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Nik Desai, DMD, MDDivision of Oral & Maxillofacial Surgery
Department of Plastic SurgeryKaiser Permanente Medical Group
Santa Clara, CA04/28/2010
Bisphosphonate Related Osteonecrosis of the Jaws
Objectives
BisphosphonatesClinical applicationsDrug chemistryBiologic actionBRONJPathogenesisTreatment of BRONJLatest management recommendationsUpdates in the literatureCase Presentations
Bisphosphonates – what are they?
Class of drugsHigh 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 inpostmenopausal womenIncrease bone mass in men with osteoporosisTx of glucocorticoid-induced osteoporosisTx of Paget’s disease of boneHypercalcemia of malignancyBone 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 osteoclast-
mediated 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 stomachInflammation/erosions of esophagus
Fever/flu-like symptomsSlight increased risk for electrolyte disturbanceUveitisMusculoskeletal joint painAnd of course…………………
BRONJ
Exposed, devitalized bone in maxillofacial region
Prior history or current use of BP
Vague pain, discomfortSpontaneous
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
More frequently Lesions more extensiveAll stages
II, III more common
Lower success with TxPatients generally sicker
BRONJ: IV BPs
Stage I Lesions
Stage II Lesions
Stage III Lesions
Stage 0 Lesions
Spontaneous onset numbness and pain
No exposed boneNo prior dental
antecedentPositive 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
usageMerck 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 BPPrevalence 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
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
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 crownsEndodontic 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 risksRegular 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:
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 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!!!!!
