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PONE-D-22-03568Characterization of Regional Variation of Bone Mineral Density in the Geriatric Human Cervical Spine by Quantitative Computer TomographyPLOS ONE

Dear Dr. Travascio,

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 each point raised during the review process. Both reviewers questioned statistical methods. Reviewer 1 pointed out inconsistencies in the abstract and study motivation, and suggested comparison to other methods and data in the literature. Reviewer 2 pointed out inconsistencies between results and conclusions.

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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?

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: Yes

Reviewer #2: No

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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 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

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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: Yes

Reviewer #2: Yes

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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: The authors present a detailed compilation of cervical spine bone mineral density values apportioned by relevant anatomical sites in a geriatric cohort. Said apportioning is achieved through an elaborate workflow where the volumetric model obtained by segmentation is processed with a variety of CAD programs. The manuscript is well-written and its contribution of data for tissue sourced from older adult donors is welcome, as there is scarce data on this topic in the literature.

However, some questions arise after reading the manuscript:

The authors state that odontoid fractures as a motivator for this research, but do not include that region in the results. Were the specimens only consisting of the base of the cranium to C5 or did they include the whole head? The materials and methods section mentions orienting the cervical column in a supine position and that the qCT image volume “included the entire head”. Please clarify this for consistency’s sake. If the head was available, why not report the base of the cranium BMD as well? Lastly, it would have been more complete reporting if C6-C7 were included, but it seems that the specimens only spanned from C1 to C5.

The abstract mentions that BMD was reported in Hounsfield Units (which is a measurement of attenuation), but the tables show data converted to g/cm3 and the charts show data in mg/cm3. Make sure this is consistent across the document.

The zone subdivision (1 through 4) makes sense anatomically and clinically. Was there any other rationale to subdivide yet even further each vertebra into the 12 or 14 smaller sub-zones?

Data about the cohort that would be useful to have in a manuscript of this type are cause of death, BMI, bone quality (osteoporotic or osteopenic), and if possible, the cervical Cobb angles to characterize the spinal curvature. This last parameter would have helped to discuss the fact that C4 and C5 higher values were reported, presumably due to load.

While the method to obtain the data is scientifically sound, comparisons to other methodologies used for this purpose would be useful, especially the use of DXA which is the clinical gold-standard to evaluate bone quality. Another method that has not been discussed by the authors and is very accurate (which would also have avoided the elaborate virtual partitioning of the vertebrae) is CT Osteoabsorptiometry. In a seminal paper by Dr Muller-Gerbl (PMID 18193299), they report these very values for the cervical spine. Comparison against this method would also be useful.

The choice of aggregating data into groups ignoring gender or level is an interesting one. Was this due to the sample size? Was a power analysis conducted for this sample? Admittedly, this is not a large population study that can provide a very large sample size, but including these divisions by level, gender, BMI, anatomical location, etc. are useful when analyzing the data looking for which factor is the more influential.

In the Discussion section, the first paragraph mentions that head loads in both genders should be similar. That is the common assumption, however, body habitus and perhaps overall proportions may play a role in this. Do you have anthropomorphometric data to this effect? (not necessarily from your donors, that is probably difficult to trace), but in general?

In summary, this is a well-received contribution to the description of the cervical spine tissue material properties, but needs some minor modifications for completeness before the manuscript can be ready for publication.

Typos/Minor changes (please include line numbers next time, for easier reporting of edits)

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The first sentence of the second paragraph in the Abstract should start with “Data trends suggest…”

Regression coefficient should be R^2 (superscript) instead of just "R2". (Journal review website does not allow superscript characters)

DISCUSSION subtitle currently reads DISUCSSION.

Figure captions, what are the error bars? (SD?)

Reviewer #2: This is a good study that expands the body of knowledge regarding BMD levels and distribution within the human spine, specifically the cervical vertebrae. The study is well-designed: the partitioning of the vertebrae helps to provide insight to BMD distribution in the analyzed vertebrae, and the statistical tests used are appropriate.

Revisions are suggested primarily due to some of the conclusions of the study. The final paragraph begins by stating that 'this study indicates that gender has an effect on bone volume and density across all levels of the cervical spine...' However, the study's statistical analysis did not find any significant differences in BMD values (p-value > 0.05). Given the relatively small sample size, and a p-value that is described only as greater than 0.05, this conclusion is not supported by the data. This conclusion also creates an inconsistency in the report, as the lack of difference between male and female BMD is used as justification for combining data samples at multiple points in the study.

In addition, the final paragraph claims that 'BMD distribution...in elderly is different from that of younger population, likely due to postural changes occurring with ageing.' I agree that it is certainly possible (even probable) that postural changes may affect this, but the way it is currently worded seems overstated, and that these changes are due solely to postural changes. Further studies/evidence would be needed to support the claim's current wording that these distribution changes are likely due to postural changes. Hormonal or metabolic changes associated with aging may play a significant or predominant role in this.

The main conclusion of the study seems to be that BMD is higher in the posterior regions of the vertebral body as compared to the anterior regions of the vertebral body. Mention could also be made that BMD was highest in the lateral/posterior regions of the vertebrae, including transverse processes/lateral masses and spinous process regions for C3-C5, as well as in the dens for C2.

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Reviewer #1: No

Reviewer #2: Yes: Tyler C. Kreipke

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Characterization of Regional Variation of Bone Mineral Density in the Geriatric Human Cervical Spine by Quantitative Computer Tomography

PONE-D-22-03568R1

Dear Dr. Travascio,

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,

James Mockridge

Staff Editor

PLOS ONE

Editor's comments:

Reviewer #2 has indicated that there are some minor text errors to correct, so please do these before submitting your final files. 

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. 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: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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4. 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

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5. 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: Yes

Reviewer #2: Yes

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6. 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: The authors have addressed satisfactorily all comments. Thank you.

Reviewer #2: Comments and questions regarding the study have been satisfactorily addressed, and I believe that the authors have produced a quality study that will advance the knowledge of the field.

Upon reading the revised manuscript, I noted few small typos that could be addressed:

1. The title currently reads "...Quantitative Computer Tomography" instead of "...Quantitative Computed Tomography".

2. In the QCT Image Acquisition subsection of Materials and Methods, it reads "...0.5 x 0.5 mm in-plane pixel resolution..." instead of "...0.5 x 0.5 mm^2 in-plane pixel resolution...".

3. Near the end of the 2nd paragraph in Discussion, it reads "Wolff Law" instead of "Wolff's Law".

4. In the caption for Figure 3, there is no space between "male" and "(black)".

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7. 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: Tyler Kreipke

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