DOI QR코드

DOI QR Code

Development of animal model for Bisphosphonates-related osteonecrosis of the jaw (BRONJ)

  • Jang, Hyo-Won (Department of Oral and Maxillofacial Surgery, College of Dentistry, Yonsei University) ;
  • Kim, Jin-Woo (Department of Oral and Maxillofacial Surgery, Mok-dong Hospital, Ewha Womans University) ;
  • Cha, In-Ho (Department of Oral and Maxillofacial Surgery, College of Dentistry, Yonsei University)
  • Received : 2015.07.07
  • Accepted : 2015.07.14
  • Published : 2015.12.31

Abstract

Background: The aim of this study is to develop a rat model of bisphosphonates-related osteonecrosis of the jaw (BRONJ) that would be verified with clinical, radiological and histological examination, and to confirm the influence of concurrent bisphosphonates and steroids use upon the occurrence and aggravation of BRONJ. Methods: Twenty seven rats were divided into 3 groups; Saline group (I), Zoledronate group (II), Zoledronate and Dexamethasone group (III). Rats got weekly intraperitoneal injection for 4 times and extraction of left maxillary and mandibular 1st, 2nd molars were followed. Consecutive injections were performed, and blood sampling for measurements of C-terminal crosslinked telopeptide of type I collagen and tartrate-resistant acid phosphate 5b rats were performed at the time of 2, 4 and 8 weeks. And then, rats were sacrificed and evaluated clinically, radiologically and histologically. Results: 12/18 (66.6 %) of experimental group were diagnosed as BRONJ. There was no significant difference in incidence between zoledronate alone group (ll) and concurrent use of zoledronate and dexamethasone group (lll). Conclusions: Concurrent use of bisphosphonates and steroids increase incidence of BRONJ compared to saline group (l). Zoledronate alone group (ll) and concurrent use of zoledronate and dexamethasone group (lll) shows same incidence of BRONJ. Based on this study, the rat treated with bisphosphonates and steroids can be considered a novel, reliable and reproducible model to understand pathology of BRONJ.

Keywords

References

  1. Rodan GA, Martin TJ (2000) Therapeutic approaches to bone diseases. Science 289(5484):1508-14 https://doi.org/10.1126/science.289.5484.1508
  2. Nussbaum SR, Younger J, Vandepol CJ, Gagel RF, Zubler MA, Chapman R, Henderson IC, Mallette LE. (1993) Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: comparison of 30-, 60-, and 90-mg dosages. Am J Med 95(3):297-304 https://doi.org/10.1016/0002-9343(93)90282-T
  3. Kremer R, Gagnon B, Meguerditchian AN, Nadeau L, Mayo N. 2014; Effect of oral bisphosphonates for osteoporosis on development of skeletal metastases in women with breast cancer: results from a pharmaco-epidemiological study. J Natl Cancer Inst. 2014;106(11). doi: 10.1093/jnci/dju264.
  4. Fleisch H (1998) Bisphosphonates: mechanisms of action. Endocr Rev 19(1):80-100 https://doi.org/10.1210/edrv.19.1.0325
  5. Van Beek ER, Lowik CW, Papapoulos SE (2002) Bisphosphonates suppress bone resorption by a direct effect on early osteoclast precursors without affecting the osteoclastogenic capacity of osteogenic cells: the role of protein geranylgeranylation in the action of nitrogen-containing bisphosphonates on osteoclast precursors. Bone 30(1):64-70 https://doi.org/10.1016/S8756-3282(01)00655-X
  6. Rosen LS, Gordon DH, Dugan W, Major P, Eisenberg PD, Provencher L, Kaminski M, Simeone J, Seaman J, Chen B, Coleman RE. (2004) Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 100(1):36-43 https://doi.org/10.1002/cncr.11892
  7. Stresing V, Fournier PG, Bellahcene A, Benzaid I, Monkkonen H, Colombel M, Ebetino FH, Castronovo V, Clezardin P. (2011) Nitrogen-containing bisphosphonates can inhibit angiogenesis in vivo without the involvement of farnesyl pyrophosphate synthase. Bone 48(2):259-66 https://doi.org/10.1016/j.bone.2010.09.035
  8. Marx RE (2003) Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61(9):1115-7 https://doi.org/10.1016/S0278-2391(03)00720-1
  9. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, Gagel RF, Gilsanz V, Guise T, Koka S, McCauley LK, McGowan J, McKee MD, Mohla S, Pendrys DG, Raisz LG, Ruggiero SL, Shafer DM, Shum L, Silverman SL, Van Poznak CH, Watts N, Woo S, Shane E. (2007) Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 22(10):1479-91 https://doi.org/10.1359/jbmr.0707onj
  10. Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G, Koutsoukou V, Gika D, Anagnostopoulos A, Papadimitriou C, Terpos E, Dimopoulos MA. (2005) Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 23(34):8580-7 https://doi.org/10.1200/JCO.2005.02.8670
  11. Thumbigere Math V, Tu L, Huckabay S, Dudek AZ, Lunos S, Basi DL, Hughes PJ, Leach JW, Swenson K, Gopalakrishnan R. (2012) A retrospective study evaluating frequency and risk factors of osteonecrosis of the jaw in 576 cancer patients receiving intravenous bisphosphonates. Am J Clin Oncol 35(4):386-92 https://doi.org/10.1097/COC.0b013e3182155fcb
  12. Pozzi S, Marcheselli R, Sacchi S, Baldini L, Angrilli F, Pennese E, Quarta G, Stelitano C, Caparotti G, Luminari S, Musto P, Natale D, Broglia C, Cuoghi A, Dini D, Di Tonno P, Leonardi G, Pianezze G, Pitini V, Polimeno G, Ponchio L, Masini L, Musso M, Spriano M, Pollastri G. (2007) Bisphosphonate-associated osteonecrosis of the jaw: a review of 35 cases and an evaluation of its frequency in multiple myeloma patients. Leuk Lymphoma 48(1):56-64 https://doi.org/10.1080/10428190600977690
  13. Kyrgidis A, Vahtsevanos K, Koloutsos G, Andreadis C, Boukovinas I, Teleioudis Z, Patrikidou A, Triaridis S. (2008) Bisphosphonate-related osteonecrosis of the jaws: a case-control study of risk factors in breast cancer patients. J Clin Oncol 26(28):4634-8 https://doi.org/10.1200/JCO.2008.16.2768
  14. Marx RE, Sawatari Y, Fortin M, Broumand V (2005) Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 63(11):1567-75 https://doi.org/10.1016/j.joms.2005.07.010
  15. Chiu C, Chiang W, Chuang C, Chang S (2010) Resolution of oral bisphosphonate and steroid-related osteonecrosis of the jaw-a serial case analysis. J Oral Maxillofac Surg 68(5):1055-63 https://doi.org/10.1016/j.joms.2009.12.030
  16. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, Gagel RF, Gilsanz V, Guise T, Koka S, McCauley LK, McGowan J, McKee MD, Mohla S, Pendrys DG, Raisz LG, Ruggiero SL, Shafer DM, Shum L, Silverman SL, Van Poznak CH, Watts N, Woo S, Shane E. (2008) Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 66(6):1320-1
  17. Chao T, Wu Y, Janckila AJ (2010) Tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) as a serum maker for cancer with bone metastasis. Clin Chim Acta 411(21-22):1553-64 https://doi.org/10.1016/j.cca.2010.06.027
  18. Kuroshima S, Go VA, Yamashita J (2012) Increased numbers of nonattached osteoclasts after long-term zoledronic acid therapy in mice. Endocrinology 153(1):17-28 https://doi.org/10.1210/en.2011-1439
  19. 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(2):164-72 https://doi.org/10.1016/j.oraloncology.2008.04.013
  20. Hokugo A, Christensen R, Chung EM, Sung EC, Felsenfeld AL, Sayre JW, Garrett N, Adams JS, Nishimura I. (2010) Increased prevalence of bisphosphonate-related osteonecrosis of the jaw with vitamin D deficiency in rats. J Bone Miner Res 25(6):1337-49 https://doi.org/10.1002/jbmr.23
  21. Johansen JR (1970) Repair of the post-extraction alveolus in the Wistar rat. A histologic and autoradiographic study. Acta Odontol Scand 28(4):441-61 https://doi.org/10.3109/00016357009028237
  22. Iizuka T, Miller SC, Marks SC (1992) Alveolar bone remodeling after tooth extraction in normal and osteopetrotic (ia) rats. J Oral Pathol Med 21(4):150-5 https://doi.org/10.1111/j.1600-0714.1992.tb00092.x
  23. Badros A, Weikel D, Salama A, Goloubeva O, Schneider A, Rapoport A, Fenton R, Gahres N, Sausville E, Ord R, Meiller T. (2006) Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol 24(6):945-52 https://doi.org/10.1200/JCO.2005.04.2465
  24. Klingenstein G, Levy RN, Kornbluth A, Shah AK, Present DH (2005) Inflammatory bowel disease related osteonecrosis: report of a large series with a review of the literature. Aliment Pharmacol Ther 21(3):243-9 https://doi.org/10.1111/j.1365-2036.2005.02231.x
  25. Hikita H, Miyazawa K, Tabuchi M, Kimura M, Goto S (2009) Bisphosphonate administration prior to tooth extraction delays initial healing of the extraction socket in rats. J Bone Miner Metab 27(6):663-72 https://doi.org/10.1007/s00774-009-0090-6
  26. Yamamoto Y, Udagawa N, Matsuura S, Nakamichi Y, Horiuchi H, Hosoya A, Nakamura M, Ozawa H, Takaoka K, Penninger JM, Noguchi T, Takahashi N. (2006) Osteoblasts provide a suitable microenvironment for the action of receptor activator of nuclear factor-kappaB ligand. Endocrinology 147(7):3366-74 https://doi.org/10.1210/en.2006-0216
  27. Martini G, Gennari L, Merlotti D, Salvadori S, Franci MB, Campagna S, Avanzati A, De Paola V, Valleggi F, Nuti R. (2007) Serum OPG and RANKL levels before and after intravenous bisphosphonate treatment in Paget's disease of bone. Bone 40(2):457-63 https://doi.org/10.1016/j.bone.2006.08.003
  28. Civitelli R, Armamento Villareal R, Napoli N (2009) Bone turnover markers: understanding their value in clinical trials and clinical practice. Osteoporos Int 20(6):843-51 https://doi.org/10.1007/s00198-009-0838-9

Cited by

  1. Bisphosphonate-related osteonecrosis of the jaw in metastatic breast cancer patients: a review of 25 cases vol.38, pp.None, 2015, https://doi.org/10.1186/s40902-016-0052-6
  2. Uncommon presentation of potential medication-related osteonecrosis of the jaw vol.5, pp.1, 2015, https://doi.org/10.1186/s40064-016-1902-5
  3. Jawbone Changes in Sodium Zoledronic Acid- and Dexamethasone-Treated Rats vol.25, pp.4, 2016, https://doi.org/10.2485/jhtb.25.383
  4. Prognostic factors for outcome of surgical treatment in medication-related osteonecrosis of the jaw vol.44, pp.4, 2015, https://doi.org/10.5125/jkaoms.2018.44.4.174
  5. Effect of Periapical Diseases in Development of MRONJ in Immunocompromised Mouse Model vol.2019, pp.None, 2015, https://doi.org/10.1155/2019/1271492
  6. Effects of zoledronic acid and dexamethasone on early phases of socket healing after tooth extraction in rats: A preliminary macroscopic and microscopic quantitative study vol.24, pp.3, 2015, https://doi.org/10.4317/medoral.22883
  7. Endothelial Progenitor Cells inhibit jaw osteonecrosis in a rat model: A major adverse effect of bisphosphonate therapy vol.9, pp.1, 2015, https://doi.org/10.1038/s41598-019-55383-5
  8. Investigation on the Action and Effect of Culture Supernatant of Human Dental Pulp Stem Cells Using Rats with Medication-Related Osteonecrosis of the Jaw vol.28, pp.4, 2015, https://doi.org/10.2485/jhtb.28.349
  9. The effects of different doses of teriparatide on bisphosphonate‐related osteonecrosis of the jaw in mice vol.26, pp.3, 2015, https://doi.org/10.1111/odi.13275
  10. Endothelial progenitors increase vascularization and improve fibroblasts function that prevent medication‐related osteonecrosis of the jaw vol.26, pp.7, 2015, https://doi.org/10.1111/odi.13412
  11. Effects of metformin on the prevention of bisphosphonate-related osteonecrosis of the jaw-like lesions in rats vol.65, pp.2, 2015, https://doi.org/10.2186/jpr.jpor_2019_629
  12. Nitrogen‐containing bisphosphonates and lipopolysaccharide mutually augment inflammation via adenosine triphosphate (ATP)‐mediated and interleukin 1β (IL‐1β)‐medi vol.36, pp.9, 2015, https://doi.org/10.1002/jbmr.4384
  13. Effects of the prevention of medication-related osteonecrosis of the jaw by local administration of a dental pulp stem cell-conditioned medium to the rat tooth extraction socket vol.109, pp.4, 2021, https://doi.org/10.1007/s10266-021-00607-2