J Korean Assoc Oral Maxillofac Surg.  2020 Aug;46(4):266-274. 10.5125/jkaoms.2020.46.4.266.

The effect of melatonin on prevention of bisphosphonate-related osteonecrosis of the jaw: an animal study in rats

• Yadegari A
• Aminzadeh A
• Seyyedkhamesi S
• Aminian M

• KMID: 2505447
• DOI: http://doi.org/10.5125/jkaoms.2020.46.4.266

Abstract

Objectives
Melatonin induces human stem cells, converts pre-osteoblasts to mature osteoblasts, and reduces the duration of this transition. However, melatonin itself prevents activation of osteoclasts. Here, we evaluate the role of melatonin in prevention of bisphosphonate-related osteonecrosis of the jaw.
Materials and Methods
In this experimental-interventional study, 30 rats were evaluated in 3 groups. The first and second groups received saline and zoledronic acid, respectively, for 4 weeks and the third group received 4 weeks of zoledronic acid and 3 weeks of melatonin simultaneously. Firstright-maxillary-molar extraction was performed for all animals, which were sacrificed after 4 weeks of recovery. The extraction sockets were examined histologically for the presence of osteonecrosis, number of osteoclasts and fibroblasts, severity of inflammation, and vascularization. Data were ana-lyzed by chi-square, one-way ANOVA, Tukey, Kruskal–Wallis and Fisher’s exact statistical tests (α=0.05).
Results
Osteonecrosis was observed in 20%, 90%, and 70% of the first, second and third groups, respectively (p=0.008). The lowest number of osteoclasts and fibroblasts was seen in the third group.
Conclusion
Melatonin may effectively prevent some undesirable side effects of bisphosphonates. However, further studies are required to confirm the results of this study.

Keyword

Bisphosphonate-related osteonecrosis of the jaw; Diphosphonates; Melatonin

Figure

• 

  Fig. 1 Foci of osteonecrosis. Osteocyte-free lacunas are visible (light microscope, ×10; H&E staining).

• 

  Fig. 2 Histopathologic fields (light microscope, ×40; H&E staining). A. Giant cell osteoclasts next to bone. B. Foci of fibroblasts. C. Foci of inflammation. D. Capillaries with engorging red blood cells.

Reference

References

1. Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, et al. American Association of Oral and Maxillofacial Surgeons. 2014; position paper on medication-related osteonecrosis of the jaw--2014 update. J Oral Maxillofac Surg. 72:1938–56. https://doi.org/10.1016/j.joms.2014.04.031 . DOI: 10.1016/j.joms.2014.04.031. PMID: 25234529.

2. Ikebe T. 2013; Pathophysiology of BRONJ: drug-related osteoclastic disease of the jaw. Oral Sci Int. 10:1–8. https://doi.org/10.1016/S1348-8643(12)00045-6 . DOI: 10.1016/S1348-8643(12)00045-6.

3. Kaibuchi N, Iwata T, Yamato M, Okano T, Ando T. 2016; Multipotent mesenchymal stromal cell sheet therapy for bisphosphonate-related osteonecrosis of the jaw in a rat model. Acta Biomater. 42:400–10. https://doi.org/10.1016/j.actbio.2016.06.022 . DOI: 10.1016/j.actbio.2016.06.022. PMID: 27326918.

4. Colella G, Campisi G, Fusco V. 2009; American Association of Oral and Maxillofacial Surgeons position paper: bisphosphonate-related osteonecrosis of the jaws-2009 update: the need to refine the BRONJ definition. J Oral Maxillofac Surg. 67:2698–9. https://doi.org/10.1016/j.joms.2009.07.097 . DOI: 10.1016/j.joms.2009.07.097. PMID: 19925998.

5. Kos M, Kuebler JF, Luczak K, Engelke W. 2010; Bisphosphonate-related osteonecrosis of the jaws: a review of 34 cases and evaluation of risk. J Craniomaxillofac Surg. 38:255–9. https://doi.org/10.1016/j.jcms.2009.06.005 . DOI: 10.1016/j.jcms.2009.06.005. PMID: 19592261.

6. Otto S, Schreyer C, Hafner S, Mast G, Ehrenfeld M, Stürzenbaum S, et al. 2012; Bisphosphonate-related osteonecrosis of the jaws - characteristics, risk factors, clinical features, localization and impact on oncological treatment. J Craniomaxillofac Surg. 40:303–9. https://doi.org/10.1016/j.jcms.2011.05.003 . DOI: 10.1016/j.jcms.2011.05.003. PMID: 21676622.

7. Pichardo SE, van Merkesteyn JP. 2013; Bisphosphonate related osteonecrosis of the jaws: spontaneous or dental origin? Oral Surg Oral Med Oral Pathol Oral Radiol. 116:287–92. https://doi.org/10.1016/j.oooo.2013.05.005 . DOI: 10.1016/j.oooo.2013.05.005. PMID: 23953415.

8. Vaszilko M, Kovacs E, Restar L, Balla B, Cseplo K, Kosa J, et al. 2014; Potential significance of antiestrogen therapy in the development of bisphosphonate related osteonecrosis of the jaw. J Craniomaxillofac Surg. 42:1932–6. https://doi.org/10.1016/j.jcms.2014.08.002 . DOI: 10.1016/j.jcms.2014.08.002. PMID: 25316650.

9. Voss PJ, Joshi Oshero J, Kovalova-Müller A, Veigel Merino EA, Sauerbier S, Al-Jamali J, et al. 2012; Surgical treatment of bisphosphonate-associated osteonecrosis of the jaw: technical report and follow up of 21 patients. J Craniomaxillofac Surg. 40:719–25. https://doi.org/10.1016/j.jcms.2012.01.005 . DOI: 10.1016/j.jcms.2012.01.005. PMID: 22336489.

10. Udell J. Osteonecrosis [Internet]. American College of Rheumatology;Atlanta (GA): Available from: https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Osteonecrosis . cited 2019 Feb 9.

11. Udell J. Osteonecrosis of the jaw [Internet]. American College of Rheumatology;Atlanta (GA): Available from: https://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Osteonecrosis . cited 2019 Feb 9.

12. Keskinruzgar A, Bozdag Z, Aras MH, Demir T, Yolcu U, Cetiner S. 2016; Histopathological effects of teriparatide in medication-related osteonecrosis of the jaw: an animal study. J Oral Maxillofac Surg. 74:68–78. https://doi.org/10.1016/j.joms.2015.07.005 . DOI: 10.1016/j.joms.2015.07.005. PMID: 26215490.

13. Dayisoylu EH, Şenel FÇ, Üngör C, Tosun E, Çankaya M, Ersöz S, et al. 2013; The effects of adjunctive parathyroid hormone injection on bisphosphonate-related osteonecrosis of the jaws: an animal study. Int J Oral Maxillofac Surg. 42:1475–80. https://doi.org/10.1016/j.ijom.2013.05.001 . DOI: 10.1016/j.ijom.2013.05.001. PMID: 23746422.

14. Zandi M, Dehghan A, Mohammadi-Mofrad A, Amini P, Vahdatinia F. 2017; Short-term perioperative teriparatide therapy for the prevention of medication-related osteonecrosis of the jaw: a randomized, controlled preclinical study in rats. J Craniomaxillofac Surg. 45:275–80. https://doi.org/10.1016/j.jcms.2016.12.010 . DOI: 10.1016/j.jcms.2016.12.010. PMID: 28087282.

15. Del Fabbro M, Gallesio G, Mozzati M. 2015; Autologous platelet concentrates for bisphosphonate-related osteonecrosis of the jaw treatment and prevention. A systematic review of the literature. Eur J Cancer. 51:62–74. https://doi.org/10.1016/j.ejca.2014.10.015 . DOI: 10.1016/j.ejca.2014.10.015. PMID: 25466505.

16. Ogata K, Katagiri W, Osugi M, Kawai T, Sugimura Y, Hibi H, et al. 2015; Evaluation of the therapeutic effects of conditioned media from mesenchymal stem cells in a rat bisphosphonate-related osteonecrosis of the jaw-like model. Bone. 74:95–105. https://doi.org/10.1016/j.bone.2015.01.011 . DOI: 10.1016/j.bone.2015.01.011. PMID: 25613174.

17. López-Jornet P, Camacho-Alonso F, Martínez-Canovas A, Molina-Miñano F, Gómez-García F, Vicente-Ortega V. 2011; Perioperative antibiotic regimen in rats treated with pamidronate plus dexamethasone and subjected to dental extraction: a study of the changes in the jaws. J Oral Maxillofac Surg. 69:2488–93. https://doi.org/10.1016/j.joms.2011.02.059 . DOI: 10.1016/j.joms.2011.02.059. PMID: 21798645.

18. Yanık S, Aras MH, Erkılıç S, Bozdağ Z, Demir T, Çetiner S. 2016; Histopathological features of bisphosphonates related osteonecrosis of the jaw in rats with and without vitamin d supplementation. Arch Oral Biol. 65:59–65. https://doi.org/10.1016/j.archoralbio.2015.10.010 . DOI: 10.1016/j.archoralbio.2015.10.010. PMID: 26854621.

19. Koneski F, Popovic-Monevska D, Gjorgoski I, Krajoska J, Popovska M, Muratovska I, et al. 2018; In vivo effects of geranylgeraniol on the development of bisphosphonate-related osteonecrosis of the jaws. J Craniomaxillofac Surg. 46:230–6. https://doi.org/10.1016/j.jcms.2017.11.007 . DOI: 10.1016/j.jcms.2017.11.007. PMID: 29233701.

20. Najeeb S, Khurshid Z, Zohaib S, Zafar MS. 2016; Therapeutic potential of melatonin in oral medicine and periodontology. Kaohsiung J Med Sci. 32:391–6. https://doi.org/10.1016/j.kjms.2016.06.005 . DOI: 10.1016/j.kjms.2016.06.005. PMID: 27523451.

21. Carpentieri AR, Peralta Lopez ME, Aguilar J, Solá VM. 2017; Melatonin and periodontal tissues: molecular and clinical perspectives. Pharmacol Res. 125(Pt B):224–31. https://doi.org/10.1016/j.phrs.2017.09.003 . DOI: 10.1016/j.phrs.2017.09.003. PMID: 28918172.

22. Gómez-Florit M, Ramis JM, Monjo M. 2013; Anti-fibrotic and anti-inflammatory properties of melatonin on human gingival fibroblasts in vitro. Biochem Pharmacol. 86:1784–90. https://doi.org/10.1016/j.bcp.2013.10.009 . DOI: 10.1016/j.bcp.2013.10.009. PMID: 24144630.

23. Ramírez-Fernández MP, Calvo-Guirado JL, de-Val JE, Delgado-Ruiz RA, Negri B, Pardo-Zamora G, et al. 2013; Melatonin promotes angiogenesis during repair of bone defects: a radiological and histomorphometric study in rabbit tibiae. Clin Oral Investig. 17:147–58. https://doi.org/10.1007/s00784-012-0684-6 . DOI: 10.1007/s00784-012-0684-6. PMID: 22323056.

24. Soybir G, Topuzlu C, Odabaş O, Dolay K, Bilir A, Köksoy F. 2003; The effects of melatonin on angiogenesis and wound healing. Surg Today. 33:896–901. https://doi.org/10.1007/s00595-003-2621-3 . DOI: 10.1007/s00595-003-2621-3. PMID: 14669079.

25. Nakamura E, Kozaki K, Tsuda H, Suzuki E, Pimkhaokham A, Yamamoto G, et al. 2008; Frequent silencing of a putative tumor suppressor gene melatonin receptor 1 A (MTNR1A) in oral squamous-cell carcinoma. Cancer Sci. 99:1390–400. https://doi.org/10.1111/j.1349-7006.2008.00838.x . DOI: 10.1111/j.1349-7006.2008.00838.x. PMID: 18452558.

26. Cutando A, Arana C, Gómez-Moreno G, Escames G, López A, Ferrera MJ, et al. 2007; Local application of melatonin into alveolar sockets of beagle dogs reduces tooth removal-induced oxidative stress. J Periodontol. 78:576–83. https://doi.org/10.1902/jop.2007.060244 . DOI: 10.1902/jop.2007.060244. PMID: 17335383.

27. Barba-Recreo P, Del Castillo Pardo de Vera JL, García-Arranz M, Yébenes L, Burgueño M. 2014; Zoledronic acid - related osteonecrosis of the jaws. Experimental model with dental extractions in rats. J Craniomaxillofac Surg. 42:744–50. https://doi.org/10.1016/j.jcms.2013.11.005 . DOI: 10.1016/j.jcms.2013.11.005. PMID: 24342733.

28. Zandi M, Dehghan A, Malekzadeh H, Janbaz P, Ghadermazi K, Amini P. 2016; Introducing a protocol to create bisphosphonate-related osteonecrosis of the jaw in rat animal model. J Craniomaxillofac Surg. 44:271–8. https://doi.org/10.1016/j.jcms.2015.12.010 . DOI: 10.1016/j.jcms.2015.12.010. PMID: 26805920.

29. Wayama MT, Yoshimura H, Ohba S, Yoshida H, Matsuda S, Kobayashi J, et al. 2015; Diminished progression of periapical lesions with zoledronic acid in ovariectomized rats. J Endod. 41:2002–7. https://doi.org/10.1016/j.joen.2015.08.029 . DOI: 10.1016/j.joen.2015.08.029. PMID: 26490005.

30. Jabbour Z, do Nascimento C, El-Hakim M, Henderson JE, de Albuquerque Junior RF. 2016; Bacterial profile and bone healing in rats receiving cancer therapeutic doses of bisphosphonates and corticosteroids: a pilot study. Int J Oral Maxillofac Surg. 45:1162–9. https://doi.org/10.1016/j.ijom.2015.12.017 . DOI: 10.1016/j.ijom.2015.12.017. PMID: 26780925.

31. Cutando A, Aneiros-Fernández J, López-Valverde A, Arias-Santiago S, Aneiros-Cachaza J, Reiter RJ. 2011; A new perspective in oral health: potential importance and actions of melatonin receptors MT1, MT2, MT3, and RZR/ROR in the oral cavity. Arch Oral Biol. 56:944–50. https://doi.org/10.1016/j.archoralbio.2011.03.004 . DOI: 10.1016/j.archoralbio.2011.03.004. PMID: 21459362.

32. Kara A, Akman S, Ozkanlar S, Tozoglu U, Kalkan Y, Canakci CF, et al. 2013; Immune modulatory and antioxidant effects of melatonin in experimental periodontitis in rats. Free Radic Biol Med. 55:21–6. https://doi.org/10.1016/j.freeradbiomed.2012.11.002 . DOI: 10.1016/j.freeradbiomed.2012.11.002. PMID: 23146767.

33. Reiter RJ, Rosales-Corral SA, Liu XY, Acuna-Castroviejo D, Escames G, Tan DX. 2015; Melatonin in the oral cavity: physiological and pathological implications. J Periodontal Res. 50:9–17. https://doi.org/10.1111/jre.12176 . DOI: 10.1111/jre.12176. PMID: 24665831.

34. Arabacı T, Kermen E, Özkanlar S, Köse O, Kara A, Kızıldağ A, et al. 2015; Therapeutic effects of melatonin on alveolar bone resorption after experimental periodontitis in rats: a biochemical and immunohistochemical study. J Periodontol. 86:874–81. https://doi.org/10.1902/jop.2015.140599 . DOI: 10.1902/jop.2015.140599. PMID: 25812911.

35. Ruggierro SL. Fonseca RJ, editor. 2018. Diagnostic and management of medication-related osteonecrosis of the jaw. Oral and maxillofacial surgery. 3rd ed. Elsevier;St. Louis: p. 507–22.