Introduction
Bisphosphonates (BPs) are synthetic drugs used in
the treatment of osteolytic bone disorders, including osteoporosis,
Paget's disease, bone metastasis and multiple myeloma (MM)
(1,2).
BPs are pyrophosphate analogues with a high affinity for
hydroxyapatite crystals (3,4). Once bound to hydroxyapatite crystals,
BPs are slowly released during bone resorption and are subsequently
internalised by osteoclasts. BPs inhibit osteoclastic bone
resorption by interfering with osteoclast recruitment,
differentiation and activity, and by promoting apoptosis (5–8). In
addition, BPs are reported to exert direct antiproliferative and
proapoptotic effects on cancer cells, thereby reducing bone
metastases (9,10). Furthermore, BPs alter angiogenesis
(11) and signal transduction between
osteoclasts and osteoblasts (12).
Depending on the presence or absence of a nitrogen atom,
nitrogen-containing and non-nitrogen-containing BPs differ in the
mechanism of action exerted on osteoclasts (13,14).
Various BPs demonstrate different relative potencies and affinities
for bone. The more recent nitrogen-containing BPs, such as
zolendronic acid (ZA), are the most potent inhibitors of bone
resorption (13,15). ZA is an agent that is administered
intravenously, and patients receiving BPs intravenously are at a
high risk of developing BP-related osteonecrosis of the jaws
(BRONJ) (16).
Different definitions make it challenging to reach
conclusions on the incidence of BRONJ, which has been reported to
be <10% in various studies, and the associated risk factors
(17–19). The present study reports a
single-centre retrospective study that was performed to determine
the frequency, risk factors and clinical presentation of BRONJ, and
to also determine the progression of malignancy in patients with
cancer treated by ZA once BRONJ develops.
Materials and methods
Study design
The present study reports a cross-sectional
retrospective analysis of all individuals that were treated with a
ZA and were diagnosed with BRONJ at Cukurova University Medical
School (Adana, Turkey) between January 2008 and December 2012. The
control group was randomly selected from the hemato-oncological
patients at the same medical centre that were treated with ZA
during the same period. All patients in the BRONJ and control
groups were examined by the same oral and maxillofacial surgeon, to
confirm or reject the diagnosis of BRONJ.
For the patient inclusion criteria, only patients
with malignancy that were treated with 4 mg of ZA once every 3 or 6
weeks due to bone metastasis were included. The diagnosis of BRONJ
was performed according to the 2009 update of the American
Association of Oral and Maxillofacial Surgeons position paper
(20), specifically exposed bone in
the maxillofacial region that had persisted for >8 weeks.
Patients with head and neck neoplasms and those who received
radiotherapy to the head and neck region were excluded.
From medical records, interviews with patients, and
questionnaires completed by patients, data were retrieved regarding
the age and gender of patients, BP treatment, indication for
treatment, drug administered, cumulative dose of agent, duration of
treatment, concomitant steroid use, diabetes status, administration
of dental treatment, smoking, use of angiogenic agents and state of
disease during the development BRONJ in the patients. Written
informed consent was obtained from all patients.
Statistical analysis
Statistical analyses in the present study were
performed using the Number Cruncher Statistical System 2007
statistical software (NCSS, LLC, Kaysville, UT, USA). To analyze
the data, in addition to the descriptive statistical methods of the
mean and standard deviation, the independent t-test was used
for the comparison of dual groups, and χ2 and Fisher's
exact tests were used for the comparison of qualitative data.
Results
Comparison between patients with and
without BRONJ
A total of 24 patients that were administered with
ZA were diagnosed with BRONJ between January 2008 and December
2012. Examinations performed by the same oral medicine specialist
confirmed the diagnoses of BRONJ in all patients in the BRONJ
group, and excluded BRONJ in all 20 patients in the control group.
The gender distribution in the patients with BRONJ was 11 males and
13 females, and the control group consisted of 8 males and 12
females. In the patients with BRONJ, 37% (n=9) possessed ONJ of the
mandibular, 20% (n=5) possessed ONJ of the maxilla, 20% (n=5)
demonstrated multiple location involvement and 6% (n=5) possessed
ONJ of unknown location. Out of the 24 patients with BRONJ and the
20 without BRONJ, the indications for ZA treatment consisted of
breast cancer in 8 patients (33%), MM in 8 patients (33%), prostate
cancer in 6 patients (25%) and other cancers in 2 patients (8%),
comprising colon cancer and renal cell carcinoma (Table I). The median usage time of ZA was
calculated to be 36 months (range, 12–84 months) in the BRONJ group
and 27 months (range, 7–65 months) in the control group. No
statistically significant difference was observed in the gender
distribution of the BRONJ and control groups (P=0.697) or the
diagnosis distribution of the BRONJ and control groups
(P=0.0090).
 | Table I.Characteristics of patients in the
BRONJ and Control groups. |
Table I.
Characteristics of patients in the
BRONJ and Control groups.
|
| Group |
|
|---|
|
|
|
|
|---|
|
| Control, n (%) | BRONJ, n (%) | P-value |
|---|
| Gender |
|
|
|
|
Female | 12 (60.00) | 13 (54.17) | 0.697 |
| Male | 8 (40.00) | 11 (45.83) |
|
| Diagnosis |
|
|
|
|
Prostate | 0 (0.00) | 6 (25.00) | 0.090 |
|
Breast | 9 (45.00) | 8 (33.33) |
|
| MM | 7 (35.00) | 8 (33.33) |
|
|
Other | 4 (20.00) | 2 (8.33) |
|
| Dental treatment |
|
|
|
| No | 14 (77.78) | 8 (38.10) | 0.013 |
| Yes | 4 (22.22) | 13 (61.90) |
|
| DM |
|
|
|
| No | 18 (94.74) | 19 (95.00) | 0.970 |
| Yes | 1 (5.26) | 1 (5.00) |
|
| Use of steroids |
|
|
|
| No | 13 (68.42) | 17 (70.83) | 0.864 |
| Yes | 6 (31.58) | 7 (29.17) |
|
| Smoker |
|
|
|
| No | 12 (75.00) | 14 (77.78) | 0.849 |
| Yes | 4 (25.00) | 4 (22.22) |
|
| Angiogenesis |
|
|
|
| No | 14 (73.68) | 14 (70.00) | 0.798 |
| Yes | 5 (26.32) | 6 (30.00) |
|
| State of disease |
|
|
|
| Bad | 11 (64.71) | 4 (26.67) | 0.031 |
| Good | 6 (35.29) | 11 (73.33) |
|
The median age of the patients with BRONJ was
significantly higher than that of the control group (P=0.049). The
cumulative dose medians of the BRONJ group were found to be
significantly higher compared with those of the control group
(P=0.037; Table II). The median
cumulative dose in the control group was found to be 88 mg (range,
36–120 mg), while in the BRONJ group the median cumulative dose was
126 mg (range, 72–168 mg).
| Table II.BRONJ and control group data
according to age and cumulative medication dosage. |
Table II.
BRONJ and control group data
according to age and cumulative medication dosage.
| Characteristic | Control group | BRONJ group | P-value |
|---|
| Age, years | 54.3±7.83 | 60.17±11.07 |
|
|
| 52
(48.25–60.75) | 60.5
(52.5–68.75) | 0.049 |
| Z, months | 26.37±16.17 | 35.45±18.69 |
|
|
| 22 (16–40) | 36 (22.5–42.5) | 0.094 |
| Cumulative dose,
mg | 94.32±65.31 | 135.45±76.35 |
|
|
| 88 (36–120) | 126 (72–168) | 0.037 |
In the BRONJ group, 13 out of 21 patients (61.9%)
underwent dental treatment for their recent medical condition
compared with 4 out of 18 patients (22.2%) in the control group,
which was a statistically significant difference (P=0.013). When
the incidences of diabetes mellitus (DM), smoking and steroid use
were compared with those of the control group, the difference was
not significant (P>0.05).
The percentage use of anti-angiogenic agents was 25%
(n=6) in the BRONJ group, with thalidomide being used by 5 patients
and bevacizumab being used by 1 patient, while the percentage use
was 25% (n=5/20) in the control group, with thalidomide being used
by four patients and bevacizumab being used by one patient. No
significant difference was observed between the control group and
the patients with BRONJ in the usage of anti-angiogenic agents
(P=0.798; Table II).
In terms of the progression of the main malignancy
during jaw osteonecrosis (ONJ) development, the results were 11/24
(45.8%) patients with BRONJ, and 6/20 (30%) control individuals,
which demonstrated a significant difference (P=0.03).
Discussion
BRONJ is a side-effect of BP therapy that is a
relatively rare complication, but may have a notable impact on the
quality of life of the affected patients. At present, the risk
factors of BRONJ have been researched in numerous studies (15,21,22).
The present study determined that the frequency of
BRONJ reached 3.6% in patients diagnosed with a malignancy that was
treated using intravenous administration of ZA. In the literature,
the rate of ONJ development in patients with malignancies treated
using intravenous BP administration has been reported as 1.2, 3.1
and 5% in different studies (18,21–25). It
was hypothesized that other factors such as the usage period of the
medication, patient diagnoses, presence of chronic disease and
presence of other medication usage may have had an effect on the
difference in these rates (23).
Also, the differences in ethnicity and particularly in dental
hygiene habits affected the risk of BRONJ (15,21–24).
In the present study, 33% of the patients with ONJ
were suffering from breast cancer (n=8), 33% (n=8) from MM, 25%
(n=6) from prostate cancer and 8% (n=2) from other cancers,
consisting of colon cancer and renal cell carcinoma. No significant
association was detected between the diagnosed malignancy and the
development of BRONJ (P=0.09). In certain previous studies, no
association was found between the diagnosis and BRONJ, while in
other studies it was identified that BRONJ was encountered at a
higher rate in patients with MM in comparison to the patients with
breast cancer (15,21–25).
While age was not assessed as a risk factor in the
present study, the development of BRONJ occurred in patients with a
mean age of 60.5 (range, 52.5–68.75), which was significantly
different (P=0.04) from the age of the control individuals. This
may be associated with the reduction in the metabolism of the
medication and insufficient mouth care and hygiene in patients of
advanced age.
The assessment of the association between the
development of BRONJ in patients receiving ZA and the cumulative
dose revealed that the cumulative dose of ZA was significantly
higher in patients with BRONJ (P=0.03). The median cumulative dose
was determined to be 88 mg (range, 36–120 mg) in the control group
and 126 mg (range, 72–168 mg) in the BRONJ group. The time of
exposure to ZA was determined to be 36 months in the BRONJ group
and 27 months in the control group. In previous studies, the time
of exposure to medication was identified as a risk factor in BRONJ
development (15,21–23).
However, an optimal treatment time or dose was not clearly
suggested with regard to these patients. In another study, no
association was determined between the cumulative BP dose and the
risk of BRONJ (26).
In the present study, the risk of BRONJ development
was found to be significantly higher in patients that underwent
tooth extraction while using ZA (P=0.01). Surgical dental
procedures have also been researched in previous studies, and the
status of surgical dental procedures as an important risk factor
for BRONJ development has been demonstrated (27).
The presence of DM and the incidence of smoking were
researched in previous studies as risk factors for the development
of BRONJ (23,28). In the present study, the association
between DM and smoking and the risk of BRONJ was assessed in the
BRONJ and control groups, and the results were not significantly
different (P=0.09 and P=0.08, respectively). When the previous
studies were considered, evaluating DM and smoking according to the
time of exposure to smoking and the time since DM diagnosis and the
state of DM regulation was considered to be an improved method for
the evaluation of their effects in BRONJ development.
It is also critical to identify the involvement of
steroid usage in this rare but important complication of ZA, since
a notable number of patients using ZA have MM, and steroids
constitute a component of the treatment for MM. Previous studies
have identified steroid usage as a risk factor in BRONJ development
(26,29). However, in the present study, steroid
usage was not monitored as a risk factor (P=0.8).
The association between an increased risk of BRONJ
and the administration of anti-angiogenic agents or other BPs has
been investigated in a number of small scale studies (23,30–32). There
is a previous study that specifies the use of sunitinib and ZA as a
predisposing factor to the development of BRONJ (30), and there are studies that report
bevacizumab to be a risk factor (31–33).
However, there are also studies stating that bevacizumab is not a
risk factor (23,34). No patients were co-administered with
sunitinib and ZA in the present study, but there were patients that
used bevacizumab and ZA together. The association of between
bevacizumab and ZA and the development of BRONJ was not determined
to be statistically significant (P=0.7).
In the present study, the course of disease was also
investigated during the period of BRONJ development, as was the
association between ONJ development and the state of malignancy.
The state of disease in patients with ONJ was monitored, and was
found to be improved during ZA usage, with a statistically
significant association (P=0.031). The most likely cause of the
situation may be associated with the long-term usage of ZA. The
antitumour effect of the medication may have slowed or stopped the
progress of malignancy, due to the long-term usage of ZA. However,
BRONJ was encountered more frequently in these patients.
According to the results of the present study,
advanced age, the application of dental treatment application and
cumulative dose of ZA (median, 126 mg), were found to be risk
factors for BRONJ development. Determination of ZA usage and net
cumulative dosage in BRONJ development may be presented through a
joint calculation to be carried out in the light of other studies
that need to be performed. Also, the state of malign disease was
determined to be improved during BRONJ development when compared
with the patients that did not develop BRONJ. BRONJ development may
therefore be a factor during ZA usage, particularly for patients
with advanced age. In addition, more frequent and regular dental
treatment should be administered to patients with ONJ development,
and cooperation between patients, doctors and dentists is required
for the treatment of these patients.
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