Case reports of BRONJ 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
General data
• Name : 葉 x 英
• Gender: Female
• Age : 76 y/o
• Native : 屏東縣
• Marriage status : Married
• Occupation : 無
Case 1
Chief Complaints
R’t submandibular swelling for 2 months
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
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 )
• Past Dental History
Extraction ,C&B,OD,RCT
• Attitude to Dental Tx : Fair
• Oral Habits
Alcohol : (-)
Betel quid : (-)
Cigarette (-)
• 3x3 cm
• Mixed RL with RO, irregular shape bony
destruction
Differential Diagnosis
●Tumor
• Benign (X)
• Malignancy
osteosacomaodontogenic malignancy tumor
●Infection
Osteomylities
Clinical impression
• Bisphosphonate- related osteonecrosis of
jaw (BRONJ)
Treatment course
• 97.12.11 (first visit) refer from LDC 97.12.11 (first visit) refer from LDC I&D
anaerobic culture, aerobic culture Rx: amoxicillin/ panadol / suwell
• 97.12.18 97.12.18
pus culture report
Clostridium bifermentans
→metronidazole(+) Ampicillin (+)
Clindamycin (+)
• 97.12.12~97.12.31 97.12.12~97.12.31 N/S irrigation
Antibiotic
• 98.1.7 98.1.7
arrange OP
• 98.1.15 98.1.15
OP: sequestrectomy +saucerization
• 98.3.4
• 98.5.6
Remove sequestrum (in OPD)
• 98.9.16 F/U
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
Chief Complaints
• Ask for oral examination for dental care after 骨針 application
• Bad smell from wound of extraction for
more than 1 year.
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.
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
Past Dental History
• Extraction, C&B fabrication, OD, scaling
Attitude to Dental Tx : Fair
Oral Habits Related to Malignancy:
• Alcohol : (-)
• Betel quid : (-)
• Cigarette : (-)
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
Panorex findings
There is an ill-defined bony destruction area
about 2x2cm in diameter over edentulous ridge of teeth 15 and 16 .
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)
Treatment Plan
• Antibiotic therapy
• Local debridement
• Advanced surgical management
98.8.13
Cases review of BRONJ
(KMUH)
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
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 %)
• BC
Z P+Z B+Z
Oral
IV 3 2
Oral+IV 1
• O
A :8 (oral)
P: pamidronate
Used form of BP
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
0 1 2 3
1(7.1%) 8(57.1%) 4(28.6%) 1(7.1%)
• Bony exposure:12/14(85.7%)
• Lesion Numbers
Location Upper Ant.
Upper premolar
Upper molar
Lower anterior
Lower premolar
Lower molar No.(%) 1 (5.6%) 2 (11.1%) 2(11.1%) 2(11.1%) 4(22.2%) 7(38.9%)
Locations
Locations
Lesion characteristics
•Symptoms and signs
Pain 14/14 100% 1
Swelling 9/14 64.3%
Delayed healing wound (sockets) 11/14 78.6% 3 neurosensory changes 3/14 21.4%
Pus 13/14 92.9% 2
Intraoral sinus tract extraoral fistula
8/14 57.1%
Tooth mobility 5/14 35.7%
X ray finding 14/14 100% 1
Clinical characteristics
Clinical characteristics
• Radiographic features
Radiolucency RO mixed
10 (71.4%) 0 4 (28.6 %)
• Lesion size
Maxium: 5*3 cm Minimum: 1*1 cm
•ONJ staging
0 1 2 3
0 1/14
(7.1%) 12/14
(85.7%)
2/14
(14.3%)
• Special events
none
extraction
Other2/14
(14.3%)
11/14 (78.6%) 1/14
(tooth Fx) (7.1%)
• 使用 bisphosphonate 到發病時間
< 1m 1m 2~3m 12m
2 4 1 1
11~30m 31~50m 51~70m 71~90m 91~110m
4 4 2 1 1
Event~ BRONJ Event~ BRONJ
Minima: 12 Maxima: 94 Average: 44.8 Minima: 12 Maxima: 94 Average: 44.8
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%)
• Periodontitis: 12/14 (85.7%)
• 感染性骨髓炎 :
Upper anterior
Upper premolar
Upper molar
Lower anterior
Lower premolar
Lower molar
3 site 0 site 0 site 3 site 7 site 8 site
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
Discussion
Discussion
INDICATIONS AND BENEFITS OF INDICATIONS AND BENEFITS OF
BISPHOSPHONATE 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 As a result, bone turnover becomes
profoundly suppressed, and over time the profoundly suppressed, and over time the
bone shows little physiologic remodeling bone shows little physiologic remodeling.
As a result, bone turnover becomes As a result, bone turnover becomes
profoundly suppressed, and over time the profoundly suppressed, and over time the
bone shows little physiologic remodeling
bone shows little physiologic remodeling.
INDICATIONS AND BENEFITS OF INDICATIONS AND BENEFITS OF
BISPHOSPHONATE THERAPY 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
• 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
Common bisphosphonates
Common bisphosphonates
Relative Potency Relative Potency
• Etidronate (Didronel) Etidronate (Didronel) 1 1
• Tiludronate (Skelide) Tiludronate (Skelide) 10 10
• Pamidronate (Aredia) Pamidronate (Aredia) 100 100
• Alendronate (Fosamax) Alendronate (Fosamax) 1,000 1,000
• Risedronate (Actonel) Risedronate (Actonel) 10,000 10,000
• Ibandronate (Boniva) Ibandronate (Boniva) 10,000 10,000
• Zolendronic acid (Zometa) Zolendronic acid (Zometa) >100,000 >100,000
*
Relative to etidronate (a non-nitrogen-containing
bisphosphonate with relative potency of 1).
BRONJ Case Definition 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
Incidence of BRONJ 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
RISK FACTORS 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
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
Staging of BRONJ 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
• Stage1 :
exposed and necrotic bone in patients who are asymptomatic and have no evidence of infection.• Stage2 : exposed and necrotic bone in patients
with pain and clinical evidence of infection(pain,
erythema , purulent drainage.)
• 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
Treatment stretagy 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
.
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.
Treatment strategy and advisements 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.
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.
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.
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 .
• 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.