What Do Prescribers of Bone Modifying Agents Know about Medication-Related Osteonecrosis of the Jaw? Is Current Prevention Enough?

Round 1

Reviewer 1 Report

The manuscript is well written and the topic is interesting, but there are important points that can be improved:

1) It is not clear the aim of the study both in the abstract and at the end of the introduction; must the dentist have a role only in the prevention or also in the treatment of MRONJ? Specify

2)On the base of the aim of the study, the title can be improved to better specify the topic of the article. 

3) The conclusions are too long and dispersive and do not focus on the true message to be transmitted to readers.

Author Response

We thank the reviewer for his evaluation of our manuscript. We are grateful for the constructive criticisms and we have addressed the issues identified. We hope that the changes incorporated into the revised text as outlined in the point-by-point responses below will answer all questions raised by the reviewer.

1) It is not clear the aim of the study both in the abstract and at the end of the introduction; must the dentist have a role only in the prevention or also in the treatment of MRONJ? Specify

The aim of our study was to investigate awareness of MRONJ among BMA prescribers, their current prescribing practices, and what preventative measures are currently used by different specialties for patients prescribed BMA. The goals of our study were to evaluate current knowledge about MRONJ caused by different BMA through a survey performed in an academic hospital, in order to evaluate current gaps in knowledge with the aim of improving the quality of care and life of MRONJ patients.

These modifications have been added at the end of the introduction section and in the abstract (lines 21-32 and 86-92). 

2) On the base of the aim of the study, the title can be improved to better -specify the topic of the article

Thank you for this comment. We have revised the title to reflect the topic of the article better. The new title is: "What do prescribers of bone modifying agents know about Medication-Related Osteonecrosis of the Jaw? Is current prevention enough?"

3) The conclusions are too long and dispersive and do not focus on the true message to be transmitted to readers. 

Thank you for your comment. We have edited the conclusions to better represent the message intended for the readers. These changes have been incorporated in lines  301-321:

"BMA prescribers of different specialties including rheumatology, oncology, endocrinology, and general medicine have relatively good awareness of MRONJ and of the drugs associated with this condition. Most physicians recommend a dental check-up prior to initiating treatment with bisphosphonates, but this practice is less prevalent for other BMA. Patients that required dental treatment while on BMA therapy were more likely to be recommended a temporary withdrawal of the drug only when using bisphosphonates, but not when using any other BMA. When providing dental care to patients with osteoporosis or bone metastases, dentists and physicians must work together to assess the patient’s drug history and general health. Attention should be paid to newer BMA like denosumab and sunitinib and not only to classic agents like bisphosphonates. Health care professionals should improve communication and clear guidelines to prevent MRONJ should be introduced while knowledge of the link between ONJ and new angiogenetic therapies are still being researched"

Reviewer 2 Report

To test and improve knowledge about MRONJ among healthcare professionals is very important topic. However this article has some major flaws.

There is referred to the old version of AAOMS recommendation (2014) instead of actual one (2022):

Ruggiero SL, Dodson TB, Aghaloo T, Carlson ER, Ward BB, Kademani D. American Association of Oral and Maxillofacial Surgeons’ Position Paper on Medication-Related Osteonecrosis of the Jaw—2022 Update. Journal of Oral and Maxillofacial Surgery. Published online February 21, 2022. doi:10.1016/j.joms.2022.02.008

Generations of bisphosphonates and their risk profiles are not mentioned. Application form (p.o. vs i.v.) has only limited relevance.

Denosumab could be applied also once a month in cancer patients. This is related to greater risk of MRONJ

Treatment strategies are mentioned both in introduction and discussion section. The posibility of mandibular resection in not mentioned, despite it is quite often needed.

I recommend to transfer MORONJ definition and stages into tables.

There is many typing errors in the text

Term oro-sinus communication in not widely used, more common is oro-antral

Author Response

We thank the reviewer for his evaluation of our manuscript. We are grateful for the constructive criticisms and we have addressed the issues identified. We hope that the changes incorporated into the revised text as outlined in the point-by-point responses below will answer all questions raised by the reviewer.

There is referred to the old version of AAOMS recommendation (2014) instead of actual one (2022):

Thank you for your comment. We have revised the references to include the newer recommendations. 

Generations of bisphosphonates and their risk profiles are not mentioned. Application form (p.o. vs i.v.) has only limited relevance.

Thank you for your comment. Our study revealed that prescribers used both second and third-generation bisphosphonates which is now mentioned in the text (line 134-135).

Denosumab could be applied also once a month in cancer patients. This is related to greater risk of MRONJ

Thank you for your comment. This information has been added in lines 200-203.

Treatment strategies are mentioned both in introduction and discussion section. The posibility of mandibular resection in not mentioned, despite it is quite often needed.

Thank you for your comment. This information has been added in lines 232-233.

I recommend to transfer MORONJ definition and stages into tables.

Thank you for your comment. The definition and staging of MRONJ has been included in table 1 as follows:

There is many typing errors in the text

Thank you for your comment. We have revised the text and corrected the typing errors identified.

Term oro-sinus communication in not widely used, more common is oro-antral

Thank you for your comment. The term has been corrected in line 63.

Reviewer 3 Report

Re: applsci-1873234

MRONJ is a refractory disease that often requires extensive jaw resection. In this respect, it is important to establish not only treatment procedures after the onset of the disease, but also effective preventive methods on MRONJ. For this purpose, it is essential to share information between medicine and dentistry and to understand the pathogenesis of MRONJ. In this study, prescribing physicians had a questionnaire to evaluate their perceptions of MRONJ, and this is an important study. However, the study only examined at the prescribers' side, and did not evaluate the level of awareness on the dental side. If the title of this study is “multidisciplinary approach”, information not only from dentists but also from dental hygienists, dental assistants, technicians, pharmacists, etc. is necessary. In addition, it is not a study of the multidisciplinary approach unless some information is disseminated and the same questionnaire is conducted before and after the information and the results are compared. This study is just the result of a survey of prescribing physicians in the current study design.

The following points need to be considered regarding the questionnaire: The questionnaire needs to be added in the text. The response rate for the questionnaire should be considered. It is necessary to evaluate the data statistically. If the response rate is low, the results may not be statistically meaningful.

Author Response

We thank the reviewer for his evaluation of our manuscript. We are grateful for the constructive criticisms and we have addressed the issues identified. We hope that the changes incorporated into the revised text as outlined in the point-by-point responses below will answer all questions raised by the reviewer.

MRONJ is a refractory disease that often requires extensive jaw resection. In this respect, it is important to establish not only treatment procedures after the onset of the disease, but also effective preventive methods on MRONJ. For this purpose, it is essential to share information between medicine and dentistry and to understand the pathogenesis of MRONJ. In this study, prescribing physicians had a questionnaire to evaluate their perceptions of MRONJ, and this is an important study. However, the study only examined at the prescribers' side, and did not evaluate the level of awareness on the dental side. If the title of this study is “multidisciplinary approach”, information not only from dentists but also from dental hygienists, dental assistants, technicians, pharmacists, etc. is necessary. In addition, it is not a study of the multidisciplinary approach unless some information is disseminated and the same questionnaire is conducted before and after the information and the results are compared. This study is just the result of a survey of prescribing physicians in the current study design.

Thank you for your comments. We have changed the title of the manuscript to better reflect the content, as also suggested by reviewer 1.

The following points need to be considered regarding the questionnaire: The questionnaire needs to be added in the text.

Thank you for your comment. The questionnaire has been added in the manuscript.

The response rate for the questionnaire should be considered. It is necessary to evaluate the data statistically. If the response rate is low, the results may not be statistically meaningful.

Thank you for your comments. For our study, we identified 90 BMA prescribers in our hospital. Out of these 14 were excluded for a lack of a valid email address or not being available for response during the time of the study. A questionnaire was sent to each of the remaining 76 prescribers, out of which 55 answered, which constitutes a response rate of 72%, which was considered relevant for our purpose. This information has been added to the manuscript in lines 126-131.

Round 2

Reviewer 1 Report

The manuscript can be accepted

Author Response

We thank the reviewer for their time and effort and for their help in improving our manuscript.

Reviewer 2 Report

The manuscript was updated appropriately and I recommend it for publication. I find only some minor errors:

Line: 160 - posology, 185 - risck

Line 201 and 213 - local hygiene In this connotation oral hygiene is more used

Author Response

We thank the reviewer for their time and effort and for their help in improving our manuscript. Regarding the minor errors identified, they have been corrected:

Line 160: Posology has been changed to dosing;

Line 185: Risck was corrected to risk

Line 201 and 213: local hygiene was changed to oral hygiene

Reviewer 3 Report

applsci-187324 ver2

The points which were figured out last time and the response from the authors were listed below;

1.     Thank you for your comments. We have changed the title of the manuscript to better reflect the content, as also suggested by reviewer 1.

This title was still not much as the context. This study showed just whether continuation of the drug or not. No prevention information was described.

2.     The following points need to be considered regarding the questionnaire: The questionnaire needs to be added to the text. Thank you for your comment. The questionnaire has been added to the manuscript.

Thank you for your effort.

3.     The response rate for the questionnaire should be considered. It is necessary to evaluate the data statistically. If the response rate is low, the results may not be statistically meaningful. Thank you for your comments. For our study, we identified 90 BMA prescribers in our hospital. Out of these 14 were excluded for a lack of a valid email address or not being available for response during the time of the study. A questionnaire was sent to each of the remaining 76 prescribers, out of which 55 answered, which constitutes a response rate of 72%, which was considered relevant for our purpose. This information has been added to the manuscript in lines 126-131.

The paragraph of line 124-131 in the text was following; “Current knowledge of the definition of MRONJ was very prevalent in our responders 124 (91%), regardless of specialty, although most prescribers preferred the previous notion of 125 bisphosphonate-related osteonecrosis of the jaw (BRONJ) to MRONJ or antiresorptive 126 drugs related osteonecrosis of the jaw (ARONJ) with 70% vs. 17% and 13% respectively. 127 Most of the physicians surveyed had encountered patients with MRONJ, with an average 128 of 62%, but there were differences related to their field of practice with all oncologists 129 having encountered this complication, 60% of endocrinologists and rheumatologists, and 130 only 36% of general practitioners.” 

Where was your update added. In addition, please describe the statistical study with considering the response rate. Moreover, your response rate was 55/90, not 55/76.

Author Response

We thank the reviewer for his continued effort in improving our manuscript. We are grateful for the constructive criticisms and we have addressed the issues identified. We hope that the changes incorporated into the revised text as outlined in the point-by-point responses below will answer all questions raised by the reviewer.

This title was still not much as the context. This study showed just whether continuation of the drug or not. No prevention information was described.

The questionnaire asked whether prescribers recommended dental check-ups before initiating BMA or if they recommended drug withdrawal before dental procedures, which we considered preventative measures. For this, we felt including the term prevention in the title was appropriate.

The paragraph of line 124-131 in the text was following; “Current knowledge of the definition of MRONJ was very prevalent in our responders 124 (91%), regardless of specialty, although most prescribers preferred the previous notion of 125 bisphosphonate-related osteonecrosis of the jaw (BRONJ) to MRONJ or antiresorptive 126 drugs related osteonecrosis of the jaw (ARONJ) with 70% vs. 17% and 13% respectively. 127 Most of the physicians surveyed had encountered patients with MRONJ, with an average 128 of 62%, but there were differences related to their field of practice with all oncologists 129 having encountered this complication, 60% of endocrinologists and rheumatologists, and 130 only 36% of general practitioners.” Where was your update added. In addition, please describe the statistical study with considering the response rate. Moreover, your response rate was 55/90, not 55/76.

Due to using the "Track changes function" the line numbers were changed in the manuscript received by the reviewers. The information has been included at the beginning of the Results section, which corresponds to lines 103-108. We apologize for this confusion. 

Regarding the response rate, we calculated it as the number of responses (55) divided by the total number of questionnaires sent (76). Taking into consideration also the number of prescribers unavailable for response (14), we calculated an attainability rate of 61% (55/90). We have included this information into the manuscript, line 108.