title: The effects of warfarin and edoxaban, an oral direct factor Xa inhibitor, on gammacarboxylated (Gla-osteocalcin) and undercarboxylated osteocalcin (uc-osteocalcin) in rats.
abstract: BACKGROUND
  Osteocalcin plays a role in bone homeostasis. The vitamin K cycle is essential for the gamma-carboxylation of glutamic acid residues in osteocalcin. Some evidence suggests that long-term warfarin therapy, which inhibits the vitamin K cycle and prevents gamma-carboxylation, is associated with increased bone-fracture risk. The aim of this study was to determine the effects of warfarin and edoxaban, a direct factor Xa inhibitor, on the serum concentration of total, gamma-carboxylated (Gla-osteocalcin) and undercarboxylated osteocalcin (uc-osteocalcin) in rats.
  
  
  METHODS
  Rats received orally administered warfarin or edoxaban, and 24h later serum and plasma were prepared. Osteocalcin level in serum was measured with ELISA. A Gla-osteocalcin was precipitated by the addition of hydroxyapatite, and the resulting supernatant was used for measuring uc-osteocalcin. Prothrombin time (PT) of plasma was also measured.
  
  
  RESULTS
  Warfarin at 1mg/kg (a dose which prolonged PT 2.62-fold) markedly increased the serum level of uc-osteocalcin and slightly increased the total osteocalcin level compared with control in rats. Serum Gla-osteocalcin significantly decreased by warfarin. Edoxaban at 1mg/kg (an antithrombotic dose) and 54mg/kg (a dose which prolonged PT 2.25-fold) had no effects on total, uc-, and Gla-osteocalcin levels.
  
  
  CONCLUSIONS
  This study demonstrates that warfarin impaired the carboxylation of osteocalcin in rats. In contrast, edoxaban at or higher doses than needed for an antithrombotic effect sustained the circulating Gla-osteocalcin level. These findings suggest that edoxaban has no effects on the production of Gla-osteocalcin and thus, may have a lower risk of adverse effects on bone health.
authors.affiliation: Biological Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Morishima
authors.forename: Chikako
authors.initials: C
authors.lastname: Kamisato
authors.forename: Yuko
authors.initials: Y
authors.lastname: Honda
authors.forename: Taketoshi
authors.initials: T
authors.lastname: Furugohri
authors.forename: Toshiro
authors.initials: T
authors.lastname: Shibano
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D002264:Carboxylic Acids / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D008297:Male; D015675:Osteocalcin / Q000097:blood*; D010024:Osteoporosis / Q000139:chemically induced; D011499:Protein Processing, Post-Translational; D011517:Prothrombin Time; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012307:Risk Factors; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D013997:Time Factors; D014812:Vitamin K / Q000037:antagonists & inhibitors / Q000378:metabolism; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D000925:Anticoagulants; D002264:Carboxylic Acids; D065427:Factor Xa Inhibitors; D011725:Pyridines; D013844:Thiazoles; D015675:Osteocalcin; D014812:Vitamin K; D014859:Warfarin; D015951:Factor Xa; C552171:edoxaban