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Oral Oncology 48 (2012) 938–947
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Oral Oncology
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Review
Bisphosphonate-related osteonecrosis of the jaws – A review
Sebastian Kühl a,⇑, Christian Walter b, Stephan Acham c, Roland Pfeffer a, J. Thomas Lambrecht a
a
School of Dental Medicine, Department of Oral Surgery, Oral Radiology and Oral Medicine, University of Basel, Hebelstrasse 3, CH-4056 Basel, Switzerland
University Medical Center Mainz, Department of Oral and Maxillofacial Surgery, Augustusplatz 2, 55131 Mainz, Germany
c
School of Dental Medicine, Department of Oral Surgery, Oral Radiology, University of Graz, Auenbruggerplatz 12, 8036 Graz, Austria
b
a r t i c l e
i n f o
Article history:
Received 6 February 2012
Received in revised form 27 March 2012
Accepted 28 March 2012
Available online 21 April 2012
Keywords:
Diphosphonates
Osteonecrosis of the jaw
Incidence
Treatment outcomes
s u m m a r y
The aim was to evaluate the knowledge about bisphosphonate-related osteonecrosis of the jaws (BRONJ).
A bibliographic search in Medline, PubMed and the Cochrane Register of controlled clinical trials was performed between 2003 and 2010 by using the terms bisphosphonate and osteonecrosis of the jaw. The
amount of publications per year, the type of journal for publication, and the evidence level of the trial
were evaluated. Next to this the incidences and the success of treatment strategies for BRONJ were identified. A total of 671 publications were reviewed. Since 2006 more than 100 publications on BRONJ per
year (with an upward trend) have been published, mostly in dental journals. The evidence level could
be determined for 176 publications and only one grade Ia study was found. The studies showed a wide
variety in design, most of them being retrospective. The incidence of BRONJ is strongly dependent on oral
or intravenous application and varies between 0.0% and 27.5%. There is no scientific data to sufficiently
support any specific treatment protocol for the management of BRONJ. Further clinical studies are needed
to evaluate the incidence and treatment strategies at a higher level of evidence. Therefore uniform study
protocols would be favourable.
Ó 2012 Elsevier Ltd. All rights reserved.
Introduction
Bisphosphonates are frequently used for the treatment of bone
metastases, multiple myeloma, osteoporosis and other bony diseases.1–3 Generally these drugs are well tolerated, rarely inducing
clinically significant side effects such as gastrointestinal symptoms
for oral bisphosphonates, elevated serum creatinine, transient
low-grade fever, arthralgias and increased bone pain for the injectable drugs. However, recent reports have described osteonecrosis
of the jaw bones (ONJ) as a potentially serious complication related
to the long-term use of these drugs. In this condition the bone tissue in the jaws often fails to heal after minor trauma, such as tooth
extraction, leaving the bone exposed.4–6 Bisphosphonate-related
osteonecrosis of the jaws (BRONJ) was first described by Marx
and Stern in 2002.7 The first extensive case series of BRONJ were
published in 2003 by Marx and in 2004 by Ruggiero et al.8,9 Since
2003 there has been an increasing number of publications about
BRONJ. One of the first retrospective studies by Estilo et al. was
published in 2004.10 Cases of BRONJ were published in refereed
journals, abstract presentations at scientific meetings, correspondence in the form of letters to the editor, author’s replies and editorials as well as medical alerts and advisories to dentists and
physicians. The similarity of BRONJ to cases of phosphorous
⇑ Corresponding author. Tel.: +41 61 267 1312; fax: +41 61 267 2607.
E-mail address: [email protected] (S. Kühl).
1368-8375/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.oraloncology.2012.03.028
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. and Donaghue.11–13 This historical fact
led to the suspicion that the phenomenon of jaw osteonecrosis
was directly linked to the bisphosphonate medications.14,15
Many groups and societies have recently published recommendations or guidelines on the prevention, staging and management
strategies for BRONJ.16–28 Despite these recommendations there is
still a lack of information concerning the incidence, pathogenesis,
treatment strategies and prevention of BRONJ. Until now a classification of all publications according to the evidence level of Shekelle
et al. has not been published.29 There is no knowledge about the
number of publications per year as well as the type of journals for
publication. The aim of the present study was to perform a literature
search in order to (a) assess the number of publications per year; (b)
evaluate the type of journals for publication; (c) determine the level
of evidence of published trials for classification; (d) retrieve information on the incidence; and (e) the treatment strategies and
results related to BRONJ.
Materials and methods
Search strategy
A bibliographical search in Medline, PubMed and the Cochrane
Register of controlled clinical trials was performed for publications
S. Kühl et al. / Oral Oncology 48 (2012) 938–947
939
Table 1
Journal types and subcategories publishing articles on bisphosphonates.
Medical field
Included journals
General dentistry
Oral and cranio- or maxillofacial surgery
Oncology
General medicine
Internal medicine
Journals of dental associations, endodontics, periodontology and oral medicine
Journals of otolaryngology, head and neck surgery, laser surgery
Other journals
Clinical oncology, palliative medicine and nuclear medicine
Journals of medical associations and public health
Journals of clinical nutrition and metabolic care, therapy, bone and mineral research, osteoporosis, rheumatology, arthritis,
haematology endocrinology and metabolism
Journals of climacterics and menopause, gynaecology, orthopaedics, paediatrics, radiology, neurology and neuroradiology, urology
and nephrology, gerontology, biochemistry and cell biology, pharmacology and pharmacotherapy, pathology and toxicology
which appeared in the period from January 2003 up to March 2010
using the terms: Bisphosphonate and osteonecrosis of the jaw. The
cited literature was evaluated and a traditional manual search and
library research was additionally performed.
obscurities were evaluated by at least two reviewers independently. A third reviewer compared the evaluation and data were
discussed. Data were only included if there was an agreement between the reviewers.
Study selection
Statistical analysis
In a first evaluation, papers were selected according to whether
or not they deal with BRONJ. All manuscripts, including case reports, were selected for evaluation of the number of publications
per year. The journals in which these publications appeared were
assigned to a specific medical field according to Table 1. In a second
step, all clinical studies were extracted and the grade of evidence
was classified for every clinical study according to the classification
of Shekelle et al.29 as follows:
All data were saved in spreadsheets. The statistics are restricted
to a descriptive analysis only. The absolute numbers and percentage distribution were calculated using Microsoft Excel (Microsoft
Office Excel 2007, Redmond, USA).
Grade
Category of evidence
Ia
Evidence from systematic reviews of randomized
controlled trials
Evidence from at least one randomized controlled trial
Evidence from at least one controlled study without
randomization
Evidence from at least one other type of quasiexperimental study, such as time series analysis or
studies in which the unit of analysis is not the
individual
Evidence from non-experimental descriptive studies,
such as comparative studies, correlation studies,
cohort studies and case-control studies
Evidence from expert committee reports or clinical
experience of respected authorities
Ib
IIa
IIb
III
IV
Results
Numerical trends
In the years 2003–2009 a total of 671 publications were found
on bisphosphonates and osteonecrosis of the jaw. Eight studies
were published in 2010 with e-pub in 2009 and were listed in
2009. Since literature research was performed up to March 2010
and there was much more published after March, it would not have
made sense to create a separate statistic for 2010. From 2003 there
was a continuous rise in the number of publications per year, with
the highest amount of publications in 2009 (Fig. 1). After 2006
there were over a hundred publications on the topic of BRONJ
every year.
Specification of journals
Most publications (n = 179; 26.7%) appeared in general dental
journals with 123 publications in journals of dental associations,
For the evaluation of the incidence and the success of therapeutic strategies of BRONJ, publications had to reach the level of evidence of at least grade IV. Studies which did not reach the lowest
grade IV, representing evidence based on expert committee reports
or clinical experience of respected authorities, were excluded from
evaluation of the incidence and therapeutic outcomes.
Therapeutic outcomes were categorised into two groups: conservative treatment and surgical treatment. Conservative treatment was defined as pain control and local disinfection by
mouth rinse and, if applied additionally, antibiotic therapy. Limited
débridement in terms of removing unfixed necrotic bone without
surgical exploration was also defined as conservative treatment.
Surgical treatment was defined as any invasive act in which rotating instruments or others were used for osteotomy and resective
surgery of necrotic bone.
Data extraction
Data were extracted based on prefabricated spreadsheets using
Microsoft Excel (Microsoft Office Excel 2007, Redmond, USA). Any
Figure 1 Number of publications on BRONJ from 2003 to 2009.
940
S. Kühl et al. / Oral Oncology 48 (2012) 938–947
Figure 2 Number of publications on BRONJ in different journals listed according to different disciplines between 2003 and 2009.
46 in oral medicine, nine in implantology, and one in endodontics
(Fig. 2). 20.1% of all publications (n = 135) appeared in oral and maxillofacial surgery journals. 122 were published in oral and cranio- or
maxillofacial surgery, seven in head and neck surgery, four in otolaryngology and two in laser surgery journals. 19.1% of all publications
(n = 128) were found in clinical oncology journals and an additional
six in nuclear and two in palliative medicine journals. 13.3% of all
publications (n = 89) appeared in general medical journals with 88
papers in journals of medical associations and one in public health.
13.0% of the papers (n = 82) were published in journals of internal
medicine (n = 9), haematology (n = 18), rheumatology (n = 17), bone
and mineral research (n = 14), endocrinology and metabolism
(n = 10), nutrition and metabolic therapy (n = 5), arthritis (n = 4),
osteoporosis (n = 4) and one in clinical nutrition and metabolic care.
Publications in other journals (n = 58) make up 3.6% of all publications, with 11 papers in pharmacology journals, 9 in radiology, 6
in urology and nephrology journals, 5 in orthopaedic, 5 in biochemistry and cell biology, 4 in pathology and neurology, 4 in journals of
climacterics and menopause, 3 in toxicology and 2 in gynaecology,
gerontology and neuroradiology.
Classification of evidence
A total of 176 publications out of 671 could be classified
(Table 2).
Only one study with evidence level Ia was found. This study by
Mauri et al. is a meta-analysis of several randomized controlled
clinical trials published in 2009.30
Eight publications showed evidence level Ib, which were the results of at least one randomized controlled clinical trial. One study
by Jeffcoat et al.31 represents an update of a trial from the year
2006.32 This article had lower evidence because it included a
non- randomized study.
Nine non-randomized studies had a level of evidence grade IIa.
The group with evidence IIb comprised 25 studies. These were
quasi-experimental studies, such as time series analyses without
randomization.
A total of 101 publications with evidence III were found. These
were the results of descriptive studies such as cohort studies or
case-control studies.
The 32 publications with evidence IV were reports by respected
authorities and their clinical experience or panels of experts from
several medical organizations.
Incidence of BRONJ according to the type of bisphosphonate
application
Intravenous application
The results were extracted from studies focusing on the
incidence of BRONJ as well as on the therapy of BRONJ. A total of
47 studies revealed information on the incidence of BRONJ after
intravenous application (Table 3). The mean incidence over all the
reviewed publications was 7% with a high variation from 0.0% published by Lyles et al., Bianchi et al. and Malmgren et al. 2008 up to
27.5% in a study by Boonyapakorn et al. (Table 3).34,55–57 Besides a
high variance in incidence, the studies showed a high variance in
design. 30 studies (63.7%) were retrospective studies, 14 (29.7%)
were prospective, two studies (4.5%) were letters to the editors
and one (2.1%) study was a review. The median duration of the
studies showed wide differences, ranging from 5 months according
to Vahtsevanos et al. to 75 months in a study published by Kanat
et al. (Table 3).106,165
Oral application
A total of 9 studies were reviewed in which information on the
incidence after oral bisphosphonate application was directly
Table 2
Publications listed according to the year of appearance and grade of evidence.170
Year
2003
2004
2005
2006
2007
2008
2009
a
Level Ia
Level Ib
Level IIa
Level IIb
Level III
Level IV
168
30
33
31,34
35–37
38,39
32
40
41–45a, 46a, 47a
Published in the year 2010 but epub ahead in 2009.
48
49,50
51–53
54–60
61–64a, 65–67a, 68–72
10,15
73–78
79–92
12,93–118
119–141
142–151a, 152,153a, 154–163a, 164–167
24
9,17,26,169–174
16,18,22,28,102,175,176
19,21,177–179
26,27,180–186
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S. Kühl et al. / Oral Oncology 48 (2012) 938–947
Table 3
Incidence of BRONJ after intravenous bisphosphonate application.
Lit. No.
Type of study
Mean duration
BRONJ ratio in
No. of patients
Incidence of
BRONJ (%)
79
Prospective
22–24 months
ND
40
62
54
55
143
56
123
81
145
146
51
63
49
41
73
10
127
Prospective
Review
Retrospective
Prospective
Retrospective
Prospective
Retrospective
Retrospective
Prospective
Retrospective
Retrospective
Prospective
Prospective
Retrospective
Letter to editor
Retrospective
Retrospective
22 months
19 months
50 months
36 months
39 months
32 months
42 months
149
103
104
178
130
131
52
106
133
34
76
57
110
134
111
37
187
112
113
115
44
87
162
188
165
138
116
117
Retrospective
Prospective
Retrospective
Retrospective
Retrospective
Retrospective
Retrospective
Letter to editor
Retrospective
Prospective
Retrospective
Retrospective
Retrospective
Retrospective
Retrospective
Prospective
Retrospective
Retrospective
Prospective
Retrospective
Retrospective
Retrospective
Retrospective
Retrospective
Prospective
Prospective
Retrospective
Retrospective
ND
ND
34 months
34 months
18–48 months
12 months
24 months
18–75 months
ND
22 months
39 months
54 months
12–24 months
ND
ND
12 months
8–12 months
7 months
19 months
18 months
ND
20 months
ND
17 months
>5 months
ND
ND
60 months
50
Prospective
24 months
6/67
11/55
11/340
0/18
10/398
22/80
17/105
7/64
5/32
4/78
7/106
ND
15/202
16/128
75/1203
13/124
35/4835
28/310f
10/345
3/104
3/57
3/57
29/3965
8/539
24/655
4/85
16/186
0/1065
9/194
0/64
114/12,970
9/178
2/243
1/81
5/178
6/52
22/311
28/1402
28/966
5/81
6/638
9/259
80/1621
8/43
5/75
11/292c
2/81d
2/69e
8/254
10.0d
4.0e
9.0
20.0
3.2
0.0
2.5
27.5
16.2
10.9
15.6
5.1
6.6
3.0
7.4
12.5
6.2
10.5
0.7
9.0f
2.9
2.9
5.0
5.0
0.7
1.5
3.2
4.7
8.6
0.0
4.6
0.0
0.9
5.1
1.4
1.2
2.8
11.5
7.1
2.0
2.9
6.2
0.9
3.5
4.9
18.6
5.3
3.8a
2.5b
2.9c
11.0
34 months
ND
ND
21 months
29 months
35 months
36 months
39 months
34 months
ND = no data available.
a
Multiple myeloma.
b
Breast cancer.
c
Prostate cancer.
d
With zoledronate.
e
With pamidronate.
f
Patients with dental examination.
retrievable or retrospectively calculated by the authors from the
published data (Table 4). The overall incidence of BRONJ after oral
bisphosphonate application was 0.12%, ranging from 0.0% in a
study by Black et al., Jeffcoat et al., Fugazotto et al., Murad et al.
and Bianchi et al. to 4.3% published by Seghizadeh et al.
(Table 4).32,33,55,111,159,189 Four studies (111, 146, 151, 189) were
retrospective studies (44%), five studies (32, 33, 55, 119, 159) were
prospective studies (55%). The mean duration of the studies ranged
from 24 months in Jeffcoat et al. and Mavrokokki et al. up to
>60 months in a study by Black et al.32,33,110
Treatment outcomes
Table 5 and 6 show different treatment concepts for 403 BRONJ
patients based on 15 studies. 123 patients had conservative treatment (Table 5), 255 patients had surgical treatment (Table 6) and
the remaining 25 patients had combinations of both. 388 out of
the 403 patients were given antibiotics.
The combination of radical surgery and antibiotics was found in
the treatment of 240 patients (59.7%). 141 (58.8%) of them had
healing of the lesion. 47 (19.6%) of them had an improvement with
942
S. Kühl et al. / Oral Oncology 48 (2012) 938–947
Table 4
Incidence of BRONJ after oral bisphosphonate application.
Lit. No.
Type of study
Mean duration
BRONJ ratio in No. of patients
Incidence of BRONJ (%)
189
111
146
151
33
32
Retrospective
Retrospective
Retrospective
Retrospective
Prospective
Prospective
110
55
159
Prospective
Prospective
Prospective
39 months
ND
ND
43 months
>60 months
24 months
>36 months
24 months
>36 months
ND
0/61
0/240
1/38
ND
0/1099
0/335
0/50
36/304,900
0/20
9/208
0.0
0.0
2.6
<0.1
0.0
0.0
0.0
0.01
0.0
4.3
ND = no data available.
Table 5
Outcomes after conservative treatment.
Staging according to Ruggiero et al.9
Study
No information available
No information available
Stage I and II
No information available
No information available
Two patients stage I, 19 with stage II and 5 with stage III
(one patient appearing in tab.6 due to resective surgery)
Nine patients stage I, 21 with stage II and 3 with stage III
53
56
148
161
69
164
71
Total
Percentage
No. of patients
4
5
19
29
8
26
33
124
100.0%
AB
H
4
5
19
29
0a
18
4
18
25
8
4
33
16
108
87.1%
B
W
NR
4
1
1
4
8
75
60.5%
13
10.5%
7
7
3
14
10
8.1%
26
20.9%
AB = antibiotic treatment, H = complete healing of the lesion, B = better (acceptable healing and resolution of pain), W = worse (refractory healing and resolution of pain),
NR = no result/same stage/lost in follow-up.
a
Biostimulation by laser (Nd:YAG) or hyperbaric oxygen.
Table 6
Outcomes after surgical treatment.
Staging according to Ruggiero et al.9
Study
No information available
No information available
No information available
Treatment according to the staging of Ruggiero et al.157
but staging not clearly mentioned in publication
No information available
Fifty-four patients with stage I, 33 with stage II and 16
with stage III included. Two patients died
No information available
Grade III
No information available
Grade III
One patient stage I, 22 stage II and 27 stage III
53
56
60
141
3
13
14
41
7
10
24
142
144
7
95
5
87
1
1
8
152
190
161
164
46
20
7
4
1
50
12
6
3
4
4
1
1
1
2
Total
Percentage
No. of patients
255
100.0%
H
B
W
NR
3
3
4
17
3
154
60.4%
43
5
51
20.0%
8
3.1%
42
16.5%
H = complete healing of the lesion, B = better (acceptable healing and resolution of pain), W = worse (refractory healing and resolution of pain), NR = no result/same stage/lost
in follow-up. Antibiotics were given in every case.
resolution of their clinical symptoms. 10 patients (4.2%) had refractory or new BRONJ.
The combination of conservative treatment with administration
of antibiotics was found in 103 patients. 66 (64.1%) of these patients had healing of their lesions. Six patients (5.8%) showed an
improvement with resolution of their clinical symptoms. Eight patients (7.8%) had refractory or new BRONJ.
In 27 patients antibiotics only were administered. In 18 (66.7%)
of these patients an improvement with resolution of their clinical
symptoms was found.
Other treatment concepts included ND:YAG laser stimulation or
pulse application in 14 patients, once in combination with antibiotic therapy in six patients and once in combination with surgical
wound débridement in eight patients. Half of the first group and
the whole of the second group of these patients had healing of their
lesions.
Discussion
Numerous studies on BRONJ have been published in the last
few years. However, there has not been any study evaluating
the level of evidence of these published data according to the
classification of Shekelle et al. Additionally there has not been
any work evaluating and classifying the number of publications
according to the different medical or dental fields, e.g. journals.
Since the first publication on the topic ‘‘BRONJ’’, a constant
S. Kühl et al. / Oral Oncology 48 (2012) 938–947
increase in terms of the numerical trend can be seen. In 2010
there were already more than 200 publications listed in PubMed,
and more than 150 in December 2011.
In accordance with the statement of the American Society for
Bone and Mineral Research (ASBMR) it is very difficult to compare
the studies because of the heterogeneity of the referred methods.22
Due to this lack of uniformity the information is not always
compatible.22
Although most of the bisphosphonates are prescribed by internists, haematologists, urologists, and gynaecologists, most of the
literature on BRONJ is published in journals of general dentistry,
and oral and cranio-maxillofacial surgery. This is not surprising
since patients suffering from BRONJ are referred to dentists or oral
and maxillofacial surgeons for treatment. However, it was interesting to find only two publications in gynaecology journals and six in
urology and nephrology. A much higher number of publications
would have been expected in these medical fields. Obviously
BRONJ seems to be of rather low interest in these fields, which contrasts with the severity and incidence of this reported effect of
intravenous bisphosphonate therapy.
The general incidence of BRONJ is difficult to determine because
of variables such as type, dosage, duration of the bisphosphonate
treatment, disease and status of disease, age, other diseases and
medications.131 Generally, the incidence of BRONJ is lower for oral
than for intravenous bisphosphonate application. Oral bisphosphonates are mostly used for the treatment of osteoporosis or Paget’s
disease. In contrast to this, intravenous BP application is used for
the treatment of malignancies, thus being related to a completely
different status of health and concurrent medication of patients. In
all studies focusing on oral bisphosphonate application with osteoporotic dosage, the BRONJ ratio in number of patients is 46/36,951
and the incidence of BRONJ is 0.12%. Without the study of Mavrokokki et al. the BRONJ ratio in number of patients is 10/2051
and the incidence of BRONJ is 0.49%.110 This South Australian experience represents a collection of all of the known cases in the state.
10 out of 25 cases were observed in osteoporosis, 4 in Paget’s disease
and 11 in bone malignancy. The population of South Australia is 1.5
million, giving a population frequency of 1 in 60,000 people. If this
experience is projected to the total Australian population of 20.3
million people, one would expect 338 cases of BRONJ. This fact of
a low incidence for oral bisphosphonate application, however, is
confirmed by other authors.36,48,66,90,129,165 When intravenously
administered in oncologic dosage, the incidence of BRONJ increases.
In 23 studies, the incidence of BRONJ was 0–20% for zoledronic acid,
0–4% for pamidronate and 0–24.7% for the combination of both.
The literature provides evidence regarding a positive correlation
of the duration and dosage of the bisphosphonate therapy with the
incidence of BRONJ. It was found to be 0–11.5% in therapies up to
one year and 0–27.5% from 1 to 4 years, confirming findings of
other studies.36,48,90,165
We conclude that BRONJ is associated with high-dose BP therapy primarily in the oncology patient population.186 BRONJ is commonly precipitated by a tooth extraction in patients treated with
long-term, potent, high-dose intravenous bisphosphonates for the
management of myeloma, breast or prostate cancer. Besides tooth
extraction, periodontal disease seems additionally to represent a
trigger for the development of BRONJ.20 Interestingly, in children
and adolescents, where bisphosphonates among others are used
for the treatment of osteogenesis imperfecta, so far there is no evidence of BRONJ. It makes no difference whether bisphosphonates
are given intravenously or orally, or whether dental extraction or
oral surgical treatments are necessary.55,122,135
There are currently many protocols for the treatment strategies
of BRONJ. These are recommendations published by manufacturers
of drugs, scientific associations or those based on literature
reviews.16–28,191,192,194,195 At present, two different approaches
943
can be differentiated: conservative approach including antibiotics,
oral rinses, pain control and limited débridement with the aim of
reducing the stage of necrosis and avoiding progression which
may be associated with surgery.16–18,21,22,25,26,195 These guidelines
recommend invasive surgery only for large and extended necrosis.16–18,21,22,25,26 In contrast to these, others already recommend
surgical treatment at lower stages with the aim of avoiding
progression of the necrosis.20 There is a consensus that cases
refractory to conservative management may benefit from investigational therapies.16–28,191–194 The roles of surgical treatment
and hyperbaric oxygen therapy are still under investigation.28
While a drug holiday is recommended by several guidelines, there
are no studies proving its efficacy. Comparing the results between
conservative and surgical treatment it seems that there is no difference regarding the success of treatment (e.g. 60.5% vs. 60.4%). This
comparison is biased since, according to some recommendations,
surgery is rather performed in cases with extended necrotic bone.
However, if the results for acceptable healing and resolution of
pain are compared between conservative and surgical treatment,
the former shows worse outcomes than the group with surgical
treatment. The group receiving surgical treatment has fewer new
cases of BRONJ than the group with conservative treatment (e.g.
3.1% vs. 8.1%). Both results are related to the fact that surgical
treatment is mostly performed in cases with a higher stage of
BRONJ than for conservative treatment. It is not known to what extent early surgery might be beneficial for patients at a low stage
when compared to conservative treatment. The higher stages are
often associated with worse general health conditions that might
negatively affect the surgical results. Unfortunately not every
study on treatment outcomes revealed information concerning
the staging and thereby extension and severity of the necrosis.
However, it seems that total healing of BRONJ after conservative
treatment is only successful in low stages. This can be assumed
based on studies by van den Wygaert et al.71 and ThumbigereMath et al.164, in which conservative treatment was also performed
in stage II and III patients. Both studies showed worse outcomes for
conservative treatment in terms of worse or refractory healing and
resolution of pain when compared to all other studies involving
conservative treatment of level I necrosis. We conclude that conservative treatment might only lead to complete healing in stage
I patients. The present review shows that surgical procedure in
terms of exploration and resection of necrotic bone results in successful healing of 60%. Although complete healing was not achievable in 20%, patients showed at least a relief of pain. With regard to
these results, almost 80% of the patients had a direct benefit related to surgical intervention. Only 3% showed worse outcomes
with refractory healing and resolution of pain after surgery and
16.5% were either lost to follow-up or showed the same stage. Most
studies with surgical procedure included patients with high stages
of necrosis. With regard to the poor conditions associated with
high stages of necrosis in these groups, it might be concluded that
surgical therapy in cases with low-grade necrosis might result in
even higher success rates than if conservative treatment is performed. Evaluating the results of this review and taking our own
experiences into account, we recommend conservative treatment
as initial treatment for pain control and chronification of acute
inflammatory signs before surgical treatment in any stage of
BRONJ. Surgery, however, seems to be inevitable in most of the
cases where complete and successful healing is the aim. Surgery
may be avoided if complete healing appears during the initial
phase of pain control, local disinfection (by mouth rinse or topical
application of disinfectant paste) and administration of antibiotics.
This, however, seems to be confined to a rather rare number of
cases.
The benefit of using ND:YAG laser stimulation or pulse application has not yet been proved.
944
S. Kühl et al. / Oral Oncology 48 (2012) 938–947
As yet there are no studies which have evaluated the level of
evidence for trials published before 2010. The results of the present study show that the overall level of evidence concerning the
incidence and treatment strategies for BRONJ is rather low. The
high number of publications reflects the increasing number of patients with BRONJ. BRONJ may be expected to gain more and
more importance in the future. With regard to these aspects,
there is a need for additional studies to achieve more evidence
concerning the pathomechanism, the incidence, treatment outcomes as well as strategies for the therapy and prevention of
BRONJ.
Conflict of interest statement
None declared.
We hereby disclose any financial and personal relationships
with other people or organizations that could inappropriately
influence (bias) our work.
20.
21.
22.
23.
24.
25.
26.
Acknowledgement
27.
The study has no funding. We extend our gratitude to Ms. Susan
Holmes for the editing.
28.
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