin and acenocoumarol, act as anticoagulants modifiable risk factors. Correspondence to through inhibition of vitamin K-dependent blood Vitamin K and vitamin K- dependent proteins, Dr Joyce B van Meurs, Internal coagulation proteins. VKAs likely also affect the ► such as matrix Gla protein (MGP), have been Medicine, Erasmus Medical functioning of other vitamin K-dependent proteins such Center, 3015 GD Rotterdam, The implicated in OA by epidemiological studies, as MGP. Netherlands; genetic studies and subsequent in functional Methods We investigated the effect of acenocoumarol j. vanmeurs@ erasmusmc. nl genomics studies, indicating vitamin K as usage on progression and incidence of radiographic OA possible modifiable risk factor for OA. Received 11 November 2020 in 3494 participants of the Rotterdam Study cohort. We Revised 19 January 2021 also examined the effect of MGP and VKORC1 single Accepted 20 January 2021 What does this study add? Published Online First nucleotide variants on this association. ► This study shows that the use of vitamin K 3 March 2021 Results Acenocoumarol usage was associated with antagonist anticoagulants (VKAs) significantly an increased risk of OA incidence and progression increases the risk of progression of hip and (OR=2.50, 95% CI=1.94–3.20), both for knee knee OA, by inhibiting the vitamin K pathway. (OR=2.34, 95% CI=1.67–3.22) and hip OA (OR=2.74, ► This study also demonstrates that known 95% CI=1.82–4.11). Among acenocoumarol users, http://ard.bmj.com/ OA genetic risk variants in MGP and carriers of the high VKORC1(BB) expression haplotype pharmacogenetic variants known to affect together with the MGP OA risk allele (rs1800801-T) vitamin K metabolism increase the risk of OA had an increased risk of OA incidence and progression progression when using VKAs. (OR=4.18, 95% CI=2.69–6.50), while this relationship was not present in non-users of that group (OR=1.01, How might this impact on clinical practice or 95% CI=0.78–1.33). future developments? on September 24, 2021 by guest. Protected copyright. Conclusions These findings support the importance of The findings suggest the consideration of novel vitamin K and vitamin K-dependent proteins, as MGP, in ► (or direct) oral anticoagulants in favour of VKAs, the pathogenesis of OA. Additionally, these results may such as acenocoumarol and warfarin, in people have direct implications for the clinical prevention of OA, with OA. supporting the consideration of direct oral anticoagulants in favour of VKAs. in OA pathogenesis through its effects on several 3 ► https:// doi. org/ 10. 1136/ vitamin K- dependent bone and cartilage proteins, annrheumdis- 2020- 219765 INTRODUCTION and therefore may represent a modifiable risk Osteoarthritis (OA) is a chronic disabling joint factor. A number of observational studies reported disease that also increases in prevalence with age. an association between vitamin K status and prev- 4–6 © Author(s) (or their It is the most common form of arthritis, one of the alence and incidence of OA. There has been one 1 employer(s)) 2021. Re- use fastest growing chronic diseases worldwide, and is modestly sized clinical trial studying the effect of permitted under CC BY. the fourth leading cause of years lived with disability vitamin K supplementation on OA progression. Published by BMJ. globally.2 To date, there are no known therapies This ancillary study, originally designed to study To cite: Boer CG, that can alter its progression or prevent its occur- vascular calcification, reported no overall beneficial Szilagyi I, Nguyen NL, rence. Apart from obesity and knee injury, very few effects of vitamin K supplementation. However, in et al. Ann Rheum Dis other modifiable risk factors have been identified. individuals with insufficient vitamin K levels at base- 2021;80:598–604. Vitamin K has been hypothesised to play a role line, a beneficial effect was observed.7 No studies to 598 Boer CG, et al. Ann Rheum Dis 2021;80:598–604. doi:10.1136/annrheumdis-2020-219483 Osteoarthritis Ann Rheum Dis: first published as 10.1136/annrheumdis-2020-219483 on 12 April 2021. Downloaded from date have evaluated the relation between vitamin K antagonist Stanford Health Assessment Questionnaire (see online supple- anticoagulants (VKAs) and OA, which can be expected to result mental text for details). in low vitamin K functioning, which may lead to increased OA The RS has been approved by the institutional review board incidence or progression.4–6 (Medical Ethics Committee) of the Erasmus Medical Center and Vitamin K is an essential cofactor in the post-translational γ‐ by the review board of The Netherlands Ministry of Health, carboxylation of glutamic acid to form γ‐carboxyglutamic acid Welfare and Sports. The approval has been renewed every 5 years (Gla) residues, which confer functionality to Gla proteins. VKAs (MEC 02.1015). All participants provided written informed deplete the active form of vitamin K by inhibiting the enzyme consent for participation in the RS. vitamin K epoxide reductase complex 1 (VKORC1). Genetic variants of VKORC1 account for approximately 25% of the 8 Incidence and progression of OA variance in VKA dose. Matrix Gla protein (MGP) is a vitamin Our study included participants of RS-I and RS- II for whom K-dependent Gla protein that is an essential inhibitor of cartilage 9 10 radiographs of knee and hip joints at baseline and follow-up and vascular mineralisation. Recently, genome- wide associa- visit were obtained and scored by trained medical professionals tion study (GWAS) and functional studies identified MGP to be 17 18 11 12 for OA severity using Kellgren and Lawrence Grade (KLG) causally involved in OA. (online supplemental figure S1). Individuals who had at baseline VKAs such as warfarin and acenocoumarol are primarily locomotor disability were excluded from our study population19 prescribed for the prevention of thromboembolic events in 13 (online supplemental figure S1). We analysed OA incidence patients with atrial fibrillation (AF). With ageing-related and progression together, as both definitions cannot be accu- increases in prevalence of AF, the projected number of individ- rately defined based on radiographic examination alone, and by uals with AF needing anticoagulation is predicted to rise to 17.9 20 14 combining both into one definition reduces this bias. We evalu- million by 2060 in the European Union. While a new class ated any OA progression, defined as an increase of KLG between of anticoagulants are available, the direct oral anticoagulants baseline and follow- up of ≥1 and/or joint replacement; if base- (DOACs), VKAs are still widely prescribed, particularly to older line KLG was 0, progression was defined as an increase of KLG 15 adults. Whether long- term VKA use with resultant impairment ≥2 (incidence).21 Joints with a baseline KLG of 4 or baseline of vitamin K-dependent proteins such as MGP increases risk joint replacement were excluded from analysis (online supple- of OA incidence or progression is not known. Given the high mental figure S1). OA progression was defined in a joint-specific prevalence of VKA users in addition to the high prevalence of and side-specific manner (knee, hip; left and right). Joints with OA globally, clarifying this relationship would have substantial no progression of OA comprised the referent group. Joints with public health impact by identifying a potentially modifiable risk missing data were excluded (online supplemental figure S1), factor for OA. with the exception of joints with missing baseline data and a We therefore examined the relation of VKA use to progres- KLG of ≤1 at follow-up, which were included in the referent sion and incidence of hip and knee OA in two subcohorts of group (online supplemental figure S1). the large prospective population- based cohort of the Rotterdam study (RS). We additionally examined how the impact of VKA use varies by the presence of the MGP risk allele that influ- Vitamin K antagonist anticoagulants ences MGP expression and single nucleotide variations (SNVs) For each participant, we extracted the usage of VKAs (aceno- affecting VKORC1 gene expression, which impact VKA dosage. coumarol) for the period between baseline visit (RS- I-1, RS- II-1) and follow- up visits (RS- I-3, RS- II-2), from computerised http://ard.bmj.com/ pharmacy data (online supplemental text). Acenocoumarol METHODS is the main prescribed VKA in the Netherlands as warfarin is Study population and clinical data not registered for use as a drug.