Does Anticoagulant Medication Alter Fracture-Healing? A Morphological and Biomechanical Evaluation of the Possible Effects of Rivaroxaban and Enoxaparin Using a Rat Closed Fracture Model

Abstract

Low molecular weight heparin (LMWH) is routinely used to prevent thromboembolism in orthopaedic surgery, especially in the treatment of fractures or after joint-replacement. Impairment of fracture-healing due to increased bone-desorption, delayed remodelling and lower calcification caused by direct osteoclast stimulation is a well-known side effect of unfractioned heparin. However, the effect of LMWH is unclear and controversial. Recent studies strongly suggest impairment of bone-healing in-vitro and in animal models, characterized by a significant decrease in volume and quality of new-formed callus. Since October 2008, Rivaroxaban (Xarelto) is available for prophylactic use in elective knee- and hip-arthroplasty. Recently, some evidence has been found indicating an in vitro dose independent reduction of osteoblast function after Rivaroxaban treatment. In this study, the possible influence of Rivaroxaban and Enoxaparin on bone-healing in vivo was studied using a standardized, closed rodent fracture-model. 70 male Wistar-rats were randomized to Rivaroxaban, Enoxaparin or control groups. After pinning the right femur, a closed, transverse fracture was produced. 21 days later, the animals were sacrificed and both femora harvested. Analysis was done by biomechanical testing (three-point bending) and micro CT. Both investigated substances showed histomorphometric alterations of the newly formed callus assessed by micro CT analysis. In detail the bone (callus) volume was enhanced (sign. for Rivaroxaban) and the density reduced. The bone mineral content was enhanced accordingly (sign. for Rivaroxaban). Trabecular thickness was reduced (sign. for Rivaroxaban). Furthermore, both drugs showed significant enlarged bone (callus) surface and degree of anisotropy. In contrast, the biomechanical properties of the treated bones were equal to controls. To summarize, the morphological alterations of the fracture-callus did not result in functionally relevant deficits.

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

“…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 .…”

“…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 . 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 .…”

“…It seems that the role of hematoma (post-traumatic or post-surgical) is essential in fracture healing as well as in osseointegration. So, increased fracture side hematoma volume as well as lacking hematoma may provide deleterious effects on physiological cascade of fracture healing 23 . A study of the effect of Enoxaparin, Fondaparinux and Rivaroxaban in fracture healing found no difference on fracture healing for the three drugs 26,27 but they used very small dose of Rivaroxaban (0,2 mg/kg) and for short period.…”

Vitamin K and Bone Health: A Review on the Effects of Vitamin K Deficiency and Supplementation and the Effect of Non-Vitamin K Antagonist Oral Anticoagulants on Different Bone Parameters

“…Studies exploring effect of NOACs in rats suggest a favorable bone-safety profile; rivaroxaban proved not to interfere with healing of rat femur fractures [50], and edoxaban did not interfere with total G1a-osteocalcin levels [51]. In a study by Prodinger et al [53], both rivaroxaban and enoxaparin induced morphological changes in the fracture callus of 70 rats, but these alterations did not result in functional deficits. In the paper by Fusaro et al [52] comparing a 6-week regimen of dabigatran, placebo, or warfarin, the administration of warfarin proved to reduce bone trabecular size and structure, increase bone turnover, and reduce mineralization compared to dabigatran.…”

“…NOAC prescription has dramatically increased in the past few years as an alternative to VKAs [49], and in contrast to the latter, NOACs do not interfere with the vitamin K cycle. Evidence exploring their bone-safety profile has been published, both in rats [50][51][52][53] and humans [49,[54][55][56][57][58].…”