Bone 73 (2015) 217222

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Original Full Length Article

Successful treatment of Bisphosphonate-Related Osteonecrosis of the Jaw

(BRONJ) patients with sitaoxacin: New strategies for the treatment
of BRONJ
Tetsuya Ikeda , Jun Kuraguchi, Yasunao Kogashiwa, Hidenori Yokoi, Takafumi Satomi, Naoyuki Kohno
Department of Oto-Rhino-Laryngology, Oral Surgery, Kyorin University School of Medicine, Tokyo, Japan

a r t i c l e

i n f o

Article history:
Received 2 June 2014
Revised 9 December 2014
Accepted 20 December 2014
Available online 27 December 2014
Edited by: Robert Recker
Keywords:
Bisphosphonates
Osteonecrosis of the jaw
Sitaoxacin
Surgical treatment
Sequestrectomy

a b s t r a c t
BRONJ has become a well-known, occasionally severe side effect of bisphosphonate therapy, as well as a clinical
problem. Although treatment recommendations exist, no standard therapy has yet been established for BRONJ.
Also, these recommendations identify several limitations that prevent clinicians from condently diagnosing
BRONJ. The aim of the present study was to establish a treatment approach in which all patients with exposed,
infected bone or intraoral/extraoral stulas were treated with sitaoxacin (STFX). We examined 20 BRONJ patients, fourteen with cancer and six with osteoporosis. We used the current updated denition of BRONJ (12), except that we included patients who had shown symptoms for a minimum of only one month, rather than two
months. Thus half of our patients had infection with no exposed, necrotic bone in the oral cavity. We purposely
excluded all patients exhibiting no signs of infection (current Stages 0 and 1). In addition, each potentially causative organism was isolated from pus collected from an intraoral or extraoral stula in ten patients on their rst
visit to our department. 90% of the patients had received a course of treatment with common antibiotics. STFX
was administered to all patients. We then re-evaluated the lesion every other week, to determine whether epithelialization was present. We recommended surgical treatment for cases without epithelialization within
4 weeks after the onset of administration of STFX even if bone was not exposed at the lesion. 19 of our 20
cases of Stages 23 BRONJ responded to 210 weeks of STFX treatment by entering either a remission or healed
phase. While surgery was done on thirteen cases, seven others reached such phases without surgery. Every patient had at least one bacterial species that showed resistance to common antibiotics. All species in all patients
were susceptible to STFX. Our results indicate that STFX, with or without minor surgery, gives a high probability
of controlling infection in BRONJ patients with persistent infection after use of common antibiotics, leading to remission and/or complete healing in 95% of patients.
2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction
Bisphosphonates (BPs) have been widely, efciently, and safely used
to treat osteoporosis, hypercalcemia of malignancy, bone metastasis of
solid malignant tumors, and Paget's disease of the bone [1]. However,
a relationship has been reported between the use of bisphosphonates
and osteonecrosis of the jaw (Bisphosphonate-Related Osteonecrosis
of the Jaw: BRONJ) [2]. BRONJ has become a well-known occasionally
severe side effect of bisphosphonate therapy as well as a clinical problem [3,4]. The clinical presentation of BRONJ generally includes gingival
ulceration with exposed necrotic bone in the oral cavity involving either
the maxilla or mandible that has persisted for at least 68 weeks. In
more severe cases, it may include inamed, infected gingival tissues,
Corresponding author at: Shinkawa 6-20-2 Mitaka city, Tokyo, Japan. Fax: +81 422 42
5968.
E-mail address: t-ikeda@ks.kyorin-u.ac.jp (T. Ikeda).

intraoral or extraoral stulas, spontaneous severe pain, mobile teeth,

and/or pathological fractures [58].
However, though treatment recommendations exist [10,11,13], a
standard therapy has not yet been established for BRONJ. Ruggiero
et al. proposed guidelines for the diagnosis, staging, and management
of BRONJ in 2006 [9]. Thereafter, Ruggiero et al. and the American Association of Oral and Maxillofacial Surgeons reported their position on
BRONJ with an update of the previous classication [1012]. A position
paper was subsequently published by the Japanese Allied Task Force
Committee of BRONJ in Japan [13]. These studies established a working
denition for BRONJ that included the following three characteristics: 1
Current or previous treatment with a BP. 2 Exposed necrotic bone in the
jaw that persisted for more than 8 weeks. 3 No history of radiation therapy to the jaw.
Staging systems have also been established based on the ndings of
these studies. BRONJ in which no apparent exposed bone area or specic
clinical ndings or symptoms are detected has been classied as stage 0.

http://dx.doi.org/10.1016/j.bone.2014.12.021
8756-3282/ 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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T. Ikeda et al. / Bone 73 (2015) 217222

Patients with Stage 1 have exposed bone, but are asymptomatic and do
not have soft tissue inammation or infection. Stage 2 is characterized
by exposed bone with associated pain, adjacent or regional soft tissue
inammatory swelling, or infection. Patients with Stage 3 have pathological fractures, extraoral stulas, or radiographical ndings of
osteolysis of the jaw in addition to the symptoms associated with
Stage 2. Though treatment recommendations exist [1012,14] no denitive standard of care has been established for BRONJ and surgery was
previously reported as capable of exacerbating bone exposure [1416].
These recommendations indicated that conservative therapies could
be applied to treat Stages 0 and 1 BRONJ and that surgical procedures
were unnecessary. Furthermore, these recommendations stated that
Stage 2 BRONJ patients were likely to benet from antibiotic therapy
to control or eliminate the infection. However, several limitations have
been identied in these recommendations that prevent clinicians from
condently diagnosing BRONJ. We previously encountered cases of
BRONJ (Stages 1 and 2) that deteriorated with conservative therapies
that included common antibiotics for Stage 2.
The aim of the present study was to establish a treatment approach
in which all patients with exposed, infected bone or intraoral/extraoral
stulas were treated with sitaoxacin (STFX). After 4 weeks of STFX
treatment, surgery was used as needed, to remove necrotic hard and
soft tissue and prevent further permanent loss/alteration of soft and
hard tissue structures.

recent mobile and infected tooth extractions in our department with

the usual method, that is, administration with common antibiotics for
1 week after extraction because we could not obtain BP receiving information at this point. Despite treatment with common antibiotics for
7 days after tooth extraction, failure to heal two weeks later was indicated when, sharp instruments could easily contact bone and there was
painful, swelling. Hence, we requested further information from patients and family about BP receiving, and then we were able to establish
a documented history of BP treatment. Four weeks later, we could
diagnose BRONJ, because the CT scan conrmed the existence of
osteosclerosis without oral cavity bone exposure, and pus discharge
and intraoral stula were detected from alveolar soft tissue wound.
We then started STFX immediately. Computed tomography (CT) is commonly used as a diagnostic tool because of its accessibility for patients
and its ability to reveal the degree of osteosclerosis on the affected
site, which is visualized as the loss of contrast denition between the
cortical bone and the bone marrow space. If a suspicious oral lesion
with no exposed bone (e.g., Fig. 1a) was found in a patient with an
intraoral stula (IOF) or extraoral stula (EOF), a CT scan was done to
check for osteosclerosis, because osteosclerosis appears to characterize
early stages of BRONJ that may precede actual bone exposure. When
osteosclerosis was found in the bone underlying such a suspicious lesion, as in #6, STFX was started immediately.
Antimicrobial susceptibility testing

Materials and methods

Ethics
The present study was approved by the Institutional Review Board,
Kyorin University School of Medicine; all patients provided written informed consent before participating in the study.
Patients
We examined 20 patients with BRONJ who presented to the Department of Otorhinolaryngology and Oral Surgery, Kyorin Hospital, Tokyo,
Japan between April 2010 and April 2013. Ten patients had prostate
cancer, two had breast cancer, one had renal cell carcinoma, one had
multiple myeloma, four had primary osteoporosis, and two had GIOP
(glucocorticoid-induced osteoporosis) (Table 1).
The working denition of BRONJ used in the present study included
a more than 1-month history of severe jaw pain, discharge of pus, and
current or previous treatment with a BP in patients who presented
with or without necrotic bone exposure. The absence of malignancy in
the area surrounding the lesion and the absence of a history of radiation
therapy to the jaw was noted. Clinical data were recorded for each patient only after all examiners completely agreed with each other. In
this series, we excluded patients who exhibited no sign of infection
(current Stages 0 and 1). Some patients presented with symptoms of
paranasal sinusitis. Those symptoms included nasal obstruction and
congestion, purulent rhinorrhea, and facial pain or pressure with occasional headache, and/or fever.
Sixteen of the twenty patients had already been given common
antibiotics for several weeks before visiting our department (except patients 6, 10, 13 and 15). Despite this antibiotic treatment, these patients'
symptoms still existed. In these 16 patients, we started STFX immediately. In patients 10 and 13, intraoral stula and exposed bone were detected at least 8 weeks before the patients' rst visit to our department
(e.g., Fig. 2). In addition, information of BP receiving for more than 6
months was known from the urology specialist. Therefore, we have diagnosed BRONJ with these ndings and information. Since we already
recognized clinical ndings of BRONJ at the rst visit, we started STFX
immediately without administration with common antibiotics in these
patients. Also, these patients had not been given common antibiotics
before visiting us. On the other hand, patients #6 and #15 both had

Each potentially causative organism was isolated from pus collected

from an intraoral or extraoral stula in ten patients on their rst visit to
our department. These isolates were rapidly identied using the API 20
Strep [17] and Vitek anaerobe identication card system (Sysmex
BioMerieux, Tokyo, Japan) [18]. Antimicrobial susceptibility testing of
the isolated bacteria to sitaoxacin and the other antimicrobial agents
was performed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines [19,20].
Treatment procedure
After 14 weeks of common antibiotic treatment, except in #10 and
#13, to whom no common antibiotics were given, STFX was administered to all patients. We then re-evaluated the lesion every other
week, to determine whether epithelialization was present. Sharp instruments could easily contact bone if the lesion was not epithelialized.
We recommended surgical treatment for thirteen patients where sequestrum and necrotic soft and hard tissue remained for a period of
4 weeks after the administration of STFX, even if the bone was not exposed denitively at the lesion. By contrast, in seven patients, sharp instruments could not contact bone, and no necrotic soft or hard tissue
remained to be removed 4 weeks after the onset of treatment with
STFX. Therefore, these seven cases were regarded as non-surgical cases.
Table 1 shows that STFX dosage varied from 1750 to 9100 mg (total
dose) and duration varied from 2 to 10 weeks. STFX was used orally and
accomplished on an outpatient basis.
In addition, 6 to 12 weeks was considered necessary from the initiation of active treatment in order for patients to achieve a completely
healed state. We did necrotic bone resection and infected soft tissue
debridement with or without tooth extraction in all operative cases
(Table 1).
The term, healed, was used to describe complete disappearance of
exposed bone and the absence of infection in the jaw of an ONJ patient,
while remission, reected the partial disappearance of exposed bone
with the absence of infection.
Results
We examined a total of 20 BRONJ patients (Table 1). We propose
that cases with an intra- or extraoral stula or maxillary sinus

Table 1
Demographic and clinical characteristics of ONJ patients.
BP

CAB

STFX

Age

Gender

Primary disease

DBP (month)

Dose

Route

Type

Region of the jaw

D (week)

Treatment

TD (mg)

D (week)

Outcome

Signicant Findings

BE

IOF

EOF

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20

77
85
75
78
70
73
69
71
77
76
49
48
67
29
73
76
76
70
84
84

M
M
M
M
M
M
M
M
M
M
F
F
M
M
F
M
F
F
F
F

Prostate cancer
Prostate cancer
Prostate cancer
Prostate cancer
Prostate cancer
Prostate cancer
Prostate cancer
Prostate cancer
Prostate cancer
Prostate cancer
Breast cancer
Breast cancer
Renal cell carcinoma
Multiple myeloma
Primary osteoporosis
GIOP-RP
Primary osteoporosis
GIOP-RA
Primary osteoporosis
Primary osteoporosis

27
10
36
29
8
24
23
5
17
33
60
58
6
18
24
96
48
60
24
12

4 mg/month
4 mg/month
4 mg/month
4 mg/month
4 mg/month
4 mg/month
4 mg/month
4 mg/month
4 mg/month
4 mg/month
4 mg/month
4 mg/month
4 mg/month
4 mg/month
35 mg/week
35 mg/week
35 mg/week
35 mg/week
35 mg/wk.
50 mg/month

IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
Oral
Oral
Oral
Oral
Oral
Oral

Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
Z
A
A
A
A
A
M

L upper molar
R upper anterior
R lower, L upper molar
L upper molar
L upper, lower molar
L upper anterior
L upper, lower molar
R and L lower molar
L upper anterior
L lower, upper molar
R upper molar
R upper molar
R,L lower molar
R lower molar
L lower molar
R upper, L lower molar
across the lower jaw
L upper molar
L lower molar
R, L lower anterior

3
2
4
4
2
1**
2
1
2

2
2

2
1**
2
2
2
4
4

STFX
STFX
STFX, SE under LA
STFX, SE under LA
STFX, SE under GA
STFX, SE under LA
STFX, SE under LA
STFX, SE, TE under GA
STFX, SE under LA
STFX, SE under GA
STFX, SE under LA
STFX, SE, TE under GA
STFX, SE, TE under GA
STFX
STFX
STFX
STFX
STFX, SE, TE under LA
STFX
STFX, SE, TE under LA

5600
2800
5600
2800
9100
9800
5600
3500
5600
5600
5600
5600
4200
5600
3500
2800
5600
1750
6300
6300

4
4
4
4
10
9
8
5
4
8
8
8
6
8
3
2
4
5
8
8

Remission
Healed
Remission
Healed
Healed
Healed
Healed
Healed
Healed
Worsening
Healed
Healed
Healed
Healed
Healed
Remission
Remission
Healed
Healed
Healed

RTE
PSUD
PSUD
RTE
RTE
RTE
RTE
periodontitis
PSUD
None noted
None noted
periodontitis
periodontitis
periodontitis
RTE
fractured tooth
PSUD
periodontitis
periodontitis
periodontitis

+
+

+
+

+
+

+
+
+
+
+
+
+
+

+
+

+
+
+
+

+*

+*

+*

+*
+
+

T. Ikeda et al. / Bone 73 (2015) 217222

Case

Abbreviations; A: alendronate, BE: bone exposure, CAB: administration of common antibiotics, D: duration, DBP: duration of BP, EOF: extraoral stula, GA: General anesthesia, GIOP: glucocorticoid-induced osteoporosis, IOF: intraoral stula, IV: intravenous, L: left side, LA: Local anesthesia, M:minodronate, PSUD: pressure sore under dentures, R: right side, RA: rheumatoid arthritis, RP: relapsing polychondritis, RTE: recent tooth extraction, SE: sequestrectomy, STFX: administration of
sitaoxacin, TD: total dose, TE: tooth extraction, Z: zoledronate, *:affected maxillary sinuses, **administration of CAB from our department.

219

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T. Ikeda et al. / Bone 73 (2015) 217222

Fig. 1. Patient number 6: non-exposed bone case. a: The maxillary left cuspid was extracted 6 weeks later. An intraoral stula (arrow head) was detected. The administration of
100 mg per day STFX was started. b: Following necrotic bone resection under local anesthesia after the administration of 100 mg per day of STFX for 3 weeks. c: Completely
healed surgical wound 3 months after surgery. d: CT scan showing the failed healing of the extracted wound (at the same time as the photo in a).

involvement without exposed oral cavity bone, as in patients 1, 2, 4, 5, 6,

9, 11, 14, 16, 18, 19, and 20, should be dened as Stage 3 BRONJ, rather
than Stage 0 BRONJ, because an active infection and a stula are clearly
involved. Patients 1, 3, 12 and 18, exhibited symptoms of paranasal sinusitis. Such patients seem likely to benet from antibiotic therapy
that would not be given to them if they were diagnosed as Stage 0.
Bacterial species were counted in patients 1, 3, 6, 14, 15, 16, 17, 18, 19
and 20. The following species were detected (number of patients
in parenthesis); Bacteroides capillosus, Corynebacterium species,
Fusobacterium nucleatum (2), Gemella species (2), Klebsiella pneumoniae,
Parvimonas micra (2), Parvimonas micra (Peptostreptococcus micros)

(3), Peptostreptococcus anaerobius, Porphyromonas asaccharolytica,

Porphyromonas endodontalis, Porphyromonas gingivalis, Prevotella buccae
(2), Prevotella disiens, Prevotella intermedia (2), Prevotella species,
Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus
agalactiae, Streptococcus anginosus (4), Streptococcus constellatus (5),
Streptococcus mitis (4), and -hemolytic Streptococcus. The clinical states
of cancer- or non-cancer-BRONJ were also not markedly different. Every
patient had at least one species that showed resistance to common antibiotics. All species in all patients were susceptible to STFX.
Infection disappeared from the area of the BRONJ lesion within
10 weeks of STFX treatment in 19 of 20 cases. While surgery was

Fig. 2. Patient number 13: exposed bone case. Exposed necrotic bone on the lingual plate in the right mandibular molar region on the rst visit (a: mirror image). b: CT showing lingual
cortical bone separation (sequestrum) of the right side of the mandible. Axial section image. c: The right side of mandible after the administration of 100 mg per day of STFX for 3 weeks.
d: A tightly sutured wound after the causative teeth were extracted and sequestrectomy was performed (e). Completely healed surgical wound 6 months after surgery (f). Exposed
necrotic bone was indicated by the arrows in a and c.

T. Ikeda et al. / Bone 73 (2015) 217222

done on 13 cases, 7 others reached such phase without surgery. Epithelialization and improvement actually occurred in 12 of 13 surgical cases
and all non-surgical cases.

Discussion
BP can accumulate in the bone and inhibit osteoclast-mediated
bone resorption, thereby reducing bone turnover at the cellular and
molecular levels [21,22]. Thus, BRONJ patients, like all patients taking
therapeutic doses of BPs for treatment of cancer and osteoporosis, are
characterized by low levels of osteoclastic activity and bone remodeling
in the whole skeleton. However, 90% of our BRONJ patients had a unique
signicant abnormal nding in the maxilla or mandible (e.g., recent
tooth extraction, pressure sore under denture, periodontitis or fracture
tooth), suggesting the possibility that local dental factors may combine
with the low levels of osteoclast activity to make an environment that
favors the development of BRONJ.
Previous studies avoided active jaw surgery in patients who were
being or had been previously treated with BPs [2327]. However, the
majority of our patients (70%) did not have dental surgical injuries;
therefore, BRONJ may have been related to other factors such as asymptomatic periodontitis and pressure sores under dentures. The benets of
BPs outweigh their minor side effects; they save the lives of osteoporotic
patients by preventing hip fractures and extend the healthy life spans of
cancer patients by preventing bone metastases and stabilizing the skeleton, thereby allowing cancer patients to endure stronger treatments
that may eventually cure them. On the other hand, the incidence of
BRONJ is very low. Physicians need to ensure that patients understand
the life-saving effects of BPs and that they obtain regular dental care
in order to maintain optimal dental health while receiving BPs.
In this series, all patients exhibited clinical evidence of infection on
their rst visit. However, we could not denitively conrm when bone
became exposed and could only obtain this information from a medical
interview. We previously encountered cases of BRONJ that deteriorated
with conservative therapies and/or treatments with common antibiotics. If the lesion did not heal within 4 weeks of conservative therapies
and/or the administration of common antibiotics, treatment with a
powerful uoroquinolone antibiotic, sitaoxacin was initiated as soon
as possible to prevent jaw resection, pathological fractures or sinus
tract complications.
Therefore, our approach to therapeutic strategies for BRONJ differed
from those reported previously [10,11,1316] because we considered
early treatment to be important; we successfully treated Stage 2 or 3
BRONJ patients with or without surgery following the administration
of STFX.
A signicant result of our study was that we could not assign ten
cases to any of the published stages [1011]. Though these cases had
no exposed necrotic bone suggesting Stage 0, they had purulent discharge from intraoral or extraoral stulas and severe pain, suggesting
active infection and Stage 3 (Fig. 1). Recently updated staging guidelines
have also identied such cases (12). We agree that BRONJ cases that
display intraoral or extraoral stulas or maxillary sinus involvement
should be dened as Stage 3, even when exposed necrotic bone in the
oral cavity cannot be found. The importance of this for our series is
clear, as half our cases met these criteria. In addition, placing such
cases in Stage 3 makes immediate antibiotic therapy appropriate, even
according to older guidelines.
Other recent studies reported that bone exposure was not always
observed in a subset of cases that otherwise exhibited the characteristic
hallmarks of BRONJ [2831]. In this series, four patients (#1, #3, #12
and #18) with Stage 2 or 3 BRONJ demonstrated paranasal sinusitis.
Like other investigators [28], we conclude that paranasal sinusitis may
be related to maxillary BRONJ. Thus, maxillary BRONJ should be considered in the differential diagnosis when persistent paranasal sinusitis is
found in a patient taking BPs.

221

Although Stage 2 or 3 BRONJ is characterized by active infection, a

denitive treatment procedure with specic antibiotics had not been reported. Antimicrobial susceptibility testing of isolated bacteria to STFX
and other antimicrobial agents was performed in ten patients. The results obtained indicated that at least one of the organisms in each patient was resistant to common antibiotics. 19 of our 20 cases of Stages
23 BRONJ responded to 210 weeks of STFX treatment by entering either a remission or healed phase (Table 1). While minor surgery was
done on thirteen cases with a favorable response in twelve, seven others
reached such phases without surgery. We speculate that the high rate of
success for STFX is because it kills quinolone-resistant bacteria.
Computed tomography (CT) can be useful for BRONJ because of
its ability to reveal osteosclerosis that appears as a loss of contrast
denition between the cortical bone and the bone marrow space
(Fig. 1d). Osteosclerosis may characterize the early stages of BRONJ
and precede the occurrence of bone exposure [32]. CT-based detection
of osteosclerosis in suspicious jaw lesions without exposed bone may
assist in diagnosing Stage 3 BRONJ [33].
In conclusion, this study shows that 19 of 20 patients with Stage 2 or
3 BRONJ, most of whom had responded poorly to 14 weeks of treatment with common antibiotics, achieved controlled or completely
healed status with or without surgery, after a maximum of ten weeks
on STFX. We also found that half our patients were affected by
recently-updated BRONJ staging criteria [12], suggesting that infection
status may be more important than exposed bone status in determining
appropriate treatment for BRONJ patients. We also found four BRONJ
patients who presented with persistent paranasal sinusitis, suggesting
that maxillary BRONJ should be considered in the differential diagnosis
of BP patients who exhibit persistent paranasal sinusitis.
A weakness of this study is that due to ethical concerns and the prior
existence of treatment guidelines for BRONJ [1011], it was not possible
to include a control group of untreated BRONJ patients. In addition, no
non-BRONJ patients were characterized for bacterial species.
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