Bisphosphonate Related

Osteonecrosis of the Jaws

Nik Desai, DMD, MD
Division of Oral & Maxillofacial Surgery
Department of Plastic Surgery
Kaiser Permanente Medical Group
Santa Clara, CA
04/28/2010

Objectives
Bisphosphonates
Clinical applications
Drug chemistry
Biologic action
BRONJ
Pathogenesis
Treatment of BRONJ
Latest management recommendations
Updates in the literature
Case Presentations

Bisphosphonates what are they?

Class of drugs
High affinity for calcium

Binds to bone surfaces

Nitrogen: increased affinity, potency

Prevent bone resorption and

remodeling
IV and oral formulations

IV: tx for bone resorption 2 metastatic

tumors, osteolytic lesions
Oral: tx for osteoporosis, osteopenia

Bisphosphonates: Common uses

Prevention and treatment of osteoporosis in

postmenopausal women
Increase bone mass in men with osteoporosis
Tx of glucocorticoid-induced osteoporosis
Tx of Pagets disease of bone
Hypercalcemia of malignancy
Bone metastases of solid tumors

breast and prostate carcinoma; other solid tumors

Osteolytic lesions of multiple myeloma

History of Bisphosphonate Development

Mid-19th Century German chemists

Anti-corrosive in pipelines

20th Century - Clinical applications

Tc99 Bone scans

Toothpaste

Anti-tartar, anti-plaque effects

Osteopathies

Anti-resorptive effect

Basic Chemical Composition

Pyrophosphate

compound
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 BRONJ cases

Antiresorptive Potency of BPs in Observed

Human Clinical Trials

Biologic Action of Bisphosphonates

Osteoclastic toxicity

Apoptosis
Inhibited release of bone
induction proteins

BMP, ILG1, ILG2

Reduced bone turnover,

resorption
Reduced serum calcium*
Hypermineralization*

sclerotic changes in
lamina dura of alveolar
bone

* = goal of medicinal use

Normal Osteoclastic Function

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

Medical Indications for Oral BPs

Pagets 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

Drug Administration and Dosage

Pharmacokinetics
Oral BPs

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 osteoclastmediated resorption

Biologic Catch 22

Etidronate (Didronel)
Available in both oral and IV

preparations
Oral: FDA approved for Pagets
disease
Dose: 5 mg/kg per day
IV: approved for use in
hypercalcemia of malignancy
Dose: 7.5 mg/kg per day for 3
days
Risk of osteomalacia w/
prolonged therapy
do not treat >2 yrs
No documented cases of BRONJ

Pamidronate (Aredia)
Available only as IV preparation

b/c of poor GI absorption and

high freq of GI symptoms
Approved for tx of

hypercalcemia of malignancy

one-time dose of 60-90 mg

Also used for Pagets disease

Also used for osteoporosis pts

who are unable to tolerate other

bisphosphonates

Zolendronate (Zometa)
Only available in IV preparation
Approved for tx of hypercalcemia of

malignancy
4mg IV over no less than 15 mins

Alendronate (Fosamax)
Available as oral preparation
Osteoporosis

Treatment dose: 10 mg/day

or 70 mg weekly
Prevention dose : 5 mg/day
or 25 mg weekly
Less inhibition of bone
mineralization
More suitable for long-term
administration

Risedronate (Actonel)
Also available as oral

preparation
Approved for tx of
osteoporosis
5 mg daily and 35 mg
weekly

Dose for prevention of

osteoporosis is same as for
treatment

Ibandronate (Boniva)
Most recently approved for tx

and prevention of osteoporosis

2.5mg daily or 150 mg monthly

Bisphosphonate Side Effects

Upset stomach
Inflammation/erosions of esophagus
Fever/flu-like symptoms
Slight increased risk for electrolyte disturbance
Uveitis
Musculoskeletal joint pain
And of course

BRONJ
Exposed, devitalized bone in

maxillofacial region
Prior history or current use
of BP
Vague pain, discomfort
Spontaneous occurrence,
or
2 surgery or trauma to oral
soft tissue/bone

BRONJ: Clinical Presentation

Exposed alveolar bone

Open mucosal wound

Necrotic bone
Spontaneous or
Traumatic
Extractions, periodontal
surgery, apicoectomy,
implant placement
Infection
Purulence, bone pain
Orocutaneous fistula

BRONJ: Clinical Presentation

Subclinical Form

asymptomatic
radiographic signs
Sclerosis of lamina
dura
Widening of PDL space

Clinical Presentation (cont)

Soft tissue abrasions

Tissues rubbing against bone

AND

Pathologic Fracture

Staging of BRONJ
Proposed by AAOMS:

Patients at risk (Subclinical)

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

Patients with BRONJ

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

Stage 2: Exposed/necrotic bone, pain, clinical evidence of infection

Stage 3: Exposed/necrotic bone, pain, infection, one or more of the

following:
Pathologic fracture, extra-oral fistula, osteolysis extending to
inferior border

BRONJ: IV BPs
More frequently
Lesions more
extensive
All stages
II, III more
common
Lower success with
Tx
Patients generally
sicker

Stage I Lesions

Stage II Lesions

Stage III Lesions

Stage 0 Lesions
Spontaneous onset

numbness and pain

No exposed bone
No prior dental antecedent
Positive image findings:

Sclerosis
Positive bone scan

BRONJ: Historical Context

Rare reports prior to 2001
2003: Marx reported 36 patients
2004: Ruggiero et al reported 63 pts (from 2001-2003)
2005: Migliorati reported 5 cases
2005: Estilo et al reported 13 cases
Sept. 2004: Novartis (manufacturer of Aredia & Zometa) altered

labeling to include cautionary language concerning osteonecrosis

of the jaws
2005: FDA issued warning for entire drug class (including oral
bisphosphonates)

Phossy-Jaw: A Historical Entity

Lorinser, 1845: first reported cases
Industrial laborers working w/ white phosphorus powder

Matchmaking, fireworks factories

Missile factories

Clinical presentation

Nonhealing mucosal wound following extraction

Pain
Fetid odor
Suppuration
Necrosis w/ bony sequestra
Extra-oral fistulae

Miles, Hunter:

20% mortality due to infections

Pre-antibiotic era

Conservative treatment

Selective debridement
Minimal mucosal manipulation
Topical agents: copper sulfate

Similar Clinical Entities

Closely resembles

Osteopetrosis
Loss of osteoclastic
function
Hypermineralization
Fractures, nonunions,
open oral wounds
Endpoint: bone necrosis,
+/- infection

NOT to be confused with these other entities:

Osteoradionecrosis

(ORN):

avascular bone necrosis 2 radiation

Osteomyelitis:

thrombosis of small blood vessels leading to

infection within bone marrow

Steroid-induced

osteonecrosis:

more common in long bones

exposed bone very rare

BRONJ: Model of Pathogenesis

Estimated Incidence of BRONJ 2 IV BPs

Limited to retrospective studies with

limited sample sizes

Marx:
Zometa: exposed bone within 6-12
months
Aredia: 10-16 months
Estimates of cumulative incidence of

BRONJ range from 0.8% to 12%

Marx: 5-15%

Including Subclinical osteonecrosis

Incidence will rise:

Increased recognition
Increased duration of exposure
Increased followup

Estimated Incidence of BRONJ 2 Oral BPs

>190 million oral BP prescriptions dispensed

worldwide

Much lower risk for BRONJ vs IV administration

Marx:

BRONJ development after 3 years of Alendronate usage

Merck study:

incidence with Alendronate usage = 0.7/100,000 person/years

of exposure

Estimated incidence of BRONJ w/ weekly

administration of alendronate:

0.01% to 0.04%
After extractions, increased to 0.09% to 0.34%

Estimated Incidence/Prevalence of BRONJ 2 Oral BPs

Australian, German Studies:
.001% to .01% prevalance
Lo, ORyan:

PROBE study, Kaiser Permanente

Survey

of 13,000 pts using oral BP

Prevalence of BRONJ: 0.06% (1:1,700)

low numbers, sowhats all the hoopla for?

Physicians prescribing these meds

Endocrinologists, Oncologists, PCPs, OB-Gyns,etc

Not well informed of adverse oral effects

Hygienists, dentists diagnosing and managing the problem

Lack of communication between Medicine and Dentistry

likelihood of many cases unreported
We are the expertstime to bridge the gap

Effects of oral BPs lagging behind IV BPs

Another few years for BRONJ to reveal itself among the oral BP
population

Why Only in the Jaws?

Dixon et al 1997

Alveolar crest has high remodeling rate

10x tibia
5x mandible at level of IA canal
3.5x mandible at inferior border
Greater uptake of Tc 99m in bone scans
Occlusal forces
Compression at root apex and furcations
Tension on lamina dura and periodontal ligament
Remodeling of lamina dura in response
Reduced remodeling with BP uptake hypermineralization
Sclerotic appearance of Lamina dura
Widening of periodontal ligament space

BRONJ Case Definition

AAOMS Position Paper (updated September 2009):

Patients considered to have BRONJ if all 3 characteristics

met:
Current or previous treatment with a bisphosphonate
Exposed, necrotic bone in maxillofacial region
persisting > 8 weeks
No history of radiation therapy to jaws

Risk Factors for Development of BRONJ

Drug-related factors

Potency of BP

Zoledronate > pamidronate > oral BPs

Duration of therapy

Local factors

Dentoalveolar surgery

Local anatomy

Extractions, implants, periapical surgery, periodontal surgery w/

osseous injury
7-fold risk for BRONJ with IV BPs
5 to 21-fold risk in some studies
lingual tori, mylohyoid ridge, palatal tori
Mandible > maxilla (2:1)

Concomitant oral disease

7-fold risk for BRONJ with IV BPs

Risk factors (continued)

Demographic/systemic factors

Age: 9% increased risk for every passing decade

Race: Caucasian
Cancer diagnosis

Multiple myeloma patients treated w/ IV BPs

multiple myeloma > breast cancer > other cancers

Osteopenia/osteoporosis diagnosis concurrent w/ cancer diagnosis

Additional risk factors:

Corticosteroid therapy
Diabetes
Smoking
EtOH
Poor oral hygiene
Chemotherapeutic drugs

Subclinical Risk Assessment

Early signs of BP toxicity:

Radiographs

Panoramic, PA films
Sclerosis of alveolus, lamina dura
Widening of PDL space

Clinical exam

Tooth mobility
Unrelated to alveolar bone loss
Deep bone pain with no apparent etiology

Risk Assessment: Bone Turnover Markers

Bone Turnover Markers

Most assess bone formation

AP, osteocalcin

Marx: Serum CTX marker

Bone resorption
Oral BP risk

Type I collagen telopeptide assay

ELISA/RIA Quest Diagnostics

Cleaved at carboxyl end by

osteoclast in bone resorption
NTX marker cleaved at
amine end
Requires 1 mL whole blood
fasting

Serum CTX Peptide

Low values = high risk

Little osteoclastic function

Marx, et al 2007 (JOMS)
17 pts on oral BPs > 5 years
CTX before/after drug holiday
(6mos)
Before drug holiday:
CTX range 30-102 pg/mL
After drug holiday:
CTX range 162-343 pg/mL over 6
months
Improved mucosal healing
Drug holiday allows for osteoclast
recovery
4-6 months: reasonable, safe, and
minimizes risk of BRONJ

Treatment Goals
Preserve Quality of Life
Pain

Control
Treat 2 infection
Prevent extension

What this means for you as a practitioner

Routine dental care a MUST for BRONJ pts and Non-

BRONJ pts taking BPs

dental prophylaxis
nonoperative periodontal care
restorative procedures
conventional fixed and removable prosthodontics

Invasive procedures on case-by-case basis

Elective oral surgery

apical surgery
periodontal bone recontouring
implants
orthodontic tooth movement

Treatment Strategies
Patients about to initiate IV bisphosphonate tx

Objective: minimize risk of developing BRONJ

Dental prophylaxis, caries control, conservative restorative
dentistry
Adjustment of denture flanges to minimize mucosal trauma
Extraction of nonrestorable teeth
Completion of elective dentoalveolar surgery
If systemic conditions permit:

Delay Bisphosphonate therapy until dental health optimized

14-21 days after extractions

Treatment Strategies
Asymptomatic patients receiving IV BPs

Maintenance of good oral hygiene, dental care

Avoid invasive procedures
Nonrestorable teeth:
Remove crowns
Endodontic treatment of remaining roots
Avoid placement of implants

Treatment Strategies
Asymptomatic patients receiving oral BPs

Less than 3 years with no clinical risk factors:

No alteration or delay in elective surgery

Implants permitted
Discuss risks
Regular recall schedule
Discuss with PCP re: alternate dosing, drug holidays,
BP alternatives

Treatment Strategies
Asymptomatic patients receiving oral BPs

(continued)

Less than 3 years, concomitant steroid use

More than 3 years, with/without concomitant steroid use

Contact PCP re: drug holiday for at least 3 months prior to

surgery
Restarted after osseous healing complete (3 months)
Contact PCP re: drug holiday for 3 months prior to oral surgery
Restarted after osseous healing complete

CTX???

Treatment Strategies
Patients with Established Diagnosis of BRONJ

Objectives: eliminate pain, control infection, minimize

progression/occurrence of necrosis
Marx:

Removal of bone serving as soft tissue irritant, loose bony

sequestra

debridement may worsen condition

Without exposure of uninvolved bone

Extraction of teeth within exposed, necrotic bone

Avoid elective dentoalveolar surgery

Treatment Strategies
Stage III disease

Pathologic fractures, refractory

cases
Preservation of function
Airway, speech compromise
with large mandible
resections
Segmental resections, titanium
plate reconstruction, external
fixation.
All infections must be cleared
first
Delay reconstruction up to
3 months
Avoid bone grafting

Summary of Treatment Strategies

Summary
BPs are associated with BRONJ

Direct causal relationship not established

Increased potency (nitrogen), dosing frequency, duration associated w/
increase risk

No recommended duration to be on drug

For Asymptomatic patients taking BPs:

Review AAOMS Guidelines

Thorough medication history dont just ask if they take BPs

Routine dental care a necessity to maintain optimal oral health

Elective surgery - Review on case-by-case basis

CTX, drug holiday

Summary
Pts with BRONJ:

Review AAOMS guidelines:

Stage I, II lesions early recognition, conservative mgmt

No debridement unless loose bony sequestrum

Stage III lesions resection and reconstruction most predictable tx outcome

Routine dental care a necessity
No Elective surgery
There is a Stage 0 bone pain, paresthesia, no open wound. Get Xray, bone
scan!

BRONJ 2 Oral BP better success rate than IVBP

Discontinuing BP improves healing over long-term
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