Differential Effects of Dabigatran and Warfarin on Bone Volume and Structure in Rats with Normal Renal Function

Abstract

BackgroundWarfarin, 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.MethodsRats 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.ResultsHistomorphometric 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.ConclusionsThese 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.

Vitamin K and bone

“…Bone was evaluated immuno-histochemically and histomorphometrically: dabigatran treated animals preserved femur and vertebral volume and structure, with higher bone volume and trabecular thickness and less trabecular separation, compared to rats treated with warfarin. The thinner trabeculae with increased separation in the marrow space of warfarin treated animals suggested a potentially increased fragility, despite similar microarchitecture (54). This finding is consistent with clinical observations from the American Atrial Fibrillation registry (37), where males treated with warfarin over one year had a higher prevalence of vertebral fractures than controls.…”

Vitamin K plasma levels determination in human health

“…Warfarin may predispose to bone fractures and vascular calcification by different mechanisms: directly, by inhibition of γ-carboxylation of OC and other bone matrix proteins; indirectly, because patients treated with warfarin may limit their dietary intake of foods rich in vitamin K. New oral anticoagulant seems to have less influence on bone metabolism, but their long-term effects need more studies [75,76].…”

Association Between Dabigatran vs Warfarin and Risk of Osteoporotic Fractures Among Patients With Nonvalvular Atrial Fibrillation

“…Although most attention has focused on its effect on stroke or bleeding, a recent animal study reported that the use of dabigatran was associated with higher bone volume, smaller trabecular separation, and lower bone turnover rate compared with warfarin in rats, suggesting potential for a lower risk of osteoporotic fracture over warfarin. 5 Osteoporotic fracture is a key clinical concern because oral anticoagulants are usually prescribed to older people for whom fracture is a significant cause of morbidity and mortality. 6 However, the actual risk of osteoporotic fracture with dabigatran in humans is undefined, and its comparison with warfarin in routine clinical practice is unknown.…”