1. 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
2. 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
ismohammed@phcc.gov.qa
3. 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
4. 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)
ismohammed@phcc.gov.qa
5. 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
ismohammed@phcc.gov.qa
6. 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
ismohammed@phcc.gov.qa
7. 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
ismohammed@phcc.gov.qa
8. 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
ismohammed@phcc.gov.qa
12. 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
ismohammed@phcc.gov.qa
14. 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
15. 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 ”
ismohammed@phcc.gov.qa
16. 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
ismohammed@phcc.gov.qa
17. 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
ismohammed@phcc.gov.qa
18. Zolendronate (Zometa)
Only available in IV preparation
Approved for tx of hypercalcemia of
malignancy
4mg IV over no less than 15 mins
ismohammed@phcc.gov.qa
19. 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
ismohammed@phcc.gov.qa
20. 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
ismohammed@phcc.gov.qa
21. Ibandronate (Boniva)
Most recently approved for tx
and prevention of osteoporosis
2.5mg daily or 150 mg
monthly
ismohammed@phcc.gov.qa
22. 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…………………
ismohammed@phcc.gov.qa
23. 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
ismohammed@phcc.gov.qa
25. 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)
ismohammed@phcc.gov.qa
27. Similar Clinical Entities
Closely resembles
Osteopetrosis
– Loss of osteoclastic
function
– Hypermineralization
– Fractures, nonunions,
open oral wounds
– Endpoint: bone necrosis,
+/- infection
ismohammed@phcc.gov.qa
28. 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
ismohammed@phcc.gov.qa
29. 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
ismohammed@phcc.gov.qa
30. 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%
ismohammed@phcc.gov.qa
31. 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
ismohammed@phcc.gov.qa
32. 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
ismohammed@phcc.gov.qa
33. 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
ismohammed@phcc.gov.qa
34. 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
ismohammed@phcc.gov.qa
35. 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
ismohammed@phcc.gov.qa
36. 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
ismohammed@phcc.gov.qa
37. BRONJ: Clinical Presentation
Subclinical Form
– asymptomatic
– radiographic signs
Sclerosis of lamina
dura
Widening of PDL
space
ismohammed@phcc.gov.qa
39. More frequently
Lesions more
extensive
All stages
II, III more
common
Lower success with
Tx
Patients generally
sicker
BRONJ: IV BPs
ismohammed@phcc.gov.qa
41. 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
ismohammed@phcc.gov.qa
42. Stage 0 Lesions
Spontaneous onset
numbness and pain
No exposed bone
No prior dental antecedent
Positive image findings:
– Sclerosis
– Positive bone scan
ismohammed@phcc.gov.qa
43. 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
ismohammed@phcc.gov.qa
44. 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
ismohammed@phcc.gov.qa
45. 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
ismohammed@phcc.gov.qa
49. Treatment Goals
Preserve Quality of Life
– Pain Control
– Treat 2° infection
– Prevent extension
ismohammed@phcc.gov.qa
50. 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
ismohammed@phcc.gov.qa
51. 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
ismohammed@phcc.gov.qa
52. 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
ismohammed@phcc.gov.qa
53. 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
ismohammed@phcc.gov.qa
54. 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???
ismohammed@phcc.gov.qa
58. 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
ismohammed@phcc.gov.qa
59. 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
ismohammed@phcc.gov.qa