Osteonecrosis of the Jaws

Ninian PeckittFRCS FFD RCS FDS RCS FACCS

Oral and Maxillofacial Surgeon / Facial Plastic Surgeon

Cbfa1

Core binding factor 1 (Cbfa1) master gene control osteoblast differentiation (6, 7)

OPG/RANKL/RANK System

RANKL binds its receptor RANK on osteoclast lineage cells

RANKL Knockout Mice• severe osteopetrosis / defects in tooth eruption (25)

• complete absence of osteoclasts

• defects of T and B cells / lack lymph nodes

– defects in thymic differentiation

– normal splenic structure and Peyer’s patches (25)

• Unexpected defects in mammary gland development (26)

OsteoclastogenesisBasic Multicellular Units.

Bone constantly resorbed and formed at specific sites

1. Osteoclast Migration to sites (activation)

2. resorption of a packet of bone

3. a reversal phase characterized by:

– apoptosis of the osteoclasts

– followed by a phase of bone formation by newly formed osteoblasts

Osteoclastogenesis

1

1 RANKL binds RANK

2 M-CSF, binds c-Fms

2

3 OPG blocks RANKL

3

TNF IL-1

Osteoclastogenesis

TNF IL-1 M-CSF

Pool of Cells Increased

TGF-ß Oestrogen - OPG PTH Glucocorticoids - RANKL OPG Vit D3 RANKL

Cbfa1 RANKL

Osteoblaststs

Osteoclasts

Bone Turnover• Bone turnover is moderate

• resorption = formation (aprox)

• Excessive remodeling

– Bone turnover Bone Strength

– Bone Cavities - “stress risers”

– Microcracks - weakening

– trabecular thinning / perforation / connectivity

– cortical thinning / cortical porosity / mineralization

– Low bone mass (osteopenia) or osteoporosis

Bone Remodelling RANKL• RANKL upregulation

– PTH, 1,25-dihydroxyvitamin D (1,25-[OH]2-D)– Calcium– Glucocorticoids– prostaglandin E2inteleukin (IL)-1α, IL-6, IL-11, and IL-17,

• RANKL downregulation

– transforming growth factor (TGF)-β

Bone Remodelling OPG• OPG

– 1,25-(OH)2-D– Calcium– IL-1α, IL-6, IL-11, IL-17– oestrogen– TGF-β– bone morphogenetic protein (BMP)-2,

• OPG – PTH– Glucocorticoids– prostaglandin E2– insulin-like growth factor 1 (Collin-Osdoby 2004).

Drug and Bone• Antiresorptive (also called anti-catabolic)

– Estrogens– bisphosphonates (eg, alendronate, risedronate, ibandronate, zoledronate), – Calcitonin– raloxifene

• Anabolic (Riggs and Parfitt 2005)

Teriparatide, recombinant human (PTH) 1–34, anabolic / bone forming - strengthens bone and reduces fracture risk increasing bone formation / size

• Antiresorbtive and Anabolic

Strontium ranelate, Dual action antiresorptive and anabolic properties.

• Stabilisationor increase BMD:

– filling in the remodeling space and prolonging secondary mineralization– maintaining bone microarchitecture– reducing trabecular perforation,– ecreasing cortical porosity.

Bisphosphonates - Basic Chemistry• Pyrophosphate

• Substitution of Carbon for Oxygen

– Resistance to hydrolysis– Bone matrix accumulation– Extremely long half-life

• Nitrogen-containing side chain

– Increases potency, toxicity– Direct link to ONJ cases

Action of Bisphosphonates

• Osteoclastic toxicity

– Apoptosis

– Inhibited release of bone induction proteins

BMP, ILG1, ILG2

– Reduced bone turnover, resorption

– Reduced serum calcium

– Hypermineralisation“sclerotic” changes lamina dura - alveolar bone

Medical Indications for IV BPs• Bone metastasis

• Hypercalcemia

• RANKL-mediated osteoclastic resorption

• Multiple myeloma, • Breast CA, Prostate CA• Paracrine-like effect

• PTH-like peptide osteoclastic resorption

• Small cell carcinoma• oropharyngeal cancers• Endocrine-like effect

Indications for Oral Bisphosphonates• Paget’s Disease of bone

– Accelerated bone turnover– Reduced compressive strength– increased vascularity– Bone pain– Elevated AP levels

• Osteoporosis

Effects of estrogen loss:– Decreased bone turnover / renewal– Adipocyte differentiation– osteoblastic differentiation– increased fibrofatty marrow– Progressively porotic bone– DEXA scan for BMD values Paget’s Disease

Pharmacokinetics• Oral Bisphosphonates

– Absorbed in small intestine– Less if taken with meal– 1-10% available to bone

• Circulating half-life: 0.5-2 hrs– Rapid uptake into bone matrix– 30-70% of IV/oral dose accumulates in bone– Remainder excreted in urine

• Repeated doses accumulate in bone– Removed only by osteoclast-mediated resorption

– “Biologic Catch 22”

Denosumab• More potent inhibitor of osteoclasts

• Binds to RANKL cf osteoprotegerin (OPG) – Longer Duration

• prevents interaction of RANKL and RANK

• reduces osteoclast

– Differentiation– Activity– survival

• inhibits bone resorption

Denosumab

Denosumab• Osteonecrosis of the Jaws (ONJ) Reported

• ONJ - Function of Osteoclast Depletion

• Common Problem with all drugs inhibiting Osteoclasis

• Denosumab ONJ reversible ?

• Note CTX levels may be very low <10pg/ml

• Rate of recovery faster than Bisphosphonates?

• CTX Monitoring required

Osteonecrosis of the Jaws

Definition ONJ (Sawatari and Marx 2007)

Exposed bone in the mandible or maxilla that fails to heal within 8 weeks in a patient receiving, or who has received, a systemic bisphosphonate, and who has not received local radiation therapy to the jaws.

ONJ

• following oral surgery (dental extraction)

• spontaneous cases are recorded

• Alveolar Bone x15 turnover (Marx)

Classification of Osteonecrosis of the Jaws

Grade Severity1 Asymptomatic2 Mild3 Moderate4 Severe

Grade Size (diameter*)

1A Single lesion, <0.5 cm

1B Multiple lesions, largest <0.5 cm

2A Single lesion <1.0 cm

2B Multiple lesions, largest <1.0 cm

3A Single lesion, ≤2.0 cm

3B Multiple lesions, largest ≤2.0 cm

4A Single lesion >2.0 cm

4B Multiple lesions, largest >2.0 cm

*Lesion size measured as the largest diameter

AAOMS Staging of ONJ• Patients at risk (Subclinical)

• No apparent exposed/necrotic bone in pts treated w/ IV or oral BPs

• Patients with ONJ

• Stage 1: Exposed/necrotic bone, asymptomatic, no infection

• Stage 2: Exposed/necrotic bone, pain, infection

• Stage 3: Exposed/necrotic bone, pain, infection + :

Pathologic fracture

or … extra-oral fistula

Or … osteolysis extending to inferior border

AAOMS Stage I Lesions

AAOMS Stage II Lesions

AAOMS Stage III Lesions

AAOMS Stage 0 Lesions• Spontaneous Numbness and Pain

• No exposed bone

• No prior dental antecedent

• Positive image findings:

– Sclerosis

– Positive bone scan

Osteonecrosis of the JawsONJ (Sawatari and Marx 2007)

• 6 doses of monthly iv biphosphonate or

• 3 yrs of weekly alendronate or risedronate

are required…….

…….. before a patient is at risk for ONJ

96% ONJ - iv bisphosphonates

4% ONJ - oral bisphosphonates

Note 25-35% non compliance for Oral Medication

Osteonecrosis of the JawsONJ http://jada.ada.org/cgi/content/full/137/8/1144

• Initially denied by Industry – (Dr R.E. Marx attacked when ONJ reported)

• ONJ Low Risk 0.7 per 100,000 person-years’ exposure to alendronate (Fosamax)

• but reported 25-35% non compliance in oral medication

• 50% compliance required for therapeutic effect www.ncbi.nlm.nih.gov/pmc/articles/PMC3017316/

• Risk is therefore underestimated by circa 35%

• Other nitrogen-containing oral bisphosphonates expected to have a similar risk profile

• ONJ can occur spontaneously

• ONJ associated with dental extractions

• ONJ increase >65 years

Risk of ONJ www.ncbi.nlm.nih.gov/pmc/articles/PMC3017316/

Risk is under-reported (Peckitt)

• 25-35% of patients non compliant on Oral Therapy

• 50% compliancy required for therapeutic effect (Oral Drugs)

• There is a move towards i.v. drugs to improve compliance

• Move to i.v. drugs will increase the risk of ONJ significantly

• Advanced ONJ is probably untreatable and causes significant morbidity

Osteonecrosis of the Jaws

Risk of ONJ www.ncbi.nlm.nih.gov/pmc/articles/PMC3017316/

The consequences of a severe complication and its treatability

• require computation into Risk/Benefit Analysis

• before safety guidelines are formulated

• A “rare” serious complication is not necessarily acceptable

– if the effect of bisphosphonates is irreversible

– if there is no effective treatment for advanced stages of ONJ

– Patient Safety takes Priority over Financial Profit

In a multibillion $ Industry - Marketing ≠ Science

Osteonecrosis of the Jaws

Osteonecrosis of the JawsONJ http://jada.ada.org/cgi/content/full/137/8/1144

• ONJ Oral gluco-corticoid use for chronic conditions

• ONJ – associated with Periodontitis

• ONJ associated with prolonged use of bisphosphonates

• ONJ bilateral and multifocal reports in cancer patients

• ONJ Tori and other bony exostoses may increase the risk of developing ONJ.

Tori

Torus Maxillaris and Mandibularis

• Midline Palate

• Lingual side of premolars (90 % Bilateral )

• Familial Incidence 5-40%

• Occur early in Life / Associated with Bruxism

• Size of Torus correlates with increased bone Density

- Post Menopausal women

http://jcem.endojournals.org/cgi/content/full/88/5/2081

Bisphosphonates and Dental Implants

Bis-Phossyjaw?• Phossy jaw - white phosphorus 19th Cent

• Phosphonecrosis of the Jaw

– Unusual necrosis of the Jaw in (Young) Match Workers

– Pain and Disfigurement

– Eerie glow in the dark (phosphorescence)

• Tip of the Iceberg – Potential Epidemic?

Estimation of Bone TurnoverThe C-terminal telopeptide (CTX) blood test (β Cross Laps)

• Fasting Saerum CTX Test - an index of bone turnover

• Cross linked octapeptide fragment from type 1 bone collagen is released (98% of bone protein)

– released when osteoclasts resorb bone– Serum CTX level α osteoclastic resorbiton at time blood is drawn

– CTX 50 pg/mL - 450pg/mL 1

– Normal values > 300pg/mL and commonly 400-550pg/mL 1

• Risk assessment,2 suggests a value of

– <100 pg/mL is high risk

– >150 pg/mL is low risk

– Australian trial 3 favours >200 pg/mL as a safe level for a bone invasive procedure.

1. Marx RE : J Oral Maxillofac Surg 65:2397-2410, 2007

2. Therapeutic Guidelines. Therapeutic guidelines: oral and dental. Melbourne: TG, 2007 3. Goss AN. CTX (the cross laps test). Australian Dental Association Bulletin 2008; 368:11

CTX and ONJ Prevention Kunchur, Need, Hughes Goss (Adelaide)

• 348 Patients Fasted Morning Test

• 222 Patients at Risk

• 15 Patients had ONJ

• 113 Controls

Kunchur R, Need A, Hughes T Goss A

Clinical Investigation of C-Terminal Cross Linking Telopeptide Test in Prevention and Management of Bisphosphonate-ssociated Osteonecrosis of the Jaws

JOMS 2009: 7, 1167-1173

Kunchur, Need, Hughes Goss (Adelaide)

Long term Bisphosphonates n=215

• Older Med Compromised Patients (71 ± 11.6 yrs)

• Average CTX 238 ± 144 pg/ml

• 98pts <200pg/ml

1pt CTX = 126pg/ml ONJ

Kunchur, Need, Hughes Goss (Adelaide)

IV Bisphosphonates

7 pts NO ONJ CTX= 329 ± 354 (with 4 < 200pg/ml)

15pt ONJ

12pts post extraction 3pts spontaneously 7 pts no drug holiday CTX = 116 pg/ml

Kunchur, Need, Hughes Goss (Adelaide)

CTX < 150pg/ml

Did not correlate with clinical risk factors of....

Age

Gender

Co-morbidities

Bone Disease

Bisphosphonate Duration

Kunchur, Need, Hughes Goss (Adelaide)

Statistical Differnece - Aledronate compared with risedronate (p< .0001)

Bisphosphonates: Anti-Resorptive potency Drug Trade Name Potency Adminitration

etidronate Osteum Difosen 1 Orally

clodronate Bonefos 10 Orally / iv

tiludronate Skelid 10 Orally

pamidronate Aredia, Linoten, Pamifos, Xinsidona 100 iv

alendronate Fosamax Fosavance 1,000 Orally risedronate Actonel Acrel 5,000 Orally ibandronate Bondronat 10,000 Orally / iv

zoledronate Zometa Aclasta 85,000 iv

Kunchur, Need, Hughes Goss (Adelaide)

Drug Holiday

CTX Value circa 25pg/ml/month

Kunchur, Need, Hughes, Goss (Adelaide)

Conclusions

• CTX not presictive of ONJ (individual patient)

• Risk Zone 150-200pg/ml

• If medically appropriate cease bisphosphonate

• Until patient out of “Risk Zone”

Medicolegal Implications

Suggested Protocol

Medicolegal Implications of ONJ

• Delay Surgery if CTX <200pg/ml

• Drug Holiday for Oral Surgery

• CTX elevation 25pg/ml/month (if Reversible)

Predicting risk Bisphosphonate-related ONJ : CTX versus radiographic markers

Fleischer et alOral Surgery Oral Medicine Oral Pathology Oral Radiology and EndodontologyVol. 110 No. 4 October 2010

Predicting risk Bisphosphonate-related ONJ : CTX versus radiographic markers

Predicting risk Bisphosphonate-related ONJ : CTX versus radiographic markers

Predicting risk Bisphosphonate-related ONJ : CTX versus radiographic markers

Dental Logistics• All Patients commencing Osteoporosis Treatment – should be “Dentally Fit”

• A “Certificate of Dental Fitness” prior to Osteoporotic Treatment is suggested

• Patients should not commence treatment until “Dentally Fit”

• Dental Treatment Planning should

– Reduce risk of oral surgical intervention for duration of treatment– Dental Sepsis should be eradicated– Periodontal Disease must be controlled– Early extraction of teeth of poor prognosis– Dental Implants not necessarily contraindicated

• IV Bisphosphonates

– Risk of ONJ – More Aggressive Dental Assement / Treatment Planning– Consider Dental Clearance

Certificate of Dental Fitness

Should be Mandatory

For any Patient being treated by any drugs that alter bone turnover

Certificate of Dental FitnessAwareness

• General Medical Practitioners

• General Dental Practitioners

• Hospital Specialists

• Chief Medical Officers MOH

• Government - Department of Health

• Drug Companies

– Should advise that Certificate of Dental Fitness is mandatory prior to commencing treatment

– Inadequate Dental Care provision and action to prevent ONJ could be considered negligent

Certificate of Dental FitnessPatient

Osteoporosis

Dental Assessment

Dentally Fit?

Certificate of Dental Fitness

Dental Disease

Treatment

Dental Fit

Certificate of Dental Fitness

Oral / IV Drug

Therapy

Malignancy

Dental Assessemnt

Dentally Fit?

Certificate of Dental Fitness

Dental Disease

Treatment

Dentally Fit

Certificate of Dental Fitness

IV Drug Therapy

Avoid Future Extractions

Poor Prognosis of Dentition

Consider Dental Clearance

ONJ Prevention

Patient

Oral Drugs

Dental AssessmentRadiographs

Treatment Plan

CTX > 200pg/ML

Oral Surgery

CTX<200pg/ML

Repeat 3monthly

IV Drugs

Dental AssessmentRadiographs

Treatment Plan

CTX>200pg/mL

Oral Surgery

CTX < 200pg/ML

Repeat 3 Monthly

Drug Holiday

Drug Holiday: CTX 25 pg/mL / month

Consider Root Canal Therapy rather than Extractions in Irreversible / High Risk Cases

Medication RelatedOsteonecrosis of the Jaws

MRONJ

AAOMS Update 2015

Antiresorbtive MedicationsIntravenous (IV) bisphosphonates (BPs)

– hypercalcemia of malignancy

– skeletal-related events (SRE) breast, prostate and lung cancers

– multiple myeloma

– improvement of survival is controversial

– significant positive effect on the quality of life for patients

– IV BPs, ie once yearly infusion of zolendronate (Reclast®) and a parenteral formulation of ibandronate (Boniva®) administered every three months, have FDA approval for management of osteoporosis

ONJ Incidence

• oncology patient population (1-15%)

• osteoporosis patient population, 0.001% - 0.01% marginally higher than the incidence in the general population (<0.001%).

New Insights of ONJ Pathophysiology

• anti-resorptive effects of Bisphosphonates and Demosumab

• effects of BPs on gamma delta T-cells

• monocyte and macrophage function,

• as well as the role of local bacterial infection, inflammation and necrosis

Other ONJ Risk Factors• glucocorticoid use

• maxillary or mandibular bone surgery

• poor oral hygiene

• chronic inflammation

• diabetes mellitus

• ill-fitting dentures

• other drugs, including anti-angiogenic agents.

Prevention Strategies for ONJ

• Elimination or stabilization of oral disease prior to initiation of anti-resorptive agents,

• As well as maintenance of good oral hygiene.

• In those patients at high risk for the development of ONJ

including cancer patients receiving high-dose BP or Dmab therapy consideration should be given to withholding anti-resorptive therapy following extensive oral surgery until the surgical site heals with mature mucosal coverage

Management of ONJ

• stage of the disease

• size of the lesions

• as well as the presence of contributing drug therapy and comorbidity

Management of ONJConservative therapy

• antibiotic oral rinses

• systemic antibiotic therapy

Localized surgical debridement

• indicated in advanced non-responsive disease and has been successful.

• enhanced osseous wound healing with teriparatide risk of osteosarcoma?

• Experimental therapy includes

– bone marrow stem cell intralesional transplantation

– low-level laser therapy

– local platelet-derived growth factor application

– hyperbaric oxygen

– tissue grafting

Definition ONJ

Original Definition

“area of exposed bone in the maxillofacial region that does not heal

within eight weeks after identification by a health care provider,

in a patient who was receiving or had been exposed to a bisphosphonate

(BP) and has not received radiation therapy to the craniofacial region”

Definition ONJ Update AAOMS

Definition Update

1. current or previous treatment with anti-resorptive or anti-angiogenic agents

2. exposed bone or bone that can be probed through an intraoral or extraoral fistula(e) in the maxillofacial region that has persisted for more than eight weeks

3. no history of radiation therapy to the jaws or obvious metastatic disease to the jaws

Task Force Definition of ONJ

AAOMS Taskforce Definition

1. Exposed bone in the maxillofacial region that does not heal within eight weeks after identification by a health care provider

2. Exposure to an anti-resorptive agent

3. No history of radiation therapy to the craniofacial region.

Oral Ulceration and Bone Sequestration OUBS

OUBS

• oral ulceration and bone sequestration (OUBS) / absence of anti-resorptive therapy

• Uncommon but typically associated with significant morbidity

• OUBS described as “lingual mandibular sequestration and ulceration” (predilection for involvement of posterior lingual mandibular bone)

• The sequestrum can slough spontaneously resulting in rapid resolution

• Some cases, conservative surgical removal of the dead bone is indicated to permit efficient healing.

OUBS

• The incidence of OUBS in the general population is not well defined

• OUBS cases captured? in data pertaining to drug-related ONJ?

• Prevalence OUBS not known

OUBS - Differential Diagnosis

• alveolar osteitis

• Sinusitis

• gingivitis/periondontitis

• periapical pathosis

• cement-osseous dysplasia showing secondary sequestration.

Bone inflammation and infection are usually present in patients with advanced ONJ, and appear to be secondary events.

Thank you for your Attention