Eur J Clin Microbiol Infect Dis
DOI 10.1007/s10096-014-2160-5
REVIEW
Actinomyces osteomyelitis in bisphosphonate-related
osteonecrosis of the jaw (BRONJ): the missing link?
J. De Ceulaer & E. Tacconelli & S. J. Vandecasteele
Received: 8 April 2014 / Accepted: 6 May 2014
# Springer-Verlag Berlin Heidelberg 2014
Abstract Bisphosphonate-related osteonecrosis of the jaw
(BRONJ) is a rare complication of bisphosphonate treatment
characterized by the development of exposed, necrotic bone in
the jaw with inflammatory signs. The pathogenesis of BRONJ
is not yet fully understood. This review analyzes the evidence
supporting the hypothesis that BRONJ may be considered as a
bisphosphonate-induced Actinomyces infection of the jaw
according to the modified Koch’s postulates. The main argu-
ments relies on the following factors: (1) the high prevalence
of isolation of Actinomyces from bone BRONJ lesions
(73.2 % in retrospective series); (2) the similar pathological
appearance of BRONJ and Actinomyces osteomyelitis in most
studies, although BRONJ lesions without inflammation have
been reported; (3) the high incidence of events that disrupt the
normal mucosal barrier as a necessary trigger to develop
BRONJ in bisphosphonate-exposed patients; (4) the predilec-
tion of bisphosphonate-induced osteonecrosis for the bones of
the jaws; and (5) the favorable response of BRONJ on treat-
ment that is active on Actinomyces. If BRONJ confirms to be a
bisphosphonate-induced Actinomyces osteomyelitis of the
jaw, this has major consequences for the prevention and
treatment of this condition.
J. De Ceulaer
Department of Maxillofacial Surgery, AZ Sint-Jan Brugge, Bruges,
Belgium
e-mail: Joke.deceulaer@azsintjan.be
E. Tacconelli
Department of Infectious Diseases, Tuebingen University, Tübingen,
Germany
e-mail: Evelina.Tacconelli@med.uni-tuebingen.de
S. J. Vandecasteele (*)
Division of Nephrology and Infectious Diseases, AZ Sint-Jan
Brugge, Bruges, Belgium
e-mail: stefaan.vandecasteele@azbrugge.be
Introduction
Since its first description in 2003 by Wang and colleagues [1],
bisphosphonate-related osteonecrosis of the jaw (BRONJ) has
been recognized as a distinct but not yet fully understood
condition that strongly resembles the “phossy jaw”, or
phosphorus-induced jaw necrosis with osteomyelitis observed
in the 19th century match factory workers [2]. In a position
paper of the American Association of Oral and Maxillofacial
Surgeons (AAOMS), BRONJ is defined as the presence of
exposed, necrotic bone in the maxillofacial region
persisting for more than 8 weeks in patients treated with
bisphosphonates and in the absence of a history of radi-
ation therapy of the jaw bones [3]. Rheumatologists,
oncologists, hematologists, maxillofacial surgeons, and
dentists are among the health care workers most fre-
quently confronted with BRONJ.
Background
Clinical picture of BRONJ
Clinically, BRONJ is characterized by necrotic bone associat-
ed with inflammatory signs with or without pain, purulent
drainage, fistulization, osteolysis, or pathological fractures
[3, 4]. The risk of BRONJ is incremental with the duration
and total dose of bisphosphonates used, and the more potent
intravenous preparations (which have a bioavailability in the
bone of 60–70 %) inherit a higher risk than the less potent oral
preparations (which have a bioavailability in the bone of only
0.4–0.6 %) [2, 4, 5]. Intravenous preparations are most fre-
quently used in the treatment of hematological malignancies,
metastatic bone disease, and hypercalcemia of malignancy,
whereas oral preparations are used mostly in the treatment of
postmenopausal osteoporosis [6]. There is a delay of several

months or even years between the first exposition of the
patient to bisphosphonates and the development of clinical
signs [5]. The mandible is affected in about two-thirds
of patients, and the maxilla in one-third [5]. In most
patients, the development of BRONJ seems to be pre-
cipitated by an incident that disrupts the normal muco-
sal barriers of the oral cavity, such as dentoalveolar
surgery, inflammatory periodontal and dental diseases,
or ill-fitting dentures [3, 4, 7, 8]. Other risk factors are
diabetes mellitus and corticosteroid treatment, observed in,
respectively, 60 and 25 % of cases [8]. The pathogenesis of
BRONJ is not yet well understood.
Bisphosphonates
Bisphosphonates (P-C-P) are chemically stable derivatives of
pyrophosphate (P-O-P), with the oxygen being replaced by a
carbon that renders protection against breakdown by hydro-
lysis and mediates a tight binding to the hydroxyapatite crys-
tals in the bone [2, 9] (see Fig. 1). The hydroxyl group on the
carbon position determines the stringent binding to bone
hydroxyapatite, from which it can only be removed by acid-
mediated bone resorption by osteoclasts, resulting in a bone
half-life for bisphosphonates of more than 10 years [2]. The
R1 substitution on the carbon position is related to the potency
of the bisphosphonate, with nitrogen-containing side chains,
as found in all commercially available preparations, providing
the most potent bisphosphonates [2, 9]. In the osteoclasts,
bisphosphonates inhibit the farnesyl pyrophosphate synthe-
tase, an enzyme involved in the mevalonate-to-cholesterol
pathway, thus suppressing the isoprenylation of small guano-
sine trisphosphates at the ruffled border of osteoclasts, even-
tually stopping bone resorption and inducing apoptotic cell
death in the osteoclasts [9]. Despite its physical hardness,
bone is normally a dynamic self-renewing structure, with a
turnover cycle of 150 to 180 days, which is called sigma, and
which is probably shorter in the jaw [2]. This bone renewal
cycle is initiated by the secretion of diverse growth factors
exactly by those cells that bisphosphonate toxicity targets: the
osteoclasts [2]. As such, bisphosphonates reduce or even
eliminate the natural bone regeneration cycle, leading to old,
adynamic bone [2].
Fig. 1 Biochemistry of bisphosphonates
Eur J Clin Microbiol Infect Dis
The phossy jaw in the 19th century
In 1839, the first reports of phosphorus-induced osteonecrosis
of the jaw emerged in otherwise healthy workmen of match
factories who were extensively exposed to white phosphor
vapors [10]. With the growth of the phosphor industry, a new
disease called “phossy jaw” came to existence, with an attack
rate of far less than 1 % of exposed workpeople [10]. The
condition consisted of a progressive necrosis of the jaw, with a
mortality as high as 50 % [10]. The condition could be
reproduced in rabbits extensively exposed to phosphorus,
but only in those animals in whom the periosteum was trau-
matically exposed to the mouth flora [10]. In an eloquent
review in 1962 on the phossy jaw, Hughes and co-authors
concluded that, “It appears to be necessary to have both
phosphorus (or other chemicals) and infection from microor-
ganisms, and the only place where the two can commonly
coexist is the jaw” [10].
A damage of the gingival margin, either by direct trauma or
from inflammation, preceded the condition in almost all affect-
ed patients [10]. Clinically, the disease started with aching in
one of the teeth, frequently accompanied by a dull red discol-
oration of the affected mucosa, usually leading to the extraction
of a tooth [10]. The subsequent wound did not heal, and slowly
evolved into a large, oozing defect in the cheek [10]. Pain was
variable in severity, and usually worse at night, but might also
have been absent [10]. In the wounds, organisms consisting of
the normal flora of a healthy mouth are usually recovered, but
in the available reports, no further specifications on the nature
of these organisms is given [10]. The phossy jaw was consid-
ered a form of osteomyelitis by contemporized physicians [2,
10]. The phossy jaw disappeared after the international Berne
Convention in 1906, which forbad the use of white phosphorus
in the match industry [10].
The case of the phossy jaw as a form of bisphosphonate-
induced osteonecrosis has been detailed by Marx in 2008 [2].
The white phosphorus vapors to which match factory workers
were exposed extensively consisted of a chemically unstable
(and, thus, easily igniting) form of phosphate oxide (P4O10) that,
when combined with H2O and CO2 available in expiration air,
and common amino acids such as lysine available in the respi-
ratory tract, forms bisphosphonates that are chemically almost
identical to alendronate and pamidronate [2].
Human Actinomyces species
The colonization of BRONJ seems to be ubiquitous, with
Actinomyces species being the dominant pathogens. However,
the role of Actinomyces in the development of BRONJ is not
clearly defined. Human actinomycosis is caused by Gram-
positive, non-sporulating bacteria that tend to produce branching
filaments and that are classified in the families of
Actinomycetaceae, Propionibacteriaceae, and Bifidobacteriacea,
Eur J Clin Microbiol Infect Dis
with Actinomyces israelii, Actinomyces gerencseriae, and Acti-
nomyces naeslundii/viscosus implying more than 75 % of the
clinical isolates [11]. The pathogenic Actinomyces species do not
exist freely in nature and are ubiquitous commensals of human
and animal mucous membranes, with a predilection for gingival
crevices, tonsillar crypts, and dental caries, where they form
biofilms [11–14]. Actinomyces species have a considerable host
specificity [12]. Actinomyces species can cause invasive disease,
most frequently presenting as slowly but progressively growing
and difficult-to-cure inflammatory masses, and more rarely pre-
senting as an acute soft tissue infection [12]. Inflammatory
pseudotumors in chronic actinomycoses consist of multilocular
cavities with central scars and more peripheral abscesses, with
fistula that discharge sulfur granules or “drusen” in about one-
fourth of the cases [8, 11]. Co-pathogens are isolated in the
majority of cases [11].
The diagnosis of invasive actinomycoses is made by tissue
culture or by pathological examination [12]. Actinomyces spe-
cies grow best under anaerobic growth conditions and are quite
fastidious concerning their nutritional requirements, and cul-
tures are easily overgrown by other bacteria [11]. On patho-
logical examination, Actinomyces species grow in clusters of
tangled filaments that are surrounded by polymorphonuclear
leukocytes and in inflammatory reactions consisting of granu-
lation tissue, extensive fibrosis, and sinus tracts [12]. Histolog-
ical diagnosis is difficult because many clinical species contain
only a few of the pathognomonic sulfur granules, and the
accompanying inflammatory reaction is non-specific [12].
Actinomyces species are in vitro susceptible to natural
penicillins, cephalosporins, carbapenems, tetracyclines, and
macrolides [12, 15]. Given the very slow clinical response to
antibiotics, and the high risk for disease relapse, antibiotics are
usually given for 3 to 12 months or longer [12]. For severe
diseases, the initial antibiotic treatment usually consists of IV
penicillin for 4–6 weeks [12]. Antibiotics targeting only
Actinomyces species and not the frequently encountered co-
pathogens seem to be sufficient to lead to cure [12].
Aim of the review
The current review aims to analyze the evidence supporting the
role of Actinomyces as a “necessary” link between the excessive
exposition of the bones to bisphosphonates and the develop-
ment of BRONJ using to the revised Koch’s postulates.
Search strategy and selection criteria
Articles presenting data pertaining to the epidemiology, patho-
genesis, diagnosis, and treatment of BRONJ were identified
through computerized literature searches using MEDLINE (Na-
tional Library of Medicine, Bethesda, MD), EMBASE, and the
Cochrane Database, and by reviewing the references of retrieved
articles. Index search terms included: [Bisphosphonate] and
[Actinomyces]. The search was restricted to full articles pub-
lished in English up to August 2013. No attempt was made to
obtain information on unpublished studies. Data were then ex-
tracted and reported according to the revised Koch’s postulates.
Does Actinomyces in BRONJ fulfil the classic Henle–Koch
postulates?
The classic Henle–Koch postulates are used as reference
criteria in the evaluation of the causal relationship between
an infectious agent and the clinical disease to which it is
associated [16]. According to the 1976 revised Henle–Koch
postulates concerning the causative relation between a micro-
organism and a chronic disease, the two essential types of
evidence necessary are: (1) the simultaneous presence of the
organism and the disease appearing in the correct sequence
and (2) the specificity of the effect of the organism on the
development of the disease, based on physiological, patho-
logical, experimental, and epidemiological grounds [16].
1. Osteomyelitis with Actinomyces is present in the majority, if
not all, of the cases of BRONJ
Actinomyces species are ubiquitous colonizers of the human
oral cavity [11, 12]. Actinomyces colonies accompanied by
clear signs of tissue invasion and reactive tissue inflammation
are almost universally observed in bone affected by BRONJ as
far as looked for [17]. Invasive Actinomyces was observed in
73.2 % (407 of 556) of the patients reported in the literature,
with half of the papers reporting bone invasion by Actinomyces
in 100 % of the cases (see Table 1). These results should be
interpreted with caution and are probably an underestimation of
the real incidence of invasive actinomycoses in BRONJ. Most
of these data rely on a retrospective analysis of pathological
records of BRONJ without clear definition of invasive actino-
mycoses. Cultures were generally not taken, or taken while the
patient was on antibiotics treatment [18]. Molecular techniques
or matrix-assisted laser desorption/ionization time-of-flight
(MALDI-TOF) were not used. The largest case series on
BRONJ which mentioned “frequent observation of invasive
Actinomyces” was excluded due to the lack of more precise
information on the number of patients included [5].
2. Arguments in favor of a pathogenic role of Actinomyces
osteomyelitis in the development of BRONJ
Pathological grounds
Shortly after the discovery of BRONJ, a German review of 79
cases defined the histological findings in BRONJ as “similar
 Eur J Clin Microbiol Infect Dis

Table 1 Literature review of the incidence of invasive Actinomyces in bisphosphonate-related osteonecrosis of the jaw (BRONJ)

Reference Year Design No. of cases No. of Percentage Remarks

positives

[8] 2013 Retrospective, clinical, and pathological BRONJ, 52 52 100.0 Healing 25 ptn. Surgery and AB. Time
54 cases 12.5 (IV) to 4.2 PO
[30] 2013 Retrospective, pathological BRONJ, 51 cases 51 44 86.3
[31] 2014 Retrospective, pathological BRONJ, 30 cases 30 16 53.3 Healing in 14/27 ptn
[32] 2012 Retrospective, clinical BRONJ, 11 cases 11 11 100.0 Favorable outcome in the 9 patients
treated with AB
[23] 2011 Prospective, clinical BRONJ, 13 cases 13 13 100.0 Treated with debridement and 3–12
months AB PO
[33] 2011 Retrospective, clinical BRONJ treated with 25 15 60.0 Treatment with debridement and
plasma, 25 cases plasma, cure in 80 %
[18] 2011 Prospective, BRONJ treated with surgery, 108 36 33.3 AB in all patients, cure 71.3 %. Not
108 patients established how diagnosis was made,
culture taken under AB
[34] 2010 Retrospective, clinical BRONJ, 18 cases 18 11 61.1 Surgical treatment, AB NA
[26] 2010 Retrospective, clinical BRONJ, 34 cases 34 18 52.9
[24] 2010 Retrospective, clinical BRONJ, 10 cases 10 9 90.0
[35] 2009 Retrospective, clinical BRONJ, 101 cases, 30 29 96.7 No cultures were positive
30 with pathology
[36] 2009 Case report 1 1 100.0 Not cured
[27] 2009 Retrospective, clinical IV-induced BRONJ, 59 cases 59 47 79.7
[37] 2009 Retrospective, clinical BRONJ, 34 cases 25 18 72.0 Best outcome in combined surgical and
AB treatment. Diagnosis based on
culture results
[38] 2008 Retrospective, clinical BRONJ, 32 cases 32 32 100.0 Radiological appearance study
[39] 2008 Retrospective, BRONJ with myeloma, 3 cases 3 3 100.0
[17] 2007 Retrospective, pathological, 45 patients with 26 26 100.0
actinomycosis, including 26 with BRONJ
[40] 2006 Retrospective, clinical BRONJ, 6 cases 6 6 100.0
[20] 2006 Retrospective, pathological BRONJ, 8 cases 8 8 100.0
[41] 2006 Retrospective, pathological and clinical BRONJ, 11 10 90.9
11 cases
[42] 2004 Retrospective, clinical BRONJ in myeloma, 3 cases 3 2 66.7
Total 556 407 73.2

to osteomyelitis with a high number of Actinomyces colonies”
[19]. Despite this striking similarity, histopathological argu-
ments on the pathogenic role of Actinomyces in the develop-
ment of BRONJ remain inconclusive as to whether
Actinomyces triggers bisphosphonate-related osteonecrosis
or whether bisphosphonate-related osteonecrosis triggers sec-
ondary colonization and infection with Actinomyces.
In all reports, BRONJ lesions are characterized by scattered
areas of necrotic bone, as evidenced by empty osteocytic
lacunae, Volkmann’s canals, and Haversian systems [8, 17,
20, 21]. Most papers describe a patchy, inhomogeneous ap-
pearance of the necrotic bone with interspersion of the med-
ullary space containing variable amounts of viable osteocytes
and a mixed inflammatory infiltrate consisting of neutrophils,
histiocytes, eosinophiles, and plasma cells with some degree
of fibrosis [8, 17, 20, 22]. Some papers, however, report a
notable absence of inflammatory cells, blood vessels, or
osteoclasts, suggestive for BRONJ lesions without signs of
suppurative osteomyelitis [21]. Vessel obliteration, which has
been thought to be a crucial factor in the pathogenesis of
BRONJ for a long time, is only observed in less than one-
third of the cases [17]. Pseudoepitheliomatous hyperplasia,
which is the invasion of hyperkeratotic epithelium in
subepithelial tissues, is noticed in up to two-thirds of BRONJ
lesions [17]. If present, Actinomyces colonies are mainly
attached to the bone in the direct absence of inflammatory
cells, while being less often present in the more superficial
parts of the fistula and inflamed soft tissues [17, 20, 21]. These
light microscopic observations have also been confirmed in
scanning electron microscopy studies [17, 23].
Differences in inflammatory response observed in different
pathological studies of BRONJ may be due to several reasons.
None of these studies were corrected for the sampling time of
the biopsy in the time course of BRONJ, nor for the use of
Eur J Clin Microbiol Infect Dis
antibiotics before biopsy or for the local biopsy policy in
BRONJ lesions in the concerning center. Moreover, the
methods used for decalcification may have a considerable
influence on the subsequent results [17].
Just like BRONJ, osteoradionecrosis of the jaw is charac-
terized by empty osteocytic lacunae, the absence of osteoblas-
tic rimming, and empty Haversian systems and Volkmann’s
canals, but the osteonecrosis is much more homogenous, and
the overall fibrosis more pronounced [7, 17, 21]. Also primary
Actinomyces of the jaw is characterized by a very similar
pathological picture in addition to the Splendore–Hoeppli
phenomenon, which consists of eosinophilic aggregates with
pseudomycotic structure [17].
Experimental grounds
Osteonecrosis can only be reproduced in animal models by
combining exposure to bisphosphonate and dental disease that
disrupts the mucosal barriers [7, 10, 24, 25]. Also, in humans,
a factor disrupting the normal mucosal barriers (surgery, tooth
extraction, periodontitis) is observed in the majority of cases,
i f r ep or t ed [3 –5 , 7 , 8 , 2 6, 27 ] . P a t h o l o g i c a l l y,
pseudoepitheliomatous hyperplasia, which is a sign of muco-
sal irritation and damage, is observed in the majority of
patients without clear history of mucosal barrier disruption
[17]. Usually, there is a delay of several weeks between the
disruption of the oral mucosal barriers and the development of
BRONJ [24]. In a rat model for BRONJ, Actinomyces colo-
nies are observed within the bone marrow of the animals,
together with a dense inflammatory infiltrate, as seen in oste-
omyelitis [24]. When using scanning electronic microscopy,
Actinomyces containing biofilms were almost universally ob-
served in samples retrieved from osteomyelitis of the jaw [14].
Response of BRONJ on therapy directed against Actinomyces
Randomized controlled trials on the ideal treatment of BRONJ
are lacking. Long-term antibiotic therapy in combination with
minimal surgery for retrieving sequesters is considered to be
the backbone of the treatment [3–5, 18, 23]. In one of the
largest observational studies on BRONJ, a positive clinical
response to an antibiotic regimen directed to Actinomyces with
suppression of the main symptoms and progression of BRONJ
is reported in 90 % of the patients [5].
Conclusion
BRONJ is a bisphosphonate-induced Actinomyces
osteomyelitis of the jaw
The current literature review on bisphosphonate-related
osteonecrosis of the jaw (BRONJ) demonstrates:
1. The almost universal presence of Actinomyces with signs
of osteomyelitis within BRONJ lesions.
2. An almost identical histomorphology of BRONJ and
Actinomyces osteomyelitis in most studies, although
BRONJ lesions with necrosis without inflammation have
been reported.
3. The devolvement of BRONJ is almost universally pre-
ceded by an event causing a disruption of the normal oral
mucosa, in both animals as well as humans. This event
precedes the development of BRONJ usually by several
weeks to months.
4. Bisphosphonate-related osteonecrosis occurs exclusively
in those bones that are in close contact with the oral
mucosa (the mandible and the maxilla).
5. BRONJ lesions seem to have a favorable response on
long-term therapy with antibiotics active on Actinomyces.
These data strongly support but do not prove the hypothesis
that BRONJ should be considered as a bisphosphonate-
induced Actinomyces osteomyelitis of the jaw. As such, bis-
phosphonate exposure should be considered as the trigger that
permits colonizing Actinomyces species to become invasive
and cause osteomyelitis after disruption of the mucosal bar-
riers. The following pathogenesis thus seems plausible:
1. Actinomyces species are among the main colonizers of the
oral cavity. Actinomyces species normally seldom cause
invasive disease.
2. Treatment with bisphosphonates renders bone more sus-
ceptible to the development of Actinomyces osteomyelitis.
Theoretically, this has two possible reasons:
a. A not yet defined role of phosphorus or
bisphosphonates in the regulation of the virulence
and growth mode of Actinomyces species. This is
suggested by some not yet fully translated Russian
studies from the 1970s demonstrating a correlation
between the phosphorus content of the culture medi-
um and the induction of filamentous growth mode
with an enhanced secretion of exoproteins, such as
antibiotics, in Actinomyces species [28, 29].
b. Bisphosphonates render bones more susceptible for
osteomyelitis, either by their mode of action of
blocking the bone regeneration cycle, by some kind
of interference with bone immunity, for example, via
the mevalonate pathway, or by their effect on neovas-
cularization of the bone [4].
3. When the bones of the jaw are exposed to the Actinomyces
species of the mouth due to trauma or periodontal disease,
there will be a higher likelihood of developing osteomy-
elitis when the patient is exposed to bisphosphonates,
whereas no disease will develop when the patient has
not been exposed to bisphosphonates.
 Eur J Clin Microbiol Infect Dis

Thus, the question seems more whether bisphosphonates are
the missing link between Actinomyces colonization of the mouth,
periodontal damage, and the development of BRONJ as a form of
Actinomyces osteomyelitis than whether Actinomyces is the miss-
ing link between exposition to bisphosphonates and BRONJ.
Eras of future research
The data summarized in this review strongly support a
prominent role of Actinomyces in the pathogenesis of
BRONJ. Based on these data alone, it remains, however,
still possible that bisphosphonates induce initially sterile
osteonecrosis that is generally followed by colonization
and secondary infection of the bone. Given the potential
therapeutic consequences, the hypothesis of an etiological
role of Actinomyces in BRONJ is worthwhile to confirm
or negate via a series of experimental and clinical stud-
ies. Experimental studies could explore whether the si-
multaneous presence of bisphosphonate exposure and
Actinomyces species suffices to cause BRONJ-like lesions
in bones that are normally not exposed to mouth flora.
Clinical studies could prospectively explore whether
Actinomyces is present in all BRONJ lesions, and which
treatment strategy (surgery, antibiotics, or a combination
of both) should be preferred in the management of
BRONJ. A prospective international registry on BRONJ
and Actinomyces would be helpful in unraveling the
nature as well as the ideal therapy of BRONJ. A better
understanding of the pathogenesis of BRONJ may also
contribute to the development of safer agents for the
treatment of osteoporosis or malignant bone disease.

Summary: Actinomyces and Bisphosphonate-related osteonecrosis of the

jaw (BRONJ)

1. BRONJ is defined as necrotic bone in the maxillofacial region persisting for

more than 8 weeks in patients treated with bisphosphonates and in the
absence of a history of radiation therapy.

2. The risk for BRONJ is incremental with the duration and dose of
bisphosphonate exposure. The more potent intraveneous bisphosphonates
inherit a higher risk to develop BRONJ.

3. According to the Koch criteria that are used to establish a causal relation
between an infectious agent and a disease, BRONJ must be considered as
an Actinomyces osteomyelitis of the jaw:
1) Actinomyces with signs of osteomyelitis is almost universally present
within BRONJ lesions
2) In most studies, BRONJ and Actinomyces osteomyelitis have an
almost identical histo-morphology
3) The devolvement of BRONJ is almost universally preceded by an
event causing a disruption of the normal oral mucosa, both in animals
as in humans. This events precedes the development of BRONJ
usually by several weeks to months.
4) Bisphosphonate related osteonecrosis occurs exclusively in those
bones that are in close contact with the oral mucosae (the mandibular
and the maxilla).
5) BRONJ lesions seem to have a favourable response on long term
therapy with antibiotics active on Actinomyces.
Eur J Clin Microbiol Infect Dis
Conflict of interest All authors declare that they have no conflict of
interest.
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