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Oral Maxillofac Surg
DOI 10.1007/s10006-014-0452-7
CASE REPORT
Miksad et al. showed that a patient’s quality of life is dramat- All patients were informed about alternative treatment op-
ically reduced by BRONJ, adversely affecting a wide range of tion, but refused regular surgery and decided for atraumatic
oral health aspects and the overall quality of life [11]. tooth removal. All patients gave their written informed
Patients receiving BP should have dental and oral investi- consent.
gations before the therapy starts. They also should have reg-
ular dental and mucosal examinations during treatment. More-
over, invasive dental surgery should be avoided, if possible [4, Cases
7]. Generally, tooth extraction, dental implants, apical surgery,
and periodontal surgery with injuries to the bone are risk Case 1
factors for the development of BRONJ [4, 7, 9, 12, 13]. Some
reports state that after such procedures the incidence of A 61-year-old female patient with non-restorable teeth in the
BRONJ increases more than sevenfold [9, 14]. Statistically lower jaw (first and second lower incisors: 31, 41, 32, 42) was
significant risk factors are the duration of BP exposure, the sent to our department in January 2011. Because of a Pancoast
number of BP infusions, the use of zoledronate, advanced age, tumor in her left lung, she underwent radiotherapy with 50 Gy
and dental extraction [7, 13, 15–17]. in 2007 and chemotherapy with cisplatin and vinorelbine. An
Dental extractions are still the major risk factor for the erlotinib therapy followed and was altered to pemetrexed by
development of BRONJ. Regarding BRONJ prevalence, the beginning of 2011. From April 2008 to September 2010, the
figures range from 41.1 to 63.7 % according to literature patient received zoledronate intravenously every 4 weeks.
[18–20]. After extraction, compromised wound healing oc- In February, the first and second teeth of both sides in the
curs. It is suspected that some BPs, like zoledronic acid, may lower jaw were moderately mobile, and signs of bone loss
have additional antiangiogenic effects that also impair wound were evident in the panoramic radiographs (Fig. 1). No per-
healing [4, 21, 22]. cussion pain was clinically manifested.
Oral prophylaxis helps to reduce the risk of extractions Because of the oncological need for continued chemother-
during BP treatment but fails to avoid the need for extractions apy and the risk of BRONJ with extraction under these cir-
entirely. Therefore, an atraumatic or low-risk method for cumstances, the patient opted for the atraumatic extraction
extractions is highly desirable [23]. method. The patient was informed about conventional extrac-
Regev et al. were the first to describe an atraumatic extrac- tions, the consecutive risk of BRONJ, and the atraumatic
tion method with elastics in 2008, intending to provide an technique as an alternative method.
alternative technique to traumatic tooth extraction and thus The indication for atraumatic teeth extraction was the need
minimizing the risk of BRONJ, although anecdotal reports of for continued chemotherapy and BP treatment for oncological
this technique show its use in hemophiliacs prior to modern reasons and the patient’s refusal to have conventional
treatments. The authors reported on ten patients who had a extractions.
total of 21 teeth or roots removed by controlled parodontitis In February 2011, orthodontic elastics were applied. At
with orthodontic elastics. None of the patients developed 4 weeks later, progress in tooth mobility was observed. There-
exposed bone after tooth removal [24]. The method of fore, a splint was made to hold the teeth in place during the
atraumatic extraction with elastics has been the subject of night. The first tooth (lower second incisor left, 32) exfoliated
discussion for a number of years now, but detailed information in April and the second (lower first incisor left, 31) in May
concerning indications and limitations is still scarce [25]. In an (Fig. 2a). The patient received a prosthodontic appliance for
attempt to shed new light on the issue, we present an overview
of literature to date with the addition of three case histories
from our department.
Fig. 2 a Intraoral situation of case 1 after exfoliation of the lower first patients and some protection against uncontrolled mobility of the lower
and second incisors left (31, 32). The elastics are visible at the first and first and second incisor right (41, 42). c Local radiograph showing
second incisor right (41, 42) with moderate sign of gingival infection. b continued bone loss. Exfoliation did not follow as soon as predicted by
Intraoral findings with a denture in situ, giving esthetic comfort to the this radiograph
Table 1 Patient characteristics of tooth, time until exfoliation and BP and chemotherapies
Case1 Lower first incisor left (31) 3.5 Zoledronate (29 months); paused 5 months before Pemetrexed
Lower second incisor left (32) 1.9
Lower first incisor right (41) 11.5 Restarted after 9 months (after exfoliation of 31, 32)
Lower second incisor right (42) 11.3
Case 2 Lower canine right (43) 3.6 Zoledronate (21 months) Goserelin acetate
Lower first premolar right (44) 4.8 Paused 10 months before
Case 3 None – Zoledronate (39 months) Trastuzumab, vinorelbine
Median time until exfoliation 4.2 months Range 1.9–11.5 months
Fig. 4 a Oral clinical appearance of a 76-year-old patient with prostate prosthesis was not possible. b Panoramic radiograph (cone beam recon-
cancer (case 2). Exposed bone (BRONJ stage 2) with moderate purulent struction) of case 2 showing a sequestrum at the left lower jaw and close
discharge on the right at the second premolar region and left at the first to the first premolar right. Clinically exposed bone was visible at these
premolar region. The remaining teeth were mobile and insertion of the sides with moderate infection signs (BRONJ stage 2)
Oral Maxillofac Surg
Fig. 5 a Oral situation after exfoliation of the lower two remaining teeth. effect of chlorhexidine rinses. b Panoramic radiograph after removal of
Closed tissues at the original tooth side (Fig. 4a). Stable BRONJ lesion the lower teeth shows stability of the sequesterious regions (Fig. 4b)
stage II with moderate infection. Black-colored exposed bone as a side
exacerbation of the infection or progressive pain ensured. The and functionally sufficient in case 1 after tooth removal
sulci were rinsed with physiological saline solution during (Figs. 2b and 3b).
each visit to clean the gingival pockets and to control paro- The mean follow-up time was 7.4±0.2 months after the last
dontitis. A 0.12 % chlorhexidine rinse followed. After com- exfoliation. No signs of exposed or palpable bone were ob-
pletion of the process of exfoliation, a follow-up period with served at the sites of successful atraumatic extraction.
regular check-ups followed.
Discussion
Results
In many cases, the precipitating events for BRONJ are dental
A total of 6 teeth were removed by atraumatic extraction in a extractions or other invasive dental procedures [6, 24, 26].
median time of 4.2 months, ranging from 1.9 to 11.5 months Yoneda et al. recommend avoiding invasive dental treatments
(26.2 weeks; range 8.3 to 49.3 weeks). Table 1 presents in patients with BRONJ because these therapies increased the
detailed information about each patient. Immediately after risk of developing exposed and necrotic bone [9].
exfoliation, the gingival tissue was swollen, but swelling
was reduced promptly (Figs. 3a and 5a). Is the main risk extraction?
In case 1, the first two teeth exfoliated after 3.5 and
1.9 months, respectively. The next two teeth exfoliated after In 20 BRONJ cases discussed by Bagan et al., 11 (55 %) of
11.3 and 11.5 months, a process possibly delayed by BP them occurred after tooth extractions [12]. A nationwide
administration. Chemotherapy continued throughout the ex- survey of Japan identified 41.1 % of BRONJ cases to have
traction period. Local control of periodontitis was sufficient in been caused by extractions [18]. Vescovi et al. reported on an
cases 1 and 2. Clinical examination of case 3 showed no signs Italian multicenter study. Extractions were the cause in 63.7 %
of aggressive infection, but intolerable local pain put an end to [13]. Otto et al. addressed 75.8 %, most of them (92.8 %) with
the method in this case. Prosthetic dentistry was esthetically intravenous BP [16]. In a prospective study regarding BRONJ
consisting mostly of multiple myeloma patients, 77 % of the
cases were linked to extractions [19].
Initial healing of dental wounds (re-epithelization) after
dental extractions as a rule takes between 1 and 2 weeks. After
clot forming, fibrin and connective tissue fills the cavity
before the epithelial wound healing is completed. Therefore,
a primary adaption of the gingival wound edges is recom-
mended [4, 17]. Usually, it takes some weeks for the under-
lying socket to fill with bone until complete healing [17]. To
complicate matters, accumulation of BP may make alveolar
bone sclerotic and thereby make extraction more difficult and
traumatic, resulting in larger wounds that consequently re-
quire a longer healing time [9]. An animal model showed
Fig. 6 Panoramic radiograph (cone beam reconstruction) of a 51-year- delayed dental healing after extractions in rats exposed to
old patient with breast cancer (case 3). Persistent socket of the first right
premolar tooth. This side showed exposed bone. First and second incisors
zoledronic acid and dexamethasone [27]. In another animal
left were painful and moderately mobile. Later, the patient developed model introduced by Allen et al., beagle dogs were treated
exposed bone between the first lower incisors with zoledronic acid. The alveolar cortical bone adjacent to
Oral Maxillofac Surg
the extraction socket was analyzed after 8 weeks. The dogs 7408) and on an oral epithelial cell line (OKF/6) in vitro and
treated with zoledronic acid showed compromised osseous found an impediment of oral wound healing by blocked
healing of the dental extraction sites and in one case even a growth and migration capacity of oral fibroblasts and a dis-
sequestrum. This sequestrum had morphological and histo- turbed re-epithelialization [31]. In other in vitro experiments,
logical similarities with BRONJ sequester [21]. Kobayashi Cozin et al. found similar results [32].
et al. examined the effects of zoledronate on wound healing Chemotherapies causing mucositis are co-risk factor for
after extractions in a mouse model. Animals treated with BRONJ [4, 7, 9]. Drugs named in this context are cyclophos-
zoledronate showed a significantly decreased amount of new phamide and thalidomide [4, 9]. The jaw bones are covered
bone and a diminished number of blood vessels in the sockets with a thin mucosa and damage (e.g., oral mucositis) may
compared to those of the control group [28]. easily cause infection of the underlying jaw bones by oral flora
Preventive protocols for extractions are a valuable help to [7, 9]. Oral mucositis is one of the most common side effects
reduce the risk of BRONJ. Lodi et al. performed 38 extrac- of chemotherapy [33–35]. Cheng et al. estimated the inci-
tions in 23 patients treated with intravenous BPs. Their ex- dence of non-severe mucositis to be 23 %, with severe cases
traction protocol included professional oral hygiene before to be around 18 % [34]. Nishimura et al. observed oral
extraction, a full-thickness mucoperiosteal flap closure of the mucositis as a side effect of chemotherapy in up to 76.5 %
extraction site, a debridement of the socket, and antibiotics for [36]. The overall range of oral mucositis lies between 10 and
20 days after extraction. The follow-up showed no cases of 75 % for chemotherapy patients depending on the primary
BRONJ [25]. Ferlito et al. described a similar protocol with disease and the chemotherapy used [35]. Many novel antitu-
102 extractions and 43 patients with zoledronate treatment. mor drugs have been introduced in recent years. Their
Antibiotics were applied intramuscularly (amoxicillin plus side effects differ from those of previous drugs, and their
clavulanate) for 2 days before and 5 days after extraction with adverse effects are sometimes highly specific, particularly
curettage, removal of adjacent alveolar bone, soft tissue clo- with respect to the skin. These cutaneous adverse effects
sure, and antimicrobial mouth rinses. In a follow-up of are the most commonly observed adverse effects of these
12 months, no case of BRONJ was reported [23]. These new antitumor drugs. They are described in up to 34 % of
authors gave no information concerning BP therapy pauses, patients receiving multikinase inhibitors, in up to 90 % of
running chemotherapies, or other co-risk factors but described those receiving selective tyrosine kinase inhibitors, and in
complex protocols concerning antibiotics and mouth rinses. up to 68 % of those receiving immunotherapeutic agents
The good results of both studies with no BRONJ cases might [37]. These cutaneous adverse effects can affect the oral
be due to the absence of co-risk factors mentioned earlier. In mucosa, resulting in exposed bone. Estilo et al. reported
contrast, a prospective study of 60 high-risk patients with on a case of a patient with breast cancer who developed
nitrogen-containing BPs and a total of 185 teeth extracted painful exposed bone after treatment with bevacizumab
found 8 % of BRONJ in the follow-up. This study protocol and capecitabine [38]. Suwattee described painful erosions
included osteoplasty, tension-free soft tissue closure, and a 7- of the buccal mucosa and lips in a patient with sunitinib
day cycle of antibiotics (amoxicillin plus clavulanic and met- treatment [39]. Sunitinib in combination with BP was
ronidazole). The BP treatment was also discontinued for recently linked to BRONJ [22, 40].
1 month [29]. These reports on exposed bone caused by chemo-
therapeutical medications support the findings considering
Co-risk factors for BRONJ compromised wound healing following extractions with these
patients. Patients with continued chemotherapy treatment are in
The pathophysiology of BRONJ may be multifactorial, in- all probability exposed to a higher risk of BRONJ with a yet
volving factors like suppressed angiogenesis, altered mucosal unknown added risk if BPs are continued. Urade et al. reported
cells, microbial flora, anti-inflammatory effects, and genetic that 9 % of their patients with BRONJ could be brought in
predisposition [15]. Some theories try to explain that the lack connection with oral BPs and the same applied to 81 % who
of epithelial repair of intraoral exposed bone, secondary to the received intravenous BPs plus anticancer drugs [18].
use of BPs, is attributable to the toxicity of BPs to the epithe- Discontinuing BP administration prior to dental treat-
lial tissue. This could be caused by the high concentration of ment is a controversial issue. BP remains bound to bone
those drugs in the jaw [6, 7]. Kim et al. studied the effect of for almost 10 years. There is no concrete evidence which
pamidronate on human oral keratinocytes and fibroblasts show that discontinuing BP reduces the incidence of BRONJ,
in vitro. The keratinocytes expressed senescence-associated nor does continued BP therapy impair BRONJ healing [9].
enzymes and interleukins, and the fibroblasts underwent apo- Nevertheless, BP should be discontinued 2 to 3 months prior
ptosis. The authors concluded that these mechanisms impaired to dental surgical treatment [4, 9], a period of time that might
re-epithelialization of the oral mucosa [30]. Ravosa et al. not, however, be realistic for oncological patients at an ad-
analyzed the effect of zoledronic acid on fibroblast (CRL- vanced stage.
Oral Maxillofac Surg
Periodontitis, a risk factor for BRONJ? Technical details and time until exfoliation
Parodontal disease is an infection caused by oral bacterial Regev et al. recommended separating multiple divergent roots
infiltration into the periodontal pockets between the teeth by placing elastics on every single root [24]. Our patients had
and the gingiva. It initiates with gingivitis and finally spreads only mono-radicular teeth, and separating divergent roots was
to the entire periodontal tissue, causing periodontitis. Inflam- therefore not necessary.
matory conditions such as periodontal diseases and periodon- Unlike Regev et al. [24], we were unable to observe any
tal abscesses can be risk factors for BRONJ [9]. The extent to “autosliding” from the larger cervical circumference towards
which periodontal disease is a common co-morbidity of the lesser apical perimeter of the root. This was mostly due to
BRONJ remains uncertain; nevertheless, it can be observed the formation of concretions in the sulcus (Fig. 7a, b). The
in the majority of BRONJ cases [41]. Up to 79 to 84 % of all elastics had to be moved forward by moderate force with a
BRONJ patients suffer from periodontal diseases [15, 42]. Heidemann spatula.
The presence of periodontal disease may necessitate invasive The biological process in connection with elastics involves
periodontal procedures or dental extraction and hence increase tissue reactions in the periodontal ligament. The physical
the risk of BRONJ [15]. pressure pushes the root out of its socket. The forces are not
Aghaloo et al. introduced a periodontal disease- sufficient to have a direct impact on the bone structure, but
triggered osteonecrosis model in rats. They caused an they are forceful enough to cause destruction of the periodon-
aggressive periodontal disease by ligature placements tal ligament. By applying only moderate force, exposure of
around crowns, applying zoledronate at the same time. the bone could be avoided. More importantly, the elastics
Up to 32 % of the group treated with zoledronate devel- cause an inflammatory reaction in the tissue, impairing the
oped sequestrum formation as opposed to 5 % of the attached tissues. The granulation tissue formed around the
control group. Histologically, manifest osteonecrosis in infection pushes out the root, while it covers potentially ex-
the zoledronate treated group was 47 % as opposed to posed bone at the same time [24].
5 % in the control group. No mouth rinses were used. Another question still remains unanswered. What is the
The fairly aggressive approach to induce parodontitis reason for bone loss under BP medication?
could be the reason for the high incidence of osteonecrosis In literature, some reports discussed the potentially benefi-
[41]. In contrast, Regev et al., and in our study, placed the cial effects of BP on periodontal diseases. Administration of
wire ligatures around the complete crown of the first systemic and topical BP reduced alveolar bone loss in the
molar. First rat molars have up to five divergent roots. majority of animal models in experimentally induced and
The ligature was supposed to damage the interradicular natural parodontitis, but without significantly affecting clini-
bone and cause BRONJ-like results. Until proven other- cal periodontal parameters [15, 44]. In contrast, clinical stud-
wise, every case of parodontitis has to be seen as a risk for the ies of humans failed to confirm these findings. No alveolar
development of BRONJ. Vescovi et al. reported BRONJ cases
caused by severe parodontitis in 2 % [13]. Regev et al. could
not see any BRONJ [24]. We did not observe any additional
cases of BRONJ in the course of our study. We managed to
control the severity of gingivitis and parodontitis by regular
brushing of the teeth and chlorhexidine mouthwashes. Chlor-
hexidine (0.12-0.2 %) significantly reduced oral inflammation
and oral ulceration associated with oral mucositis in patients
undergoing intensive chemotherapy [33]. Additionally, mouth
rinses with green tea were recommended. Mouth rinses with
green tea are willingly accepted by most patients and have
been shown to have tissue-protective and anti-inflammatory
qualities. Its components, for example, catechin, inhibit peri-
odontal pathogens, inhibit the production of toxic metabolites
of some microorganisms and also have some antioxidative
activities [43]. The patient in case 3 received antibiotics to
control the pain caused by elastics and the patient in case 2 to
control BRONJ. The patient in case 1 was able to control the
Fig. 7 a The first lower incisor of case 1 with the elastics still in place.
inflammation solely by using the methods mentioned earlier. The elastics were fixed with concretions. b The lower second incisor after
Additional therapies with antibiotics were not necessary in exfoliation. Concretions apical to the elastic prevent the elastics from
this latter case. “autosliding” to the apex. The elastics had to be re-placed forward
Oral Maxillofac Surg
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