Advertisement

Journal of Bone and Mineral Metabolism

, Volume 28, Issue 2, pp 165–175 | Cite as

Zoledronic acid delays wound healing of the tooth extraction socket, inhibits oral epithelial cell migration, and promotes proliferation and adhesion to hydroxyapatite of oral bacteria, without causing osteonecrosis of the jaw, in mice

  • Yasuyoshi Kobayashi
  • Toru Hiraga
  • Akimi Ueda
  • Liyang Wang
  • Michiyo Matsumoto-Nakano
  • Kenji Hata
  • Hirofumi Yatani
  • Toshiyuki Yoneda
Original Article

Abstract

Nitrogen-containing bisphosphonates such as zoledronic acid (ZOL) and pamidronate have been widely and successfully used for the treatment of cancer patients with bone metastases and/or hypercalcemia. Accumulating recent reports have shown that cancer patients who have received these bisphosphonates occasionally manifest bisphosphonate-related osteonecrosis of the jaw (BRONJ) following dental treatments, including tooth extraction. However, little is known about the pathogenesis of BRONJ to date. Here, to understand the underlying pathogenesis of BRONJ, we examined the effects of ZOL on wound healing of the tooth extraction socket using a mouse tooth extraction model. Histomorphometrical analysis revealed that the amount of new bone and the numbers of blood vessels in the socket were significantly decreased in ZOL-treated mice compared to control mice. Consistent with these results, ZOL significantly inhibited angiogenesis induced by vascular endothelial growth factor in vivo and the proliferation of endothelial cells in culture in a dose-dependent manner. In contrast, etidronate, a non-nitrogen-containing bisphosphonate, showed no effects on osteogenesis and angiogenesis in the socket. ZOL also suppressed the migration of oral epithelial cells, which is a crucial step for tooth socket closure. In addition, ZOL promoted the adherence of Streptococcus mutans to hydroxyapatite and the proliferation of oral bacteria obtained from healthy individuals, suggesting that ZOL may increase the bacterial infection. In conclusion, our data suggest that ZOL delays wound healing of the tooth extraction socket by inhibiting osteogenesis and angiogenesis. Our data also suggest that ZOL alters oral bacterial behaviors. These actions of ZOL may be relevant to the pathogenesis of BRONJ.

Keywords

Osteogenesis Osteoclasts Bacterial adhesion Angiogenesis 

Notes

Acknowledgments

We are grateful to Dr. Yoshinosuke Hamada and Dr. Nariaki Matsuura (Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine) for technical support and helpful discussion. This work was supported in part by Ministry of Education, Science, Sports and Culture Grants-in-Aid for Scientific Research A (TY) and The 21st Century COE Program (TY).

References

  1. 1.
    Rogers MJ, Watts DJ, Russell RG (1997) Overview of bisphosphonates. Cancer (Phila) 80:1652–1660CrossRefGoogle Scholar
  2. 2.
    Licata AA (2005) Discovery, clinical development, and therapeutic uses of bisphosphonates. Ann Pharmacother 39:668–677CrossRefPubMedGoogle Scholar
  3. 3.
    Michaelson MD, Smith MR (2005) Bisphosphonates for treatment and prevention of bone metastases. J Clin Oncol 23:8219–8224CrossRefPubMedGoogle Scholar
  4. 4.
    Delmas PD (2005) The use of bisphosphonates in the treatment of osteoporosis. Curr Opin Rheumatol 17:462–466PubMedGoogle Scholar
  5. 5.
    DiCaprio MR, Enneking WF (2005) Fibrous dysplasia. Pathophysiology, evaluation, and treatment. J Bone Joint Surg [Am] 87:1848–1864CrossRefGoogle Scholar
  6. 6.
    Reid IR, Miller P, Lyles K, Fraser W, Brown JP, Saidi Y, Mesenbrink P, Su G, Pak J, Zelenakas K, Luchi M, Richardson P, Hosking D (2005) Comparison of a single infusion of zoledronic acid with risedronate for Paget’s disease. N Engl J Med 353:898–908CrossRefPubMedGoogle Scholar
  7. 7.
    Hortobagyi GN, Theriault RL, Porter L, Blayney D, Lipton A, Sinoff C, Wheeler H, Simeone JF, Seaman J, Knight RD (1996) Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19. Aredia Breast Cancer Study Group. N Engl J Med 335:1785–1791CrossRefPubMedGoogle Scholar
  8. 8.
    Ashcroft AJ, Davies FE, Morgan GJ (2003) Aetiology of bone disease and the role of bisphosphonates in multiple myeloma. Lancet Oncol 4:284–292CrossRefPubMedGoogle Scholar
  9. 9.
    Berenson JR, Hillner BE, Kyle RA, Anderson K, Lipton A, Yee GC, Biermann JS (2002) American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple myeloma. J Clin Oncol 20:3719–3736CrossRefPubMedGoogle Scholar
  10. 10.
    Coleman RE (2002) Future directions in the treatment and prevention of bone metastases. Am J Clin Oncol 25:S32–S38CrossRefPubMedGoogle Scholar
  11. 11.
    Djulbegovic B, Wheatley K, Ross J, Clark O, Bos G, Goldschmidt H, Cremer F, Alsina M, Glasmacher A (2001) Bisphosphonates in multiple myeloma. Cochrane Database Syst Rev 4:CD003188Google Scholar
  12. 12.
    Ferretti G, Fabi A, Carlini P, Papaldo P, Cordiali Fei P, Di Cosimo S, Salesi N, Giannarelli D, Alimonti A, Di Cocco B, D’Agosto G, Bordignon V, Trento E, Cognetti F (2005) Zoledronic-acid-induced circulating level modifications of angiogenic factors, metalloproteinases and proinflammatory cytokines in metastatic breast cancer patients. Oncology 69:35–43CrossRefPubMedGoogle Scholar
  13. 13.
    Hillner BE, Ingle JN, Chlebowski RT, Gralow J, Yee GC, Janjan NA, Cauley JA, Blumenstein BA, Albain KS, Lipton A, Brown S (2003) American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21:4042–4057CrossRefPubMedGoogle Scholar
  14. 14.
    Hillner BE, Weeks JC, Desch CE, Smith TJ (2000) Pamidronate in prevention of bone complications in metastatic breast cancer: a cost-effectiveness analysis. J Clin Oncol 18:72–79PubMedGoogle Scholar
  15. 15.
    Osanai T, Tsuchiya T, Ogino T, Nakahara K (2006) Long-term prevention of skeletal complications by pamidronate in a patient with bone metastasis from endometrial carcinoma: a case report. Gynecol Oncol 100:195–197CrossRefPubMedGoogle Scholar
  16. 16.
    Smith MR (2005) Zoledronic acid to prevent skeletal complications in cancer: corroborating the evidence. Cancer Treat Rev 31(Suppl 3):19–25CrossRefPubMedGoogle Scholar
  17. 17.
    Rogers MJ, Gordon S, Benford HL, Coxon FP, Luckman SP, Monkkonen J, Frith JC (2000) Cellular and molecular mechanisms of action of bisphosphonates. Cancer (Phila) 88:2961–2978CrossRefGoogle Scholar
  18. 18.
    Luckman SP, Hughes DE, Coxon FP, Graham R, Russell G, Rogers MJ (1998) Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res 13:581–589CrossRefPubMedGoogle Scholar
  19. 19.
    Russell RG, Rogers MJ (1999) Bisphosphonates: from the laboratory to the clinic and back again. Bone (NY) 25:97–106Google Scholar
  20. 20.
    Marx RE (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61:1115–1117CrossRefPubMedGoogle Scholar
  21. 21.
    Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL (2004) Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 62:527–534CrossRefPubMedGoogle Scholar
  22. 22.
    Pires FR, Miranda A, Cardoso ES, Cardoso AS, Fregnani ER, Pereira CM, Correa ME, Almeida JP, Alves Fde A, Lopes MA, de Almeida OP (2005) Oral avascular bone necrosis associated with chemotherapy and biphosphonate therapy. Oral Dis 11:365–369CrossRefPubMedGoogle Scholar
  23. 23.
    Assael LA (2004) New foundations in understanding osteonecrosis of the jaws. J Oral Maxillofac Surg 62:125–126CrossRefPubMedGoogle Scholar
  24. 24.
    Hellstein JW, Marek CL (2004) Bis-phossy jaw, phossy jaw, and the 21st century: bisphosphonate-associated complications of the jaws. J Oral Maxillofac Surg 62:1563–1565CrossRefPubMedGoogle Scholar
  25. 25.
    Jimenez-Soriano Y, Bagan JV (2005) Bisphosphonates, as a new cause of drug-induced jaw osteonecrosis: an update. Med Oral Patol Oral Cir Bucal 10(Suppl 2):E88–E91PubMedGoogle Scholar
  26. 26.
    Melo MD, Obeid G (2005) Osteonecrosis of the jaws in patients with a history of receiving bisphosphonate therapy: strategies for prevention and early recognition. J Am Dent Assoc 136:1675–1681PubMedGoogle Scholar
  27. 27.
    Olson KB, Hellie CM, Pienta KJ (2005) Osteonecrosis of jaw in patient with hormone-refractory prostate cancer treated with zoledronic acid. Urology 66:658CrossRefPubMedGoogle Scholar
  28. 28.
    Vannucchi AM, Ficarra G, Antonioli E, Bosi A (2005) Osteonecrosis of the jaw associated with zoledronate therapy in a patient with multiple myeloma. Br J Haematol 128:738CrossRefPubMedGoogle Scholar
  29. 29.
    Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B (2009) American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws: 2009 update. J Oral Maxillofac Surg 67:2–12PubMedGoogle Scholar
  30. 30.
    Fournier P, Boissier S, Filleur S, Guglielmi J, Cabon F, Colombel M, Clezardin P (2002) Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 62:6538–6544PubMedGoogle Scholar
  31. 31.
    Wood J, Bonjean K, Ruetz S, Bellahcene A, Devy L, Foidart JM, Castronovo V, Green JR (2002) Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 302:1055–1061CrossRefPubMedGoogle Scholar
  32. 32.
    Hellstein JW, Marek CL (2005) Bisphosphonate osteochemonecrosis (bis-phossy jaw): is this phossy jaw of the 21st century? J Oral Maxillofac Surg 63:682–689CrossRefPubMedGoogle Scholar
  33. 33.
    Sedghizadeh PP, Kumar SK, Gorur A, Schaudinn C, Shuler CF, Costerton JW (2008) Identification of microbial biofilms in osteonecrosis of the jaws secondary to bisphosphonate therapy. J Oral Maxillofac Surg 66:767–775CrossRefPubMedGoogle Scholar
  34. 34.
    Oikawa T, Sasaki M, Inose M, Shimamura M, Kuboki H, Hirano S, Kumagai H, Ishizuka M, Takeuchi T (1997) Effects of cytogenin, a novel microbial product, on embryonic and tumor cell-induced angiogenic responses in vivo. Anticancer Res 17:1881–1886PubMedGoogle Scholar
  35. 35.
    Hata K, Nishimura R, Muramatsu S, Matsuda A, Matsubara T, Amano K, Ikeda F, Harley VR, Yoneda T (2008) Paraspeckle protein p54nrb links Sox9-mediated transcription with RNA processing during chondrogenesis in mice. J Clin Invest 118:3098–3108CrossRefPubMedGoogle Scholar
  36. 36.
    Yang J, Nandi S (1983) Growth of cultured cells using collagen as substrate. Int Rev Cytol 81:249–286CrossRefPubMedGoogle Scholar
  37. 37.
    Kubota Y, Kleinman HK, Martin GR, Lawley TJ (1988) Role of laminin and basement membrane in the morphological differentiation of human endothelial cells into capillary-like structures. J Cell Biol 107:1589–1598CrossRefPubMedGoogle Scholar
  38. 38.
    Matsumoto M, Tsuji M, Sasaki H, Fujita K, Nomura R, Nakano K, Shintani S, Ooshima T (2005) Cariogenicity of the probiotic bacterium Lactobacillus salivarius in rats. Caries Res 39:479–483CrossRefPubMedGoogle Scholar
  39. 39.
    Muller S, Migianu E, Lecouvey M, Kraemer M, Oudar O (2005) Alendronate inhibits proliferation and invasion of human epidermoid carcinoma cells in vitro. Anticancer Res 25:2655–2660PubMedGoogle Scholar
  40. 40.
    Ribatti D, Nico B, Mangieri D, Maruotti N, Longo V, Vacca A, Cantatore FP (2007) Neridronate inhibits angiogenesis in vitro and in vivo. Clin Rheumatol 26:1094–1098CrossRefPubMedGoogle Scholar
  41. 41.
    Yamagishi S, Abe R, Inagaki Y, Nakamura K, Sugawara H, Inokuma D, Nakamura H, Shimizu T, Takeuchi M, Yoshimura A, Bucala R, Shimizu H, Imaizumi T (2004) Minodronate, a newly developed nitrogen-containing bisphosphonate, suppresses melanoma growth and improves survival in nude mice by blocking vascular endothelial growth factor signaling. Am J Pathol 165:1865–1874PubMedGoogle Scholar
  42. 42.
    Reid IR (2009) Osteonecrosis of the jaw: who gets it, and why? Bone (NY) 44:4–10Google Scholar
  43. 43.
    Allen MR, Burr DB (2008) Mandible matrix necrosis in beagle dogs after 3 years of daily oral bisphosphonate treatment. J Oral Maxillofac Surg 66:987–994CrossRefPubMedGoogle Scholar
  44. 44.
    Sonis ST, Watkins BA, Lyng GD, Lerman MA, Anderson KC (2009) Bony changes in the jaws of rats treated with zoledronic acid and dexamethasone before dental extractions mimic bisphosphonate-related osteonecrosis in cancer patients. Oral Oncol 45:164–172CrossRefPubMedGoogle Scholar
  45. 45.
    Dimopoulos MA, Kastritis E, Bamia C, Melakopoulos I, Gika D, Roussou M, Migkou M, Eleftherakis-Papaiakovou E, Christoulas D, Terpos E, Bamias A (2009) Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid. Ann Oncol 20:117–120CrossRefPubMedGoogle Scholar
  46. 46.
    Montefusco V, Gay F, Spina F, Miceli R, Maniezzo M, Teresa Ambrosini M, Farina L, Piva S, Palumbo A, Boccadoro M, Corradini P (2008) Antibiotic prophylaxis before dental procedures may reduce the incidence of osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates. Leuk Lymphoma 49:2156–2162CrossRefPubMedGoogle Scholar
  47. 47.
    Ripamonti CI, Maniezzo M, Campa T, Fagnoni E, Brunelli C, Saibene G, Bareggi C, Ascani L, Cislaghi E (2009) Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan. Ann Oncol 20:137–145CrossRefPubMedGoogle Scholar
  48. 48.
    Clezardin P (2005) Anti-tumour activity of zoledronic acid. Cancer Treat Rev 31(Suppl 3):1–8Google Scholar
  49. 49.
    Winter MC, Holen I, Coleman RE (2008) Exploring the antitumour activity of bisphosphonates in early breast cancer. Cancer Treat Rev 34:453–475Google Scholar
  50. 50.
    Montalvetti A, Bailey BN, Martin MB, Severin GW, Oldfield E, Docampo R (2001) Bisphosphonates are potent inhibitors of Trypanosoma cruzi farnesyl pyrophosphate synthase. J Biol Chem 276:33930–33937CrossRefPubMedGoogle Scholar
  51. 51.
    Martin MB, Grimley JS, Lewis JC, Heath HT III, Bailey BN, Kendrick H, Yardley V, Caldera A, Lira R, Urbina JA, Moreno SN, Docampo R, Croft SL, Oldfield E (2001) Bisphosphonates inhibit the growth of Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum: a potential route to chemotherapy. J Med Chem 44:909–916CrossRefPubMedGoogle Scholar
  52. 52.
    Frith JC, Monkkonen J, Blackburn GM, Russell RG, Rogers MJ (1997) Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5′-(beta, gamma-dichloromethylene) triphosphate, by mammalian cells in vitro. J Bone Miner Res 12:1358–1367CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society for Bone and Mineral Research and Springer 2009

Authors and Affiliations

  • Yasuyoshi Kobayashi
    • 1
    • 2
  • Toru Hiraga
    • 3
  • Akimi Ueda
    • 1
  • Liyang Wang
    • 1
  • Michiyo Matsumoto-Nakano
    • 4
  • Kenji Hata
    • 1
  • Hirofumi Yatani
    • 2
  • Toshiyuki Yoneda
    • 1
  1. 1.Department of Molecular and Cellular BiochemistryOsaka University Graduate School of DentistryOsakaJapan
  2. 2.Department of Fixed ProsthodonticsOsaka University Graduate School of DentistryOsakaJapan
  3. 3.Department of Histology and Cell BiologyMatsumoto Dental UniversityNaganoJapan
  4. 4.Department of Pediatric DentistryOsaka University Graduate School of DentistryOsakaJapan

Personalised recommendations