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

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

2003

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

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

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

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

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

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

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

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)

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

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

gross bone destruction osteosclerotic areas lamellated periostal reaction fistula tract

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

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

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

EPIDEMIOLOGY ONJ associated with oral BP Incidence is very low: < 1% (0.01-0.34%) 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

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 ?

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

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

Why only the jawbones?

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

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)

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

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

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 ??

ONJ - risk reduction strategies BP 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

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

Genomewide association for rs12440268 and rs4340077 (Validated).

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