title: Differential Effects of Dabigatran and Warfarin on Bone Volume and Structure in Rats with Normal Renal Function.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: National Research Council (CNR)-Neuroscience Institute, Padova, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Fusaro
authors.affiliation: Department of Medicine, Section of Internal Medicine D, University of Verona, Verona, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Dalle Carbonare
authors.affiliation: Division of Experimental Nephrology, IRB Lleida (Lleida Institute for Biomedical Research), Lleida, Spain.
authors.forename: Adriana
authors.initials: A
authors.lastname: Dusso
authors.affiliation: Division of Experimental Nephrology, IRB Lleida (Lleida Institute for Biomedical Research), Lleida, Spain.
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Arcidiacono
authors.affiliation: Department of Medicine, Section of Internal Medicine D, University of Verona, Verona, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Valenti
authors.affiliation: Nephrology Unit, University of Padua, Padua, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Aghi
authors.affiliation: Nephrology and Dialysis Unit, Ospedale San Carlo Borromeo and Department of Clinical and Biomedical Sciences "Luigi Sacco", University of Milano, Milano, Italy.
authors.forename: Sabina
authors.initials: S
authors.lastname: Pasho
authors.affiliation: Nephrology and Dialysis Unit, Ospedale San Carlo Borromeo and Department of Clinical and Biomedical Sciences "Luigi Sacco", University of Milano, Milano, Italy; Department of Clinical and Biomedical Sciences "Luigi Sacco", University of Milano, Milano, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Gallieni
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology* / Q000633:toxicity; D000991:Antithrombins / Q000494:pharmacology* / Q000633:toxicity; D001011:Aorta / Q000473:pathology; D001851:Bone Diseases, Metabolic / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D016723:Bone Remodeling / Q000187:drug effects*; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D002114:Calcinosis / Q000473:pathology; D000069604:Dabigatran / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D005598:Fractures, Spontaneous / Q000517:prevention & control; D007083:Iliac Artery / Q000473:pathology; D007668:Kidney / Q000502:physiology; D008903:Minerals / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014652:Vascular Diseases / Q000473:pathology; D014812:Vitamin K / Q000037:antagonists & inhibitors / Q000502:physiology; D014859:Warfarin / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D008903:Minerals; D014812:Vitamin K; D014859:Warfarin; D000069604:Dabigatran