Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This well-written, exhaustive narrative review concerns bone health and screening strategies in patients with Atopic Dermatitis.

The approach underlines the importance of preventing overdiagnosis and identifying high-risk patients.

I suggest only one minor revision to improve the manuscript:

1. Lines 110-113: Detail the impact on bone metabolism of the targeted therapies recommended to replace standard systemic steroids.

Author Response

Author's Reply to the Review Report (Reviewer 1)

Dear Reviewer,

We sincerely thank you for the time and effort you devoted to reviewing our manuscript. We deeply appreciate your thoughtful evaluation, encouraging remarks, and constructive suggestions. Your feedback has been invaluable in improving the quality and clarity of our work, and we truly appreciate your insightful contributions.

We made all the recommended typing changes in the body of the manuscript, with Track Changes enabled.

Comments and Suggestions for Authors

Comment 1: This well-written, exhaustive narrative review concerns bone health and screening strategies in patients with Atopic Dermatitis.

The approach underlines the importance of preventing overdiagnosis and identifying high-risk patients.

I suggest only one minor revision to improve the manuscript:

1. Lines 110-113: Detail the impact on bone metabolism of the targeted therapies recommended to replace standard systemic steroids.

 

Response 1: We thank the reviewer for this valuable suggestion. We have revised the Introduction to provide a more detailed explanation of the potential effects of targeted systemic therapies on bone metabolism. Specifically, we have clarified the possible indirect skeletal benefits associated with reduced systemic glucocorticoid exposure and improved disease control, as well as the mechanistic implications of IL-4/IL-13 blockade and JAK inhibition for bone remodeling. We have also incorporated the emerging pediatric evidence regarding dupilumab-associated improvements in linear growth and bone-related biomarkers, while emphasizing that direct evidence concerning bone mineral density and fracture prevention remains insufficient. These additions complement the more extensive discussion already provided in Section 6, "Targeted Systemic Therapy and the Bone Paradox", and distinguish established clinical benefits from theoretical skeletal effects and unresolved questions. The corresponding changes have been incorporated into the revised manuscript.

 

Reviewer 2 Report

Comments and Suggestions for Authors

The abstract reports the inclusion of 75 publications, whereas Section 2.3 indicates that the final evidence base comprised 69 peer-reviewed publications. This discrepancy should be clarified and corrected to ensure consistency throughout the manuscript.

Although the authors describe a structured literature search, additional methodological details would improve reproducibility. Providing the complete search strategy, including Boolean combinations, search dates, and the criteria used for selecting the final publications, would strengthen the methodological rigor of the review.

The association between atopic dermatitis and osteoporosis or fracture risk is adequately discussed. However, the substantial heterogeneity reported in the included meta-analyses warrants further emphasis. The authors should continue to distinguish epidemiological associations from causal relationships, particularly when discussing the potential effects of chronic inflammation on skeletal health.

The proposed risk-adapted approach to skeletal assessment is clinically relevant. Nevertheless, the authors should clarify which recommendations are supported by established clinical guidelines and which represent expert interpretation derived from the available evidence. The absence of a validated atopic dermatitis-specific screening algorithm should be explicitly acknowledged when presenting clinical recommendations.

The discussion of the RANK–RANKL, osteoprotegerin system and the roles of IL-4, IL-13, IL-31, and IL-33 is informative. However, the authors should more clearly differentiate findings obtained from experimental models from those supported by direct clinical evidence in patients with atopic dermatitis.

The discussion of systemic glucocorticoids and targeted therapies, particularly dupilumab, is relevant. The authors should emphasize that the currently available evidence does not establish a direct protective or detrimental effect of dupilumab on fracture incidence. Further longitudinal clinical studies are necessary to clarify its potential skeletal implications.

Author Response

Author's Reply to the Review Report (Reviewer 2)

Dear Reviewer,

We sincerely thank you for the time and effort you devoted to reviewing our manuscript. We deeply appreciate your thoughtful evaluation, encouraging remarks, and constructive suggestions. Your feedback has been invaluable in improving the quality and clarity of our work, and we truly appreciate your insightful contributions.

We made all the recommended typing changes in the body of the manuscript, with Track Changes enabled.

 

Comments and Suggestions for Authors

Comment 1: The abstract reports the inclusion of 75 publications, whereas Section 2.3 indicates that the final evidence base comprised 69 peer-reviewed publications. This discrepancy should be clarified and corrected to ensure consistency throughout the manuscript.

Response 1: We thank the reviewer for identifying this inconsistency. We have corrected the number of included publications in the Abstract to ensure consistency with Section 2.3.

 

Comment 2: Although the authors describe a structured literature search, additional methodological details would improve reproducibility. Providing the complete search strategy, including Boolean combinations, search dates, and the criteria used for selecting the final publications, would strengthen the methodological rigor of the review.

Response 2: We thank the reviewer for this thoughtful suggestion and appreciate the emphasis on methodological transparency. However, we would respectfully like to clarify that the present manuscript was intentionally designed as a critical narrative review rather than a systematic review. As explicitly stated in Section 2.1, the narrative approach was selected to accommodate the substantial heterogeneity of the available literature, which encompasses epidemiological studies, clinical investigations, experimental research, systematic reviews, meta-analyses, and clinical guidelines.

 

Comment 3: The association between atopic dermatitis and osteoporosis or fracture risk is adequately discussed. However, the substantial heterogeneity reported in the included meta-analyses warrants further emphasis. The authors should continue to distinguish epidemiological associations from causal relationships, particularly when discussing the potential effects of chronic inflammation on skeletal health.

Response 3: We thank the reviewer for this important observation. We have strengthened the discussion of between-study heterogeneity in Section 3.1, explicitly highlighting the high I² values reported for osteoporosis and fracture outcomes. We have also clarified that differences in study populations, disease severity, treatment exposure, outcome definitions, and residual confounding limit the generalizability of pooled estimates. The revised text further emphasizes that the available observational evidence supports an association between AD and skeletal outcomes but does not establish a direct causal relationship between chronic cutaneous inflammation and bone fragility.

 

Comment 4: The proposed risk-adapted approach to skeletal assessment is clinically relevant. Nevertheless, the authors should clarify which recommendations are supported by established clinical guidelines and which represent expert interpretation derived from the available evidence. The absence of a validated atopic dermatitis-specific screening algorithm should be explicitly acknowledged when presenting clinical recommendations.

Response 4: We thank the reviewer for highlighting the importance of distinguishing established clinical recommendations from our proposed risk-adapted framework. We have revised Section 7.10 to clarify that the algorithm incorporates guideline-supported indications for osteoporosis assessment, including age, sex, previous fragility fractures, systemic glucocorticoid exposure, and appropriate DXA interpretation. We now explicitly identify the integration of AD-specific characteristics as an evidence-informed interpretation proposed by the authors. Furthermore, we have clarified in both the manuscript and the legend of Figure 2 that no validated AD-specific skeletal screening algorithm currently exists and that the proposed framework has not undergone prospective validation.

 

Comment 5: The discussion of the RANK–RANKL, osteoprotegerin system and the roles of IL-4, IL-13, IL-31, and IL-33 is informative. However, the authors should more clearly differentiate findings obtained from experimental models from those supported by direct clinical evidence in patients with atopic dermatitis.

Response 5: We thank the reviewer for this valuable suggestion. We have revised Section 4.6 to more clearly distinguish experimental findings from direct clinical evidence in patients with AD. The revised text specifies that most mechanistic data regarding IL-4, IL-13, IL-31, IL-33, and RANK–RANKL–OPG signaling originate from in vitro studies, animal models, or inflammatory conditions other than AD. We have also highlighted the limited direct clinical evidence, including the cross-sectional findings reported by Sakai et al. [14], while emphasizing that these observations do not establish a causal relationship between cytokine signaling and osteoporosis or fracture risk in AD.

 

Comment 6: The discussion of systemic glucocorticoids and targeted therapies, particularly dupilumab, is relevant. The authors should emphasize that the currently available evidence does not establish a direct protective or detrimental effect of dupilumab on fracture incidence. Further longitudinal clinical studies are necessary to clarify its potential skeletal implications.

Response 6: We thank the reviewer for this important clarification. We have strengthened the concluding discussion of Section 6 to explicitly state that current evidence does not establish either a protective or a detrimental effect of dupilumab on fracture incidence. We have further distinguished the potentially favorable indirect consequences of improved AD control and reduced glucocorticoid exposure from direct effects on skeletal outcomes. The revised manuscript also emphasizes the need for prospective longitudinal studies incorporating DXA, bone turnover markers, appropriate comparator groups, and adjudicated fracture outcomes to clarify the long-term skeletal implications of dupilumab and other targeted therapies.

 

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

One of the main strengths of this review is its critical and objective assessment of the existing literature, with particular attention to differentiating observed epidemiological associations from established causal mechanisms. The discussion of IL-4/IL-13 blockade and its possible effects on bone metabolism, particularly in relation to dupilumab, appropriately acknowledges the limitations of current evidence.

Furthermore, the proposed individualized, risk-based approach to skeletal assessment enhances the clinical relevance of the manuscript. Nevertheless, these recommendations should be regarded as preliminary guidance based on available evidence, pending validation through prospective clinical studies.