Clinical Orthopaedics and Related Research®

, Volume 469, Issue 8, pp 2399–2403

Emerging Ideas: Can Erythromycin Reduce the Risk of Aseptic Loosening?

Emerging Ideas

Abstract

Background

Persistent inflammatory reaction to wear debris causes periprosthetic osteolysis and loosening. Some authors have advocated pharmaceutical approaches to reduce the inflammatory reaction. Erythromycin has antiinflammatory effects independent of its antimicrobial properties. Although oral erythromycin reportedly inhibits periprosthetic tissue inflammation in patients with aseptic loosening, long-term systematic erythromycin treatment is not recommended owing to its side effects. Therefore, it would be advantageous to restrict erythromycin delivery to the inflammatory periprosthetic tissue without causing side effects.

Questions/hypotheses

Erythromycin eluted from hydroxyapatite-coated titanium (Ti) pins inhibits periprosthetic tissue inflammation and osteolysis.

Method of study

We propose restricting erythromycin delivery to the inflammatory periprosthetic site. A previously described rat model of ultrahigh molecular weight polyethylene (UHMWPE) particle-induced periprosthetic tissue inflammation and osteolysis will be used to test the effect of local delivery of erythromycin via Peri-ApatiteTM-coated Ti implants. The outcome measures will include bone ingrowth (μCT), implant stability (pullout test), and histologic analysis of periprosthetic tissues.

Significance

Pharmacologic intervention aimed at slowing, preventing, or reversing the aseptic loosening process would represent an advance in the management of joint replacement. Erythromycin may be appropriate for prophylactically treating patients who have repeated revision surgery and/or show early signs of progressive osteolysis after arthroplasty.

References

  1. 1.
    al-Saffar N, Revell PA. Pathology of the bone-implant interfaces. J Long Term Eff Med Implants. 1999;9:319–347.PubMedGoogle Scholar
  2. 2.
    Allen M, Brett F, Millett P, Rushton N. The effects of particulate polyethylene at a weight-bearing bone-implant interface: a study in rats. J Bone Joint Surg Br. 1996;78:32–37.PubMedGoogle Scholar
  3. 3.
    Cervin A. The anti-inflammatory effect of erythromycin and its derivatives, with special reference to nasal polyposis and chronic sinusitis. Acta Otolaryngol. 2001;121:83–92.PubMedCrossRefGoogle Scholar
  4. 4.
    Chang YS, Kobayashi M, Li ZL, Oka M, Nakamura T. Significance of peak value and duration of the interfacial shear load in evaluation of the bone-implant interface. Clin Biomech (Bristol, Avon). 2003;18:773–779.Google Scholar
  5. 5.
    Childs LM, Goater JJ, O’Keefe RJ, Schwarz EM. Efficacy of etanercept for wear debris-induced osteolysis. J Bone Miner Res. 2001;16:338–347.PubMedCrossRefGoogle Scholar
  6. 6.
    Childs LM, Paschalis EP, Xing L, Dougall WC, Anderson D, Boskey AL, Puzas JE, Rosier RN, O’Keefe RJ, Boyce BF, Schwarz EM. In vivo RANK signaling blockade using the receptor activator of NF- kappaB:Fc effectively prevents and ameliorates wear debris-induced osteolysis via osteoclast depletion without inhibiting osteogenesis. J Bone Miner Res. 2002;17:192–199.PubMedCrossRefGoogle Scholar
  7. 7.
    Cowles VE, Nellans HN, Seifert TR, Besecke LM, Segreti JA, Mohning KM, Faghih R, Verlinden MH, Wegner CD. Effect of novel motilide ABT-229 versus erythromycin and cisapride on gastric emptying in dogs. J Pharmacol Exp Ther. 2000;293:1106–1111.PubMedGoogle Scholar
  8. 8.
    Dean JC, Tisdel CL, Goldberg VM, Parr J, Davy D, Stevenson S. Effects of hydroxyapatite tricalcium phosphate coating and intracancellous placement on bone ingrowth in titanium fibermetal implants. J Arthroplasty. 1995;10:830–838.PubMedCrossRefGoogle Scholar
  9. 9.
    El-Warrak AO, Olmstead M, Apelt D, Deiss F, Noetzli H, Zlinsky K, Hilbe M, Bertschar-Wolfsberger R, Johnson AL, Auer J, von Rechenberg B. An animal model for interface tissue formation in cemented hip replacements. Vet Surg. 2004;33:495–504.PubMedCrossRefGoogle Scholar
  10. 10.
    Giamarellos-Bourboulis EJ. Macrolides beyond the conventional antimicrobials: a class of potent immunomodulators. Int J Antimicrob Agents. 2008;31:12–20.PubMedCrossRefGoogle Scholar
  11. 11.
    Glant TT, Jacobs JJ. Response of three murine macrophage populations to particulate debris: bone resorption in organ cultures. J Orthop Res. 1994;12:720–731.PubMedCrossRefGoogle Scholar
  12. 12.
    Goodman S, Ma T, Trindade M, Ikenoue T, Matsuura I, Wong N, Fox N, Genovese M, Regula D, Smith RL. COX-2 selective NSAID decreases bone ingrowth in vivo. J Orthop Res. 2002;20:1164–1169.PubMedCrossRefGoogle Scholar
  13. 13.
    Jones HA, Valind SO, Clark IC, Bolden GE, Krausz T, Schofield JB, Boobis AR, Haslett C. Kinetics of lung macrophages monitored in vivo following particulate challenge in rabbits. Toxicol Appl Pharmacol. 2002;183:46–54.PubMedCrossRefGoogle Scholar
  14. 14.
    Jones LC, Frondoza C, Hungerford DS. Immunohistochemical evaluation of interface membranes from failed cemented and uncemented acetabular components. J Biomed Mater Res. 1999;48:889–898.PubMedCrossRefGoogle Scholar
  15. 15.
    Junck L, Olson JM, Ciliax BJ, Koeppe RA, Watkins GL, Jewett DM, McKeever PE, Wieland DM, Kilbourn MR, Starosta-Rubinstein S, et al. PET imaging of human gliomas with ligands for the peripheral benzodiazepine binding site. Ann Neurol. 1989;26:752–758.PubMedCrossRefGoogle Scholar
  16. 16.
    Kudoh S. Erythromycin treatment in diffuse panbronchiolitis. Curr Opin Pulm Med. 1998;4:116–121.PubMedCrossRefGoogle Scholar
  17. 17.
    Kudoh S, Azuma A, Yamamoto M, Izumi T, Ando M. Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin. Am J Respir Crit Care Med. 1998;157:1829–1832.PubMedGoogle Scholar
  18. 18.
    Kumar A, Muzik O, Chugani D, Chakraborty P, Chugani HT. PET-derived biodistribution and dosimetry of the benzodiazepine receptor-binding radioligant (11)C-(R)-PK11195 in children and adults. J Nucl Med. 2010;51:139–144.PubMedCrossRefGoogle Scholar
  19. 19.
    Lodder MC, Van Pelt PA, Lems WF, Kostense PJ, Koks CH, Dijkmans BA. Effects of high dose IV pamidronate on disease activity and bone metabolism in patients with active RA: a randomized, double-blind, placebo-controlled trial. J Rheumatol. 2003;30:2080–2081.PubMedGoogle Scholar
  20. 20.
    Ma T, Nelson ER, Mawatari T, Oh KJ, Larsen DM, Smith RL, Goodman SB. Effects of local infusion of OP-1 on particle-induced and NSAID-induced inhibition of bone ingrowth in vivo. J Biomed Mater Res A. 2006;79:740–746.PubMedGoogle Scholar
  21. 21.
    Millett PJ, Allen MJ, Bostrom MP. Effects of alendronate on particle-induced osteolysis in a rat model. J Bone Joint Surg Am. 2002;84:236–249.PubMedGoogle Scholar
  22. 22.
    Miltyk W, Pallka M, Karna E, Jarzabek K, Boujrad N, Knapp P. Antimitotic activity of high affinity ligands for peripheral benzodiazepine receptor (PBR) in some normal and neoplastic cell lines. Adv Med Sci. 2006;51:156–159.PubMedGoogle Scholar
  23. 23.
    Morawietz L, Classen RA, Schroder JH, Dynybil C, Perka C, Skwara A, Neidel J, Gehrke T, Frommelt L, Hansen T, Otto M, Barden B, Aigner T, Stiehl P, Schubert T, Meyer-Scholten C, Konig A, Strobel P, Rader CP, Kirschner S, Lintner F, Ruther W, Bos I, Hendrich C, Kriegsmann J, Krenn V. Proposal for a histopathological consensus classification of the periprosthetic interface membrane. J Clin Pathol. 2006;59:591–597.PubMedCrossRefGoogle Scholar
  24. 24.
    Persson PE, Nilsson OS, Berggren AM. Do non-steroidal anti-inflammatory drugs cause endoprosthetic loosening? A 10-year follow-up of a randomized trial on ibuprofen for prevention of heterotopic ossification after hip arthroplasty. Acta Orthop. 2005;76:735–740.PubMedCrossRefGoogle Scholar
  25. 25.
    Peter B, Pioletti DP, Laib S, Bujoli B, Pilet P, Janvier P, Guicheux J, Zambelli PY, Bouler JM, Gauthier O. Calcium phosphate drug delivery system: influence of local zoledronate release on bone implant osteointegration. Bone. 2005;36:52–60.PubMedCrossRefGoogle Scholar
  26. 26.
    Phillips TW, Gurr KR, Rao DR. Hip implant evaluation in an arthritic animal model. Arch Orthop Trauma Surg. 1990;109:194–196.PubMedCrossRefGoogle Scholar
  27. 27.
    Pollice PF, Rosier RN, Looney RJ, Puzas JE, Schwarz EM, O’Keefe RJ. Oral pentoxifylline inhibits release of tumor necrosis factor-alpha from human peripheral blood monocytes : a potential treatment for aseptic loosening of total joint components. J Bone Joint Surg Am. 2001;83:1057–1061.PubMedGoogle Scholar
  28. 28.
    Ramsay SC, Weiller C, Myers R, Cremer JE, Luthra SK, Lammertsma AA, Frackowiak RS. Monitoring by PET of macrophage accumulation in brain after ischaemic stroke. Lancet. 1992;339:1054–1055.PubMedCrossRefGoogle Scholar
  29. 29.
    Ren W, Blasier R, Peng X, Shi T, Wooley PH, Markel D. Effect of oral erythromycin therapy in patients with aseptic loosening of joint prostheses. Bone. 2009;44:671–677.PubMedCrossRefGoogle Scholar
  30. 30.
    Ren W, Li XH, Chen BD, Wooley PH. Erythromycin inhibits wear debris-induced osteoclastogenesis by modulation of murine macrophage NFkB activity. J Orthop Res. 2004;22:21–29.PubMedCrossRefGoogle Scholar
  31. 31.
    Ren W, Wu B, Peng X, Mayton L, Yu D, Ren J, Chen BD, Wooley PH. Erythromycin inhibits wear debris-induced inflammatory osteolysis in a murine model. J Orthop Res. 2006;24:280–290.PubMedCrossRefGoogle Scholar
  32. 32.
    Ren W, Zhang R, Hawkins M, Shi T, Markel DC. Efficacy of periprosthetic erythromycin delivery for wear debris-induced inflammation and osteolysis. Inflamm Res. 2010;59:1091–1097.PubMedCrossRefGoogle Scholar
  33. 33.
    Rogers MJ. New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des. 2010;59:1091–1097.Google Scholar
  34. 34.
    Schwarz EM, Campbell D, Totterman S, Boyd A, O’Keefe RJ, Looney RJ. Use of volumetric computerized tomography as a primary outcome measure to evaluate drug efficacy in the prevention of peri-prosthetic osteolysis: a 1-year clinical pilot of etanercept vs. placebo. J Orthop Res. 2003;21:1049–1055.PubMedCrossRefGoogle Scholar
  35. 35.
    Schwarz EM; Implant Wear Symposium 2007 Biologic Work Group. What potential biologic treatments are available for osteolysis? J Am Acad Orthop Surg. 2008;16 Suppl 1:S72–S75.Google Scholar
  36. 36.
    Shanahan JC, St Clair W. Tumor necrosis factor-alpha blockade: a novel therapy for rheumatic disease. Clin Immunol. 2002;103:231–242.PubMedCrossRefGoogle Scholar
  37. 37.
    Stadelmann VA, Gauthier O, Terrier A, Bouler JM, Pioletti DP. Implants delivering bisphosphonate locally increase periprosthetic bone density in an osteoporotic sheep model: a pilot study. Eur Cell Mater. 2008;16:10–16.PubMedGoogle Scholar
  38. 38.
    Stigter M, Bezemer J, de Groot K, Layrolle P. Incorporation of different antibiotics into carbonated hydroxyapatite coatings on titanium implants, release and antibiotic efficacy. J Control Release. 2004;99:127–137.PubMedCrossRefGoogle Scholar
  39. 39.
    Stolina M, Kostenuik PJ, Dougall WC, Fitzpatrick LA, Zack DJ. RANKL inhibition: from mice to men (and women). Adv Exp Med Biol. 2007;602:143–150.PubMedCrossRefGoogle Scholar
  40. 40.
    Sundfeldt M, Carlsson LV, Johansson CB, Thomsen P, Gretzer C. Aseptic loosening, not only a question of wear: a review of different theories. Acta Orthop. 2006;77:177–197.PubMedCrossRefGoogle Scholar
  41. 41.
    Suratwala SJ, Cho SK, van Raalte JJ, Park SH, Seo SW, Chang SS, Gardner TR, Lee FY. Enhancement of periprosthetic bone quality with topical hydroxyapatite-bisphosphonate composite. J Bone Joint Surg Am. 2008;90:2189–2196.PubMedCrossRefGoogle Scholar
  42. 42.
    Tanzer M, Karabasz D, Krygier JJ, Cohen R, Bobyn JD. The Otto Aufranc Award: bone augmentation around and within porous implants by local bisphosphonate elution. Clin Orthop Relat Res. 2005;441:30–39.PubMedCrossRefGoogle Scholar
  43. 43.
    Trnka HJ, Zenz P, Zembsch A, Easley M, Ritschl P, Salzer M. Stable bony integration with and without short-term indomethacin prophylaxis: a 5-year follow-up. Arch Orthop Trauma Surg. 1999;119:456–460.CrossRefGoogle Scholar
  44. 44.
    Turner AS. Animal models of osteoporosis: necessity and limitations. Eur Cell Mater. 2001;1:66–81.PubMedGoogle Scholar
  45. 45.
    Valleala H, Laasonen L, Koivula MK, Mandelin J, Friman C, Risteli J, Konttinen YT. Two year randomized controlled trial of etidronate in rheumatoid arthritis: changes in serum aminoterminal telopeptides correlate with radiographic progression of disease. J Rheumatol. 2003;30:468–473.PubMedGoogle Scholar
  46. 46.
    Vuolteenaho K, Moilanen T, Moilanen E. Non-steroidal anti-inflammatory drugs, cyclooxygenase-2 and the bone healing process. Basic Clin Pharmacol Toxicol. 2008;102:10–14.PubMedGoogle Scholar
  47. 47.
    Wooley PH, Schwarz EM. Aseptic loosening. Gene Ther. 2004;11:402–407.PubMedCrossRefGoogle Scholar
  48. 48.
    Zavala F, Lenfant M. Benzodiazepines and PK 11195 exert immunomodulating activities by binding on a specific receptor on macrophages. Ann N Y Acad Sci. 1987;496:240–249.PubMedCrossRefGoogle Scholar
  49. 49.
    Zhang Q, Badell IR, Schwarz EM, Boulukos KE, Yao Z, Boyce BF, Xing L. Tumor necrosis factor prevents alendronate-induced osteoclast apoptosis in vivo by stimulating Bcl-xL expression through Ets-2. Arthritis Rheum. 2005;52:2708–2718.PubMedCrossRefGoogle Scholar
  50. 50.
    Zhang R, An Y, Toth CA, Draughn RA, Dimaano NM, Hawkins MV. Osteogenic protein-1 enhances osseointegration of titanium implants coated with peri-apatite in rabbit femoral defect. J Biomed Mater Res B Appl Biomater. 2004;71:408–413.PubMedCrossRefGoogle Scholar
  51. 51.
    Zhang R, Xu D, Landeryou T, Toth C, Dimaano N, Berry J, Evans J, Hawkins M. Ectopic bone formation using osteogenic protein-1 carried by a solution precipitated hydroxyapatite. J Biomed Mater Res A. 2004;71:412–418.PubMedCrossRefGoogle Scholar

Copyright information

© The Association of Bone and Joint Surgeons® 2011

Authors and Affiliations

  1. 1.Department of Biomedical EngineeringWayne State UniversityDetroitUSA
  2. 2.Department of Orthopaedic SurgeryWayne State University School of MedicineSouthfieldUSA

Personalised recommendations