symposium article Annals of Oncology 18 (Supplement 6): vi168–vi172, 2007

doi:10.1093/annonc/mdm250

Bisphosphonate-related osteonecrosis of the jaw

(BRONJ): run dental management designs and issues
in diagnosis
G. Campisi1*, O. Di Fede1, A. Musciotto1, A. Lo Casto1, L. Lo Muzio2, F. Fulfaro3,
G. Badalamenti3, A. Russo3 & N. Gebbia3
1
Section of Oral Medicine, Department of Oral Sciences, Università di Palermo, Palermo; 2Department of surgical Sciences, University of Foggia, Foggia; 3Section of
Medical Oncology, Department of Surgery and Oncology, Universitá di Palermo, Palermo, Italy

Recently, jawbone osteonecrosis has been largely reported as a potential adverse effect of bisphosphonate (BP)
administration. Because of the peculiar pharmacokinetic and pharmacodynamic features of the BF (mainly for
i.v. administration), their efficacy and large use, some major issues have to be taken into account extendedly
both by oncologists and by dentists: 1) therapeutic dental protocol for patients with diagnosis of bisphosphonate-
related osteonecrosis of the jaw (BRONJ); 2) dental strategies for patients in former or current i.v. BF treatment and in
absence of BRONJ signs; 3) strategies for patients before i.v. BF treatment. Clinical features and guidelines for the
management of this condition have been investigated and reported, sometimes with unclear indications; hence, on the
basis of the literature and our clinical experience, major end points of this paper are providing our run protocols for the
issues above described and, finally, focusing on a crucial, but not extensively investigated point: the early and correct
symposium

diagnosis of BRONJ versus metastatic jaw lesions in cancer patients.

article

Key words: bisphosphonates, metastatic bone disease

introduction pain. The current nomenclature for bisphosphonate-related

osteonecrosis of jawbone (BRONJ) lesions reflects the
Osteonecrosis of the jaws has been recently recognized as prevailing hypothesis that such a condition is a form of
a potential complication of BF treatment [1–12], mainly by osteonecrosis. The need for a higher level of scientific evidence
i.v. regimen, for malignancy-associated hypercalcemia and has been already underlined [3]. In fact, the pathogenesis of
prevention of bone fractures in patients with metastatic bone jawbone disease in patients receiving BF is largely unknown and
disease or multiple myeloma [13–15]. With regard to the social the biological mechanisms by which BF are responsible for
impact and limitedly to the underestimated cumulative bone remodeling and angiogenesis impairment in human jaws
incidence, as taken from retrospective studies among patients are still uncertain.
receiving i.v. BF, it has been calculated a range from 0.8% to Risk factors for BRONJ occurrence are usually grouped in
12% [8, 16]. Pathogenetic mechanisms of this condition are not three great categories: (i) drug-related risk factors, (ii) local risk
completely understood and management of affected patients is factors, and (iii) demographic/systemic risk factors as
mostly on the basis of the clinical guidelines drawn from expert extensively reported [16–21]; furthermore, other factors have
opinions and case series analysis [17, 18]. Among amino- been recently thought to be linked, such as corticosteroids,
bisphosphonates, pamidronate and zoledronate have shown the thalidomide, diabetes, smoking, alcohol use, poor
most consistent effects for the treatment of bone metastases in oral hygiene and chemotherapeutic agents [22–27] (Table 1).
cancer, with zoledronate being more potent in vitro than Because of the proven benefits of i.v. BF, their high BF half-
pamidronate [19]. Amino-bisphosphonates inhibit osteoclasts life [28–30] and the considerable number of prescriptions,
at different stages, binding selectively to hydroxyapatite and some major issues have to be taken into account extendedly
accumulating in sites of active bone remodeling. Once BF are both by oncologists and by dentists: (1) therapeutic dental
stored in bone, their release is dependent on the rate of bone protocol for patients with diagnosis of BRONJ, (2) dental
remodeling [20]. In addition, amino-bisphosphonates have strategies for patients in former or current i.v. BF treatment and
antiangiogenic properties both in vitro and in vivo. Clinically, in absence of BRONJ signs, and (3) strategies for patients
these lesions appear as nonhealing-exposed bone areas, which before i.v. BF treatment. On the basis of the literature as
can be accompanied by fistulization, purulent discharge and providing sometimes unclear indications and our clinical
experience, major end points of this paper are providing our
*Correspondence to: G. Campisi, Department of Oral Sciences, University of protocols for the issues above described and, finally, focusing
Palermo, Palermo, Italy. E-mail: giuca1@inwind.it on a crucial, but not extensively investigated point: the early

ª 2007 European Society for Medical Oncology

Annals of Oncology symposium article
Table 1. Risk factors for the development of BRONJ -Local or general swellings of the soft intraoral tissues
-Degree of dental mobility
Drug-related risk factors
Symptoms
Potency of the bisphosphonate (zoledronate > pamidronate >
alendronate > clodronate) -Pain
Way of administration (i.v. > oral) -Aesthesia/dysesthesia (e.g. numbness, feeling of a Ôheavy jawÕ)
Duration of therapy
Local risk factors
2. Appraisal of BRONJ
Dentoalveolar surgery (e.g. extractions, dental implant placement,
periodontal surgery involving osseous injury, periapical surgery)  Periodic clinical follow-up (1–2 months)
Trauma to the jaw bones  X-ray of jaws every 4–6 months
Poor oral hygiene  Computed tomography dental scan every 6 months
Periodontal disease
 Staging (early versus late)
Inflammatory dental disease (e.g. periodontal abscesses,
dental abscesses)
3. Special investigations
Palatal and lingual tori, bony exostoses, mylohyoid ridge
Trauma from poorly fitting dentures  Microbiological cultures should be collected to identify
Alcohol and tobacco abuse
bacterial or mycological pathogens with potential to cause
History of osteonecrosis/osteomyelitis of the jaws
secondary infections
History of head and neck radiotherapy (?)1
 Halitosis evaluation (e.g. by Halimeter
, OralChroma
)
Demographic and systemic risk factors
Elderly (>65 years)
4. Nonsurgery therapy
Gender: female > male (?)
Caucasian race (?)  Achievement and/or maintenance of optimal periodontal
Chronic corticosteroid therapy
and dental health
Chemotherapy
 To avoid procedures that involve direct osseous injury to
Estrogenic therapy
prevent other bony exposures
Alcohol and cigarettes abuse
Cancer diagnosis (increased risk for multiple myeloma > breast
 To avoid the use of vasoconstrictor associated with local
cancer > prostate cancer > other cancers) anesthetics
Osteopenia/osteoporosis diagnosis concurrent with cancer diagnosis
 To eliminate sharp edges of dental crowns, inadequate
Malnutrition dental prosthesis, inadequate conservative restorative
Diabetes treatments to prevent other bony exposures. To settle if
Acquired or induced immunodeficiency required.
Anemia and thalassemia  To examine patients with full or partial dentures for areas of
Coagulopathies, blood dyscrasias and vascular disorders mucosal trauma, especially along the lingual flange region
Hyperlipemia (i.e. mylohyoid ridge) and where palatal and lingual tori and
Connective tissue diseases bone exostoses can be present.
GaucherÕs disease  To make stable teeth with grade 1 or 2 of dental mobility
Systemic lupus erythematous  To make conservative restorative and prosthesis treatments
Hypothyroidism  To make acrylic stents or individual trays to cover areas of
1 exposed bone, to protect adjacent soft tissue, to improve
AAOMS (American Association of Oral and Maxillofacial Surgeons), in
comfort and to maintain therapeutic agents in situ
the ‘‘Position Paper on BRONJ’’, asserts that patients may be considered to
 In case of necessary tooth extraction (see Table 2)
have BRONJ only if they have no history of radiation therapy to the jaws.
5. Achievement and/or maintenance of a good oral hygiene
and correct diagnosis of BRONJ versus metastatic jaw lesions in
cancer patients.  Over-gingival scaling
As follows, some schemes are provided about the issues 1, 2  Instruction to oral self-hygiene
and 3, respectively.  Prescription of antiseptic rinses, such as chlorhexidine 0.12%
without alcohol (three times/day)
Issue 1: dental management of patients under treatment (or  Local application of fluorine
with history of treatment) with BF presence of clinical  Motivation of patients regarding the importance of good
BRONJ lesions dental hygiene

1. Thorough oral examination 6. Patient education and reassurance about BRONJ

 Signs  Delivery of informative papers (e.g. letter to dentistry,

information for the patients)
-Grade of bony exposure  Instruction to avoid every elective dental or surgical
-Oral/skin fistulas procedures involving osseous injury during the treatment

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symposium article Annals of Oncology

Table 2. Pharmacological therapy  Partial, marginal or segmental resection, eventually followed

by a reconstructive therapeutic phase
Antibacterial Initial dose Maintenance dose
9. Alternative therapy in case of exposed/necrotic bone
FIRST RATE
Penicillin 500 mg 3-4 times/ 500 mg every 12 h  Low-level laser therapy using He-Ne or diode laser.
die for 10 days
Amoxicillin 500 mg 3-4 times/ 500 mg every 12 h
die for 10 days
Issue 2: dental management of patients under treatment (or
IN CASE OF PENICILLIN
ALLERGY
with history of treatment) with i.v. and oral BF (for oral
Clindamicin 150-300 mg 4 times/die
BF duration of therapy >3 years)—no clinical lesions
Erythromicin 100 mg 4 times/die
Azithromycin 400 mg 4 times/die
NON-RESPONSIVE 1. Early diagnosis of Ôearly stageÕ BRONJ
PATIENTS OR IN CASE
OF SEVERE  Compilation of Ôcase history paperÕ
SIMPTOMATOLOGY  Clinical follow-up (every 3–4 months)
(IN ADDITION TO THE  X-ray of jaws every 6 months
PREVIOUS ONE)  Prescription of computed tomography dental scan when
Metronidazole 250-500 mg 3 times/
X-ray is doubtful
die for 14 days  Prescription of bony scintigraphy to evaluate the early bone
IN CASE OF SEVERE
involvement
INFECTION
 In case of necessary tooth extraction (see Table 3)
Ampicillin 1 gr 4 times/die
Clavulanic acid 500 mg 4 times/die 2. Thorough oral examination
Metronidazole 500 mg 3 times/die
IN CASE OF PENICILLIN
 Signs
ALLERGY
-Bony exposure
Ciprofloxacine + 500 mg 2 times/die
-Dental forcations exposure
Metronidazole 500 mg 3 times/die
Erythromicin + 400 mg 3 times/die
-Oral/cutaneous fistulas
Metronidazole 500 mg 3 times/die
-Local or general swellings of the soft intraoral tissues
Antifungal (when required) -Mobility of teeth that were stable in the preceding
On the basis of inspection
susceptibility test -Sudden change in the health of periodontal or mucosal
Antiviral (when required) tissues
Acyclovir 400 mg 2 times/die
Valacyclovir 500 mg-2 gr 2 times/die Symptoms

-Undiagnosed oral pain

-Dysesthesias (e.g. numbness, feeling of a Ôheavy jawÕ)
with BF and at least 5 years after the cessation of
bisphosphonate therapy 3. Achievement and/or maintenance of optimal periodontal
 Education to periodic clinical and radiographic follow-up, and dental health
with frequency depending on seriousness of BRONJ
 To avoid procedures that involve direct osseous
7. Pharmacological therapy  To avoid the use of vasoconstrictor associated with local
anesthetics
 Broad-spectrum antibiotic therapy before antibiotic assay
 To eliminate the local risk factors (e.g. sharp edges of
according to the regimens described in Table 2
dental crowns, inadequate dental prosthesis, inadequate
 Antifungals, if required, should be prescribed
conservative restorative treatments)
 If patient refers pain, systemic analgesics should be prescribed
 To examine patients with full or partial dentures for areas
in order to mitigate symptoms
of mucosal trauma, especially along the lingual flange
8. Surgery therapy in case of exposed/necrotic bone region (i.e. mylohyoid ridge) and where palatal and
lingual tori and bony exostoses are represented. To settle if
 Debridement and/or sequestrectomy less traumatic as required.
possible, also by means of piezosurgery [31–38]  To make stable teeth with grade 1 or 2 of dental mobility
 To avoid the use of vasoconstrictor associated with local  To make conservative restorative and prosthesis treatments.
anesthetics Nonrestorable teeth may be treated by removal of the
 Resection of the affected bony tissue, less traumatic as crown and endodontic treatment of the remaining roots.
possible, also by means of piezosurgery [31–38] No surgical treatment is indicated.

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Annals of Oncology symposium article
Table 3. Protocol in case of not postponed tooth extractions in patients receiving IV BF

Discontinuation of BF from 1 to 3 months before and after dento-alveolar surgery, till a complete healing of tissue1
Broad-spectrum antibiotic therapy 5 days before and 20 days after tooth extraction, until a complete healing of treated tissues occurs, in combination
with topical applications of chlorexidine gluconate
LLLT both during intra-surgical phase and 1 week after surgical treatment. Five topical applications for 1 minute should be performed. At least three
periodic meetings are necessary. The LLLT improve tissue regeneration and decrease the bacterial colonization in the site of surgical procedure.

1
Currently, there is no published evidence to support or oppose discontinuation therapy of BF (both IV and per os) before required dentoalveolar surgery.
However, the removal of the anti-angiogenic effects of the drug on the soft tissues and periosteum may play an important role in a better vascularization and
a more rapid healing after surgical treatment.

4. Achievement and/or maintenance of a good oral hygiene 4. Achievement of a good oral hygiene
 Over-gingival scaling  Scaling and root planning
 Instruction to oral self-hygiene  Instruction to oral self-hygiene
 Prescription of antiseptic rinses, such as chlorhexidine 0.12%  Prescription of antiseptic rinses, such as chlorhexidine 0.12%
 Local application of fluorine  Local application of fluorine
 Motivation for the importance of good dental hygiene  Motivation of patients regarding the importance of good
dental hygiene
5. Patient education and reassurance about BRONJ
 Delivery of informative papers (e.g. letter to dentistry, 5. Valuation of risks/benefits to delay the BF therapy
information for the patients)
 Information against every elective dental or surgical
 Initiation of bisphosphonate therapy should be delayed until
procedures involving osseous injury periodontal and dental health is optimized. In order to get
 Instruction to report every early symptom or clinical sign clinical and radiographic healing, all invasive dental
(e.g. pain, swelling) procedures should be completed at least 3–4 weeks before
 Education to clinical and X-ray follow-up, with frequency starting BF therapy
depending on the number of concomitant risk factors and
 Collaboration among treating physician, oncologist, dentist
general dental health and other specialists involved in the care of the patient.

6. Patient education and reassurance about BRONJ

Issue 3: dental management of patients before treatment
with BF  Delivery of informative papers (e.g. letter to dentistry,
information for the patients)
 Instructions to avoid every elective dental or surgical
1. Thorough examination of hard and soft intraoral tissues procedures involving osseous injury during the treatment
2. X-ray of jaws to evaluate the general oral status with BF and at least 5 years after the cessation of
3. Achievement of optimal periodontal and dental health bisphosphonate therapy
 Instructions to report every early symptom or clinical sign
 Extraction of teeth with partial inclusion (only mucosal
(e.g. pain, swelling)
inclusion, not bone inclusion) and of teeth with a poor
 Education to periodic clinical and radiographic follow-up,
prognosis (e.g. teeth with serious periodontal disease,
with frequency depending on the number of concomitant
nonrestorable teeth or unsalvageable with prosthesis)
risk factors and general dental health.
 Extraction, in the children, of deciduous teeth with a certain
grade of mobility Issue 4: diagnosis of BRONJ vs metastatic jaw lesions in cancer
 Etiological periodontal therapy and stabilization of teeth with patients
grade 1 or 2 of dental mobility
 Endodontic treatment of teeth with chronic periodontal
lesions It appears that one of the issues requiring to be further
 Conservative restorative and prosthesis treatments, when addressed are challenges in suspecting and diagnosing
necessary metastatic jaw lesions in cancer patients affected by BRONJ due
 Patients with full or partial dentures should be examined for to overlapping clinical and/or radiological appearance. In fact,
areas of mucosal trauma, especially along the lingual flange considering the nature of tumors that generally affect patients
region requiring bisphosphonates administration and developing jaw
 Elimination of local risk factors (e.g. sharp edges of dental osteonecrosis, the occurrence of jawbone metastases is an
crowns, inadequate dental prosthesis, inadequate expectable event. Thus, in a correct diagnostic process it should
conservative restorative treatments) be always kept in mind, suspected and excluded. This is

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symposium article Annals of Oncology

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