Dear Dr. Rysinska,

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.

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Nan Jiang

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: No

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Dear Dr. Rysinska,

Thank you for publishing your insightful study, "Asymptomatic Osteolysis as a Risk Factor for Cardiovascular Disease." I have previously read your work and find this study to be a compelling and logical extension of your earlier findings. It offers valuable perspectives on the potential link between bone health and cardiovascular risk, contributing to a deeper understanding of this important topic.

I have a question regarding the variability in surgical procedures. Since these surgeries were performed by different surgeons at various times and under different conditions, how did you account for potential individual surgical errors or differences in technique? Could this variability have influenced the outcomes, and if so, how was it addressed in your analysis?

Additionally, I would like to inquire about the use of Cox regression analysis in your study. Given that only 16 patients (11%) were diagnosed with cardiovascular disease (CVD), the number of events is quite low, which may affect the reliability and statistical power of the Cox model. The wide confidence interval (HR: 1.6, 95% CI: 0.4–5.8) indicates a high level of uncertainty in the effect estimate. Considering the limited number of events, did you assess the adequacy of the Cox model for this dataset? Would alternative statistical methods, such as Poisson regression or Firth’s penalized Cox regression, be more appropriate to enhance the robustness of the estimates?

I look forward to your response.

Best regards,

Dr.Farzan Azodi

Reviewer #2: The study addresses an important clinical question about the possible association between periacetabular osteolysis and cardiovascular disease (CVD).The use of the Swedish Hip Arthroplasty Register (SHAR), a well-established national registry with a high capture rate, adds credibility to the dataset. The study carefully selected patients with primary osteoarthritis treated with uncemented THA, ensuring a homogeneous sample. CT scans were used for osteolysis detection, and ECG/blood markers were analyzed for CVD assessment, providing a comprehensive approach.

Patients who died of CVD before study inclusion were not accounted for, possibly underestimating the actual cardiovascular risk. This can be added if authors agree. While ECG was used for cardiovascular assessment, it is not the most reliable predictor of future cardiovascular events. More advanced cardiac imaging or functional tests could have provided stronger evidence.

Needs a plausible explanation. The study only measured hs-CRP, leukocytes, and lipid levels once, missing potential variations over time. It’s important limitation. The study does not fully control confounders for lifestyle factors, comorbidities, or other medications that may affect cardiovascular outcomes.

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Reviewer #1: Yes:  Farzan Azodi

Reviewer #2: Yes:  Syed Muhammad Azfar

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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.

Dear Dr. Rysinska,

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 Sep 08 2025 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.

• 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: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Nan Jiang

Academic Editor

PLOS ONE

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #3: (No Response)

Reviewer #4: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #3: Yes

Reviewer #4: Partly

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3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #3: Yes

Reviewer #4: I Don't Know

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4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #3: Yes

Reviewer #4: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #3: Yes

Reviewer #4: Yes

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Reviewer #3: I am honored to have the opportunity to review this first study investigating the incidence of CVD in patients with or without asymptomatic osteolysis.

1. Inclusion Criteria for Study Population

The manuscript states that patients treated with uncemented THA with metal-on-polyethylene articulation were considered eligible for inclusion. Were ceramic-on-polyethylene and other bearing combinations excluded? If so, what was the rationale for this exclusion? Similarly, what was the reasoning behind excluding cemented cups and cemented stems?

2. Exclusion of Bisphosphonate Users

Could you please clarify the rationale for excluding patients who were using bisphosphonates?

3. Baseline Characteristics and Statistical Adjustment

The results indicate that "the proportion of patients with previous myocardial infarction was higher in the osteolysis group." Was this baseline imbalance ultimately adjusted for in the final analysis? Is the adjusted hazard ratio of 1.6 (95% CI, 0.5-5.8) the value after adjusting for this and other confounders? I apologize for my limited comprehension, but I would appreciate clarification on this point.

4. Sample Size and Study Conclusions

The study found no significant differences between groups in inflammatory markers (hs-CRP, leukocyte count), lipid levels, or frequency of ECG abnormalities, and the authors attributed this to insufficient sample size. If this is indeed the case, should publication be deferred until a larger sample size can be obtained?

I believe there is a substantial possibility that the true conclusion might be that asymptomatic osteolysis is not associated with CVD development. This alternative interpretation should be acknowledged and discussed. Furthermore, I suggest that the value of this paper would be enhanced by addressing how large a sample size would be needed to definitively conclude "no association" and providing your expert opinion on this matter.

Such discussion would provide important guidance for future research design and help readers better interpret the clinical significance of these findings.

Reviewer #4: I appreciate the effort made by the authors in this interesting study

As an observational retrospective study there are some flaws

1- The definite association between periprosthetic osteolysis and the resulted inflammatory response that causes CVS and cardiac disease has not been proven.

2- The multifactorial etiology of cardiovascular disease makes an obvious difficulty of establishing correlation between osteolysis and CVD.

3- It is very difficult to find matched patients’ characteristics in each group with many variables that will affect the result.

4- The small number of patients studied is another weak point

5- The mere comparison made for the same patients before surgery and at least 10 years after surgery is invalid as the risk of CVD increases with age.

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what does this mean? ). If published, this will include your full peer review and any attached files.

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Reviewer #3: No

Reviewer #4: No

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[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.

Dear Dr. Rysinska,

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 04 2025 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.

• 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: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Nan Jiang

Academic Editor

PLOS ONE

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #3: Yes

**********

Reviewer #3: It is a great honor to have the opportunity to review this valuable manuscript.

The authors state that they "previously showed an increased long-term risk of cardiovascular-related mortality in patients treated with THA [16], and an increased relative risk of cerebrovascular events (CVE) in patients with osteoarthritis who received THA and subsequently underwent revision surgery due to loosening of the prosthesis [17]. Similarly, cardiovascular mortality following total knee arthroplasty exceeds that of the general population after 10 years [18]."

I was completely unaware of these findings and found them highly informative. However, I am disappointed that the direct relationship could not be statistically demonstrated in this study. I would encourage the authors to consider whether statistical significance could be achieved through increased sample size or more rigorous matching.

The authors also state that "the absence of notable differences in this study does not conclusively negate the possibility of osteolysis serving as a causal factor for CVD, as the chronic low-grade inflammation in osteolysis could hypothetically contribute to development of atherosclerosis." In this regard, I wonder whether it would be possible to examine the association between atherosclerotic burden and the presence or absence of osteolysis.

The manuscript would benefit from including representative CT images: at least one demonstrating periacetabular osteolysis and one without osteolysis.

Finally, regardless of whether an association between osteolysis and CVD is confirmed, the manuscript would provide greater clinical value if the authors could offer recommendations for orthopedic surgeons regarding strategies to reduce CVD risk in THA patients during long-term follow-up.

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what does this mean? ). If published, this will include your full peer review and any attached files.

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Reviewer #3: No

**********

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To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures 

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NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

Asymptomatic Osteolysis as a Risk Factor for Cardiovascular Disease After Total Hip Arthroplasty:

A retrospective cohort study

PONE-D-24-55835R3

Dear Dr. Rysinska,

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.

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Kind regards,

Nan Jiang

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #3: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously? -->?>

Reviewer #3: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #3: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #3: (No Response)

**********

Reviewer #3: (No Response)

**********

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 #3: No

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