warfarin and Bone-Diseases--Metabolic

Topics: Administration, Oral; Anticoagulants; Antiphospholipid Syndrome; Aspirin; Blood Coagulation Tests; Bone Diseases, Metabolic; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fetus; Fibrinolytic Agents; Gestational Age; Heart Valve Prosthesis; Heparin; Heparin, Low-Molecular-Weight; Humans; Injections, Subcutaneous; Platelet Aggregation Inhibitors; Pregnancy; Pregnancy Complications, Cardiovascular; Prospective Studies; Pulmonary Embolism; Risk Factors; Thrombocytopenia; Thrombophilia; Thrombophlebitis; Thrombosis; Time Factors; Warfarin

Topics: Amino Acid Sequence; Animals; Bone and Bones; Bone Diseases, Metabolic; Calcitriol; Calcium-Binding Proteins; Chemotactic Factors; Durapatite; Growth Plate; Humans; Hydroxyapatites; Osteocalcin; Vitamin K; Warfarin

Warfarin, a widely used anticoagulant, is a vitamin K antagonist impairing the activity of vitamin K-dependent Bone Gla Protein (BGP or Osteocalcin) and Matrix Gla Protein (MGP). Because dabigatran, a new anticoagulant, has no effect on vitamin K metabolism, the aim of this study was to compare the impact of warfarin and dabigatran administration on bone structure and vascular calcification.. Rats with normal renal function received for 6 weeks warfarin, dabigatran or placebo. Bone was evaluated immuno-histochemically and hystomorphometrically after double labelling with declomycin and calcein. Aorta and iliac arteries were examined histologically.. Histomorphometric analysis of femur and vertebrae showed significantly decreased bone volume and increased trabecular separation in rats treated with warfarin. Vertebra analysis showed that the trabecular number was higher in dabigatran treated rats. Osteoblast activity and resorption parameters were similar among groups, except for maximum erosion depth, which was higher in warfarin treated rats, suggesting a higher osteoclastic activity. Therefore, warfarin treatment was also associated with higher bone formation rate/bone surface and activation frequency. Warfarin treatment may cause an increased bone turnover characterized by increased remodelling cycles, with stronger osteoclast activity compared to the other groups. There were no differences among experimental groups in calcium deposition either in aortic or iliac arteries.. These findings suggest for the first time that dabigatran has a better bone safety profile than warfarin, as warfarin treatment affects bone by reducing trabecular size and structure, increasing turnover and reducing mineralization. These differences could potentially result in a lower incidence of fractures in dabigatran treated patients.

Topics: Animals; Anticoagulants; Antithrombins; Aorta; Bone and Bones; Bone Diseases, Metabolic; Bone Remodeling; Calcinosis; Dabigatran; Female; Fractures, Spontaneous; Iliac Artery; Kidney; Minerals; Osteoblasts; Osteoclasts; Random Allocation; Rats; Rats, Sprague-Dawley; Vascular Diseases; Vitamin K; Warfarin

The physiologic role of osteocalcin (OC), a vitamin K-dependent protein specific to bone, remains elusive. It has been shown that rats maintained on chronic treatment with vitamin K1 and its antagonist warfarin exhibit a marked decrease in bone osteocalcin because noncarboxylated osteocalcin does not bind to bone hydroxyapatite. To assess the role of OC in bone remodeling, we applied the warfarin model to growing lambs. We analyzed the bone changes after 3 months of concurrent warfarin and vitamin K1 treatment. Four groups of four lambs were constituted at birth and received daily a saline solution (control group, CT), 4 mg/kd/day of vitamin K1 (vitamin K group), 4 mg/kg/day of vitamin K1 + 75 or 150 mg/kg/day of warfarin (W75 and W150 group, respectively). In warfarin-treated animals, bone osteocalcin levels were decreased, both in the metaphysis (9% compared to controls) and the diaphysis (30% compared to controls) of the metacarpals. The fraction of noncarboxylated osteocalcin measured every month in the serum was significantly higher in warfarin-treated lambs than in controls at each timing point (37.6 +/- 2.6% in W75 and 48.7 +/- 5.2% in W150 versus 14.4 +/- 3.8% in controls at 3 months). Compared to non-warfarin-treated animals (NW), the main histomorphometric parameters measured on the iliac crest after tetracycline double labeling were significantly reduced in the warfarin-treated lambs: 12.2 +/- 5.2 versus 18.6 +/- 4.7% in NW (p < 0.03) for the cancellous bone area, which reflects the trabecular bone density; 14.7 +/- 6.1 versus 21.0 +/- 3.6% in NW (p < 0.03) for the eroded perimeter, and 0.315 +/- 0.064 versus 0.561 +/- 0.23 microns 3/microns 2/day in NW (p < 0.02) for the tetracycline-based bone formation rate. In conclusion, the depletion of osteocalcin in the bone of lambs induced within 3 months a marked osteopenia that resulted from a decrease in resorption and a more pronounced decrease in bone formation. Our data suggest that the presence of osteocalcin, the major gla-containing protein of bone, may be important for the maintenance of a normal bone mass and remodeling of trabecular bone.

Topics: Animals; Animals, Newborn; Body Weight; Bone and Bones; Bone Diseases, Metabolic; Bone Remodeling; Calcium; Creatinine; Disease Models, Animal; Male; Osteocalcin; Parathyroid Hormone; Radioimmunoassay; Random Allocation; Sheep; Vitamin K 1; Warfarin