Cindy Boer

Vitamin K Antagonist Anticoagulants and Osteoarthritis | 135 3.2 Introduction Osteoarthritis (OA) is a chronic disabling joint disease that also increases in prevalence with age. It is the most common form of arthritis, one of the fastest growing chronic dis- eases worldwide[1], and is the fourth leading cause of years lived with disability global- ly[2]. To date, there are no known therapies that can alter its progression or prevent its occurrence. Apart from obesity and knee injury, very few other modifiable risk factors have been identified. Vitamin K has been hypothesized to play a role in OA pathogene- sis through its effects on several vitamin K-dependent bone and cartilage proteins, and therefore may represent a modifiable risk factor. A number of observational studies re- ported an association between vitamin K status and prevalence and incidence of OA[3- 5]. There has been one modestly sized clinical trial studying the effect of Vitamin K supplementation on OA progression. This ancillary study, originally designed to study vascular calcification, reported no overall beneficial effects of vitamin K supplementa- tion. However, in individuals with insufficient Vitamin K levels at baseline a beneficial effect was observed [6]. No studies to date have evaluated the relation of Vitamin K antagonists anticoagulants (VKAs), which can be expected to result in low vitamin K functioning, which may lead to OA incidence or progression[3-5]. Vitamin K is an essential cofactor in the posttranslational γ‐carboxylation of glu- tamic acid to form γ‐carboxyglutamic acid (Gla) residues, which confer functionality to Gla-proteins. VKAs deplete the active form of vitamin K by inhibiting the enzyme vitamin K epoxide reductase complex 1 (VKORC1). Genetic variants of VKORC1 account for approximately 25% of the variance in VKA dose[7]. Matrix Gla protein (MGP) is a vitamin K-dependent Gla- protein that is an essential inhibitor of cartilage and vascu- lar mineralization[8, 9]. Recent, genome-wide association study (GWAS) and functional studies identified MGP to be causally involved in osteoarthritis[10]. Vitamin K antagonists anticoagulants (VKAs) such as warfarin and acenocouma- rol are primarily prescribed for the prevention of thromboembolic events in patients with atrial fibrillation (AF)[11]. With aging-related increases in prevalence of AF, the projected number of individuals with AF needing anti-coagulation is predicted to rise to 17.9 million by 2060 in the European Union[12]. While a new class of anti-coagulants are available, the non-vitamin K oral anti-coagulants (NOACs), VKAs are still widely pre- scribed, particularly to older adults[13]. Whether long-term VKA use with resultant im- pairment of vitamin K-dependent proteins such as MGP increases risk of OA incidence or progression is not known. Given the high prevalence of VKA users in addition to the high prevalence of OA globally, clarifying this relationship would have substantial public health impact by identifying a potentially modifiable risk factor for OA.