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Vet Comp Orthop Traumatol 2010; 23(06): 385-392
DOI: 10.3415/VCOT-10-01-0017
Review Article
Schattauer GmbH

Non-steroidal anti-inflammatory drugs inhibit bone healing: A review

S. Barry
1   Washington State University, Department of Veterinary Clinical Sciences, Veterinary Teaching Hospital, Pullman, Washington, USA
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Further Information

Publication History

Received: 31 January 2010

Accepted: 23 June 2010

Publication Date:
19 December 2017 (online)

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Summary

The ability of non-steroidal anti-inflammatory drugs (NSAID) to inhibit bone healing has been established in experimental animal models using mice, rats, and rabbits. The mechanism of action is largely unknown but stems from prostaglandin inhibition and is likely multifactorial. In human medicine NSAID are known to prevent heterotopic ossification, however the clinical importance of their effects on bone healing remains controversial. Although a small handful of reports suggest that NSAID suppress bone healing in dogs and horses, there is little published information to direct veterinary practice in domestic species.

Keywords

Non-steroidal anti-inflammatory drugs - NSAID - bone healing
 

  • References

  • 1 Ro J, Sudmann E, Marton PF. Effect of indomethacin on fracture healing in rats. Acta Orthop Scand 1976; 47: 588-599.
    CrossrefPubMedGoogle Scholar
  • 2 Sudmann E, Hagen T. [Indomethacin-induced delayed fracture healing]. Arch Orthop Unfall-Chir 1976; 85: 151-154.
    CrossrefPubMedGoogle Scholar
  • 3 O’Connor JP, Lysz T. Celecoxib, NSAIDs and the skeleton. Drugs Today 2008; 44: 693-709.
    CrossrefPubMedGoogle Scholar
  • 4 Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 1971; 231: 232-235.
    CrossrefPubMedGoogle Scholar
  • 5 Clark TP. The clinical pharmacology of cyclooxygenase-2–selective and dual inhibitors. Vet Clin Small Anim 2006; 36: 1061-1085.
    CrossrefPubMedGoogle Scholar
  • 6 Dekel S, Lenthall G, Francis MJO. Release of pros-taglandins from bone and muscle after tibial fracture. J Bone Joint Surg 1981; 63–B: 185-189.
    PubMedGoogle Scholar
  • 7 Simon AM, O’Connor JP. Dose and time-dependent effects of cyclooxygenase-2 inhibition on fracture-healing. J Bone Joint Surg Am 2007; 89: 500-511.
    CrossrefPubMedGoogle Scholar
  • 8 Gerstenfeld LC, Al-Ghawas M, Alkhiary YM. et al. Selective and nonselective cyclooxygenase-2 inhibitors and experimental fracture-healing. Reversibility of effects after short-term treatment. J Bone Joint Surg Am 2007; 89: 114-125.
    CrossrefPubMedGoogle Scholar
  • 9 Blackwell KA, Raisz LG, Pilbeam CC. Prostaglandins in bone: bad cop, good cop?. Trends Endocrinol Metab 2010; 21: 294-301.
    CrossrefPubMedGoogle Scholar
  • 10 McKibben B. The biology of fracture healing in long bones. J Bone Joint Surg Br 1978; 60B: 150-162.
    PubMedGoogle Scholar
  • 11 Einhorn TA. The cell and molecular biology of fracture healing. Clin Orthop Relat Res 1998; 355S: S7-S21.
    CrossrefPubMedGoogle Scholar
  • 12 Frost HM. The regional acceleratory phenomenon: A review. Henry Ford Hosp Med J 1983; 31: 3-9.
    PubMedGoogle Scholar
  • 13 Einhorn TA. The science of fracture healing. J Orthop Traum 2005; 19 (Suppl. 10) Suppl S4-S6.
    CrossrefPubMedGoogle Scholar
  • 14 Cho TJ, Gerstenfeld LC, Einhorn TA. Differential temporal expression of members of the transforming growth factor ß superfamily during murine fracture healing. J Bone Miner Res 2002; 17: 513-520.
    CrossrefPubMedGoogle Scholar
  • 15 Tsiridis E, Upadhyay N, Giannoudis P. Molecular aspects of fracture healing: Which are the important molecules?. Injury 2007; 38 (S1) S11-S25.
    PubMedGoogle Scholar
  • 16 Al-Aql ZS, Alagl AS, Graves DT. et al. Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis. J Dent Res 2008; 87: 107-118.
    CrossrefPubMedGoogle Scholar
  • 17 Shih MS, Norridin RW. Effects of prostaglandins on regional remodeling changes during tibial healing in beagles: a histomorphometric study. Calcif Tissue Int 1986; 39: 191-197.
    CrossrefPubMedGoogle Scholar
  • 18 Shih MS, Norridin RW. Effects of prostaglandin E2 on rib fracture healing in beagles: histomorpho-metric study on periosteum adjacent to the fracture site. Am J Vet Res 1986; 47: 1561-1564.
    PubMedGoogle Scholar
  • 19 Paralkar VM, Borovecki F, Cameron KO. et al. An EP2 receptor-selective prostaglandin E2 agonist induces bone healing. Proc Natl Acad Sci USA 2003; 100: 6736-6740.
    CrossrefPubMedGoogle Scholar
  • 20 Tanaka M, Sakai A, Uchida S. et al. Prostaglandin E2 receptor (EP4) selective agonist (ONO-4819.CD) accelerates bone repair of femoral cortex after drill-hole injury associated with local upregulation of bone turnover in mature rats. Bone 2004; 34: 940-948.
    CrossrefPubMedGoogle Scholar
  • 21 Zhang X, Schwarz EM, Young DA. et al. Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. J Clin Invest 2002; 109: 1405-1415.
    CrossrefPubMedGoogle Scholar
  • 22 Kellinsalmi M, Parikka V, Risteli J. et al. Inhibition of cyclooxygenase-2 down-regulates osteoclast and osteoblast differentiation and favours adipocyte formation in vitro. Eur J Pharmacol 2007; 572: 102-110.
    CrossrefPubMedGoogle Scholar
  • 23 Krischak GD, Augat P, Blakytny R. et al. The nonsteroidal anti-inflammatory drug diclofenac reduces appearance of osteoblasts in bone defect healing in rats. Arch Orthop Trauma Surg 2007; 127: 453-458.
    CrossrefPubMedGoogle Scholar
  • 24 Arikawa T, Omura K, Morita I. Regulation of bone morphogenetic protein-2 expression by endogenous prostaglandin E2 in human mesenchymal stem cells. J Cell Physiol 2004; 200: 400-406.
    CrossrefPubMedGoogle Scholar
  • 25 Chikazu D, Li X, Kawaguchi H. et al. Bone morpho-genetic protein 2 induces cyclo-oxygenase 2 in osteoblasts via a Cbfa1 binding site: Role in effects of bone morphogenetic protein 2 in vitro and in vivo. J Bone Miner Res 2002; 17: 1430-1440.
    CrossrefPubMedGoogle Scholar
  • 26 Spiro AS, Beil FT, Baranowsky A. et al. BMP-7–induced ectopic bone formation and fracture healing is impaired by systemic NSAID application in C57BL/6–mice. J Orthop Res 2010; 28: 785-791.
    PubMedGoogle Scholar
  • 27 Sahin M, Sahin E, Gümüslü S. Cyclooxygenase-2 in cancer and angiogenesis. Angiology 2009; 60: 242-253.
    CrossrefPubMedGoogle Scholar
  • 28 Hausman MR, Schaffler MB, Majeska RJ. Prevention of fracture healing in rats by an inhibitor of angiogenesis. Bone 2001; 29: 560-564.
    CrossrefPubMedGoogle Scholar
  • 29 Murnaghan M, Li G, Marsh DR. Nonsteroidal anti-inflammatory drug-induced fracture nonunion: An inhibition of angiogenesis?. J Bone Joint Surg Am 2006; 88: 140-147.
    PubMedGoogle Scholar
  • 30 Keller J, Kjærsgaard-Andersen P, Bayer-Kristensen I. et al. Indomethacin and bone trauma. Effects on remodeling of rabbit bone. Acta Orthop Scand 1990; 61: 66-69.
    PubMedGoogle Scholar
  • 31 Reikeraas O, Engebretsen L. Effects of ketorolac tromethamine and indomethacin on primary and secondary bone healing. An experimental study in rats. Arch Orthop Trauma Surg 1998; 118: 50-52.
    CrossrefPubMedGoogle Scholar
  • 32 Long J, Lewis S, Kuklo T. et al. The effect of cyclooxygenase-2 inhibitors on spinal fusion. J Bone Joint Surg Am 2002; 84 A 1763-1768.
    CrossrefPubMedGoogle Scholar
  • 33 Nyangoga H, Aguado E, Goyenvalle E. et al. A nonsteroidal anti-inflammatory drug (ketoprofen) does not delay β-TCP bone graft healing. Acta Bio-mater 2010; 6: 3310-3317.
    CrossrefPubMedGoogle Scholar
  • 34 Gerstenfeld LC, Thiede M, Seibert K. et al. Differential inhibition of fracture healing by non-selective and cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs. J Orthop Res 2003; 21: 670-675.
    CrossrefPubMedGoogle Scholar
  • 35 Simon AM, Manigrasso MB, O’Connor JP. Cyclooxygenase 2 function is essential for bone fracture healing. J Bone Miner Res 2002; 17: 963-976.
    CrossrefPubMedGoogle Scholar
  • 36 Brown KM, Saunders MM, Kirsch T. et al. Effect of COX-2–specific inhibition on fracture-healing in the rat femur. J Bone Joint Surg 2004; 86: 116-123.
    CrossrefPubMedGoogle Scholar
  • 37 Endo K, Sairyo K, Komatsubara S. et al. Cyclooxygenase-2 inhibitor delays fracture healing in rats. Acta Orthop 2005; 76: 470-474.
    CrossrefPubMedGoogle Scholar
  • 38 Beck A, Krischak G, Sorg I. et al. Influence of diclofenac (group of nonsteroidal anti-inflammatory drugs) on fracture healing. Arch Orthop Trauma Surg 2003; 123: 327-332.
    CrossrefPubMedGoogle Scholar
  • 39 Krischak G, Augat P, Sorg T. et al. Effects of diclofenac on periosteal callus maturation in osteotomy healing in an animal model. Arch Orthop Trauma Surg 2007; 127: 3-9.
    PubMedGoogle Scholar
  • 40 Dimmen S, Nordsletten L, Engebretsen L. et al. Negative effect of parecoxib on bone mineral during fracture healing in rats. Acta Orthop 2008; 79: 438-444.
    CrossrefPubMedGoogle Scholar
  • 41 Goodman SB, Ma T, Mitsunaga L. et al. Temporal effects of a COX-2 selective NSAID on bone in-growth. J Biomed Mater Res 2005; 72: 279-287.
    PubMedGoogle Scholar
  • 42 Leonelli SM, Goldberg BA, Safanda J. et al. Effects of a cyclooxygenase-2 inhibitor (rofecoxib) on bone healing. Am J Orthop 2006; 35: 79-84.
    PubMedGoogle Scholar
  • 43 Dimmen S, Nordsletten L, Madsen JE. Parecoxib and indomethacin delay early fracture healing: a study in rats. Clin Orthop Rel Res 2009; 467: 1992-1999.
    CrossrefPubMedGoogle Scholar
  • 44 Ochi H, Hara Y, Asou Y. et al. Effect of long-term administration of non-steroidal anti-inflammatory drugs on fracture healing in dogs. (Poster presentation) ACVS Veterinary Symposium 2009 October 8-10;Washington DC, USA.
    PubMedGoogle Scholar
  • 45 Giordano V, Giordano M, Knackfuss IG. et al. Effect of tenoxicam on fracture healing in rat tibiae. Injury 2003; 34: 85-94.
    CrossrefPubMedGoogle Scholar
  • 46 Riew KD, Long J, Rhee J. et al. Time-dependent inhibitory effects of indomethacin on spinal fusion. J Bone Joint Surg Am 2003; 85: 632-634.
    CrossrefPubMedGoogle Scholar
  • 47 Allen HL, Wase A, Bear WT. Indomethacin and aspirin: effect of nonsteroidal anti-inflammatory agents on the rate of fracture repair in the rat. Acta Orthop Scand 1980; 51: 595-600.
    CrossrefPubMedGoogle Scholar
  • 48 Fransen M, Neal B. Non-steroidal anti-inflammatory drugs for preventing heterotopic bone formation after hip arthroplasty. Cochrane Database Syst Rev 2004; 3: CD160
    PubMedGoogle Scholar
  • 49 Almåsbakk K, Røysland P. Does indomethacin (IMC) prevent postoperative ectopic ossification in total hip replacement?. (Abstract) Acta Orthop Scand 1977; 48: 556
    PubMedGoogle Scholar
  • 50 Burd TA, Hughes MS, Anglen JO. Heterotopic ossification prophylaxis with indomethacin increases the risk of long bone nonunion. J Bone Joint Surg Br 2003; 85 B 700-705.
    PubMedGoogle Scholar
  • 51 Adolphson P, Abbaszadegan H, Jonsson U. et al. No effects of piroxicam on osteopenia and recovery after Colles’ fracture. Arch Orthop Trauma Surg 1993; 112: 127-130.
    CrossrefPubMedGoogle Scholar
  • 52 Davis TRC, Ackroyd CE. Non-steroidal anti-inflammatory agents in the management of Colles’ fractures. Br J Clin Pract 1988; 42: 184-189.
    PubMedGoogle Scholar
  • 53 Bhattacharyya T, Levin R, Vrahas MS. et al. Nonsteroidal antiinflammatory drugs and nonunion of humeral shaft fractures. Arthritis Rheum 2005; 53: 364-367.
    CrossrefPubMedGoogle Scholar
  • 54 Rohde C, Anderson DE, Bertone AL. et al. Effects of phenylbutazone on bone activity and formation in horses. Am J Vet Res 2000; 61: 537-543.
    CrossrefPubMedGoogle Scholar
  • 55 Mbugua SW, Skoglund LA, Løkken P. Effects of phenylbutazone and indomethacin on the post-operative course following experimental orthopaedic surgery in dogs. Acta Vet Scand 1989; 30: 27-35.
    PubMedGoogle Scholar
  • 56 Pountos I, Georgouli T, Blokhuis TJ. et.al. Pharmacological agents and impairment of fracture healing. What is the evidence? Injury 2008; 39: 384-394.
    PubMedGoogle Scholar
  • 57 Sudmann E, Bang G. Indomethacin-induced inhibition of Haversian remodelling in rabbits. Acta Orthop Scand 1979; 50: 621-627.
    CrossrefPubMedGoogle Scholar
  • 58 Törnkvist H, Lindholm TS. Effect of ibuprofen on mass and composition of fracture callus and bone. Scand J Rheumatol 1980; 9: 167-171.
    CrossrefPubMedGoogle Scholar
  • 59 Elves MW, Bayley I, Roylance PJ. The effect of indomethacin upon experimental fractures in the rat. Acta Orthop Scand 1982; 53: 35-41.
    CrossrefPubMedGoogle Scholar
  • 60 Persson P, Sisask G, Nilsson O. Indomethacin inhibits bone formation in inductive allografts but not in autografts. Acta Orthop 2005; 76: 465-469.
    CrossrefPubMedGoogle Scholar
  • 61 O’Connor JP, Capo JT, Tan V. et al. A comparison of the effects of ibuprofen and rofecoxib on rabbit fibula osteotomy healing. Acta Orthop 2009; 80: 597-605.
    CrossrefPubMedGoogle Scholar
  • 62 Rueben SS, Ekman EF. The effect of cyclooxygenase-2 inhibition on analgesia and spinal fusion. J Bone Joint Surg Am 2005; 87: 536-542.
    CrossrefPubMedGoogle Scholar
  • 63 Deguchi M, Rapoff AJ, Zdeblick TA. Posterolateral fusion for isthmic spondylolisthesis in adults: Analysis of fusion rate and clinical results. J Spinal Disord 1998; 11: 459-464.
    PubMedGoogle Scholar
  • 64 Glassman SD, Rose SM, Dimar JR. The effect of postoperative nonsteroidal anti-inflammatory drug administration on spinal fusion. Spine 1998; 23: 834-838.
    CrossrefPubMedGoogle Scholar
  • 65 Giannoudis PV, MacDonald DA, Matthews SJ. et al. Nonunion of the femoral diaphysis: The influence of reaming and non-steroidal anti-inflammatory drugs. J Bone Joint Surg Br 2000; 82B: 655-658.
    PubMedGoogle Scholar
  • 66 Reuben SS, Ablett D, Kaye R. High dose nonsteroidal anti-inflammatory drugs compromise spinal fusion. Can J Anesth 2005; 52: 506-512.
    CrossrefPubMedGoogle Scholar
  • 67 Pradhan BB, Tatsumi RL, Gallina J. et al. Ketorolac and spinal fusion: Does the perioperative use of ketorolac really inhibit spinal fusion?. Spine 2008; 33: 2079-2082.
    CrossrefPubMedGoogle Scholar