journal of prosthodontic research 59 (2015) 3–5
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Letter to the editor
Osteonecrosis of the jaw in patients
with dental prostheses being treated
with bisphosphonates or denosumab
Keywords:
Medication-related osteonecrosis of
the jaw (MRONJ)
Bisphosphonate
Denosumab
Removable denture
Fixed partial denture
Dear Editor,
Bisphosphonates are used in the treatment of bone-resorbing
diseases such as osteoporosis, malignancy-related hypercal-
cemia, multiple myeloma, and bone metastasis from solid
cancers [1]. The treatment is administered orally for osteopo-
rosis, and by intravenous injection for cancer metastasis
cases. However, recent studies have reported instances of
bisphosphonate-related osteonecrosis of the jaw (BRONJ),
raising concerns for all dentists about this type of treatment.
Although the developmental mechanism of BRONJ is still not
fully understood, some studies have reported that BRONJ is
caused by (1) apoptosis of osteoclasts [2]; (2) disturbance of
osteoclast progenitor cell differentiation [2]; (3) disturbance of
osteoclast enzyme activity [3]; (4) destruction of bone
microstructure caused by drug deposition [4]; and (5) anti-
neovascularization [5]. Denosumab (Ranmark1), an IgG2
monoclonal antibody that binds to receptor activator of
nuclear factor-kB ligand (RANKL), is not a bisphosphonate-
related preparation, but some studies have reported compli-
cations of osteonecrosis of the jaw (ONJ) from denosumab [6].
Therefore, the ONJ has been recently termed medication-
related ONJ (MRONJ) [7]. Although specific guidelines have
been developed for treatment and prevention of ONJ [8], they
are limited to symptomatic treatment or infection prevention,
rather than fundamental prevention. According to the
guideline, one of the risk factors of ONJ is a history of
inflammatory dental disease [8]. The oral mucosal inflamma-
tion associated with ill-fitting dental prostheses is a common
clinical case for prosthodontists; however, information on the
occurrence of dental prosthesis-related ONJ is limited [9,10].
Indeed, no report has been found in the literature that
investigates the incidence of MRONJ by denosumab in relation
to dental prostheses. This gap in the literature prompted us to
perform a pilot clinical study investigating the relationship
between MRONJ and dental prostheses.
This study was approved by the Ethics Committee of the
School of Medicine, Keio University (Approval number:
20110018). Intended subjects were 424 patients (male: 125;
female: 299) with a mean age of 64.8 years who were seeking
treatment for dental problems at the Department of Dentistry
and Oral Surgery, Keio University Hospital from June 2013 to
May 2014. The subjects were already being treated with oral or
intravenous bisphosphonates, or denosumab.
To diagnose MRONJ, we applied the diagnostic criteria of
the American Association of Oral and Maxillofacial Surgeons
for definitive diagnosis of BRONJ [8]. A total of 21 cases of
MRONJ were detected in the subjects (5.0%: 21/424 subjects). It
should be noted that MRONJ was only found in subjects who
were intravenously treated with bisphosphonates or denosu-
mab (16.4%: 21/128 intravenous subjects). Among the 21
MRONJ cases, seven subjects were treated with zoledronic
acid-hydrate (Zometa1) only, two subjects were treated with
denosumab only, and 12 subjects had changed medication
from zoledronic acid-hydrate to denosumab before they
visited our dental clinic. Four cases of MRONJ were related
to post-extraction dental sockets, and we could not explain the
specific cause of MRONJ in nine cases in this study (Table 1).
To examine the association between wearing a dental
prosthesis and the occurrence of MRONJ, the 128 subjects who
were intravenously treated with bisphosphonates or denosu-
mab were separated into three groups: (1) no prosthesis
(n = 60), (2) removable denture (RD: n = 34), and (3) fixed partial
denture (FPD: n = 34). The incidence of MRONJ in the RD group
was 32.4% (11/34 subjects), which is significantly higher than
that in the no prosthesis group (8.3%: 5/60 subjects) (Table 1).
Among the 11 MRONJ cases in the RD group, seven subjects
had changed medication from zoledronic acid-hydrate to
denosumab before they visited our dental clinic. These
findings suggest that wearing an RD is a risk factor for MRONJ
in patients being treated with bisphosphonates or denosumab
intravenously. In the 11 RD-related MRONJ cases, the ONJ
lesions were all observed in the tissue under the RD in the
mandibular molar region. The fit of the RD was evaluated
using either pressure indicator paste or a polyaddition-type
silicone, and seven out of the 11 RD-related MRONJ cases
were found to have an ill-fitting denture (Table 1). A
4 journal of prosthodontic research 59 (2015) 3–5

Table 1 – Clinical profile of 128 subjects being treated with intravenous bisphosphonates or denosumab.
Dental prosthesis Subjects ONJ cases Clinical features of ONJ

With In extraction With severe Undetermined

ill-fitting RD socket periodontitis cause
No prosthesis 60 (45) 5 (5) – 1 (1) 0 4 (4)
RD 34## (18#) 11** (7*) 7 (5) 2 (1) 0 2 (1)
FPD 34 (21) 5y (2) – 1 (1) 1 3 (1)
Total 128 (84) 21 (14) 7 (5) 4 (3) 1 9 (6)
ONJ: osteonecrosis of the jaw, RD: removable denture, FPD: fixed partial denture. Parentheses indicate the number of patients who were
treated with denosumab only or those who had changed medication from zoledronic acid-hydrate to denosumab before they visited our dental
clinic. Six (##) or three (#) of these subjects had both RD and FPD. A statistically significant difference (**p < 0.01, *p < 0.05) between ONJ cases in
the RD group and the no prosthesis group, calculated with a Fisher’s exact test. yNote that all ONJ lesions in the FPD group (n = 5) were found
under the pontic.

Fig. 1 – (A) A 60-year-old Japanese female who changed medication from zoledronic acid hydrate (ZAH) to denosumab for
breast cancer. Osteonecrosis of the jaw (ONJ) was observed in the mandibular right molar region (left) under the ill-fitting
removable denture (right). (B) A 67-year-old Japanese female being treated with ZAH for breast cancer. ONJ was observed
under the pontic of the fixed partial denture associated with severe periodontitis in the maxillary first premolar region.

representative clinical case is shown in Fig. 1A. Interestingly,
we found five ONJ lesions in the tissue under the FPD pontic
(Table 1) in patients with breast cancer (two cases) and
multiple myeloma (three cases) as the primary disease. Two of
these MRONJ patients had changed medication from zole-
dronic acid-hydrate to denosumab before they visited our
dental clinic. The incidence of MRONJ in the FPD group was
14.7% (5/34 subjects). It should be noted that all ONJ lesions in
the FPD group were observed under the pontic. In one out of
the five cases, the ONJ lesion was associated with severe
periodontitis of the abutment tooth (Fig. 1B). Because dental
extractions and a history of inflammatory dental disease are
risk factors for BRONJ [8], denture use and recurrent lesions
caused by ill-fitting dentures could be responsible for the
occurrence of MRONJ in this study. Additionally, poor oral
hygiene is thought to be a risk factor for BRONJ [8]; therefore,
poor oral hygiene under the pontic may, in part, cause
infection of the underlying mucosa. The mechanism by which
MRONJ occurs in the region of the pontic is unclear; it would be
valuable to analyze the pontic shape, distance to the gingiva,
and dental hygiene in a future study. Future research should
focus on factors such as bone metabolism, dental plaque
retention, and mechanical trauma by the dental prosthesis to
clarify the association of dental prostheses with MRONJ.
In summary, this clinical survey showed that dental
prostheses, such as RDs and FPDs, are a possible risk factor
for MRONJ in patients being treated intravenously with
bisphosphonates or denosumab. However, the study popula-
tion was relatively small, and thus the result may be specific to
this study sample. Nevertheless, patients being treated with
bisphosphonates or denosumab who use dental prostheses,
not only RDs but also FPDs, should be encouraged to seek
regular dental follow-up.
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Kunimichi Niibe DDS, PhD*
Takehito Ouchi DDS
Ryotaro Iwasaki DDS, PhD
Taneaki Nakagawa DDS, PhD
Nobuyuki Horie DDS, PhD
Department of Dentistry and Oral Surgery, School of Medicine, Keio
University, 35 Shinanomachi, Shinjuku-ku, Tokyo 150-8582, Japan
*Corresponding author. Tel.: +81 3 3353 1211; fax: +81 3 3357 1593
E-mail address: kunimichi@z6.keio.jp (K. Niibe)
18 July 2014
Available online 8 September 2014
http://dx.doi.org/10.1016/j.jpor.2014.08.001
1883-1958/# 2014 Japan Prosthodontic Society. Published by
Elsevier Ireland. All rights reserved.