Exodontia Masterclass: Chapter 9 Medication Related Osteonecrosis of the Jaws

1. Osteonecrosis of the Jaws
Ninian Peckitt
FRCS FFD RCS FDS RCS FACCS
Oral and Maxillofacial Surgeon / Facial Plastic Surgeon

2. Cbfa1
Core binding factor 1 (Cbfa1) mastergene control osteoblast differentiation (6, 7)

3. OPG/RANKL/RANK System
RANKL binds its receptor RANK on osteoclast lineage cells

4. 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)

5. Osteoclastogenesis
Basic 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

6. Osteoclastogenesis
1
1 RANKL binds RANK
2 M-CSF, binds c-Fms
2
3 OPG blocks RANKL
3
TNF IL-1

7. Osteoclastogenesis
TNF IL-1  M-CSF
Pool of Cells Increased

TGF-ß Oestrogen - OPG 
PTH Glucocorticoids - RANKL  OPG 
Vit D3 RANKL 
Cbfa1  RANKL

8. 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

9. 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

10. 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).

11. 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.

12. 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

13. 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

14. 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

15. 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

16. 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”

17. 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

18. Denosumab

19. 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

20. 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)

21. Classification of Osteonecrosis of the Jaws
Grade Severity
1 Asymptomatic
2 Mild
3 Moderate
4 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

22. 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

23. AAOMS Stage I Lesions

24. AAOMS Stage II Lesions

25. AAOMS Stage III Lesions

26. AAOMS Stage 0 Lesions
• Spontaneous Numbness and Pain
• No exposed bone
• No prior dental antecedent
• Positive image findings:
– Sclerosis
– Positive bone scan

27. Osteonecrosis of the Jaws
ONJ (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

28. Osteonecrosis of the Jaws
ONJ 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

29. 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

30. 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

31. Osteonecrosis of the Jaws
ONJ 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.

32. 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

33. Bisphosphonates and Dental Implants

34. 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?

35. Estimation of Bone Turnover
The 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

36. 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

37. 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

38. 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

39. Kunchur, Need, Hughes Goss (Adelaide)
CTX < 150pg/ml
Did not correlate with clinical risk factors of....
 Age
 Gender
 Co-morbidities
 Bone Disease
 Bisphosphonate Duration

40. 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

41. Kunchur, Need, Hughes Goss (Adelaide)
Drug Holiday
 CTX Value  circa 25pg/ml/month

42. 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”

43. 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)

44. Predicting risk Bisphosphonate-related ONJ :
CTX versus radiographic markers
Fleischer et al
Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology
Vol. 110 No. 4 October 2010

45. Predicting risk Bisphosphonate-related ONJ :
CTX versus radiographic markers

46. Predicting risk Bisphosphonate-related ONJ :
CTX versus radiographic markers

47. Predicting risk Bisphosphonate-related ONJ :
CTX versus radiographic markers

48. 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

49. Certificate of Dental Fitness
Should be Mandatory
For any Patient being treated by any drugs that alter bone turnover

50. Certificate of Dental Fitness
Awareness
• 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

51. Certificate of Dental Fitness
Patient
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

52. ONJ Prevention
Patient
Oral Drugs
Dental Assessment
Radiographs
Treatment Plan
CTX > 200pg/ML
Oral Surgery
CTX<200pg/ML
Repeat 3monthly
IV Drugs
Dental Assessment
Radiographs
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

53. Medication Related
Osteonecrosis of the Jaws
MRONJ
AAOMS Update 2015

54. Antiresorbtive Medications
Intravenous (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

55. 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%).

56. 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

57. 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.

58. 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

59. Management of ONJ
• stage of the disease
• size of the lesions
• as well as the presence of contributing drug therapy and comorbidity

60. Management of ONJ
Conservative 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

61. 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”

62. 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

63. 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.

64. 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.

65. 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

66. 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.

67. Thank you for your Attention