The 2024 Endocrine Society Guideline on Vitamin D: Comprehensive Summary and Critical Appraisal

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This paper, entitled "The 2024 Endocrine Society Guideline on Vitamin D: Comprehensive Summary and Critical Appraisal", presents a narrative review and critical review of the Endocrine Society's new 2024 guidelines on the use of vitamin D in disease prevention. The authors systematically analyze the recommendations for specific population groups (children, older than 75 years, pregnant women and people with prediabetes) and point out significant uncertainties that these guidelines leave open.
However, there are parts that require refinement and clarification, namely the following:
- The authors themselves admit that their approach is unsystematic (narrative review), which is a limitation of the work, and although they consciously gave up formal evaluation of the guidelines using a tool such as AGREE II, the work would be much stronger if they at least briefly included a tabular presentation of the key quality criteria according to that framework, which would ensure greater objectivity of the review.
- The main criticism of the authors is focused on the fact that the original guidelines do not specify optimal doses for empirical supplementation, leaving clinicians in uncertainty, and although the authors state in the text that they consider a daily dose of 2000 IU effective and safe for most adults, that part should be more clearly highlighted as their expert recommendation (expert opinion) that fills the gap in the guidelines. Also, it is necessary to define more clearly what exactly is meant by the terms "low dose" and "high dose" (bolus), which the guidelines mention and do not specify.
- The new 2024 guidelines replace those of 2011, but do not cover groups that were previously included (eg, people with malabsorption, obesity, or chronic kidney disease), and the authors should provide a more specific algorithm or advice for clinicians: should they continue to rely on the withdrawn 2011 guidelines (as Michael Holick suggests) for these "left out" populations, or are there more recent documents from other societies that they should consult.
- The guidelines oppose routine testing of 25(OH)D levels, but do not provide instructions on what to do when a patient already has a finding indicating deficiency or toxicity, so practical recommendations should be developed for "real-life" scenarios in which 25(OH)D levels are known, especially in the context of the risk of overdose if empirical supplementation is initiated in individuals who already have high baseline levels.
- The paper rightly emphasizes that sunlight is the main source of vitamin D, which the guidelines ignore, however, to make the paper more comprehensive, the authors could add brief instructions on how to safely balance the risks and benefits of UV exposure (e.g., mentioning "safe time" in the sun), as merely mentioning the importance of the sun without practical instructions leaves the recommendation incomplete.
- It is stated that new evidence has emerged since the publication of the systematic review that supported the guidelines (December 2023) (e.g., the updated Cochrane review on pregnancy), so it is necessary to emphasize even more clearly whether these new data, which show somewhat less statistically significant effects than earlier studies, will potentially weaken the strength of the empirical recommendations in future revisions.

The paper is certainly an excellent critical analysis that justifiably points out the "gaps" in the new guidelines, however, it is crucial to translate the criticisms into concrete clinical advice (e.g., through tables or flowcharts) to facilitate the implementation of the guidelines in everyday medical practice, where patients and doctors are looking for clear answers to the question "how much vitamin D and to whom".

Sincerely,

Author Response

Comments and Suggestions for Authors

This paper, entitled "The 2024 Endocrine Society Guideline on Vitamin D: Comprehensive Summary and Critical Appraisal", presents a narrative review and critical review of the Endocrine Society's new 2024 guidelines on the use of vitamin D in disease prevention. The authors systematically analyze the recommendations for specific population groups (children, older than 75 years, pregnant women and people with prediabetes) and point out significant uncertainties that these guidelines leave open.

However, there are parts that require refinement and clarification, namely the following:
- The authors themselves admit that their approach is unsystematic (narrative review), which is a limitation of the work, and although they consciously gave up formal evaluation of the guidelines using a tool such as AGREE II, the work would be much stronger if they at least briefly included a tabular presentation of the key quality criteria according to that framework, which would ensure greater objectivity of the review.

Response: We thank the reviewer for this comment. We now include a supplementary table (Table S1) with the AGREE II evaluation of the guideline including a column describing how an item might not fully capture issues with the guideline. As this assessment with AGREE II was not pre-specified and has only been included due to the comment of this reviewer during the revision, we decided to include it only in the supplements. We included the following sentence. “We aimed to be reasonable and balanced in our guideline appraisal, but we cannot exclude our own confirmation bias regarding our previous publications and opinions, though we partly addressed this by finally considering the AGREE II framework during the revision of this manuscript (see supplementary Table S1 for our AGREE II appraisal).”

- The main criticism of the authors is focused on the fact that the original guidelines do not specify optimal doses for empirical supplementation, leaving clinicians in uncertainty, and although the authors state in the text that they consider a daily dose of 2000 IU effective and safe for most adults, that part should be more clearly highlighted as their expert recommendation (expert opinion) that fills the gap in the guidelines. Also, it is necessary to define more clearly what exactly is meant by the terms "low dose" and "high dose" (bolus), which the guidelines mention and do not specify.

Response: We thank the reviewer for this valuable comment. We now specify the recommendation of 2000 IU daily as an expert opinion. In detail we write that “..this is only an expert opinion that is subject to discussion”. Regarding the comment regarding clarification of “low dose” and “high dose” bolus, we referred to the guideline that notes “potential risks for fractures and falls with intermittent vitamin D doses exceeding 100,000 IU as a bolus and higher fall risk with dosing intervals greater than 12 weeks”. In addition, we included the following sentence regarding “low dose”: “In this context, we would consider doses up to 2000 IU daily as “low doses” in adults, though this is just an expert opinion based on general dosage ranges according to the guideline and safety considerations.”

- The new 2024 guidelines replace those of 2011, but do not cover groups that were previously included (eg, people with malabsorption, obesity, or chronic kidney disease), and the authors should provide a more specific algorithm or advice for clinicians: should they continue to rely on the withdrawn 2011 guidelines (as Michael Holick suggests) for these "left out" populations, or are there more recent documents from other societies that they should consult.

Response: We thank the reviewer for this comment. We already referenced some documents that address this issue, but we believe that we are not in the position to recommend sources for all “left out” populations. However, we do agree that this is a major issue and instead of providing another expert opinion on how to approach this gap, we urge the guideline committee to use their authority to address this issue by providing appropriate sources to consult. We now explicitly include this plea in the manuscript: “We urge the guideline committee to provide official guidance to sources that address the populations who were covered in the 2011 guideline but not in the current guideline.”

- The guidelines oppose routine testing of 25(OH)D levels, but do not provide instructions on what to do when a patient already has a finding indicating deficiency or toxicity, so practical recommendations should be developed for "real-life" scenarios in which 25(OH)D levels are known, especially in the context of the risk of overdose if empirical supplementation is initiated in individuals who already have high baseline levels.

Response: We thank the reviewer for this comment. While we had already partially covered this issue, we now extended the discussion on this issue as follows: “Thus, there is an unmet need for practical recommendations that cover individuals with previous 25(OH)D tests, even if the current guideline does not recommend routine screening.” As for the answer to the comment above, it is the task of a guideline to provide guidance for this issue rather than by us.

- The paper rightly emphasizes that sunlight is the main source of vitamin D, which the guidelines ignore, however, to make the paper more comprehensive, the authors could add brief instructions on how to safely balance the risks and benefits of UV exposure (e.g., mentioning "safe time" in the sun), as merely mentioning the importance of the sun without practical instructions leaves the recommendation incomplete.

Response: We agree with the reviewer and added the following:

“The amount of sun exposure for optimal health is currently unknown and recommendations must consider several factors such as latitude, season, time of the day, skin type, sun exposed skin area and sun protective behaviors. There is no consensus on this issue, but common recommendations or estimates suggest a daily sun exposure time between late morning and afternoon (e.g., between 10 am and 4 pm) during warmer months in the range of about 5 to 25 minutes for sufficient vitamin D synthesis.” 

- It is stated that new evidence has emerged since the publication of the systematic review that supported the guidelines (December 2023) (e.g., the updated Cochrane review on pregnancy), so it is necessary to emphasize even more clearly whether these new data, which show somewhat less statistically significant effects than earlier studies, will potentially weaken the strength of the empirical recommendations in future revisions.

Response: We totally agree with the reviewer that this issue requires clarification and we included the following sentence. “Thus, these new data do, in our opinion, not question the recommendations for empirical vitamin D supplementation in pregnancy.”

 

The paper is certainly an excellent critical analysis that justifiably points out the "gaps" in the new guidelines, however, it is crucial to translate the criticisms into concrete clinical advice (e.g., through tables or flowcharts) to facilitate the implementation of the guidelines in everyday medical practice, where patients and doctors are looking for clear answers to the question "how much vitamin D and to whom".

Sincerely,

Response: We thank the reviewer for the valuable comments.

Reviewer 2 Report

Comments and Suggestions for Authors

An Endocrine Society Clinical Practice Guideline on vitamin D  was published in 2024. Main objective was the use of vitamin D to lower the risk of disease in individuals without established indications for vitamin D treatment or 25-hydroxavitamin D (25(OH)D) testing.  The authors of the current review stated that 2024 Endocrine Society Clinical Practice Guideline on vitamin D followed a rigorous methodological approach with high quality standards but it leaves many open questions and uncertainties warranting clarification.

Some suggestions:

1. Line 66-67 – please add more details related to “Evidence from randomized controlled trials (RCTs) retrieved by a systematic review was prioritized to inform this guideline”.

2. Main recommendations of the Endocrine Society guideline 2024 are that “the panel  suggests empiric vitamin D supplementation for those aged years and older because of its potential to lower the risk of mortality. How has it been shown to reduce the risk of mortality? Add please an explanation. 

3.Lines 106-112 - What else is new in the 2024 Endocrine Society guideline on vitamin D compared to the 2011 guide? Please specify. 

4. I agree that the authors of this article are right when they point out some shortcomings in the 2024 guide, shortcomings presented at point 4. Critical appraisal of this guideline.

5. Line 264-266 – the study is from 2018. Replace it please with a newer study. 

The authors consider as an urgent and imperative  task to translate the existing knowledge on vitamin D including the Endocrine Society  guideline into clinical practice. In their opinion a daily vitamin D supplement dose of 2000 IU may be suitable for the prevention and treatment of vitamin D deficiency in most adults.

 

Author Response

Comments and Suggestions for Authors

An Endocrine Society Clinical Practice Guideline on vitamin D  was published in 2024. Main objective was the use of vitamin D to lower the risk of disease in individuals without established indications for vitamin D treatment or 25-hydroxavitamin D (25(OH)D) testing. The authors of the current review stated that 2024 Endocrine Society Clinical Practice Guideline on vitamin D followed a rigorous methodological approach with high quality standards but it leaves many open questions and uncertainties warranting clarification.

Some suggestions:

1. Line 66-67 – please add more details related to “Evidence from randomized controlled trials (RCTs) retrieved by a systematic review was prioritized to inform this guideline”.

 

Response: We extended this point as follows:
“Evidence from randomized controlled trials (RCTs) retrieved by a systematic review was prioritized to inform this guideline. If available RCTs were insufficient, large longitudinal observational cohort studies (>1000 participants) were permitted if they included appropriate comparison groups and outcomes.”

2. Main recommendations of the Endocrine Society guideline 2024 are that “the panel  suggests empiric vitamin D supplementation for those aged years and older because of its potential to lower the risk of mortality. How has it been shown to reduce the risk of mortality? Add please an explanation. 

Response: According to this comment we now mention that “In the systematic review and meta-analysis informing this guideline, all-cause mortality was reduced by vitamin D with high certainty and a RR (95% CI) of 0.96 (0.93-1.00).”

3. Lines 106-112 - What else is new in the 2024 Endocrine Society guideline on vitamin D compared to the 2011 guide? Please specify. 

Response: We agree that it is important to specify what is new in the 2024 compared to the 2011 guideline. We already outlined several issues regarding the differences in the 2024 versus 2011 guideline throughout the manuscript. According to this comment, we now list the main difference also in this section: “While the objective of the 2011 guideline was to provide guidelines to clinicians for the evaluation, treatment and prevention of vitamin D deficiency with an emphasis on the care of patients who are at risk for deficiency, the 2024 guideline addresses individuals without established indications for vitamin D treatment or 25(OH)D testing”. We hope that the reviewer agrees with this but we are, of course, willing to include more content in this section (though this may lead to some redundancy with other parts of this manuscript.

4. I agree that the authors of this article are right when they point out some shortcomings in the 2024 guide, shortcomings presented at point 4. Critical appraisal of this guideline.

Response: We thank the reviewer for this encouragement.

5. Line 264-266 – the study is from 2018. Replace it please with a newer study. 

Response: We thank the reviewer for carefully reading our manuscript. There are indeed newer studies on this and we now mention the following “but testing may have decreased to roughly 10% in 2022, which was mainly a consequence of a national coverage restriction.”

The authors consider as an urgent and imperative  task to translate the existing knowledge on vitamin D including the Endocrine Society  guideline into clinical practice. In their opinion a daily vitamin D supplement dose of 2000 IU may be suitable for the prevention and treatment of vitamin D deficiency in most adults.

Response: We thank the reviewer for carefully reading and reviewing our manuscript. We now make clear that the recommendation for 2000 IU is just an expert opinion. In detail we write that “..this is only an expert opinion that is subject to discussion”. We also stress that “Importantly, a daily vitamin D dose of 2000 IU is within the dosage range of clinical trials providing data for all recommendations regarding empiric vitamin D supplementation of this guideline (see Table 1).” Therefore, our suggestion for 2000 IU per day may be viewed as in line with the 2024 guideline.

Reviewer 3 Report

Comments and Suggestions for Authors

At times (such as when discussing vitamin D dosage), the writers bring up their own preferred approaches (e. g. 2000 IU daily). How do they separate evidence-based criticism of the guideline from expert opinion? 

The review has a strong focus on the doubts and flaws of the guideline. Firstly, is the authors' stand on the guideline's conservative approach being reasonable? Secondly, if it is, then why did they leave these points nearly unseen?

Considering the authors' previous extensive publications supporting wider vitamin D supplementation, what measures did they take to avoid confirmation bias when analyzing the disputes about the guideline?

The authors argue the guideline's failure to mention the best doses. However, is it really possible or even appropriate for a GRADEbased guideline to advise exact doses when the dose-response data are very mixed?

Besides, the authors ask why the guideline didn't provide the upper intake limits, but they also express their doubts on existing safety thresholds (e. g. 25(OH)D >125 nmol/L). What concrete safety framework do the authors propose instead?

The authors argue that replacing the 2011 guideline creates a “gap” for certain high‑risk populations. Do they propose a coherent interim strategy for clinicians, or should older guidelines be selectively retained, and on what evidentiary basis?

How do the authors reconcile their critique of the Endocrine Society guideline with the continued endorsement of Institute of Medicine DRIs, which are also largely population‑based and conservative?

The authors critique the lack of guidance for individuals who already have measured 25(OH)D levels. How do they propose integrating test‑based decision‑making without undermining the guideline’s explicit recommendation against routine testing?

The article frames the guideline as effectively endorsing supplementation for nearly half of the population. How do the authors envision operationalizing this at scale without medicalizing the general population or increasing inappropriate supplementation?

Author Response

Comments and Suggestions for Authors

At times (such as when discussing vitamin D dosage), the writers bring up their own preferred approaches (e. g. 2000 IU daily). How do they separate evidence-based criticism of the guideline from expert opinion? 

Response: We thank the reviewer for this comment and now make clear that the recommendation for 2000 IU is just an expert opinion. In detail we write that “..this is only an expert opinion that is subject to discussion”. We also stress that “Importantly, a daily vitamin D dose of 2000 IU is within the dosage range of clinical trials providing data for all recommendations regarding empiric vitamin D supplementation of this guideline (see Table 1).” Therefore, our suggestion for 2000 IU per day may be viewed as in line with the 2024 guideline.   

The review has a strong focus on the doubts and flaws of the guideline. Firstly, is the authors' stand on the guideline's conservative approach being reasonable? Secondly, if it is, then why did they leave these points nearly unseen?

Response: We thank the reviewer for this comment. In general, we are of the opinion that a critical appraisal of guidelines is important and of value for future guideline revisions and implementation in clinical routine. As noted in the last sentence of the Abstract, we emphasize the “high quality standards” of this guideline and we also mentioned in the text that “we appreciate the work of the panel …and that we agree with many of their statements.” As outlined in the manuscript, we are of the opinion that guidelines should provide guidance, even if the evidence is not solid. We do not have the impression that the points we raise were unseen, but the panel decided to refrain from specific recommendations if the evidence was considered insufficient. We have already discussed this in the text and hope that the reviewer agrees with this as we will also touch on this issues in further comments of this reviewer.

Considering the authors' previous extensive publications supporting wider vitamin D supplementation, what measures did they take to avoid confirmation bias when analyzing the disputes about the guideline?

Response: We thank the reviewer for this particularly important comment as we agree that we may have a confirmation bias regarding our own previous publications and opinions. Therefore, we included the following sentence. “We aimed to be reasonable and balanced in our guideline appraisal, but we cannot exclude our own confirmation bias regarding our previous publications and opinions, though we partly addressed this by finally considering the AGREE II framework during the revision of this manuscript (see supplementary Table S1 for our AGREE II appraisal).” According to this comment and the comment of another reviewer, we now include a supplementary table (Table S1) with the AGREE II evaluation of the guideline including a column describing how an item might not fully capture issues with the guideline. As this assessment with AGREE II was not pre-specified and has only been included during the revision, we decided to include it only in the supplements.

The authors argue the guideline's failure to mention the best doses. However, is it really possible or even appropriate for a GRADEbased guideline to advise exact doses when the dose-response data are very mixed?

Response: We appreciate the thoughtful comment on this topic. We agree that identifying a single “optimal” dose may not be feasible within a GRADE-based framework when dose-response evidence is heterogeneous or of low certainty. However, the absence of any actionable dosing guidance risks shifting complex decisions to end users without sufficient support and expertise. Even under uncertainty, guidelines are expected to provide structured recommendations, while communicating the underlying evidence limitations. We discussed this issue in our initial submission. According to this comment we now include the following additional sentence: “At least a dosage range for vitamin D supplementation with a clear upper limit would be important regarding safety issues”. 

Besides, the authors ask why the guideline didn't provide the upper intake limits, but they also express their doubts on existing safety thresholds (e. g. 25(OH)D >125 nmol/L). What concrete safety framework do the authors propose instead?

Response: This is an extremely critical issue. We wanted to make the reader aware that issues regarding safety including upper intake levels are not clearly specified in the guideline. We do not think to be in the position to propose updated recommendations for safety but rather want to stress that if empirical vitamin D supplementation is widely implemented, a certain proportion of individuals will achieve 25(OH)D concentrations above 125 nmol/L. According to this comment of the reviewer, we included the following sentence: “We propose an update on the safety of vitamin D supplementation by e.g. following the framework of the IOM report on vitamin D, including a clarification on the upper intake levels and the threshold of 25(OH)D (e.g. can it be increased to 150 nmol/L?) by the Endocrine Society guideline.” We hope that the reviewer agrees with this.

The authors argue that replacing the 2011 guideline creates a “gap” for certain high‑risk populations. Do they propose a coherent interim strategy for clinicians, or should older guidelines be selectively retained, and on what evidentiary basis?

Response: We thank the reviewer for this comment. We believe that we are not in the position to recommend interim strategies or appropriate sources for all “left out” populations. However, we do agree that this is a major issue and instead of independently adding to the expert opinions on how to approach this gap, we urge the guideline committee to use their authority to address this issue by providing appropriate sources to consult. We now explicitly include this plea in the manuscript:

“We urge the guideline committee to provide official guidance to sources that address the populations who were covered in the 2011 guideline, but not in the current guideline.”

How do the authors reconcile their critique of the Endocrine Society guideline with the continued endorsement of Institute of Medicine DRIs, which are also largely population‑based and conservative?

Response: We critically appraised the Endocrine Society guideline and not the DRIs for vitamin D of the Institute of Medicine. Thus, we do not see any inconsistency or discrepancy, particularly as the target populations of these two guidelines do not overlap. We hope that this answers the question of the reviewer, but we are, of course, willing to further elaborate on this issue if there are remaining specific comments.

The authors critique the lack of guidance for individuals who already have measured 25(OH)D levels. How do they propose integrating test‑based decision‑making without undermining the guideline’s explicit recommendation against routine testing?

Response: We suggest guidance towards other resources that cover handling of individuals with an existing 25(OH)D measurement. Once again, we do not feel that we are in a position to make the decision on which resources are referenced. To further clarify the need for such resources we added the following:

“Thus, there is an unmet need for practical recommendations that cover individuals with previous 25(OH)D tests, even if the current guideline does not recommend routine screening.”

 

The article frames the guideline as effectively endorsing supplementation for nearly half of the population. How do the authors envision operationalizing this at scale without medicalizing the general population or increasing inappropriate supplementation?

Response: This is a good point by the reviewer that was barely covered in the guideline. We already touched on this issue in the manuscript at the end of the section 4.3. According to this reviewer comment we now also include the following sentence: “This could include information campaigns and adoption and inclusion of information on empiric vitamin D supplementation in general clinical guidelines for children, pregnant women, persons with prediabetes and individuals aged 75 years and older.”

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

All changes in the work were done correctly and I have no additional comments.