Keywords
Awareness - bisphosphonate-related osteonecrosis of the jaw - bisphosphonates - osteonecrosis
- physicians
Introduction
Over the years, several developments in the field of oncology have dramatically changed
the course of the disease and improved the survival and quality of life of patients,
who were once considered incurable. The advances in the imaging modalities help in
early detection of metastatic disease so that aggressive therapeutic regimens are
instituted even in Stage IV disease. Several agents have been introduced to reduce
the skeletal morbidity of metastatic bone disease, among which bisphosphonates (BP)
play a major role. BP are antiresorptive agents that have been used for more than
a decade, for the treatment of metabolic bone diseases, such as osteoporosis and osteopenia,
and to control the skeletal complications associated with metastatic bone disease.[1] Despite their proven efficacy as antiresorptive drugs, a devastating side effect,
“bisphosphonate-related osteonecrosis of the jaw” (BRONJ), has been documented over
the past decade.[2]
[3] Marx reported the first case in 2003,[4] following which several cases of osteonecrosis have been reported.[5]
[6] The American Association of Oral and Maxillofacial Surgery (AAOMS) in its position
paper in 2014[7] recommended changing the nomenclature of BRONJ to medication-related osteonecrosis
of the jaw (MRONJ) due to the growing number of reports of cases of osteonecrosis
associated with other antiresorptive and antiangiogenic medications. AAOMS defined
BRONJ as “exposed bone or bone that can be probed through an intraoral or extraoral
fistula in the maxillofacial region that has persisted for more than eight weeks in
a patient with current or previous history of bisphosphonate therapy and no history
of radiation therapy or obvious metastatic disease to the jaws.”[7]
BRONJ is a relatively new entity, and the treating physicians and even the dental
professionals may not be very much aware of this complication in patients on BP. A
history of bisphosphonate use for osteoporosis or metastatic cancer should make the
dentists wary about the risk of osteonecrosis of jaw (ONJ). The physicians prescribing
BP for osteoporosis, metastatic bone disease, or hypercalcemia may not be very observant
about the oral health [8] of these patients and complications such as jaw osteonecrosis may go undetected.
At the same time, details of bisphosphonate use may not come to the notice of the
treating dental professionals, either due to incomplete history or the patient himself
being ignorant of the drug, and its possible side effects due to which the history
is not contributory. Pathophysiology of BRONJ is still unclear, but poor oral hygiene
and oral health and invasive dental procedures have been proposed as risk factors.[9] Hence, good knowledge of the drug, its indications and adverse effects are essential
for possible prevention, early detection, and management of this not so common complication.
This would help them to identify patients at risk, and educate them about the prevention
and management of BRONJ and thus make them aware of the associated signs and symptoms.
In cancer patients, receiving intravenous bisphosphonate therapy, ONJ can be easily
mistaken for a metastatic lesion due to its clinical presentation and imaging characteristics.[10] The practicing oncologist, the radiologist, the nuclear medicine specialist, and
the dental specialist must all be aware of BRONJ as an entity mimicking bone metastasis.
Early recognition will facilitate early diagnosis, minimize the need for biopsies,
and multiple unnecessary imaging studies, and most importantly, allow appropriate
treatment measures to be initiated. Other health-care professionals such as orthopedicians
and general physicians prescribe BP and other antiresorptive agents for osteoporosis
and hypercalcemia and hence should be aware of the adverse effects of the drug and
the risk factors. The ear-nose-throat (ENT) surgeons and the dental professionals
share a common work area, the oral cavity, and hence should be able to identify exposed,
necrotic bone or stages leading to it; so that early diagnosis, intervention, and
patient education are possible. Our study aimed to assess the knowledge and awareness
of physicians regarding BRONJ and practices related to bisphosphonate use.
Subjects and Methods
A questionnaire tool* was developed to assess the awareness of physicians about BRONJ
and practices related to bisphosphonate use. The questionnaire consisted of 21 questions,
of which 12 were knowledge based and 9 were practice based. Of the 12 knowledge-based
questions, three were on BP, and nine on BRONJ. Each question had three to four options
and each option had a “Yes” or “No” response.
The questionnaire was assessed by three experts separately for evaluation of its content
validity. Each validator was provided with a criteria checklist for validation, where
they would rate each question on a scale of “0” to “5,” “0” being the least score
suggesting inappropriateness of the question and “5” being the best score suggesting
it to be most appropriate.
[INLINE:1]
The modifications suggested were incorporated and the tool was finalized for the main
study.
A pilot study was then conducted among five physicians. The responses were given scores,
“1” for correct response and “0” for wrong response in case of the questions pertaining
to knowledge assessment; and the responses to the practice-based questions were scored
as “1” for “Yes” and “2” for “No.”
To calculate the reliability of the knowledge questionnaire, Cronbach’s alpha was
used. The following formula was used for the calculation:
[INLINE:2]
Where k is the number of items (37).
[INSIDE:1] is the variance of the “i”th item ([INSIDE:2] = 7).
[INSIDE:3] is the variance of the total score formed by summing all the items ([INSIDE:4]
= 55.8).
Cronbach’s alpha = 0.898 (0.9) was obtained which proved the tool to be reliable.
The results of the pilot study conducted were used to calculate the sample size. It
was observed that 40% of the physicians in the pilot study had good knowledge (Score
≥29) regarding BP and ONJ. The sample size was then computed using the technique of
estimation of proportion:
[INLINE:3]
Where, α = level of significance = 5%.
d = precision = 15%p = anticipated knowledge = 40%.
The calculated sample size was 41. The questionnaire was distributed among 113 health-care
professionals in various tertiary care hospitals in Mangalore; their responses assigned
scores, tabulated, and their awareness, knowledge, and practices regarding BP and
BRONJ were assessed. The results obtained were subjected to statistical analysis.
Results
The scores were assigned as “0” for wrong response and “1” for correct response. Thus,
the maximum possible score in the section on knowledge assessment was 36. The study
population consisted of medical professionals, 68 consultants and 44 residents (one
person did not mention his designation), from the specialties of oncology (7), orthopedics
(28), urology (13), ENT (11), general medicine (39), and general surgery (15).
The years of experience in the specialty ranged from 1 month to 35 years, with a mean
of 5.17 years and a standard deviation of 5.89. The maximum score attained in the
knowledge section of the questionnaire was 33 out of 36, and the minimum score obtained
was 5. The average score attained was 16 (44.4%) with a standard deviation of 6.17.
In more than 50% of the doctors, the responses to 22 out of 36 items were either wrong
or no response marked, which showed lack of knowledge about BP and BRONJ. About 53%
of the doctors obtained a score of >50% in the questions on the drug BP, but in the
section of BRONJ, 71% of them scored <50%. With regard to BP, 51.3% and 53.1% doctors
did not know their use in the treatment of hypercalcemia and bone metastases, respectively.
About 63% of the physicians did not know BRONJ as a complication in patients on oral
BP, and 76% did not know that BRONJ could occur in patients with a history of BP therapy.
BRONJ was considered, as a self-limiting condition by 76% and 83.2% believed that
it regresses after stoppage of BP therapy, and 60.2% did not consider it to be a challenging
condition to treat. BRONJ could be treated medically alone was the assumption of 77%
of the physicians. 45% of the medical professionals in the study group failed to identify
the clinical features of BRONJ, and 67.26% were unaware of the risk associated with
tooth extractions and oral surgical procedures in the development of the condition.
Based on the response to the practice-based questions, it was found that among the
doctors who see 5–10 patients/month on BP, 69.2% got a score <50% and only one secured
>80%. Majority of them got a score <40%; four out of seven doctors who see more than
10 patients/month on BPs secured <50%.
The comparison of the scores obtained by the consultants and residents was done using
the unpaired t-test, the significance set at the level of 0.05. P value obtained was 0.046, and therefore, it was found that there was a difference
between the knowledge scores of consultants and residents at 5% level of significance
[Table 1].
Table 1
Comparison of knowledge scores obtained by consultants and residents
|
Designation
|
n
|
Mean score
|
SD
|
t
|
P
|
|
SD - Standard deviation
|
|
Consultants
|
68
|
16.8824
|
6.73492
|
2.018
|
0.046
|
|
Residents
|
44
|
14.6364
|
5.01667
|
|
|
The mean scores in each specialty were obtained, and comparison of the scores in each
specialty was performed using the one-way analysis of variance [Table 2]. The results showed that the highest mean score obtained was by the oncologists
(23), followed by the urologists (20), orthopaedicians (18), general surgeons (13.7),
general physicians (13.69), and the ENT surgeons attained the least score (12).
Table 2
Comparison of mean knowledge scores according to specialty by using one-way analysis
of variance
|
Specialty
|
n
|
Mean score
|
SD
|
F
|
P
|
|
SD - Standard deviation; ENT - Ear-nose-throat
|
|
Oncology
|
7
|
23.0000
|
7.09460
|
8.050
|
<0.001
|
|
Urology
|
13
|
20.3846
|
6.34479
|
|
|
|
Orthopedics
|
28
|
18.0714
|
5.27698
|
|
|
|
General surgery
|
15
|
13.7333
|
3.36933
|
|
|
|
General medicine
|
39
|
13.6923
|
5.76356
|
|
|
|
ENT
|
11
|
12.0909
|
3.75379
|
|
|
The comparison of the specialties, with respect to the scores attained in the knowledge
questionnaire, was carried out using the Tukey test, with the significance set at
0.05 [Table 3]. There was no significant difference between the scores obtained by the urologists
and the oncologists. It was found that there was a significant difference between
the scores obtained by the specialists in urology, and the specialties of ENT (P = 0.004), general medicine (P = 0.002), and general surgery (P = 0.018). A significant difference was also noted between the knowledge scores of
oncology, and that of ENT (P = 0.001), general medicine (P = 0.001), and general surgery (P = 0.004). There was also a significant difference between the mean scores of the
orthopedicians and the ENT surgeons (P = 0.027), and the specialists in general medicine (P = 0.017).
Table 3
Multiple comparison of knowledge by using Tukey test
|
Specialty
|
Specialty
|
Mean difference
|
P
|
|
The mean difference is significant at the 0.05 level. ENT - Ear-nose-throat
|
|
Urology
|
ENT
|
8.29371
|
0.004
|
|
Urology
|
General medicine
|
6.69231
|
0.002
|
|
Urology
|
General surgery
|
6.65128
|
0.018
|
|
Orthopedics
|
ENT
|
5.98052
|
0.027
|
|
Oncology
|
ENT
|
10.90909
|
0.001
|
|
Orthopedics
|
General medicine
|
4.37912
|
0.017
|
|
Oncology
|
General medicine
|
9.30769
|
0.001
|
|
Oncology
|
General surgery
|
9.26667
|
0.004
|
Questions based on practice revealed that osteoporosis and metastatic cancer were
the indications for BP in the patients seen by these professionals, intravenous was
the most common route of administration, and cancer chemotherapy was the concomitant
drug therapy in the majority of them.
Discussion
Physicians should inform the patients, in whom bisphosphonate therapy is to be initiated,
about the benefits and risks of therapy, including BRONJ. If the systemic condition
permits, treatment with BP should be delayed until the dentist evaluates the patient.[11] It is recommended that dental surgeons evaluate and treat patients scheduled to
receive an intravenous BP, similar to those patients scheduled to initiate radiotherapy
to the head and neck. Once bisphosphonate therapy is initiated, the maintenance of
good oral hygiene and dental care is of paramount importance in preventing a dental
disease that might require dentoalveolar surgery. Stopping BP before invasive dental
surgery does not seem to decrease the chance of developing BRONJ given the very long
half-life in bone.[12] Moreover, oncology patients benefit greatly from the therapeutic effects of BP,
because they control bone pain and incidence of pathological fractures and discontinuation
of BP at this stage does not offer any short-term benefit.[11]
A recent study conducted among Lebanese physicians showed an alarmingly deficient
knowledge regarding BRONJ. It was observed that they were unaware that ONJ could be
a bisphosphonate-related undesirable event, which is similar to the findings in our
study. They had confused ideas regarding the clinical features, diagnosis, and management
of the condition. It was recommended that more research should be conducted to better
establish the level of knowledge in different settings, and also that international
studies with different groups of physicians might help understand, how medical education
can be compared in different physician cohorts around the world with regard to this
devastating complication.[13]
The knowledge of dental professionals and dental students about BP: and BRONJ has
been found to be poor as evidenced in a study on Brazilian dentists. They were unable
to identify the drugs belonging to the class of BP, their medical indications, and
also the risk factors for BRONJ. The findings reflect the lack of awareness and recognition
of the importance of awareness.[14]
Al-Mohaya et al.[15] in their questionnaire survey found that physicians and dentists have low awareness
and deficient knowledge regarding BRONJ, although most of them do prescribe BP to
their patients. Less than one-third of the participants (31.5%) were aware of ONJ.
In our study, conducted among medical professionals alone, 71% of the doctors scored
<50% in the questionnaire section on BRONJ.
The results of our study are in concordance with a similar study carried out in the
North East of England during the same period among general practitioners and pharmacists.
There was uncertain knowledge among the participants about BRONJ, its prevalence,
the risk factors for its development, and also had limited exposure to the condition.[16]
Another questionnaire survey conducted in North Wales among general practitioners
and pharmacists, describing their attitudes toward, their perceptions of, and their
roles in preventive strategies for BRONJ reported awareness of the side effects of
BP; however, only 11.8% of general practitioners (GPs), and 9.7% of pharmacists specifically
identified osteonecrosis as a potential unwanted effect of therapy.[17]
A recent study was conducted to review legal databases in the USA to research judicial
processes against doctors as a consequence of misconduct in the diagnosis and treatment
of oral cancer, in addition to inadequate practices with regard to oral side effects
caused by oncological treatment and antiresorptive therapies, including BRONJ. The
data revealed that one of the highest recoveries was $10,450,000, which was paid to
a patient with breast cancer, who had been under treatment with BP, and the professional
failed to recognize the risk for BRONJ. Thus, to minimize the possibility of such
processes and financial indemnifications, dental and medical professionals must be
trained to identify the oral side effects of certain medications with emphasis on
BP. Lack of prevention, recognition, and management of oral complications can lead
to medico-legal action.[18]
Because ONJ is associated with drugs like bisphosphonate which decrease bone turnover
by inhibiting osteoclast, any new inhibitors of osteoclast differentiation and function
that enter the pharmacologic armamentarium for the treatment of diseases, with increased
bone turnover must be closely studied and observed for potential ONJ as a side effect.
Few drugs have been added to the class of drugs associated with ONJ such as denosumab,
a human monoclonal antibody which inhibits receptor activator of nuclear factor kappa-B
ligand (RANKL), used in the treatment of postmenopausal osteoporosis and metastatic
bone cancers; bevacizumab, a vascular endothelial growth factor inhibitor; and tyrosine
kinase inhibitors such as sunitinib and sorafenib. Several cases of ONJ have been
reported in patients on these drugs. Data are emerging to show that BP or denosumab
in combination with targeted antiangiogenic therapies [19] increase the likelihood of Medication Related Osteonecrosis of the Jaw (MRONJ).
The risk of ONJ in patients on oral BP used for the management of osteoporosis, namely
alendronate, ibandronate, and risedronate, is less compared to that with intravenous
BP and is estimated to be around one in 10,000/year of use.[20]
Conclusion
The medical practitioners in our study reported uncertain knowledge about the side
effects of BP and BRONJ in particular. This could be attributed to BRONJ being a new
and rare disease entity, described in the past decade due to the increasing use of
BP. Moreover, in this era of subspecialization, the involvement of the primary physicians
in advanced cancer care seems to be limited. As dedicated oncology departments are
getting established in most centers in recent years and are involved in upfront chemotherapy,
the role of other specialists in managing cancer is limited to the diagnosis and initial
management. Lack of tumor board discussions and multispecialty interactions could
be a contributing factor to the low level of understanding of this rare side effect
of a standard drug therapy.
Bisphosphonate-related osteonecrosis is almost exclusively seen in the jaws and hence
the diagnosis usually made by a dental practitioner. Lack of awareness of jaw osteonecrosis
among the medical practitioners can result in delay in providing the right treatment
and has in a few instances resulted in unnecessary investigations, and biopsies due
to misdiagnosis of the condition as a metastatic bony lesion. Hence, a good knowledge
of the probable causes and the clinical features can help in the prevention, early
diagnosis and prompt management of a not so common complication. Better interaction
between the medical and dental fraternity and continuing medical education programs
may play a major role in enhancing the knowledge and awareness among medical professionals.
Questionnaire*
Questionnaire: Questionnaire tool used for study
Specialty: ______________________________________________
Designation: ____________________________________________
Years of Experience in specialty: ___________________________
1) Bisphosphonates (BP) are drugs used to treat:
a) Hypercalcemia of malignancy [Yes/No]
b) Osteopenia [Yes/No]
c) Bone metastases [Yes/No]
2) Which of the following drugs belong to the class of Bisphosphonates?
a) Zoledronic acid [Yes/No]
b) Pamidronate [Yes/No]
c) Ibandronate [Yes/No]
3) How many patients do you see on bisphosphonates per month?
a) <5 [Yes/No]
b) 5–10 [Yes/No]
c) >10 [Yes/No]
4) What is the indication of BP therapy in these patients?
a) Osteopenia [Yes/No]
b) Cancer [Yes/No]
c) Osteoporosis [Yes/No]
5) What is the route of administration of BP in these patients?
a) Oral [Yes/No]
b) Intravenous [Yes/No]
c) Both oral and intravenous [Yes/No]
6) What are the other adjuvant medications in these patients?
a) Steroid [Yes/No]
b) Chemotherapy [Yes/No]
c) Others [Yes/No]
7) Do you examine the oral cavity of patients on BP therapy? [Yes/No]
8) Do you recommend dental checkup in patients before BP therapy? [Yes/No]
9) Do you recommend regular dental checkups in patients on BP therapy? [Yes/No]
10) Have you ever noticed exposed necrotic bone of the jaw among these patients? [Yes/No]
11) Which of the following are the adverse effects noted with BP therapy?
a) Bone pain [Yes/No]
b) Osteonecrosis [Yes/No]
c) Flu-like symptoms [Yes/No]
12) Bisphosphonate-induced osteonecrosis is known to occur in the:
a) Spine [Yes/No]
b) Jaws [Yes/No]
c) Ribs [Yes/No]
13) How many patients have you seen with osteonecrosis as a complication of BP therapy?
a) 1-5 [Yes/No]
b) 6-10 [Yes/No]
c) >10 [Yes/No]
d) Nil [Yes/No]
14) Bisphosphonate-induced osteonecrosis can occur in patients:
a) On oral bisphosphonates [Yes/No]
b) On intravenous bisphosphonate therapy [Yes/No]
c) With past history of bisphosphonate therapy [Yes/No]
15) The following drugs have been implicated to cause osteonecrosis of the jaws:
a) Denosumab [Yes/No]
b) Zoledronic acid [Yes/No]
c) Sunitinib [Yes/No]
16) The development of bisphosphonate-related osteonecrosis of the jaw maybe:
a) Spontaneous [Yes/No]
b) Following surgical procedures in the jaws [Yes/No]
c) Following dental extractions [Yes/No]
17) The signs and symptoms of osteonecrosis of jaws include:
a) Pain [Yes/No]
b) Exposed bone [Yes/No]
c) Oro-cutaneous fistula [Yes/No]
18) Diagnosis of osteonecrosis of jaws is mainly:
a) Clinical [Yes/No]
b) Radiological [Yes/No]
c) Histopathological [Yes/No]
19) Management of bisphosphonate-induced osteonecrosis of jaws includes:
a) Medical management only [Yes/No]
b) Surgical management only [Yes/No]
c) Combination of medical and surgical therapy [Yes/No]
20) Bisphosphonate-induced osteonecrosis of jaws:
a) Is a self-limiting condition [Yes/No]
b) Regresses after stoppage of bisphosphonate therapy [Yes/No]
c) Is a challenging condition to treat. [Yes/No]
21) Bisphosphonate-induced osteonecrosis of jaws can be prevented to a large extent
by:
a) Strict oral hygiene measures/practices [Yes/No]
b) Dental checkups/treatment before initiation of BP therapy [Yes/No]
c) Regular dental checkup [Yes/No]
