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  2. 2. Osteoradionecrosis (ORN), also known as post radiation osteonecrosis (PRON). <br />It was first described by Regaud 1920.<br />A serious, debilitating and deforming potential complication of radiation therapy<br />
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  4. 4. Radiation injury<br /><ul><li>An early and late phase.
  5. 5. Early radiation injury is secondary to depletion of frequently dividing cells (Labile cells)
  6. 6. Late radiation injury occurs in those tissues that proliferate slowly or not at all (Stable cells)</li></li></ul><li>Pathophysiology of osteoradionecrosis<br />Meyer in 1970 – <br /> Triad of radiation, trauma, and infection<br /> - development of osteoradionecrosis.<br /> Irradiated bone +<br /> Traumatic event +<br /> Ingress of microorganisms =<br />Osteoradionecrosis<br />
  7. 7. Failure to demonstrate bacterial invasion in compromised bone, <br />Occurrence with no definable traumatic event, <br />Poor response to treatment with antibiotic therapy .<br /> ..... Forced to think in another way<br />
  8. 8. Pathophysiology of osteoradionecrosis<br />Marx 1983…...<br />Osteoradionecrosis - cumulative tissue damage<br /> induced by radiation rather than trauma or bacterial invasion of bone.<br /> Complex metabolic and tissue homeostatic <br /> deficiency seen in hypocellular, hypovascular, and <br /> hypoxic tissue. <br />Three "H" principle. <br />
  9. 9. Three "H" principle<br />Radiation damaged cells not replaced by cells of the same type<br />Results in less cellular, more extracellular elements – collagen.<br />Fibrotic and poorly vascularized tissue – absent healing ability.<br />Breakdown becos – absent cellular turnover<br /> Spontaneous breakdown.<br />
  10. 10. Role of trauma <br />collagen lysis and induced cellular death.<br />This creates a wound with an oxygen requirement<br /> and a demand for the basic elements of tissue repair<br />that are beyond the capabilities of the local tissue to<br /> provide.<br />
  11. 11. Effects of radiation on bone<br />Depletion of osteoblasts - Increased osteoclastic resorption of bone <br /> Reduced bone rebuilding potential<br /> +<br />Progressive endarteritis - reduction of blood flow through the Haversian and Volkmann’s canals<br /> =<br />OSTEOPOROSIS<br /> OSTEONECROSIS<br />
  12. 12. Ultimate effect<br />Radiation<br /> Hypoxic – Hypovascular - Hypocellular tissue<br /> Tissue breakdown - Cellular death and collagen lysis exceed synthesis and cellular replication<br />Progression to non-healing wound - Energy, oxygen, and metabolic demands clearly exceed the supply <br />
  13. 13. radiation-inducedfibroatrophic theory<br />key event in the progression of ORN is the activation and dysregulationof fibroblastic activity that leads to atrophic tissue within a previously irradiated area.<br />
  14. 14. Three distinct phases are seen:<br />prefibrotic phase in which changes in endothelial cells predominate,with the acute inflammatory response.<br />constitutive organised phase in which abnormal fibroblastic activity predominates, and there is disorganisation of the extracellular matrix<br />late fibroatrophic phase, attempted tissue remodelling occurs with the formation of fragile healed tissues that carry a serious inherent risk of late reactivated inflammation in the event of local injury<br />
  15. 15. endothelial cells are injured<br />cells produce chemotactic cytokines that trigger an acute inflammatory response<br />vascular thrombosis<br />local ischaemia and tissue loss.<br />seepage of various cytokines that cause fibroblasts to become myofibroblasts.<br />unusually high rates of proliferation, secretion of abnormal products of the extracellular matrix, and a reduced ability to degrade such components.<br />
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  17. 17. Microradiographic analysis<br />Of bone in ORN suggests four possible mechanisms<br /> of bony destruction: <br />progressive resorption of osteoclasts mediated by macrophages that are unaccompanied by osteogenesis;<br />periosteocyticlysis, pathognomic of ORN; <br />Extensive demineralisation that is secondary to external stimuli such as saliva and bacterial products; and<br />accelerated aging of bone<br />
  18. 18. Osteoradionecrosis<br />In the head and neck region <br />Commonest site is mandible. <br />Also reported in maxilla, temporal bone, sphenoid and base of skull.<br />
  19. 19. Why mandible at an increased risk?<br />Generally a bone – with more tenuous blood supply and more mechanically stress - more susceptible to the development of osteoradionecrosis. <br />The craniofacial skeleton receives its blood supply in three distinct manners: <br /> 1. vessels that enter the bone via direct muscular attachments,<br /> 2. periosteal perforators, and <br /> 3. intramedullary vessels<br />
  20. 20. Why mandible at an increased risk?<br />Mandible - different dominant pattern of blood supply according to various anatomical regions in the bone itself.<br />The posterior segment of the mandible (condyle process and neck, coronoid, angle, and upper ramus) - redundant blood supply from the surrounding musculature, either from direct muscular attachments or through muscular perforators penetrating the periosteum.<br />Because of this redundancy, the posterior segment is typically less susceptible to radiation induced ischemia.<br />
  21. 21. The anterior segment of the mandible - no prominent nutrient vessel supply through the muscular attachments.<br />Injection studies in the mandible - primary nutrient source for the body, parasymphyseal, and symphyseal regions is through an intramedullary source, the inferior alveolar artery.<br />In a study by Bras, et. al., radiation induced obliteration of the inferior alveolar artery was consistently found in osteoradionecrosis of mandible and was felt to be a dominant factor in the onset of the disease.<br />Bras J, DeJonge HKT, VanMerkestyen JPR. Osteoradionecrosis of the Mandible: Pathogenesis. American Journal of Otolaryngology. 11: pgs 244 - 250. 1990. <br />
  22. 22. Incidence of osteoradionecrosis<br />The overall incidence of ORN in pooled studies <br /> among radiation patients has dramatically declined. <br />11.8% (391 of 3,312 patients) before 1968<br />5.4% (602 of 11,077 patients) from 1968 to 1992<br /> due to more efficient techniques in radiation <br /> therapy.<br />Clayman L. Management of dental extractions in irradiated jaws: A protocol <br />without hyperbaric oxygen therapy. J Oral MaxillofacSurg1997;55:275–281.<br />
  23. 23. Incidence of osteoradionecrosis<br />Since 1997, lower incidence of 3.0%.<br /> Michael J. Wahl, D.D.S. Osteoradionecrosis prevention myths. Int. J. Radiation Oncology Biol. Phys., Vol. 64, No. 3, pp. 661–669, 2006<br />
  24. 24. Overall incidence of ORN in radiation patients since 1997- Contd<br />Patients (n) ORN cases (n) Study<br />151 3 Ang et al., 2001 (3)<br />636 14 Babik et al., 2000 (4)<br />1 0 Berg et al., 2000 (5)<br />334 5 Bernier et al., 2004 (6)<br />116 2 Brizel et al., 1998 (7)<br />8 0 Carl and Ikner, 1998 (8)<br />107 1 Chaux-Bodard et al., 2004 (9)<br />35 4 Chavez and Adkinson, 2001 (10)<br />1,758 61 Cheng et al., 2006 (11)<br />413 10 Cooper et al., 2004 (12)<br />24 0 David et al., 2001 (13)<br />918 9 Dische et al., 1997 (14)<br />
  25. 25. Overall incidence of ORN in radiation patients since 1997- Contd<br />Patients (n) ORN cases (n) Study<br />759 17 Fu et al., 2000 (15)<br />83 1 Gwozdz et al., 1997 (16)<br />47 0 Lambert et al., 1997 (17)<br />100 10 Lozza et al., 1997 (18)<br />1,495 27 Mendenhall, 2004 (19)<br />1 1 Németh et al., 2000 (20)<br />81 4 Oh et al., 2004 (21)<br />830 68 Reuther et al., 2003 (22)<br />268 27 Studer et al., 2004 (23)<br />1,194 11 Sulaiman et al., 2003 (24)<br />193 9 Toljanic et al., 1998 (25)<br />44 4 Tong et al., 1999 (26)<br />36 2 Vudiniabola et al., 1999 (27)<br />9,632 290 3.0%<br />
  26. 26. Types of osteoradionecrosis<br />SPONTANEOUS ORN (39%) – degradative function exceeds new bone production. <br />TRAUMA INDUCED ORN (61%) – reparative capacity of bone is insufficient to overcome an insult.<br />Bone injury can occur through direct trauma -<br /> 1. tooth extraction [84%], <br /> 2. related cancer surgery or biopsy [12%], <br /> 3. denture irritation [1%]) or<br /> 4. by exposure of the oral cavity to the environment<br /> secondary to overlying soft tissue necrosis.<br />Remy H Blanchaert, Jr, MD, DDS, Osteoradionecrosis of the Mandible<br />eMedicine Specialties > Otolaryngology and Facial Plastic Surgery > Head<br /> And Neck Oncology <br />
  27. 27. Classification of osteoradionecrosis<br />By Marx(1983)<br />Type I – Develops shortly after radiation, <br /> Due to synergistic effects of surgical <br /> trauma and radiation injury.<br />Type II – Develops years after radiation and follows a trauma<br /> Rarely occurs before 2 year after treatment & <br /> commonly occurs after 6 years. <br /> Due to progressive endarteritis and vascular effusion.<br />
  28. 28. Type III<br /> Occurs spontaneously without a preceding a traumatic event.<br /> Usually occurs between 6 months and 3 years after radiation. <br /> Due to immediate cellular damage and death due to radiation<br /> treatment.<br />
  29. 29. Stage I – Resolved healed osteonecrosis<br /> (A) – No pathologic fracture<br /> (B) – Pathologic fracture<br />Stage II – Chronic persistent and non-progressive osteonecrosis<br /> (A) – No pathologic fracture<br /> (B) – Pathologic fracture<br />Stage III – Active progressive osteonecrosis<br /> (A) – No pathologic fracture<br /> (B) – Pathologic fracture<br />
  30. 30. grade I, ORN confined to alveolar bone; <br />grade II, ORN limited to the alveolar bone and/or mandible above the level of inferior alveolar canal; <br />grade III, ORN involving the mandible below the level of inferior alveolar canal and ORN with a skin fistula and/or pathologic fracture.<br />Notani K, Yamazaki Y, Kitada H, Sakakibara N, Fukuda H, Omori K, Nakamura M. Management of mandibularosteroradionecrosis corresponding to the severity of osteoradionecrosis and the method of radiotherapy. Head Neck 2003: 25: 181–186.<br />
  31. 31. Contributing factors of osteoradionecrosis<br />Radiation factors<br />Tumor factors<br />Dental factors<br />Others<br />
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  33. 33. Radiation factors<br />Mechanism of radiation delivery – impact on the development and severity of necrosis.<br />Brachytherapy implants have the greatest relative risk in combination with external beam exposures of 6500 cGy<br /> (12 - 15 times).<br />Sanger JR, Matloub HS, Yousif NJ, Larson DL. Management of Osteoradionecrosis of the Mandible. Clinics in Plastic Surgery. 20(3): pg 520. 1993. <br />
  34. 34. Tumor factors<br />Statistically significant incidence of osteoradionecrosis with <br /> 1. more advanced tumors (stage III or IV)<br /> 2. recurrent tumors<br /> 3. tumors involving the tongue, retromolar<br />trigone, and floor of mouth, and <br /> 4. tumors invading bone<br />Kuluth EV, Jain PR, Stutchell RN, Frich JC. A Study of Factors Contributing to the Development of Osteoradionecrosis of the Jaws. The Journal of Prosthetic Dentistry. 59 (2): pg 200. 1988. <br />
  35. 35. Incidence of ORN according to anatomic site of the tumor<br />
  36. 36. Dental factors<br />Presence of carious and periodontally compromised teeth in the irradiated mandible - associated with osteoradionecrosis. <br />The current school of thought - grossly carious, periodontally "hopeless," or those teeth deemed to have poor prognosis for retention beyond twelve months should be removed prior to the initiation of radiation therapy - this avoids dental manipulations in the post irradiation period.<br />Clayman L. Management of Dental Extractions in Irradiated Jaws: A Protocol Without Hyperbaric Oxygen Therapy. Journal of Oral and Maxillofacial Surgery. 55: pg 275. 1997.<br />
  37. 37. Dental factors<br />The post surgical healing time prior to starting radiation treatment -under debate.<br />Marx and Johnson - compared the incidence of osteoradionecrosis in pre-treatment tooth removal patients to the timing of the surgical insult.<br />From their collected data, most of the osteoradionecrosis developed - in those patents in which treatment was begun within the first two weeks post extraction.<br />No cases of osteoradionecrosis, when the tissue was allowed to heal for 21 days or more.<br />Marx RE, Johnson RP. Studies in the Radiobiology of Osteoradionecrosis and Their Clinical Significance. Oral Surgery Oral Medicine Oral Pathology. 64 (4): pg 384. 1987. <br />
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  40. 40. Signs and symptoms<br />Pain <br />Swelling <br />Trismus<br />Halitosis<br />Food impaction in the area of the lesion<br />Exposed bone <br />Pathologic fracture <br />Oro-cutaneous fistula<br />
  41. 41. Symptomatology of patients with ORN<br />E. Ang, C. Black, J. Irish, D.H. Brown, P. Gullane, B. O’Sullivan and P.C. Neligan ,Reconstructive options in the treatment of osteoradionecrosis of the craniomaxillofacial skeleton, British Journal of Plastic Surgery (2003), 56, 92–99<br />
  42. 42. Evaluation of osteoradionecrosis<br />A high index of suspicion that this presentation may be recurrent, or persistent, or even metastatic malignancy.<br />Deep biopsy of the lesion is helpful<br />Review of the pertinent radiation therapy records including the ports of radiation therapy, the total dose, dose per fraction, and timing of therapy.<br />A through dental examination - in those patients with remaining dentition.<br />
  43. 43. Imaging Studies<br />Plain radiography of the mandible - depicts areas of local decalcification or sclerosis. <br />The formation of sequestra or involucra occur late or not at all in irradiated bone because of the severely compromised blood supply.<br />
  44. 44. Pathologic fracture<br />
  45. 45. Management Of Osteoradionecrosis<br />Initial treatment – control of infection if present. <br />Gentle irrigation of the soft tissue margins - removes debris and reduces inflammation. <br />Supportive treatment with fluids and a liquid or semi liquid diet high in proteins and vitamins.<br />
  46. 46. Management Of Osteoradionecrosis<br />Pain may be controlled with narcotic analgesics, bupivacaine or alcohol nerve blocks, nerve avulsion or rhizotomy.<br />
  47. 47. An area of irradiated bone and mucosa that breaks down, whatever the cause, has a much greater oxygen and metabolic demand than it had prior to being wounded.<br />
  48. 48. Hyperbaric oxygen therapy<br />HBO is an adjuvant to surgery rather than an independent therapy.<br />It was first recommended by Valenzuela (1887) as a treatment for bacterial infections. <br />Reports of the benefits of HBO in osteoradionecrosis were first reported in the 1970’s by Mainous, Hart and Boyne.<br />
  49. 49. Hyperbaric oxygen therapy<br />The basic mechanism of hyperbaric oxygen therapy is endothelial cell proliferation resulting in neovascularisation and collagen synthesis.<br />It consists of exposing a patient to intermittent short term 100% oxygen inhalation at a pressure greater than 1 atmosphere.<br />
  50. 50. Hyperbaric oxygen therapy<br />Marx (1983) presented a new concept in osteoradionecrosis management - Marx HBO / surgical protocol. <br />The compromised bone and soft tissues are improved and revascularised with HBO and then if necessary, the necrotic bone is surgically removed.<br />The patient’s response or lack of response to HBO is the main indicator for surgery.<br /> The primary thrust is to distinguish dead bone from merely compromised bone and to surgically resect all dead bone. <br />
  51. 51. Three treatment stages of advancing clinical severity.<br /> All patients who meet the definition of osteoradionecrosis (exposed bone present for six months or longer with no healing), begin stage I treatment. <br /> If the disease does not resolve, Stage II treatment is begun. <br /> Three exceptions representing advanced disease: patients with pathologic fractures, fistulas or radiographic evidence of osteolysis to the inferior border begin directly with stage III treatment and usually require discontinuity resection.<br />
  52. 52. Stage I<br />Perform 30 HBO dives (1 dive per day, Monday-Friday) to 2.4 atmospheres for 90 minutes in a multiplace chamber or 2.0 ATA for 120 min in a monoplace chamber.<br /> Reassess the patient to evaluate decreased bone exposure, granulation tissue covering exposed bone, resorption of nonviable bone, and absence of inflammation.<br /> For patients who respond favorably, continue treatment to a total of 40 dives.<br /> For patients who are not responsive, advance to stage II.<br />
  53. 53. Stage 2<br />Perform transoralsequestrectomywith primary wound closure followed by continued HBO to a total of 40 dives.<br /> If wound dehiscence occurs, advance patients to stage III. <br />
  54. 54. Stage 3<br />Patients who present with orocutaneous fistula, pathologic fracture, or resorption to the inferior border of the mandible advance to stage III immediately after the initial 30 dives. <br />Perform transcutaneousmandibular resection, wound closure, and mandibular fixation with an external fixator or maxillomandibular fixation, followed by an additional 10 postoperative HBO dives. <br />
  55. 55. Stage 3 R<br />Perform mandibular reconstruction 10 weeks after successful resolution of mandibular ORN. <br />Reconstruction of the mandible in these patients consisted of either autogenous particulate bone and marrow within a custom-made stainless steel metal crib or autogenous particulate bone and marrow within a freeze-dried allogenic bone framework .<br />Complete 10 additional postoperative HBO dives. <br />
  56. 56. With adherence to this protocol, Marx noted resolution of all cases of osteoradionecrosis within one of the stages. <br />More specifically, 15% resolved in stage I, 15% resolved during stage II, and the remainder (70%) resolved in stageIII.<br />Results<br />
  57. 57. Contraindications for HBO therapy<br />1. Untreated pneumothorax - (Absolute contraindication)<br />2. Pregnancy<br />3. Emphysema<br />4. Upper respiratory tract infection <br />5. Uncontrollable fever<br />6. Optic neuritis<br />7. Ear problems<br />
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  63. 63. Role of Pentoxyphylline in osteoradionecrosis<br />Pentoxyphylline (Trental) is a member of the methylxanthine class of drugs as are caffeine and theophylline.<br />  <br />exerts an anti-TNF effect, increases erythrocyte flexibility, dilates blood vessels, inhibits inflammatory reactions in vivo, inhibits proliferation of human dermal fibroblasts and the production of extracellular matrix, and increases collagenase activity in vitro.<br />The overall effect - blood more liquid and enable the red blood cells to travel deeper into tissues.<br />This enables better oxygen delivery to tissues and improved microcirculation. <br />
  64. 64. Delanian S, Depondt J, Lefaix JL: Major healing of refractory mandible osteoradionecrosis after treatment combining pentoxifylline and tocopherol: A phase II trial. Head Neck 27:114, 2005<br />Between June 1995 and January 2002, 18 patients were given a daily oral combination of 800 mg of PTX and 1000 IU of vitamin E for 6 to 24 months. <br />In addition, the last eight patients who were the worst cases were given 1600 mg/day clodronate 5 days a week. <br />RESULTS: Sixteen (89%) of 18 patients achieved complete recovery. The remaining two patients exhibited a 75% response at 6 months. <br />
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  67. 67. Prevention of osteoradionecrosis<br />Prior to radiation therapy- Dental consultation - To achieve optimal oral health.<br />Sleeper (1950) and Meyer (1958) - recommendationsbefore irradiation is started. <br />1. The mouth should be made as clean as possible by scaling and irrigation.<br />2. All infections of soft tissues should be eliminated.<br />3. All infected and non-vital teeth should be extracted. All teeth in the line of irradiation, good or bad, also should be extracted.<br />
  68. 68. Prevention of osteoradionecrosis<br />4. All teeth periodontally involved should be extracted.<br />5. If the parotid and submandibular glands are to receive heavy irradiation, all teeth should be extracted.<br />6. If the mouth shows much neglect throughout, all teeth should be extracted.<br />7. The use of antibiotic prophylaxis b4 extraction, though common practise, has not been validated in any study. However, prophylaxis could be incorporated into the protocol if desired. <br />
  69. 69. Prevention of osteoradionecrosis<br />8. The patient should be thoroughly instructed in the<br /> maintenance of absolute hygienic care of the mouth.<br /> 9. Fluoride therapy should be used to prevent irradiation <br /> caries of any remaining teeth.<br /> 10. No radiotherapy should be attempted for 7-10 days <br /> following extractions in the mandible or for 3-6 days in the<br /> maxilla. If possible the radiation should start only 21 days<br /> after the tooth extractions.<br />
  70. 70. ORN after preradiation extraction and postradiation extraction<br />Since 1986, the incidence of ORN after preradiation extraction (3.0 –3.2%; 23 of 711–756 patients) was approximately the same as the incidence of ORN after postradiation extraction (3.1–3.5%; 16 of 461–508 patients) in pooled studies <br />Osteoradionecrosis can also occur in edentulous patients or spontaneously, and preradiation extractions cannot prevent these. <br />Michael J. Wahl, D.D.S. Osteoradionecrosis Prevention Myths <br />Int. J.Radiation Oncology Biol. Phys., Vol. 64, No. 3, pp. 661–669, 2006<br />
  71. 71. Delay radiation therapy?<br /> “Because the risk of ORN is approximately the same with postradiation as with preradiation extractions, it might be more important not to delay radiation therapy than to wait for preradiation extraction sites to heal”.<br />Michael J. Wahl, D.D.S. Osteoradionecrosis Prevention Myths <br />Int. J.Radiation Oncology Biol. Phys., Vol. 64, No. 3, pp. 661–669, 2006<br />
  72. 72. Int. J. Radiation Oncology Biol. Phys., Vol. 64, No. 3, pp. 661–669, 2006<br />
  73. 73. Instructions after radiotherapy of the jaws<br />1. Strict oral hygiene. <br />2. If future work on the teeth or an operation - patients must inform the physician or dentist that their jaws have been previously irradiated.<br />3. Preferably no further extractions. If a tooth in the area of irradiation becomes caries - extraction must be done as atraumatically as possible under a course of antibiotics both preoperatively and postoperatively.<br />4. Dentures should not be used in the irradiated arch for one year after therapy.<br />
  74. 74. Osteoradionecrosis of the temporal bone<br />Following the treatment of nasopharyngeal carcinoma by external-beam radiotherapy.<br />Ramsden et al classified osteoradionecrosis of the temporal bone as either local or diffuse.<br />The local type is characterized by the presence of a bone sequestrum that is confined to the external auditory canal.<br /> Patients usually present with chronic, offensive otorrhea and occasionally otalgia.<br />
  75. 75. Osteoradionecrosis of the temporal bone<br />In the diffuse type - widespread ischemic osteonecrosis of the skull base and adjacent structures. <br />These patients have usually received higher doses of external irradiation to the temporal bone. <br />Severe otalgia and pulsatile, offensive otorrhea are common. Cranial nerve palsies might also be present.<br />Diffuse osteoradionecrosis is associated with a recognized incidence of local or regional complications, such as suppurative labyrinthitis, trismus, meningitis, cerebrospinal fluid leakage, and internal carotid aneurysm.<br />
  76. 76. Management of osteoradionecrosis in the temporal bone<br />Controversial. <br />For localized osteoradionecrosis - Conservative treatment with frequent aural toileting and topical antibiotics.<br />Rudge described complete success with the use of hyperbaric oxygen therapy specifically for osteoradionecrosis of the temporal bone.<br />
  77. 77. Management of osteoradionecrosis in the temporal bone<br />Other alternatives, such as modified radical mastoidectomy, have been performed in selected cases with good initial results, but no long-term follow up is available to validate this choice of treatment.<br /> Temporal bone resection for diffuse osteoradionecrosis is reported to be an effective treatment.<br />
  78. 78. Bisphosphonate related osteonecrosis of the jaw<br />First recognized in 2003 as a complication of bisphosphonate therapy<br />Higher frequency in the mandible (63%) than in the maxilla (38%)<br />Etiology is unclear and is the subject of current research and investigation.<br />
  79. 79. Bisphosphonate related osteonecrosis of the jaw<br />True incidence is difficult to estimate.<br />Depending on recent retrospective reports could be <1%-9% of cancer patients receiving bisphosphonates.<br />Seen in cancer patients with multiple antineoplastic medications as well as bisphosphonates.<br />Multiple myeloma, breast cancer and prostate cancer are the primary neoplasms affected.<br />
  80. 80. Bisphosphonate related osteonecrosis of the jaw<br />Current management is empiric. <br />A conservative approach is recommended - includes antibiotics, oral rinses, pain control, and limited debridement.<br />The roles of surgical treatment and hyperbaric oxygen therapy are still under investigation.<br />
  81. 81. Conclusion<br />The aim should be its prevention.<br />An understanding of the risk factors is important in preventing ORN after radiation therapy.<br />
  82. 82. THANK YOU<br />