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MRONJ
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Islam Kassem, BDS , MSc, MOMS RCPS Glasg, FFD RCSI Oral & Maxillofacial Surgeon Doha, Qatar 21 February 2015 Bisphosphonate Related Osteonecrosis of the Jaws [email protected] BRONJ
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Transcript of MRONJ
Islam Kassem, BDS , MSc, MOMS RCPS Glasg, FFD RCSI
Oral & Maxillofacial Surgeon
Doha, Qatar 21 February 2015
Bisphosphonate Related Osteonecrosis of the Jaws
BRONJ
Declaration
There is no conflict of interest in this Lecture .
I have no monetary benefit from this Lecture.
No implied sponsorship by any company to the speaker
All patients in the presentation had an informed consent for photography & publication
Islam Kassem, BDS , MSc, MOMS RCPS Glasg
Oral & Maxillofacial Surgeon
Alexandria university Hospital
Cairo
National institute of cancer
Scientific day of Head & neck surgery unit 12 March 2009
Bisphosphonate & Osteonecrosis of the mandible, case report
Objectives
Bisphosphonates
Clinical applications
Drug chemistry
Biologic action
BRONJ
Pathogenesis
Treatment of BRONJ
Latest management recommendations
Updates in the literature
Case Presentations
Latest PubMed search produced 1473 articles on Bisphosphonate
Related Osteonecrosis of the Jaw. (BRONJ)
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
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
Bone metastasis, hypercalcemia
– 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
Vitamen D diffenecy in adolecent
Review article International Jounal of Pediatrics , 2014
Soliman ,Kassem et al
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
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 ”
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: Time line
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
– Non-healing 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
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%
low numbers, so…what’s all the hoopla for?
Physicians prescribing these meds – Endocrinologists, Oncologists, GPs, OB-Gyns,etc
– Not well informed of adverse oral effects
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 2014): – 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
Poor oral hygiene
Chemotherapeutic drugs
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………
More frequently Lesions more extensive All stages II, III more
common Lower success with Tx Patients generally sicker
BRONJ: IV BPs
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
Stage 0 Lesions
Spontaneous onset numbness and pain
No exposed bone
No prior dental antecedent
Positive image findings:
– Sclerosis
– Positive bone scan
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:
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
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