Title: Effects of early estradiol valerate administration on bone turnover markers in surgically
induced menopausal women
Version: 2 Date: 13 Jul 2021
Reviewer's report:
Thank you so much for your manuscript submission.
Summary:
This study evaluated the effect of estradiol treatment on bone markers in surgically menopausal
women when initiated at early postoperative period. It was a prospective, non-randomized study
comparing bone markers levels at baseline and 12 weeks after treatment. The results showed
a significant decrease in bone markers levels after 12 weeks of estradiol treatment, however,
resulted in a significant increase levels with placebo treatment.
Abstract:
-In method section, the authors should also mention the statistical method used in the study.
Background:
-There are clear rationales for the study to evaluate the possible benefit of estradiol therapy
among surgically menopausal women on osteoporosis prevention.
Methods:
-The authors mentioned in the background section that the main objective of this study was
to evaluate the effects of early estrogen therapy on the levels of bone turn over markers, and
the sample size was calculated based on the reduction in bone markers after 12 weeks of
HT. However, the main objective and sample size calculation did not match with the primary
outcome to compare the levels of bone markers between HT and placebo. I would suggest the
author to revise the main objective, sample size and outcome to be consistent.
Results:
-From Table 1, P1NP was significant lower in HT, the author should adjust for the baseline level
when comparing level at 12 weeks.
-As BMI was lower in HT, the authors should consider adjustment for BMI as P1NP levels are
lower in obese postmenopausal women (https://pubmed.ncbi.nlm.nih.gov/24289763/).
-As the two groups in comparison are not randomly assigned and had statistically different in
baseline variables, another approach  may be comparison of changes from baseline between two
groups.
-The different in bone markers could be subjected to selection bias of treatment assignment.
Are there any evidence reporting difference in bone marker levels based on early menopause or
vasomotor symptoms as the authors used as indication to assign HT.
-A figure of study flow may be added to clearly explain the sample, treatment assignment and
analysis sample.
-Are there any adverse effects of treatment especially among participant assigned to HT (with
high dose and early after surgery)?
Discussion:
-According to the use of bone markers (CTX and P1NP) as main outcomes of interest, the authors
should discuss in more details in terms of the metabolism (such as half-life) and their associations
with BMD to better infer the results to bone metabolism after estradiol treatment.
-As unrandomized design of this study has been addressed, however, the author did not mention
how to improve this major limitation of the study.
Conclusion:
-Regarding the fact that this study did not designed to compare the levels of bone markers
between HT and placebo, the conclusion is likely to be from overinterpretation of results. I
would suggest to conclude on the main objective addressing the significant change of bone
markers levels between baseline and after 12 weeks of estradiol treatment as proposed in the
main objective.
Language:
-There are several grammatically error and typos. Please review carefully and revise accordingly.
For example; Table 1; No “Treatmen” group, in the second paragraph in Background section;
Around 2-3 years before the final menstrual period, estrogen gradually declines concurrently
with “elevates” follicle-stimulating hormone (FSH) levels.