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The Role of Microbial Biofilms in Osteonecrosis of the Jaw Associated with Bisphosphonate Therapy

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Abstract

Microbial biofilms have been observed and described in bone specimens of patients with bisphosphonate (BP)-associated osteonecrosis of the jaw (BONJ) and investigators are more recently suggesting that this condition essentially represents an osteomyelitis of the jaw clinically, with greater susceptibility in some patients on BP therapy. This article explains the role of microbial biofilms in BONJ and also discusses associated factors in the disease pathogenesis, which include BP effects on bone remodeling, anti-angiogenesis, matrix necrosis, microcracks, soft tissue toxicity, and inflammation and wound healing. Recent findings suggest a key role for microbial biofilms in the pathogenesis of BONJ; this has important therapeutic implications because biofilm organisms represent a clinical target for prevention and treatment efforts aimed at reducing the significant morbidity and costs associated with this condition.

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References

Papers of particular interest, published recently, have been highlighted as follows: •Of importance ••Of major importance

  1. Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003, 61:1115–1117.

    Article  PubMed  Google Scholar 

  2. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL: Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004, 62:527–534.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Hansen T, Kunkel M, Weber A, James Kirkpatrick C: Osteonecrosis of the jaws in patients treated with bisphosphonates—histomorphologic analysis in comparison with infected osteoradionecrosis. J Oral Pathol Med 2006, 35:155–160.

    Article  PubMed  Google Scholar 

  5. Hansen T, Kunkel M, Springer E, et al.: Actinomycosis of the jaws—histopathological study of 45 patients shows significant involvement in bisphosphonate-associated osteonecrosis and infected osteoradionecrosis. Virchows Arch 2007, 451:1009–1017.

    Article  PubMed  Google Scholar 

  6. • Sedghizadeh PP, Kumar SK, Gorur A, et al.: Identification of microbial biofilms in osteonecrosis of the jaws secondary to bisphosphonate therapy. J Oral Maxillofac Surg 2008, 66:767–775. This study showed the presence of microbial biofilms in BONJ using conventional histopathologic techniques and scanning electron microscopy.

    Article  PubMed  Google Scholar 

  7. Dunstan CR, Felsenberg D, Seibel MJ: Therapy insight: the risks and benefits of bisphosphonates for the treatment of tumor-induced bone disease. Nat Clin Pract Oncol 2007, 4:42–55.

    Article  CAS  PubMed  Google Scholar 

  8. •• Weinstein RS, Roberson PK, Manolagas SC: Giant osteoclast formation and long-term oral bisphosphonate therapy. N Engl J Med 2009, 360:53–62. This study provides evidence that BPs may prolong the life span of osteoclasts and cause protracted apoptosis.

    Article  CAS  PubMed  Google Scholar 

  9. Djulbegovic B, Wheatley K, Ross J, et al.: Bisphosphonates in multiple myeloma. Cochrane Database Syst Rev 2002, (3):CD003188.

  10. Wells GA, Cranney A, Peterson J, et al.: Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev (1)2008:CD001155.

  11. Assouline-Dayan Y, Chang C, Greenspan A, et al.: Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 2002, 32:94–124.

    PubMed  Google Scholar 

  12. Gliklich R, Wilson J: Epidemiology of bisphosphonate-related osteonecrosis of the jaws: the utility of a national registry. J Oral Maxillofac Surg 2009, 67:71–74.

    Article  PubMed  Google Scholar 

  13. • Khan AA, Sandor GK, Dore E, et al.: Bisphosphonate associated osteonecrosis of the jaw. J Rheumatol 2009, 36:478–490. This study is a systematic review of the incidence, risk factors, diagnosis, prevention, and treatment of BONJ based on studies published before February 2008.

    Article  PubMed  Google Scholar 

  14. •• Lesclous P, Abi Najm S, Carrel JP, et al.: Bisphosphonate-associated osteonecrosis of the jaw: a key role of inflammation? Bone 2009, 45:843–852. This study provides evidence for the role of local inflammation in initiation of BONJ.

    Article  CAS  PubMed  Google Scholar 

  15. Mauri D, Valachis A, Polyzos IP, et al.: Osteonecrosis of the jaw and use of bisphosphonates in adjuvant breast cancer treatment: a meta-analysis. Breast Cancer Res Treat 2009, 116:433–439.

    Article  CAS  PubMed  Google Scholar 

  16. Sedghizadeh PP, Stanley K, Caligiuri M, et al.: Oral bisphosphonate use and the prevalence of osteonecrosis of the jaw: an institutional inquiry. J Am Dent Assoc 2009, 140:61–66.

    PubMed  Google Scholar 

  17. Boonyapakorn T, Schirmer I, Reichart PA, et al.: Bisphosphonate-induced osteonecrosis of the jaws: prospective study of 80 patients with multiple myeloma and other malignancies. Oral Oncol 2008, 44:857–869.

    Article  CAS  PubMed  Google Scholar 

  18. Walter C, Al-Nawas B, Grotz KA, et al.: Prevalence and risk factors of bisphosphonate-associated osteonecrosis of the jaw in prostate cancer patients with advanced disease treated with zoledronate. Eur Urol 2008, 54:1066–1072.

    Article  PubMed  Google Scholar 

  19. Kyrgidis A, Vahtsevanos K, Koloutsos G, et al.: Bisphosphonate-related osteonecrosis of the jaws: a case-control study of risk factors in breast cancer patients. J Clin Oncol 2008, 26:4634–4638.

    Article  PubMed  Google Scholar 

  20. •• Ripamonti CI, Maniezzo M, Campa T, et al.: 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 2009, 20:137–145. This study reports reduced incidence of BONJ in cancer patients after implementation of dental preventive measures when starting BP therapy.

    Article  CAS  PubMed  Google Scholar 

  21. •• Dimopoulos MA, Kastritis E, Bamia C, et al.: Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid. Ann Oncol 2009, 20:117–120. This study also reports reduced incidence of BONJ in multiple myeloma patients on zoledronic acid therapy after implementation of dental preventive measures.

    Article  CAS  PubMed  Google Scholar 

  22. •• Burr DB, Allen MR: Mandibular necrosis in beagle dogs treated with bisphosphonates. Orthod Craniofac Res 2009, 12:221–228. This is an animal study showing matrix necrosis in the mandible of beagle dogs on 3 years of alendronate treatment.

    Article  CAS  PubMed  Google Scholar 

  23. • Landesberg R, Cozin M, Cremers S, et al.: Inhibition of oral mucosal cell wound healing by bisphosphonates. J Oral Maxillofac Surg 2008, 66:839–847. This study reports pretreatment of nitrogen-containing BP on oral mucosal cells inhibits proliferation and wound healing.

    Article  PubMed  Google Scholar 

  24. • Scheper MA, Badros A, Chaisuparat R, et al.: Effect of zoledronic acid on oral fibroblasts and epithelial cells: a potential mechanism of bisphosphonate-associated osteonecrosis. Br J Haematol 2009, 144:667–676. This is an in vitro study showing the deleterious effects of zoledronic acid on human gingival fibroblast and keratinocyte cell lines.

    Article  CAS  PubMed  Google Scholar 

  25. • Favia G, Pilolli GP, Maiorano E: Histologic and histomorphometric features of bisphosphonate-related osteonecrosis of the jaws: an analysis of 31 cases with confocal laser scanning microscopy. Bone 2009, 45:406–413. This study shows prominent and dense woven bone formation with fewer and distant blood vessels along with reduced osteoclastic activity in BONJ bone using light microscopic and confocal scanning laser microscopic examination.

    Article  CAS  PubMed  Google Scholar 

  26. • Christodoulou C, Pervena A, Klouvas G, et al.: Combination of bisphosphonates and antiangiogenic factors induces osteonecrosis of the jaw more frequently than bisphosphonates alone. Oncology 2009, 76:209–211. This study shows higher incidence of BONJ in patients who were taking BP and anti-angiogenic medications compared with those who were taking BP alone.

    Article  CAS  PubMed  Google Scholar 

  27. • Hoefert S, Schmitz I, Tannapfel A, Eufinger H: Importance of microcracks in etiology of bisphosphonate-related osteonecrosis of the jaw: a possible pathogenetic model of symptomatic and non-symptomatic osteonecrosis of the jaw based on scanning electron microscopy findings. Clin Oral Investig 2009, Jun 18 [Epub ahead of print]. This study uses scanning electron microscopy to show the presence of increased number of microcracks in patients with BONJ compared to patients without BONJ but taking BP.

  28. Schaudinn C, Gorur A, Keller D, et al.: Periodontitis: an archetypical biofilm disease. J Am Dent Assoc 2009, 140:978–986.

    PubMed  Google Scholar 

  29. •• Sedghizadeh PP, Kumar SK, Gorur A, et al.: Microbial biofilms in osteomyelitis of the jaw and osteonecrosis of the jaws secondary to bisphosphonate therapy. J Am Dent Assoc 2009, 140:1259–1265. This study shows the presence of microbial biofilms in BONJ and osteomyelitis of jaw without BP therapy using conventional histopathologic techniques and scanning electron microscopy.

    PubMed  Google Scholar 

  30. Marx RE, Sawatari Y, Fortin M, Broumand V: Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 2005, 63:1567–1575.

    Article  PubMed  Google Scholar 

  31. • Siqueira JF Jr, Rocas IN: Community as the unit of pathogenicity: an emerging concept as to the microbial pathogenesis of apical periodontitis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009, 107:870–878. This is a recent review on the complex endodontic microbial community and pathogenesis.

    Article  PubMed  Google Scholar 

  32. Epstein J, van der Meij E, McKenzie M, et al.: Postradiation osteonecrosis of the mandible: a long-term follow-up study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997, 83:657–662.

    Article  CAS  PubMed  Google Scholar 

  33. Waguespack SG, Hui SL, Dimeglio LA, Econs MJ: Autosomal dominant osteopetrosis: clinical severity and natural history of 94 subjects with a chloride channel 7 gene mutation. J Clin Endocrinol Metab 2007, 92:771–778.

    Article  CAS  PubMed  Google Scholar 

  34. Almazrooa SA, Woo SB: Bisphosphonate and nonbisphosphonate-associated osteonecrosis of the jaw: a review. J Am Dent Assoc 2009, 140:864–875.

    CAS  PubMed  Google Scholar 

  35. Meghji S, Henderson B, Nair SP, Tufano MA: Bacterial porins stimulate bone resorption. Infect Immun 1997, 65:1313–1316.

    CAS  PubMed  Google Scholar 

  36. Nelson CL, McLaren AC, McLaren SG, et al.: Is aseptic loosening truly aseptic? Clin Orthop Relat Res 2005, 437:25–30.

    Article  PubMed  Google Scholar 

  37. Blacksin MF, Finzel KC, Benevenia J: Osteomyelitis originating in and around bone infarcts: giant sequestrum phenomena. AJR Am J Roentgenol 2001, 176:387–391.

    CAS  PubMed  Google Scholar 

  38. He H, Liu R, Desta T, et al.: Diabetes causes decreased osteoclastogenesis, reduced bone formation, and enhanced apoptosis of osteoblastic cells in bacteria stimulated bone loss. Endocrinology 2004, 145:447–442.

    Article  CAS  PubMed  Google Scholar 

  39. Diel IJ, Fogelman I, Al-Nawas B, et al.: Pathophysiology, risk factors and management of bisphosphonate-associated osteonecrosis of the jaw: is there a diverse relationship of amino- and non-aminobisphosphonates? Crit Rev Oncol Hematol 2007, 64:198–207.

    Article  PubMed  Google Scholar 

  40. Silverman SL, Landesberg R: Osteonecrosis of the jaw and the role of bisphosphonates: a critical review. Am J Med 2009, 122:S33–S45.

    Article  CAS  PubMed  Google Scholar 

  41. Stockmann P, Hinkmann FM, Lell MM, et al.: Panoramic radiograph, computed tomography or magnetic resonance imaging. Which imaging technique should be preferred in bisphosphonate-associated osteonecrosis of the jaw? A prospective clinical study. Clin Oral Investig 2009, Jun 10 [Epub ahead of print].

  42. •• Hall-Stoodley L, Stoodley P: Evolving concepts in biofilm infections. Cell Microbiol 2009, 11:1034–1043. This is a review on the current understanding and challenges in studying biofilm infections.

    Article  CAS  PubMed  Google Scholar 

  43. Gorby YA, Yanina S, McLean JS, et al.: Electrically conductive bacterial nanowires produced by Shewanella oneidensis strain MR-1 and other microorganisms. Proc Natl Acad Sci U S A 2006, 103:11358–11363.

    Article  CAS  PubMed  Google Scholar 

  44. Kuramitsu HK, He X, Lux R, et al.: Interspecies interactions within oral microbial communities. Microbiol Mol Biol Rev 2007, 71:653–670.

    Article  CAS  PubMed  Google Scholar 

  45. Parsek MR, Singh PK: Bacterial biofilms: an emerging link to disease pathogenesis. Annu Rev Microbiol 2003, 57:677–701.

    Article  CAS  PubMed  Google Scholar 

  46. Hall V: Actinomyces—gathering evidence of human colonization and infection. Anaerobe 2008, 14:1–7.

    Article  CAS  PubMed  Google Scholar 

  47. Ganguli A, Steward C, Butler S, et al.: Bacterial adhesion to bisphosphonate coated hydroxyapatite. J Mater Sci Mater Med 2005, 16:283–287.

    Article  CAS  PubMed  Google Scholar 

  48. Henderson B, Nair SP: Hard labour: bacterial infection of the skeleton. Trends Microbiol 2003, 11:570–577.

    Article  CAS  PubMed  Google Scholar 

  49. Harrington DJ: Bacterial collagenases and collagen-degrading enzymes and their potential role in human disease. Infect Immun 1996, 64:1885–1891.

    CAS  PubMed  Google Scholar 

  50. Silverman SL: New therapies for osteoporosis: zoledronic acid, bazedoxifene, and denosumab. Curr Osteoporos Rep 2009, 7:91–95.

    Article  PubMed  Google Scholar 

  51. • Cummings SR, San Martin J, McClung MR, et al.: Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009, 361:756–765. This study is a pivotal clinical trial showing a significant reduction in vertebral, nonvertebral, and hip fracture risk with denosumab.

    Article  CAS  PubMed  Google Scholar 

  52. •• Stopeck A, Body JJ, Fujiwara Y, et al.: Denosumab versus zoledronic acid for the treatment of breast cancer patients with bone metastases: results of a randomized phase 3 study. Eur J Cancer Suppl 2009, 7:2, abstract 2LBA. This abstract presents the first report that jaw osteonecrosis cases occur with denosumab and zoledronic acid at similar frequencies as cancer therapy dosages.

    Article  Google Scholar 

  53. del Pozo JL, Patel R: The challenge of treating biofilm-associated bacterial infections. Clin Pharmacol Ther 2007, 82:204–209.

    Article  PubMed  Google Scholar 

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Acknowledgments

Owing to journal requirements for references, certain key contributions in the field of BONJ and microbial biofilms may not have been cited in this manuscript and the authors would like to acknowledge all such scientific contributions.

Disclosure

No potential conflicts of interest relevant to this article were reported.

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Authors and Affiliations

  1. Clinical Dentistry, Orofacial Pain and Oral Medicine Center, Division of Diagnostic Sciences, School of Dentistry, University of Southern California, Los Angeles, CA, USA

    Satish K. S. Kumar

  2. Center for Biofilms, School of Dentistry, University of Southern California, Los Angeles, CA, USA

    Amita Gorur & Christoph Schaudinn

  3. School of Dentistry, University of British Columbia, Vancouver, Canada

    Charles F. Shuler

  4. Microbiology Research, Department of Orthopedic Surgery, Allegheny General Hospital and Center for Genomics, Allegheny-Singer Research Institute, Pittsburgh, PA, USA

    J. William Costerton

  5. USC School of Dentistry, Center for Biofilms, 925 West 34th Street #4110A, Los Angeles, CA, 90089-0641, USA

    Parish P. Sedghizadeh

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  1. Satish K. S. Kumar
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  2. Amita Gorur
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  3. Christoph Schaudinn
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  4. Charles F. Shuler
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  5. J. William Costerton
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  6. Parish P. Sedghizadeh
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Correspondence to Parish P. Sedghizadeh.

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Kumar, S.K.S., Gorur, A., Schaudinn, C. et al. The Role of Microbial Biofilms in Osteonecrosis of the Jaw Associated with Bisphosphonate Therapy. Curr Osteoporos Rep 8, 40–48 (2010). https://doi.org/10.1007/s11914-010-0008-1

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  • DOI: https://doi.org/10.1007/s11914-010-0008-1

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