Radyoterapiyi takiben kritik boyutta oluşturulan kemik defektlerinde antibiyotiklerin etkinliğinin deneysel olarak incelenmesi

Year 2020, Volume: 7 Issue: 2, 294 - 303, 01.08.2020

Özgün Günay Özge Doğanay , Olgu Enis Tok Alper Alkan

https://doi.org/10.15311/selcukdentj.695767

Abstract

Amaç: Çenelerin osteoradyonekrozu (ORN), baş ve boyun kanserlerinde radyasyon tedavisinin bir komplikasyonu olarak karşımıza çıkmaktadır. Tanımı ve sınıflandırması yıllar içinde değişiklik göstermiş, patofizyolojisine dair teorileri geliştirilmiş ve buna bağlı olarak farklı tedavi prensipleri denenmiştir. Çalışmadaki amacımız, radyoterapiyi takiben alt çene kemiğinde cerrahi olarak oluşturulan kritik boyuttaki defektlerde klindamisin, metronidazol, rifamisin ve doksisiklin grubu antibiyotiklerin kemik iyileşmesi üzerindeki etkilerini incelemekti.
Gereç ve Yöntem: Anti-enflamatuar etkinliğin kemik iyileşmesi üzerindeki etkilerini değerlendirmek için, 50 adet Wistar cinsi albino türü sıçanlar kullanılmıştır. Tüm gruplara genel anestezi altında 30 Gy dozda radyoterapi uygulandıktan 8 hafta sonra sıçanların sağ mandibulasında 5 mm çapında bikortikal hazırlanan kemik defektlerine deney gruplarında ksenogreft ile karıştırılan antibiyotikler, kontrol gruplarında ise sadece ksenogreft partikülleri uygulanarak cerrahi saha iyileşmeye bırakılmıştır. Sakrifikasyon sonrasında elde edilen örneklerde enflamasyon, nekroz, fibrozis, yeni kemik yapım alanı, kalsifiye olmuş kemik alanı ve kapiller sayısı histopatolojik ve histomorfometrik olarak değerlendirildi.
Bulgular: İncelenen kesitlerde nekroz, enfeksiyon ya da fibrozis bulgusuna rastlanmamıştır. Kontrol grubu ile yapılan karşılaştırmalarda metronidazol ve klindamisin gruplarında yeni kemik yapım alanlarının anlamlı derecede yüksek olduğu görülmüştür (p<0.01, p<0.01). Kalsifiye kemik trabekül alanları incelendiğinde kontrol grubu ile klindamisin grubu arasında istatistiksel olarak ileri derecede anlamlı fark tespit edilmiştir (p<0.01). Klindamisin ile diğer gruplar karşılaştırıldığında ise aradaki fark anlamlı (p<0.05) bulunmuştur. Kontrol grubu ile yapılan karşılaştırmalarda kapiller sayısı metronidazol grubunda anlamlı (p<0.05), klindamisin grubunda (p<0.01) ise ileri derecede anlamlı olarak farklı bulunmuştur.
Sonuç: Antibiyotik uygulanan gruplarda iltihabi alanların sayısında azalma, yeni kemik yapım alanlarında ve damarlanmada artış gözlenmiştir. Çalışmada kullandığımız antibiyotiklerin antibakteriyel aktiviteden bağımsız olarak anti- enflamatuar etkinliklerinin olabileceği düşünülmektedir.

Keywords

Osteoradyonekroz, kemik iyileşmesi, klindamisin, antibiyotik, sıçan, radyoterapi, anti-enflamatuar etki

References

• 1. Ruggiero S, Gralow J, Marx RE, Hoff AO, Schubert MM, Huryn JM et al. Practical guidelines for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in patients with cancer. J Oncol Pract. 2006;2(1):7-14.
• 2. Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B et al. American Association of Oral and Maxillofacial Surgeons position paper on medicationrelated osteonecrosis of the jaw. J Oral Maxillofac Surg. 2014;72(10):1938-56.
• 3. de Souza Tolentino E, de Castro TF, Michellon FC, Passoni ACC, Ortega LJA, Iwaki LCV et al. Adjuvant therapies in the management of medication-related osteonecrosis of the jaws: Systematic review. Head Neck. 2019;41(12):4209-28.
• 4. Shuster A, Reiser V, Trejo L, Ianculovici C, Kleinman S, Kaplan I. Comparison of the histopathological characteristics of osteomyelitis, medication-related osteonecrosis of the jaw, and osteoradionecrosis. Int J Oral Maxillofac Surg. 2019 ;48(1):17-22.
• 5. Cheriex KC, Nijhuis TH, Mureau MA. Osteoradionecrosis of the jaws: a review of conservative and surgical treatment options. J Reconstr Microsurg. 2013; 29(2):69-76.
• 6. Ogawa K, Kohshi K, Ishiuchi S, Matsushita M, Yoshimi N, Murayama S. Old but new methods in radiation oncology: hyperbaric oxygen therapy Int J Clin Oncol. 2013;18(3):364-70.
• 7. Al Ruhaimi KA. Bone graft substitutes: a comparative qualitative histologic review of current osteoconductive grafting materials. Int J Oral Maxillofac Implants. 2001;16(1):105-14.
• 8. Rubin BK, Tamaoki J. Antibiotics as anti-inflammatory and immunomodulatory agents. Vol. 48. 2005: Springer Science & Business Media.
• 9. Garrido-Mesa J, Rodríguez-Nogales A, Algieri F, Vezza T, Hidalgo-Garcia L, Garrido-Barros M et al. Immunomodulatory tetracyclines shape the intestinal inflammatory response inducing mucosal healing and resolution. Br J Pharmacol 2018;175(23):4353-70.
• 10. Al-Bazie SA, Bahatheq M, Al-Ghazi M, Al-Rajhi N, Ramalingam S. Antibiotic protocol for the prevention of osteoradionecrosis following dental extractions in irradiated head and neck cancer patients: A 10 years prospective study. J Cancer Res Ther. 2016;12(2):565-70.
• 11. Rivero JA, Shamji O, Kolokythas A. Osteoradionecrosis: a review of pathophysiology, prevention and pharmacologic management using pentoxifylline, α-tocopherol, and clodronate. Oral Surg Oral Med Oral Pathol Oral Radiol 2017;124(5):464-71.
• 12. Sathasivam HP, Davies GR, Boyd NM. Predictive factors for osteoradionecrosis of the jaws: A retrospective study. Head & neck 2018;40(1): 46-54.
• 13. Marx RE. A new concept in the treatment of osteoradionecrosis. J Oral Maxillofac Surg 1983;41: 351–57.
• 14. Withers HR, Peters LJ, Taylor JM, Owen JB, Morrison WH, Schultheiss TE et al.Late normal tissue sequelae from radiation therapy for carcinoma of the tonsil: patterns of fractionation study of radiobiology. Int J Radiat Oncol Biol Phys 1995;33: 563-68.
• 15. Reuther T, Schuster T, Mende U, Kübler A. Osteoradionecrosis of the jaws as a side effect of radiotherapy of head and neck tumour patients—a report of a thirty year retrospective review. Int J Oral Maxillofac Surg 2003 32: 289–95.
• 16. Grötz KA, Riesenbeck D, Brahm R, Seegenschmiedt MH, al-Nawas B, Dörr W et al.Chronic radiation effects on dental hard tissue (radiation caries). Classification and therapeutic strategies. Strahlenther Onkol 2001;177: 96–104.
• 17. Oh HK, Chambers MS, Martin JW, Lim HJ, Park HJ. Osteoradionecrosis of the mandible: treatment outcomes and factors influencing the progress of osteoradionecrosis. J Oral Maxillofac Surg 2009 67: 1378–86.
• 18. Reuther T, Schuster T, Mende U, Kübler A. Osteoradionecrosis of the jaws as a side effect of radiotherapy of head and neck tumour patients—a report of a thirty year retrospective review. Int J Oral Maxillofac Surg 2003;32(3):289-95.
• 19. Mendenhall WM. Mandibular osteoradionecrosis. J Clin Oncol 2004 22: 4867–68.
• 20. Sciubba JJ, Goldenberg D. Oral complications of radiotherapy. Lancet Oncol. 2006;7(2):175-83.
• 21. Berger A, Bensadoun RJ. Normal tissue tolerance to external beam radiation therapy: the mandible. Cancer Radiother 2010; 4: 295–300.
• 22. Chronopoulos A. Clinical presentation and risk factors of osteoradionecrosis (Doctoral dissertation). Available from: https://edoc.ub.uni-muenchen.de/18089/ and https://edoc.ub.uni- muenchen.de/18089/1/Chronopoulos_Aristeidis.pdf (Persistent Identifier URN: urn:nbn:de:bvb:19-180892). Accessed 15 April 2015.
• 23. Harris M. The conservative management of osteoradionecrosis of the mandible with ultrasound therapy. Br J Oral Maxillofac Surg 1992; 30(5):313-8.
• 24. Jereczek-Fossa BA Orecchia R. Radiotherapy-induced mandibu- lar bone complications. Cancer Treat Rev 2002;28:65-74.
• 25. Nabil S, Samman N. Incidence and prevention of osteoradionecrosis after dental extraction in irradiated patients: a systematic review. Int J Oral Max Surg 2011;40:229-43.
• 26. Chronopoulos A, Zarra T, Ehrenfeld M, Otto S. Osteoradionecrosis of the jaws: definition, epidemiology, staging and clinical and radiological findings. A concise review. Int Dent J 2018;68(1):22-30.
• 27. Nabil S, Samman N. Risk factors for osteoradionecrosis after head and neck radiation: a systematic review. Oral Surg Oral Med Oral Pathol Oral Radiol 2012;113(1):54-69.
• 28. Delanian S, Lefaix JL. The radiation-induced fibroatrophic process: therapeutic perspective via the antioxidant pathway. Radiother Oncol. 2004;73:119-31.
• 29. Delanian S, Porcher R, Balla-Mekias S, Lefaix JL. Randomized,placebo-controlled trial of combined pentoxifylline and tocopherol for regression of superficial radiation-induced fibrosis. J Clin Oncol. 2003;21:2545-50.
• 30. Aviado DM, Porter JM. Pentoxifylline: a new drug for the treatment of intermittent claudication; mechanism of action, pharmacokinetics, clinical efficacy and adverse effects. Pharmacotherapy 1984;4(6):297-307.
• 31. Ersoy B, Aktan B, Kilic K, Sakat MS, Sipal S. The anti-inflammatory effects of erythromycin, clarithromycin, azithromycin and roxithromycin on histamine-induced otitis media with effusion in guinea pigs. J Laryngol Otol 2018;132(7):579-83.
• 32. Wax S, Piecyk M, Maritim B, Anderson P. Geldanamycin inhibits the production of inflammatory cytokines in activated macrophages by reducing the stability and translation of cytokine transcripts. Arthritis Rheum 2003;48(2):541-50.
• 33. Bisht KS, Bradbury CM, Mattson D, Kaushal A, Sowers A, Markovina S, et al. Geldanamycin and 17-allylamino-17-demethoxygeldanamycin potentiate the in vitro and in vivo radiation response of cervical tumor cells via the heat shock protein 90-mediated intracellular signaling and cytotoxicity. Cancer Res 2003;63(24):8984-95.
• 34. Ianaro A, Ialenti A, Maffia P, Sautebin L, Rombolà L, Carnuccio R et al. Anti-inflammatory activity of macrolide antibiotics. Journal of Pharmacology and Experimental Therapeutics, 2000;292(1):156-63.
• 35. Yrjänheikki J, Tikka T, Keinänen R, Goldsteins G, Chan PH, Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci 1999; 96(23): 13496–500.
• 36. Shapira L, Soskolne WA, Houri Y, Barak V, Halabi A, Stabholz A. Protection against endotoxic shock and lipopolysaccharide-induced local inflammation by tetracycline: correlation with inhibition of cytokine secretion. Infect Immun 1996;64(3):825-8.
• 37.Norden CW, Wentzel H, Keleti E. Comparison of techniques for measurement of in vitro antibiotic synergism. J Infect Dis 1979;140(4):629-33
• 38. Curis E, Pestre V, Jullien V, Eyrolle L, Archambeau D, Morand P et al. Pharmacokinetic variability of clindamycin and influence of rifampicin on clindamycin concentration in patients with bone and joint infections. Infection 2015;43(4):473-81.
• 39. Zeller V, Dzeing-Ella A, Kitzis MD, Ziza JM, Mamoudy P, Desplaces N. Continuous clindamycin infusion, an innovative approach to treating bone and joint infections. Antimicrob Agents Chemother. 2010; 54(1): 88–92.
• 40. Taha Ö. Histomorphometric and radiologic evaluation of local alendronate administration on experimental bone defect healing. Thesis in Oral Surgery Ankara: Hacettepe University Institue of Health Science, Ph.D.; 2017.
• 41. Rice N, Polyzois I, Ekanayake K, Omer O, Stassen LF. The management of osteoradionecrosis of the jaws-a review. Surgeon. 2015;13(2):101-9.
• 42. Reuther T, Schuster T, Mende U, Kübler A. Osteoradionecrosis of the jaws as a side effect of radiotherapy of head and neck tumour patients a report of a thirty year retrospective review. Int J Oral Maxillofac Surg. 2003;32(3):289-95.
• 43. Glanzmann C, Grätz KW. Radionecrosis of the mandibula: a retrospective analysis of the incidence and risk factors. Radiother Oncol 1995;36(2):94-100.
• 44. Semrau R, Mueller RP, Stuetzer H, Staar S, Schroeder U, Guntinas-Lichius O et al. Efficacy of intensified hyperfractionated and accelerated radiotherapy and concurrent chemotherapy with carboplatin and 5-fluorouracil: updated results of a randomized multicentric trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2006;64(5):1308-16.
• 45. Donneys A, Nelson NS, Page EE, Deshpande SS, Felice PA, Tchanque–Fossuo CN et al. Targeting angiogenesis as a therapeutic means to reinforce osteocyte survival and prevent nonunions in the aftermath of radiotherapy. Head & neck 2015;37(9):1261-7.
• 46. Batista JD, Zanetta-Barbosa D, Cardoso SV, Dechichi P, Rocha FS, Pagnoncelli RM. Effect of low- level laser therapy on repair of the bone compromised by radiotherapy. Lasers Med Sci. 2014 ;29(6):1913-8.
• 47. Arnold M, Stas P, Kummermehr J, Schultz-Hector S, Trott KR. Radiation-induced impairment of bone healing in the rat femur: Effects of radiation dose, sequence and interval between surgery and irradiation. Radiother Oncol. 1998;48(3):259-65.
• 48. Lerouxel E, Moreau A, Bouler JM, Giumelli B, Daculsi G, Weiss P et al. Effects of high doses of ionising radiation on bone in rats: A new model for evaluation of bone engineering. Br J Oral Maxillofac Surg. 2009;47(8):602-7.
• 49. Grisar K, Schol M, Schoenaers J, Dormaar T, Coropciuc R, Vander Poorten V et al. Osteoradionecrosis and medication related osteonecrosis of the jaw: similarities and differences. Int J Oral Maxillofac Surg. 2016;45(12):1592-9.
• 50. Magremanne M, Picheca S, Reychler H. Etiologic diagnosis of jaw osteonecrosis, other than bisphosphonate and radiotherapy related osteonecrosis. Rev Stomatol Chir Maxillofac Chir Orale 2014;115(1):45-50.
• 51. Buchholz HW, Engelbrecht H. Depot effects of various antibiotics mixed with Palacos resins. Chirurg 1970;41(11):511-5.