Ceren ÖZBEK, Revan Birke KOCA-ÜNSAL, Merva SOLUK TEKKEŞİN, Faruk ÇELİK, Hayriye Arzu ERGEN, Ümit ZEYBEK, Kıvanç BEKTAŞ KAYHAN, Meral ÜNÜR

Histopathological and Serum Biomarkers Analyses in MRONJ due to Periodontal Disease in Rats: Comparison of Zoledronic Acid and Denosumab

Objective: This study aimed to investigate the bisphosphonate and denosumab effects in medication-related osteonecrosis of the jaws (MRONJ) caused by periodontal disease with analyses of serum biomarkers and histopathology. Materials and Methods: Forty Copenhagen rats were used in the study. A ligature wire was wrapped around the first molars to induce periodontal disease. The rats were divided into a zoledronic acid group (ZG) (n=12), a denosumab group (DG) (n=12), a saline group (SG) (n=10), and a control group (CG) (n=6). Prostate cancer was induced by injections for ZG, DG, and SG following the ligature application, and injections were repeated on the 14th and 21st days. While periodontal disease was evaluated clinically with gingival edema, swelling and redness, serum osteocalcin, osteopontin, parathormone and receptor activator of nuclear factor-kappa B ligand (RANKL) levels were evaluated using the LUMINEX technique. The Mann-Whitney U test was used for the comparison of parameters between groups (p<0.05). Results: The osteocalcin levels were increased in CG, RANKL levels were decreased in DG, osteopontin levels were increased in ZG, and parathormone levels were increased in both ZG and CG. Conclusion: Since the long-term use of bisphosphonates can cause osteonecrosis in the jaw bones, it should not be overlooked that this can also be caused by chronic inflammatory conditions such as periodontal disease.

Keywords:

Bisphosphonates, denosumab, osteonecrosis, periodontal diseases, rats,

PDF

___

1. Nazir MA. Prevalence of periodontal disease, its association with systemic diseases and prevention. Int J Health Sci (Qassim) 2017; 11: 72-80. google scholar
2. Listgarten MA. Pathogenesis of periodontitis. J Clin Periodontol 1986; 13: 418-30. [CrossRef] google scholar
3. Sroussi HY, Epstein JB, Bensadoun RJ, Saunders DP, Lalla RJ, Migliorati CA et al. Common oral complications of head and neck cancer radiation therapy: mucositis, infections, saliva change, fibrosis, sensory dysfunctions, dental caries, periodontal disease, and osteoradionecrosis. Cancer Med 2017; 6: 2918-31. [CrossRef] google scholar
4. Kmetec A and Hajdinjak T. Evaluation of safety and analgesic consumption in patients with advanced cancer treated with zoledronic acid. Radiol Oncol 2013; 47: 289-95. [CrossRef] google scholar
5. Wu S, Dahut WL and Gulley JL. The use of bisphosphonates in cancer patients. Acta Oncol 2007; 46: 581-91. [CrossRef] google scholar
6. Mehrotra B. Bisphosphonates--role in cancer therapies. J Oral Maxillofac Surg 2009; 67: 19-26. [CrossRef] google scholar
7. Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc 2008; 83: 103245. [CrossRef] google scholar
8. Hughes DE, Wright KR, Uy HL, Sasaki A, Yoneda T, Roodman GD et al. Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res 1995; 10: 1478-87. [CrossRef] google scholar
9. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003; 61: 1115-7. [CrossRef] google scholar
10. Rustemeyer J and Bremerich A. Bisphosphonate-associated osteonecrosis of the jaw: what do we currently know? A survey of knowledge given in the recent literature. Clin Oral Investig 2010; 14: 59-64. [CrossRef] google scholar
11. Sivolella S, Lumachi F, Stellini E, Favero L. Denosumab and anti-angiogenetic drug-related osteonecrosis of the jaw: an uncommon but potentially severe disease. Anticancer Res 2013; 33: 1793-7. google scholar
12. Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B et al. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw-2014 update. J Oral Maxillofac Surg 2014; 72: 1938-56. [CrossRef] google scholar
13. Delmas PD. Clinical potential of RANKL inhibition for the management of postmenopausal osteoporosis and other metabolic bone diseases. J Clin Densitom 2008; 11: 325-38. [CrossRef] google scholar
14. Yee AJ and Raje NS. Denosumab, a RANK ligand inhibitor, for the management of bone loss in cancer patients. Clin Interv Aging 2012; 7: 331-8. [CrossRef] google scholar
15. Lorenzo-Pouso AI, Perez-Sayans M, Chamorro-Petronacci C, Gandara-Vila P, Lopez-Jornet P, Carballo J et al. Association between periodontitis and medication-related osteonecrosis of the jaw: A systematic review and meta-analysis. J Oral Pathol Med 2020; 49: 190-200. [CrossRef] google scholar
16. Wei R, Wong JPC and Kwok HF. Osteopontin -- a promising biomarker for cancer therapy. J Cancer 2017; 8: 2173-83. [CrossRef] google scholar
17. Mergoni G, Vescovi P, Sala R, Merigo E, Passerini P, Maestri R et al. The effect of laser therapy on the expression of osteocalcin and osteopontin after tooth extraction in rats treated with zoledronate and dexamethasone. Support Care Cancer 2016; 24: 807-13. [CrossRef] google scholar
18. Zhao H, Chen Q, Alam A, Cui J, Suen KC, Soo AP et al. The role of osteopontin in the progression of solid organ tumour. Cell Death Dis 2018; 9: 356. [CrossRef] google scholar
19. Silva BC and Bilezikian JP. Parathyroid hormone: anabolic and catabolic actions on the skeleton. Curr Opin Pharmacol 2015; 22: 41-50. [CrossRef] google scholar
20. Wong SK, Mohamad NV, Giaze TR, Chin KY, Mohamed N, Ima-Nirwana S. Prostate cancer and bone metastases: The underlying mechanisms. Int J Mol Sci 2019; 20(10): 2587. [CrossRef] google scholar
21. Gerstenfeld LC, Sacks DJ, Pelis M, Mason ZD, Graves DT, Barrero M et al. Comparison of effects of the bisphosphonate alendronate versus the RANKL inhibitor denosumab on murine fracture healing. J Bone Miner Res 2009; 24(2): 196-208. [CrossRef] google scholar
22. Erdem MA, Cankaya AB, Isler SC, Demircan S, Soluk M, Kasapoglu C et al. Extraction socket healing in rats treated with bisphosphonate: animal model for bisphosphonate related osteonecrosis of jaws in multiple myeloma patients. Med Oral Patol Oral Cir Bucal 2011;16(7): e879-e883. [CrossRef] google scholar
23. Ozkahraman N,Balcioglu NB,SolukTekkesin M,Altundag Y, Yalcin S. Evaluation of the efficacy of mineralized dentin graft in the treatment of intraosseous defects: An experimental in vivo study. Medicina (Kaunas) 2022; 58(1): 103. [CrossRef] google scholar
24. Lamb DJ and Zhang L. Challenges in prostate cancer research: animal models for nutritional studies of chemoprevention and disease progression. J Nutr 2005; 135: 3009S-3015S. [CrossRef] google scholar
25. Macari S, Duffles LF, Queiroz-Junior CM, Madeira MFM, Dias GJ, Teixeira MM et al. Oestrogen regulates bone resorption and cytokine production in the maxillae of female mice. Arch Oral Biol 2015; 60: 333-41. [CrossRef] google scholar
26. Vieweg J, Rosenthal FM, Bannerji R, Heston WD, Fair WF, Gansbacher B, et al. Immunotherapy of prostate cancer in the Dunning rat model: Use of cytokine gene modified tumor vaccines. Cancer Res 1994; 54: 1760-5. google scholar
27. Halin S, Rudolfsson SH, Van Rooijen N, Bergh A. Extratumoral macrophages promote tumor and vascular growth in an orthotopic rat prostate tumor model. Neoplasia 2009; 11: 177-86. [CrossRef] google scholar
28. Liepe K, Geidel H, Haase M, Hakenberg OW, Runge R, Kotzerke J. New model for the induction of osteoblastic bone metastases in rat. Anticancer Res 2005; 25: 1067-73. google scholar
29. Oz HS and Puleo DA. Animal models for periodontal disease. J Biomed Biotechnol 2011; 2011: 754857. [CrossRef] google scholar
30. de Molon RS, Park CH, Jin Q, Sugai J, Cirelli JA. Characterization of ligature-induced experimental periodontitis. Microsc Res Tech 2018; 81: 1412-21. [CrossRef] google scholar
31. Messer JG, Mendieta Calle JL, Jiron JM, Castillo EJ, Poznak CV, Bhattacharyya N. et al. Zoledronic acid increases the prevalence of medication-related osteonecrosis of the jaw in a dose dependent manner in rice rats (Oryzomys palustris) with localized periodontitis. Bone 2018; 108: 79-88. [CrossRef] google scholar
32. Bhadricha H, Khatkhatay MI and Desai M. Development of an in house ELISA for human intact osteocalcin and its utility in diagnosis and management of osteoporosis. Clin Chim Acta 2019; 489: 117-23. [CrossRef] google scholar
33. Buduneli E, Buduneli N, Vardar-Sengul S, Kardesler L, Atilla G, Lappin D et al. Systemic low-dose doxycycline and alendronate administration and serum interleukin-1beta, osteocalcin, and C-reactive protein levels in rats. J Periodontol 2005; 76: 1927-33. [CrossRef] google scholar
34. Kido J, Nakamura T, Asahara Y, Sawa T, Kohri K, Nagata T. Osteopontin in gingival crevicular fluid. J Periodontal Res 2001; 36: 328-33. [CrossRef] google scholar
35. Nakashima K, Giannopoulou C, Andersen E, Roehrich N, Brochut P, Dubrez B et al. A longitudinal study of various crevicular fluid components as markers of periodontal disease activity. J Clin Periodontol 1996; 23: 832-38. [CrossRef] google scholar
36. Erten Taysi A, Cevher E, Sessevmez M, Olgac V, Taysi NM, Atalay B. The efficacy of sustained-release chitosan microspheres containing recombinant human parathyroid hormone on MRONJ. Braz Oral Res 2019; 33: e086. [CrossRef] google scholar
37. Jilka RL. Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone 2007; 40: 1434-46. [CrossRef] google scholar
38. Stutz C, Batool F, Petit C, Strub M, Buchler-Bopp S, Benkirane-Jessel N et al. Influence of parathyroid hormone on periodontal healing in animal models: A systematic review. Arch Oral Biol 2020; 120: 104932. [CrossRef] google scholar
39. Corrado A, Neve A, Maruotti N, Gaudio A, Marucci A, Cantatore FP. Dose-dependent metabolic effect of zoledronate on primary human osteoblastic cell cultures. Clin Exp Rheumatol 2010; 28: 873-9. [CrossRef] google scholar
40. De Castro J, Garcia R, Garrido P, Isla D, Massuti B, Blanca B et al. Therapeutic potential of denosumab in patients with lung cancer: Beyond prevention of skeletal complications. Clin Lung Cancer 2015; 16: 431-46. [CrossRef] google scholar
41. Altintas A, Saruhan-Direskeneli G, Benbir G, Demir M, Purisa S. The role of osteopontin: a shared pathway in the pathogenesis of multiple sclerosis and osteoporosis? J Neurol Sci 2009; 276: 41-4. [CrossRef] google scholar
42. Liu H, Cui J, Sun J, Du J, Feng W, Sun B et al. Histochemical evidence of zoledronate inhibiting c-src expression and interfering with CD44/OPN-mediated osteoclast adhesion in the tibiae of mice. J Mol Histol 2015; 46: 313-23. [CrossRef] google scholar
43. Ng PY, Ong AJ, Gale LS, Dass CR. Treatment of bone disorders with parathyroid hormone: success and pitfalls. Pharmazie 2016; 71: 427-33. google scholar
44. Leder BZ. Parathyroid hormone and parathyroid hormone-related protein analogs in osteoporosis therapy. Curr Osteoporos Rep 2017; 15: 110-9. [CrossRef] google scholar
45. Curtis RC, Custis JT, Ehrhart NP, Ehrhart EJ, Condon KW, Gookin SE et al. Combination therapy with zoledronic acid and parathyroid hormone improves bone architecture and strength following a clinically-relevant dose of stereotactic radiation therapy for the local treatment of canine osteosarcoma in athymic rats. PLoS One 2016; 11: e0158005. [CrossRef] google scholar