Download Bisphosphonate Related Osteonecrosis: Update

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 Paget’s 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
 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
Drug Administration and Dosage
Pharmacokinetics
 Oral BP’s
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 Paget’s
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 Paget’s disease
 Also used for osteoporosis pt’s
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
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
avascular
(ORN):
bone necrosis 2° radiation
 Osteomyelitis:
thrombosis
of small blood vessels leading to
infection within bone marrow
 Steroid-induced
more
osteonecrosis:
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, O’Ryan:

 PROBE
study, Kaiser Permanente
 Survey
of 13,000 pts using oral BP
 Prevalence of BRONJ: 0.06% (1:1,700)
low numbers, so…what’s 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 “experts”…time 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
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


Local anatomy
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
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
 Contact
PCP re: drug holiday for at least 3 months prior to
surgery
 Restarted after osseous healing complete (3 months)

More than 3 years, with/without concomitant steroid use
 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 – don’t 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
 TALK to the Medicine folks….share your knowledge!!!!!