The effects of warfarin and edoxaban, an oral direct factor Xa inhibitor, on gammacarboxylated (Gla-osteocalcin) and undercarboxylated osteocalcin (uc-osteocalcin) in rats

Morishima, Yasuo; Kamisato, Chikako; Honda, Yuko; Furugohri, Taketoshi; Shibano, Toshiro

doi:10.1016/j.thromres.2012.08.304

Cited by 28 publications

(20 citation statements)

References 19 publications

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“…Finally, a study was recently performed to determine the effects of warfarin and edoxaban, a novel direct factor Xa inhibitor, on the serum concentration of total, γ-carboxylated osteocalcin (Gla-Oc) and Glu-Oc in rats. 34 Animals received orally administered warfarin or edoxaban, and 24 hours later serum and plasma samples were obtained for osteocalcin and prothrombin time (PT) measurements. Warfarin at 1 mg/kg markedly increased serum levels of Glu-Oc and slightly increased those of total osteocalcin compared with control rats.…”

Section: Strategies For Preventing Osteoporosis In Patients On Vitamimentioning

confidence: 99%

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Oral Anticoagulant Drugs and the Risk of Osteoporosis: New Anticoagulants Better than Old?

Tufano

Coppola

Contaldi

et al. 2015

Semin Thromb Hemost

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Several drugs have been associated with an increased risk of osteoporosis when used chronically. Coumarins (warfarin, acenocoumarol, phenprocoumon, and fluindione) are oral anticoagulants widely used for the prevention and treatment of arterial and venous thromboembolic diseases. These drugs are vitamin K antagonists that interfere with γ-carboxyglutamate formation, and consequently inhibit the carboxylation of glutamate residues of proteins that are synthesized in the bone. These effects on bone turnover and dietary restrictions in patients on anticoagulation are possible mechanisms inducing osteoporosis in coumarin users. However, conflicting evidence is available concerning the risk of osteoporosis and bone fractures in patients on treatment with these drugs. This risk is likely to be clinically relevant in long-term (more than 1 year) coumarin users. Novel direct oral anticoagulants, recently introduced in clinical practice, exert reduced interference on bone metabolism; however, limited in vitro and animal data are currently available, and their long-term effects will only become apparent in time.

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Section: Strategies For Preventing Osteoporosis In Patients On Vitamimentioning

confidence: 99%

“…This study demonstrates that in rats, at variance with warfarin, edoxaban, at doses higher than those needed for its antithrombotic activity, has no effects on the production of Gla-Oc and thus, may have a lower risk of adverse effects on bone health. 34…”

Section: Strategies For Preventing Osteoporosis In Patients On Vitamimentioning

confidence: 99%

Oral Anticoagulant Drugs and the Risk of Osteoporosis: New Anticoagulants Better than Old?

Tufano

Coppola

Contaldi

et al. 2015

Semin Thromb Hemost

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“…Studies exploring effect of NOACs in rats suggest a favorable bone-safety profile; rivaroxaban proved not to interfere with healing of rat femur fractures [50], and edoxaban did not interfere with total G1a-osteocalcin levels [51]. In a study by Prodinger et al [53], both rivaroxaban and enoxaparin induced morphological changes in the fracture callus of 70 rats, but these alterations did not result in functional deficits.…”

Section: Noacs and Fracturesmentioning

confidence: 99%

“…NOAC prescription has dramatically increased in the past few years as an alternative to VKAs [49], and in contrast to the latter, NOACs do not interfere with the vitamin K cycle. Evidence exploring their bone-safety profile has been published, both in rats [50][51][52][53] and humans [49,[54][55][56][57][58].…”

Section: Noacs and Fracturesmentioning

confidence: 99%

Vitamin K and Bone Health: A Review on the Effects of Vitamin K Deficiency and Supplementation and the Effect of Non-Vitamin K Antagonist Oral Anticoagulants on Different Bone Parameters

Rodríguez

Curiel

2019

Journal of Osteoporosis

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Although known for its importance in the coagulation cascade, vitamin K has other functions. It is an essential vitamin for bone health, taking part in the carboxylation of many bone-related proteins, regulating genetic transcription of osteoblastic markers, and regulating bone reabsorption. Vitamin K deficiency is not uncommon, as deposits are scarce and dependent upon dietary supplementation and absorption. Vitamin K antagonist oral anticoagulants, which are prescribed to many patients, also induce vitamin K deficiency. Most studies find that low serum K1 concentrations, high levels of undercarboxylated osteocalcin (ucOC), and low dietary intake of both K1 and K2 are associated with a higher risk of fracture and lower BMD. Studies exploring the relationship between vitamin K supplementation and fracture risk also find that the risk of fracture is reduced with supplements, but high quality studies designed to evaluate fracture as its primary endpoint are needed. The reduction in risk of fracture with the use of non-vitamin K antagonist oral anticoagulants instead of warfarin is also of interest although once again, the available evidence offers disparate results. The scarce and limited evidence, including low quality studies reaching disparate conclusions, makes it impossible to extract solid conclusions on this topic, especially concerning the use of vitamin K supplements.

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“…Whereas both VKA and DOACs are equally suitable for treating hypercoagulability, VKA induces vascular calcification thereby affecting the vessel wall in a negative way ( Figure 2 a). Effects of DOACs on vascular calcification are not known yet, but are unlikely to affect VKDP activity ( Figure 2 b) [ 137 ]. Moreover, high intake of vitamin K has shown to inhibit and even reverse warfarin-induced vascular calcification in experimental animals [ 56 , 138 ] and in adenine treated rats [ 52 ].…”

Section: Vitamin K and Direct Oral Anticoagulationmentioning

confidence: 99%

New Insights into the Pros and Cons of the Clinical Use of Vitamin K Antagonists (VKAs) Versus Direct Oral Anticoagulants (DOACs)

Gorp

Schurgers

2015

Nutrients

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Vitamin K-antagonists (VKA) are the most widely used anticoagulant drugs to treat patients at risk of arterial and venous thrombosis for the past 50 years. Due to unfavorable pharmacokinetics VKA have a small therapeutic window, require frequent monitoring, and are susceptible to drug and nutritional interactions. Additionally, the effect of VKA is not limited to coagulation, but affects all vitamin K-dependent proteins. As a consequence, VKA have detrimental side effects by enhancing medial and intimal calcification. These limitations stimulated the development of alternative anticoagulant drugs, resulting in direct oral anticoagulant (DOAC) drugs, which specifically target coagulation factor Xa and thrombin. DOACs also display non-hemostatic vascular effects via protease-activated receptors (PARs). As atherosclerosis is characterized by a hypercoagulable state indicating the involvement of activated coagulation factors in the genesis of atherosclerosis, anticoagulation could have beneficial effects on atherosclerosis. Additionally, accumulating evidence demonstrates vascular benefit from high vitamin K intake. This review gives an update on oral anticoagulant treatment on the vasculature with a special focus on calcification and vitamin K interaction.

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The effects of warfarin and edoxaban, an oral direct factor Xa inhibitor, on gammacarboxylated (Gla-osteocalcin) and undercarboxylated osteocalcin (uc-osteocalcin) in rats

Cited by 28 publications

References 19 publications

Oral Anticoagulant Drugs and the Risk of Osteoporosis: New Anticoagulants Better than Old?

Oral Anticoagulant Drugs and the Risk of Osteoporosis: New Anticoagulants Better than Old?

Vitamin K and Bone Health: A Review on the Effects of Vitamin K Deficiency and Supplementation and the Effect of Non-Vitamin K Antagonist Oral Anticoagulants on Different Bone Parameters

New Insights into the Pros and Cons of the Clinical Use of Vitamin K Antagonists (VKAs) Versus Direct Oral Anticoagulants (DOACs)

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