Stage-Dependent Changes in Subchondral Trabecular Bone Mechano-Structure in Primary Knee Osteoarthritis with Varus Malalignment

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript entitled “Stage‑dependent Changes in Subchondral Trabecular Bone Mechano‑structure in Primary Knee Osteoarthritis with Varus Malalignment” examines subchondral bone microarchitecture in patients with moderate to end‑stage knee osteoarthritis and varus malalignment. The manuscript is clearly written and the analyses are well executed; however, several important issues require attention.

1. The authors report significant alterations in subchondral bone microarchitecture and sclerosis in varus‑aligned knees with moderate to end‑stage OA. However, it remains unclear how much of the observed change is attributable specifically to varus malalignment versus typical end‑stage primary OA. Inclusion of a primary OA control group (neutral alignment) would allow the authors to distinguish varus‑specific remodeling from generalized OA‑related changes. This limitation should be explicitly acknowledged in the manuscript.
2. The authors suggest that subchondral bone sclerosis may serve as a predictor of implant loosening and failure. While bone quality is relevant, the manuscript does not address the well‑established primary contributors to loosening in varus knees—namely varus malalignment, ligament imbalance, chronic medial compartment overload, and tibial component malposition. These factors are consistently identified as the dominant mechanical drivers of implant–cement interface failure, with subchondral sclerosis acting as a secondary amplifier rather than a primary cause. The Discussion section should be expanded to reflect this broader biomechanical context.
3. One of the principal mechanisms underlying implant failure in varus knees is ligament imbalance. The manuscript does not address how ligament pathology interacts with subchondral bone changes or how much the observed bone alterations may actually contribute to implant failure relative to soft‑tissue imbalance. This should be discussed both in the Discussion and as a limitation of the study.

Author Response

Reviewer 1, Comment 1: The manuscript entitled “Stage‑dependent Changes in Subchondral Trabecular Bone Mechano‑structure in Primary Knee Osteoarthritis with Varus Malalignment” examines subchondral bone microarchitecture in patients with moderate to end‑stage knee osteoarthritis and varus malalignment. The manuscript is clearly written, and the analyses are well executed; however, several important issues require attention.

Authors’ response: Thank you for your overall positive and constructive comments, which have helped us to prepare a substantially improved version of the manuscript. A point-by-point response to the reviewer's comments is provided below.

 

Reviewer 1, Comment 2: The authors report significant alterations in subchondral bone microarchitecture and sclerosis in varus‑aligned knees with moderate to end‑stage OA. However, it remains unclear how much of the observed change is attributable specifically to varus malalignment versus typical end‑stage primary OA. Inclusion of a primary OA control group (neutral alignment) would allow the authors to distinguish varus‑specific remodeling from generalized OA‑related changes. This limitation should be explicitly acknowledged in the manuscript.

Authors’ response: Thank you for your comment. Per your suggestion, the limitation section was broadened to include this point (discussion section, page 11, lines 366-369).

 

Reviewer 1, Comment 3: The authors suggest that subchondral bone sclerosis may serve as a predictor of implant loosening and failure. While bone quality is relevant, the manuscript does not address the well‑established primary contributors to loosening in varus knees—namely varus malalignment, ligament imbalance, chronic medial compartment overload, and tibial component malposition. These factors are consistently identified as the dominant mechanical drivers of implant–cement interface failure, with subchondral sclerosis acting as a secondary amplifier rather than a primary cause. The Discussion section should be expanded to reflect this broader biomechanical context.

Authors’ response: Thank you for your comment. In an attempt to stay within the formatting limits set by the Journal's author guidelines, we have made numerous revisions to synthesize the available results more effectively and provide a more coherent narrative on the relationship between KOA-induced microstructural alterations, implant instability and loosening, and the effect on outcomes of total knee arthroplasty. For more specific details, please look at page 11 (discussion section, lines 336-343), page 11 (discussion section, lines 357-360) and page 12 (discussion section, lines 375-378). To provide the scientific basis for our additional reasoning, the reference list was also expanded, and the changes are available for review on page 16 (lines 524-530).

 

Reviewer 1, Comment 4: One of the principal mechanisms underlying implant failure in varus knees is ligament imbalance. The manuscript does not address how ligament pathology interacts with subchondral bone changes or how much the observed bone alterations may actually contribute to implant failure relative to soft‑tissue imbalance. This should be discussed both in the Discussion and as a limitation of the study.

Authors’ response: Thank you for your interesting suggestion. Our study did not analyze implant survival or the influence of ligamentous balance; it examined only the structure of the subchondral bone in primary knee arthroplasty.  Still, we recognize the importance of this comment and the contribution of ligament imbalance in implant loosening, so we revised the manuscript per the reviewer's suggestion. The corrections related to this comment can be found on page 11 (discussion section, lines 336-343 and discussion section, lines 366-369).

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you for providing me with the opportunity to review the manuscript entitled « Stage-dependent Changes in Subchondral Trabecular Bone  Mechanostructure in Primary Knee Osteoarthritis with Varus Malalignment”

 

This article represents an evident interest as for orthopedic surgeons as for pathologists.

There are numerous advantages and strong aspects of the study

• Well-structured design
• Enough large series of specimens
• Detailed information about health conditions of individuals who underwent surgery
• High level of morphologic studies
• Comprehensive discussion,
• Relevant conclusions

 

But there are major revisions to be considered

• Clear null hypothesis should be added
• A radiologic preoperative lower limb deformity analysis (at least MAD, LDFA and MPTA) using full-size standing AP views is mandatory

Minor revisions:

• Line 100-101: The individuals were excluded from this study based on previously published criteria . Please, explain this sentence.
• Criteria of inclusion and criteria of exclusion should de clearly exposed.

Author Response

Reviewer 2, comment 1: Thank you for providing me with the opportunity to review the manuscript entitled « Stage-dependent Changes in Subchondral Trabecular Bone  Mechanostructure in Primary Knee Osteoarthritis with Varus Malalignment”. This article represents an evident interest as for orthopedic surgeons as for pathologists. There are numerous advantages and strong aspects of the study: Well-structured design, Enough large series of specimens, Detailed information about health conditions of individuals who underwent surgery, High level of morphologic studies, Comprehensive discussion, Relevant conclusions; But there are major revisions to be considered.

Authors’ response: Thank you very much for your overall affirmative view of our manuscript. The detailed author's response to the comment is provided in the following list of responses.

 

Reviewer 2, comment 2: Clear null hypothesis should be added.

Authors’ response: Thank you very much for raising this very important point. The hypothesis of our study was incorporated in the revised manuscript (introduction, page 3, lines 93-95).

 

Reviewer 2, comment 3: A radiologic preoperative lower limb deformity analysis (at least MAD, LDFA and MPTA) using full-size standing AP views is mandatory.

Authors’ response: Thank you very much for constructive criticism that enhances the scientific merit of our manuscript. In the revised manuscript, we included the representative finding from the preoperative lower-limb deformity analysis using long-standing radiographs obtained during this study (Figure 1A, lines 138-152). Given the potential underpower of statistical analysis in other approaches, we decided to use only negative arithmetic hip-knee-ankle-angle values on preoperative long-standing radiographs to confirm varus knee malalignment in the included individuals, without assessing the relationship between the severity of the knee malalignment and micro-scale mechano-structural changes in the subchondral bone of individuals with primary KOA. Recognizing the significance of this comment, we revised the manuscript to include this point in the discussion section (page 12, lines 370-374).

 

Reviewer 2, comment 4: Line 100-101: The individuals were excluded from this study based on previously published criteria. Please, explain this sentence. Criteria of inclusion and criteria of exclusion should de clearly exposed.

Authors’ response: Thank you for highlighting a more detailed explanation of the study design, which enhances its reproducibility. Per your suggestion, the full list of exclusion criteria has been incorporated into the revised manuscript (in the materials and methods section, page 3, lines 104-118).

 

Reviewer 2, comment 5: Figures and tables can be improved.

Authors’ response: Thank you for the comment. We incorporated the suggestions to improve figures by including preoperative lower-limb deformity analysis based on long-standing radiographs (Figure 1A, page 4, lines 138-152). Furthermore, Figure 2 has been improved by adding a scale bar to the measurement figures (page 5, lines 162-169). The printing-quality (300 DPI, high-quality TIFF format) figures are included in the revised manuscript and submitted as separate files. These figures (Figures 1, 2, 3, and 4) are the original work of the authors (hand-generated or prepared using licensed vector graphic editor software). Scientific illustrator responsible for the production of figures signed them where appropriate. Since the authors do not have special funds designated to cover figure editing costs for this manuscript (meaning we would have to use our personal funds), we kindly request that the editorial service team reevaluate the need for figure/table improvements, as no other suggestions for improvement were provided. We welcome any constructive suggestions regarding this matter.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have satisfactorily addressed all of my comments. The revisions have improved the overall presentation of the manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

All raised points have been evaluated and addressed in the revised manuscript. I find no objections to publication of the work.