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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

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bisphosphonate related osteonecrosis of the jaws

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
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
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
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
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
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
biologic action of bisphosphonates
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

medical indications for iv bps
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
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
pharmacokinetics
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 osteoclast-mediated resorption
    • “Biologic Catch 22”
etidronate didronel
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
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
Zolendronate (Zometa)
  • Only available in IV preparation
  • Approved for tx of hypercalcemia of malignancy
  • 4mg IV over no less than 15 mins
alendronate fosamax
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
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
Ibandronate (Boniva)
  • Most recently approved for tx and prevention of osteoporosis
  • 2.5mg daily or 150 mg monthly
bisphosphonate side effects
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
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
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 presentation23
BRONJ: Clinical Presentation

Subclinical Form

asymptomatic

radiographic signs

Sclerosis of lamina dura

Widening of PDL space

clinical presentation cont
Clinical Presentation (cont)…

Soft tissue abrasions

Tissues rubbing against bone

AND………

staging of bronj
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
BRONJ: IV BPs
  • More frequently
  • Lesions more extensive
  • All stages
    • II, III more common
  • Lower success with Tx
  • Patients generally sicker
stage 0 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
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
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
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
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

estimated incidence of bronj 2 iv bps
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
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
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
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
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
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
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
Risk factors (continued)
  • Demographic/systemic factors
    • Age: 9% increased risk for every passing decade
      • Multiple myeloma patients treated w/ IV BPs
    • Race: Caucasian
    • Cancer diagnosis
      • 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
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
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
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

Treatment Goals
what this means for you as a practitioner
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
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 strategies51
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 strategies52
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 strategies53
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 strategies54
Treatment Strategies
  • Patients with Established Diagnosis of BRONJ
    • Objectives: eliminate pain, control infection, minimize progression/occurrence of necrosis
    • Marx:
      • debridement may worsen condition
    • Removal of bone serving as soft tissue irritant, loose bony sequestra
      • Without exposure of uninvolved bone
    • Extraction of teeth within exposed, necrotic bone
    • Avoid elective dentoalveolar surgery
treatment strategies58
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
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

summary61
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!!!!!