Nik Desai, DMD, MD

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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

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Objectives

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

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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

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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

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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

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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

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Antiresorptive Potency of BPs in Observed Human
Clinical Trials
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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

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Normal Osteoclastic Function
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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

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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 gt osteoblastic
  differentiation
• increased fibrofatty marrow
• Progressively porotic bone
• DEXA scan for BMD values

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Drug Administration and Dosage
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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 osteoclast-mediated resorption
• Biologic Catch 22

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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 gt2 yrs
• No documented cases of BRONJ

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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

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Zolendronate (Zometa)

• Only available in IV preparation
• Approved for tx of hypercalcemia of malignancy
• 4mg IV over no less than 15 mins

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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

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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

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Ibandronate (Boniva)

• Most recently approved for tx and prevention of
  osteoporosis
• 2.5mg daily or 150 mg monthly

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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

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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

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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

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BRONJ Clinical Presentation

• Subclinical Form
• asymptomatic
• radiographic signs
• Sclerosis of lamina dura
• Widening of PDL space

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Clinical Presentation (cont)

• Soft tissue abrasions
• Tissues rubbing against bone
• AND

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Pathologic Fracture
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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

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BRONJ IV BPs

• More frequently
• Lesions more extensive
• All stages
• II, III more common
• Lower success with Tx
• Patients generally sicker

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Stage I Lesions
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Stage II Lesions
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Stage III Lesions
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Stage 0 Lesions

• Spontaneous onset numbness and pain
• No exposed bone
• No prior dental antecedent
• Positive image findings
• Sclerosis
• Positive bone scan

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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)

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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

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Similar Clinical Entities

• Closely resembles Osteopetrosis
• Loss of osteoclastic function
• Hypermineralization
• Fractures, nonunions, open oral wounds
• Endpoint bone necrosis, /- infection

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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

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BRONJ Model of Pathogenesis
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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

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Estimated Incidence of BRONJ 2 Oral BPs

• gt190 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

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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 (11,700)

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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

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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

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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 gt 8 weeks
• No history of radiation therapy to jaws

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Risk Factors for Development of BRONJ

• Drug-related factors
• Potency of BP
• Zoledronate gt pamidronate gt 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 gt maxilla (21)
• Concomitant oral disease
• 7-fold risk for BRONJ with IV BPs

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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 gt breast cancer gt other cancers
• Osteopenia/osteoporosis diagnosis concurrent w/
  cancer diagnosis
• Additional risk factors
• Corticosteroid therapy
• Diabetes
• Smoking
• EtOH
• Poor oral hygiene
• Chemotherapeutic drugs

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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

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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

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Serum CTX Peptide

• Low values high risk
• Little osteoclastic function
• Marx, et al 2007 (JOMS)
• 17 pts on oral BPs gt 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

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Treatment Goals

• Preserve Quality of Life
• Pain Control
• Treat 2 infection
• Prevent extension

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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

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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

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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

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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

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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???

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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

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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

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Summary of Treatment Strategies
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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

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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!!!!!