Clinical Orthopaedics and Related Research®

, Volume 469, Issue 2, pp 514–522 | Cite as

Bisphosphonate Remains Highly Localized After Elution From Porous Implants

  • Kimberly McKenzie
  • J. Dennis Bobyn
  • Jacintha Roberts
  • Dorota Karabasz
  • Michael Tanzer
Symposium: Papers Presented at the Hip Society Meetings 2010

Abstract

Background

Local elution of zoledronic acid from a porous implant reportedly enhances periimplant bone formation and implant fixation. However, there is no information in the literature on the extent to which eluted bisphosphonate remains localized around the implant or becomes systemically distributed.

Questions/purposes

We ascertained to what extent eluted zoledronic acid remains local and whether there is systemic exposure after local elution from porous implants.

Methods

A hydroxyapatite-coated porous tantalum implant dosed with 100 μg 14C-labeled zoledronic acid was implanted into the left femoral intramedullary canal of six dogs. Bone samples near to and distant from the implant were harvested from three dogs at 6 weeks and three dogs at 52 weeks. The concentration of radiolabeled bisphosphonate in each sample was quantified using liquid scintillation spectrophotometry and its distribution in periimplant bone was revealed by exposing histologic sections to autoradiography film.

Results

In all six dogs, the concentration of zoledronic acid in immediate periimplant bone was two orders of magnitude higher than in any other sampled tissue, averaging 732.6 ng/g at 6 weeks and 377.2 ng/g at 52 weeks. Minute amounts of zoledronic acid (≤ 7.2 ng/g) were detected throughout the skeleton, indicating some escape into the circulation after local elution. Autoradiographs revealed the greatest concentration of zoledronic acid on and within the implant, with rapid decrease short distances away and no uptake within the femoral cortex.

Conclusions

Zoledronic acid eluted from an implant remains mainly localized with minimal systemic distribution.

Clinical Relevance

Local bisphosphonate elution reduces the risk of systemic side effects and skeletal bisphosphonate exposure.

References

  1. 1.
    Allen MR, Iwata K, Phipps R, Burr DB. Alterations in canine vertebral bone turnover, microdamage accumulation, and biomechanical properties following 1-year treatment with clinical treatment doses of risedronate or alendronate. Bone. 2006;39:872–879.CrossRefPubMedGoogle Scholar
  2. 2.
    Amanat N, McDonald M, Godfrey C, Bilston L, Little D. Optimal timing of a single dose of zoledronic acid to increase strength in rat fracture repair. J Bone Miner Res. 2007;22:867–876.CrossRefPubMedGoogle Scholar
  3. 3.
    Åstrand J, Aspenberg P. Topical, single dose bisphosphonate treatment reduced bone resorption in a rat model for prosthetic loosening. J Orthop Res. 2004;22:244–249.CrossRefPubMedGoogle Scholar
  4. 4.
    Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809–1822.CrossRefPubMedGoogle Scholar
  5. 5.
    Bobyn JD, McKenzie K, Karabasz D, Krygier JJ, Tanzer M. Locally delivered bisphosphonate for enhancement of bone formation and implant fixation. J Bone Joint Surg Am. 2009;91:23–31.CrossRefPubMedGoogle Scholar
  6. 6.
    Drake MT, Clarke BT, Khosla S. Bisphosphonates: mechanisms of action and role in clinical Practice. Mayo Clin Proc. 2008;83:1032–1045.CrossRefPubMedGoogle Scholar
  7. 7.
    Gao Y, Zou S, Liu X, Bao C, Hu J. The effect of surface immobilized bisphosphonates on the fixation of hydroxyapatite-coated titanium implants in ovariectomized rats. Biomaterials. 2009;30:1790–1796.CrossRefPubMedGoogle Scholar
  8. 8.
    Garbuz DS, Hu Y, Kim WY, Duan K, Masri BA, Oxland TR, Burt H, Wang R, Duncan CP. Enhanced gap filling and osteoconduction associated with alendronate-calcium phosphate-coated porous tantalum. J Bone Joint Surg Am. 2008;90:1090–1100.CrossRefPubMedGoogle Scholar
  9. 9.
    Goh SK, Yang KY, Koh JS, Wong MK, Chua SY, Chua DT, Howe TS. Subtrochanteric insufficiency fractures in patients on alendronate therapy: a caution. J Bone Joint Surg Br. 2007;89:349–353.CrossRefPubMedGoogle Scholar
  10. 10.
    Hilding M, Aspenberg P. Local peroperative treatment with a bisphosphonate improves the fixation of total knee prostheses. A randomized, double-blind radiostereometric study of 50 patients. Acta Orthop. 2007;78:795–799.CrossRefPubMedGoogle Scholar
  11. 11.
    Hilding M, Ryd L, Toksvig-Larsen S, Aspenberg P. Clodronate prevents prosthetic migration: a randomized radiostereometric study of 50 total knee patients. Acta Orthop Scand. 2000;71:553–557.CrossRefPubMedGoogle Scholar
  12. 12.
    Jakobsen T, Baas J, Kold S, Bechtold JE, Elmengaard B, Soballe K. Local bisphosphonate treatment increases fixation of hydroxyapatite-coated implants inserted with bone compaction. J Orthop Res. 2009;27:189–194.CrossRefPubMedGoogle Scholar
  13. 13.
    Kwek EB, Koh JS, Howe TS. More on atypical fractures of the femoral diaphysis [Letter]. N Engl J Med. 2008;359:316–318.CrossRefPubMedGoogle Scholar
  14. 14.
    Legay F, Gauron S, Deckert F, Gosset G, Pfaar U, Ravera C, Wiegand H, Schran H. Development and validation of a highly sensitive RIA for zoledronic acid, a new potent heterocyclic bisphosphonate in human serum, plasma and urine. J Pharm Biomed Anal. 2002;30:897–911.CrossRefPubMedGoogle Scholar
  15. 15.
    Lenart BA, Lorich DG, Lane JM. Atypicial fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med. 2008;358:1304–1306.CrossRefPubMedGoogle Scholar
  16. 16.
    Lyles KW, Colón-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007:357:1799–1809.CrossRefPubMedGoogle Scholar
  17. 17.
    Mashiba T, Hirano T, Turner CH, Forwood MR, Johnston CC, Burr DB. Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res. 2000;15:613–620.CrossRefPubMedGoogle Scholar
  18. 18.
    Mashiba T, Turner CH, Hirano T, Forwood MR, Johnston CC, Burr DB. Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone. 2001;28:524–531.CrossRefPubMedGoogle Scholar
  19. 19.
    Papapetrou PD. Bisphosphonate-associated adverse events. Hormones. 2009;8:96–110.PubMedGoogle Scholar
  20. 20.
    Peter B, Gauthier O, Laïb S, Bujoli B, Guicheux J, Janvier P, van Lenthe GH, Müller R, Zambelli PY, Bouler JM, Pioletti DP. Local delivery of bisphosphonate from coated orthopedic implants increases implants mechanical stability in osteoporotic rats. J Biomed Mat Res Part A. 2006;76:133–143.CrossRefGoogle Scholar
  21. 21.
    Peter B, Pioletti DP, Laïb 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.CrossRefPubMedGoogle Scholar
  22. 22.
    Russell RG, Xia Z, Dunford JE, Oppermann U, Kwaasi A, Hulley PA, Kavanagh KL, Triffitt JT, Lundy MW, Phipps RJ, Barnett BL, Coxon FP, Rogers MJ, Watts NB, Ebetino FH. Bisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy. Ann NY Acad Sci. 2007;1117:209–257.CrossRefPubMedGoogle Scholar
  23. 23.
    Saleh KJ, Mulhall KJ, Hofmann AA, Bolognesi MP, Laskin RS. Primary total knee arthroplasty outcomes. In: Barrack RL, Booth RE Jr, Lonner JH, McCarthy JC, Mont MA, Rubash HE, eds. Orthopaedic Knowledge Update 3 - Hip and Knee Reconstruction. Rosemont, IL: Amer Acad Orthop Surg; 2006:93–110.Google Scholar
  24. 24.
    Sporer S, Paprosky WG, Berry DJ. Hip revision. In: Barrack RL, Booth RE Jr, Lonner JH, McCarthy JC, Mont MA, Rubash HE, eds. Orthopaedic Knowledge Update 3 - Hip and Knee Reconstruction. Rosemont, IL: Amer Acad Orthop Surg; 2006:457–474.Google Scholar
  25. 25.
    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
  26. 26.
    Suratwala SJ, Cho SK, van Raalte JJ, Park SH, Seo SW, Chang SS, Gardner TR, Lee FY. Enhancement of periprosthetic bone qwuality with topical hydroxyapatite-bisphosphonate composite. J Bone Joint Surg Am. 2008;90:2189–2196.CrossRefPubMedGoogle Scholar
  27. 27.
    Tanzer M, Karabasz D, Krygier JJ, Cohen R, Bobyn JD. Bone augmentation around and within porous implants by local bisphosphonate elution. Clin Orthop Relat Res. 2005;441:30–39.CrossRefPubMedGoogle Scholar
  28. 28.
    Yaffe A, Binderman I, Breuer E, Pinto T, Golomb G. Disposition of alendronate following local delivery in a rat jaw. J Periodontol. 1999;70:893–895.CrossRefPubMedGoogle Scholar

Copyright information

© The Association of Bone and Joint Surgeons® 2010

Authors and Affiliations

  • Kimberly McKenzie
    • 1
  • J. Dennis Bobyn
    • 1
    • 2
  • Jacintha Roberts
    • 1
  • Dorota Karabasz
    • 1
  • Michael Tanzer
    • 1
  1. 1.Jo Miller Orthopaedic Research LaboratoryMontreal General HospitalMontrealCanada
  2. 2.Division of OrthopaedicsMcGill UniversityMontrealCanada

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