OSTEONECROSIS OF THE JAW

Muhesh Rao
• MRONJ: Medication-related osteonecrosis of the jaw
• ORN: avascular bone necrosis 2° to radiation
• Osteomyelitis: thrombosis of small blood vessels leading to infection
within bone marrow
 MRONJ

• Pt may be considered to have MRONJ if ALL of the following

characteristics are present:
1. Current or previous tx with antiresorptive or antiangiogenic meds
2. Exposed bone or bone that can be probed through an intra oral or extra oral
fistula in the maxillofacial region that has persisted for more than 8 weeks
3. No hx of radiation therapy to the jaws or obvious metastatic diseases to the
jaw

• Ddx: alveolar osteitis, sinusitis, gingivitis/periodontitis, caries,

periapical pathology, fibro-osseous lesions, sarcoma, chronic sclerosing
osteomyelitis, TMJ disorders
BACKGROUND
Antiresorptive preparations commonly used in the US
Antiresorptive preparations commonly used in the UK
Medications used in the tx of various cancer that are antiangiogenic or targets of
the Vascular Endothelial Growth Factor (VEGF) pathway that have been
associated with jaw necrosis
Antiangiogenic drugs commonly used in the UK that have been associated with
jaw necrosis
 PATHOPHYSIOLOGY

1. Inhibition of osteoclastic bone resorption and remodelling

2. Inflammation/Infection
3. Inhibition of angiogenesis
4. Other hypotheses: soft tissue toxicity, innate or acquired immunity
dysfunction,
INHIBITION OF OSTEOCLASTIC BONE
RESORPTION AND REMODELING
INHIBITION OF ANGIOGENESIS
 RISK FACTOR FOR MRONJ

• Medication related risk factors among cancer patients

1. The risk of ONJ among cancer pt in placebo group = 0-1.9 cases/10000 pt1,2
2. The risk of ONJ among cancer pt exposed to zoledronate = 100
cases/10000 pt1,2
3. The risk of OMJ among cancer pt exposed to denosumab comparable to pt
exposed to zoledronate = 70-90 cases/10000 pt3,4
4. TKI (sunitinib) – disease improved on discontinuation and then rapidly
worsened with resumption of sunitinib5

Conclusion: When compared to cancer patients receiving antiresorptive

treatments, the risk of ONJ for patients without exposure to antiresorptive
medications is about 100x smaller6
1. Qi WX, Tang LN, He AN, et al: Risk of osteonecrosis of the jaw in cancer patients receiving denosumab: a meta-analysis of seven randomized controlled trials. Int J Clin Oncol, 2013.
2. Mauri D, Valachis A, Polyzos IP, et al: Osteonecrosis of the jaw and use of bisphosphonates in adjuvant breast cancer treatment: a meta-analysis. Breast Cancer Res Treat 116:433, 2009.
3. Fizazi K, Carducci M, Smith M, et al: Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377:813, 2011.
4. Stopeck A, Body JJ, Fujiwara Y, et al: Denosumab versus zoledronic acid for the treatment of breast cancer patients with bone metastases: results of a randomized phase 3 study. Eur J Cancer Supplements [EJC
supplements] 7:2, 2009.
5. Brunello A, Saia G, Bedogni A, et al: Worsening of osteonecrosis of the jaw during treatment with sunitinib in a patient with metastatic renal cell carcinoma. Bone 44:173, 2009.
6. Lo JC, O'Ryan FS, Gordon NP, et al: Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg 68:243, 2010.
 • Local factors
• Operative tx: xla 16-fold increased risk for ONJ when compared to cancer
patients without ONJ7
• Dental implant placement and endodontic or periodontal procedures is
unknown8

• Anatomic factor
• Mandible 73%, maxilla 22.5%, both jaws 4.5%8
• Denture wearers associated with increased risk of ONJ among cancer
patients exposed to zolendronate9

• Demographic and systemic factors and other medications

• Higher in female
• Tobacco use, corticosteroid and co-morbid conditions all have shown
increased risk for MRONJ9
7. Saad F, Brown JE, Van Poznak C, et al: Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases.
Ann Oncol 23:1341, 2012.
8. Fehm T, Beck V, Banys M, et al: Bisphosphonate-induced osteonecrosis of the jaw (ONJ): Incidence and risk factors in patients with breast cancer and gynecological malignancies. Gynecol Oncol 112:605, 2009.
9. Kyrgidis A, Vahtsevanos K, Koloutsos G, et al: Bisphosphonate-related osteonecrosis of the jaws: a case-control study of risk factors in breast cancer patients. J Clin Oncol 26:4634, 2008.
 DIAGNOSING

• ONJ is a clinical diagnosis based on history and physical exam. Radiographic

features of ONJ remain relatively nonspecific.10
• Plain film radiography is usually unremarkable in the early stages of the
disease because decalcification is limited. 10
• Imaging modalities used as adjunctive assessment in the evaluation of the ONJ
patient may include plain radiographs, CT, magnetic resonance imaging (MRI),
and functional imaging with bone scintigraphy and positron emission
tomography (PET).10
• Presence of localized or diffuse osteosclerosis or a thickening of the lamina
dura on plain film imaging may predict future sites of exposed necrotic bone. 10

10. Hutchinson M, O’Ryan F, Chavez V, et al. Radiographic findings in bisphosphonate-treated patients with stage 0 disease in the absence of bone exposure. J Oral Maxillofac Surg. 2010;68:2232–40.
STAGING
 STAGE DESCRIPTION
At risk category No apparent necrotic bone in patients who have been
treated with either oral or IV bisphosphonates
Stage 0 No clinical evidence of necrotic bone, but non-specific
clinical findings, radiographic changes and symptoms
Stage 1 Exposed and necrotic bone, or fistulae that probes to bone,
in patients who are asymptomatic and have no evidence of
infection
Stage 2 Exposed and necrotic bone, or fistulae that probes to bone,
associated with infection as evidenced by pain and
erythema in the region of the exposed bone with or without
purulent drainage
Stage 3 Exposed and necrotic bone or a fistula that probes to bone
in patients with pain, infection, and one or more of the
following:
• exposed and necrotic bone extending beyond the region of
alveolar bone,(i.e., inferior border and ramus in the mandible,
maxillary sinus and zygoma in the maxilla) resulting in
pathologic fracture
• extra-oral fistula,
• oral antral/oral nasal communication
• osteolysis extending to the inferior border of the mandible or
sinus floor
 Asymptomatic, nonhealing extraction site in a patient Exposed, necrotic palatal torus associated with localized mucosal
with metastatic prostate cancer and a history of zoledronate inflammation in a patient with a long history of
therapy (Stage 1 MRONJ). alendronate exposure (Stage 2 MRONJ).
Large segment of necrotic right mandible in a patient with end-stage breast cancer and a history of zoledronate exposure (Stage 3 MRONJ)
Exposed necrotic bone, redness and suppuration in the A necrotic bone exposure in the region of tooth 37
area of previously extracted 38
Clinical view of exposed necrotic bone Panoramic radiography of the patient’s jaw
 A-before the demarcation of
the necrotic bone

B-after the demarcation of

the necrotic bone

C-immediately after
sequestrectomy

D-the surgically removed

sequester is shown

Bone necrosis on the hard palate related to chemotherapy

Panoramic radiograph. Radiologic image shows a full thickness right jaw fracture.
Computed tomography scan of the head; coronal view. Coronal view shows bisphosphonate-related osteonecrosis lesions, fracture of right jaw and thickening
of the soft tissue adjacent the inferior right hemi mandibular surface in a 69-year-old woman with breast cancer history and treated with zoledronic acid for 23
administrations.
Computed tomography (CT) scan of the head; transversal view. CT scan of the face, neck and chest was performed without contrast,
showing pathological fracture of right jaw and periosteal reaction, besides mixed lytic and sclerotic lesion of the jaw.
Three-dimensional computed tomography reconstruction of the head. Radiological image shows a noticeable pathological
fracture of right jaw in a 69-year-old woman with breast cancer history and treated with zoledronic acid.
TREATMENT
 INITIAL MANAGEMENT OF PATIENTS
AT RISK OF MRONJ

• Before starting on anti-resorptive or anti-angiogenic drug therapy, or as soon as

possible thereafter aim to get the patient as dentally fit as possible, prioritizing
preventive care.
• Preventive dental regimes can decrease the risk of oral complications in this
patient group by reducing the need for subsequent extractions or other
procedures which impact on bone. 11-14

11. Kyrgidis A, Tzellos TG, Toulis K, Arora A, Kouvelas D, Triaridis S. An evidence-based review of risk-reductive strategies for osteonecrosis of the jaws among cancer patients. Current Clinical Pharmacology.
2013;8(2):124-134.
12. Bramati A, Girelli S, Farina G, et al. Prospective, mono-institutional study of the impact of a systematic prevention program on incidence and outcome of osteonecrosis of the jaw in patients treated with bisphosphonates
for bone metastases. Journal of Bone and Mineral Metabolism. 2015;33(1):119-124.
13. Vandone AM, Donadio M, Mozzati M, et al. Impact of dental care in the prevention of bisphosphonateassociated osteonecrosis of the jaw: a single-center clinical experience. Annals of Oncology. 2012;23(1):193-200.
14. Bonacina R, Mariani U, Villa F, Villa A. Preventive strategies and clinical implications for bisphosphonate-related osteonecrosis of the jaw: a review of 282 patients. Journal of the Canadian Dental Association.
2011;77:b147.
 CONTINUING MANAGEMENT OF
PATIENTS AT RISK OF MRONJ

Low Risk Patients

• If an extraction or another procedure that impacts on bone is required:

• Discuss the risks and benefits associated with treatment with the patient (or
carer, where appropriate) to ensure valid consent.
• Proceed with the treatment as clinically indicated
• Do not prescribe antibiotic or antiseptic prophylaxis unless required for other
clinical reasons
• Advise the patient to return if they have any concerns, such as unexpected
pain, tingling, numbness, altered sensation or swelling in the extraction area
• Review healing. If the extraction socket is not healed at 8 weeks you can
suspect that the patient has MRONJ.
 High Risk Patients

• If an extraction is indicated, explore all possible alternatives where

teeth could potentially be retained e.g. retaining roots in absence of
infection.
• If extraction remains the most appropriate treatment:
• Discuss the risks and benefits associated with treatment with the patient (or
carer, where appropriate) to ensure valid consent.
• Proceed with the extraction as clinically indicated
• Do not prescribe antibiotic or antiseptic prophylaxis unless required for other
clinical reasons
• Advise the patient to return if they have any concerns, such as unexpected
pain, tingling, numbness, altered sensation or swelling in the extraction area
• Review healing. If the extraction socket is not healed at 8 weeks you can
suspect that the patient has MRONJ
 STAGE TREATMENT
At risk category • No treatment indicated
• Patient education
Stage 0 • Systemic management, including the use of
pain medication
and antibiotics
Stage 1 • Antibacterial mouth rinse
• Clinical follow-up on a quarterly basis
• Patient education and review of indications
for continued bisphosphonate therapy

Stage 2 • Symptomatic treatment with oral antibiotics

• Oral antibacterial mouth rinse
• Pain control
• Debridement to relieve soft tissue irritation
and infection control

Stage 3 • Antibacterial mouth rinse

• Antibiotic therapy and pain control
• Surgical debridement/resection for longer
term palliation of infection and pain
 OSTEORADIONECROSIS

• Exposed irradiated bone that fails to heal over a period of 3 months without
any evidence of persisting or recurrent tumour15
• Most frequently reported reason is radiation arteritis
• Triple ‘H’ – hypocellular, hypovascular, hypoxic environment leads to
pathological outcome.
• Hypocellular and fibroatrophic component is suggested by some authors 16
• Radiation dose between 60 and 72 Grays has an effect on the endothelial
linings of the blood vessels, causing vasculitis and endarteritis, which lead to
ischemia and hypoxia due to hypovascularity17

15. Marx RE. Osteoradionecrosis; a new concept of its pathophysiology. J Oral Maxillofac Surg 1983 41: 283–288.
16. Teng MS, Futran ND. Osteoradionecrosis of the mandible. Curr Opin Otolaryngol Head Neck Surg, 2005; 13(4):217- 221.
17. Marx RE. A new concept in the treatment of osteoradionecrosis. J Oral Maxillofac Surg, 1983; 41:351- 357.
 INDUCING FACTOR

• Surgical trauma, commonly a dental extraction.

• Mechanical injuries, poor oral health can induce the necrosis as well
• Some systemic and chronic diseases (diabetes, cardiovascular diseases) and
bad habits (smoking, alcohol consuming) can worsen the condition18
• less than 10%, ORN occurs spontaneously18
• Prevalence of ORN in those with cancer of the head and neck is around 7.4%
after conventional radiotherapy, 5.1% after intensity-modulated radiotherapy
(IMRT) and 6.8% after chemo-radiotherapy19

18. Vanderpuye V, Goldson A. Osteoradionecrosis of the mandible. A case report. J Natl Med Assoc, 2009; 92:579- 584.
19. Peterson DE, Doerr W, Hovan A, et al. Osteoradionecrosis in cancer patients: the evidence base for treatmentdependent frequency, current management strategies, and future studies. Support Care Cancer, 2010;
18:1089-1098.
 STAGING

Marx classification based on response to HBO therapy

STAGE DESCRIPTION

Stage I Exposed alveolar bone without

pathologic fracture, which responds to
HBO therapy

Stage II Disease does not respond to HBO

therapy, and requires sequestrectomy
and saucerization

Stage III Full-thickness bone damage or

pathological fracture, usually requires
complete resection and reconstruction
with free tissue
Kagan and Schwartz (2002) based on clinical finding and treatment
STAGE DESCRIPTION TREATMENT
Stage 1 Superficial involvement, Majority improve with
only cortical bone exposed conservative management
& minimal soft tissue
ulceration
Stage 2 Localized involvement of Majority improve with
A. Minimal soft tissue ulceration mandible, exposed cortical conservative management,
B. Soft tissue necrosis and medullary bone are surgical procedures or
necrotic & possible or HBO
cutaneous fistula
Stage 3 Diffuse involvement of the
A. Minimal soft tissue ulceration mandible, including the
B. Soft tissue necrosis lower border. Pathologic
fracture may occur
Notani et al. based on clinical findings
STAGE DESCRIPTION
Stage I ORN confined to alveolar bone
Stage II ORN limited to the alveolar bone
and/or mandible above the level of the
inferior alveolar canal
Stage III ORN involving the mandible below the
level of the inferior alveolar canal and/
or skin fistula and/or pathological
fracture
 CLINICAL FINDINGS

• Ulceration or necrosis of the mucosa with exposure of necrotic bone for longer
than 3 months
• Pain
• Trismus
• Suppuration in the area
• Dysaesthesia or paraesthesia
• Fetor oris
• Dysgeusia
• Progression of ORN may lead to pathological fractures, intra-oral or extra-oral
fistulae and local or systemic infection
• Difficulties in mouth opening, mastication and speech
• External beam radiation therapy (EBRT), osseous alterations usually appear in
the body of the mandible (premolar and molar regions)
• Pt treated with brachytherapy, the lingual or buccal surfaces are affected
69-year-old man presented with pain and a non-healing wound in The orthopantomogram revealed pathologic fracture of the left lower jaw
the left lower jaw. The patient was an active smoker, suffered from
pharynx cancer and had received radiotherapy (external beam
radiotherapy with standard field sizes, conventional fractionation
and mean dose 64 Gy) and chemotherapy. Clinically, exposed
necrotic bone in the left lower jaw, inflammation, swelling and
inferior alveolar nerve hypesthesia was present
 TREATMENT

• Recent studies have shown that incidence the ORN decreased to be

lower than 5%
• Prevention of ORN is an extremely important part of the
comprehensive management of patients who undergo external beam
radiation therapy to the head and neck.
• Eduardo PG, et al (2013):
• Teeth with poor prognosis should be extracted 21 days before initiation of
radiation therapy
• Maintenance of meticulous oral hygiene and fluoride should be applied to
the dentition daily via custom molded trays.
• Weekly check up during RT and monthly follow- ups for the first six months
 • Conservative mx
• long- term antibiotics, local wound irrigation, debridement, sequestrectomy
and hyperbaric oxygen therapy.
• Surgical approaches such as small sequesters removal and debridement of
superficial bone until bleeding occurs are regarded in many studies as
conservative management
• Marx’s protocol, which means that the patient should receive HBO of 30
sessions before and 10 sessions after operation at 2.4 atm. for 90 minutes
sessions
• HBO is nowadays recommended for use as adjuvant therapy, its
effectiveness has been questioned and most cases of ORN can be managed
successfully without HBO according to the most recent literature. 20-22

20. Annane D, Depondt J, Aubert P et al. Hyperbaric oxygen therapy for radionecrosis of the jaw—a randomized, placebo-controled, double-blind trial from the ORN96 study group. J Clin Oncol 2004 22: 4893–4900.
21. Bessereau J, Annane D. Treatment of osteoradionecrosis of the jaw: the case against the use of hyperbaric oxygen. J Oral Maxillofac Surg 2010 68: 1907–1910.
22. Pitak-Arnnop P, Hemprich A, Dhanuthai K et al. A systematic review in 2008 did not show value of hyperbaric oxygen therapy for osteoradionecrosis. J Oral Maxillofac Surg 2010 68: 2644–2645.
• Surgical intervention
• only option in patients with late stage of ORN
• extension of surgical removing of bone tissue depends of the severity of
necrosis (highly recommended to remove all necrotic tissue)
• complete removing of the fistulous tract is recommended as well
• Reconstruction if large amount of bone loss post surgery
• PENTOCLO therapy
• based on the concept of antioxidant and anti-fibrotic treatment of fibro-
atrophy
• 1st phase: 2g Amoxicillin-clavulanic acid + 1g Ciprofloxacin + 50mg
Fluconazole + 20mg Prednisolone + 20mg Omeprazole (4-6 weeks)
• 2nd phase: 800mg Pentoxifylline + 1g Tocopherol + 1600mg Clodronate (5x
a week, Mon-Fri) + 20mg Prednisolone (2x a week, Sat-Sun)
• combination is initiated to reduce the already constituted fibrotic process
(pentoxifylline vitamin E combination), reduce bone destruction (clodronate)
and stimulate healing.
• Medical treatment by PENTOCLO appears to be an effective, inexpensive
treatment that is almost devoid of adverse effects.
 REFERENCES

• Qi WX, Tang LN, He AN, et al: Risk of osteonecrosis of the jaw in cancer patients receiving denosumab: a
meta-analysis of seven randomized controlled trials. Int J Clin Oncol, 2013.
• Mauri D, Valachis A, Polyzos IP, et al: Osteonecrosis of the jaw and use of bisphosphonates in adjuvant breast
cancer treatment: a meta-analysis. Breast Cancer Res Treat 116:433, 2009.
• Fizazi K, Carducci M, Smith M, et al: Denosumab versus zoledronic acid for treatment of bone metastases in
men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377:813, 2011.
• Stopeck A, Body JJ, Fujiwara Y, et al: Denosumab versus zoledronic acid for the treatment of breast cancer
patients with bone metastases: results of a randomized phase 3 study. Eur J Cancer Supplements [EJC
supplements] 7:2, 2009.
• Brunello A, Saia G, Bedogni A, et al: Worsening of osteonecrosis of the jaw during treatment with sunitinib in
a patient with metastatic renal cell carcinoma. Bone 44:173, 2009.
• Lo JC, O'Ryan FS, Gordon NP, et al: Prevalence of osteonecrosis of the jaw in patients with oral
bisphosphonate exposure. J Oral Maxillofac Surg 68:243, 2010.
• . Saad F, Brown JE, Van Poznak C, et al: Incidence, risk factors, and outcomes of osteonecrosis of the jaw:
integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases.
Ann Oncol 23:1341, 2012.
• Fehm T, Beck V, Banys M, et al: Bisphosphonate-induced osteonecrosis of the jaw (ONJ): Incidence and risk
factors in patients with breast cancer and gynecological malignancies. Gynecol Oncol 112:605, 2009.
• Kyrgidis A, Vahtsevanos K, Koloutsos G, et al: Bisphosphonate-related osteonecrosis of the jaws: a case-
control study of risk factors in breast cancer patients. J Clin Oncol 26:4634, 2008.
• Hutchinson M, O’Ryan F, Chavez V, et al. Radiographic findings in bisphosphonate-treated patients with stage
0 disease in the absence of bone exposure. J Oral Maxillofac Surg. 2010;68:2232–40
• . Kyrgidis A, Tzellos TG, Toulis K, Arora A, Kouvelas D, Triaridis S. An evidence-based review of risk-
reductive strategies for osteonecrosis of the jaws among cancer patients. Current Clinical Pharmacology.
2013;8(2):124-134.
• Bramati A, Girelli S, Farina G, et al. Prospective, mono-institutional study of the impact of a systematic
prevention program on incidence and outcome of osteonecrosis of the jaw in patients treated with
bisphosphonates for bone metastases. Journal of Bone and Mineral Metabolism. 2015;33(1):119-124.
• Vandone AM, Donadio M, Mozzati M, et al. Impact of dental care in the prevention of
bisphosphonateassociated osteonecrosis of the jaw: a single-center clinical experience. Annals of Oncology.
2012;23(1):193-200.
• Bonacina R, Mariani U, Villa F, Villa A. Preventive strategies and clinical implications for bisphosphonate-
related osteonecrosis of the jaw: a review of 282 patients. Journal of the Canadian Dental Association.
2011;77:b147.
• Marx RE. Osteoradionecrosis; a new concept of its pathophysiology. J Oral Maxillofac Surg 1983 41: 283–288.
• Teng MS, Futran ND. Osteoradionecrosis of the mandible. Curr Opin Otolaryngol Head Neck Surg, 2005;
13(4):217- 221.
• Marx RE. A new concept in the treatment of osteoradionecrosis. J Oral Maxillofac Surg, 1983; 41:351- 357.
Vanderpuye V, Goldson A. Osteoradionecrosis of the mandible. A case report. J Natl Med Assoc, 2009; 92:579-
584.
• Peterson DE, Doerr W, Hovan A, et al. Osteoradionecrosis in cancer patients: the evidence base for
treatmentdependent frequency, current management strategies, and future studies. Support Care Cancer, 2010;
18:1089-1098
• Annane D, Depondt J, Aubert P et al. Hyperbaric oxygen therapy for radionecrosis of the jaw—a randomized,
placebo-controled, double-blind trial from the ORN96 study group. J Clin Oncol 2004 22: 4893–4900.
• Bessereau J, Annane D. Treatment of osteoradionecrosis of the jaw: the case against the use of hyperbaric
oxygen. J Oral Maxillofac Surg 2010 68: 1907–1910.
• Pitak-Arnnop P, Hemprich A, Dhanuthai K et al. A systematic review in 2008 did not show value of hyperbaric
oxygen therapy for osteoradionecrosis. J Oral Maxillofac Surg 2010 68: 2644–2645
THANK YOU