Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management.

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Bisphosphonate-related osteonecrosis of the jaw: background
and guidelines for diagnosis, staging and management
Salvatore L. Ruggiero, DMD, MD,aJohn Fantasia, DDS,band Eric Carlson, DMD, MDc, New
Hyde Park, NY, and Knoxville, TN
LONG ISLAND JEWISH MEDICAL CENTER AND UNIVERSITY OF TENNESSEE
Bisphosphonates are a class of agents used to treat
osteoporosis and malignant bone metastases. Despite
these benefits, osteonecrosis of the jaws is a significant
complication in a subset of patients receiving these
drugs. Based on a growing number of case reports and
institutional reviews, bisphosphonate therapy may
cause exposed and necrotic bone that is isolated to the
jaw. This complication usually presents after simple
dentoalveolar surgery. The pathogenesis for this com-
plication appears to be related to the profound inhibi-
tion of osteoclast function and bone remodeling. This
report serves to alert dentists and dental specialists
about the potential complication of maxillary and man-
dibular bone necrosis in patients receiving bisphospho-
nate therapy, and proposes a guideline for diagnosis,
staging, and management.
Bisphosphonates are a new class of agents that have
been increasingly recommended for use in patients with
osteoporosis, Paget’s disease of bone, hypercalcemia of
malignancy, osteolytic bone metastases, and osteolytic
lesions of multiple myeloma. Despite the benefits re-
lated to use of these medications, osteonecrosis of the
jaws is a significant complication in a subset of patients
receiving these drugs. The phenomenon of bisphospho-
nate-related osteonecrosis (BRON) was recognized a
few years after their approval for use. Reports first
appeared in 2003, alerting the dental and medical com-
munities of this complication.1-4 There is an increasing
number of BRON cases being diagnosed, and BRON is
recognized as occurring in all countries where bisphos-
phonates are prescribed. Cases of BRON have been
reported in scientific articles in refereed journals, ab-
stract presentations at national scientific meetings, cor-
respondence in the form of letters to the editor, authors
replies, and editorials, and medical alerts and advisories
to dentists and physicians.1-24 Some have questioned
the association of bisphosphonates and osteonecrosis of
the jaw, suggesting that a causal relationship has not
been definitively proven.25,26 The similarity of BRON
to cases of phosphorous necrosis of the jaw in workers
exposed to white phosphorus (phossy jaw) during the
late 19th and early 20th century has been reported by
Hellstein et al.14,16 and Donaghue.23 This historical fact
lends support to the phenomenon of jaw osteonecrosis
being linked directly to the bisphosphonate medica-
tions. Also of historical note is a 1995 case report by
Starck and Epker27 describing the failure of osseointe-
grated implants after bisphosphonate therapy for osteo-
porosis. However, that article does not describe osteo-
necrosis,anda direct
bisphosphonate use and implant failure is difficult to
establish based on the single case report. However,
there is increasing concern that the oral bisphospho-
nates are implicated in osteonecrosis of the jaws, albeit
less commonly than that observed with the more potent
intravenously administered bisphosphonates. Based on
the available data, and the authors’ experiences, we
review the background of this phenomenon and offer
guidelines in the diagnosis and treatment of BRON and
cause andeffect of
aChief, Division of Oral and Maxillofacial Surgery, Long Island
Jewish Medical Center.
bChief, Division of Oral and Maxillofacial Pathology, Long Island
Jewish Medical Center.
cChairman, Department of Oral and Maxillofacial Surgery, Univer-
sity of Tennessee.
Received for publication Mar 21, 2006; returned for revision May 6,
2006; accepted for publication Jun 1, 2006.
1079-2104/$ - see front matter
© 2006 Mosby, Inc. All rights reserved.
doi:10.1016/j.tripleo.2006.06.004
433
Vol. 102 No. 4 October 2006
ORAL AND MAXILLOFACIAL SURGERY
Editor: James R. Hupp

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emphasize the important role of the general dentist and
the dental specialist in the diagnosis and management
of affected patients.
INDICATIONS FOR BISPHOSPHONATE USE
Cancer patients with metastatic or primary bone le-
sions often develop sequential skeletal complications.
These complications may include pain, pathologic frac-
ture, spinal cord compression, and hypercalcemia of
malignancy.28 Activation of osteoclasts, mediated by
cytokines produced by tumor cells, leads to disruption
of normal bone metabolism.29 Patients with metabolic
bone disease such as osteoporosis30 and Paget’s dis-
ease31,32 similarly have decreased bone strength and
increased susceptibility to bone pain and fracture.
Bisphosphonates are nonmetabolized analogs of pyro-
phosphate that localize to bone and prevent or amelio-
rate skeletal complications. The various bisphospho-
nates, approved for clinical use, differ based on
structural alterations of the so-called R-2 side chain.
These R-2 side chains determine the cellular effects and
efficiencies as inhibitors of bone resorption. Once de-
posited on the surface of bone, bisphosphonates are
internalized by osteoclasts, causing disruption of oste-
oclast-mediated bone resorption.29 Bisphosphonates
also have antiangiogenic properties, resulting in de-
creased circulating levels of vascular endothelial
growth factor (VEGF).33-37 Antineoplastic effects of
bisphosphonates also have been suggested.38 The effi-
cacy of these agents in reducing bone pain, skeletal
complications, and hypercalcemia has been extensively
documented in patients with metastatic breast cancer
and multiple myeloma.39-41 Efficacy of bisphospho-
nates in patients with progressive metastatic prostate
carcinoma and other solid tumors has been reported,
though not as extensively studied as with the aforemen-
tioned malignancies.42,43
There are a variety of bisphosphonates that are ap-
proved for clinical use in the United States (Table I).
The intravenous bisphosphonates are approved for pa-
tients with metastatic breast cancer, multiple myeloma,
hypercalcemia of malignancy, and Paget’s disease of
bone and for treatment of documented bone metastases
from any solid tumor. These intravenous bisphospho-
nates include pamidronate (Aredia), a second-genera-
tion bisphosphonate that is administered intravenously
every 3 to 4 weeks at a typical dose of 90 mg, and
zoledronic acid (Zometa), a third-generation bisphos-
phonate, administered intravenously every 3 to 4 weeks
at a dose of 4 mg. In comparison with pamidronate,
zoledronate is significantly more potent and more ef-
fective in controlling hypercalcemia of malignancy and
reducing the overall number of skeletal complica-
tions.41 It is estimated that over 2.8 million cancer
patients worldwide have received intravenous bisphos-
phonate treatment since it was introduced.44 A far
greater number of patients are receiving oral bisphos-
phonates, such as alendronate (Fosomax) and residr-
onate (Actonel), for the treatment of postmenopausal
osteoporosis and glucocorticoid induced osteoporosis.
These medications are usually given once a week:
alendronate 70 mg once weekly for the treatment of
osteoporosis or less if it is being given for prevention of
osteoporosis and risedronate 35 mg once weekly. Iban-
dronate (Boniva) is the most recent bisphosphonate to
receive FDA approval (March 2005) for the treatment
of osteoporosis and is dosed on a monthly regimen.
BISPHOSPHONATE-RELATED OSTEONECROSIS
OF THE JAW
There are a growing number of cancer patients re-
ceiving intravenous bisphosphonate therapy who have
developed exposed and necrotic bone of the mandible
and maxilla. This complication has occurred either
spontaneously or after simple dentoalveolar surgery.
Similar troublesome clinical findings have been noted
in some patients taking the less potent oral bisphospho-
nates for the treatment or prevention of osteoporo-
sis.2,6,10,14,17,45 Novartis, the pharmaceutical company
that manufactures pamidronate and zolendronate, re-
ceived documentation of more than 600 cases of osteo-
necrosis of the jaw since they began tracking this com-
plication.44 This prompted the drug manufacturer to
modify the U.S. package inserts for both Aredia and
Zometa, listing osteonecrosis of the jaw as a potential
complication. In addition, an expert panel was created
to establish recommendations for the prevention, diag-
nosis, and treatment of osteonecrosis.46 In September
2004, warning letters were issued to oncologists and
oral and maxillofacial surgeons detailing these poten-
tial complications and alerting them of the potential for
osteonecrosis. In May 2005, following a recommenda-
Table I. Bisphosphonate medications approved for use
in the United States
Generic
Name deliveryManufacturer
Brand name,
RPFDA-a
Pamidronate Aredia, IV
Tiludronate
Alendronate
sodium
Etidronate
Risedronate
Zoledronic
acid
Ibandronate
Novartis
Sanofi
Merck
100
10
1,000
1991
1997
1997
Skelid, PO
Fosamax, PO
Didronel, PO
Actonel, PO
Zometa, IV
Proctor & Gamble
Proctor & Gamble
Novartis
1 1997
1998
2001
5,000
100,000
Boniva, PORoche 10,0002005
Modified from Berenson et al.41 RP, relative potency; FDA-a, Food
and Drug Administration approval; PO, oral; IV, intravenous.
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October 2006
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tion from an Advisory Committee to the Food and Drug
Administration, Novartis sent a similar alert to all den-
tal health professionals, emphasizing potential oral
complications.
Clinical features
Patients who present with BRON of the jaw are
typically oncology patients with metastatic disease in-
volving bone. Except for bisphosphonate treatment, the
individual chemotherapeutic regimens for these pa-
tients vary in accordance with the tumor type. Osteo-
necrosis of the jaw may remain asymptomatic for
weeks, months, or years and may result in pain or
exposed maxillary or mandibular bone. These lesions
are most frequently symptomatic when surrounding
tissues become inflamed or there is clinical evidence of
infection. Signs and symptoms that may occur before
the development of clinically detectable osteonecrosis
include pain, tooth mobility, mucosal swelling, ery-
thema, and ulceration. These may occur spontaneously
(Fig. 1) or more commonly at the site of earlier den-
toalveolar surgery (Fig. 2). Some patients may also
present with complaints of altered sensation in the
affected area. Chronic maxillary sinusitis secondary to
osteonecrosis with or without an oral-antral fistula can
be the presenting symptom in patients with maxillary
involvement. Similar clinical findings have been ob-
served in some patients taking oral bisphosphonates for
osteoporosis.
Radiographic changes are not evident until there is
significant bone involvement. Therefore, panoramic
and periapical radiographs may not reveal significant
changes in the early stages of osteonecrosis. Early or
late radiographic changes may mimic classic periapical
pathology or osteomyelitis or in cancer patients raise
the suspicion of primary (myeloma) or metastatic bone
disease. When there is extensive bone involvement,
regions of mottled bone similar to that of diffuse os-
teomyelitis are noted. Widening of the periodontal lig-
ament space may also be noted radiographically (Figs.
3 and 4). After prolonged exposure to the intravenous
bisphosphonates, osteosclerosis of the bone may be
noted radiographically, especially osteosclerotic lamina
dura.
Potential risk factors
Recent retrospective clinical studies have identified
several potential risk factors associated with the devel-
opment of BRON.47-54 These include a history of den-
toalveolar trauma, duration of bisphosphonate expo-
sure, and the type of bisphosphonate. In the majority of
BRON cases reported to date, recent dentoalveolar
trauma was the most prevalent and consistent risk fac-
tor.45,54 This underscores the importance of maintain-
ing good oral health and avoiding extractions in this
population. The duration of bisphosphonate therapy
also appears to be related to the likelihood of develop-
ing necrosis with longer treatment regimens associated
with a greater risk of developing disease.19 In addition,
the more potent intravenous bisphosphonates, such as
pamidronate and especially zolendronate, appear to be
significantly more problematic than the oral bisphos-
phonate medications.19
Staging
The extent of symptoms and clinical disease associ-
ated with BRON can vary despite similar disease pro-
cesses, bisphosphonate dosage regimens, and treatment
duration. Based on our observations and experience in
diagnosis and management of 141 patients with this
Fig. 1. Spontaneous bone exposure of the posterior mandible,
lingual aspect.
Fig. 2. Nonhealing extraction sites with exposed alveolar
bone.
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complication, we have implemented a staging system to
stratify these patients (Table II).
Stage 1: disease characterized by exposed bone that
is asymptomatic with no evidence of any significant
adjacent or regional soft tissue inflammatory swelling
or infection. It is recognized that patients may have
symptoms of pain prior to the development of radio-
graphic changes suspicious for osteonecrosis or clinical
evidence of exposed bone.
Stage 2: disease characterized by exposed bone with
associated pain, with adjacent or regional soft tissue
inflammatory swelling or secondary infection.
Stage 3: Disease characterized by exposed bone as-
sociated with pain, adjacent or regional soft tissue
inflammatory swelling, or secondary infection that is
difficult to manage with oral or intravenous antibiotic
therapy. The presence of an extraoral cutaneous fistula
secondary to jaw osteonecrosis or a pathologic fracture
is common for patients at this stage. Often because of a
greater volume of necrotic bone, these patients may
require surgical therapy to debride troublesome ne-
crotic bone.
Pathogenesis
It appears that the pathogenesis of this process is
most consistent with a defect in jawbone physiologic
remodeling or wound healing.29 Hypothetically, the
mechanism by which bisphosphonates can have this
effect centers on osteoclast inhibition and apoptosis.
Impaired osteoclast function interferes with normal
bone turnover and resorption. Bisphosphonates also
have demonstrated effects unrelated to osteoclast inhi-
bition. Pamidronate was reported to significantly de-
press bone blood flow in rats.35,36 The mechanism of
this effect may be attributable to a complex interaction
of pamidronate with growth hormone and insulin-like
growth factor I, both of which are thought to play a role
in the regulation of blood circulation in bones.35,36
Bisphosphonates inhibit endothelial cell function in
vitro and in vivo.37 Cells treated with bisphosphonates
Fig. 3. A, Panoramic radiograph of nonhealing extraction
sites in a breast cancer patient receiving bisphosphonate ther-
apy. B, Panoramic radiograph of the same site 12 months later
demonstrating a large area of bone sequestration and necrosis.
Fig. 4. Panoramic radiograph of a nonhealing extraction site
and widening of the periodontal ligament space in a breast
cancer patient receiving bisphosphonate treatment.
Table II. Clinical staging of BRON of the jaw
Stage 1
Exposed, necrotic bone that is asymptomatic
Stage 2
Exposed, necrotic bone associated with pain and
infection
Stage 3
Exposed, necrotic bone in patients with pain, infection,
and pathologic fracture, extraoral fistula, or osteolysis
extending to the inferior border
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demonstrate decreased proliferation, increased rate of
apoptosis, and a decrease in capillary-tube formation.37
Bisphosphonatesalso demonstrate
properties owing to their ability to significantly de-
crease circulating levels of the potent angiogenic factor
VEGF, as demonstrated in breast cancer patients with
bone metastases.33,34 These properties could also con-
tribute to the apparent ischemic changes noted in the
affected patients’ jawbones.
antiangiogenic
Why are the jaws at increased risk?
Apparently, BRON exclusively affects the jaws.
Most cases of BRON occur in patients who have un-
dergone tooth extraction or some other form of surgical
insult; however, a subset of edentulous and dentate
patients have developed necrotic bone spontaneously
(Fig. 1). The apparent selective involvement of the
maxilla and mandible may be a reflection of the unique
environment of the oral cavity. Typically, healing of an
open bony wound (e.g., extraction socket) in the pres-
ence of normal oral microflora occurs quickly and
without complication. However, when the healing po-
tential or the vascular supply of the mandible or maxilla
is compromised either by tumorcidal radiation doses or
some other agent(s) or pathologic process, then minor
injury or disease in these sites increases risk for osteo-
necrosis and possible secondary osteomyelitis. Also,
bisphosphonates are preferentially deposited in bones
with high turnover rates; because the maxilla and man-
dible are sites of significant remodeling, it is possible
that the levels of bisphosphonate within the jaw are
selectively elevated. However, we are not aware of
studies demonstrating selective increase in bisphospho-
nate localization to certain bones such as the jaws.
Other medications in addition to bisphosphonates
may also affect wound healing and also must be con-
sidered as possible cofactors. The similarity of BRON
to a 19th century disease known as phossy jaw is
striking and has been outlined by Hellstein et al.14,16
Phossy jaw represents osteonecrosis of the jawbones
that developed in some employees working with white
phosphorus in the munitions, fertilizer, and match-man-
ufacturing industries. Affected individuals developed
jaw necrosis, which clinically and histologically is sim-
ilar to current cases of BRON.
Protocol and Treatment Recommendations
Patients who are about to start intravenous bisphos-
phonate therapy. The main (Table III) emphasis at this
time should be to minimize the risk of occurrence of
BRON. Although a small percentage of patients receiv-
ing bisphosphonates develop osteonecrosis of the jaw
spontaneously, the majority of affected patients expe-
rience this complication following simple dentoalveo-
lar surgery (i.e., extraction, dental implant placement,
or apical surgery). Therefore, measures optimizing den-
tal health should be the main goal in patients who will
receive bisphosphonate therapy. Initiation of bisphos-
phonate therapy should be delayed, if possible, until the
dental health is optimized. This decision must be made
in conjunction with the treating physician and dentist
and other specialists involved in the care of the patient.
Nonrestorable teeth and those with a poor prognosis
should be extracted. Other necessary elective dentoal-
veolar surgery should also be completed at this time. It
appears advisable that bisphosphonate therapy should
be delayed at least 4-6 weeks to ensure adequate osse-
ous healing. Dental prophylaxis, caries control, and
conservative restorative dentistry are critical to main-
taining functionally sound teeth. This level of care must
be continued indefinitely. Patients with full or partial
dentures should be examined for areas of mucosal
trauma, especially along the lingual flange region. It is
critical that patients are educated as to the importance
of dental hygiene and regular dental evaluations and
specifically instructed to report any pain, swelling, or
exposed bone that would either predict or characterize
BRON. It is important for us to inform the treating
oncologists that these patient should be managed as if
there were about to receive radiation therapy to the
head and neck region. Osteoradionecrosis prevention
protocols are guidelines that are familiar to most on-
cologists.
Patients receiving bisphosphonates with no evidence
of osteonecrosis. The risk of developing osteonecrosis
in asymptomatic patients who are receiving bisphos-
phonates (intravenous or oral) remains unknown. How-
ever, a recent web-based survey of 1,203 oncology
patients (904 multiple myeloma and 229 breast cancer
patients) reported that 6.9% of multiple myeloma pa-
tients and 4.3% of breast cancer patients had osteone-
crosis of the jaw.19 Patients with “prior dental prob-
lems” were significantly more likely to develop these
Table III. Treatment regimens
Stage 1
Daily oral antimicrobial rinses or irrigations
(0.12% chlorhexidine) and regular
clinical follow-up as disease activity
dictates
Antimicrobial therapies based on culture
and sensitivity data; analgesia and daily
oral antimicrobial rinses or irrigations
(0.12% chlorhexidine)
Surgical debridement of necrotic bone,
antimicrobial therapy (oral or
intravenous), and analgesia and daily oral
antimicrobial rinses (0.12%
chlorhexidine)
Stage 2
Stage 3
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complications. The data also suggested that those pa-
tients receiving zoledronate developed osteonecrosis
more quickly (within 6 months of treatment) than those
taking pamidronate.19 This likely reflects the increased
potency of zoledronate compared with pamidronate.
Patients receiving oral bisphosphonates were not in-
cluded in the survey. Our experience indicates that
patients with an established diagnosis of BRON are
certainly at higher risk of developing osteonecrosis
after any type of dentoalveolar surgery. Maintaining
good oral hygiene and dental care is of paramount
importance in preventing dental disease that may re-
quire dentoalveolar surgery. If the tooth is considered
nonrestorable the crown portion of the tooth can be
removed and the endodontically treated roots left in
place. Placement of dental implants should be avoided
in the patient population exposed to the more potent
intravenous bisphosphonate medications (zoledronic
acid and pamidronate).
Patients who are receiving oral bisphosphonate ther-
apy for the treatment of osteoporosis are also at risk for
compromised jawbone healing but likely to a much
lesser degree. Our data6 and those of others17,45 indi-
cated that approximately 10% of BRON patients were
receiving oral bisphosphonates. Thus BRON can man-
ifest in this cohort of patients as jawbone osteonecrosis
or osteonecrosis of tori either spontaneously or after
minor trauma. Bisphosphonate-related osteonecrosis in
this patient population may develop into a more signif-
icant problem than now realized, given the large num-
ber of patients taking oral bisphosphonates. In general,
these patients seem to have less severe manifestations
of necrosis and respond more readily to sequestrectomy
or marginal resection. Although we do not consider oral
bisphosphonate therapy an absolute contraindication in
patients who require elective dentoalveolar surgery, we
do suggest that patients be adequately informed of the
potential risk of compromised bone healing and risk of
BRON. The potential for complications in patients with
a history of oral bisphosphonate use is probably related
to the duration of exposure. The potential problems
related to oral bisphosphonate clearly require further
analysis and continued observation.
Patients with established BRON. Panoramic and to-
mographic imaging may be performed if osteonecrosis
is suspected. Intraoral films can also be used to more
accurately demonstrate subtle bone changes. However,
a thorough history and intraoral clinical exam, coupled
with radiographs, is the most effective way to establish
the diagnosis. Microbial cultures may define comorbid
oral infections and facilitate the selection of an appro-
priate antibiotic regimen. Tissue biopsy should be per-
formed only if metastatic disease is strongly suspected
or detection of such would alter clinical treatment de-
cisions. We have not identified evidence of metastatic
disease or myeloma in the jawbone of those cancer
patients biopsied for histopathologic diagnosis or de-
brided for clinical BRON. Although identification of
these disease processes in the jawbones is certainly
recognized, it has not been our experience to recognize
neoplastic disease in the anatomic location of the ne-
crosis. The microscopic examination of debrided or
resected BRON specimens demonstrates necrotic bone
with associated bacterial debris and granulation tissue.
Notable is the absence of osteoclasts. We caution
against the specific diagnosis of actinomycosis based
purely on histologic grounds in the absence of micro-
bial culture data.
The management of the symptomatic patient with
BRON is difficult. These cases respond less predictably to
the established surgical treatment algorithms for osteomy-
elitis or osteoradionecrosis. Surgical debridement has not
been uniformly effective in eradicating the necrotic bone,
and hyperbaric oxygen therapy has not been effective in
limiting the progression of this process in the few patients
who received it.6,45 It is difficult to obtain a surgical
margin with viable bleeding bone, because the entire
jawbone has been exposed to the pharmacologic influence
of the bisphosphonate. Therefore, surgical treatment
should be delayed if possible. Areas of necrotic bone that
are a constant source of soft tissue irritation should be
removed or trimmed, attempting to minimize exposure of
additional bone. However, it is likely that the margin of
the debridement will remain exposed and granulation tis-
sue will surround the area of exposed bone. Epithelializa-
tion is an unlikely or transient phenomenon. Patients with
established BRON should avoid elective dentoalveolar
surgical procedures (i.e., extractions, dental implants, or
apical surgery), because these surgical sites will likely
result in additional areas of exposed necrotic bone. Symp-
tomaticpatientswithpathologicmandibularfracturesmay
require segmental resection and immediate reconstruction
with a reconstruction plate. The potential for failure of the
reconstruction plate because of the generalized effects of
the bisphosphonate exposure needs to be recognized by
the clinician and patient. Immediate reconstruction of
these patients with nonvascularized or vascularized bone
is not advocated, given the likelihood that necrotic bone
may develop at the recipient site. It is important to realize
thatinthispatientpopulationthetreatmentojectivesareto
eliminate pain, control infection of the soft and hard
tissue, and minimize the progression or occurrence of
bone necrosis
Stage 1 disease may benefit from the use of oral anti-
microbial rinses such as 0.12% chlorhexidine. In our ex-
perience, patients who present with stage 1 disease have
done well with this type of conservative treatment. Stage
2 disease is more problematic. Use of oral antimicrobial
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rinses and antibiotic therapy tailored to the culture and
sensitivity results obtained from the necrotic bone and
wound exudates may prove beneficial. It must be recog-
nized that the pathogenesis of BRON is likely related to
factors adversely influencing bone remodeling and not
that of a primary infectious etiology. In our experience,
most of the isolated microbes have been sensitive to the
penicillin group of antibiotics. In some refractory cases,
however, patients may require long-term antibiotic main-
tenanceoracourseofintravenousantibiotictherapy.Most
of the BRON patients (67%) at our institution had stage 2
disease. In this group, 75% were stabilized with this
treatment regimen.
Stage 3 disease represents the most challenging group
of patients. A large burden of necrotic bone with second-
ary soft tissue swellings or cutaneous fistulae and second-
ary infection that is refractory to antibiotic therapy char-
acterizes this stage. In addition, the pain that accompanies
this necrotic bone impacts the quality of life. The surgeon
is often compelled to offer resection of the maxilla or
mandibleinsuchcases.Ourexperienceisthatresectionof
the maxilla follows a more predictably successful course
after surgery than marginal or segmental resections of the
mandible. This notwithstanding, aggressive surgical man-
agement of stage 3 disease of the mandible is sometimes
indicated and may offer long-term palliation with resolu-
tion of acute infection and pain. In our experience, 12 of
15 patients (85%) with stage 3 disease that were managed
in this fashion are currently stable with resolution of the
pain and infection. The patient and treating clinician’s
expectations must again recognize that BRON is quite
different than osteoradionecrosis and bacterial-related os-
teomyelitis albeit similar clinically and radiographically.
Oncology patients benefit greatly from the therapeutic
effects of bisphosphonates by controlling bone pain and
incidence of pathologic fractures; thus, oncologists have
been reluctant to stop bisphosphonate treatment. The ces-
sation of intravenous bisphosphonate treatment in our
experience has not had a major impact on the progression
or treatment of this process. This is likely related to
bisphosphonates avidly binding to bone and not being
metabolized. Thus bisphosphonate levels remain high in
bone for years. Therefore, discontinuation of intravenous
bisphosphonate therapy is not likely to alter the clinical
course of BRON and could result in a recurrence of bone
pain and progression of metastases or lytic bone lesions. It
is the responsibility of the oncologist, with input from the
dental specialist or dentist, to determine if bisphosphonate
therapy should continue.
CONCLUSION
Although the pathogenesis of BRON remains unclear,
it appears that bisphosphonates are responsible for the
emergence of this relatively new clinical entity. Because
pamidronate and zolendronic acid have become standard
regimens for patients with breast cancer, multiple my-
eloma, and other selected malignancies, awareness of this
complication and its clinical significance is critical. There
is emerging evidence from clinical observations and early
clinical trials suggesting that bisphosphonates may have
antitumor activity, which in turn could broaden the indi-
cations for their use in the near future.38 It is critical that
the dentist be aware of this significant complication which
can occur spontaneously or after any dentoalveolar pro-
cedure in the population at risk. Because review of the
patient’s medical history and the oral examination is cur-
rently the most effective and sensitive means of detecting
BRON, dental professionals are in a unique position to
identify and diagnose this disease process early in its
course.
This report serves to alert dentists and dental spe-
cialists about the potential complication of bone necro-
sis in patients receiving bisphosphonate therapy and
proposes a guideline for diagnosis, staging, and treat-
ment.Further modifications of these guidelines will
likely occur over time. Research is ongoing which will
hopefully elucidate the pathogenesis as well as the
precise relationship between bisphosphonates and os-
teonecrosis.
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Reprint requests:
Dr. Salvatore L. Ruggiero
Department of Dental Medicine
Long Island Jewish Medical Center
270-05 76th Avenue
New Hyde Park, NY 11040
ruggiero@lij.edu
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Volume 102, Number 4Ruggiero et al. 441