Rivaroxaban does not impair fracture healing in a rat femur fracture model: an experimental study

Abstract

BackgroundThe prescription of the oral anticoagulant rivaroxaban to prevent thromboembolic episodes associated with orthopaedic surgery has dramatically increased since it was introduced. Rivaroxaban is beeing prescribed although recent in-vitro studies revealed that it impaired osteoblast metabolism. In this study we analysed the effect of rivaroxaban on fracture healing in a rat femur fracture model.MethodsFemur fractures were created by a 3-point-bending device in 48 Wistar rats and subsequently stabilized by intramedullary nailing. After the surgical procedure animals were randomised into four groups. Two groups were fed with 3 mg rivaroxaban per kg body weight per day and two control groups were fed with chow only. Animals were euthanized 28 or 49 days after surgical procedure. Femurs underwent undecalcified histologic staining micro CT scanning and biomechanical testing. The statistical significance was evaluated using one-way Anova with Bonferroni correction.ResultsMicro CT-scans revealed significantly increased volume of bone tissue in the fracture zone between day 28 and 49. During the same time callus volume decreased significantly. Comparing the fracture zone of the rivaroxaban group to the control group the treated group revealed a larger callus and a marginal increase of the tissue mineral density. The torsional rigidity was not influenced by the treatment of rivaroxaban.ConclusionIn the present study we were able to demonstrate that rivaroxaban does not impair fracture healing in a rat femur fracture model. Considering the fact that low molecular weight heparins delay fracture healing significantly, rivaroxaban might be an improved alternative.

Comparison of the effects of heparin and the direct factor Xa inhibitor, rivaroxaban, on bone microstructure and metabolism in adult rats

“…Preclinical studies have come to differing conclusions. Klüter et al (16) (17). Rivaroxaban inhibited the stimulation of cell proliferation, energy metabolism, alkaline phosphatase specific activity and mRNA modulation by a variety of hormones, i.e.…”

The effect of a new oral anticoagulant (Rivaroxaban) on implants pull-out strength. An experimental study in rats

“…The new orally administrated anticoagulant drugs are equally effective and safe with LMWH but there are also some indications that they do not affect bone healing 23,24 . Kluter et al in an experimental study found that Rivaroxaban does not impair fracture healing in a rat femur fracture model after analysis of callus by histology and the quality of the callus by CT scans 12 . Recent work from Israel 11 showed no delay in bone healing as well as no affection of cell mineralization after the administration of high doses of Rivaroxaban.…”

“…Although the exact mechanism for this effect of LMWH on bone biology is not clear, it seems that LMWH reduce cancellous bone volume, affecting osteoblasts and human mesenchymal stromal cells in the early stages of bone healing 21,22 . In addition, LMWH seem to bind the vascular endothelium which disrupts callus vascular assembly and also increase the hematoma and cytotoxic effects on cells of the medullary callus 12,23 . The new orally administrated anticoagulant drugs are equally effective and safe with LMWH but there are also some indications that they do not affect bone healing 23,24 .…”

“…Recent work from Israel 11 showed no delay in bone healing as well as no affection of cell mineralization after the administration of high doses of Rivaroxaban. This phenomenon can be explained by the effect of the drug being transient or by an adaptation of the cells to the inhibiting effect and compensation by some other mechanism 12,25 . It seems that the role of hematoma (post-traumatic or post-surgical) is essential in fracture healing as well as in osseointegration.…”

“…This dose is the maximum dose for the human according to previous studies 11,12 and the solution was prepared after pulverization of the tablets, dialysis with 99,5% DMSO (dimethyl-sulphoxide) stirring in Vortex apparatus and centrifugal force at 15000g for 5min. The animals of group B received intraperitoneal equal amount of normal saline every day.…”