1. Case reports of BRONJ 指導老師 : 王文岑醫師暨口腔病理科全體醫師 實習 E 組 Intern 廖昱豪 張庭維 謝旻芸 黃于芳 曾家展

2. General data Name : 葉 x 英 Gender: Female Age : 76 y/o Native : 屏東縣 Marriage status : Married Occupation : 無 Case 1

3. Chief Complaints R’t submandibular swelling for 2 months

4. Present Illness 97.12.11 –This 74 y/o female was suffered from the above episode, at first she went to LDC, the dentist suggest ed her to come to our OPD for further examination. She took Fosamax. –2 polyps at right edentulous ridge, local pus (+) –Right submandibular swelling about 5*7cm

5. Past History Past Medical History Hypertension(+) DM(-) denied other systemic illness Hospitalized: 置換人工膝關節 osteoporosis drug or food allergy: penicillin Medication: drug for hypertension control 膝關節藥物 Forsamax (alendronate( 口服 ) 次 / 週 for 4~5 yrs )

6. Past Dental History Extraction,C&B,OD,RCT Attitude to Dental Tx ： Fair Oral Habits Alcohol : (-) Betel quid : (-) Cigarette (-)

7. 3x3 cm Mixed RL with RO, irregular shape bony destruction

9. Differential Diagnosis ● Tumor Benign (X) Malignancy osteosacoma odontogenic malignancy tumor ● Infection Osteomylities

10. Clinical impression Bisphosphonate- related osteonecrosis of jaw (BRONJ)

11. Treatment course 97.12.11 (first visit) refer from LDC97.12.11 (first visit) refer from LDC I&D anaerobic culture, aerobic culture Rx: amoxicillin/ panadol / suwell 97.12.1897.12.18 pus culture report Clostridium bifermentans →metronidazole(+) Ampicillin (+) Clindamycin (+)

12. 97.12.12~97.12.3197.12.12~97.12.31 N/S irrigation Antibiotic 98.1.798.1.7 arrange OP 98.1.1598.1.15 OP: sequestrectomy +saucerization

13. 98.3.4

14. 98.5.6 Remove sequestrum (in OPD)

15. 98.9.16 F/U

16. General data Name : 涂沈秀月 Gender: Female Age : 51 y/o Native : Kaohsiung Marriage status : Married First Visit : 97/12/18 Case 2

17. Chief Complaints Ask for oral examination for dental care after 骨針 application Bad smell from wound of extraction for more than 1 year.

18. Present Illness 97/12/18 This 49 y/o female has received Zometa IV monthly for bone metastasis for about 3 years. And the nurse of cancer center suggested her to visit our OPD for oral examination. She stated she had extraction experience of teeth 15 and 16 more than 1 year ago in LDC.

19. Past History  Past Medical History Breast carcinoma with bone metastasis (T1N2M1)s/p operation, systemical chemotherapy and radiotherapy. Serous microcystic adenoma over pancreatic tail s/p partial pancreatectomy Otitis media s/p eardrum reconstraction Tonsil excision

20.  Past Dental History Extraction, C&B fabrication, OD, scaling  Attitude to Dental Tx ： Fair  Oral Habits Related to Malignancy: Alcohol : (-) Betel quid : (-) Cigarette : (-)

21. Oral Examination A fistula was found on edentulous ridge of teeth 15 &16, tracing with GP to take a periapical film. Missing: –15,16,17,18,27,28,37,38,45,46,48 Caries : 13(D),14(M),34(B) Metal crown : 22,23,24,25,26,35,36,44xx47 PFM crown: 42

22. Panorex findings There is an ill-defined bony destruction area about 2x2cm in diameter over edentulous ridge of teeth 15 and 16.

23. Differential diagnosis Bisphosphonate related osteomyelitis over R’t post. Maxilla Breast carcinoma with bone metastasis of jaw Osteoradionecrosis of the jaw (ORN) Clinical Impression : Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ)

24. Treatment Plan Antibiotic therapy Local debridement Advanced surgical management

25. 98.8.13

26. Cases review of BRONJ (KMUH)

27. Cases review Patient source: 14 BRONJ patients in KMUH dental dept. Methods: chart review 1.bisphosponate(BP) usage 2.radiographic evaluation 3.systemic condition 4.oral hygiene and dental condition

28. General data Sex: Male : Female = 0:14 (female 100%) Age: 21-50 y/o: 1 (7.1%) 51-60 y/o: 2 (14.2%) 61-70 y/o: 3 (21.3%) 71-80 y/o: 6 (42.6%) 81-90 y/o: 2 (14.2%) Range: 42-82, average : 69 y/o Reason for BP usage: Breast ca (BC) with bone meta or prevention: 6(42.8%), Osteoporosis: 8(57.2%) DM: 5 (35.5 %)

29. BC ZP+ZB+Z Oral IV32 Oral+IV1 O A :8 (oral) P: pamidronate Used form of BP

30. Using time of BP(months) 11-30m: 3 31-50m: 6 51-70m: 1 71-90m: 2 101-110m: 1 Minimum: 13m (A/oral) Maximum:103m (A/oral) Average: 47m Side effect: not obvious

31. 0123 1(7.1%)8(57.1%)4(28.6%)1(7.1%) Bony exposure:12/14(85.7%) Lesion Numbers LocationUpper Ant. Upper premolar Upper molar Lower anterior Lower premolar Lower molar No.(%)1 (5.6%)2 (11.1%) 4(22.2%)7(38.9%) Locations Locations Lesion characteristics

32. Symptoms and signs Pain14/14 100% 1 Swelling9/14 64.3% Delayed healing wound (sockets)11/14 78.6% 3 neurosensory changes3/14 21.4% Pus13/14 92.9% 2 Intraoral sinus tract extraoral fistula 8/14 57.1% Tooth mobility5/14 35.7% X ray finding14/14 100% 1 Clinical characteristics

33. Radiographic features RadiolucencyROmixed 10 (71.4%)04 (28.6 %) Lesion size Maxium: 5*3 cm Minimum: 1*1 cm

34. ONJ staging 0123 01/14 (7.1%) 12/14 (85.7%) 2/14 (14.3%) Special events noneextraction Other 2/14 (14.3%) 11/14 (78.6%)1/14 (tooth Fx) (7.1%)

35. 使用 bisphosphonate 到發病時間 < 1m1m2~3m12m 2411 11~30m31~50m51~70m71~90m91~110m 44211 Event~ BRONJ Event~ BRONJ Minima: 12 Maxima: 94 Average: 44.8

36. Clincal procedures & treatments Biopsy: 7/14 (50%) Bacterial culture: 6/14 (42.9%) Clostridium bifermentans staphylococus epidermidis propionibacterium species Antibiotic: 14/14 (100%) amoxicillin, clindamycin, metronidazole, clindamycin, Local irrigation and debridement: 12/14 (85.7%) Operation (in OR) : 6/14 (42.9%) HBO : 4/14 (28.6%)

37. Periodontitis: 12/14 (85.7%) 感染性骨髓炎 : Upper anterior Upper premolar Upper molar Lower anterior Lower premolar Lower molar 3 site0 site 3 site7 site8 site

38. conclusion 更年期過後的婦女因為罹患乳癌和骨質疏鬆症的 機率增加，用藥機率增加，所以為高危險群 藥物本身副作用不明顯，所以使用普遍 11/14 (78.6%) 的病人是因為拔牙傷口不癒合，且 大多數病灶部位都在下顎後牙區 病患大多在服藥後 1~5 年內發病，平均 44.8m 所有來診的患者皆有疼痛 (100%) 的情況，其次為 化膿 (92.9%) ，可見一般民眾會因為疼痛尋求解 決，或是化膿意識到嚴重性求診

39. Discussion

40. INDICATIONS AND BENEFITS OF BISPHOSPHONATE Bps. have high affinity for hydroxyapatite, remaining unmetabolized for long periods of time. During bone remodeling, the drug is taken up by osteoblast and internalized in the cell cytoplasm. Reducing recruitment and proliferation of osteoclast precursors and inducing osteoclast apoptosis. Bps. also have antiangiogenic properties and may be directly tumoricidal. As a result, bone turnover becomes profoundly suppressed, and over time the bone shows little physiologic remodeling As a result, bone turnover becomes profoundly suppressed, and over time the bone shows little physiologic remodeling.

41. INDICATIONS AND BENEFITS OF BISPHOSPHONATE THERAPY IV Bisphosphonates  cancer-related conditions 1.hypercalcemia of malignancy 2.bone metastases (breast cancer, prostate cancer, lung cancer) 3.lytic lesions of multiple myeloma Pamidronate(Aredia), Zoledronic acid(Zometa), Zoledronate(Reclast), Ibandronate(Boniva) J Oral Maxillofac Surg 67:2-12, 2009, Suppl

42. Oral Bisphosphonates 1.most prevalent and common indication  osteoporosis 2.Paget’s disease of bone and osteogenesis imperfecta of childhood. Off-label uses  Numerous other conditions where a decrease in bone remodeling by bisphosphonates might aid in disease management: –giant cell lesions of the jaw –pediatric osteogenesis imperfecta –fibrous dysplasia –Gaucher’s disease J Oral Maxillofac Surg 67:2-12, 2009, Suppl

43. Common bisphosphonates

44. Relative Potency Etidronate (Didronel)1Etidronate (Didronel)1 Tiludronate (Skelide)10Tiludronate (Skelide)10 Pamidronate (Aredia)100Pamidronate (Aredia)100 Alendronate (Fosamax)1,000Alendronate (Fosamax)1,000 Risedronate (Actonel)10,000Risedronate (Actonel)10,000 Ibandronate (Boniva)10,000Ibandronate (Boniva)10,000 Zolendronic acid (Zometa)>100,000Zolendronic acid (Zometa)>100,000 * Relative to etidronate (a non-nitrogen-containing bisphosphonate with relative potency of 1).

45. BRONJ Case Definition  Patients may be considered to have BRONJ 1. Current or previous treatment with a bisphosphonate. 2. Exposed bone in the maxillofacial region that has persisted for more than 8 weeks. 3. No history of radiation therapy to the jaws J Oral Maxillofac Surg 67:2-12, 2009, Suppl

46. Incidence of BRONJ IV BISPHOSPHONATES  0.8% to 12% ORAL BISPHOSPHONATES  0.7/100,000 person-years of exposure(Merck)  underreporting.  Surveillance data from Australia (patients treated weekly with alendronate )  0.01% to 0.04%  13,000 Kaiser-Permanente members( long-term oral bps)  0.06%  IV>>oral. Independent epidemiological efforts from clinicians and the International Myeloma Foundation reported incidence estimates between 5% ~ 10%. J Oral Maxillofac Surg 67:2-12, 2009, Suppl

47. RISK FACTORS 1. Drug-related risk factors A. Bisphosphonate potency zoledronate (Zometa)> pamidronate(Aredia)> oral bps. B. Duration of therapy 2. Local risk factors A. Dentoalveolar surgery: 5-~21-fold increased risk in IV Bps. treated cancer patients. B. Local anatomy : Mandible : Maxilla=2:1 (Thin mucosa overlying bony prominences such as tori, bony exostoses, and the mylohyoid ridge) C. Concomitant oral disease: history of inflammatory dental disease are at a 7-fold increased risk. J Oral Maxillofac Surg 67:2-12, 2009, Suppl

48. 3. Demographic and systemic factors A. increasing age ; whites. B. systemic factor (renal dialysis, low hemoglobin, obesity, and diabetes) C. chemotherapeutic agents (cyclophosphamide, erythropoietin, and steroids) D. tobacco users, alcohol exposure(X) … Wessel et al 4. Genetic factors  single nucleotide polymorphisms, in the cytochrome P450-2C gene [CYP2C8] ……… Sarasquete et al J Oral Maxillofac Surg 67:2-12, 2009, Suppl

49. Staging of BRONJ Patient at risk : no apparent necrotic bone in asymptomatic patients who have been treated with IV or oral Bps. Stage 0 : no clinical evidence of necrotic bone, present with nonspecific symptoms or findings, include Symptoms: 1. Odontalgia not by an odontogenic cause 2. Dull, aching bone pain in the body of the mandible 3. Sinus pain 4. Altered neurosensory function Clinical findings: 1. Loosening of teeth not explained 2. Fistula not associated with pulpal necrosis Radiographic findings: 1. Persistence of unremodeled bone in sockets 2. Thickening/obscuring of periodontal ligament 3. Inferior alveolar canal narrowing

50. Stage1 : exposed and necrotic bone in patients who are asymptomatic and have no evidence of infection.

51. Stage2 : exposed and necrotic bone in patients with pain and clinical evidence of infection(pain, erythema, purulent drainage.)

52. Stage3: exposed and necrotic bone in patients with pain, infection, and one or more of the following: 1.Exposed necrotic bone extending beyond the region of alveolar bone 2. Pathologic fracture 3. Extraoral fistula 4. Oral antral/oral nasal communication 5. Osteolysis extending to the inferior border of the mandible or sinus floor

53. Treatment stretagy  At risk: Not require any treatment. Patient education.  Stage 0: Systemic management, including use of pain medication and antibiotics  Stage 1: Antibacterial mouth rinse(0.12% CHX) Clinical follow-up No surgical treatment is indicated.

54.  Stage2: Symptomatic treatment with oral antibiotics (adjusted according to culture ) Oral antibacterial mouth rinse Pain control Superficial debridement to relieve soft tissue irritation.  Stage3: Antibacterial mouth rinse Antibiotic therapy and pain control Surgical debridement / resection for longer term palliation of infection and pain.

55. Treatment strategy and advisements Patients About to Initiate IV: If systemic conditions permit, initiation of Bps. therapy should be delayed until the dental health has been optimized. if systemic conditions permit, until the extraction site has mucosalized (14 to 21days) or until adequate osseous healing has occurred. Patients be educated as to the importance of dental hygiene and regular dental evaluations and specifically instructed to report any pain, swelling, or exposed.

56. Asymptomatic Patients Receiving IV Bisphosphonates: Avoid direct osseous injury. The efficacy of a drug holiday for patients receiving yearly zoledronic acid therapy and the appropriate timing of dentoalveolar surgery is unknown. Asymptomatic Patients Receiving Oral Bisphosphonate : A. Patients are adequately informed of the small risk of compromised bone healing. B. The use of bone turnover marker levels, in conjunction with a drug holiday, has been reported as an additional tool to guide treatment decision.

57. C. For individuals taken an oral bps. for fewer than 3 years and have no clinical risk factors.  no alteration or delay in the planned surgery is necessary. D. For fewer than 3 years and have also taken corticosteroids concomitantly  consider discontinuation of the oral bps. for at least 3 months before & after oral surgery.

58. Patients with BRONJ Treatment objectives  eliminate pain, control infection of the soft and hard tissue, and minimize the progression or occurrence of bone necrosis. Surgical debridement is variably effective  Difficult to obtain a surgical margin in early stage.  Surgical treatment should be delayed if possible. Stage 3 disease might require resection and immediate reconstruction with a reconstruction plate or an obturator.

59. Hyperbaric oxygen therapy has some improvement in wound healing and long-term pain scores, but its use as the sole treatment modality for BRONJ cannot be supported at this time. Other non-invasive treatment: platelet-rich plasma, parathyroid hormone, and bone morphogenic protein..-->need more study. J Oral Maxillofac Surg 67:96-106, 2009, Suppl 1 J Oral Maxillofac Surg 2007; 65: 573- 80.

60. Mobile segments of bony sequestrum should be removed. Extraction of symptomatic teeth within exposed, necrotic bone should be considered because it is unlikely that extraction will exacerbate established necrotic process. Long-term discontinuation of IV Bps might be beneficial. (1~2 years) Discontinuation of oral Bps for 6-12 months may result in either spontaneous sequestration or resolution after debridement surgery.

61. Thank you for your attention!!