Skip to main content

Advertisement

Log in

Oral mucosa produces cytokines and factors influencing osteoclast activity and endothelial cell proliferation, in patients with osteonecrosis of jaw after treatment with zoledronic acid

  • Original Article
  • Published:
Clinical Oral Investigations Aims and scope Submit manuscript

Abstract

Objectives

The intravenous injection of bisphosphonates, currently used as treatment for osteoporosis, bone Paget’s disease, multiple myeloma, or bone metastases, can cause jaw bone necrosis especially in consequence of trauma. The present research aimed to clarify the mechanisms underlying bone necrosis, exploring involvement of the oral mucosa “in vivo.”

Patients and methods

Specimens of oral mucosa were removed from bisphosphonate-treated patients with or without jaw bone necrosis. In mucosa specimens, expression was evaluated of: cytokines involved in the inflammatory process, factors involved in osteoclast activity, i.e., receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin, a factor involved in cell proliferation, namely hydroxymethylglutaryl coenzyme A reductase, and a factor involved in angiogenesis, namely vascular endothelial growth factor (VEGF).

Results

Interleukin (IL)-6 and the RANK/osteoprotegerin ratio were significantly elevated in mucosa from patients with versus without jaw necrosis, whereas hydroxymethylglutaryl coenzyme A reductase and VEGF were significantly decreased.

Conclusions

Our results suggest that mucosa, stimulated by bisphosphonate released from the bone, can contribute to the development of jaw necrosis, reducing VEGF, and producing IL-6 in consequence of hydroxymethylglutaryl coenzyme A reductase reduction. In turn, IL-6 stimulates osteoclast activity, as shown by the increased RANKL/osteoprotegerin ratio.

Clinical relevance

The results of this study suggest the importance of evaluating during bisphosphonate treatment the production of IL-6, RANKL, osteoprotegerin, and VEGF, in order to monitor the jaw osteonecrosis onset. To avoid repeated mucosa excisions, the determination of these factors could be carried out in crevicular fluid.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Pazianas M (2011) Osteonecrosis of the jaw and the role of macrophages. J Natl Cancer Inst 103:232–240

    Article  PubMed  Google Scholar 

  2. Mehrotra B (2009) Bisphosphonates—role in cancer therapies. J Oral Maxillofac Surg 67:19–26

    Article  PubMed  Google Scholar 

  3. Dunford JE, Kwaasi AA, Rogers MJ et al (2008) Structure–activity relationships among the nitrogen containing bisphosphonates in clinical use and other analogues: time-dependent inhibition of human farnesyl pyrophosphate synthase. J Med Chem 51:2187–2195

    Article  PubMed  Google Scholar 

  4. Marcus R, Feldman D, Nelson D et al (2008) Bisphosphonates: pharmacology and use in the treatment of osteoporosis. In: Marcus R, Feldman D, Nelson D, Rosen C (eds) Osteoporosis, 3rd edn. Elsevier, Burlington, pp 1725–1742

    Google Scholar 

  5. Frei M, Bornstein MM, Schaller B et al (2010) Bisphosphonate-related osteonecrosis of the jaw combined with jaw metastasis of prostate adenocarcinoma: report of a case. J Oral Maxillofac Surg 68:863–867

    Article  PubMed  Google Scholar 

  6. Treister NS, Sook-Bin W (2009) Bisphosphonate-associated osteonecrosis of the jaws. In: Rosen CJ, Compston JE, Lian JB (eds) Primer on the metabolic bone diseases and disorders of mineral metabolism, 7th edn. Wiley, Hoboken, pp 505–509

    Google Scholar 

  7. Santini D, Vincenzi B, Dicuonzo G et al (2003) Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients, and by “in vitro” research. Clin Cancer Res 9:2893–2897

    PubMed  Google Scholar 

  8. Fournier P, Boissier S, Filleur S et al (2002) Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 62:6538–6544

    PubMed  Google Scholar 

  9. Hansen T, Kunkel M, Weber A et al (2006) Osteonecrosis of the jaws in patients treated with bisphosphonates-histomorphologic analysis in comparison with infected osteoradionecrosis. J Oral Pathol Med 35:155–160

    Article  PubMed  Google Scholar 

  10. Hellstein JW, Marek CL (2005) Bisphosphonate osteochemonecrosis (bis-phossy jaw): is this phossy jaw of the 21st century? J Oral Maxillofac Surg 63:682–689

    Article  PubMed  Google Scholar 

  11. Reid IR (2009) Osteonecrosis of the jaw: who gets it, and why? Bone 44:4–10

    Article  PubMed  Google Scholar 

  12. Ohe JY, Kwon YD, Lee HW (2012) Bisphosphonates modulate the expression of OPG and M-CSF in hMSC-derived osteoblasts. Clin Oral Investig 16:1153–1159

    Article  PubMed  Google Scholar 

  13. Koch FP, Merkel C, Ziebart T et al (2012) Influence of bisphosphonates on the osteoblast RANKL and OPG gene expression in vitro. Clin Oral Investig 16:79–86

    Article  PubMed  Google Scholar 

  14. Mozzati M, Gallesio G, Arata V et al (2012) Platelet-rich therapies in the treatment of intravenous bisphosphonate-related osteonecrosis of the jaw: a report of 32 cases. Oral Oncol 48:469–474

    Article  PubMed  Google Scholar 

  15. Mozzati M, Martinasso G, Cocero N et al (2011) Influence of superpulsed laser therapy on healing processes following tooth extraction. Photomed Laser Surg 29:565–571

    Article  PubMed  Google Scholar 

  16. Bianchi SD, Scoletta M, Cassione FB et al (2007) Computerized tomographic findings in bisphosphonate-associated osteonecrosis of the jaw in patients with cancer. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 104:249–258

    Article  PubMed  Google Scholar 

  17. Pavlakis N, Schmidt R, Stockler M (2005) Bisphosphonates for breast cancer. Cochrane Database Syst Rev 3:CD003474

    Google Scholar 

  18. Aapro M, Abrahamsson PA, Body JJ et al (2008) Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol 19:420–432

    Article  PubMed  Google Scholar 

  19. La Verde N, Bareggi C, Garassino M et al (2008) Osteonecrosis of the jaw (ONJ) in cancer patients treated with bisphosphonates: how the knowledge of a phenomenon can change its evolution. Support Care Cancer 16:1311–1315

    Article  PubMed  Google Scholar 

  20. Ruggiero S, Gralow J, Marx RE et al (2006) Practical guidelines for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in patients with cancer. J Oncol Pract 2:7–14

    Article  PubMed  Google Scholar 

  21. Vandone AM, Donadio M, Mozzati M et al (2011) Impact of dental care in the prevention of bisphosphonate-associated osteonecrosis of the jaw: a single-center clinical experience. Ann Oncol 23:193–200

    Article  PubMed  Google Scholar 

  22. Lo JC, O’Ryan FS, Gordon NP et al (2010) Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg 68:243–253

    Article  PubMed  Google Scholar 

  23. Shannon J, Shannon J, Modelevsky S et al (2011) Bisphosphonates and osteonecrosis of the jaw. J Am Geriatr Soc 340:c246. doi:10.1111/j.1532-5415.2011.03713.x

    Google Scholar 

  24. Russell RG, Croucher PI, Rogers MJ (1999) Bisphosphonates: pharmacology, mechanisms of action and clinical uses. Oteoporos Int 9:S66–S80

    Article  Google Scholar 

  25. Santini D, Vincenzi B, Caraglia M et al (2007) A hitherto unreported high incidence of zoledronic acid-induced acute phase reaction in patients with cancer treatment-induced bone loss. Ann Oncol 18:201–202

    Article  PubMed  Google Scholar 

  26. Rufo A, Del Fattore A, Capulli M et al (2011) Mechanisms inducing low bone density in Duchenne muscular dystrophy in mice and humans. J Bone Miner Res 26:1891–1903. doi:10.1002/jbmr.410

    Article  PubMed  Google Scholar 

  27. Jimi E, Furuta H, Matsuo K et al (2010) The cellular and molecular mechanisms of bone invasion by oral squamous cell carcinoma. Oral Dis 17:462–468. doi:10.1111/j.1601-0825.2010.01781.x

    Article  PubMed  Google Scholar 

  28. Hewitt RE, Lissina A, Green AE et al (2005) The bisphosphonate acute phase response: rapid and copious production of proinflammatory cytokines by peripheral blood γδ T cells in response to aminobisphosphonates is inhibited by statins. Clin Exp Immunol 139:101–111

    Article  PubMed  Google Scholar 

  29. Woo SB, Hellstein JW, Kalmar JR (2006) Narrative review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 144:753–761

    Article  PubMed  Google Scholar 

  30. Kraus D, Deschner J, Jäger A et al (2012) Human β-defensins differently affect proliferation, differentiation, and mineralization of osteoblast-like MG63 cells. J Cell Physiol 227:994–1003. doi:10.1002/jcp.22808

    Article  PubMed  Google Scholar 

  31. Krishnan V, Shuman LA, Sosnoski DM et al (2011) Dynamic interaction between breast cancer cells and osteoblastic tissue: comparison of two- and three-dimensional cultures. J Cell Physiol 226:2150–2158

    Article  PubMed  Google Scholar 

  32. Landesberg R, Woo V, Cremers S et al (2011) Potential pathophysiological mechanisms in osteonecrosis of the jaw. Ann N Y Acad Sci 1218:62–79. doi:10.1111/j.1749-6632.2010.05835.x

    Article  PubMed  Google Scholar 

  33. Rustemeyer J, Bremerich A (2010) Bisphosphonate-associated osteonecrosis of the jaw: what do we currently know? A survey of knowledge given in the recent literature. Clin Oral Investig 14:59–64

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The work was supported by grants from Regione Piemonte and University of Turin, Italy.

Conflicts of interest

The authors declared no conflicts of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rosa Angela Canuto.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mozzati, M., Martinasso, G., Maggiora, M. et al. Oral mucosa produces cytokines and factors influencing osteoclast activity and endothelial cell proliferation, in patients with osteonecrosis of jaw after treatment with zoledronic acid. Clin Oral Invest 17, 1259–1266 (2013). https://doi.org/10.1007/s00784-012-0800-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00784-012-0800-7

Keywords

Navigation