Transcript Surgical Management of Bisphosphonate Related

Surgical Management of Bisphosphonate
Related Osteonecrosis of the Jaw
By David Telles, DDS
Diplomate of the American Board
of Oral and Maxillofacial Surgeons
Overview
• Background
• Review of AAOMS Position Paper
▫ Oral vs IV Bisphosphonate Therapy
▫ Recommendations
▫ Staging
• Surgical Management Review
• Conclusions
Background
• The rise in bisphosphonate treatment of degenerative osseous diseases is
accompanied by a proportional increase in the number of reported cases of
bisphosphonate related osteonecrosis of the jaw (BRONJ precipitated by
surgical procedures and may occur spontaneously (Marx et al.)
• presentation of this pathology varies by route of administration
▫ Ruggiero7 et al. demonstrated a more aggressive clinical course in cases of
intravenous administration in contrast to administration per os (po).
▫ correlated with a potential difference in the relative potency of the different drug
forms, the intravenous suspension being more potent
▫ intravenous form is more efficacious, the relative ease of administration in oral
form translates into a greater prevalence of this drug among patients.
• As the use of bisphosphonates increases, dental practitioners are
encountering BRONJ more often.
• Typical clinical
▫ exposed bone or dehisced tissue with or without pain and swelling
▫ untreated cases -- sites of osteonecrosis can progress into orocutaneous fistulas
which may become secondarily infected.
Background
• Dentists must determine how to treat BRONJ
without further challenging the compromised
bone
• Treatment modalities
▫ conservative measures, such as antibiotics and
antimicrobial rinses
▫ superficial debridement
▫ sequestrectomy
▫ resection of the involved bone
Background
• Uses of bisphosphonates
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Inhibition of bone resorption
Osteolytic disease (Paget’s, Multiple Myeloma)
Metastatic bone disease
Hypercalcemia associated with malignancy
Osteoporosis
Anti-tumor activity (Rosen, Theriault et.al. 2001)
• Mechanism of Action
▫ Effects on osteoclasts- Precursor cells, cytoskeleton, apoptosis4 (Hughes et.al.
1995)
▫ Anti-angiogenesis - Zometa study8
▫ known that they inhibit osteoclastic function, increase osteoclast
apoptosis, inhibit osteoclast differentiation, and stimulate osteoclast
inhibitory factor, all of which may lead to inhibition of bone resorption
and increase in bone mass (Curi M et. al.)
IV vs Oral
• Ruggiero et. al. (2004) study - 63 cases oral
osteonecrosis (56 on IV treatment, 7 on oral treatment)
• Association between IV bisphosphonate exposure
and BRONJ may be hypothesized based on the
following observations
▫ 1) a positive correlation between bisphosphonate
potency and risk for developing BRONJ
▫ 2) a negative correlation between bisphosphonate
potency and duration of bisphosphonate exposure
prior to developing BRONJ
▫ 3) a positive correlation between duration of
bisphosphonate exposure and developing BRONJ.
IV vs Oral
• Incidence
▫ IV bisphosphonates and incidence of BRONJ
 clinical efficacy of IV bisphosphonates for the
treatment of hypercalcemia and bone metastases is
well established
 exposure in the setting of managing malignancy
remains the major risk factor for BRONJ
 Based on case series, case-controlled and cohort
studies, estimates of the cumulative incidence of
BRONJ range from 0.8%-12% (AAOMS Position
paper)
IV vs Oral
• Incidence: Oral
▫ over 190 million oral bisphosphonate prescriptions
have been dispensed worldwide.
▫ several BRONJ cases related to oral bisphosphonates
▫ Patients under treatment with oral bisphosphonate
therapy are at a considerably lower risk for BRONJ
than cancer patients treated with monthly IV
bisphosphonates
▫ Data from the manufacturer of alendronate (Merck),
the incidence of BRONJ was calculated to be
0.7/100,000 person/years of exposure
IV vs Oral
• Incidence: Oral
▫ Surveillance data from Australia estimated the
incidence of BRONJ for patients treated weekly
with alendronate as 0.01-0.04%.
▫ In a survey study of over 13, 000 KaiserPermanente members, the prevalence of BRONJ
in patients receiving long-term oral
bisphosphonate therapy was reported at 0.06%
(1:1,700).
▫ When PO given > 3 yrs – correlation to increased
risk for developing BRONJ
Risk Factors
Systemic Factors
Local Factors
-Potency of bisphosphonate
-Length of bisphosphonate treatment
-Race (usually Caucasians)
-Age (usually >60)
-Primary disease
multiple myeloma >breast CA>other
CA
-Misc-steroid treatment, diabetes,
smoking, alcohol, poor oral hygiene,
concurrent chemo therapy
-Recent history of invasive dental
surgery (dentoalveolar surgery i.e.
exodontias, implants, periodontal
surgery is 7x more likely to develop
BRONJ)
-Anatomy – tori, mylohyoid ridge,
palatal tori
-Concomitant oral disease –
periodontal and dental abscesses are
at a 7x increase for BRONJ
BRONJ
• Case Definition
▫ Current or previous treatment with a
bisphosphonate
▫ Exposed bone in the maxillofacial region that has
persisted for more than eight weeks
▫ No history of radiation therapy to the jaws
Staging
• Stage 0
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Symptoms
 • odontalgia not explained by an odontogenic cause
 • dull, aching bone pain in the body of the mandible, which may radiate to the
temporomandibular joint region
 • sinus pain, which may be associated with inflammation and thickening of the maxillary sinus
wall
 • altered neurosensory function
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Clinical Findings
 • loosening of teeth not explained by chronic periodontal disease
 • periapical/periodontal fistula that is not associated with pulpal necrosis due to caries
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Radiographic Findings
 • alveolar bone loss or resorption not attributable to chronic periodontal disease
 • changes to trabecular pattern—dense woven bone and persistence of unremodeled bone in
extraction sockets
 thickening/obscuring of periodontal ligament (thickening of the lamina dura and decreased size
of the periodontal ligament space)
 inferior alveolar canal narrowing
Staging and Treatment strategies
Clinical Staging of BRONJ
Stage 0: No exposed bone but history of
oral/IV bisphosphonate treatment
Treatment
Perceived risk, but no treatment necessary
Encourage oral hygiene, preventive strategies
Stage 1: exposed/necrotic bone in patients
who have no infection/ no pain
Chlorhexidine gluconate, encourage oral
hygiene, no surgery
Stage 2: exposed bone in patients with pain
and evidence of infection
Chlorhexidine gluconate, antimicrobial
therapy with cultures taken to determine if
actinomyces species present
Stage 3:exposed bone in patients with pain
and infection, and one or more of the
following: pathologic fracture, extraoral
fistula or osteolysis extending to the inferior
border, exposed necrotic bone extending
beyond the region of alveolar bone, i.e.,
inferior border and ramus in the mandible,
maxillary sinus and zygoma in the maxilla,
oral antral/oral nasal communication
Surgical debridement/resection in
combination with antibiotics, removal of
mobile segments of sequestrum
-If pathologic fracture present, pt may require
removal of compromised bone and
reconstruction (vascularized fibular flap,
Engroff et al)
Treatment cond..
• Regardless of the disease stage, mobile segments of bony sequestrum
should be removed without exposing uninvolved bone
▫ extraction of symptomatic teeth within exposed, necrotic bone should be
considered since it is unlikely that the extraction will exacerbate the established
necrotic process.
• Discontinuation of bisphosphonate therapy
▫ IV bisphosphonates
 Discontinuation of IV bisphosphonates offers no short-term benefit
 if systemic conditions permit, long-term discontinuation may be beneficial
 stabilizing established sites of BRONJ
 reducing the risk of new site development and reducing clinical symptoms
 risks and benefits of continuing bisphosphonate therapy should be made only by the
treating oncologist in consultation with the OMS and the patient.
▫ Oral bisphosphonates
 Discontinuation of oral bisphosphonate therapy in patients with BRONJ has been
associated with gradual improvement in clinical disease.
 Discontinuation for 6-12 months may result in either spontaneous sequestration or
resolution following debridement surgery
Literature review
• Treatment options
▫ Conservative treatment
 Long term Abx
 Chlorhexidine gluconate 0.12% rinse bid
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Sequestrectomy/Surgical Debridement
Resection
Drug holidays
HBO therapy
PRP Supplementation
Literature review - Curri M et al
• Treatment of Avascular Osteonecrosis of the Mandible in Cancer Patients
With a History of Bisphosphonate Therapy by Combining Bone Resection
and Autologous Platelet-Rich Plasma: Report of 3 Cases
▫ Case series of 3 cases and lit review
▫ Outline refractory cases of BROJN requiring resection
▫ Tx comprised of surigcal debridement/sequestrectomy supplemented with PRP
▫ 3 cases resolved without further bony exposures
▫ PRP – factors
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Plateletderived growth factor (PDGF)
Transforming growth factor- (TGF-)
vascular endothelial growth factor
epidermal growth factor
…..can induce paracrine effects on stimulated cells
Several studies reported a positive effect in bone regeneration and soft tissue healing
when PRP was applied in oral and maxillofacial reconstructive surgeries, cosmetic
surgeries, periodontal and peri-implant defects
Literature review – Carlson E et. al.
• Role of Surgical Resection in the Management of
Bisphosphonate-Related Osteonecrosis of the Jaws
• 103 sites of BRONJ in 82 patients
▫ 32 maxilla and 71 mandible
▫ 30 were taking an oral bisphosphonate and 52 taking
parenteral bisphosphonate
• Resection performed in 95 sites in 74 patients, whereas 8 sites
diagnosed in 8 patients were not resected
• 27 sites resected in patients treated with oral bisphosphonates
• 68 sites resected in patients treated with parenteral
bisphosphonates
Literature review – Carlson E et. al.
• Role of Surgical Resection in the Management of
Bisphosphonate-Related Osteonecrosis of the Jaws
▫ 95 resected sites, 87 (91.6%) healed in an acceptable fashion with resolution of
disease.
▫ 27 resected sites in patients taking an oral bisphosphonate medication, 26
(96.3%) healed satisfactorily refractory disease developing in 1 site
▫ Of 68 resected sites in patients taking a parenteral bisphosphonate medication,
 61 (89.7%) healed satisfactorily
 refractory disease developing in 7 sites
▫ All 29 patients(100%) undergoing resection of the maxilla related to either an oral
or parenteral bisphosphonate healed acceptably
▫ Refractory cases: 8 patients -- did so with a range of 7 to 250 days postoperatively
(mean, 73 days).
 6 developed after a marginal resection of the mandible for BRONJ
 Three sites = new primary disease developed in 2 patients postoperatively
-- Both were taking parenteral BP
▫ Histologic examination of the resected specimens identified malignant disease in
4 specimens in 3 patients
Literature review – Carlson E et. al.
• Role of Surgical Resection in the Management of
Bisphosphonate-Related Osteonecrosis of the Jaws
• Resection of BRONJ permits acceptable healing in patients taking
an oral bisphosphonate medication
• Resection of maxilla in patients taking an oral or parenteral
bisphosphonate medication follows a predictable course with regard
to healing
• Resection of mandible in patients taking a parenteral
bisphosphonate medication follows a variable postoperative course
▫ Although a high degree of success is realized
• Consider resection of necrotic bone of the maxilla and mandible that
develops in patients taking bisphosphonate medications.
• Refractory disease
▫ successfully managed with a more aggressive resection, specifically, a
segmental resection of the mandible after a marginal resection of the
mandible where refractory disease developed
Literature Review – Marx et al
• Oral Bisphosphonate-Induced Osteonecrosis: Risk Factors,
Prediction of Risk Using Serum CTX Testing, Prevention and
Treatment
▫ CTX (C-terminal telopeptide)
- a breakdown product of bone resorption
- used pre-operatively as a determinant for BRONJ
- inverse relationship between the risk for BRONJ and the level of
CTX
- less than 100pg/mL pose a high risk
- between 100 and 150 are at moderate risk
- over 150 are minimal risk.
▫ With cessation of the drug, values increased an average of 25.9
pg/mL per month, therefore justifying the implementation of a
drug holiday.
Literature review – Stanton, D. et. al.
• Outcome of Surgical Management of BisphosphonateRelated Osteonecrosis of the Jaws: Review of 33 Surgical
Cases
• 33 BRONJ cases treated surgically by a single surgeon at the
Hospital of the University of Pennsylvania
• 30 debridement patients, 25 (including 1 sequestrectomy patient
who required formal debridement) healed completely
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Of 30 pts who underwent surgical debridement
18 healed following this initial treatment and remained healed
4 patients requiring sequestrectomy, 3 healed after the initial treatment
28 of 33 patients healed completely with complete mucosal coverage and
elimination of pain
▫ Four patients developed occurrence of BRONJ at a separate site
• 32 of 37 BRONJ occurrences healed with surgical debridement
protocol or sequestrectomy.
• Follow-up range was 1 to 40 months (average 10.7).
Literature Review
• Abu-Id et al recommended
▫ radical surgical resection up to the vital bone,
because their study found conservative treatment
to be unsuccessful in 61.5% of cases
Literature Review: Wongchuensoontorn, C. et al
• Pathological Fractures in Patients Caused by
Bisphosphonate-Related Osteonecrosis of the Jaws:
Report of 3 Cases
▫ Case series of 3 pts with pathologic fracture – whom were taking
bisphosphonate therapy
▫ 2 of the cases
 undergone previous treatment with marginal resection of the mandible
 3rd case patient suffered from a pathological fracture after teeth
extractions and debridement
▫ ORIF with osteosynthesis
 the management of pathological fractures resulting from BRONJ may
require segmental resection and immediate reconstruction with a
reconstruction plate, as seen in our second case
▫ Applied 2.4-mm reconstruction plate is the standard implant for
fractures of an atrophic mandible
Future research
• The National Institutes of Health have provided funding opportunities for
research on the pathophysiology of bisphosphonate-associated
osteonecrosis of the jaw.
▫ resulted in multiple research efforts focusing on several facets of this disease
entity.
▫ 1) the effect of bisphosphonates on intra-oral soft tissue wound healing
▫ 2) analysis of alveolar bone hemostasis and the response to bisphosphonate
therapy
▫ 3) antiangiogenic properties of bisphosphonates and their effects on jaw bone
healing
▫ 4) pharmacogenetic research; 5) development of valid BRONJ risk assessment
tools.
• Continued governmental and institutional support is required in order to
elucidate the underlying pathophysiological mechanisms of BRONJ at the
cellular and molecular level.
• Novel strategies for: the prevention
▫ risk reduction
▫ treatment of BRONJ need to be developed
References
•
American Association of Oral and Maxillofacial Surgeons Position Paper on Bisphosphonate-Related
Osteonecrosis of the Jaws. JOMS, 65: 369-376, 2007.
•
Engroff SL. Et al Treating Bisphosphonate Osteonecrosis of the Jaws: Is there a Role for Resection and
Vascularized Reconstruction? JOMS, 65:2374-2385, 2007.
•
Grant, BT, et al Outcomes of Placing Dental Implants in Patients Taking Oral Bisphosphonates: A
Review of 115 Cases. JOMS. 66:223-230, 2008
•
Ito M, Chokki M, , Ogino Y, Satomi Y, Azuma Y, Ohta T, Kiyoki M. Comparison of cytotoxic effects of
bisphosphonates in vitro and in vivo. Calcif Tissue Int 1998:63:143-147
•
Marx, RE. Oral Bisphosphonate-Induced Osteonecrosis: Risk Factors, Prediction of Risk Using Serum
CTX Testing, Prevention and Treatment. JOMS, 65: 2397-2410, 2007.
•
Rogers MJ, Watts DJ, Russell RG. Overview of Bisphosphonates. CANCER supplement 1997;80:16521660
•
Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of
bisphosphonates: A review of 63 cases. Journal of Oram and Maxillofacial Surg 2004;62:527-534
•
Wood J, Bonjean K, Ruetz S. Novel antiangiogenic effects of the bisphosphonate compound zoledronic
acid. J Pharmacol Exp Ther 2002: 302: 1055-1061.
References
•
Curi, M et al. . Treatment of Avascular Osteonecrosis of the Mandible in Cancer Patients With a
History of Bisphosphonate Therapy by Combining Bone Resection and Autologous Platelet-Rich
Plasma: Report of 3 Cases. J Oral Maxillofac Surg 65:349-355, 2007
•
Carlson, E et al. The Role of Surgical Resection in the Management of Bisphosphonate-Related
Osteonecrosis of the Jaws. J Oral Maxillofac Surg 67:85-95, 2009
•
Stanton, D. et al. Outcome of Surgical Management of Bisphosphonate-Related Osteonecrosis of
the Jaws: Review of 33 Surgical Cases. J Oral Maxillofac Surg 67:943-950, 2009
•
Wongchuensoontorn, C. et al. Pathological Fractures in Patients Caused by BisphosphonateRelated Osteonecrosis of the Jaws: Report of 3 Cases. J Oral Maxillofac Surg 67:1311-1316, 2009