Bisphosphonate and Medication-Related Osteonecrosis of the Jaw: A Review

Abstract

For patients with malignant disease taking bisphosphonates and denosumab, the incidence of medication-related osteonecrosis of the jaw (MRONJ) is up to 15% in contrast to 0.01% in patients with osteoporosis. Clinical presentation of MRONJ extends from asymptomatic exposure of bone in 94% of patients to severe cases of mandibular fractures in a minority of 4.5%. The strongest risk factors for MRONJ are invasive dental procedures and dental infections. Advances in imaging provide more preoperation information compared with panoramic radiograph. Prevention strategies are the elimination of potential risk factors leading to invasive dental procedures and maintenance of good oral hygiene prior to the administration of antiresorptive agents. Management of MRONJ depends on the underlying disease, extent of the necrosis, and the presence of contributing therapy. Conservative therapies include topical anti-infective rinses and systemic antibiotic therapy. The most important part of surgical therapy is to remove the exposed and necrotic bone. Several options for defect closure are possible from local tissue flaps to microvascular free flap procedures. The development of MRONJ in conjunction with dental implants is a severe side effect and should be avoided if potentially harmful medication has already been administered.

Keywords

osteonecrosis of the jaw - bisphosphonates - denosumab - osteoporosis - computed tomography - magnetic resonance imaging - dental radiographs

• References

• 1 Migliorati CA. Bisphosphanates and oral cavity avascular bone necrosis. J Clin Oncol 2003; 21 (22) 4253-4254
• 2 Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003; 61 (9) 1115-1117
• 3 Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004; 62 (5) 527-534
• 4 Aghaloo TL, Felsenfeld AL, Tetradis S. Osteonecrosis of the jaw in a patient on denosumab. J Oral Maxillofac Surg 2010; 68 (5) 959-963
• 5 Stopeck AT, Lipton A, Body JJ , et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 2010; 28 (35) 5132-5139
• 6 Fusco V, Galassi C, Berruti A , et al. Osteonecrosis of the jaw after zoledronic acid and denosumab treatment. J Clin Oncol 2011; 29 (17) e521-e522 ; author reply e523–e524
• 7 Henry DH, Costa L, Goldwasser F , et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 2011; 29 (9) 1125-1132
• 8 Holzinger D, Seemann R, Matoni N, Ewers R, Millesi W, Wutzl A. Effect of dental implants on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2014; 72 (10) 1937
• 9 Ruggiero SL, Dodson TB, Fantasia J , et al; 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) 1938-1956
• 10 Bedogni A, Saia G, Ragazzo M , et al. Bisphosphonate-associated osteonecrosis can hide jaw metastases. Bone 2007; 41 (6) 942-945
• 11 Weinstein RS, Roberson PK, Manolagas SC. Giant osteoclast formation and long-term oral bisphosphonate therapy. N Engl J Med 2009; 360 (1) 53-62
• 12 Hansen T, Kunkel M, Weber A, James Kirkpatrick C. Osteonecrosis of the jaws in patients treated with bisphosphonates—histomorphologic analysis in comparison with infected osteoradionecrosis. J Oral Pathol Med 2006; 35 (3) 155-160
• 13 Thumbigere-Math V, Sabino MC, Gopalakrishnan R , et al. Bisphosphonate-related osteonecrosis of the jaw: clinical features, risk factors, management, and treatment outcomes of 26 patients. J Oral Maxillofac Surg 2009; 67 (9) 1904-1913
• 14 Mücke T, Jung M, Mitchell DA , et al. Are infective blood measurements predictors of recurrence in patients with bisphosphonate-related osteonecrosis of the jaws?. Br J Oral Maxillofac Surg 2016;
• 15 Ali SM, Esteva FJ, Hortobagyi G , et al. Safety and efficacy of bisphosphonates beyond 24 months in cancer patients. J Clin Oncol 2001; 19 (14) 3434-3437
• 16 Bagan JV, Murillo J, Jimenez Y , et al. Avascular jaw osteonecrosis in association with cancer chemotherapy: series of 10 cases. J Oral Pathol Med 2005; 34 (2) 120-123
• 17 Fournier P, Boissier S, Filleur S , et al. Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 2002; 62 (22) 6538-6544
• 18 Abu-Id MH, Warnke PH, Gottschalk J , et al. “Bis-phossy jaws”—high and low risk factors for bisphosphonate-induced osteonecrosis of the jaw. J Craniomaxillofac Surg 2008; 36 (2) 95-103
• 19 Bamias A, Kastritis E, Bamia C , et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol 2005; 23 (34) 8580-8587
• 20 Mücke T, Koschinski J, Deppe H , et al. Outcome of treatment and parameters influencing recurrence in patients with bisphosphonate-related osteonecrosis of the jaws. J Cancer Res Clin Oncol 2011; 137 (5) 907-913
• 21 Otto S, Schreyer C, Hafner S , et al. Bisphosphonate-related osteonecrosis of the jaws - characteristics, risk factors, clinical features, localization and impact on oncological treatment. J Craniomaxillofac Surg 2012; 40 (4) 303-309
• 22 Then C, Hörauf N, Otto S , et al. Incidence and risk factors of bisphosphonate-related osteonecrosis of the jaw in multiple myeloma patients having undergone autologous stem cell transplantation. Onkologie 2012; 35 (11) 658-664
• 23 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) 568-585
• 24 Rugani P, Luschin G, Jakse N, Kirnbauer B, Lang U, Acham S. Prevalence of bisphosphonate-associated osteonecrosis of the jaw after intravenous zoledronate infusions in patients with early breast cancer. Clin Oral Investig 2014; 18 (2) 401-407
• 25 Assaf AT, Jürgens TP, Benecke AW , et al. Numb chin syndrome: a rare and often overlooked symptom. J Oral Facial Pain Headache 2014; 28 (1) 80-90
• 26 Otto S, Hafner S, Grötz KA. The role of inferior alveolar nerve involvement in bisphosphonate-related osteonecrosis of the jaw. J Oral Maxillofac Surg 2009; 67 (3) 589-592
• 27 Otto S, Pautke C, Hafner S , et al. Pathologic fractures in bisphosphonate-related osteonecrosis of the jaw—review of the literature and review of our own cases. Craniomaxillofac Trauma Reconstr 2013; 6 (3) 147-154
• 28 Hanasono MM, Militsakh ON, Richmon JD, Rosenthal EL, Wax MK. Mandibulectomy and free flap reconstruction for bisphosphonate-related osteonecrosis of the jaws. JAMA Otolaryngol Head Neck Surg 2013; 139 (11) 1135-1142
• 29 Mücke T, Haarmann S, Wolff KD, Hölzle F. Bisphosphonate related osteonecrosis of the jaws treated by surgical resection and immediate osseous microvascular reconstruction. J Craniomaxillofac Surg 2009; 37 (5) 291-297
• 30 Spinelli G, Torresetti M, Lazzeri D , et al. Microsurgical reconstruction after bisphosphonate-related osteonecrosis of the jaw: our experience with fibula free flap. J Craniofac Surg 2014; 25 (3) 788-792
• 31 Vercruysse Jr H, 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) 377-386
• 32 Di Fede O, Fusco V, Matranga D , et al. Osteonecrosis of the jaws in patients assuming oral bisphosphonates for osteoporosis: a retrospective multi-hospital-based study of 87 Italian cases. Eur J Intern Med 2013; 24 (8) 784-790
• 33 Fedele S, Bedogni G, Scoletta M , et al. Up to a quarter of patients with osteonecrosis of the jaw associated with antiresorptive agents remain undiagnosed. Br J Oral Maxillofac Surg 2015; 53 (1) 13-17
• 34 Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 2005; 63 (11) 1567-1575
• 35 Wessel JH, Dodson TB, Zavras AI. Zoledronate, smoking, and obesity are strong risk factors for osteonecrosis of the jaw: a case-control study. J Oral Maxillofac Surg 2008; 66 (4) 625-631
• 36 Boonyapakorn T, Schirmer I, Reichart PA, Sturm I, Massenkeil G. Bisphosphonate-induced osteonecrosis of the jaws: prospective study of 80 patients with multiple myeloma and other malignancies. Oral Oncol 2008; 44 (9) 857-869
• 37 Dimopoulos MA, Kastritis E, Anagnostopoulos A , et al. Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphonates: evidence of increased risk after treatment with zoledronic acid. Haematologica 2006; 91 (7) 968-971
• 38 Hoff AO, Toth BB, Altundag K , et al. Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 2008; 23 (6) 826-836
• 39 Vahtsevanos K, Kyrgidis A, Verrou E , et al. Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol 2009; 27 (32) 5356-5362
• 40 Jadu F, Lee L, Pharoah M, Reece D, Wang L. A retrospective study assessing the incidence, risk factors and comorbidities of pamidronate-related necrosis of the jaws in multiple myeloma patients. Ann Oncol 2007; 18 (12) 2015-2019
• 41 Khamaisi M, Regev E, Yarom N , et al. Possible association between diabetes and bisphosphonate-related jaw osteonecrosis. J Clin Endocrinol Metab 2007; 92 (3) 1172-1175
• 42 Badros A, Terpos E, Katodritou E , et al. Natural history of osteonecrosis of the jaw in patients with multiple myeloma. J Clin Oncol 2008; 26 (36) 5904-5909
• 43 Durie BG, Katz M, Crowley J. Osteonecrosis of the jaw and bisphosphonates. N Engl J Med 2005; 353 (1) 99-102 , discussion 99–102
• 44 Otto S, Tröltzsch M, Jambrovic V , et al. Tooth extraction in patients receiving oral or intravenous bisphosphonate administration: A trigger for BRONJ development?. J Craniomaxillofac Surg 2015; 43 (6) 847-854
• 45 Landesberg R, Cozin M, Cremers S , et al. Inhibition of oral mucosal cell wound healing by bisphosphonates. J Oral Maxillofac Surg 2008; 66 (5) 839-847
• 46 Otto S, Hafner S, Mast G , et al. Bisphosphonate-related osteonecrosis of the jaw: is pH the missing part in the pathogenesis puzzle?. J Oral Maxillofac Surg 2010; 68 (5) 1158-1161
• 47 Tsao C, Darby I, Ebeling PR , et al. Oral health risk factors for bisphosphonate-associated jaw osteonecrosis. J Oral Maxillofac Surg 2013; 71 (8) 1360-1366
• 48 Manfredi M, Merigo E, Guidotti R, Meleti M, Vescovi P. Bisphosphonate-related osteonecrosis of the jaws: a case series of 25 patients affected by osteoporosis. Int J Oral Maxillofac Surg 2011; 40 (3) 277-284
• 49 O'Ryan FS, Lo JC. Bisphosphonate-related osteonecrosis of the jaw in patients with oral bisphosphonate exposure: clinical course and outcomes. J Oral Maxillofac Surg 2012; 70 (8) 1844-1853
• 50 Lesclous P, Abi Najm S, Carrel JP , et al. Bisphosphonate-associated osteonecrosis of the jaw: a key role of inflammation?. Bone 2009; 45 (5) 843-852
• 51 Khan AA, Morrison A, Hanley DA , et al; 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
• 52 Li G. Patient radiation dose and protection from cone-beam computed tomography. Imaging Sci Dent 2013; 43 (2) 63-69
• 53 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) 236-243
• 54 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) 249-258
• 55 Stockmann P, Hinkmann FM, Lell MM , et al. 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) 311-317
• 56 Arce K, Assael LA, Weissman JL, Markiewicz MR. Imaging findings in bisphosphonate-related osteonecrosis of jaws. J Oral Maxillofac Surg 2009; 67 (5, Suppl): 75-84
• 57 Guggenberger R, Fischer DR, Metzler P , et al. Bisphosphonate-induced osteonecrosis of the jaw: comparison of disease extent on contrast-enhanced MR imaging, [18F] fluoride PET/CT, and conebeam CT imaging. AJNR Am J Neuroradiol 2013; 34 (6) 1242-1247
• 58 Otto S, Pautke C, Opelz C , et al. Osteonecrosis of the jaw: effect of bisphosphonate type, local concentration, and acidic milieu on the pathomechanism. J Oral Maxillofac Surg 2010; 68 (11) 2837-2845
• 59 Chuah C, Barnes DJ, Kwok M , et al. Zoledronate inhibits proliferation and induces apoptosis of imatinib-resistant chronic myeloid leukaemia cells. Leukemia 2005; 19 (11) 1896-1904
• 60 Abu-Id MH, Açil Y, Gottschalk J, Kreusch T. Bisphosphonate-associated osteonecrosis of the jaw [in German]. Mund Kiefer Gesichtschir 2006; 10 (2) 73-81
• 61 Pautke C, Bauer F, Tischer T , et al. Fluorescence-guided bone resection in bisphosphonate-associated osteonecrosis of the jaws. J Oral Maxillofac Surg 2009; 67 (3) 471-476
• 62 Stockmann P, Vairaktaris E, Wehrhan F , et al. Osteotomy and primary wound closure in bisphosphonate-associated osteonecrosis of the jaw: a prospective clinical study with 12 months follow-up. Support Care Cancer 2010; 18 (4) 449-460
• 63 Vescovi P, Merigo E, Meleti M, Manfredi M. Bisphosphonate-associated osteonecrosis (BON) of the jaws: a possible treatment?. J Oral Maxillofac Surg 2006; 64 (9) 1460-1462
• 64 Wutzl A, Eisenmenger G, Hoffmann M , et al. Osteonecrosis of the jaws and bisphosphonate treatment in cancer patients. Wien Klin Wochenschr 2006; 118 (15–16) 473-478
• 65 Carlson ER, Basile JD. The role of surgical resection in the management of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2009; 67 (5, Suppl): 85-95
• 66 Pautke C, Bauer F, Otto S , et al. Fluorescence-guided bone resection in bisphosphonate-related osteonecrosis of the jaws: first clinical results of a prospective pilot study. J Oral Maxillofac Surg 2011; 69 (1) 84-91
• 67 Voss PJ, Joshi Oshero J, Kovalova-Müller A , et al. Surgical treatment of bisphosphonate-associated osteonecrosis of the jaw: technical report and follow up of 21 patients. J Craniomaxillofac Surg 2012; 40 (8) 719-725
• 68 Miksad RA, Lai KC, Dodson TB , et al. Quality of life implications of bisphosphonate-associated osteonecrosis of the jaw. Oncologist 2011; 16 (1) 121-132
• 69 Nocini PF, Saia G, Bettini G , et al. Vascularized fibula flap reconstruction of the mandible in bisphosphonate-related osteonecrosis. Eur J Surg Oncol 2009; 35 (4) 373-379
• 70 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
• 71 Engroff SL, Kim DD. Treating bisphosphonate osteonecrosis of the jaws: is there a role for resection and vascularized reconstruction?. J Oral Maxillofac Surg 2007; 65 (11) 2374-2385
• 72 Wutzl A, Pohl S, Sulzbacher I , et al. Factors influencing surgical treatment of bisphosphonate-related osteonecrosis of the jaws. Head Neck 2012; 34 (2) 194-200
• 73 Mücke T, Jung M, Koerdt S, Mitchell DA, Loeffelbein D, Kesting MR. Free flap reconstruction for patients with bisphosphonate related osteonecrosis of the jaws after mandibulectomy. J Craniomaxillofac Surg 2016; 44 (2) 142-147
• 74 Ferrari S, Bianchi B, Savi A , et al. Fibula free flap with endosseous implants for reconstructing a resected mandible in bisphosphonate osteonecrosis. J Oral Maxillofac Surg 2008; 66 (5) 999-1003
• 75 Murray DJ, Vesely MJ, Novak CB, Irish J, Crump M, Neligan PC. Bisphosphonates and avascular necrosis of the mandible: case report and review of the literature. J Plast Reconstr Aesthet Surg 2008; 61 (1) 94-98
• 76 Seth R, Futran ND, Alam DS, Knott PD. Outcomes of vascularized bone graft reconstruction of the mandible in bisphosphonate-related osteonecrosis of the jaws. Laryngoscope 2010; 120 (11) 2165-2171
• 77 Bodem JP, Kargus S, Engel M, Hoffmann J, Freudlsperger C. Value of nonsurgical therapeutic management of stage I bisphosphonate-related osteonecrosis of the jaw. J Craniomaxillofac Surg 2015; 43 (7) 1139-1143
• 78 Kim BD, Ver Halen JP, Mlodinow AS, Kim JY. Intraoperative transfusion of packed red blood cells in microvascular free tissue transfer patients: assessment of 30-day morbidity using the NSQIP dataset. J Reconstr Microsurg 2014; 30 (2) 103-114
• 79 Chadha GK, Ahmadieh A, Kumar SK, Sedghizadeh PP. Osseointegration of dental implants and osteonecrosis of the jaw in patients treated with bisphosphonate therapy: a systematic review. J Oral Implantol 2012;
• 80 Lazarovici TS, Yahalom R, Taicher S, Schwartz-Arad D, Peleg O, Yarom N. Bisphosphonate-related osteonecrosis of the jaw associated with dental implants. J Oral Maxillofac Surg 2010; 68 (4) 790-796
• 81 Javed F, Almas K. Osseointegration of dental implants in patients undergoing bisphosphonate treatment: a literature review. J Periodontol 2010; 81 (4) 479-484
• 82 Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws, American Association of Oral and Maxillofacial Surgeons. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2007; 65 (3) 369-376
• 83 Jeffcoat MK. Safety of oral bisphosphonates: controlled studies on alveolar bone. Int J Oral Maxillofac Implants 2006; 21 (3) 349-353
• 84 Grant BT, Amenedo C, Freeman K, Kraut RA. Outcomes of placing dental implants in patients taking oral bisphosphonates: a review of 115 cases. J Oral Maxillofac Surg 2008; 66 (2) 223-230
• 85 Bell BM, Bell RE. Oral bisphosphonates and dental implants: a retrospective study. J Oral Maxillofac Surg 2008; 66 (5) 1022-1024
• 86 Fugazzotto PA, Lightfoot WS, Jaffin R, Kumar A. Implant placement with or without simultaneous tooth extraction in patients taking oral bisphosphonates: postoperative healing, early follow-up, and the incidence of complications in two private practices. J Periodontol 2007; 78 (9) 1664-1669
• 87 Im GI, Qureshi SA, Kenney J, Rubash HE, Shanbhag AS. Osteoblast proliferation and maturation by bisphosphonates. Biomaterials 2004; 25 (18) 4105-4115
• 88 Prieto-Alhambra D, Javaid MK, Judge A , et al. Association between bisphosphonate use and implant survival after primary total arthroplasty of the knee or hip: population based retrospective cohort study. BMJ 2011; 343: d7222
• 89 Bedogni A, Bettini G, Totola A, Saia G, Nocini PF. Oral bisphosphonate-associated osteonecrosis of the jaw after implant surgery: a case report and literature review. J Oral Maxillofac Surg 2010; 68 (7) 1662-1666
• 90 Yuan K, Chen KC, Chan YJ, Tsai CC, Chen HH, Shih CC. Dental implant failure associated with bacterial infection and long-term bisphosphonate usage: a case report. Implant Dent 2012; 21 (1) 3-7
• 91 Marx RE, Cillo Jr JE, Ulloa JJ. Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 2007; 65 (12) 2397-2410
• 92 Lo JC, O'Ryan FS, Gordon NP , et al; Predicting Risk of Osteonecrosis of the Jaw with Oral Bisphosphonate Exposure (PROBE) Investigators. Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg 2010; 68 (2) 243-253
• 93 Grbic JT, Landesberg R, Lin SQ , et al; Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial Research Group. Incidence of osteonecrosis of the jaw in women with postmenopausal osteoporosis in the health outcomes and reduced incidence with zoledronic acid once yearly pivotal fracture trial. J Am Dent Assoc 2008; 139 (1) 32-40
• 94 Kühl S, Walter C, Acham S, Pfeffer R, Lambrecht JT. Bisphosphonate-related osteonecrosis of the jaws—a review. Oral Oncol 2012; 48 (10) 938-947
• 95 Eberhardt C, Habermann B, Müller S, Schwarz M, Bauss F, Kurth AH. The bisphosphonate ibandronate accelerates osseointegration of hydroxyapatite-coated cementless implants in an animal model. J Orthop Sci 2007; 12 (1) 61-66
• 96 Greiner S, Kadow-Romacker A, Lübberstedt M, Schmidmaier G, Wildemann B. The effect of zoledronic acid incorporated in a poly(D,L-lactide) implant coating on osteoblasts in vitro. J Biomed Mater Res A 2007; 80 (4) 769-775
• 97 Shirota T, Nakamura A, Matsui Y, Hatori M, Nakamura M, Shintani S. Bisphosphonate-related osteonecrosis of the jaw around dental implants in the maxilla: report of a case. Clin Oral Implants Res 2009; 20 (12) 1402-1408
• 98 Favia G, Piattelli A, Sportelli P, Capodiferro S, Iezzi G. Osteonecrosis of the posterior mandible after implant insertion: a clinical and histological case report. Clin Implant Dent Relat Res 2011; 13 (1) 58-63