Long-term warfarin therapy and biomarkers for osteoporosis and atherosclerosis

Abstract

BackgroundStroke prevention by warfarin, a vitamin K antagonist, has been an integral part in the management of atrial fibrillation. Vitamin K-dependent matrix Gla protein (MGP) has been known as a potent inhibitor of arterial calcification and osteoporosis. Therefore, we hypothesized that warfarin therapy affects bone mineral metabolism, vascular calcification, and vascular endothelial dysfunction.MethodsWe studied 42 atrial fibrillation patients at high-risk for atherosclerosis having one or more coronary risk factors. Twenty-four patients had been treated with warfarin for at least 12 months (WF group), and 18 patients without warfarin (non-WF group). Bone alkaline phosphatase (BAP) and under carboxylated osteocalcin (ucOC) and receptor activator of nuclear factor-kappa B ligand (RANKL) were measured as bone metabolism markers. Reactive hyperemia-peripheral arterial tonometry (RH-PAT) index measured by Endo-PAT2000 was used as an indicator of vascular endothelial function.ResultsThere were no significant differences in patient background characteristics and other clinical indicators between the two groups. In WF group, the ucOC levels were significantly higher than those in the non-WF group (10.3 ± 0.8 vs. 3.4 ± 0.9 ng/mL; P < 0.01), similarly, the RANKL levels in the WF group were higher than those in the non-WF group (0.60 ± 0.06 vs. 0.37 ± 0.05 ng/mL; P = 0.007). Moreover, RH-PAT index was significantly lower in the WF group compared to those in the non-WF group (1.48 ± 0.11 vs. 1.88 ± 0.12; P = 0.017).ConclusionsLong-term warfarin therapy may be associated with bone mineral loss and vascular calcification in 60–80 year old hypertensive patients.

Vitamin K2 and Bone Health

“…These observational studies have focused on clinical fractures as endpoints below follow-up time at 5-10 years, but the thesis that warfarin-induced clinical fractures was not confirmed. This may be due to the beneficial effect of MK-7 on bone mass, which appears to stay unaffected by the impact of warfarin on vitamin K1, which again reinforces the notion that vitamin K2 status (measured as ucOC) per se is a good marker of bone homeostasis [58].…”

“…In an observational study conducted in Japan by Namba et al 2015, the biomarkers during warfarin use in a 1-year follow-up on 42 patients treated for atrial fibrillation were described. Twenty-four patients received warfarin (WF group) and 18 patients received non-warfarin treatment (Non-WF group).…”

“…It was concluded long-term use of warfarin might be associated with high risk of osteoporosis but also risk of ectopic calcification in blood vessels. Further randomized studies are needed to evaluate these patients [58].…”

New Perspectives for the Nutritional Value of Vitamin K in Human Health

“…Interestingly, extra-hepatic Gla proteins have been shown to be present as incompletely γ-carboxylated forms in the majority of healthy adults [4,25], and thus the biological activity of these proteins could be considered sub-optimal. Since VKOR is a dithiol dependent enzyme known to be inhibited by 4-hydroxycoumarin anticoagulant drugs, such as warfarin, acenocoumarol, and phenprocoumon, the widely use of these oral anticoagulants acting as vitamin K antagonists (VKAs), has also been linked to unwanted side effects in several extra-hepatic tissues with adverse clinical outcomes [4,[7][8][9]11,12]. Remarkably, despite the long use of VKA the exact mechanism of inhibition of VKOR remains to be elucidated [26].…”

“…Vitamin K is an essential micronutrient acting as cofactor for the post-translational modification of vitamin K-dependent proteins (VKDPs), where specific glutamic acid (Glu) residues can be modified to calcium binding γ-carboxyglutamic acid (Gla) residues, through the action of γ-glutamyl carboxylase (GGCX) enzyme [6][7][8]. The use of vitamin K antagonists (VKAs) such as warfarin, known to influence the carboxylation of Glu residues of the coagulation factors in liver, has been shown to also impair the γ-carboxylation of extra-hepatic VKDPs, resulting in unwanted pathological side-effects in tissues such as bone and blood vessels [6,7,[9][10][11][12]. Recently, additional functions of vitamin K, such as anti-inflammatory, transcriptional regulator of osteoblastic genes, and inhibition of tumor progression, have been proposed to be mediated by a direct vitamin K effect rather than through VKDPs action [13,14].…”