Current practice patterns of osteoporosis treatment in cancer patients and effects of therapeutic interventions in a tertiary center

Nasa Fujihara; Yuki Fujihara; Shunsuke Hamada; Masahiro Yoshida; Satoshi Tsukushi

doi:10.1371/journal.pone.0248188

Peer Review History

Original SubmissionOctober 23, 2020
2 Nov 2020 Decision Letter - Robert Daniel Blank, Editor PONE-D-20-33343 Current practice patterns of osteoporosis treatment in cancer patients and effects of therapeutic interventions in a tertiary center PLOS ONE Dear Dr. Fujihara, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Dec 17 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols We look forward to receiving your revised manuscript. Kind regards, Robert Daniel Blank, MD, PhD Academic Editor PLOS ONE Additional Editor Comments: There are several important issues that you must address before I send this MS to other reviewers. 1. Please check your MS against STROBE standards for cohort studies and add the STROBE checklist to your MS. 2. Please show p-values for table 1. My inspection of the table suggests that the treated/untreated groups differ. This should be checked explicitly, as it is an important potential source of confounding in your subsequent analysis. 3. Date of entry into study should be explicitly defined, and survival curves plotted based on study entry, not diagnosis of osteoporosis. It is necessary to unpack those who were already being treated prior to cancer diagnosis. 4. What about osteoporosis based on other low trauma fractures beside vertebral or femoral? Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). 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We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. In your revised cover letter, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). 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Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0248188.r001
Revision 1
8 Dec 2020 Author Response November, 30, 2020 Dear Editor: Thank you for checking the manuscript. We have summarized the corrections below based on your review. Thank you in advance for your kind help. Best regards, Nasa Fujihara Additional Editor Comments: 1. Please check your MS against STROBE standards for cohort studies and add the STROBE checklist to your MS. ⇒ The checklist is attached at the end of the manuscript. 2. Please show p-values for table 1. My inspection of the table suggests that the treated/untreated groups differ. This should be checked explicitly, as it is an important potential source of confounding in your subsequent analysis. ⇒ We have included it because it affects the results of the analysis as you pointed out. Although there were fewer women in the untreated group, which may lead to a lower risk of fracture, the results actually showed a higher risk of fracture. 3. Date of entry into study should be explicitly defined, and survival curves plotted based on study entry, not diagnosis of osteoporosis. It is necessary to unpack those who were already being treated prior to cancer diagnosis. ⇒As you pointed out, the starting point was the time of participation in the study, and we have corrected this to include the notation in the graph. Also, patients with a diagnosis of osteoporosis prior to the start of the study were excluded and this has been noted. 4. What about osteoporosis based on other low trauma fractures beside vertebral or femoral? ⇒ To clarify the definition, we only included the cases with vertebral or low-energy femoral fractures, or less than 70% of YAM value according to the Japanese diagnostic criteria of osteoporosis. So as you pointed out, the other low trauma fracture with high YAM value cases are not included. However, results includes all fragility fractures caused from low energy trauma. Journal Requirements: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at ⇒Done 2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information. ⇒ I have changed the manuscript following above. 3. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. In your revised cover letter, please address the following prompts: b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. ⇒Done Attachments Attachment Submitted filename: Responce to Reviewer.docx https://doi.org/10.1371/journal.pone.0248188.r002
23 Dec 2020 Decision Letter - Robert Daniel Blank, Editor PONE-D-20-33343R1 Current practice patterns of osteoporosis treatment in cancer patients and effects of therapeutic interventions in a tertiary center PLOS ONE Dear Dr. Fujihara, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Reviewer 1 wishes a few additional details regarding drug treatment. Reviewer 2 wishes a higher standard of English syntax and usage. Editor agrees with both reviewers. Please submit your revised manuscript by Feb 06 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols We look forward to receiving your revised manuscript. Kind regards, Robert Daniel Blank, MD, PhD Academic Editor PLOS ONE [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: (No Response) Reviewer #2: (No Response) ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: No ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The result is somehow expected where those being treated should have a lower incidence of fragility fracture. It is supported by this piece of research. 9% of the patients were being treated with Vitamin D. Many current studies showed the important role of Vitamin D in patients with cancer especially breast cancer. Is Vitamin D considered a treatment for osteoporosis in patient with cancer in your centre? What kind of Vitamin D was being used? Was it single therapy or in combination with anti-osteoporosis medicines? Did you look at the vitamin D level of your patients, both baseline and after treatment? Although it was mentioned in your document that there might be a role of teriparatide in treating cancer patients with osteoporosis, it is clearly stated in the teriparatide product information that it should not be used in cancer patients with skeletal metastatic lesion. What is your view on this? Reviewer #2: The paper is scientifically sound and presents useful information. However, the written language used in the manuscript is not appropriate for a scientific publication (For example: first person used not be in scientific manuscript. Editing of the paper by an individual scientist with English as their language would aid in acceptance of the paper. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0248188.r003
Revision 2
3 Feb 2021 Author Response February 3, 2021 Dear Dr. Blank, Academic Editor PLOS ONE Dear Editor: We would like to thank you for your response and for giving us the opportunity to improve and resubmit our manuscript (PONE-D-20-33343R1) entitled "Current practice patterns of osteoporosis treatment in cancer patients and effects of therapeutic interventions in a tertiary center." We are hereby resubmitting a revised manuscript conforming to all of the reviewers’ comments. In particular, we have addressed all the reviewers’ comments in a point-by-point manner and revisions are indicated in red font in the revised manuscript. We hope that the revised manuscript is now suitable for publication in your journal. Thank you for your consideration. I look forward to hearing from you. Sincerely, Nasa Fujihara, Section of Orthopedic Surgery, Aichi Cancer Center 1-1 Kanokoden Tikusa-ku, Nagoya City, Aichi, Japan 464-8681 Email: nfujihara@aichi-cc.jp Phone: 052-762-6111 FAX: 052-762-6111 Reviewer #1: The result is somehow expected where those being treated should have a lower incidence of fragility fracture. It is supported by this piece of research. 9% of the patients were being treated with Vitamin D. Many current studies showed the important role of Vitamin D in patients with cancer especially breast cancer. Is Vitamin D considered a treatment for osteoporosis in patient with cancer in your centre? What kind of Vitamin D was being used? Was it single therapy or in combination with anti-osteoporosis medicines? Did you look at the vitamin D level of your patients, both baseline and after treatment? Although it was mentioned in your document that there might be a role of teriparatide in treating cancer patients with osteoporosis, it is clearly stated in the teriparatide product information that it should not be used in cancer patients with skeletal metastatic lesion. What is your view on this? Response We would like to thank the reviewer for evaluating our manuscript and for these constructive comments. First, regarding vitamin D, we did use not the natural form of vitamin D that is often discussed nowadays. “Vitamin D” described in this study was actually “eldecalcitol” or “alfacalcidol,” which is an active vitamin D3 prodrug. Besides, we do not have a specific hospital or medical department protocol for applying Vitamin D drugs. Probably, the use of Vitamin D has been reported in some cases of breast cancer, as the reviewer stated. However, in Japan, “eldecalcitol” or “alfacalcidol” is often prescribed as an initial drug for osteoporosis treatment. Please note that we have edited the text and figures to make it clear that we used an active vitamin D3 prodrug. Especially, we have added the following sentences in the revised manuscript: “An active vitamin D3 form, the one most commonly prescribed in general practice, was used in 9% of all cases.” (Lines 137–138) “The active form of vitamin D3 included eldecalcitol and alfacalcidol.” (Line 147) Moreover, teriparatide's contraindication for cancer patients with skeletal metastatic lesion is mainly based on past studies showing that teriparatide increased osteosarcoma in rats. However, in this study on rats, the used doses were dozens of times higher and provided for a longer period of time than those given to humans. Therefore, there are many arguments regarding whether it can directly apply to humans. In fact, as a recent study that analyzed the data of patients from a US database did not show any evidence concerning the role of teriparatide in increasing osteosarcoma or malignant bone tumors, we believe that the indications for teriparatide will be expanded in the future. Alternatively, another new osteoporosis drug, romosozumab, is indicated for cancer patients and may be a useful treatment option. Please note that we have included these issues in the discussion of the revised manuscript as follows: “However, recent research has provided new evidence concerning the use of teriparatide (25, 30, 31). Interestingly, Gilsenan et al. reported that the incidence of osteosarcoma associated with teriparatide use during a 15-year period was not different than what was expected based on the background incidence rate of osteosarcoma after examining data from a US database (30). Besides, other new agents, such as romosozumab, humanized IgG2 monoclonal antibody, or annual zoledronic acid, were allowed to be used for the treatment of cancer patients. These relatively new drugs will be used more aggressively for such patients in the future.” (Lines 256–263) Reviewer #2: The paper is scientifically sound and presents useful information. However, the written language used in the manuscript is not appropriate for a scientific publication (For example: first person used not be in scientific manuscript. Response We would like to thank the reviewer for evaluating our manuscript and for this comment. Please note that we have sent our manuscript to an English editing company (Editage) for English proofreading. We hope that the level of English has significantly improved in the revised manuscript. Attachments Attachment Submitted filename: Responce_to_Reviewers_0203.docx https://doi.org/10.1371/journal.pone.0248188.r004
22 Feb 2021 Decision Letter - Robert Daniel Blank, Editor Current practice patterns of osteoporosis treatment in cancer patients and effects of therapeutic interventions in a tertiary center PONE-D-20-33343R2 Dear Dr. Fujihara, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Robert Daniel Blank, MD, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Change all DEXA to DXA. The question about the use of vitamin D has been well explained. Agreed with the input on the role of teriparatide. Reviewer #2: (No Response) ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No https://doi.org/10.1371/journal.pone.0248188.r005
Formally Accepted
1 Mar 2021 Acceptance Letter - Robert Daniel Blank, Editor PONE-D-20-33343R2 Current practice patterns of osteoporosis treatment in cancer patients and effects of therapeutic interventions in a tertiary center Dear Dr. Fujihara: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Professor Robert Daniel Blank Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0248188.r006

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