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Pharmacological agents and impairment of fracture healing: What is the evidence?

      Summary

      Bone healing is an extremely complex process which depends on the coordinated action of several cell lineages on a cascade of biological events, and has always been a major medical concern. The use of several drugs such as corticosteroids, chemotherapeutic agents, non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, anticoagulants and drugs which reduce osteoclastic activity have been shown to affect bone healing. This review article presents our current understanding on this topic, focusing on data illustrating the effect of these drugs on fracture healing and bone regeneration.

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      References

        • Abu E.O.
        • Horner A.
        • Kusec V.
        • et al.
        The localization of the functional glucocorticoid receptor alpha in human bone.
        J Clin Endocrinol Metab. 2000; 85: 883-889
        • Adolphson P.
        • Abbaszadegan H.
        • Jonsson U.
        • et al.
        No effects of piroxicam on osteopenia and recovery after Colles’ fracture. A randomized, double-blind, placebo-controlled, prospective trial.
        Arch Orthop Trauma Surg. 1993; 112: 127-130
        • Alkan A.
        • Erdem E.
        • Gunhan O.
        • Karasu C.
        Histomorphometric evaluation of the effect of doxycycline on the healing of bone defects in experimental diabetes mellitus: a pilot study.
        J Oral Maxillofac Surg. 2002; 60: 898-904
        • Amanat N.
        • Brown R.
        • Bilston L.E.
        • Little D.G.
        A single systemic dose of pamidronate improves bone mineral content and accelerates restoration of strength in a rat model of fracture repair.
        J Orthop Res. 2005; 235: 1029-1034
        • 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
        • Aslan M.
        • Simsek G.
        • Yildirim U.
        Effects of short-term treatment with systemic prednisone on bone healing: an experimental study in rats.
        Dent Traumatol. 2005; 21: 222-225
        • Augat P.
        • Margevicius K.
        • Simon J.
        • et al.
        Local tissue properties in bone healing: influence of size and stability of the osteotomy gap.
        J Orthop Res. 1998; 16: 475-481
        • Augat P.
        • Merk J.
        • Ignatius A.
        • et al.
        Early, full weightbearing with flexible fixation delays fracture healing.
        Clin Orthop Relat Res. 1996; 328: 194-202
        • Beck A.
        • Krischak G.
        • Sorg T.
        • et al.
        Influence of diclofenac (group of nonsteroidal anti-inflammatory drugs) on fracture healing.
        Arch Orthop Trauma Surg. 2003; 123: 327-332
        • Beck A.
        • Salem K.
        • Krischak G.
        • et al.
        Nonsteroidal anti-inflammatory drugs (NSAIDs) in the perioperative phase in traumatology and orthopedics effects on bone healing.
        Oper Orthop Traumatol. 2005; 17: 569-578
        • Beljan J.R.
        Osseous malrepair in calcium-deficient states.
        Life Sci Space Res. 1974; 12: 133-139
        • Blasingame J.P.
        • Resnick D.
        • Coutts R.D.
        • Danzig L.A.
        Extensive spinal osteophytosis as a risk factor for heterotopic bone formation after total hip arthroplasty.
        Clin Orthop Relat Res. 1981; 161: 191-197
        • Blunt J.W.
        • Plotz C.M.
        • Lattes R.
        • et al.
        Effect of cortisone on experimental fractures in the rabbit.
        Proc Soc Exp Biol Med. 1950; 73: 678-681
        • Brown K.M.
        • Saunders M.M.
        • Kirsch T.
        • et al.
        Effect of COX-2-specific inhibition on fracture-healing in the rat femur.
        J Bone Joint Surg Am. 2004; 86-A: 116-123
        • Burchardt H.
        • Glowczewskie Jr., F.P.
        • Enneking W.F.
        The effect of adriamycin and methotrexate on the repair of segmental cortical autografts in dogs.
        J Bone Joint Surg Am. 1983; 65: 103-108
        • Burd T.A.
        • Hughes M.S.
        • Anglen J.O.
        Heterotopic ossification prophylaxis with indomethacin increases the risk of long-bone nonunion.
        J Bone Joint Surg Br. 2003; 85: 700-705
        • Burssens A.
        • Thiery J.
        • Kohl P.
        • et al.
        Prevention of heterotopic ossification with tenoxicam following total hip arthroplasty: a double-blind, placebo-controlled dose-finding study.
        Acta Orthop Belg. 1995; 61: 205-211
        • Camu F.
        • Beecher T.
        • Recker D.P.
        • Verburg K.M.
        Valdecoxib, a COX-2-specific inhibitor, is an efficacious, opioid-sparing analgesic in patients undergoing hip arthroplasty.
        Am J Ther. 2002; 9: 43-51
        • Castella F.B.
        • Garcia F.B.
        • Berry E.M.
        • et al.
        Nonunion of the humeral shaft: long lateral butterfly fracture—a nonunion predictive pattern?.
        Clin Orthop Relat Res. 2004; 424: 227-230
        • Chahal J.
        • Stephen D.J.
        • Bulmer B.
        • et al.
        Factors associated with outcome after subtalar arthrodesis.
        J Orthop Trauma. 2006; 20: 555-561
        • Claes L.E.
        • Wilke H.J.
        • Augat P.
        • et al.
        Effect of dynamization on gap healing of diaphyseal fractures under external fixation.
        Clin Biomech (Bristol, Avon). 1995; 10: 227-234
        • Cruess R.L.
        • Dumont J.
        Fracture healing.
        Can J Surg. 1975; 18: 403-413
        • Davis T.R.
        • Ackroyd C.E.
        Non-steroidal anti-inflammatory agents in the management of Colles’ fractures.
        Br J Clin Pract. 1988; 42: 184-189
        • Day S.M.
        • DeHeer D.H.
        Reversal of the detrimental effects of chronic protein malnutrition on long bone fracture healing.
        J Orthop Trauma. 2001; 15: 47-53
        • Deguchi M.
        • Rapoff A.J.
        • Zdeblick T.A.
        Posterolateral fusion for isthmic spondylolisthesis in adults: analysis of fusion rate and clinical results.
        J Spinal Disord. 1998; 11: 459-464
        • Dekel S.
        • Lenthall G.
        • Francis M.J.
        Release of prostaglandins from bone and muscle after tibial fracture. An experimental study in rabbits.
        J Bone Joint Surg Br. 1981; 63-B: 185-189
        • Dimitriou R.
        • Tsiridis E.
        • Giannoudis P.V.
        Current concepts of molecular aspects of bone healing.
        Injury. 2005; 36: 1392-1404
        • Dodds R.A.
        • Catterall A.
        • Bitensky L.
        • Chayen J.
        Effects on fracture healing of an antagonist of the vitamin K cycle.
        Calcif Tissue Int. 1984; 36: 233-238
        • Duck H.J.
        • Mylod Jr., A.G.
        Heterotopic bone in hip arthroplasties. Cemented versus noncemented.
        Clin Orthop Relat Res. 1992; 282: 145-153
        • Duthie R.B.
        • Barker A.N.
        The histochemistry of the preosseous stage of bone repair studied by autoradiography; the effect of cortisone.
        J Bone Joint Surg Br. 1955; 37-B: 691-700
        • Ehrilch P.
        • Harold T.
        • Hunt T.K.
        Effects of vitamin A and glucocorticoids upon inflammation and collagen synthesis.
        Ann Surg. 1973; 177: 222-227
        • Ehrlich P.
        • Hunt T.
        Effects of cortisone & vit A on wound healing.
        Ann Surg. 1968; 167: 324-328
        • Einhorn T.A.
        The cell and molecular biology of fracture healing.
        Clin Orthop Relat Res. 1998; 355: S7-S21
        • Elves M.W.
        • Bayley I.
        • Roylance P.J.
        The effect of indomethacin upon experimental fractures in the rat.
        Acta Orthop Scand. 1982; 53: 35-41
        • Endo K.
        • Sairyo K.
        • Komatsubara S.
        • et al.
        Cyclooxygenase-2 inhibitor delays fracture healing in rats.
        Acta Orthop. 2005; 76: 470-474
        • Endo K.
        • Sairyo K.
        • Komatsubara S.
        • et al.
        Cyclooxygenase-2 inhibitor inhibits the fracture healing.
        J Physiol Anthropol Appl Hum Sci. 2002; 21: 235-238
        • Friedlaender G.E.
        • Tross R.B.
        • Doganis A.C.
        • et al.
        Effects of chemotherapeutic agents on bone. I. Short-term methotrexate and doxorubicin (adriamycin) treatment in a rat model.
        J Bone Joint Surg Am. 1984; 66: 602-607
        • Gajraj N.M.
        The effect of cyclooxygenase-2 inhibitors on bone healing.
        Reg Anesth Pain Med. 2003; 28: 456-465
        • Gebuhr P.
        • Sletgard J.
        • Dalsgard J.
        • et al.
        Heterotopic ossification after hip arthroplasty: a randomized double-blind multicenter study tenoxicam in 147 hips.
        Acta Orthop Scand. 1996; 67: 29-32
        • Gerstenfeld L.C.
        • 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
        • Giannoudis P.V.
        • MacDonald D.A.
        • Matthews S.J.
        • et al.
        Nonunion of the femoral diaphysis. The influence of reaming and non-steroidal anti-inflammatory drugs.
        J Bone Joint Surg Br. 2000; 82: 655-658
        • Giordano V.
        • Giordano M.
        • Knackfuss I.G.
        • et al.
        Effect of tenoxicam on fracture healing in rat tibiae.
        Injury. 2003; 34: 85-94
        • Glassman S.D.
        • Rose S.M.
        • Dimar J.R.
        • Puno R.M.
        • et al.
        The effect of postoperative nonsteroidal anti-inflammatory drug administration on spinal fusion.
        Spine. 1998; 23: 834-838
        • Goodman S.B.
        • Ma T.
        • Mitsunaga L.
        • et al.
        Temporal effects of a COX-2-selective NSAID on bone ingrowth.
        J Biomed Mater Res A. 2005; 72: 279-287
        • Goodman S.
        • Ma T.
        • Trindade M.
        • et al.
        COX-2 selective NSAID decreases bone ingrowth in vivo.
        J Orthop Res. 2002; 20: 1164-1169
        • Goodship A.E.
        • Walker P.C.
        • McNally D.
        • et al.
        Use of a bisphosphonate (pamidronate) to modulate fracture repair in ovine bone.
        Ann Oncol. 1994; 5: S53-S55
        • Gravel C.A.
        • Le T.T.
        • Chapman M.W.
        Effect of neoadjuvant chemotherapy on distraction osteogenesis in the goat model.
        Clin Orthop Relat Res. 2003; 412: 213-224
        • Guarniero R.
        • de Barros Filho T.E.
        • Tannuri U.
        • et al.
        Study of fracture healing in protein malnutrition.
        Rev Paul Med. 1992; 110: 63-68
        • Gudmundson C.
        Oxytetracycline-induced disturbance of fracture healing.
        J Trauma. 1971; 11: 511-517
        • Gullihorn L.
        • Karpman R.
        • Lippiello L.
        Differential effects of nicotine and smoke condensate on bone cell metabolic activity.
        J Orthop Trauma. 2005; 19: 17-22
        • Gurpinar A.N.
        • Balkan E.
        • Kilic N.
        • et al.
        The effects of a fluoroquinolone on the growth and development of infants.
        Int Med Res. 1997; 25: 302-306
        • Hak D.J.
        • Stewart R.L.
        • Hazelwood S.J.
        Effect of low molecular weight heparin on fracture healing in a stabilized rat femur fracture model.
        J Orthop Res. 2006; 24: 645-652
        • Haleem A.A.
        • Rouse M.S.
        • Lewallen D.G.
        • et al.
        Gentamicin and vancomycin do not impair experimental fracture healing.
        Clin Orthop Relat Res. 2004; 427: 22-24
        • Hausman M.R.
        • Schaffler M.B.
        • Majeska R.J.
        Prevention of fracture healing in rats by an inhibitor of angiogenesis.
        Bone. 2001; 29: 560-564
        • Hazan E.J.
        • Hornicek F.J.
        • Tomford W.
        • et al.
        The effect of adjuvant chemotherapy on osteoarticular allografts.
        Clin Orthop Relat Res. 2001; 385: 176-181
        • Hellewell A.B.
        • Beljan J.R.
        • Goldman M.
        Effect of chronic administration of glucocorticoid (prednisolone) on the rate of healing of experimental osseous defects.
        Clin Orthop Relat Res. 1974; 100: 349-355
        • Hilibrand A.S.
        • Fye M.A.
        • Emery S.E.
        • et al.
        Impact of smoking on the outcome of anterior cervical arthrodesis with interbody or strut-grafting.
        J Bone Joint Surg Am. 2001; 83-A: 668-673
        • Hogevold H.E.
        • Grogaard B.
        • Reikeras O.
        Effects of short-term treatment with corticosteroids and indomethacin on bone healing. A mechanical study of osteotomies in rats.
        Acta Orthop Scand. 1992; 63: 607-611
        • Hornicek F.J.
        • Gebhardt M.C.
        • Tomford W.W.
        • et al.
        Factors affecting nonunion of the allograft-host junction.
        Clin Orthop Relat Res. 2001; 382: 87-98
        • Huddleston P.M.
        • Steckelberg J.M.
        • Hanssen A.D.
        • et al.
        Ciprofloxacin inhibition of experimental fracture healing.
        J Bone Joint Surg Am. 2000; 82: 161-173
        • Isefuku S.
        • Joyner C.J.
        • Simpson A.H.
        Gentamicin may have an adverse effect on osteogenesis.
        J Orthop Trauma. 2003; 17: 212-216
        • Jee W.S.
        • Ma Y.F.
        The in vitro anabolic actions of prostaglandins in bone.
        Bone. 1997; 21: 297-304
        • Jee W.S.
        • Park H.Z.
        • Roberts W.E.
        • Kenner G.H.
        Corticosteroid and bone.
        Am J Anat. 1970; 129: 477-479
        • Ke H.Z.
        • Jee W.S.
        • Mori S.
        • et al.
        Effects of long-term daily administration of prostaglandin-E2 on maintaining elevated proximal tibial metaphyseal cancellous bone mass in male rats.
        Calcif Tissue Int. 1992; 50: 245-252
        • Keller J.
        • Kjaersgaard-Andersen P.
        • Bayer-Kristensen I.
        • Melsen F.
        Indomethacin and bone trauma. Effects on remodelling of rabbit bone.
        Acta Orthop Scand. 1990; 61: 66-69
        • Keller J.
        • Klamer A.
        • Bak B.
        • Suder P.
        Effect of local prostaglandin E2 on fracture callus in rabbits.
        Acta Orthop Scand. 1993; 64: 59-63
        • Key J.A.
        • Odell R.T.
        • Taylor L.W.
        Failure of cortisone to delay or to prevent the healing of fractures in rats.
        J Bone Joint Surg Am. 1952; 24: 665-675
        • Khoo D.B.
        The effect of chemotherapy on soft tissue and bone healing in the rabbit model.
        Ann Acad Med Singapore. 1992; 21: 217-221
        • Kim S.G.
        • Chung T.Y.
        • Kim M.S.
        • Lim S.C.
        The effect of high local concentrations of antibiotics on demineralized bone induction in rats.
        J Oral Maxillofac Surg. 2004; 62: 708-713
        • Kock H.J.
        • Werther S.
        • Uhlenkott H.
        • Taeger G.
        Influence of unfractionated and low-molecular-weight heparin on bone healing: an animal model.
        Unfallchirurg. 2002; 105: 791-796
        • Krischak G.D.
        • 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
        • Lamparter S.
        • Slight S.H.
        • Weber K.T.
        Doxycycline and tissue repair in rats.
        J Lab Clin Med. 2002; 139: 295-302
        • Lee O.K.
        • Coathup M.J.
        • Goodship A.E.
        • Blunn G.W.
        Use of mesenchymal stem cells to facilitate bone regeneration in normal and chemotherapy-treated rats.
        Tissue Eng. 2005; 11: 1727-1735
        • Leonelli S.M.
        • Goldberg B.A.
        • Safanda J.
        • et al.
        Effects of a cyclooxygenase-2 inhibitor (rofecoxib) on bone healing.
        Am J Orthop. 2006; 35: 79-84
        • Li J.
        • Law H.K.
        • Lau Y.L.
        • Chan G.C.
        Differential damage and recovery of human mesenchymal stem cells after exposure to chemotherapeutic agents.
        Br J Haematol. 2004; 127: 326-334
        • Li J.
        • Mori S.
        • Kaji Y.
        • et al.
        Effect of bisphosphonate (incadronate) on fracture healing of long bones in rats.
        J Bone Miner Res. 1999; 14: 969-979
        • Long J.
        • Lewis S.
        • Kuklo T.
        • et al.
        The effect of cyclooxygenase-2 inhibitors on spinal fusion.
        J Bone Joint Surg Am. 2002; 84: 1763-1768
        • Luppen C.A.
        • Blake C.A.
        • Ammirati K.M.
        • et al.
        Recombinant human bone morphogenetic protein-2 enhances osteotomy healing in glucocorticoid-treated rabbits.
        J Bone Miner Res. 2002; 17: 301-310
        • Ma Y.F.
        • Li X.J.
        • Jee W.S.
        • et al.
        Effects of prostaglandin E2 and F2 alpha on the skeleton of osteopenic ovariectomized rats.
        Bone. 1995; 17: 549-554
        • Madsen J.E.
        • Berg-Larsen T.
        • Kirkeby O.J.
        • et al.
        No adverse effects of clodronate on fracture healing in rats.
        Acta Orthop Scand. 1998; 69: 532-536
        • Mashiba T.
        • Hirano T.
        • Turner C.H.
        • et al.
        Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib.
        J Bone Miner Res. 2000; 15: 613-620
        • Matta J.
        • Siebenrock K.
        Does indomethacin reduce heterotopic bone formation after operation for acetabular fractures—a prospective randomized study?.
        J Bone Joint Surg (Br). 1997; 79: 959-963
        • Mont M.A.
        • Mathur S.K.
        • Frondoza C.G.
        • Hungerford D.S.
        The effects of ciprofloxacin on human chondrocytes in cell culture.
        Infection. 1996; 24: 151-155
        • Muir J.M.
        • Andrew M.
        • Hirsh J.
        • et al.
        Histomorphometric analysis of the effects of standard heparin on trabecular bone in vivo.
        Blood. 1996; 88: 1314-1320
        • Muir J.M.
        • Hirsh J.
        • Weitz J.I.
        • et al.
        A histomorphometric comparison of the effects of heparin and low-molecular-weight heparin on cancellous bone in rats.
        Blood. 1997; 89: 3236-3242
        • Murakami H.
        • Kowalewski K.
        Effects of cortisone and an anabolic androgen on the fractured humerus in guinea pigs: clinical and histological study over a six-week period of fracture healing.
        Can J Surg. 1966; 9: 425-434
        • Neal B.C.
        • Rodgers A.
        • Clark T.
        • et al.
        A systematic survey of 13 randomized trials of non-steroidal anti-inflammatory drugs for the prevention of heterotopic bone formation after major hip surgery.
        Acta Orthop Scand. 2000; 71: 122-128
        • Nilsson O.S.
        • Bauer F.C.
        • Brostrom L.A.
        • Nilsonne U.
        Effect of the antineoplastic agent methotrexate on experimental heterotopic new bone formation in rats.
        Cancer Res. 1984; 44: 1653-1656
        • O’Brien C.A.
        • Jia D.
        • Plotkin L.I.
        • et al.
        Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength.
        Endocrinology. 2004; 145: 1835-1841
        • Paralkar V.M.
        • Grasser W.A.
        • Mansolf A.L.
        • et al.
        Regulation of BMP-7 expression by retinoic acid and prostaglandin E(2).
        J Cell Physiol. 2002; 190: 207-217
        • Parker M.J.
        • Raghavan R.
        • Gurusamy K.
        Incidence of fracture-healing complications after femoral neck fractures.
        Clin Orthop Relat Res. 2007; 458: 175-179
        • Perry A.C.
        • Prpa B.
        • Rouse M.S.
        • et al.
        Levofloxacin and trovafloxacin inhibition of experimental fracture-healing.
        Clin Orthop Relat Res. 2003; 14: 95-100
        • Persson P.E.
        • Sisask G.
        • Nilsson O.
        Indomethacin inhibits bone formation in inductive allografts but not in autografts: studies in rat.
        Acta Orthop. 2005; 76: 465-469
        • Peter C.P.
        • Cook W.O.
        • Nunamaker D.M.
        • et al.
        Effect of alendronate on fracture healing and bone remodeling in dogs.
        J Orthop Res. 1996; 14: 74-79
        • Petri W.H.
        Osteogenic activity of antibiotic-supplemented bone allografts in the guinea pig.
        J Oral Maxillofac Surg. 1984; 42: 631-636
        • Pountos I.
        • Georgouli T.
        • Jones E.
        • et al.
        The effect of NSAIDs on the proliferation of mesenchymal stem cells and bone healing.
        Injury. 2006; 37: 3
        • Pritchett J.W.
        Ketorolac prophylaxis against heterotopic ossification after hip replacement.
        Clin Orthop Relat Res. 1995; 314: 162-165
        • Puzas J.E.
        • O’Keefe R.J.
        • Schwarz E.M.
        • Zhang X.
        Pharmacologic modulators of fracture healing: the role of cyclooxygenase inhibition.
        J Musculoskelet Neuronal Interact. 2003; 3: 308-312
        • Radi Z.A.
        • Khan N.K.
        Effects of cyclooxygenase inhibition on bone, tendon, and ligament healing.
        Inflamm Res. 2005; 54: 358-366
        • Reikeraas O.
        • Engebretsen L.
        Effects of ketoralac tromethamine and indomethacin on primary and secondary bone healing. An experimental study in rats.
        Arch Orthop Trauma Surg. 1998; 118: 50-52
        • Reuben S.S.
        • Ablett D.
        • Kaye R.
        High dose nonsteroidal anti-inflammatory drugs compromise spinal fusion.
        Can J Anaesth. 2005; 52: 506-512
        • Reuben S.S.
        • Ekman E.F.
        The effect of cyclooxygenase-2 inhibition on analgesia and spinal fusion.
        J Bone Joint Surg Am. 2005; 87: 536-542
        • Reuben S.S.
        • Fingeroth R.
        • Krushell R.
        • Maciolek H.
        Evaluation of the safety and efficacy of the perioperative administration of rofecoxib for total knee arthroplasty.
        J Arthroplasty. 2002; 17: 26-31
        • Riew K.D.
        • Long J.
        • Rhee J.
        • et al.
        Time-dependent inhibitory effects of indomethacin on spinal fusion.
        J Bone Joint Surg Am. 2003; 85: 632-634
        • Ritter M.A.
        • Vaughan R.B.
        Ectopic ossification after total hip arthroplasty. Predisposing factors, frequency, and effect on results.
        J Bone Joint Surg Am. 1977; 59: 345-351
        • Sato S.
        • Kim T.
        • Arai T.
        • et al.
        Comparison between the effects of dexamethasone and indomethacin on bone wound healing.
        Jpn J Pharmacol. 1986; 42: 71-78
        • Sawin P.D.
        • Dickman C.A.
        • Crawford N.R.
        • et al.
        The effects of dexamethasone on bone fusion in an experimental model of posterolateral lumbar spinal arthrodesis.
        J Neurosurg. 2001; 94: 76-81
        • Sell S.
        • Teschner M.
        • Gaissmaier C.
        • et al.
        Effect of diclofenac on human osteoblasts and their stromal precursors in vitro in relation to arthroplasty.
        Z Rheumatol. 1999; 58: 13-20
        • Shaughnessy S.G.
        • Hirsh J.
        • Bhandari M.
        • et al.
        A histomorphometric evaluation of heparin-induced bone loss after discontinuation of heparin treatment in rats.
        Blood. 1999; 93: 1231-1236
        • Simmons D.J.
        • Chang S.L.
        • Russell J.E.
        • et al.
        The effect of protracted tetracycline treatment on bone growth and maturation.
        Clin Orthop Relat Res. 1983; 180: 253-259
        • Sisson H.A.
        • Hadfield G.J.
        The influence of cortisone on the repair of experimental fracture in rabbit.
        Br J Surg. 1951; 38: 172-178
        • Sommer-Tsilenis E.
        • Sauer H.D.
        • Kruse H.P.
        Delaying effect of cyclophosphamide on bone fracture healing chemical analyses of rat femora.
        Arch Orthop Trauma Surg. 1983; 101: 89-93
        • Stinchfield F.E.
        • Sankaran B.
        • Samilson R.
        The effect of anticoagulant therapy on bone repair.
        J Bone Joint Surg Am. 1956; 38: 270-282
        • Street J.T.
        • McGrath M.
        • O’Regan K.
        • et al.
        Thromboprophylaxis using a low molecular weight heparin delays fracture repair.
        Clin Orthop Relat Res. 2000; 381: 278-289
        • Subasi M.
        • Kapukaya A.
        • Kesemenli C.
        • et al.
        Effect of chemotherapeutic agents on distraction osteogenesis. An experimental investigation in rabbits.
        Arch Orthop Trauma Surg. 2001; 121: 417-421
        • Sudmann E.
        • Bang G.
        Indomethacin-induced inhibition of haversian remodelling in rabbits.
        Acta Orthop Scand. 1979; 50: 621-627
        • Tortolani P.J.
        • Park A.E.
        • Louis-Ugbo J.
        • et al.
        The effects of doxorubicin (adriamycin) on spinal fusion: an experimental model of posterolateral lumbar spinal arthrodesis.
        Spine J. 2004; 4: 669-674
        • Tuncay I.
        • Ozbek H.
        • Kosem M.
        • Unal O.
        A comparison of effects of fluoroquinolones on fracture healing (an experimental study in rats).
        Ulus Travma Acil Cerrahi Derg. 2005; 11: 17-22
        • Turner D.M.
        • Warson J.S.
        • Wirt T.C.
        • et al.
        The use of ketorolac in lumbar spine surgery: a cost-benefit analysis.
        J Spinal Disord. 1995; 8: 206-212
      1. Vigorita JV. Orthopaedic pathology. 1st ed. Lippincott & Wilkins. p. 85–97.

        • Wahlstrom O.
        • Risto O.
        • Djerf K.
        • Hammerby S.
        Heterotopic bone formation prevented by diclofenac. Prospective study of 100 hip arthroplasties.
        Acta Orthop Scand. 1991; 62: 419-421
        • Waters R.V.
        • Gamradt S.C.
        • Asnis P.
        • et al.
        Systemic corticosteroids inhibit bone healing in a rabbit ulnar osteotomy model.
        Acta Orthop Scand. 2000; 71: 316-321
        • Weinstein R.S.
        • Jilka R.L.
        • Parfitt A.M.
        • Manolagas S.C.
        Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone.
        J Clin Invest. 1998; 102: 274-282
        • Weiss R.
        • Ickowich M.
        The influence of cortisone on the healing of experimental fractures in rats.
        Acta Anat (Basel). 1964; 59: 163-181
        • Wiancko K.B.
        • Kowalewski K.
        Strength of callus in fractured humerus of rat treated with anti-anabolic and anabolic compounds.
        Acta Endocrinol (Copenh). 1961; 36: 310-318
        • Wurnig C.
        • Schwameis E.
        • Bitzan P.
        • Kainberger F.
        Six-year results of a cementless stem with prophylaxis against heterotopic bone.
        Clin Orthop Relat Res. 1999; 361: 150-158
        • Yamaji T.
        • Ando K.
        • Wolf S.
        • et al.
        The effect of micromovement on callus formation.
        J Orthop Sci. 2001; 6: 571-575