1. OSTEONECROSIS DE LOS MAXILARES ASOCIADA A BIFOSFONATOS Enrico A. Escobar López 2. O P C P O OH OH OH OH R1 R2 Cuando R1 es un grupo hidroxilo se realiza la unión a hidroxipatita R2 determina potencia P-C-P es esencial para la actividad biológica y la unión a hidroxiapatita Licata AA. Discovery, Clinical Development, and Therapeutic Uses of Bisphosphonates. Ann Pharmacother 2005;39:668-77 BIFOSFONATOS Subclase Nombre genérico Nombre comercial Vía de administración Contiene nitrógeno zoledr ó nico Zometa IV Contiene nitrógeno Pamidronato Aredia IV Contiene nitrógeno Alendronato Fosamax Oral Contiene nitrógeno Ibandronato Boniva Oral - IV Contiene nitrógeno Risedronato Actonel Oral No contiene nitrógeno Tiludronato Skelid Oral No contiene nitrógeno clod r onato Bonefos, Ostec Oral No contiene nitrógeno etidronato Didronel Oral - IV 3. ACTIVIDAD BIOL Ó GICA Y PROPIEDADES DE LOS BIFOSFONATOS <ul><li>Reabsorción ósea osteocl á stica </li></ul><ul><li>Rogers MJ, Gordon S, Benford HL, Coxon FP, Luckman SP, Monkkonen J, Frith JC. Cellular and molecular mechanisms of action of bisphosphonates. Cancer 2000;86:2961-2978. </li></ul>Inducción a los osteoblasto para secretar un inhibidor de la secreción ósea mediada por osteoclastos Vitté C, Fleisch H, Guenther HL. Bisphosphonates induce osteoblasts to secrete an inhibitor of osteoclast-mediated resorption. Endocrinology. 1996;137: 2324-33. Inducen apoptosis en osteoclastos Hughes DE, Wright KR, Uy HL, Sasaki A, Yoneda T, Roodman GD, Mundy GR, Boyce BF. Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res 1995;10:1478-1487. Inhiben la apoptosis de osteocitos y células de la línea osteoblástica Plotkin LI, Agurre JI, Kousteni S, Manolagas SC, Bellido T. Bisphosphonates and Estrogens Inhibit Osteocyte Apoptosis via Distinct Molecular Mechanisms Downstream of Extracellular Signal-regulated Kinase Activation. J Biol Chem 2005;280(8):7317-7325. 4. PROPIEDADES ANTITUMORALES DE LOS BIFOSFONATOS <ul><li>Proliferación e invasión células tumorales </li></ul><ul><li>Lee MV, Fong EM, Singer FR, Guenette RS. Bisphosphonate tretment inhibits the growth of prostate cancer cells. Cancer 2001;61:2602-8. </li></ul>Adhesión células tumorales al tejido óseo Boissier S, Magnetto S, Frappart L, Cuzin B, Ebetino FH, Delmas PD, Clezardin P. Bisphosphonates inhibit prostate and breast carcinoma cell adhesion to unmineralized and mineralized bone extracellular matrices. Cancer 1997;57:3890-94. Efecto antiangiogenico Wood J, Bonjean K, Ruetz S, Bellahce`ne A, Devy L, Foidart JM, et al. Novelantiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther. 2002;302:1055-61. Apoptosis en células tumorales Tassone P, Tagliaferri P, Viscomi C. Zoledronic acid induces antiproliferative and apoptotic effects in human pancreatic cancer cells in vitro. Br J Cancer 2003;88:1971-78. 5. Efecto antitumoral directo Adhesión e invasión Ca. Proliferación Ca. Apopt o sis Ca. EFECTO ANTITUMORALES DE LOS BFs Efecto antitumoral indirecto Actividad osteocl á stica Angiogenesis tumoral Actividad antitumoral células T Invasión células tumorales Proliferación células tumorales Estimulación Actividad osteoclastica Vaso sanguíneo Metástasis ósea Osteoclastos 6. APLICACIONES CL Í NICAS MAS HABITUALES DE LOS BIFOSFONATOS Osteoporosis post menopausia Osteoporosis inducida por corticoides Enfermedad de Paget (refractaria a otros tratamientos) Hipercalcemia inducida por tumor Lesiones osteolíticas en Mieloma Múltiple Metástasis óseas predominantemente lítica: Ca. Mama, Ca. Próstata. Licata AA. Discovery, Clinical Development, and Therapeutic Uses of Bisphosphonates. Ann Pharmacother 2005;39:668-77 7. Reacciones inflamatorias agudas sistémicas: fiebre mialgia, artralgia, nausea, vómitos y edema en el sitio de la infusión. Trastornos oculares: conjuntivitis. Trastornos renales Anormalidades electrolíticas: hipocalcemia, hipofosfatemia, hipomagnesemia. Osteonecrosis de los maxilares Reacciones alérgicas menos del 1 %. EFECTOS ADVERSOS ASOCIADOS CON BIFOSFONATOS INTRAVENOSOS Tanvetyanon T, Stiff PJ. Management of the adverse effects associated witith intravenous bisphosphonates. Annals of oncologyAnn Oncol. 2006 Jun;17(6):897-907. 8. FACTORES DE RIESGO <ul><li>Terapia concomitante con corticoides, radioterapia, quimioterapia y Bisfosfonatos. </li></ul><ul><li>Condiciones patológicas concomitantes: anemias. </li></ul><ul><li>Infecciones pulpares, periapicales o periodontales marginales. </li></ul><ul><li>Exodoncias previas </li></ul><ul><li>Trauma mecánico (protésico) </li></ul><ul><li>Mala condición de salud oral </li></ul>Expert Panel Recommendations for the Prevention, Diagnosis, and Treatment of Osteonecrosis of the Jaws: June 2004. Professional Education Material. East Hanover, NJ: Novartis; 2004. Migliorati CA, Casiglia J, Epstein J, Jacobsen PL, Siegel MA, Woo SB. Managing the care of patients with bisphosphonate-associated osteonecrosis. JADA 2005;136:1658-68. 9. Bifosfonatos + Infección y Trauma Intervención preventiva BIFOSFONATOS Bifosfonatos + Quimioterapia Reabsorción de Hueso Diminuye actividad celular ósea + Efecto antiangiogenicos Exodoncias previas Trauma Infecciones Necrosis No reparación ni regeneración ósea Osteonecrosis de los maxilares asociada a bifosfonatos 10. <ul><li>Osteonecrosis fosforosa de los maxilares causada por la exposición laboral al fósforo blanco </li></ul>Donoghue AM. Bisphosphonates and osteonecrosis: analogy to phossy jaw . Med J Aust 2005;183(3):163-64. Enfermedades ocupacionales New york 1914 Museo Hospital Universitario de Londres 1884 Hellstein JW, Marek CL.Bisphosphonate osteochemonecrosis (bis-phossy jaw): is this phossy jaw of the 21st century?. J Oral Maxillofac Surg. 2005 May;63(5):682-9. 11. Primeros informes sobre Osteonecrosis en los maxilares asociada a Bifosfonatos Marx RE. Pamidronate (Aredia) and Zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61: 1115-8. Migliorati CA. Bisphosphanates and oral cavity avascular bone necrosis. J Clin Oncol 2003; 21(22): 4253–4254. Wang J, Goodger NM, Pogrel MA. Osteonecrosis of the jaws associated with cancer chemotherapy. J Oral Maxillofac Surg. 2003;61:1104-7. 2003 12. Expert Panel Recommendations for the Prevention, Diagnosis, and Treatment of Osteonecrosis of the Jaws: June 2004. Professional Education Material. East Hanover, NJ: Novartis; 2004. Numero de publicaciones en la literatura especializada No se habían detectado en las ensayos clínicos previos 2004 13. Por que en los Maxilares ? Osteonecrosis avascular por Bifofonatos + MAXILARES Expuesto al exterior por el surco gingival Arterias terminales (mandíbula) ? Otros Huesos* Cofactores previos: patología pulpar, periapical, periodontal marginal,otros Marx RE. Pamidronate (Aredia) and Zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61: 1115-8. 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;62:527-34. Bagán JV, Murillo J, Jiménez Y, Poveda R, Milián MA, Sanchis JM, et al. Cancer chemotherapy induced avascular jaw osteonecrosis: series of 10 cases. J oral Pathol Med 2005;34:120-3. 14. * Osteonecrosis asociada a Bifosfonatos en el canal auditivo izquierdo. 64/M, Mieloma múltiple, pamidronato-zoledrónico. Antecedente quirurgico: remoción de exostosis ósea en en el conducto auditivo externo. 1 er caso no maxilares??? TRAUMA Polizzotto MN, Cousins V, Schwarer AP. Bisphosphonate-associates of the auditory canal British Journal of Haematology 2005;132:114-117 . 15. CLÍNICA Badros A ,Weikel D , Salama A , Goloubeva O , Schneider A , Rapoport A , Fenton R , Gahres N, Sausville E , Ord R , Meiller T. Osteonecrosis of the Jaw in Multiple Myeloma Patients: Clinical Features and Risk Factors . J Clin Oncol 2006;24(6):945-952. 16. Badros A ,Weikel D , Salama A , Goloubeva O , Schneider A , Rapoport A , Fenton R , Gahres N, Sausville E , Ord R , Meiller T. Osteonecrosis of the Jaw in Multiple Myeloma Patients: Clinical Features and Risk Factors . J Clin Oncol 2006;24(6):945-952. 17. Melo MD, Obeid G. Osteonecrosis of the maxilla in a patient with a history of bisphosphonate therapy. J Can Dent Assoc. 2005; 71(2): 111–113. 72/F Zoledrónico Ca. mama Exo. 2.6 18. 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;62:527-34. Zoledrónico Exo. previa 19. 72/F mieloma multiple Zoledrónico Exo. previas 69/F Ca. mama Pamidronato zoledrónico Exo. previas Post operatorio: Antibioterapia Secuestrectomia Dimitrakopoulos I, Magopoulos C, Karakasis D. Bisphosphonate-induced avascular osteonecrosis of the jaws: a clinical report of 11 cases. Int. J. Oral Maxillofac. Surg. 2006; 35(6):480-85 . 20. 57/F Ca. mama Pamidronato zoledronico Maxilectomia parcial Farrugia MC, Summerlin DJ, Krowiak E,Huntley T, Freeman S, Borrowdale R, Tomich C. Osteonecrosis of the Mandible or Maxilla Associated with the use of New Generation Bisphosphonates. Laryngoscope 2006; 116:115–120. 21. 60/F Mieloma multiple Pamidronato zoledronato Katz H . Endodontic implications of bisphosphonate-associated osteonecrosis of the jaws: a report of three cases. J Endod. 2005;31:831-4. Pre tratamiento Post tratamiento 22. RADIOLOGÍA E IMAGENOLOGÍA TAC Destrucción ósea significativa en maxilar derecho Carter G , Goss AN , Doecke C. Bisphosphonates and avascular necrosis of the jaw: a possible association . Med J Aust 2005:182(8):413-15. Rx. Panorámica radiolucidez asociada al alveolo del tercer molar inf. Izq . Wang J, Goodger NM, Pogrel MA. Osteonecrosis of the jaws associated with cancer chemotherapy. J Oral Maxillofac Surg 2003; 61: 1104-1107. 23. Sarathy AP, Bourgeois SL Jr, Goodell GG. Bisphosphonate-associated osteonecrosis of the jaws and endodontic treatment: two case reports. J Endod. 2005;31:759-63. 24. HISTOPATOLOGÍA Hansen1 T , Kunkel M , Weber A , Kirkpatrick CA. Osteonecrosis of the jaws in patients treated with bisphosphonates – histomorphologic analysis incomparison with infected osteoradionecrosis . J Oral Pathol Med (2006) 35: 155–60 Osteonecrosis por BFs Osteoradionecrosis 10 casos total 10 actinomices 7 infiltrado inflamatorio mixto 7 osteoclastos 7 hiperplasia pseudoepiteliomatosa 8 casos total 8 actinomices 5 infiltrado inflamatorio mixto 7 osteoclastos 5 hiperplasia pseudoepiteliomatosa Extensa regiones homogeneas de hueso necrotico Areas multiples parcialmente confluyentes de hueso necrotico en disposición de panal de abejas con residuos de hueso vital 25. Actinomyces Hiperplasia pseudoepiteliomatosa Mas comun en osteomielitis crónica de los huesos largos (tibia), en el maxilar es muy incomun osteoclastos Nair SP, Meghij S, Wilson M, Reddi K, White P, Henderson B. Bacterially induced bone destruction: mechanisms and misconceptions. Infect immun 1996;64:2371-80 Numero y actividad de los osteoclastos Interacción entre osteoclastos,citokinas y destrucción ósea mediada por bacterias 26. Hui L, Wiernik PH. Avascular Necrosis of bone after adult acute lymphocytic leukemia treatment with methotrexate, vincristine, L-asparaginase and dexamethasone (MOAD). Am J Hematol 1996 Jul; 52(3):184-8 Sung Ec, Chan Sm, Sakurai K, Chung E. Osteonecrosis of the maxilla as a complication to chemotherapy: a case report. Spec Care Dentist 2002;22:142-46 Lenz JH, Steiner-Krammer B, Schmidt W, Fietkau R, Mueller PC, Gundlach KKH. Does avascular necrosis of the jaws in cancer patients only occur following treatment with bisphosphonates?. J Craniomaxillofac Surg 2005;33(6):395-403. OSTEONECROSIS ASOCIADA A QUIMIOTERAPIA 27. REVISIÓN SISTEMATICA: BIFOSFONATOS Y OSTEONECROSIS DE LOS MAXILARES MEDLINE ( www.pubmed.com ): bisphosphonates, oral necrosis, avascular necrosis, osteonecrosis, jaw necrosis. Autor y n año Autor y n año Katz 2005 3 Sarathy 2005 2 Shirmer 2005 6 Guarnery 2005 3 Markiewicz 2005 1 Bamias 2005 17 Dimitrakopoulos 2006 11 Mignogna 2006 1 Badros 2006 22 Farrugia 2006 23 Hansen 2006 8 Zuazaga 2006 3 Zarychanskiu 2006 12 Carneiro 2006 1 Soileau 2006 1 Marx 2003 36 Wang 2003 3 Ruggiero 2004 63 Lugassy 2004 3 Thakkar 2004 14 Schuster 2004 2 Pires 2005 14 Bagan 2005 20 Gibbs 2005 8 Merigo 2005 4 Carter 2005 5 Lenz 2005 3 Ficarra 2005 9 Melo 2005 11 Migliorati 2005 18 Olson 2005 1 Purcell 2005 13 Vanucchi 2005 1 28. TOTAL: 340 casos Rango de edad: 36 – 92 años Promedio de edad: 65,46 años OMB= Osteonecrosis de los maxilares asociada con Bifosfonatos 35. Ulceras orales por administración de alendronato Krasagakis K, Krüger-Krasagakis S, Ioannidou D, Tosca A. J Am Acad Dermatology 2004; 50(4): 671-72 . Gonzalez-Moles MA, Bagan-Sebastian JV. Alendronate-related oral mucosa ulcerations. J Oral Pathol Med. 2000;29:514-8. Demerjian N, Bolla G, Spreux A. Severe oral ulcerations induced by alendronate. Clin Rheumatol. 1999;18:349-50. 39. Tratamiento dental para pacientes en terapia con BFs <ul><li>Control riguroso higiene y salud oral </li></ul><ul><li>Control prótesis removibles </li></ul><ul><li>Manejo no quirúrgico de las infecciones dentales en lo posible (endodoncia) </li></ul>Expert Panel Recommendations for the Prevention, Diagnosis, and Treatment of Osteonecrosis of the Jaws: June 2004. Professional Education Material. East Hanover, NJ: Novartis; 2004. Migliorati CA, Casiglia J, Epstein J, Jacobsen PL, Siegel MA, Woo SB. Managing the care of patients with bisphosphonate-associated osteonecrosis. JADA 2005;136:1658-68. 40. TRATAMIENTO CON OSTEONECROSIS DE LOS MAXILARES ASOCIADA A BIFOSFONATOS No Quirúrgico: Antibioterapia Amoxilina + Ac. Clavulamico Clindamicina Eritromicina Antimicoticos Nystatina oral Miconazol Fluconazol Antivirales Acyclovir Expert Panel Recommendations for the Prevention, Diagnosis, and Treatmentof Osteonecrosis of the Jaws: June 2004. Professional Education Material. East Hanover, NJ: Novartis; 2004. 41. Badros A , Weikel D, Salama A, Goloubeva O, Schneider A, Rapoport A, Fenton R, Gahres N, Sausville E, Ord R, Meiller T. Journal of Clinical Oncology 2006 ;24(6) :945-952. Lenz JH , Steiner-Krammer B, Schmidt W, Fietkau R, Mueller PC, Gundlach KK. Does avascular necrosis of the jaws in cancer patients only occur following treatment with bisphosphonates? J Craniomaxillofac Surg. 2005;33: 395-403. Katz H . Endodontic implications of bisphosphonate-associated osteonecrosis of the jaws: a report of three cases. J Endod. 2005;31:831-4. 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;62:527-34. 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;63:1567-75. Migliorati CA, Schubert MM, Peterson DE, Seneda LM. Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone: an emerging oral complication of supportive cancer therapy. Cancer. 2005;104:83-93. Purcell PM, Boyd IW. Bisphosphonates and osteonecrosis of the jaw. Med JAust. 2005;182:417-8. Bagan JV, Jimenez Y, Murillo J, Hernandez S, Poveda R, Sanchis JM, et al. Jaw osteonecrosis associated with bisphosphonates: multiple exposed areas and its relationship to teeth extractions. Study of 20 cases [Letter]. Oral Oncol. 2006; 42:327-9. Pires FR, Miranda A, Cardoso ES, Cardoso AS, Fregnani ER, Pereira CM, et al. Oral avascular bone necrosis associated with chemotherapy and biphosphonate therapy. Oral Dis. 2005;11:365-9. Bamias A, Kastritis E, Bamia C, Moulopoulos LA, Melakopoulos I, Bozas G, et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: incidence and risk factors. J Clin Oncol. 2005;23:8580-7. Melo MD, Obeid G. Osteonecrosis of the jaws in patients with a history of receiving bisphosphonate therapy: strategies for prevention and early recognition. J Am Dent Assoc. 2005;136:1675-81. Zarychanski R, Elphee E, Walton P, Johnston J. Osteonecrosis of the jawassociated with pamidronate therapy. Am J Hematol. 2006;81:73-5. Wang J, Goodger NM, Pogrel MA. Osteonecrosis of the jaws associated with cancer chemotherapy. J Oral Maxillofac Surg. 2003;61:1104-7. Lugassy G, Shaham R, Nemets A, Ben-Dor D, Nahlieli O. Severe osteomyelitis of the jaw in long-term survivors of multiple myeloma: a new clinicalentity. Am J Med. 2004;117:440-1. 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