MRONJ with Current Diagnostic and Treatment Approaches

Abstract

ABSTRACT Osteonecrosis of the jaw bones is a persistent and rare pathology that develops with progressive bone destruction and bone necrosis as a result of impaired blood supply in the mandible and maxilla. The key point to the prevention and treatment of MRONJ is screening high-risk patients (eg, AAOMS stage 0) predisposed to the disease to detect it at an early stage to effectively prevent the risk of progression and occurrence. Although no exposed bone is seen in clinical examination, osteonecrosis can be diagnosed early by radiographic examination. Therefore, advanced imaging techniques such as MR, SPECT/PET and VELscope are important in the early diagnosis of MRONJ. There is no defined gold standard treatment in the literature and the treatment of MRONJ is often very difficult. Treatment strategies are mainly focused on minimizing the progression or formation of bone necrosis, eliminating pain, controlling infection and optimizing the patient's quality of life. The AAOMS recommends stage-based treatment planning in MRONJ patients. In addition to the treatment methods recommended by the AAOMS, there are research showing that some adjuvant treatments have a positive effect on recovery in MRONJ patients. For example, the use of platelet-rich plasma/fibrin in addition to surgical treatment increasing the success of surgery is one of them. Alternative treatment options are low-level laser therapy, surgical debridement with laser, surgical debridement under the guidance of fluorescent staining method, use of platelet concentrates, ozone and hyperbaric oxygen therapy, pentoxifylline, alpha-tocopherol, photo-bio modulation, use of parathormone or stem cell transplantation into the lesion. In this review, we aimed to update the knowledge, attitudes and behaviors of dentists about MRONJ and to shape the approach to MRONJ with the guidance of current literature.

Keywords

• Medication-related osteonecrosis of the jaw
• diagnosis
• treatment
• İlaca bağlı çene kemiği osteonekrozu
• teşhis
• tedavi

Güncel Tanı ve Tedavi Yaklaşımlarıyla MRONJ

Öz

Çene kemiklerinin osteonekrozu, mandibula ve maksillada kanlanmanın bozulması sonucu ilerleyici kemik yıkımı ve kemik nekrozu ile gelişen, inatçı ve nadir bir patolojidir. MRONJ'un önlenmesi ve tedavisinin anahtarı, hastalığa yatkın olan yüksek riskli hastaları (örn. AAOMS evre 0) tarayarak ilerleme riskini ve oluşumunu etkili bir şekilde engellemek için erken aşamada saptanmasıdır. Klinik muayenede ekspoze kemik görülmediği halde radyografik inceleme ile osteonekroz erken teşhis edilebilir. Bundan dolayı MR, SPECT/PET, VELscope gibi ileri düzey görüntüleme teknikleri MRONJ’un erken teşhisinde önem taşımaktadır. Tedavi stratejileri esas olarak kemik nekrozunun oluşumunu veya ilerlemesini en aza indirmeye, ağrıyı ortadan kaldırmaya, enfeksiyonu kontrol etmeye ve hastanın yaşam kalitesini optimize etmeye odaklanmıştır. AAOMS, MRONJ hastalarında evreye bağlı tedavi uygulamasını önermektedir. AAOMS’un önerdiği tedavi yöntemlerine ek olarak bazı yardımcı tedavilerin de iyileşmeyi olumlu etkilediğine dair araştırmalar mevcuttur. Bu derlemenin amacı diş hekimlerinin MRONJ konusunda bilgi, tutum ve davranışlarının güncellenmesi ve MRONJ’a yaklaşımın güncel literatür rehberliğinde şekillendirilmesidir.

Anahtar Kelimeler

• İlaca bağlı çene kemiği osteonekrozu
• teşhis
• tedavi

Kaynakça

1. 1. Russell RGG. Bisphosphonates: the first 40 years. Bone. 2011; 49(1):2-19.
2. 2. Aslan Ö, Vural H, Kömürcü Ş, Özet A. Kemoterapi alan kanser hastalarina verilen eğitimin kemoterapi semptomlarina etkisi. CÜ Hemsirelik Yüksekokulu Dergisi. 2006; 10(1):15-28.
3. 3. Ribeiro GH, Chrun ES, Dutra KL, Daniel FI, Grando LJ. Osteonecrosis of the jaws: a review and update in etiology and treatment. Braz J Otorhinolaryngol. 2017; 84(1):102–8.
4. 4. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003; 61(9):1115-7.
5. 5. Santos-Silva AR, Belizário Rosa GA, Castro Júnior Gd, Dias RB, Prado Ribeiro AC, Brandão TB. Osteonecrosis of the mandible associated with bevacizumab therapy. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013; 115(6):32-6.
6. 6. Ramírez L, López-Pintor RM, Casañas E, Arriba Ld, Hernández G. New Non-Bisphosphonate Drugs that Produce Osteonecrosis of the Jaws. Oral Health Prev Dent. 2015;13(5):385-93.
7. 7. Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, O'Ryan F; American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update. J Oral Maxillofac Surg. 2014; 72(10):1938-56.
8. 8. Ruggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B; American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws--2009 update. J Oral Maxillofac Surg. 2009; 67(5 Suppl):2-12.

9. 9. Bozdemir E, Yılmaztürk SS. İlaç Kullanımına Bağlı Çene Kemiklerinin Osteonekrozunun Ortaya Çıkmasında Rol Oynayan Risk Faktörleri ve Klinik, Radyografik Özellikleri. Dental and Medical Journal-Review 2020; 2(3): 95-110.
10. 10. Crépin S, Laroche ML, Sarry B, Merle L. Osteonecrosis of the jaw induced by clodronate, an alkylbiphosphonate: case report and literature review. Eur J Clin Pharmacol. 2010; 66(6):547-54.
11. 11. Otto S, Hafner S, Mast G, Tischer T, Volkmer E, Schieker M, Stürzenbaum SR, von Tresckow E, Kolk A, Ehrenfeld M, Pautke C. Bisphosphonate-related osteonecrosis of the jaw: is pH the missing part in the pathogenesis puzzle?. J Oral Maxillofac Surg. 2010; 68(5):1158-61.
12. 12. Yoneda T, Hagino H, Sugimoto T, Ohta H, Takahashi S, Soen S, Taguchi A, Nagata T, Urade M, Shibahara T, Toyosawa S. Antiresorptive agent-related osteonecrosis of the jaw: Position Paper 2017 of the Japanese Allied Committee on Osteonecrosis of the Jaw. J Bone Miner Metab. 2017; 35(1):6-19.
13. 13. Otto S, Schreyer C, Hafner S, Mast G, Ehrenfeld M, Stürzenbaum S, Pautke C. Bisphosphonate-related osteonecrosis of the jaws - characteristics, risk factors, clinical features, localization and impact on oncological treatment. J Craniomaxillofac Surg. 2012; 40(4):303-9.
14. 14. Thumbigere-Math V, Ma'Ann CS, Gopalakrishnan R, Huckabay S, Dudek AZ, Basu S, Basi DL. Bisphosphonate-related osteonecrosis of the jaw: clinical features, risk factors, management and treatment outcomes of 26 patients. J Oral Maxillofac Surg. 2009; 67(9):1904-13.
15. 15. Yapijakis C, Papakosta V, Vassiliou S. ACE Gene Variant Causing High Blood Pressure May Be Associated With Medication-related Jaw Osteonecrosis. In Vivo. 2019; 33(2):559-562.
16. 16. Otto S, Marx RE, Tröltzsch M, Ristow O, Ziebart T, Al‐Nawas B, Fedele S. Comments on “diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus”. J Bone Miner Res. 2015; 30(6):1113-15.
17. 17. Vercruysse H Jr, Backer TD, Mommaerts MY. Outcomes of osseous free flap reconstruction in stage III bisphosphonate-related osteonecrosis of the jaw: systematic review and a new case series. J Craniomaxillofac Surg. 2014; 42(5):377-86.
18. 18. Vescovi P, Manfredi M, Merigo E, Meleti M, Fornaini C, Rocca JP, Nammour S. Surgical approach with Er:YAG laser on osteonecrosis of the jaws (ONJ) in patients under bisphosphonate therapy (BPT). Lasers Med Sci. 2010; 25(1):101-13.
19. 19. Stockmann P, Hinkmann FM, Lell MM, Fenner M, Vairaktaris E, Neukam FW, Nkenke E. 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. 2010; 14(3):311-7.
20. 20. Ertaş ET, Atıcı MY. Bifosfonatlar ve çene kemiğinde görülen osteonekroz. Selcuk Dental Journal 2015; 2(2):91-101.
21. 21. Schiffman E, Ohrbach R, Truelove E, Look J, Anderson G, Goulet JP, List T, Svensson P, Gonzalez Y, Lobbezoo F, Michelotti A, Brooks SL, Ceusters W, Drangsholt M, Ettlin D, Gaul C, Goldberg LJ, Haythornthwaite JA, Hollender L, Jensen R, John MT, De Laat A, de Leeuw R, Maixner W, van der Meulen M, Murray GM, Nixdorf DR, Palla S, Petersson A, Pionchon P, Smith B, Visscher CM, Zakrzewska J, Dworkin SF; International RDC/TMD Consortium Network, International association for Dental Research; Orofacial Pain Special Interest Group, International Association for the Study of Pain. Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) for Clinical and Research Applications: recommendations of the International RDC/TMD Consortium Network* and Orofacial Pain Special Interest Group†. J Oral Facial Pain Headache. 2014; 28(1):6-27.
22. 22. Wongratwanich P, Shimabukuro K, Konishi M, Nagasaki T, Ohtsuka M, Suei Y, Nakamoto T, Verdonschot RG, Kanesaki T, Sutthiprapaporn P, Kakimoto N. Do various imaging modalities provide potential early detection and diagnosis of medication-related osteonecrosis of the jaw? A review. Dentomaxillofac Radiol. 2021; 50(6):20200417.
23. 23. Khan AA, Morrison A, Hanley DA, Felsenberg D, McCauley LK, O'Ryan F, Reid IR, Ruggiero SL, Taguchi A, Tetradis S, Watts NB, Brandi ML, Peters E, Guise T, Eastell R, Cheung AM, Morin SN, Masri B, Cooper C, Morgan SL, Obermayer-Pietsch B, Langdahl BL, Al Dabagh R, Davison KS, Kendler DL, Sándor GK, Josse RG, Bhandari M, El Rabbany M, Pierroz DD, Sulimani R, Saunders DP, Brown JP, Compston J; International Task Force on Osteonecrosis of the Jaw. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res. 2015; 30(1):3-23.
24. 24. Kubo R, Ariji Y, Taniguchi T, Nozawa M, Katsumata A, Ariji E. Panoramic radiographic features that predict the development of bisphosphonate-related osteonecrosis of the jaw. Oral Radiol. 2018; 34(2):151-160.
25. 25. Bianchi SD, Scoletta M, Cassione FB, Migliaretti G, Mozzati M. Computerized tomographic findings in bisphosphonate-associated osteonecrosis of the jaw in patients with cancer. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007; 104(2):249-58.
26. 26. Bedogni A, Saia G, Ragazzo M, Bettini G, Capelli P, D'Alessandro E, Nocini PF, Lo Russo L, Lo Muzio L, Blandamura S. Bisphosphonate-associated osteonecrosis can hide jaw metastases. Bone. 2007; 41(6):942-5.
27. 27. Leite AF, Ogata Fdos S, de Melo NS, Figueiredo PT. Imaging findings of bisphosphonate-related osteonecrosis of the jaws: a critical review of the quantitative studies. Int J Dent. 2014;784348.
28. 28. Ariji Y, Izumi M, Gotoh M, Naitoh M, Katoh M, Kuroiwa Y, Obayashi N, Kurita K, Shimozato K, Ariji E. MRI features of mandibular osteomyelitis: practical criteria based on an association with conventional radiography features and clinical classification. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008; 105(4):503-11.
29. 29. Ueno S, Gamoh S, Akiyama H, Tsuji K, Morita S. Image-based differentiation of osteomyelitis, especially between osteoradionecrosis and medication-related osteonecrosis of the jaw. Journal of Osaka Dental University 2018; 52(1):31-35.
30. 30. Bisdas S, Chambron Pinho N, Smolarz A, Sader R, Vogl TJ, Mack MG. Biphosphonate-induced osteonecrosis of the jaws: CT and MRI spectrum of findings in 32 patients. Clin Radiol. 2008; 63(1):71-7.
31. 31. García-Ferrer L, Bagán JV, Martínez-Sanjuan V, Hernandez-Bazan S, García R, Jiménez-Soriano Y, Hervas V. MRI of mandibular osteonecrosis secondary to bisphosphonates. AJR Am J Roentgenol. 2008; 190(4):949-55.
32. 32. Berg BI, Mueller AA, Augello M, Berg S, Jaquiéry C. Imaging in Patients with Bisphosphonate-Associated Osteonecrosis of the Jaws (MRONJ). Dentistry Journal. 2016; 4(3):29.
33. 33. Vandone AM, Donadio M, Mozzati M, Ardine M, Polimeni MA, Beatrice S, Ciuffreda L, Scoletta M. Impact of dental care in the prevention of bisphosphonate-associated osteonecrosis of the jaw: a single-center clinical experience. Ann Oncol. 2012; 23(1):193-200.
34. 34. Dore F, Filippi L, Biasotto M, Chiandussi S, Cavalli F, Di Lenarda R. Bone scintigraphy and SPECT/CT of bisphosphonate-induced osteonecrosis of the jaw. J Nucl Med. 2009; 50(1):30-5.
35. 35. Chiandussi S, Biasotto M, Dore F, Cavalli F, Cova MA, Di Lenarda R. Clinical and diagnostic imaging of bisphosphonate-associated osteonecrosis of the jaws. Dentomaxillofac Radiol. 2006; 35(4):236-43.
36. 36. Baba A, Ojiri H, Ikeda K, Yamauchi H, Ogino N, Seto Y, Kobashi Y, Yamazoe S, Mogami T. Essentials on Oncological Imaging: Postoperative Computed Tomography and Magnetic Resonance Imaging of Oral Tongue Cancer. Can Assoc Radiol J. 2018; 69(4):458-467.
37. 37. Wilde F, Steinhoff K, Frerich B, Schulz T, Winter K, Hemprich A, Sabri O, Kluge R. Positron-emission tomography imaging in the diagnosis of bisphosphonate-related osteonecrosis of the jaw. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009; 107(3):412-9.
38. 38. Miyashita H, Shiba H, Kawana H, Nakahara T. Clinical utility of three-dimensional SPECT/CT imaging as a guide for the resection of medication-related osteonecrosis of the jaw. Int J Oral Maxillofac Surg. 2015; 44(9):1106-9.
39. 39. Popovic KS, Kocar M. Imaging findings in bisphosphonate-induced osteonecrosis of the jaws. Radiol Oncol. 2010; 44(4):215-9.
40. 40. Hutchinson M, O'Ryan F, Chavez V, Lathon PV, Sanchez G, Hatcher DC, Indresano AT, Lo JC. Radiographic findings in bisphosphonate-treated patients with stage 0 disease in the absence of bone exposure. J Oral Maxillofac Surg. 2010; 68(9):2232-40.
41. 41. Yarom N, Shapiro CL, Peterson DE, Van Poznak CH, Bohlke K, Ruggiero SL, Migliorati CA, Khan A, Morrison A, Anderson H, Murphy BA, Alston-Johnson D, Mendes RA, Beadle BM, Jensen SB, Saunders DP. Medication-Related Osteonecrosis of the Jaw: MASCC/ISOO/ASCO Clinical Practice Guideline. J Clin Oncol. 2019; 37(25):2270-90.
42. 42. Sim IW, Sanders KM, Borromeo GL, Seymour JF, Ebeling PR. Declining Incidence of Medication-Related Osteonecrosis of the Jaw in Patients With Cancer. J Clin Endocrinol Metab. 2015; 100(10):3887-93.
43. 43. Hong CHL, Hu S, Haverman T, Stokman M, Napeñas JJ, Braber JB, Gerber E, Geuke M, Vardas E, Waltimo T, Jensen SB, Saunders DP. A systematic review of dental disease management in cancer patients. Support Care Cancer. 2018; 26(1):155-174.
44. 44. Rabelo GD, Assunção JNR, Chavassieux P, Soares HA, Alves FA, Lemos CA. Bisphosphonate-related osteonecrosis of the jaws and its array of manifestations. J. Maxillofac. Oral Surg. 2015; 14(3):699-705.
45. 45. Ferlito S, Puzzo S, Palermo F, Verzì P. Treatment of bisphosphonate-related osteonecrosis of the jaws: presentation of a protocol and an observational longitudinal study of an Italian series of cases. Br J Oral Maxillofac Surg. 2012; 50(5):425-9.
46. 46. Damm DD, Jones DM. Bisphosphonate-related osteonecrosis of the jaws: a potential alternative to drug holidays. Gen Dent. 2013; 61(5):33-8.
47. 47. Matsui A, Kurihara J, Morishima H, Suzuki H, Sato S, Yamauchi K, Takahashi T. Medication related osteonecrosis of the jaw (MRONJ): a retrospective survey of a series of patients treated according to the AAOMS guidelines. Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology 2015; 27(6):757-63.
48. 48. Rosella D, Papi P, Giardino R, Cicalini E, Piccoli L, Pompa G. Medication-related osteonecrosis of the jaw: Clinical and practical guidelines. J Int Soc Prev Community Dent. 2016; 6(2):97-104.
49. 49. Pimolbutr K, Porter S, Fedele S. Osteonecrosis of the Jaw Associated with Antiangiogenics in Antiresorptive-Naïve Patient: A Comprehensive Review of the Literature. Biomed Res Int. 2018; 23:2018:8071579
50. 50. Ristow O, Rückschloß T, Müller M, Berger M, Kargus S, Pautke C, Engel M, Hoffmann J, Freudlsperger C. Is the conservative non-surgical management of medication-related osteonecrosis of the jaw an appropriate treatment option for early stages? A long-term single-center cohort study. J Craniomaxillofac Surg. 2019; 47(3):491-499.
51. 51. Bermúdez-Bejarano EB, Serrera-Figallo MÁ, Gutiérrez-Corrales A, Romero-Ruiz MM, Castillo-de-Oyagüe R, Gutiérrez-Pérez JL, Torres-Lagares D. Prophylaxis and antibiotic therapy in management protocols of patients treated with oral and intravenous bisphosphonates. J Clin Exp Dent. 2017; 9(1):141-9.
52. 52. Lorenzo SD, Trapassi A, Corradino B, Cordova A. Histology of the Oral Mucosa in Patients With BRONJ at III Stage: A Microscopic Study Proves the Unsuitability of Local Mucosal Flaps. J Clin Med Res. 2013; 5(1):22-5.
53. 53. Otto S, Baumann S, Ehrenfeld M, Pautke C. Successful surgical management of osteonecrosis of the jaw due to RANK-ligand inhibitor treatment using fluorescence guided bone resection. J Craniomaxillofac Surg. 2013; 41(7):694-8.
54. 54. Pichardo SE, Kuijpers SC, van Merkesteyn JP. Bisphosphonate-related osteonecrosis of the jaws: Cohort study of surgical treatment results in seventy-four stage II/III patients. J Craniomaxillofac Surg. 2016; 44(9):1216-20.
55. 55. Cella L, Oppici A, Arbasi M, Moretto M, Piepoli M, Vallisa D, Zangrandi A, Di Nunzio C, Cavanna L. Autologous bone marrow stem cell intralesional transplantation repairing bisphosphonate related osteonecrosis of the jaw. Head Face Med. 2011; 17(7):1-6.
56. 56. Fliefel R, Tröltzsch M, Kühnisch J, Ehrenfeld M, Otto S. Treatment strategies and outcomes of bisphosphonate-related osteonecrosis of the jaw (BRONJ) with characterization of patients: a systematic review. Int J Oral Maxillofac Surg. 2015; 44(5):568-85.
57. 57. Ripamonti CI, Cislaghi E, Mariani L, Maniezzo M. Efficacy and safety of medical ozone (O(3)) delivered in oil suspension applications for the treatment of osteonecrosis of the jaw in patients with bone metastases treated with bisphosphonates: Preliminary results of a phase I-II study. Oral Oncol. 2011; 47(3):185-90.
58. 58. Freiberger JJ, Padilla-Burgos R, McGraw T, Suliman HB, Kraft KH, Stolp BW, Moon RE, Piantadosi CA. What is the role of hyperbaric oxygen in the management of bisphosphonate-related osteonecrosis of the jaw: a randomized controlled trial of hyperbaric oxygen as an adjunct to surgery and antibiotics. J Oral Maxillofac Surg. 2012; 70(7):1573-83.
59. 59. Atalay B, Yalcin S, Emes Y, Aktas I, Aybar B, Issever H, Mandel NM, Cetin O, Oncu B. Bisphosphonate-related osteonecrosis: laser-assisted surgical treatment or conventional surgery? Lasers Med Sci. 2011; 26(6):815-23.
60. 60. Epstein MS, Wicknick FW, Epstein JB, Berenson JR, Gorsky M. Management of bisphosphonate-associated osteonecrosis: pentoxifylline and tocopherol in addition to antimicrobial therapy. An initial case series. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010; 110(5):593-6.
61. 61. Da Silva JP, Da Silva MA, Almeida AP, Lombardi Junior I, Matos AP. Laser therapy in the tissue repair process: a literature review. Photomed Laser Surg. 2010; 28(1):17-21.
62. 62. Martins MA, Martins MD, Lascala CA, Curi MM, Migliorati CA, Tenis CA, Marques MM. Association of laser phototherapy with PRP improves healing of bisphosphonate-related osteonecrosis of the jaws in cancer patients: a preliminary study. Oral Oncol. 2012; 48(1):79-84.
63. 63. Cipriani C, Irani D, Bilezikian JP. Safety of osteoanabolic therapy: a decade of experience. J Bone Miner Res. 2013; 28(2):431.
64. 64. Bashutski JD, Eber RM, Kinney JS, Benavides E, Maitra S, Braun TM, Giannobile WV, McCauley LK. Teriparatide and osseous regeneration in the oral cavity. N Engl J Med. 2010; 363(25):2396-405.
65. 65. Di Ianni M, Del Papa B, De Ioanni M, Moretti L, Bonifacio E, Cecchini D, Sportoletti P, Falzetti F, Tabilio A. Mesenchymal cells recruit and regulate T regulatory cells. Exp Hematol. 2008; 36(3):309-18.
66. 66. Kikuiri T, Kim I, Yamaza T, Akiyama K, Zhang Q, Li Y, Chen C, Chen W, Wang S, Le AD, Shi S. Cell-based immunotherapy with mesenchymal stem cells cures bisphosphonate-related osteonecrosis of the jaw-like disease in mice. J Bone Miner Res. 2010; 25(7):1668-79.
67. 67. Campisi G, Mauceri R, Bertoldo F, Bettini G, Biasotto M, Colella G, Consolo U, Di Fede O, Favia G, Fusco V, Gabriele M, Lo Casto A, Lo Muzio L, Marcianò A, Mascitti M, Meleti M, Mignogna MD, Oteri G, Panzarella V, Romeo U, Santarelli A, Vescovi P, Marchetti C, Bedogni A. Medication-Related Osteonecrosis of Jaws (MRONJ) Prevention and Diagnosis: Italian Consensus Update 2020. Int J Environ Res Public Health. 2020; 17(16):5998.
68. 68. Nowicki B, Nehrbass D, Arens D, Stadelmann VA, Zeiter S, Otto S, Kircher P, Stoddart MJ. Medication-related osteonecrosis of the jaw in a minipig model: Parameters for developing a macroscopic, radiological, and microscopic grading scheme. J Craniomaxillofac Surg. 2019; 47(7):1162-9.
69. 69. Moretti F, Pelliccioni GA, Montebugnoli L, Marchetti C. A prospective clinical trial for assessing the efficacy of a minimally invasive protocol in patients with bisphosphonate-associated osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011; 112(6):777-82.
70. 70. Fortunato L, Bennardo F, Buffone C, Giudice A. Is the application of platelet concentrates effective in the prevention and treatment of medication-related osteonecrosis of the jaw? A systematic review. J Craniomaxillofac Surg. 2020; 48(3):268-285.