title: 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.
authors.affiliation: Klinik und Poliklinik für Orthopädie und Sportorthopädie, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Straße 22, D-81675, München, Germany.
authors.forename: Peter Michael
authors.initials: PM
authors.lastname: Prodinger
authors.affiliation: Klinik und Poliklinik für Orthopädie und Sportorthopädie, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Straße 22, D-81675, München, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Burgkart
authors.affiliation: Klinik und Poliklinik für Mund-, Kiefer- und Gesichtschirurgie, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.
authors.forename: Kilian
authors.initials: K
authors.lastname: Kreutzer
authors.affiliation: Klinik und Poliklinik für Orthopädie und Sportorthopädie, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Straße 22, D-81675, München, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Liska
authors.affiliation: Orthopädische Klinik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität, Moorenstraße 5, D-40225, Düsseldorf, Germany.
authors.forename: Hakan
authors.initials: H
authors.lastname: Pilge
authors.affiliation: Klinik und Poliklinik für Orthopädie und Sportorthopädie, Abteilung für Sportorthopädie, Klinikum rechts der Isar der TU München, Ismaninger Straße 22, D-81675, München, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schmitt
authors.affiliation: Klinik und Poliklinik für Orthopädie und Sportorthopädie, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Straße 22, D-81675, München, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Knödler
authors.affiliation: Regenerative Medicine Group, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.
authors.forename: Boris Michael
authors.initials: BM
authors.lastname: Holzapfel
authors.affiliation: Institut für Medizinische Statistik und Epidemiologie, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Straße 22, D-81675, München, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hapfelmeier
authors.affiliation: Orthopädische Klinik und Poliklinik, Universität Rostock, Doberaner Straße 142, D-18057, Rostock, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tischer
authors.affiliation: Klinik und Poliklinik für Mund-, Kiefer- und Gesichtschirurgie, Klinikum rechts der Isar, Technische Universität München, Ismaninger Straße 22, D-81675, München, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Bissinger
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects / Q000494:pharmacology*; D001696:Biomechanical Phenomena / Q000187:drug effects; D004195:Disease Models, Animal; D017984:Enoxaparin / Q000494:pharmacology; D017102:Fracture Healing / Q000187:drug effects*; D005596:Fractures, Closed / Q000000981:diagnostic imaging / Q000473:pathology; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology; D008297:Male; D051381:Rats; D000069552:Rivaroxaban / Q000494:pharmacology; D055114:X-Ray Microtomography
chemical_list: D000925:Anticoagulants; D017984:Enoxaparin; D006495:Heparin, Low-Molecular-Weight; D000069552:Rivaroxaban