An Overview of Drug Effects on Bone Healing on Animal Research Models

Nguyen Hoai Nam 1 and Naruepon Kampa 2

1Faculty of Veterinary Medicine, Vietnam National University of Agriculture, Hanoi 131000, Vietnam
2Faculty of Veterinary Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
Received: May 19, 2019 /
Published: Jun 18, 2021

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Bone fracture is a common health problem in humans and animals, and the healing of the bone fracture is a complicated process. Several drugs may be used concurrently with the treatment of fractures, but they may interfere with the healing process of the bone. The present research reviewed previously published studies with the objective to enhance the understandings of the effects of different drugs on bone healing. There is clear evidence that antibiotics, corticosteroids, non-steroidal inflammatory drugs, and chemotherapeutic drugs all affect bone healing. By contrast, the effect of anticoagulants on bone healing is controversial, so more research is needed to determine its efficacy. In addition, there is no direct evidence to approve the effect of anesthetics on bone healing, so this is another area in need of further research.

Keywords: Animal model, bone healing, drug, rat femur

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How to Cite
Nam, N., & Kampa, N. (2021). An Overview of Drug Effects on Bone Healing on Animal Research Models. Vietnam Journal of Agricultural Sciences, 4(1), 978-988.


    Aslan M., Simsek G. & Yildirim U. (2005). Effects of short-term treatment with systemic prednisone on bone healing: an experimental study in rats. Dental Traumatology. 21(4): 222-225.
    Bissinger O., Kreutzer K., Götz C., Hapfelmeier A., Pautke C., Vogt S., Wexel G., Wolff K. D., Tischer T. & Prodinger P. M. (2016). A biomechanical, micro-computertomographic and histological analysis of the influence of diclofenac and prednisolone on fracture healing in vivo. BMC Musculoskeletal Disorders. 17(1): 383.
    Bostrom M. P., Gamradt S. C., Asnis P., Vickery B., Hill E., Avnur Z. & Waters R. V. (2000). Parathyroid hormone-related protein analog RS-66271 is an effective therapy for impaired bone healing in rabbits on corticosteroid therapy. Bone. 26(5): 437-442.
    Brown K. M., Saunders M. M., Kirsch T., Donahue H. J. & Reid J. S. (2004). Effect of COX-2-specific inhibition on fracture-healing in the rat femur. The Journal of Bone and Joint Surgery. 86A(1): 116-123.
    Cappello T, Nuelle J. A., Katsantonis N., Nauer R. K., Lauing K. L., Jagodzinski J. E. & Callaci J. J. (2013). Ketorolac administration does not delay early fracture healing in a juvenile rat model: a pilot study. Journal of Pediatric Orthopaedics. 33(4): 415-421.
    Cavalcanti S. C., Correa L., Mello S. B. & Luz J. G. (2014). The effect of methotrexate on the bone healing of mandibular condylar process fracture: an experimental study in rats. Journal of Cranio-Maxillofacial Surgery. 42(7): 1133-1139.
    Curcelli E. C., Müller S. S., Ueda A. K., Padovani C. R., Maffei F. H. & Hossne W. S. (2005). Effect of heparin-sodium and enoxaparin on rats tibial fracture healing: clinical, anatomopathological, and biomechanical approach. Acta Ortopédica Brasileira. 13(1): 13-16.
    Demirtas A., Azboy I., Bulut M., Ucar B. Y., Alabalik U. & Necmioglu N. S. (2013). Investigation of the effects of Enoxaparin, Fondaparinux, and Rivaroxaban used in thromboembolism prophylaxis on fracture healing in rats. European Review for Medical andPharmacological Sciences. 17(14): 1850-1856.
    Endo K., Sairyo K., Komatsubara S., Sasa T., Egawa H., Yonekura D., Adachi K., Ogawa T., Murakami R. & Yasui N. (2002). Cyclooxygenase-2 inhibitor inhibits the fracture healing. Journal of Physiological Anthropology and Applied Human Science. 21(5): 235-238.
    Erli H., Melchert M. & Rüger M. (2006). The effect of low-dosed unfractioned and low-molecular weight heparins on bone healing in vivo. The Internet Journal of Orthopedic Surgery. 3 (2).
    Fassbender M., Minkwitz S., Kronbach Z., Strobel C., Kadow-Romacker A., Schmidmaier G. & Wildemann B. (2013). Local gentamicin application does not interfere with bone healing in a rat model. Bone. 55(2): 298-304.
    Flondor M., Hofstetter C., Boost K. A., Betz C., Homann M. & Zwissler B. (2008). Isoflurane inhalation after induction of endotoxemia in rats attenuates the systemic cytokine response. European Surgical Research. 40(1): 1-6.
    Fracon R.N., Teofilo J. M., Moris I. C. & Lamano T. (2010). Treatment with paracetamol, ketorolac or etoricoxib did not hinder alveolar bone healing: a histometric study in rats. Journal of Applied Oral Science. 18(6): 630-634.
    Gerstenfeld L. C., Thiede M., Seibert K., Mielke C., Phippard D., Svagr B., Cullinane D. & Einhorn T. A. (2003). Differential inhibition of fracture healing by non-selective and cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs. Journal of Orthopaedic Research. 21(4): 670-675.
    Gough A., Johnson R., Campbell E., Hall L., Tylor J., Carpenter A., Black W., Basrur P. K., Baragi V. M., Sigler R. & Metz A. (1996). Quinolone arthropathy in immature rabbits treated with the fluoroquinolone, PD 117596. Experimental and Toxicologic Pathology. 48(4): 225-232.
    Hak D. J., Stewart R. L. & Hazelwood S. J. (2006). Effect of low molecular weight heparin on fracture healing in a stabilized rat femur fracture model. Journal of Orthopaedic Research. 24(4): 645-652.
    Haleem A. A., Rouse M. S., Lewallen D. G., Hanssen A. D., Steckelberg J. M. & Patel R. (2004). Gentamicin and vancomycin do not impair experimental fracture healing. Clinical Orthopaedics and Related Research. 427: 22-24.
    Hausman M. R., Schaffler M. B. & Majeska R. J. (2001). Prevention of fracture healing in rats by an inhibitor of angiogenesis. Bone. 29(6): 560-564.
    Histing T., Garcia P., Holstein J. H., Klein M., Matthys R., Nuetzi R., Steck R., Laschke M. W., Wehner T., Bindl R., Recknagel S., Stuermer E. K., Vollmar B., Wildemann B., Lienau J., Willie B., Peters A., Ignatius A., Pohlemann T., Claes L. & Menger M. D. (2011). Small animal bone healing models: standards, tips, and pitfalls results of a consensus meeting. Bone. 49(4): 591-599.
    Hogevold H. E., Grogaard B. & Reikeras O. (1992). Effects of short-term treatment with corticosteroids and indomethacin on bone healing A mechanical study of osteotomies in rats. Acta Orthopaedica Scandinavica. 63(6): 607-611.
    Huddleston P. M., Steckelberg J. M., Hanssen A. D., Rouse M. S., Bolander M. E. & Patel R. (2000). Ciprofloxacin inhibition of experimental fracture healing. The Journal of Bone and Joint Surgery. 82(2): 161-173.
    Inal S., Kabay S., Cayci M. K., Kuru H. I., Altikat S., Akkas G. & Deger A. (2014). Comparison of the effects of dexketoprofen trometamol, meloxicam and diclofenac sodium on fibular fracture healing, kidney and liver: an experimental rat model. Injury. 45(3): 494-500.
    Jahangir A., Nunley R. M., Mehta S. & Sharan A. (2008). Bone-graft substitutes in orthopaedic surgery American Academy of Orthopaedics Surgeons.[online]. Retrieved from http ://wwwaaos org/news/aaosnow/jan08/reimbursement2asp on November 15, 2017.
    Kapetanakis S., Nastoulis E., Demesticha T. & Demetriou T. (2015). The effect of low molecular weight heparins on fracture healing. The Open Orthopaedics Journal. 9: 226-236.
    Kawasaki T., Ogata M., Kawasaki C., Ogata J., Inoue Y. & Shigematsu A. (1999). Ketamine suppresses proinflammatory cytokine production in human whole blood in vitro. Anesthersia and Analgesia. 89(3): 665-669.
    Kidd L. J., Cowling N. R., Wu A. C., Kelly W. L. & Forwood M. R. (2013). Selective and non-selective cyclooxygenase inhibitors delay stress fracture healing in the rat ulna. Journal of Orthopaedic Research. 31(2): 235-242.
    Kim S. G., Chung T. Y., Kim M. S. & Lim S. C. (2004). The effect of high local concentrations of antibiotics on demineralized bone induction in rats. Journal of Oral and Maxillofacial Surgery. 62(6): 708-713.
    Klüter T., Weuster M., Brüggemann S., Menzdorf L., Oestern S. F., Steubesand N., Acil Y., Pufe T., Varoga D., Seekamp A. & Lippross S. (2015). Rivaroxaban does not impair fracture healing in a rat femur fracture model: an experimental study. BMC Musculoskeletal Disorders. 16(79). DOI: 10.1186/s12891-015-0502-9.
    Koga K., Ogata M., Takenaka I., Matsumoto T. & Shigematsu A. (1994). Ketamine suppresses tumor necrosis factor-alpha activity and mortality in carrageenan-sensitized endotoxin shock model. Circulatory Shock. 44(3): 160-168.
    Krischak G. D., Augat P., Sorg T., Blakytny R., Kinzl L., Claes L. & Beck A. (2007). Effects of diclofenac on periosteal callus maturation in osteotomy healing in an animal model. Archives of Orthopaedic and Trauma Surgery. 127(1): 3-9.
    Lack W.D., Fredericks D., Petersen E., Donovan M., George M., Nepola J., Smucker J. & Femino J. E. (2013). Effect of aspirin on bone healing in a rabbit ulnar osteotomy model. The Journal of Bone and Joint Surgery. 95(6): 488-496.
    Leonelli S. M., Goldberg B. A., Safanda J., Bagwe M. R., Sethuratnam S. & King S. J. (2006). Effects of a cyclooxygenase-2 inhibitor (rofecoxib) on bone healing. American Journal of Orthopedics. 35(2): 79-84.
    Luppen C. A., Blake C. A., Ammirati K. M., Stevens M. L., Seeherman H. J., Wozney J. M. & Bouxsein M. L. (2002). Recombinant human bone morphogenetic protein-2 enhances osteotomy healing in glucocorticoid-treated rabbits. Journal of Bone and Mineral Research. 17(2): 301-310.
    Morcuende J. A., Gomez P., Stack J., Oji G., Martin J., Fredericks D. C. & Buckwalter J. A. (2004). Effect of chemotherapy on segmental bone healing enhanced by rhBMP-2. Archive of The Iowa Orthopaedic Journal. 24: 36-42.
    Natividad-Pedreno M., Nunez-Chia A., Cobo-Valenzuela N., Alcantara-Martos T., Carrascal M. T. & Delgado-Martinez A. D. (2016). Effect of cefazolin and cefuroxime on fracture healing in rats. Injury. 47(3): S3-S6.
    Perry A. C., Prpa B., Rouse M. S., Piper K. E., Hanssen A. D., Steckelberg J. M. & Patel R. (2003). Levofloxacin and trovafloxacin inhibition of experimental fracture-healing. Clinical Orthopaedics and Related Research. 414: 95-100.
    Porter J. R, Ruckh T. T. & Popat K. C. (2009). Bone tissue engineering: a review in bone biomimetics and drug delivery strategies. Biotechnology Progress. 25(6): 1539-1560.
    Prodinger P. M., Burgkart R., Kreutzer K., Liska F., Pilge H., Schmitt A., Knodler M., Holzapfel B. M., Hapfelmeier A., Tischer T. & Bissinger O. (2016). 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. Public Library of Science One. 11(7): e0159669.
    Satoh K., Mark H., Zachrisson P., Rydevik B., Byrod G., Kikuchi S., Konno S. & Sekiguchi M. (2011). Effect of methotrexate on fracture healing. Fukushima Journal of Medical Science. 57(1): 11-18.
    Sawin P. D., Dickman C. A., Crawford N. R., Melton M. S., Bichard W. D. & Sonntag V. K. (2001). The effects of dexamethasone on bone fusion in an experimental model of posterolateral lumbar spinal arthrodesis. Journal of Neurosurgery. 94(1): 76-81.
    Say F., İltar S., Alemdaroğlu K. B., Özel İ., Aydoğan N. H. & Gönültaş M. (2013). The effect of various types low molecular weight heparins on fracture healing. Thrombosis Research. 131(3): e114-e119.
    Simon A. M. & O'Connor J. P. (2007). Dose and time-dependent effects of cyclooxygenase-2 inhibition on fracture-healing. The Journal of Bone and Joint Surgery. 89(3): 500-511.
    Sissons H. A. & Hadfield G. J. (1955). The influence of cortisone on the structure and growth of bone. Journal of Anatomy. 89(1): 69-78.
    Street J. T., McGrath M., O'Regan K., Wakai A., McGuinness A. & Redmond H. P. 2000. Thromboprophylaxis using a low molecular weight heparin delays fracture repair. Clinical Orthopaedics and Related Research. 381: 278-289.
    Strickland D. (2014). Wearing your seat belt costs you nothing but not wearing one certainly will.[online]. Retrieved from on June 9, 2018.
    Suliburk J. W., Helmer K. S., Gonzalez E. A., Robinson E. K. & Mercer D. W. (2005). Ketamine attenuates liver injury attributed to endotoxemia: role of cyclooxygenase-2. Surgery. 138(2): 134-140.
    Sun J., Li F., Chen J. & Xu J. (2004). Effect of ketamine on NF-kappa B activity and TNF-alpha production in endotoxin-treated rats. Annals of Clinical and Laboratory Science. 34(2): 181-186.
    Taniguchi T., Shibata K. & Yamamoto K. (2001). Ketamine inhibits endotoxin-induced shock in rats. Anesthesiology. 95(4): 928-932.
    Tortolani P. J., Park A. E., Louis-Ugbo J., Attallah-Wasef E. S., Kraiwattanapong C., Heller J. G., Boden S. D. & Yoon S. T. (2004). The effects of doxorubicin (adriamycin) on spinal fusion: an experimental model of posterolateral lumbar spinal arthrodesis. The Spine Journal. 4(6): 669-674.
    Vnuk D., Pirkic B., Maticic D., Radisic B., Stejskal M., Babic T., Kreszinger M. & Lemo N. (2004). Feline high-rise syndrome: 119 cases (1998-2001). Journal of Feline Medicine and Surgery. 6(5): 305-312.
    Waters R. V, Gamradt S. C, Asnis P., Vickery B. H., Avnur Z., Hill E. and Bostrom M. (2000). Systemic corticosteroids inhibit bone healing in a rabbit ulnar osteotomy model. Acta Orthopaedica Scandinavica. 71(3): 316-321.
    Xie X. H., Wang X. L., Zhang G., Liu Z., Yao D., Hung L. K., Hung V. W. & Qin L. (2011). Impaired bone healing in rabbits with steroid-induced osteonecrosis. Journal of Bone and Joint Surgery. 93(4): 558-565.
    Yaghini J., Abed A. M., Izadi M., Birang R., Torabinia N. & Tavakoli M. (2017). Effect of short-term steroid use (Prednisolone) on bone healing around implants: An experimental study on dogs. Journal of Oral Health and Dental Management. 16(2): 1-4.
    Zhang C., Tang T. T., Ren W. P., Zhang X. L. & Dai K. R. (2007). Inhibiting wear particles-induced osteolysis with doxycycline. Acta Pharmacologica Sinica. 28(10): 1603-1610.