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Bisphosphonate Related Osteonecrosis: Update
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Bisphosphonate Related Osteonecrosis: Update

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  • 1. Nik Desai, DMD, MD Division of Oral & Maxillofacial Surgery Department of Plastic Surgery Kaiser Permanente Medical Group Santa Clara, CA 04/28/2010 Bisphosphonate Related Osteonecrosis of the Jaws
  • 2. Objectives
    • Bisphosphonates
    • Clinical applications
    • Drug chemistry
    • Biologic action
    • BRONJ
    • Pathogenesis
    • Treatment of BRONJ
    • Latest management recommendations
    • Updates in the literature
    • Case Presentations
  • 3. 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
  • 4. 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
  • 5. History of Bisphosphonate Development
    • Mid-19 th Century German chemists
      • Anti-corrosive in pipelines
    • 20 th Century - Clinical applications
      • Tc99 Bone scans
      • Toothpaste
        • Anti-tartar, anti-plaque effects
      • Osteopathies
        • Anti-resorptive effect
  • 6. 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
  • 7. Antiresorptive Potency of BPs in Observed Human Clinical Trials
  • 8. 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
  • 9. Normal Osteoclastic Function
  • 10. 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
  • 11. 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
  • 12. Drug Administration and Dosage
  • 13. 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 ”
  • 14. 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
  • 15. 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
  • 16. Zolendronate (Zometa)
    • Only available in IV preparation
    • Approved for tx of hypercalcemia of malignancy
    • 4mg IV over no less than 15 mins
  • 17. 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
  • 18. 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
  • 19. Ibandronate (Boniva)
    • Most recently approved for tx and prevention of osteoporosis
    • 2.5mg daily or 150 mg monthly
  • 20. 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…………………
  • 21. 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
  • 22. 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
  • 23. BRONJ: Clinical Presentation
    • Subclinical Form
      • asymptomatic
      • radiographic signs
        • Sclerosis of lamina dura
        • Widening of PDL space
  • 24. Clinical Presentation (cont)…
    • Soft tissue abrasions
      • Tissues rubbing against bone
    • AND………
  • 25. Pathologic Fracture
  • 26. 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
  • 27. BRONJ: IV BPs
    • More frequently
    • Lesions more extensive
    • All stages
      • II, III more common
    • Lower success with Tx
    • Patients generally sicker
  • 28. Stage I Lesions
  • 29. Stage II Lesions
  • 30. Stage III Lesions
  • 31. Stage 0 Lesions
    • Spontaneous onset numbness and pain
    • No exposed bone
    • No prior dental antecedent
    • Positive image findings:
      • Sclerosis
      • Positive bone scan
  • 32. 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)
  • 33. 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
  • 34. Similar Clinical Entities
    • Closely resembles Osteopetrosis
      • Loss of osteoclastic function
      • Hypermineralization
      • Fractures, nonunions, open oral wounds
      • Endpoint: bone necrosis, +/- infection
  • 35. 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
  • 36. BRONJ: Model of Pathogenesis
  • 37. 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
  • 38. 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%
  • 39. 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)
  • 40. 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
  • 41. 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
  • 42. 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
  • 43. 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
  • 44. 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
  • 45. 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
  • 46. 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
  • 47. 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
  • 48. Treatment Goals
    • Preserve Quality of Life
      • Pain Control
      • Treat 2° infection
      • Prevent extension
  • 49. 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
  • 50. 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
  • 51. 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
  • 52. 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
  • 53. 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???
  • 54. 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
  • 55.  
  • 56.  
  • 57.  
  • 58. 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
  • 59. Summary of Treatment Strategies
  • 60. 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
  • 61. 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!!!!!