MRONJ

Islam Kassem, BDS , MSc, MOMS RCPS Glasg, FFD RCSI
Oral & Maxillofacial Surgeon
Doha, Qatar
21 February 2015
Bisphosphonate Related
Osteonecrosis of the Jaws
ismohammed@phcc.gov.qa
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
ikassem@dr.com

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

Normal Osteoclastic Function

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 ismohammed@phcc.gov.qa

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 ismohammed@phcc.gov.qa

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

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

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

Stage I Lesions

Stage II Lesions

Stage III Lesions

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

 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

 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

 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???

Conservative extraction??
ikassem@dr.com

 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

 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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google & download the lectures

An ounce of prevention is worth
a pound of cure.
Thank you

MRONJ

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