1. Osteonecrosis of the jaws
An update
Dr Stefano Fedele DMD PhD
Head of Department of Clinical Research
Senior Clinical Lecturer/Honorary Consultant in Oral Medicine
UCL/UCLH Eastman Institute and Hospital

2. BISPHOSPHONATES
Inhibitors of osteoclast activity
More than 190 million prescriptions dispensed globally
$ 8,000 million in revenue
Used in several clinical scenarios
Relatively safe profile

5. 2003

7. Medication-Related OsteoNecrosis of the Jaws (MRONJ)
Associate medications
ONJ Definition
Clinical features
Radiological features (X-ray, CT, MRI, functional imaging)
Epidemiology
Risk factors
Pathogenesis
Management and current research

8. OsteoNecrosis of the Jaws (ONJ): Associated agents
ANTIRESORPTIVES
Bisphosphonates (zoledronic acid, pamidronate, sodium clodronate, ibandronate, etidronate, alendronate)
Denosumab
ANTIANGIOGENICS
Bevacizumab
Sunitinib
Cabozantinib
Temsirolimus
Aflibercept
Sorafenib

10. Definition of MRONJ (traditional)
Clinical diagnosis
Imaging can support diagnosis
Biopsy usually not needed
6-8 weeks exposure of jaw bone (transmucosal or trans-cutaneous)
History of BP, denosumab or antiangiogenic therapy
No history of radiotherapy to the H&N

11. Clinical features
Trans-mucosal bone exposure
Avascular necrotic ischaemic bone
(yellowish/greyish/brownish discolouration)
Trans-cutaneous bone exposure
Inflammation (swelling and erythema) of surrounding soft tissues

16. Additional clinical features
Mucosal sinus tract
Cutaneous sinus tract
Bone/gingival swelling
Pain (from mild to severe)
Infection (local)
Infection (spreading to loco-regional deep spaces)
Sinusitis
Trauma to adjacent soft tissues
Tooth mobility
Paresthaesia
Cervical lymphadenopathy

24. Non-exposed MRONJ
~25% of MRONJ present with non-exposed variant

26. Clinical features of non-exposed MRONJ
Jaw bone pain – dentally unexplained (often mimicking
toothache) ( )
Sinus tract (++++)
Gingival swelling/bone enlargement
Radiological abnormalities (in 30% of cases)
Less commonly: paraesthesia/anaesthesia, tooth mobility, mandibular fracture

30. RADIOLOGICAL FEATURES
Not always parallel clinical features
Can be non-specific
CT and MRI are superior to X-ray in (i) identifying necrotic areas
and (ii) defining necrosis extension
Bone Scintigraphy/PET is non-specific but very sensitive
CT, MRI and Scintigraphy can identify necrotic areas in absence
of obvious clinical features (bone exposure)

31. X-ray features Osteolysis/bone destruction Sclerotic changes
Narrowing/sclerosis of the marrow space
Fractures

34. CT features
Osteolysis/bone destruction associated with sclerotic changes
Cortex erosion
Periostal reaction
Narrowing/sclerosis of the marrow space
Fractures

35. gross bone
destruction
osteosclerotic areas
lamellated periostal
reaction
fistula tract

38. Bone scintigraphy, PET
Functional imaging can support diagnosis in up to 90% of MRONJ
patients
Can identify early non-exposed necrotic areas
Further research needed

39. EPIDEMIOLOGY
Controversial and inconsistent data
Variable definition/diagnostic criteria
Small single centre studies
Two different populations:
1) oral BP and low dose denosumab
2) iv BP and high dose denosumab

40. EPIDEMIOLOGY
MRONJ associated with iv BP and high dose denosumab
Incidence ranges from 2% to 28%
The majority of studies: 5-8% (<10%)
70-80% cases: multiple myeloma and breast cancer patients
Incidence is time-dependent and dose-dependent
Time to onset ranges from 4 to 120 months
A number of risk factors have been identified

43. EPIDEMIOLOGY
ONJ associated with oral BP
Incidence is very low: < 1% ( %)
But million of individuals use oral BP worldwide long-term
Incidence is time-dependent and dose-dependent
Time to onset ranges from 3 to 10 years

44. RISK FACTORS
Length of therapy (cumulative dosage) > 90%
Dental surgery (e.g. extraction) or infection = 40-50%
Corticosteroid therapy
Thalidomide
Chemotherapy
Anti-angiogenic drugs
Diabetes
Smoking
Predisposing genetic factors ?

48. PATHOGENESIS
Unclear
Little experimental evidence
4 major theories/hypotheses
- Infection
- Excessive reduction of bone turn-over
- Impaired angiogenesis Toxicity to soft tissues

49. Over-reduction of turn-over
Avascular/acellular bone
Ischaemic Necrosis/Inflammation
Accumulation of micro-cracks
Bone exposure (?)
Secondary infection

51. Why only the jawbones?

55. STAGING
Accurate staging requires CT scan (CBCT)
Staging guides treatment > inaccurate staging can result into wrong therapeutic choice
Staging also helps to
predict prognosis

56. MANAGEMENT
Little high quality evidence
Most studies reported no consistent benefits from surgery
Most studies reported no notable benefit from HBO
Symptomatic therapy and infection control is advised in most cases
No evidence that suspension of BP therapy translates into a better prognosis or improvement in symptoms (ZOL half-life is 10+ years)

57. SYMPTOMATIC THERAPY
Intermittent/long-term pain control
Intermittent/long-term antibiotics (with culture/sensitivity studies where needed)
Topical antibacterials (chlorhexidine; hydrogen peroxide) to minimize bacterial deposits on the exposed bone
Wound cleaning/Irrigation of exposed bone/fistulas

59. Surgical therapy
Conservative surgery (sequestrectomy +/- currettage)
Resective surgery
Resection and flap reconstruction
Nd: YAG Laser

62. Surgical therapy
More recent papers have reported positive outcomes with surgical therapy
Large resection with margins in clinically uninvolved bone
Patient selection is important
Possible alternative to medical management ??

64. ONJ - risk reduction strategiesBP
BP withdrawal (permanent or temporary)
Trigger factors
Dental screening before starting BP therapy
Extraction/surgery before starting BP therapy
Prevention of dental infection (via accurate preventive dentistry plan) and gingival/mucosal trauma during BP therapy
Avoid surgery whenever possible during BP therapy
Antibiotics
When surgery to the jawbones is needed
Individual risk calculation
Serum CTX levels

65. 4. Individual risk calculation - GWAs
Large Network of clinical centres to collect blood/DNA and
detailed phenotype from ONJ patients and controls
25 sites
8 countries (Europe and Asia)
600+ recruited, of whom ~400 are ONJ cases
Discovery and validation phase completed
Next step: replication in a new cohort

66. Genomewide association for rs12440268 and rs4340077 (Validated).

67. Osteonecrosis of the jaws
An update
Dr Stefano Fedele DMD PhD
Head of Department of Clinical Research
Senior Clinical Lecturer/Honorary Consultant in Oral Medicine
UCL/UCLH Eastman Institute and Hospital