Oral Oncology 48 (2012) 817821

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Oral Oncology
journal homepage: www.elsevier.com/locate/oraloncology

Tooth extraction in patients on zoledronic acid therapy

Marco Mozzati, Valentina Arata, Giorgia Gallesio
Department of Clinical Physiopathology, Oral Surgery Unit, Dentistry Section, University of Turin, Turin 10126, Italy
Department of Biomedical Sciences and Human Oncology, Dentistry Section, University of Turin, Turin 10126, Italy

a r t i c l e i n f o s u m m a r y

Article history: Objectives: Surgical management of patients following zoledronic acid therapy is particularly difcult,
Received 31 January 2012 since the dental extraction is the main cause of BRONJ.
Received in revised form 12 March 2012 Methods: A case-control study was conducted on 176 patients treated with intravenous (IV) bisphospho-
Accepted 13 March 2012
nates for oncologic pathologies who also underwent dental extractions. The study was divided randomly
Available online 5 April 2012
into two groups: 91 were treated with Plasma Rich in Growth Factor Plasma (PRGF) (study group) and the
other 85 were not treated with the growth factor preparation (control group).
Keywords:
Results: Panoramic X-ray and computed tomography were performed both before and 60 months after
Acid zoledronic
Bisphosphonates
surgery. By clinical and radiological diagnosis, BRONJ was diagnosed in only 5 patients in the control
BRONJ group at an average of 91, 6 days after tooth extraction.
Tooth extraction Conclusions: We hypothesize that Plasma Rich in Growth Factor (PRGF) is important for the successful
PRGF treatment of patients on bisphosphonates to restore the osteoblast/osteoclast homeostatic cycles via
Bone healing autologous cytokines. Moreover, this protocol reduces the risk of BRONJ when it is necessary to perform
Socket healing dental extractions in patients undergoing IV bisphosphonate treatment.
Wound healing 2012 Elsevier Ltd. All rights reserved.

Introduction Conversely, an associated inhibition of osteoclastic activity has also

Osteonecrosis of the Jaw (ONJ) has been associated with the use
of bisphosphonates. BRONJ (Bisphosphonate-Related Osteonecro-
sis of the Jaw) is dened as a necrotic bone area with or without
an area of exposed avascular necrotic bone in the maxillofacial re-
gion. BRONJ is usually associated with bone that has been exposed
for at least 8 weeks, in a patient who received and/or is receiving
bisphosphonates, with no previous history of irradiation to the
maxillofacial region.1 Over the past few years, the number of ONJ
cases associated with intravenously administered bisphosphonate
treatment has risen, in particular among oncology patients with
bone metastasis.2
Although Marx,3 rst reported in 2003 that bone necrosis might
be a side effect of the use of zoledronate or pamidronate, the
underlying pathophysiology of bisphosphonate-associated osteo-
necrosis of the jaw is still an issue of debate in international liter-
ature, which reports several theories and an exhaustive list of
proposed mechanisms. Ruggiero et al.4 have reported that the eti-
ology of bone osteonecrosis is related to an excess of osteoclast
activity, resulting in an alteration of normal bone turnover.5
Corresponding author. Address: Department of Biomedical Sciences and Human
Oncology, Dentistry Section, UNITO LINGOTTO DENTAL INSTITUTE c/o Lingotto, Via
Nizza 230, Turin 10126, Italy. Fax: +39 0116331503.
E-mail addresses: marco.mozzati@libero.it (M. Mozzati), arata.valentina@libero.
it (V. Arata), giorgiagallesio@libero.it (G. Gallesio).
been reported.6,7
However, these hypotheses do not justify the onset of BRONJ
exclusively in the jaw. It is also hypothesized that bisphosphonates
trigger osteonecrosis by inhibiting angiogenesis, which is essential
for the healing process of a fresh extraction socket.810 This
hypothesis was further supported by Fournier et al. in 2002 via
an in vitro and in vivo study that documented how bisphospho-
nates reduced endothelial cell proliferation by inducing apoptosis,
which consequently resulted in lower vessel densities due to a
reduction in the formation of new capillaries.11 The literature also
reports a possible connection between osteonecrosis of the jaw
and the toxic effects of bisphosphonates on the oral mucosa.12
The toxic effects of bisphosphonates on gastric mucous have also
been established.13,14 Indeed, a study carried out in 2008 docu-
mented how pamidronate suppressed cell proliferation, leading
to the inhibition of oral wound healing.15 Most of the BRONJ cases
reported in literature show a strong correlation with dental extrac-
tions and/or oral surgical procedures (69% cases).1618
This is why management protocols of these patients now tend
to be preventive approaches. Such prevention and treatment strat-
egies include the elimination of any potential infection sites in pa-
tients who are treated with IV bisphosphonates, in an effort to
guarantee sufcient oral health status and to reduce the risk of
BRONJ related to dental pathologies and/or prospective oral
surgical procedures.7,19

1368-8375/$ - see front matter 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.oraloncology.2012.03.009
818 M. Mozzati et al. / Oral Oncology 48 (2012) 817821

Despite growing evidence of the risks of surgery in patients Table 1

treated with IV bisphosphonates, the necessity to remove strongly Dental extractions performed in a group of patients receiving zoledronic acid.

compromised dental elements does arise. Therefore, the need to Tooth pathology Study group Control group
identify treatment protocols that can reduce the incidence of this (dental elements (dental elements
newly recognized oral syndrome is ever more pressing. extracted) extracted)

Consequently, surgical protocols that favor both bone and Residual roots 75 92
mucosal healing processes while concurrently limiting surgical Semi-impacted third molars 8 11
with pericoronitis
damage to minimum levels must be researched and adopted for Root fracture 11 17
patients who are treated with IV bisphosphonates. A 2 to 3 grade mobility 67 75
In the present study, preparations rich in growth factors were Destructive tooth decay 47 51
used as a means of biotechnological support to accelerate post- involving the roots
Apical granuloma (untreatable 67 21
extraction alveolar bone regeneration.20 Among these preparations
by any means other than
rich in growth factors, in literature we can nd Platelet Rich Plasma extraction)
(PRP)21 and Plasma Rich in Growth Factors (PRGF). In this study we
considered PRGF, in fact, the hypothesized efcacy of using it to
support surgical dental procedures in patients on IV bisphospho-
nates is based on the contribution PRGF makes in accelerating Table 2
the healing process where these drugs have been a source of inhi- Principal patient characteristics included in the study.
bition.22 The growth factors in PRGF, which are usually inhibited by Study group Control group
bisphosphonates, are a supplementary source of stimulation to the (number) (number)
physiological decit, and they promote angiogenesis as well as Gender Males 36 39
bone and mucosal wound healing.23 Females 55 46
The aim of the study is to conrm PRGF effectiveness in the Teeth extracted Mandible 142 145
treatment of patients following a zoledronic acid therapy who Maxilla 133 122
need dental extractions. Age 4460 22 27
6070 43 36
7083 26 22
Materials and methods Smoking habit No 76 64
<15/die 11 15
The study was carried out in the Oral Surgery Department of the >15/die 4 6

Dental School of the University of Torino, Italy, from January 2005 Systemic pathology Prostatic 33 27
to December 2009. carcinoma
Breast 17 34
The study design was reviewed by a senior specialists about the Carcinoma
treatment of patients who take IV bisphosphonate therapy. Multiple 36 21
176 patients (75 males and 101 females), with ages ranging myeloma
from 44 to 83 years, were included in this study. Lung 3 2
Carcinoma
At the time of the rst visit, patients were included in a comput-
Ovarian 2 1
erized clinical le, which also recorded information on age, gender, Carcinoma
smoking habits, systemic pathology and use of any drugs were also
Other medications (at the Steroids 47 58
detailed. In particular, we asked if they were taking steroids or they time of the study) Chemotherapy 21 15
were undergoing chemotherapy.
Inclusion criteria were (1) current IV bisphosphonate therapy
and (2) the necessity for removal of strongly compromised dental
elements (Table 1). Exclusion criteria included (1) any previous A professional oral hygiene session was given to each patient
history of irradiation to the maxillofacial area and (2) dental one week before surgery. All patients were administered the anti-
extractions before the study period. The local ethics committee ap- biotics amoxicillin/clavulanate potassium, at a dosage of 1-g tablet
proved the clinical protocol used for the study, and all enrolled every 8 h for a total of 6 days, starting from the evening before the
study patients provided written informed consent. The patients surgical appointment or erythromycin, at a dosage of 600-mg tab-
had been prescribed IV bisphosphonates for oncological patholo- lets every 8 h for 6 days, when an allergy to penicillin was declared.
gies, which included breast carcinomas, prostatic carcinomas, A 15 ml blood sample was drawn from the peripheral veins of
ovarian carcinomas, lung carcinoma and multiple myeloma the 91 patients in the study group before surgery. The sample
(Table 2). was centrifuged into 5 mL blood-collecting tubes with anticoagu-
All patients were taking zoledronic acid. Patients on zoledronic lants at 580 g for 8 min at 1800 rpm in an appropriate system
acid preparations had a 4-mg infusion every 21 days. (PRGF System, Biotechnology Institute [BTI], Vitoria, Spain). Two
The surgical protocol involved a delicate surgery and closure by main fractions were obtained: (1) red blood cells at the bottom
rst intention. The study cohort was divided into two similar of the test tube and (2) the uppermost plasma fractions from above
groups: 91 patients were treated with PRGF (study group) and 85 the red blood cells. The plasma fraction was divided into 2 parts
patients were not treated with the growth factor preparation (con- with disposable sterile pipettes, PRGF and autologous brin mem-
trol group). The randomized group distribution was set up specif- brane, which were activated with 50 ll of calcium chloride (CaCl2
ically to obtain groups that were homogenous for gender, age, for each millimeter of PRGF) and introduced into the post-extrac-
smoking habits, systemic pathology based on the computerized tion alveolus.
clinical le we used in the rst visit. A total of 542 extractions were An alveolar troncular nerve block was administered to both
necessary: 287 in the mandible and 255 in the maxilla (Table 1). groups via local or regional anesthesia (3% mepivacaine with
The surgical protocol included investigative radiology: ortho- 1:100,000 epinephrine), depending on the dental site. To prevent
pantomography and CT (Fig. 1). Scans were done to evaluate the interference with the healing process, no intraligamentous or
extraction sites preoperatively and six months postoperatively. intrapapillary inltrations were made. Surgical extractions were
 M. Mozzati et al. / Oral Oncology 48 (2012) 817821
Figure 1 Panoramic lm revealing severe generalized dental caries and retained
roots in a patient with multiple myeloma, in therapy with zoledronic acid. Because
of several episodes of infection in the right mandibular quadrant and the mobility of
teeth 28 and 29, surgeons decided to extract teeth 28, 29, and 30.
Figure 2 Clinical view of the same patient. The dental extraction was followed by
delicate curettage and osteoplastic procedures on the most fragile bone septum and
cortical bone areas.
carried out via intrasulcular incisions and detachment of full thick-
ness aps to allow wound healing via primary intention to leave
the post-extraction alveolus in contact with the oral cavity bacte-
ria. To ensure nontraumatic avulsion, the dental extraction was fol-
lowed by delicate curettage and osteoplastic procedures on the
more fragile bone septum and cortical bone areas (Fig. 2).
Lastly, the patients in the study group were treated with a PRGF
fraction inserted into the alveolus. A membrane comprised of a
plasma fraction poor in growth factors was then placed between
the bone tissue and the mucosal ap to promote healing (Fig. 3).
Conversely, no material was placed into the post-extraction alveo-
lus in the control group, where coagulation and stabilization took
place. Suturing was done in all cases with resorbable material
(Vycril 4/0, Ethicon, Inc., Somerville, New Jersey, US) using a sim-
ple detached technique ensuring a hermetic closure at the wound
margins to enable healing via primary intention (Fig. 4). Written
oral hygiene and postoperative instructions were then given to
all of the patients.
Clinically programmed monitoring of mucosal healing was car-
ried out at 3, 7, and 14 days postoperatively, when suturing was re-
moved. Monitoring was continued at 21, 30, 60, 90 and 120 days.
The patients were always examined by evaluating the clinical signs
of BRONJ that were mentioned above: pain, swelling, non-healing,
819
Figure 3 Bone surface was covered with PRGF fraction. A membrane made up of a
plasma fraction poor in growth factors was placed between the bone tissue and the
mucosal ap, to promote healing processes.
Figure 4 Suturing was done in all cases using a simple detached technique ensuring
a hermetic closure at the wound margins to enable healing via primary intention.
exposed necrotic bone, and/or stulas with connection to the bone.
The absence of these clinical signs was determined to indicate suc-
cessful treatment.
Radiographic control was carried out 6 months after surgery by
orthopantomography and CT scans (Fig. 5).24
Subsequently, the follow-up protocol included 6 monthly
orthopantomography and concomitant professional hygiene ses-
sions, followed by annual CT scans. The study group had a total fol-
low-up period of 2460 months.
Results
No intraoperative complications were observed in either of the
two groups. There was no evidence of postoperative bisphospho-
nate-associated osteonecrosis of the jaw in any of the extractions
in the study group at the time of follow up (542 extractions). Five
(out of 267 extractions) early symptomatic osteonecrotic lesions
with diameters <0.5 cm of exposed mandibular bone were diag-
nosed in the control group. The average period of BRONJ occur-
rence was 91.6 days postoperative, and it was diagnosed at the
clinical evaluation and radiographic control examinations using
standards proposed in the literature.2,24 All patients who showed
820 M. Mozzati et al. / Oral Oncology 48 (2012) 817821
Figure 5 Ct scan at 1 year shows no evidence of postoperative bisphosphonate-associated osteonecrosis of the jaw and conrms that use of PRGF may enhance regeneration
of osseous and epithelial tissues.
these osteonecrotic lesions had multiple myeloma, and they were
all taking zoledronic acid (more than 12 months). Moreover, at
the time of BRONJ diagnosis, the ve patients had not yet com-
pleted their chemotherapy cycles with Vincristine. All ve BRONJs
were surgically treated: during bone excision surgery PRGF was
used with excellent success.36
Discussion
Bisphosphonate compounds have the capacity to reduce sec-
ondary skeletal-related events (SREs) due to bone metastasis from
solid tumors and myelomas. As such, they are increasingly incor-
porated in the treatment of oncologic pathologies, with the aim
of improving patient quality of life. Investigators rst reported an
apparent association between bisphosphonate use and the oral
syndrome of osteonecrosis of the jaw in oncologic patients in
2003.25 The American Association of Oral and Maxillofacial
Surgeons (AAOMS) report a 0.812% incidence of BRONJ in patients
on IV bisphosphonate therapy, which is frequently associated with
dental extractions and/or oral surgery procedures.19,26
Such publications gave rise to the development of prevention-
oriented management protocols. These protocols include establish-
ing as good a health status as possible under the circumstances for
all patients before administration of these drugs, as is common
practice for those scheduled to receive irradiation of the head
and neck areas. The literature on the implementation of these den-
tal preventive measures reports a decrease in the occurrence of
osteonecrosis of the jaw in solid tumor patients with bone metas-
tasis treated with bisphosphonates.27 However, despite these ef-
forts, there are clinical situations in which surgical intervention
in these patients cannot be avoided.
The protocols proposed in the literature for such cases recom-
mend a conservative approach associated with antibiotic prophy-
laxis and a debridement cleaning with chlorhexidine. Some
authors recommend a 20-day period of antibiotics and chlorhexi-
dine cleansing, twice daily for a two-month postoperative period.28
However, to the best of our knowledge, there has been no protocol
proposed to date for tooth extractions in patients on IV bisphosph-
onate treatment. Therefore, this study was developed to meet the
demand for such a protocol in an attempt to enhance healing
and reduce the risk of BRONJ. The use of preparations rich in
growth factors was investigated to address this issue.
Bisphosphonates accumulate in the mineralized matrices of bone
and are taken up by osteoclasts, leading to an inhibition of
osteoclast activity that compromises the physiological activity of
bone remodeling and deposition.29 Moreover, as demonstrated
by Landesberg et al.,15 bisphosphonates also inhibit the prolifera-
tion of oral mucosal cells and, consequently, hinder the healing
processes. These results have recently been conrmed by
Kobayashi et al. 30 using an animal model. The authors demon-
strated that zoledronic acid reduced the migration of epithelial
cells, which had a negative effect on the healing process of the
post-extraction alveolus. Delaying the re-epithelization process
seems to prolong alveolus exposure to the oral cavity bacteria,
increasing the risk of BRONJ.31
In 2009, Hikita et al.32 analyzed the effect of bisphosphonates
on the post-extraction alveolus healing process in rats. The histo-
logical and morphometric data demonstrated that inhibiting osteo-
clast activity delayed the post-extraction alveolus healing
processes when treated with bisphosphonates when compared to
untreated rats. The rst 7 postoperative days seem to be the most
critical for the onset of inammatory processes that may inhibit
healing processes and induce osteonecrosis. Not only does the
use of compounds rich in growth factors seem to reduce these
untoward events, it also appears to enhance hemostatic action
and accelerate epithelial closure. Indeed, Anitua et al. demon-
strated in that epithelization was accelerated in post-extraction
sites treated with PRGF and that the trabecular bone thus obtained
was more organized than that of untreated post-extraction sites.33
These results demonstrated that lling the post-extraction alveolus
with PRGF offers clear advantages in the early healing phases,
improving hemostasis and protecting the alveolus during the early
stages to promote epithelization.34 The rapid epithelization
 M. Mozzati et al. / Oral Oncology 48 (2012) 817821
triggered by the potent mitogens vascular endothelial growth fac-
tor (VEGF) and platelet-derived growth factor (PDGF) (versus
endothelial and osteoblastic cells) protects the alveolus in the early
healing stages, reducing the risk of infection and the onset of
BRONJ. All of these benets indicate that the use of platelet-rich
compounds may provide support in both single and multiple
extractions, especially in cases associated with the need to stimu-
late the healing process.
The study reported here in conrms the aforementioned data
with a 100% success rate for the surgical treatment of patients on
IV bisphosphonate treatment (study group). Conversely, ve pa-
tients in the untreated control group had BRONJ in the mandible.
All these patients had multiple myeloma. They were taking zoled-
ronic acid more than 12 months and have been undergoing active
chemotherapy with Vincristine at the time of the study (Table 2).
According to another study of ours, the 5 BRONJ were surgically
treated: during bone excision surgery PRGF was used with excel-
lent success.35 Results seem to show how patients with multiple
myeloma have difcult management and healing and is better to
use PRGF with them.
Finally these results conrm a previous case-control study of
100 patients survey, that we recently published.36
Conclusions
In conclusion, our data on the use of compounds rich in growth
factors further enhance the results published in the international
literature. Therefore, we believe that the clinical protocol herein
reported is a valid proposal when dental extraction surgery is inev-
itable in patients on IV bisphosphonate treatment because the pro-
tocol may reduce healing times and it is a user-friendly technique
with a good cost-benet ratio.
Conict of interest statement
None declared.
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