PONE-D-25-04756Prolonged secondary hyperparathyroidism in adenine-induced CKD leads to skeletal changes consistent with skeletal hyporesponsiveness to PTHPLOS ONE

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This study was funded by the Department of Veterans Affairs via grants I01BX003025 and IK6-BX006479 awarded to MRA. Histological processing was completed through the Histology Lab Core Service in the Indiana Center for Musculoskeletal Health (P30-AR083854 to AG Robling).

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This study was funded by the Department of Veterans Affairs via grants I01BX003025 and IK6-BX006479 awarded to MRA.

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Reviewers' comments:

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Reviewer #1: Partly

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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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: The longitudinal design of the study is a notable strength, as it captures the progression of skeletal changes over time—a feature often lacking in animal models of CKD.

However, there are several areas where the study could be improved. First, the exclusive use of male mice limits the generalizability of the findings, given the well-documented sex-specific differences in bone metabolism and CKD progression. Including female mice in future studies would provide a more comprehensive understanding of these dynamics. Second, while the study identifies altered osteocyte characteristics and reduced expression of PTH receptor 1 (PTHR1) and receptor activator of nuclear factor κB ligand (RANKL) as potential mechanisms, it does not explore the role of other CKD-related factors, such as uremic toxins or systemic inflammation, which may also contribute to skeletal hypo responsiveness.

Reviewer #2: The manuscript entitled "Prolonged secondary hyperparathyroidism in adenine-induced CKD leads to skeletal

changes consistent with skeletal hyporesponsiveness to PTH" have designed and written well. No any major correction and grammatical mistake reported at present as per my view. The present manuscript can be accepted for publication.

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Reviewer #1: Yes: Dr.Zena A.A.Hadedy

Reviewer #2: No

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Attachments

Attachment

Submitted filename: Article (6).pdf

Prolonged secondary hyperparathyroidism in adenine-induced CKD leads to skeletal changes consistent with skeletal hyporesponsiveness to PTH

PONE-D-25-04756R1

Dear Dr. Corinne Metzger,

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.

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Kind regards,

Ewa Tomaszewska, DVM Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Dear Authors,

Thank you for the submitted revisions. I confirm that you have appropriately addressed the reviewer’s comments, including the limitation of using only male mice and the potential roles of systemic inflammation, oxidative stress, and uremic toxins. These points have been properly incorporated into the revised manuscript.

with best regards

Ewa Tomaszewska

Reviewers' comments:

Attachments

Attachment

Submitted filename: PONE-D-25-04756_R1.pdf