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Drug Induced

Osteonecrosis

Of The Jaws (DIONJ)

A Problem That every

Dentist Especially Oral

Surgeons Face

Robert E. Marx, DDS

Professor of Surgery

Director of Research

University of Miami

Miller School of Medicine

Vishy Broumand,

DMD,MD

Asst. Professor of Surgery

University of Miami

Miller School of Medicine

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Disclosure - Active

1. Medtronics Consultant

2. Harvest Technologies Consultant

3. KLS Martin Residency support

4. Synthes CMF Residency support

5. Bio-Met Microfixation Residency support

6. Biomet 3i Residency support

Disclosure - Past

1. Novartis Consultant

2. Merck Co. Consultant

3. Amgen Consultant

Goals Of This Presentation

1. Review the mechanism of these

drugs

2. Reveal the magnitude of the problem

3. Discuss specific preventative

measures

4. Discuss specific treatment measures

for several specific presentations

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Marx RE.

Pamidronate (Aredia) and

Zoledronate (Zometa) induces

avascular necrosis of the jaws.

A growing epidemic.

J Oral Maxillofac Surg 61:1115, 2003

Osteonecrosis Articles Year Number of Articles

1999 - 2002 0

2003 4

2004 7

2005 62

2006 136

2007 175

2008

2009

2010

2011

200+

200+

200+

200+

Total DIONJ

Articles

2003 - 2012

1,300+

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Drug Induced

Osteonecrosis Of The Jaws

1. Over 17,000 cases reported in the

literature so far

2. Over 12,300 cases reported to the FDA

3. Over 14,000 publications to date

4. More than 12 organizations posting

position papers

5. Numerous lectures and courses

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Drug induced osteonecrosis

is the only correct term

because bisphosphonates

and Denosumab are the

cause of exposed bone

osteonecrosis in the jaws

Now Isolated Reports of

DIONJ Due To:

1. Avastin (Bevacizumab)

2. SUTENT (Sunitinib)

Clinical Disease And History

Drug Induced

Osteonecrosis

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Drug Induced ONJ

Definition Exposed non-healing bone in the

mandible or maxilla that persists

for more than eight weeks in a

person who received a systemic

bisphosphonate but who has not

received local radiation to the jaws.

DIONJ Staging

Stage O: Radiographic evidence of bisphosphonate toxicity

Stage I: Exposed bone limited to one quadrant

Stage II: Exposed bone involving two quadrants

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DIONJ Staging

Stage III:

1. exposed bone involving three or four quadrants

2. a pathologic fracture

3. extension into the maxillary sinus or nasal cavity

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Incidence Of IV

BIONJ

Drug Company Sponsored Studies

0.8% to 2.4%

Independent Studies

8% to 18%

Proof of

Causation

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Marx RE, Tursun R. Suppurative osteomyelitis,

bisphosphonate induced

osteonecrosis: A blinded

histopathologic comparison and

its implications for the

mechanisms of each disease.

Int J Oral Maxillofac Surg

2012 Mar;41(3):283-9

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The Mechanism

Of

Bisphosphonates

On Bone

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Bisphosphonates 1. Etidronate (Didronel)

2. Tiludronate (Skelid)

3. Residronate (Actonel)

4. Alendronate (Fosamax)

5. Ibandronate (Boniva)

6. Pamidronate (Aredia)*

7. Zolendronate (Zometa)*

8. Zolendronate (Reclast)* * Intravenous bisphosphonates

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Bisphosphonates

act immediately

and accumulate

in bone.

Bisphosphonate

half life is

eleven years

to infinity.

Oral Bisphosphonate Cases

Fosamax 104

Actonel 3

Boniva 2

Prolia (s.c.) 2

TOTAL 111

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Why Is Oral BIONJ More

Prevalent With Fosamax Use?

1. Residronate (Actonel) 35 mg/week

2. Ibandronate (Boniva) 150 mg/month

3. Alendronate (Fosamax) 70 mg/week

Fosamax is twice

the dose of

other oral

bisphosphonates.

Lenart BA, Lorich DG, Lane JM.

Atypical Fracture Of The

Femoral Diaphasis In

Postmenopausal Women

Taking Alendronate.

N Engl J Med

358:1304 - 1305, 2008

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Neviaser MD, Lane JM, Lenart

BA, Edobar-Osula F, Lorich DG.

Low-energy Femoral Shaft

Fracture Association With

Alendronate Use.

J Orthop Trauma

22:346 - 351, 2008

IV Bisphosphonate &

SC Denosumab Cases

Aredia/Zometa 214

Reclast 3

Xgeva 4

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Case Experience

1. Intravenous bisphosphonate

induced osteonecrosis: 221 cases

2. Oral bisphosphonate induced

osteonecrosis: 111 cases

3. Subcutaneous Xgeva cases: 3

4. Total: 335 cases

The IV route has

140 times the bone

bioavailability of an

oral dose.

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Bisphosphonate

induced osteonecrosis

is due to the

accumulation of toxic

levels in bone.

What would happen to the

individuals who take 81 mg

of ASA daily if the ASA

half life was 11 years?

They would bleed to death in

less than a year!

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Why The Jaws? 1. Concentrated in the jaws due to

continuous bone remodeling

2. Teeth and dental disease

a. periodontitis

b. tooth removals

3. Thin overlying mucosa e.g. tori

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Occlusion Plays

A Significant Role

In Initiating

DIONJ

Beware of Denosumab 1. Prolia 60 mg SC q 6 months for

osteoporosis

2. Xgeva 120 mg SC q 1 month for:

A. bone metastases

B. hypercalcemia of malignancy

Conclusion:

Treat Denosumab patients the same as

bisphosphonate patients.

Denosumab Is An

Inhibitor Of RANK

Ligand (RANKL)

Therefore, it prevents

osteoclast bone resorption

and renewal

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Anti-RANK

Ligand drugs

impair

osteoclasts.

Osteonecrosis Of The

Jaws Induced By Anti-

RANK Ligand Therapy,

i.e. Denosumab (Prolia).

Brit J. Oral Max Fac

Surg. 2010, 48:221-223

Aghaloo TL, Felsenfeld AL,

Attradis S.

Osteonecrosis of the jaw in

a patient on Denosumab.

J Oral Maxillofac Surg 2010

May 68(5)959-63

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Denosumab 1. Prolia 60 mg s.c. q 6 months

for osteoporosis

2. Xgeva 120 mg s.c. q 1 month

for metastatic cancers

Note: not to be used in multiple

myeloma patients

Recommend

1. Treat Denosumab (Prolia)

as you would a Fosamax

patient

2. Treat Denosumab (Xgeva)

as you would an IV Zometa

or Aredia patient

Key Difference

Half Life In Bone

Bisphosphonates 11+ years

Denosumab 26 days

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The Incidence, Risk,

Prediction of Risk,

Prevention, And Treatment

Oral Bisphosphonates

Oral

Bisphosphonate

Induced

Osteonecrosis

Oral Bisphosphonates (vs.)

Intravenous Bisphosphonates ONJ

Oral Bisphosphonate ONJ

• Has a lower incidence (0.11% to 4.0%) to (0.8% - 18%)

• Is less severe

• Is more reversible

• Is more amenable to surgical resolution

• Is more predictable

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Predicting Risk Of Osteonecrosis Of

The Jaw With Oral Bisphosphonate

Exposure (PROBE) Investigators.

Prevalance of osteonecrosis of the

jaw in patients with oral

bisphosphonate exposure.

Lo JC, O’Ryan FS, Gordon NP, et.al

J Oral Maxillofac Surg

68:243-253, 2010

Incidence Of

BIONJ

1/952 = 0.11 %

Estimated 11 To 17 Million

US Women Taking Oral

Bisphosphonates

0.11 % x 11 x 106 =

12,000 Patients

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Oral Bisphosphonates

Induced Osteonecrosis:

Risk Factors, Prediction of Risk

Using Serum CTX Testing,

Prevention, and Treatment

Marx RE, Cillo JE, Ulloa JJ

J Oral Maxillofac Surg

65:2397-2410, 2007

A Primer On

Osteopenia/

Osteoporosis

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BMD Is A Poor Surrogate

Marker For Osteoporosis

1. Inter-device variation

2. Inter-operator variation

3. A denser bone is not necessarily a stronger bone

4. Denser bone may actually be more brittle and weaker (sorry Sally Fields!)

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Osteoporosis And BMD

1. Normal = T-score: < -1

2. Osteopenia = T-score: -1 to -2.5

3. Osteoporosis = T-score: < -2.5

4. Severe osteoporosis = T-score: < -2.5

with a non-trauma related fracture

The Goal In

Oral Bisphosphonate

Therapy

In Osteoporosis

Is Prevention

Of Fracture

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Drugs For Pre-Osteoporosis:

Prevention Or Disease

Mongering:

Alonso-Cuello P, Garcia-Franco AL,

Guyatt C, and Moynihan R.

British Medical Journal, 2008

336:126-129

Shifting The Focus In

Fracture Prevention From

Osteoporosis To Falls

Jarwen TLN, Sievanen H, Khan KM,

Heinonen A, Kannus P.

British Medical Journal, 2008

336:124-126

Osteoporosis Treatment

And Fracture Incidence:

The ICARO

Longitudine Study

Adami S, Isaia G, Luisetto G, et al.

Osteoporosis Int. 11, Jan. 2008

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Conclusions 1. The effectiveness of oral bisphosphonates

is much lower than drug company sponsored RCT.

2. One must treat 270 women for osteopenia 3 years to prevent one fracture

3. One must treat 88 osteoporotic women for 5 years to prevent one hip fracture.

4. Prevention of falls not oral bisphosphonates prevents fractures

The FDA And Bone Science On

Fosamax For Fracture

Prevention From Osteoporosis

1. No benefit for first 18 months

2. Benefit beyond placebo 18 months – 36 months

3. No benefit beyond 18 months

4. Risk for BIONJ and femur fractures sharp increase beyond 36 months

FDA September 2011

1. Every woman on BP’s for osteoporosis must be re-examined after 3 years

1. No one needs to take BP’s for osteoporosis for more than 5 years

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Oral

Bisphosphonate

Induced

Osteonecrosis

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Oral Bisphosphonates

Induced Osteonecrosis:

Risk Factors, Prediction of Risk

Using Serum CTX Testing,

Prevention, and Treatment

Marx RE, Cillo JE, Ulloa JJ

J Oral Maxillofac Surg

65:2397-2410, 2007

Clinical Investigation Of C-Terminal

Cross-Linking Telopeptide Test In

Prevention And Management Of

Bisphosphonate-Associated

Osteonecrosis Of The Jaws

Kunchur R, Need A, Hughes T, Goss A

J Oral Maxillofac Surg

67(12):2644-2648, 2009

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CTX

1. Is a specific marker of bone

turnover and therefore

healing

2. Is an octapeptide fragment

cleaved by the osteoclast

during bone resorption

The Serum C-Terminal Telopeptide

CTX Can Predict Risk Related To

Oral Bisphosphonates

CTX < 100 pg/ml = high risk

CTX 101 to 150 pg/ml = moderate risk

CTX > 151 pg/ml = little or no risk

CTX values improve significantly with

discontinuance of the oral bisphosphonates

How Useful

Is The

CTX?

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Fosamax For 4 Years

CTX = 72 pg/ml

Fosamax “Drug Holiday”

For 9 Months

CTX = 212 pg/ml

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Fosamax For 5.5

Years

CTX = 84 pg/ml

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Fosamax “Drug Holiday”

For 8 Months

CTX = 191 pg/ml

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Fosamax For 6 years

CTX = 55 pg/ml

Fosamax “Drug Holiday”

For 9 Months

CTX = 243 pg/ml

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Prolia “Drug Holiday”

3 Months

CTX = not tested

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Prevention OF DIONJ

1. Non-invasive dentistry is safe at all times

2. Oral bisphosphonate:

a. CTX > 150 pg/ml

b. nine month drug holiday

3. Prolia: three month drug holiday

4. Reclast: procedure nine months after

last dose – three months before next

dose

Note: The recovery from oral

bisphosphonates bone turn

over suppression as measured

by CTX testing is delayed by:

1. Greater that 8 year use

2. Methotrexate

3. Steroids

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CTX Is Not Useful

1. In cancer patients (reading is

too high)

2. Patients who used methotrexate

(reading too low)

3. Patients who used steroids

(reading too low)

In Patients With 8

Years Or More Of An

Oral Bisphosphonate

The CTX will first rise then

decrease. Therefore, use 9-12

month drug holiday

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Resolution Of Oral Bisphosphonate

Induced Osteonecrosis

1. Drug holiday alone 43/84 (52%)

2. Drug holiday and local debridement 34/84 (40.5%)

3. Drug holiday and resection 7/84 (8.3%)

Effects Of Continuing

Or Stopping Alendronate

After 5 Years Of Treatment

Black DM, Schwartz AV,

Ensrud KE, et. al.

JAMA December 27, 2006

Vol. 296 No 24

Conclusions: Women who discontinued

alendronate after 5 years showed a moderate

decline in BMD and a gradual rise in

biochemical markers but no higher fracture risk

other than for clinical vertebral fractures

compared with those who continued

alendronate. These results suggest that for many

women, discontinuation of alendronate for up to

5 years does not appear to significantly increase

fracture risk. However, women at very high risk

of clinical vertebral fractures may benefit by

continuing beyond 5 years.

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Editorial Comment

Alendronate:

“Five years of a good

thing is enough”

Editor JAMA

Drug Holidays

Are Safe

And Effective

FDA September 2011

1. Every woman on BP’s for osteoporosis must be re-examined after 3 years

2. No one needs to take BP’s for osteoporosis for more than 5 years

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Black DM. et al:

Once Yearly Zoledronic Acid For

Treatment Of Postmenopausal

Osteoporosis:

N Engl J Med 2007, 356:1809-1822

1. Used CTX as bone suppression marker

2. Required a 2 year oral bisphosphonate

“wash out” (drug holiday) to enter

study

Reclast Zoledronate

5 mg IV Once Yearly

Is too new to draw reliable conclusions

at this time.

Reclast We have seen four

cases already.

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Reclast - Zolendronate

5 mg IV once/year

1. Risk increases sharply with 4th dose

2. Least risk period: nine months after

previous dose and 3 months after next

dose

3. Request delay in following dose until

clinically healed

4. Consider CTX at 6-9 months after last dose

The End

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Prevention

And Treatment

Intravenous

Bisphosphonate

Induced Osteonecrosis

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Marx RE, Sawatari Y,

Fortin M, Broumand V.

Bisphosphonate-induced exposed

bone (osteonecrosis/osteopetrosis)

of the jaws: Risk factors,

recognition, prevention, and

treatment.

J Oral Maxillofac Surg

63:1567-1575, 2005

Presenting Findings

1. Asymptomatic exposed bone 52/180 (29%)

2. Painful exposed bone 128/180 (71%)

Presenting Signs And

Symptoms

1. Mobile teeth 47/180 (26.1%)

2. Drainage 58/180 (32.2%)

3. Edema 66/180 (36.6%)

4. OC fistula 32/180 (17.7%)

5. Pathologic fracture 17/180 (9.4%)

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Initiating Events

1. Spontaneous 52/180 (29.0%)

2. Tooth removal 111/180 (61.6%)

3. Dental implant placement 4/180 (2.2%)

4. Periodontal surgery 10/180 (5.6%)

5. Biopsy 2/180 (1.1%)

6. Apicoectomy 1/180 (0.59%)

BIONJ Staging

Stage O: Radiographic evidence of bisphosphonate toxicity

Stage I: Exposed bone limited to one quadrant

Stage II: Exposed bone involving two quadrants

BIONJ Staging

Stage III:

1. exposed bone involving three or four quadrants

2. a pathologic fracture

3. extension into the maxillary sinus or nasal cavity

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What To Do With

Exposed Bone Due To

Bisphosphonate Therapy

(Aredia/Zometa)

IV Bisphosphonates

Recommendations Before Therapy

1. Remove unsalvageable teeth

2. Prophylaxis

3. Treat caries

4. Treat periodontitis

5. Defer bisphosphonates for 2 months

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Extraction,

Traumatic Occlusion,

Periodontal Disease

Are The Main

Initiators Of Oral

DIONJ

IV Bisphosphonates

Recommendations During Therapy

1. Avoid invasive procedures (extractions, periosurgery, implants)

2. Treat caries: if needed, RCT and amputate crown

3. Supragingival scaling

4. Splint mobile teeth

5. If extractions are unavoidable, provide informed consent of increased risk

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IV Bisphosphonates Recommendations With Exposed Bone

1. Avoid debridements

2. Smooth sharp edges

3. Treat with PCN VK 500 mg qid and Peridex TID

4. Use Levaquin or Zithromycin or Doxycycline in PCN allergic patients

5. Add Flagyl 500 mg tid x 10 day in refractory cases

6. If surgery unavoidable, alveolectomy or continuity resection

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Microorganisms Most Commonly

Found in Bisphosphonate

Induced Osteonecrosis

1. Actinomyces

2. Veillonella

3. Eikenella

4. Moraxella

Ineffective Therapies

Frequently Recommended

For ONJ

1. Clindamycin

2. Hyperbaric oxygen

3. Ozone

4. Laser

Indications For Resection

1. Symptomatic cases

refractory to nonsurgical

treatment

2. Pathologic fractures

3. Direct sinus

communication

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Reconstructing IV

DIONJ Cases Is

Problematic Because:

1. Disease free donor bone is

limited or nonexistent

2. rhBMP-2/ACS is contraindicated

in cancer patients

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Outcome Analysis OF

200 IV BIONJ Cases

1. Died from their cancer 36/200 (18.0%)

2. Required a resection 62/200 (31.0%)

3. Pain free living with exposed bone 102/200 (51.0%)

Conclusions

1. DIONJ is a real entity caused by bisphosphonates and denosumab

2. Prevention can be accomplished in many ways

3. A sub clinic bone toxicity from bisphosphonates exists

4. Oral and IV DIONJ are different

5. Oral DIONJ is resolvable in many cases

Conclusions

6. Resolved oral DIONJ can be reconstructed

7. It is problematic to reconstruct IV DIONJ cases

8. IV DIONJ cases can be managed or resolved with aggressive surgery

9. Resection of DIONJ cases should meet specific criteria

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The End