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

Case reports of BRONJCase 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 HistoryPast 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

osteosacoma

odontogenic malignancy tumor

●Infection

Osteomylities

Clinical impression• Bisphosphonate- related osteonecrosis of

jaw (BRONJ)

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 (+)

• 97.12.12~97.12.3197.12.12~97.12.31 N/S irrigation Antibiotic • 98.1.7 98.1.7 arrange OP• 98.1.1598.1.15 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 HistoryPast 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, scalingAttitude 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 dataSex: 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/oReason 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%)

LocationsLocations

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 Other

2/14

(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~ BRONJEvent~ BRONJ

Minima: 12 Maxima: 94 Average: 44.8Minima: 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

DiscussionDiscussion

INDICATIONS AND BENEFITS OF INDICATIONS AND BENEFITS OF BISPHOSPHONATEBISPHOSPHONATE

• 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 remodelingbone 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 remodelingbone shows little physiologic remodeling.

INDICATIONS AND BENEFITS OF INDICATIONS AND BENEFITS OF BISPHOSPHONATE THERAPYBISPHOSPHONATE 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 Bisphosphonates1. 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


Common bisphosphonatesCommon bisphosphonates

Relative PotencyRelative Potency

• Etidronate (Didronel)Etidronate (Didronel) 11

• Tiludronate (Skelide)Tiludronate (Skelide) 1010

• Pamidronate (Aredia)Pamidronate (Aredia) 100100

• Alendronate (Fosamax)Alendronate (Fosamax) 1,0001,000

• Risedronate (Actonel)Risedronate (Actonel) 10,00010,000

• Ibandronate (Boniva)Ibandronate (Boniva) 10,00010,000

• Zolendronic acid (Zometa)Zolendronic acid (Zometa) >100,000>100,000

*Relative to etidronate (a non-nitrogen-containingbisphosphonate with relative potency of 1).

BRONJ Case DefinitionBRONJ 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


Incidence of BRONJIncidence 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%.


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.


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


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 necrosisRadiographic 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 fracture3. Extraoral fistula4. Oral antral/oral nasal communication5. Osteolysis extending to the inferior border of the

mandible or sinus floor

Treatment stretagyTreatment stretagyAt 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 advisementsTreatment strategy and advisementsPatients 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.

• 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.

Thank you for your attention!!Thank you for your attention!!

Documents

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

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