Original Article

Yonago Acta medica 2016;59:45–53

Associations between Systemic Markers of Bone Turnover or Bone Mineral
Density and Anti-Resorptive Agent-Related Osteonecrosis of the Jaw in Patients
Treated with Anti-Resorptive Agents
Kazuhito Tohashi,* Motoki Nakabayashi,*† Isamu Kodani,* Kazunori Kidani‡ and Kazuo Ryoke**Division of Oral and Maxillofacial Biopathological Surgery, Department of Medicine of Sensory and Motor Organs, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan, †Department of Oral and Maxillofacial Surgery, Matsue Red
Cross Hospital, Matsue 690-8506, Japan and ‡Department of Dentistry and Oral Surgery, Tottori Prefectural Central Hospital, Tottori
680-0901, Japan

ABSTRACT

patients exhibited higher mandibular BMD values thanthe control group. BMD was not associated with healingor the clinical stage of ARONJ.
Conclusion These results suggest that increased
mandibular BMD values are associated with ARONJ.
Furthermore, mandibular BMD might serve as a novel
marker for predicting the risk of ARONJ in patients thatare taking anti-resorptive agents and are about to undergo tooth extraction. Accordingly, mandibular BMD
could be a useful tool for aiding risk assessments andguiding treatment decisions.

BackgroundSome previous studies have examinedanti-resorptive agent-related osteonecrosis of the jaw(ARONJ) prediction using systemic markers of boneturnover as risk factors. Radiographic imaging is also
effective at detecting ARONJ. In this study, computed
tomography (CT)-derived bone mineral density (BMD)
values and the levels of systemic markers of bone turnover were evaluated, and then each parameter was compared between patients that developed ARONJ and those
who did not after treatment with systemic anti-resorptive
agents. The aim of this study was to determine whether
systemic markers of bone turnover and/or BMD values
can be used to predict the risk of ARONJ.
Methods The subjects’ serum levels of cross-linked
N-terminal telopeptide of type I collagen (NTX) andbone alkaline phosphatase (BAP) (systemic markers ofbone turnover) were measured. BMD was calibrated to
CT values using a medical imaging phantom. Then, thesubjects’ BMD were assessed using quantitative computed tomography. Fifty-six patients who had received
systemic anti-resorptive agents were included in thisstudy. Thirty-two of the patients developed ARONJ after
receiving the drugs whereas the remaining 24 did not.
Results No correlation was observed between the serum levels of the systemic markers of bone turnover andthe incidence of ARONJ. On the other hand, the ARONJ

Key words

anti-resorptive agent-related osteonecrosisof the jaw; bone mineral density; quantitative computed
tomography; systemic markers of bone turnover

Bisphosphonates are potent inhibitors of oeoclast activity1–3 and are widely used in the clinical setting to inhibit
osteoclast activity in malignant and benign disordersthat are characterized by excessive bone resorption, suchas tumor-induced osteolysis and osteoporosis.4–15 Worldwide, more than 200 million patients with commonbone disorders are currently being treated with anti-resorptive agents.16 However, the long-term administrationof bisphosphonates adversely affects bone quality andmetabolism. Since the first report of 3 cases of bisphosphonate-related osteonecrosis of the jaw (BRONJ) was
published in 2003,17 a growing number of studies haveexamined the condition.18–22 In recent years, denosumab,
an anti-resorptive agent with a novel mechanism of action, has been developed, and several reports have been
published on osteomyelitis and/or necrosis of the jaw
associated with the use of denosumab.23–25 The receptor
activator of nuclear factor kB ligand (RANKL) inhibitor
is a fully humanized antibody against RANKL that acts
an anti-resorptive agent and inhibits osteoclast activity
and the associated bone resorption. Due to the development of such drugs, the term BRONJ was changed toanti-resorptive agent-related osteonecrosis of the jaw(ARONJ), which encompasses the adverse effects ofCorresponding author: Motoki Nakabayashi, DDS, PhD
nakabayashi_motoki@matsue.jrc.or.jp
Received 2015 December 7
Accepted 2015 December 21
Abbreviations: AAOMS, American Association of Oral and Maxillofacial Surgeons; ARONJ, anti-resorptive agent-related osteonecrosis of the jaw; BAP, bone alkaline phosphatase; BCE, bone collagenequivalents; BMD, bone mineral density; BRONJ, bisphosphonaterelated osteonecrosis of the jaw; CT, computed tomography; DICOM, Digital Imaging and Communications in Medicine; NTX,
cross-linked N-terminal telopeptide of type I collagen; QCT, quantitative computed tomography; RANKL, receptor activator of nuclear
factor kappa-B ligand; ROI, regions of interest

45

K. Tohashi et al.

other anti-resorptive agents. There have been a numberof studies on the incidence of ARONJ, but no consensus
has been reached.18, 21, 26 ARONJ is extremely intractable. In addition, there are no established therapies for thecondition. Therefore, the prevention and early diagnosis
of ARONJ are very important.
The use of anti-resorptive agents significantly reduces the risk of fractures and skeletal-related troubles.
In addition, it increases the bone mineral density (BMD)of the lumbar vertebra, etc.27 Systemic markers of boneturnover can provide clinically useful evidence of reflectbone cell activity in the skeleton during medical treatment. Such markers have gained widespread acceptanceand are routinely used in the clinical setting. However,they are not currently employed in dentistry.
Although various radiological studies of ARONJ
have been published, patients who had been administered anti-resorptive agents did not exhibit consistent radiological jaws changes. Thus, imaging tools that could
aid the detection of bone changes associated with antiresorptive agents are required.
In this study, computed tomography (CT)-derived
BMD values and the levels of systemic markers of boneturnover were evaluated, and then each parameter wascompared between patients that developed ARONJ andthose who did not after treatment with systemic antiresorptive agents.

sequester.
The control group consisted of 24 patients who had
a history of treatment with anti-resorptive agents, had
never developed mandibular lesions or ARONJ, and had
undergone a CT scan and blood sampling of their mandible prior to tooth extraction. In the control group, tooth
extraction was clinically necessary in all subjects. Approval for the study was obtained from the institutional
review board of the Faculty of Medicine, Tottori University.
Staging categories

ARONJ was staged according to the 2007 AAOMS
guidelines29:
Stage 1: Exposed/necrotic bone in patients who are asymptomatic and have no evidence of infection.
Stage 2: Exposed/necrotic bone in patients with pain andclinical evidence of infection.
Stage 3: Exposed/necrotic bone in patients with pain; infection; and one or more of the following: a pathologicalfracture, extraoral fistula, or osteolysis extending to theinferior border.
Blood collection and measurement of systemic
markers of bone turnover

We collected blood samples from each patient andmeasured the blood levels of cross-linked N-terminal
telopeptide of type I collagen (NTX) and bone alkaline
phosphatase (BAP).

MATERIALS AND METHODSPatients

CT and bone mineral density measurements

This present study was performed with patients who
were referred to the Division of Oral and Maxillofacial
Biopathological Surgery, Tottori University Faculty of
Medicine from March 2008 to August 2014. The study
group consisted of 32 patients who had been receiving
anti-resorptive agents (administered intravenously andorally in 13 and 19 cases, respectively), had undergone a
CT scan of their mandible and had a blood test at thefirst medical examination with or without developing
ARONJ. ARONJ was diagnosed according to the criteria proposed by The American Association of Oral andMaxillofacial Surgeons (AAOMS) and the American
Society for Bone and Mineral Research28: i) current
or previous treatment with anti-resorptive agents; ii)
exposed bone or bone that could be probed through an
intraoral or extraoral fistula in the maxillofacial region
that had persisted for more than 8 weeks and iii) no history of radiotherapy involving the jaws or obvious metastasis to the jaws. The criteria between the healing andnon-healing groups were decided by the response frompatients with conservative treatments such as antibiotic
medication, irrigation and/or extirpation of separated

CT images were obtained using an Aquilion64 64-slice
spiral CT scanner (Toshiba, Tokyo, Japan). A medical
imaging phantom (Kyoto Kagaku, Kyoto, Japan) was
employed during the CT imaging (Fig. 1A). The resultant Digital Imaging and Communications in Medicine(DICOM) data were evaluated with ImageJ (National
Institute of Health, Bethesda, MD). BMD was measured
using quantitative computed tomography (QCT). Regions of interest (ROI) were drawn on axial images thatpassed through the mental foramen (Fig. 1B). The ROI
were drawn so that they only included spongiotic bone.
In order to exclude soft tissue, bone was defined as tissue that exhibited attenuation values of ≥ 300 Hounsfield
units.
Statistical analysis

Statistical analyses were performed using Excel 2010
(Microsoft, Redmond, WA).
The correlation between control, ARONJ (healing)and ARONJ (non-healing) groups was calculated using
the Tukey-Kramer test or Steel-Dwass test. Student’s t46

Associations with bone markers or BMD and ARONJ

A

B

Fig. 1. Use of the calibration phantom.
A: Photograph showing the calibration phantom. B: ROI (arrow) were drawn on an axial image passing through the mental foramen. The
ROI were drawn so that they only included spongiotic bone. CT image showing the calibration phantom (arrowhead). CT, computed tomography; ROI, regions of interest.

Table 1. Characteristics of the 32 patients with ARONJ and the 24 control patients

GenderMale
FemaleMean age
DiseaseAdministration method
Type of drug

Bony metastasis
Osteoporosis
Multiple myeloma
Other
Intravenous
Oral
Bisphosphonate
Denosumab

Control (n = 24)

ARONJ (n = 32)
Healing (n = 15)
No healing (n = 17)1
2367.6 y (48–83 y)
2
20
0
2
2
22
24
0

3
12
75.1 y (61–93 y)
1
12
1
1
2
13
15
0

8
9
69.0 y (40–80 y)
11
3
1
2
11
6
16
1

ARONJ, anti-resorptive agent-related osteonecrosis of the jaw; y, year(s).

test was used for comparisons between pairs of categorical variables. P-values of < 0.05 were considered to bestatistically significant.

groups. The patients’ other characteristics are shown in
Table 1. In addition, 4 patients (14.3%) that underwent
tooth extraction subsequently developed ARONJ. Thesepatients were not included in the control group. The
mandibular BMD values of the 4 patients were 504 mg/
mL, 564 mg/mL, 519 mg/mL and 412 mg/mL, respectively. 2 (50.0%) of 4 patients were healing.

RESULTSThe control, ARONJ (healing), and ARONJ (non-healing) groups contained 24, 15, and 17 patients, respectively. The mean ages of the control, ARONJ (healing)and ARONJ (non-healing) groups were 67.6 years (range,
48–83 years), 75.1 years (range, 61–93 years) and 69.0
years (range, 40–80 years), respectively. No significant
difference was detected among the mean ages of 3

Patients’ serum NTX and BAP levels

The mean serum NTX levels (± standard deviation)of the control and ARONJ groups were 9.8 ± 1.1 nmolbone collagen equivalents (BCE)/L and 12.8 ± 3.2 nmol
47

K. Tohashi et al.

BCE/L, respectively. The mean serum BAP levels of thecontrol and ARONJ groups were 17.9 ± 1.8 U/L and 21.8
± 8.5 U/L, respectively (Fig. 2). The differences between
the two groups were not significant.

NTX (nmol BCE/L)

In addition, the mean NTX levels of the ARONJ(healing) and ARONJ (non-healing) groups were 10.4
± 1.4 nmol BCE/L and 14.8 ± 3.9 nmol BCE/L, respectively, and the mean BAP levels of the ARONJ (healing)and ARONJ (non-healing) groups were 18.3 ± 4.2 U/
L and 24.8 ± 10.9 U/L, respectively (Fig. 3). The NTX
levels of non-healing ARONJ groups were significantly
higher than that of control group (P < 0.01) and similarly
higher than that of healing ARONJ groups (P < 0.05).
However, there were no significant differences among
the BAP levels of the control, ARONJ (healing) and
ARONJ (non-healing) groups.

BAP (U/L)

Levels of systemic markers of bone turnover according to the clinical stage of ARONJ(n = 24)(n = 32)(n = 24)(n = 32)

Control

ARONJ

Control

ARONJ

There were 6, 19, and 7 patients with stage 1, 2 and 3
ARONJ, respectively. The mean NTX levels of the stage
1, 2 and 3 patients were 11.3 ± 3.1 nmol BCE/L, 11.6 ±1.4 nmol BCE/L and 16.7 ± 5.4 nmol BCE/L, respectively. The mean BAP levels of the stage 1, 2, and 3
patients were 28.2 ± 14.4 U/L, 18.7 ± 4.7 U/L and 24.4 ±10.8 U/L, respectively (Fig. 4). No significant difference
was detected among the systemic marker levels of thecontrol, stage 1, stage 2, and stage 3 patients.

t-testFig. 2. The levels of systemic markers of bone turnover in the control and ARONJ groups.
The left figure shows serum NTX levels, and the right figure
shows serum BAP levels. The correlation between control and
ARONJ group was calculated using the Student’s t-test. No significant differences were detected between the local mandibular
statuses of the two groups with regard to NTX or BAP. ARONJ,
anti-resorptive agent-related osteonecrosis of the jaw; BAP, bonealkaline phosphatase; NTX, cross-linked N-terminal telopeptideof type I collagen.

BAP (U/ )NTX (nmol BCE/L)

45
40
35

NTX (nmol BCE/L)**

BAP (U/ )

30

***

25
20
15
10
5
(n = 24)(n = 6)(n = 19)(n = 7)

Control Stage 1 Stage 2 Stage 30(n = 24)(n = 6)(n = 19)

Control Stage 1 Stage 2(n = 7)

Stage 3

Steel-Dwass test(n = 24)(n = 15)

Control

ARONJ ARONJ(healing) (no healing)(n = 17)(n = 24)(n = 15)

Control

ARONJ ARONJ(healing) (no healing)

Fig. 4. Levels of systemic markers of bone turnover according to
the clinical stage of ARONJ.
The left figure shows serum NTX levels and the right figure shows
serum BAP levels. The correlation between control and eachclinical stage of ARONJ was calculated using the Steel-Dwass
test. No significant differences were detected among the 4 groups.
ARONJ, anti-resorptive agent-related osteonecrosis of the jaw;
BAP, bone alkaline phosphatase; NTX, cross-linked N-terminal
telopeptide of type I collagen.

(n = 17)

Tukey-Kramer test ** P < 0.01

< 0.05
Fig. 3. Levels of systemic markers of bone turnover***P
accordingtothe outcome of ARONJ.
The left figure shows serum NTX levels and the right figure shows
serum BAP levels. The correlation between control, ARONJ(healing) and ARONJ (non-healing) groups was calculated using
the Tukey-Kramer test. The NTX levels of ARONJ (no healing)groups were significantly higher than that of the control group and
ARONJ (healing) group (**P < 0.01,***P < 0.05). However, there
was no significant difference among the BAP levels of the control,
ARONJ (healing) and ARONJ (no healing) groups. ARONJ, antiresorptive agent-related osteonecrosis of the jaw; BAP, bone alkaline phosphatase; NTX, cross-linked N-terminal telopeptide oftype I collagen.

Patients’ mandibular BMD values

The mandibular BMD values of the control and ARONJ
groups are shown in Fig. 5. The mean BMD values of
the control and ARONJ groups were 403.5 ± 31.7 mg/
48

Associations with bone markers or BMD and ARONJmL and 522.4 ± 58.7 mg/mL, respectively. The mean
mandibular BMD value of the ARONJ group was significantly higher than that of the control group (P < 0.001).
In addition, the mandibular BMD values of the
ARONJ (healing) and ARONJ (non-healing) groups areshown in Fig. 6. The mean mandibular BMD values of
the ARONJ (healing) and ARONJ (non-healing) groups
were 534.1 ± 67.9 mg/mL and 512.2 ± 51.1 mg/mL,
respectively. The BMD values of both groups were significantly higher than that of the control group (P < 0.01).
However, there was no significant difference between

the BMD values of the ARONJ (healing) and ARONJ(non-healing) groups.
Mandibular BMD values according to the clinicalstage of ARONJ

The mean BMD values of the stage 1, 2 and 3 patientswere 522.7 ± 45.2 mg/mL, 522.7 ± 67.9 mg/mL and
522.0 ± 51.4 mg/mL, respectively (Fig. 7).
The BMD values of all ARONJ stages were significantly higher than that of the control group (P < 0.05),
but no significant differences were detected among the
BMD values of the stage 1, 2 and 3 patients.

BMD (mg/mL)

BMD (mg/mL)

*

***
***

(n = 24)(n = 32)

Control

ARONJ
t-test *P < 0.001

Fig. 5. The correlation BMD values between control and ARONJ
group was calculated using the Student’s t-test.
The mean BMD value of the ARONJ group was greater than thatof the control (*P < 0.001). ARONJ, anti-resorptive agent-related
osteonecrosis of the jaw; BMD, bone mineral density.

BMD (mg/mL)(n = 15)
ARONJ (healing)(n = 19)(n = 7)

Stage 1

Stage 2

Stage 3**P < 0.01

DISCUSSION
The first case of ARONJ was reported over a decadeago,17 but the pathophysiology of the disease has notbeen fully elucidated. Various hypotheses have been
proposed to explain the exclusive localization of ARONJ
in the jaws, including altered bone remodeling or theexcessive suppression of bone resorption, a reduction inblood supply, continuous dentoalveolar trauma, the suppression of innate or acquired immunity, vitamin D deficiency, soft tissue bisphosphonate toxicity, inflammationand infection.30–38
Patients that are treated with anti-resorptive agentsand undergo dentoalveolar surgery are at least 7 times
more likely to develop ARONJ than patients who do
not undergo dentoalveolar surgery. However, patients
who receive anti-resorptive agents and do not develop(n = 17)
ARONJ (no healing)

Tukey-Kramer test(n = 6)

Control

Fig. 7. The correlation BMD values according to the clinical***P < stage
0.05
of ARONJ was calculated using the Steel-Dwass test.
The BMD values of the patients with each clinical stage of
ARONJ were significantly higher than that of the control group(**P < 0.01,***P < 0.05). However, the BMD values of the stage
1, 2 and 3 ARONJ patients did not differ significantly. ARONJ,
anti-resorptive agent-related osteonecrosis of the jaw; BMD, bonemineral density.

**

Control(n = 24)

Steel-Dwass test**(n = 24)****P < 0.01

Fig. 6. The correlation BMD values between control, ARONJ(healing) and ARONJ (non-healing) groups was calculated using
the Tukey-Kramer test.
The BMD values of the ARONJ (healing) and ARONJ (non-healing) groups were higher than those of the control group (*P < 0.01).
In contrast, no significant difference was detected between the
BMD values of the ARONJ (healing) and ARONJ (non-healing)groups. ARONJ, anti-resorptive agent-related osteonecrosis of thejaw; BMD, bone mineral density.

49

K. Tohashi et al.

ARONJ after undergoing dentoalveolar surgery remains
unclear.39 The present study is the first to examine
ARONJ risk prediction using such patients as a control
group.
The imaging findings of ARONJ are similar to thoseof common osteomyelitis of the jaw, and there is essentially no difference between the two conditions.40–42
In addition, the hematological and histopathologicalfindings of the two conditions are also similar. Thus,
ARONJ is primarily diagnosed based on its clinicalfindings, but radiographic imaging is essential for determining the extent of the disease, diagnosing ARONJ
in its early stages, identifying metastatic disease, andexcluding fractures.42, 43
The main characteristic of ARONJ is that it is intractable. In this study, we noticed that many ARONJ
patients with bone metastasis does not show a healing
tendency especially when they receive intravenous antiresorptive agents.
Furthermore, patients with cancer generally have aweakened immune system, so we thought that intractability was promoted by declining immunity. This makes
early detection very important. Various methods forearly diagnosis of ARONJ have been examined.
A number of studies have investigated ARONJ risk
prediction based on serum NTX levels.40, 41, 44–46 However, the utility of systemic markers of bone turnover forassessing the risk of jaw necrosis has not been validated.
This study was not able to validate its utility either.
Markers of bone turnover are influenced by both local
and systemic factors. Moreover, NTX levels increase inpatients who did not show any sign of healing. Generally, bone turnover is inhibited by anti-resorptive agents.
We speculate that the systemic factors affecting suchmarkers might include circadian rhythms, dietary effects, systemic bone disease and bone metastases. Therefore, systemic markers of the effects of bisphosphonatesmight not be indicative of the local bone changes that directly influence the risk of ARONJ or factors such as theregional toxic effects of bisphosphonate on bone quality
and local circulation.47
Radiographic imaging is an effective method for
diagnosing ARONJ as the BMD of the jaws is affectedless by systemic factors than by bone turnover. In patients that have been treated with anti-resorptive agents,
CT images of the mandible show osteosclerotic changes.
Thus, the mandibular bone might reflect the effects
of drugs to a greater extent than other bones. Several
reports have evaluated the appearance of ARONJ on
different imaging modalities.48–61 However, there is noestablished method for diagnosing the condition.
We were concerned that our results might be af-

fected by inter-reader variability, such as that caused byvagueness regarding the location of the measurementsite or the use of ROI that were too small. Therefore,
we developed a measurement method to decrease interreader variability. The mental foramen is a characteristic
anatomical feature of the mandible and is located below
the roots of the teeth. Thus, an axial CT section thatpassed through the mental foramen was chosen, and the
ROI was drawn so that it included the mental foramen.
This approach makes sense as it has been reported that
ARONJ most commonly affects sites in the mandibularmolar region.56, 60 In addition, we minimized the effects of inflammation caused by ARONJ or periodontal
disease on our findings by obtaining measurements inthe anterior mandible. In a pilot study, the results we obtained in the anterior mandible were more accurate thanthose obtained in the mandibular molar region (data notshown).
In the present study, the mandibular BMD of the
ARONJ group was significantly greater than that of thecontrol group. The 4 patients that developed ARONJ
after undergoing tooth extraction exhibited a high mean
pre-tooth extraction BMD (499 mg/mL), and 3 of these4 patients displayed mandibular BMD values of ≥ 500
mg/mL. Our results support the findings of a previous
study48, 50 in which the ARONJ group exhibited higher
BMD values than the control group. The control patientsin the present study received an anti-resorptive agent before tooth extraction and did not develop ARONJ. This
study demonstrated that patients with high BMD values
are at a high risk for ARONJ. These results suggest that
promotion of osteosclerosis of the jaw mainly due totreatment with systemic anti-resorptive agents. ARONJ
may result from a decreased blood flow in the cancellous
bone.
We did not detect a significant difference between
the BMD values of patients with different stages of
ARONJ or between those of the healing and non-healing
groups, which agrees with the findings of previous studies.48, 50 In addition, our findings are similar to thoseseen in cases of stage 1 to 3 ARONJ involving exposedbone.
Bone turnover occurs at a faster rate in cancellous
bone than in cortical bone; thus, the BMD of cancellous
bone is a good indicator of bone turnover and might offer a simple, quantitative means of detecting ARONJ
early. Therefore, we examined cancellous bone in thepresent study. However, we were not able to detect
the relationship between BMD and several stages of
ARONJ. Thus, changes associated with the stages of osteosclerotic responses might not be detectable on imaging scans.63, 64 Further studies are needed to examine the50Associations with bone markers or BMD and ARONJ

pharmacokinetics of anti-resorptive agents and the local
changes that they induce during the stages of ARONJ.
In conclusion, patients that had developed ARONJ
after receiving systemic anti-resorptive agents exhibited
higher mandibular BMD values than patients who had
been treated with systemic anti-resorptive agents without
developing ARONJ. These results suggest that increases
in mandibular BMD are associated with ARONJ. Furthermore, mandibular BMD might be a useful marker
for predicting the risk of ARONJ prior to tooth extraction or jaw surgery in patients that have been treatedwith anti-resorptive agents. Accordingly, mandibular
BMD could be a useful clinical parameter for aiding risk
assessment and guiding therapeutic decision-making.

et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysisof two randomized, controlled clinical trials. J Clin Oncol.
2001;19:558-67. PMID: 11208851.
11 Nussbaum SR, Younger J, Vandepol CJ, Gagel RF, Zubler MA,
Chapman R, et al. Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy:
comparison of 30-, 60-, and 90-mg dosages. Am J Med.
1993;95:297-304. PMID: 8368227.
12 Rosen LS, Gordon D, Kaminski M, Howell A, Belch A,
Mackey J, et al. Zoledronic acid versus pamidronate in thetreatment of skeletal metastases in patients with breast cancer
or osteolytic lesions of multiple myeloma: a phase III, doubleblind, comparative trial. Cancer J. 2001;7:377-87. PMID:
15197804.
13 Rosen LS, Gordon D, Tchekmedyian NS, Yanagihara R,
Hirsh V, Krzakowski M, et al. Long-term efficacy and safetyof zoledronic acid in the treatment of skeletal metastases inpatients with non-small cell lung carcinoma and other solid
tumors: a randomized, Phase III, double-blind, placebocontrolled trial. Cancer. 2004;100:2613-21. PMID: 11693896.
14 Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P,
Lacombe L, et al. Long-term efficacy of zoledronic acid forthe prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst.
2004;96:879-82. PMID: 15173273.
15 Bravenboer N, Papapoulos SE, Holzmann P, Hamdy NA,
Netelenbos JC, Lips P. Bone histomorphometric evaluationof pamidronate treatment in clinically manifest osteoporosis.
Osteoporos Int. 1999;9:489-93. PMID: 10624455.
16 Licata AA. Discovery, clinical development, and therapeutic
uses of bisphosphonates. Ann Pharmacother. 2005;39:668-77.
PMID: 15755793.
17 Marx RE. Pamidronate (Aredia) and zoledronate (Zometa)induced avascular necrosis of the jaws: a growing epidemic. J
Oral Maxillofac Surg. 2003;61:1115-7. PMID: 12966493.
18 Bagan JV, Jimenez Y, Murillo J, Hernandez S, Poveda R,
Sanchis JM, et al. Jaw osteonecrosis associated with bisphosphonates: multiple exposed areas and its relationship to teeth
extractions. Study of 20 cases. Oral Oncol. 2006;42:327-9.
PMID: 16275156.
19 Migliorati CA, Schubert MM, Peterson DE, Seneda LM.
Bisphosphonate-associated osteonecrosis of mandibular andmaxillary bone: an emerging oral complication of supportive
cancer therapy. Cancer. 2005;104:83-93. PMID: 15929121.
20 Pires FR, Miranda A, Cardoso ES, Cardoso AS, Fregnani
ER, Pereira CM, et al. Oral avascular bone necrosis associated with chemotherapy and biphosphonate therapy. Oral Dis.
2005;11:365-9. PMID: 16269027.
21 Purcell PM, Boyd IW. Bisphosphonates and osteonecrosis of
the jaw. Med J Aust. 2005;182:417-8. PMID: 15850440.
22 Woo SB, Hellstein JW, Kalmar JR. Narrative [corrected]
review: bisphosphonates and osteonecrosis of the jaws. Ann
Intern Med. 2006;144:753-61. PMID: 16702591.
23 Aghaloo TL, Felsenfeld AL, Tetradis S. Osteonecrosis of
the jaw in a patient on Denosumab. J Oral Maxillofac Surg.
2010;68:959-63. PMID: 20149510.
24 Lipton A, Fizazi K, Stopeck AT, Henry DH, Brown JE,
Yardley DA, et al. Superiority of denosumab to zoledronic
acid for prevention of skeletal-related events: a combined
analysis of 3 pivotal, randomized, phase 3 trials. Eur J Cancer.
2012;48:3082-92. PMID: 22975218.
25 Sinningen K, Tsourdi E, Rauner M, Rachner TD, Hamann C,

The authors declare no conflict of interest.

REFERENCES
1 Allen MR, Burr DB. Bisphosphonate effects on bone turnover, microdamage, and mechanical properties: what we
think we know and what we know that we don’t know. Bone.
2011;49:56-65. PMID: 20955825.
2 Arce K, Assael LA, Weissman JL, Markiewicz MR. Imaging
findings in bisphosphonate-related osteonecrosis of jaws. J
Oral Maxillofac Surg. 2009;67:75-84. PMID: 19371818.
3 Greenspan SL, Perera S, Recker R, Wagner JM, Greeley P,
Gomberg BR, et al. Changes in trabecular microarchitecture
in postmenopausal women on bisphosphonate therapy. Bone.
2010;46:1006-10. PMID: 20051275.
4 Berenson JR, Hillner BE, Kyle RA, Anderson K, Lipton A,
Yee GC, et al. American Society of Clinical Oncology clinical practice guidelines: the role of bisphosphonates in multiple
myeloma. J Clin Oncol. 2002;20:3719-36. PMID: 8559201.
5 Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA,
Bordoni R, George S, et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple
myeloma. Myeloma Aredia Study Group. N Engl J Med.
1996;334:488-93. PMID: 9469347.
6 Berenson JR, Lichtenstein A, Porter L, Dimopoulos MA,
Bordoni R, George S, et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group. J Clin Oncol.
1998;16:593-602. PMID: 12202673.
7 Hillner BE, Ingle JN, Chlebowski RT, Gralow J, Yee GC,
Janjan NA, et al. American Society of Clinical Oncology 2003
update on the role of bisphosphonates and bone health issues
in women with breast cancer. J Clin Oncol. 2003;21:4042-57.
PMID: 12963702.
8 Hortobagyi GN, Theriault RL, Lipton A, Porter L, Blayney D,
Sinoff C, et al. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol.
1998;16:2038-44. PMID: 9626201.
9 Hortobagyi GN, Theriault RL, Porter L, Blayney D, Lipton A,
Sinoff C, et al. Efficacy of pamidronate in reducing skeletal
complications in patients with breast cancer and lytic bonemetastases. Protocol 19 Aredia Breast Cancer Study Group. N
Engl J Med. 1996;335:1785-91. PMID: 8965890.
10 Major P, Lortholary A, Hon J, Abdi E, Mills G, Menssen HD,

51

K. Tohashi et al.
Hofbauer LC. Skeletal and extraskeletal actions of denosumab. Endocrine. 2012;42:52-62. PMID: 22581255.
26 Ficarra G, Beninati F, Rubino I, Vannucchi A, Longo G,
Tonelli P, et al. Osteonecrosis of the jaws in periodontal patients with a history of bisphosphonates treatment. J Clin Periodontol. 2005;32:1123-8. PMID: 16212571.
27 Braga V, Gatti D, Colapietro F, Battaglia E, Righetti D,
Prizzi R, et al. Intravenous intermittent neridronate in thetreatment of postmenopausal osteoporosis. Bone. 2003;33:3425. PMID: 13678775.
28 Ruggiero SL, Dodson TB, Fantasia J, Goodday R,
Aghaloo T, Mehrotra B, et al. American Association of Oraland Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update. J Oral Maxillofac
Surg. 2014;72:1938-56. PMID: 25234529.
29 Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws AeAoOaMS. American Association of Oraland Maxillofacial Surgeons position paper on bisphosphonaterelated osteonecrosis of the jaws. J Oral Maxillofac Surg.
2007;65:369-76. PMID: 17307580.
30 Bamias A, Kastritis E, Bamia C, Moulopoulos LA,
Melakopoulos I, Bozas G, et al. Osteonecrosis of the jaw incancer after treatment with bisphosphonates: incidence andrisk factors. J Clin Oncol. 2005;23:8580-7. PMID: 16314620.
31 Bi Y, Gao Y, Ehirchiou D, Cao C, Kikuiri T, Le A, et al.
Bisphosphonates cause osteonecrosis of the jaw-like disease inmice. Am J Pathol. 2010;177:280-90. PMID: 20472893.
32 Hokugo A, Christensen R, Chung EM, Sung EC, Felsenfeld AL,
Sayre JW, et al. Increased prevalence of bisphosphonaterelated osteonecrosis of the jaw with vitamin D deficiency inrats. J Bone Miner Res. 2010;25:1337-49. PMID: 20200938.
33 Mehrotra B, Ruggiero S. Bisphosphonate complications including osteonecrosis of the jaw. Hematology Am Soc Hematol Educ Program. 2006:356-60, 515. PMID: 17124083.
34 Mortensen M. Lawson W, Montazem A. Osteonecrosis of thejaw associated with bisphosphonate use: Presentation of sevencases and literature review. Laryngoscope. 2007;117:30-4.
PMID: 17202926.
35 Reid IR, Bolland MJ, Grey AB. Is bisphosphonate-associatedosteonecrosis of the jaw caused by soft tissue toxicity? Bone.
2007;41:318-20. PMID: 17572168.
36 Sonis ST, Watkins BA, Lyng GD, Lerman MA, Anderson KC.
Bony changes in the jaws of rats treated with zoledronic acidand dexamethasone before dental extractions mimic bisphosphonate-related osteonecrosis in cancer patients. Oral Oncol.
2009;45:164-72. PMID: 18715819.
37 Ruggiero SL, Fantasia J, Carlson E. Bisphosphonate-related
osteonecrosis of the jaw: background and guidelines fordiagnosis, staging and management. Oral Surg Oral Med
Oral Pathol Oral Radiol Endod. 2006;102:433-41. PMID:
16997108.
38 Wood J, Bonjean K, Ruetz S, Bellahcène A, Devy L, Foidart JM,
et al. Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther. 2002;302:105561. PMID: 12183663.
39 Badros A, Weikel D, Salama A, Goloubeva O, Schneider A,
Rapoport A, et al. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol.
2006;24:945-52. PMID: 16484704.
40 Fleisher KE, Welch G, Kottal S, Craig RG, Saxena D,
Glickman RS. Predicting risk for bisphosphonate-related
osteonecrosis of the jaws: CTX versus radiographic markers. Oral Surg Oral Med Oral Pathol Oral Radiol Endod.

2010;110:509-16. PMID: 20674404.
41 Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR,
Felsenberg D, et al. Bisphosphonate-associated osteonecrosisof the jaw: report of a task force of the American Society forBone and Mineral Research. J Bone Miner Res. 2007;22:147991. PMID: 17663640.
42 Morag Y, Morag-Hezroni M, Jamadar DA, Ward BB,
Jacobson JA, Zwetchkenbaum SR, et al. Bisphosphonate-related osteonecrosis of the jaw: a pictorial review. Radiographics.
2009;29:1971-84. PMID: 19926757.
43 Krishnan A, Arslanoglu A, Yildirm N, Silbergleit R, Aygun N.
Imaging findings of bisphosphonate-related osteonecrosis of
the jaw with emphasis on early magnetic resonance imaging
findings. J Comput Assist Tomogr. 2009;33:298-304. PMID:
19346864.
44 Marx RE, Cillo JE, Ulloa JJ. Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX
testing, prevention, and treatment. J Oral Maxillofac Surg.
2007;65:2397-410. PMID: 18022461.
45 Kunchur R, Need A, Hughes T, Goss A. Clinical investigation of C-terminal cross-linking telopeptide test in prevention
and management of bisphosphonate-associated osteonecrosisof the jaws. J Oral Maxillofac Surg. 2009;67:1167-73. PMID:
19446200.
46 Lehrer S, Montazem A, Ramanathan L, Pessin-Minsley M,
Pfail J, Stock RG, et al. Normal serum bone markers inbisphosphonate-induced osteonecrosis of the jaws. Oral Surg
Oral Med Oral Pathol Oral Radiol Endod. 2008;106:389-91.
PMID: 18554944.
47 Takaishi Y, Ikeo T, Nakajima M, Miki T, Fujita T. A pilot
case-control study on the alveolar bone density measurement
in risk assessment for bisphosphonate-related osteonecrosis of
the jaw. Osteoporos Int. 2010;21:815-25. PMID: 19705049.
48 Bagan JV, Cibrian RM, Lopez J, Leopoldo-Rodado M,
Carbonell E, Bagán L, et al. Sclerosis in bisphosphonaterelated osteonecrosis of the jaws and its correlation with theclinical stages: study of 43 cases. Br J Oral Maxillofac Surg.
2015;53:257-62. PMID: 25560326.
49 Bianchi SD, Scoletta M, Cassione FB, Migliaretti G, Mozzati M.
Computerized tomographic findings in bisphosphonate-associated osteonecrosis of the jaw in patients with cancer. Oral
Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;104:24958. PMID: 17560140.
50 Hamada H, Matsuo A, Koizumi T, Satomi T, Chikazu D. A
simple evaluation method for early detection of bisphosphonate-related osteonecrosis of the mandible using computed
tomography. J Craniomaxillofac Surg. 2014;42:924-9. PMID:
24503386.
51 Hutchinson M, O’Ryan F, Chavez V, Lathon PV, Sanchez G,
Hatcher DC, et al. Radiographic findings in bisphosphonatetreated patients with stage 0 disease in the absence of bone
exposure. J Oral Maxillofac Surg. 2010;68:2232-40. PMID:
20728032.
52 O’Ryan FS, Khoury S, Liao W, Han MM, Hui RL, Baer D,
et al. Intravenous bisphosphonate-related osteonecrosis of thejaw: bone scintigraphy as an early indicator. J Oral Maxillofac
Surg. 2009;67:1363-72. PMID: 22595135.
53 O’Ryan FS, Lo JC. Bisphosphonate-related osteonecrosis of
the jaw in patients with oral bisphosphonate exposure: clinicalcourse and outcomes. J Oral Maxillofac Surg. 2012;70:184453. PMID: 19531404.
54 Popovic KS, Kocar M. Imaging findings in bisphosphonateinduced osteonecrosis of the jaws. Radiol Oncol. 2010;44:215-

52

Associations with bone markers or BMD and ARONJ
9. PMID: 22933918.
55 Raje N, Woo SB, Hande K, Yap JT, Richardson PG, Vallet S,
et al. Clinical, radiographic, and biochemical characterizationof multiple myeloma patients with osteonecrosis of the jaw.
Clin Cancer Res. 2008;14:2387-95. PMID: 18413829.
56 Rocha GC, Jaguar GC, Moreira CR, Neves EG, Fonseca FP,
Pedreira EN. Radiographic evaluation of maxillofacial region
in oncology patients treated with bisphosphonates. Oral Surg
Oral Med Oral Pathol Oral Radiol. 2012;114:S19-25. PMID:
23083951.
57 Rugani P, Luschin G, Jakse N, Kirnbauer B, Lang U, Acham S.
Prevalence of bisphosphonate-associated osteonecrosis of thejaw after intravenous zoledronate infusions in patients withearly breast cancer. Clin Oral Investig. 2014;18:401-7. PMID:
23749244.
58 Stockmann P, Hinkmann FM, Lell MM, Fenner M,
Vairaktaris E, Neukam FW, et al. Panoramic radiograph,computed tomography or magnetic resonance imaging. Whichimaging technique should be preferred in bisphosphonateassociated osteonecrosis of the jaw? A prospective clinicalstudy. Clin Oral Investig. 2010;14:311-7. PMID: 19513765.
59 Treister NS, Friedland B, Woo SB. Use of cone-beam computerized tomography for evaluation of bisphosphonate-associat-

ed osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol
Oral Radiol Endod. 2010;109:753-64. PMID: 20303301.
60 Treister N, Sheehy N, Bae EH, Friedland B, Lerman M, Woo S.
Dental panoramic radiographic evaluation in bisphosphonateassociated osteonecrosis of the jaws. Oral Dis. 2009;15:88-92.
PMID: 18992020.
61 Walter C, Al-Nawas B, Grötz KA, Thomas C, Thüroff JW,
Zinser V, et al. Prevalence and risk factors of bisphosphonateassociated osteonecrosis of the jaw in prostate cancer patientswith advanced disease treated with zoledronate. Eur Urol.
2008;54:1066-72. PMID: 18602738.
62 Walter C, Laux C, Sagheb K. Radiologic bone loss in patientswith bisphosphonate-associated osteonecrosis of the jaws: acase-control study. Clin Oral Investig. 2014;18:385-90. PMID:
23525860.
63 Matsuo A, Chiba H, Takahashi H, Toyoda J, Hasegawa O,
Hojo S. Bone quality of mandibles reconstructed with particulate cellular bone and marrow, and platelet-rich plasma. J
Craniomaxillofac Surg. 2011;39:628-32. PMID: 21419639.
64 Walter C, Grötz KA, Kunkel M, Al-Nawas B. Prevalence ofbisphosphonate associated osteonecrosis of the jaw within thefield of osteonecrosis. Support Care Cancer. 2007;15:197-202.
PMID: 16941133.

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