Predictors for self-discontinuation of anti-osteoporosis medication: A hospital-based real-world study

Ya-Lian Deng; Chun-Sheng Hsu; Chiann-Yi Hsu; Chih-Hui Chen; Shiang-Ferng Ou; Chin-Feng Liu; Shu-Hui Yang; Chun-Hsi Shih; Yi-Ming Chen; Hsu-Tung Lee

doi:10.1371/journal.pone.0275020

Peer Review History

Original SubmissionOctober 30, 2021
14 Jul 2022 Decision Letter - Maria Maddalena Sirufo, Editor PONE-D-21-34699Predictors for Self-Discontinuation of Anti-osteoporosis Medication: a Hospital-based Real-world StudyPLOS ONE Dear Dr. Chen, 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 Aug 28 2022 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. 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Additional Editor Comments (if provided): Specify better why denosumab is the drug most subject to interruption, as in our experience it is the most tolerated and least subject to interruption. specify the concept [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. 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: Partly Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. 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 ****** 4. 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: No Reviewer #2: Yes ****** 5. 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: lines 8-10: "Comparisons among groups and risks of self-discontinuation were analyzed. Among 695 patients, 375 (54%) self-discontinued, 64 (9.2%) discontinued due to physicians’ suggestion, and 256 (36.8%) died." The death may not be considered a cause of discontinued therapy. The authors may explain better the concept. paragraph 2.2: the authors considered a cause of discontinuation of medication the death. This event can't be compared with the others two causes (self-discontinuation and discontinuation due to the physician’s recommendation) if the scope of this study is "to investigate risk factors and causes of poor medication adherence in patients with osteoporosis, with a view to improving medication persistence." Please expose better the concept. Reviewer #2: Dear authors, Thank you for completing this work for me to review. Very interesting cohort study, PONE-D-21-34699, entitled “Predictors for Self-Discontinuation of Anti-osteoporosis Medication: a Hospital-based Real-world Study”. Only two questions were aroused while reading through your work. First, what were the definitions of discontinuation of all the medication except for the denosumab and teriparatide mentioned in the method part? Do you think it is more reasonable to set up the definition of discontinuation according to the half-life of each of the selected medication? Or, please state your criteria accordingly. Second, why the discontinuation rate of denosumab is the highest among all the medications, which is contrary to our clinical experiences, especially compared to those short half-life oral medications? Is it due to the definition of inclusion criteria or selection bias? Thank you. ****** 6. 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: Yes: Yu-Jih Su, MD, PhD. ******** [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.0275020.r001
Revision 1
6 Sep 2022 Author Response Dear reviewers and editor, We would like to express our sincere thanks to you and the reviewers for your thorough review of our manuscript and for the opportunity to submit a revised and improved version. We believe that by addressing the concerns, we have considerably improved our manuscript. We have provided point-by-point responses to the reviewers’ comments. Below is the author’s response to reviewer’s comments and suggestions. Reviewer #1 Point 1: lines 8-10: "Comparisons among groups and risks of self-discontinuation were analyzed. Among 695 patients, 375 (54%) self-discontinued, 64 (9.2%) discontinued due to physicians’ suggestion, and 256 (36.8%) died." The death may not be considered a cause of discontinued therapy. The authors may explain better the concept. Author’s response: Thank you for the comment. We agree with the reviewer’s opinion that the death may not be considered a cause of self-discontinuation of anti-osteoporosis therapy. Mortality should be considered as unintended discontinuation of treatment. Patients enrolled in the unintended discontinuation group mainly included patients with good adherence to anti-osteoporotic medication before death, and they stopped using anti-osteoporotic medication due to mortality. To avoid confusion, we have revised the aim of our study as “to investigate the causes of anti-osteoporosis medication discontinuation and to explore risk factors for self-discontinuation” (Please see page 5, lines 15-17). We also revised Table 2 and Figure 1 to re-categorize the study population. Point 2: paragraph 2.2: the authors considered a cause of discontinuation of medication the death. This event can't be compared with the others two causes (self-discontinuation and discontinuation due to the physician’s recommendation) if the scope of this study is "to investigate risk factors and causes of poor medication adherence in patients with osteoporosis, with a view to improving medication persistence." Please expose better the concept. Author’s response: Thank you for the suggestion. We agree with the reviewer’s comment that the death can’t be compared with the others two causes if the scope of this study is "to investigate risk factors and causes of poor medication adherence in patients with osteoporosis. We believed that mortality contributes to medication discontinuation and should be classified as unintended discontinuation. As mentioned in the previous reply to reviewer’s comment, we have revised the aim of our study, and re-classify this group to “unintended discontinuation” (Please see page 7, lines 13-14, Table 2 and Figure 1). Reviewer #2 First, what were the definitions of discontinuation of all the medication except for the denosumab and teriparatide mentioned in the method part? Do you think it is more reasonable to set up the definition of discontinuation according to the half-life of each of the selected medication? Or, please state your criteria accordingly. Author’s response: Thank you for bringing up this critical comment. We have added the definition of bisphosphonate or raloxifene discontinuation as ≥12 months without any anti-osteoporosis medication prescription claims after prior bisphosphonate or raloxifene treatment (please see page 6, line 26; page 7, lines 1-2). We agree with the reviewer’s opinion that it seems to be reasonable to set up the definition of discontinuation according to the half-life of each of the selected medication. However, the dosing frequency may last beyond the half-life of each medication in blood, i.e., biologic effect might be different from pharmacokinetics of medication. For example, the half-life of denosumab is less than 30 days but the dosing frequency is every 6 months. Therefore, we defined the duration of discontinuation of each anti-osteoporosis medication according to previous publications [1-5]. Reference 1. Silverman SL, Siris E, Kendler DL, Belazi D, Brown JP, Gold DT, et al. Persistence at 12 months with denosumab in postmenopausal women with osteoporosis: interim results from a prospective observational study. Osteoporos Int. 2015;26(1):361-72. Epub 2014/09/23. doi: 10.1007/s00198-014-2871-6. PubMed PMID: 25236877; PubMed Central PMCID: PMCPMC4286624. 2. Migliaccio S, Francomano D, Romagnoli E, Marocco C, Fornari R, Resmini G, et al. Persistence with denosumab therapy in women affected by osteoporosis with fragility fractures: a multicenter observational real practice study in Italy. J Endocrinol Invest. 2017;40(12):1321-6. doi: 10.1007/s40618-017-0701-3. PubMed PMID: 28589380. 3. Burge R, Sato M, Sugihara T. Real-world clinical and economic outcomes for daily teriparatide patients in Japan. Journal of bone and mineral metabolism. 2016;34(6):692-702. Epub 2016/11/01. doi: 10.1007/s00774-015-0720-0. PubMed PMID: 26661475. 4. Chen Q, Guo M, Ma X, Pu Y, Long Y, Xu Y. Adherence to Teriparatide Treatment and Risk of Fracture: A Systematic Review and Meta-Analysis. Horm Metab Res. 2019;51(12):785-91. doi: 10.1055/a-1062-9447. PubMed PMID: 31826274. 5. Adami G, Jaleel A, Curtis JR, Delzell E, Chen R, Yun H, et al. Temporal Trends and Factors Associated with Bisphosphonate Discontinuation and Restart. J Bone Miner Res. 2020;35(3):478-87. doi: 10.1002/jbmr.3915. PubMed PMID: 31714637; PubMed Central PMCID: PMCPMC7401723. Second, why the discontinuation rate of denosumab is the highest among all the medications, which is contrary to our clinical experiences, especially compared to those short half-life oral medications? Is it due to the definition of inclusion criteria or selection bias? Author’s response: Thank you for the comment. In our study, patients discontinuing denosumab accounts for the majority among 3 groups of different discontinuation causes (Table 2). It could be resulted both from the inclusion criteria and selection bias. We enrolled participants who discontinued anti-osteoporosis medication between June 2016 and June 2018. Because the denominators of the discontinuation rates were not calculated, the highest proportion that denosumab accounted for might be due to the largest market share of it. However, our retrospective study design prevented us from comparing discontinuation rates among various anti-osteoporosis medication. We discussed this point in the limitation section (please see page 17, lines 9-12). Attachments Attachment Submitted filename: rebuttal letter.docx https://doi.org/10.1371/journal.pone.0275020.r002
9 Sep 2022 Decision Letter - Maria Maddalena Sirufo, Editor Predictors for Self-Discontinuation of Anti-osteoporosis Medication: a Hospital-based Real-world Study PONE-D-21-34699R1 Dear Dr. Chen, 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, Maria Maddalena Sirufo Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0275020.r003
Formally Accepted
12 Sep 2022 Acceptance Letter - Maria Maddalena Sirufo, Editor PONE-D-21-34699R1 Predictors for Self-Discontinuation of Anti-osteoporosis Medication: a Hospital-based Real-world Study Dear Dr. Chen: 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 Dr. Maria Maddalena Sirufo Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0275020.r004

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