ORIGINAL ARTICLE

Journal of Bone and Mineral Metabolism

, Volume 23, Issue 5, pp 366-372

First online:

Comparison of inhibitory effects of warfarin on γ-carboxylation between bone and liver in rats

  • Kuniko HaraAffiliated withDepartment of Applied Drug Research, Pharmacological Evaluation Section, Clinical Research Center, Eisai Co., Ltd. Email author 
  • , Masatoshi KobayashiAffiliated withDepartment of Applied Drug Research, Pharmacological Evaluation Section, Clinical Research Center, Eisai Co., Ltd.
  • , Yasuhiro AkiyamaAffiliated withDepartment of Applied Drug Research, Pharmacological Evaluation Section, Clinical Research Center, Eisai Co., Ltd.

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access

Abstract

The purposes of this study were to clarify that warfarin (WF, vitamin K antagonist) levels that inhibit γ-carboxylation are different in liver and bone (experiment 1), and to investigate whether the plasma osteocalcin (OC) level reflects bone OC levels (experiments 2 and 3). Four-week-old male rats were treated with 0.2, 0.4, 0.6, 0.8, 1.0, or 1.2 mg/l of WF solution as drinking water for 4 weeks. Blood coagulation activity, an index of γ-carboxylation of prothrombin in the liver, was significantly decreased in rats receiving 0.8 mg/l or larger doses of WF. A significant decrease of plasma γ-carboxylated OC (GlaOC), an index of γ-carboxylation of OC in bone, was shown in rats receiving 0.2 mg/l or larger doses. Significantly lower OC levels in the femoral diaphysis and metaphysis were shown in the 0.2 mg/l and 0.4 mg/l groups. However, femoral bone mineral density (BMD) values in the WF-treated groups were almost the same as those in the intact group. In experiment 2, we evaluated changes in bone OC levels 4 weeks after discontinuing an 8-week WF treatment. Four-week-old male rats received 0.8 mg/l WF as drinking water for 8 or 12 weeks. Recovery of the OC level after discontinuing the WF treatment was shown in the femoral metaphysis, but not in the diaphysis. In experiment 3, 0.3 mg/kg WF was administrated to 25-week-old male rats three times a week for 8, 12, or 16 weeks. In aged rats, decreased bone OC was shown in the femoral metaphysis, but not in the diaphysis. From these findings, it is suggested that the effects of WF on γ-carboxylation are likely to appear in bone at lower doses than in the liver, that the bone OC level does not always correspond directly to plasma GlaOC, and that the bone OC level is not directly linked with BMD.

Key words

Warfarin Osteocalcin Blood coagulation Bone mineral density Rats