The Role of Tocotrienol in Preventing Male Osteoporosis—A Review of Current Evidence

First,   the article needs to be edited for English as there are several grammatical   mistakes, mainly about the used propositions and in some phases the correct   tense of the verbs are not used.

Thank   you for the suggestion. We have invited a native speaker to proofread the   manuscript and put it through a language editing software.

For me the title of the article is kind of   misleading. The article contains mixed information about animal and human studies, so I don’t feel   using "evidence from preclinical model" is correct. Moreover, the   title shows the focus of the article is on male osteoporosis, which is kind   of correct but based on the title the reader expect the conclusion to be on   male osteoporosis and contain recommendations in this regard. This is while   the conclusion in quite broad with no   mention of male osteoporosis.

Thank   you for the suggestion. We have deleted “evidence from preclinical model”   from the title.

We have   also amended the conclusion so that it is more relevant to male osteoporosis.  

The   section, "the significance of bone parameters" does not really fit   in this article. The results of the reported studies do not focus on BMD or   bone histomorphometry results so I dont   feel the need for this section.

Thank   you for the suggestion. We have removed the section as per your suggestion.

In my opinion it would also make more sense to   first discuss the mechanisms and then the effect on bone loss due to various risk   factors. Moreover, the fact that for some risk factors the results are from   animal studies and for the others human   studies is also confusing. The authors   should also mention why they have selected these risk factors from among the   long list of risk factors linked with osteoporosis

Thank   you for the suggestion. We have added the mechanisms and risk factors of bone   loss in the introduction (2^nd paragraph).

The   risk factors elaborated in each section are based on the models of bone loss   which tocotrienols have been tested on (as stated in the last sentence of   introduction).

In   each section, the relationship between risk factors and osteoporosis is first   explained using animal and human studies. Then, the effects of tocotrienol as   illustrated using relevant models of bone loss are highlighted.

As   mentioned earlier, the conclusion needs to be rewritten. Based on the topic,   the conclusion should at least contain some kind of recommendation for T3   usage and also should focus on male osteoporosis

Thank   you for the suggestion. We have rectified the conclusion so that it is more   relevant to male osteoporosis.

“As a conclusion, evidence accumulated thus   far has demonstrated promising effects of T3 as a preventive agent against   male osteoporosis in models of bone loss induced by testosterone deficiency   (surgical or chemical ablation), metabolic syndrome, cigarette-smoking and   alcoholism. Men with these risk factors or osteopenia could benefit from T3 supplementation to stop the   progression of bone loss. The human equivalent dose of T3 proven to prevent   osteoporosis is approximately 600 mg/day, to be taken after meals to enhance   absorption. The bone-sparing effects of T3 could be mediated by its   antioxidant, anti-inflammatory and mevalonate-suppressive effects. However,   more studies are needed to illustrate its mechanism of actions and its   effects on men suffering from   osteopenia and osteoporosis.”

The   author should refer to LOH (late-onset hypogonadism) syndrome in section 5.   In this setting of androgen deficiency, male osteoporosis is one of the main   features of the LOH syndrome. The concept of LOH syndrome is gathering   attention. By referring the concept, the clinical impact of this section will   be strengthened. 

Thank   you for the suggestion. We have added some descriptions on late-onset   hypogonadism in men in Section 4 (renumbered).

The   author should include tables to summarize main findings of each models.

Thank   you for the suggestion. The main findings for each model have been summarized   in Table 2.

Though   the authors described main findings of each model at each section, it’s hard   to follow, because the measurement parameters which the authors introduced   are inconsistence among sentences. Tabular forms should be prepared by   referring main measurement parameters, e.g. BV/TV, TbN, TbTh, ObN, OcN,   ES/BS, as the author published previously in table 2 of Drug Des Devel Ther.   2015 Apr 8;9:2049-61.

Thank   you for your suggestion. We have added a similar table as Table 2.

Structures   of tocotrienol and tocopherol could be provided.

Thank   you for the suggestion. We have added the molecular structure of tocopherol   and tocotrienol as Figure 1.

Abbreviation   should be used in the following parts once the abbreviation is defined, e.g.   tocotrienol at Page 2, lines 59, 62, and 95, and in table 1 

Thank   you for the reminder. We have changed “tocotrienol” to T3 in the manuscript.

The   authors have done a great job revising the article but there are still some   parts that need to be revised. First of all the classification for the male   osteoporosis is not completely correct. This should be divided into primary   and secondary osteoporosis and then metabolic syndrome and .... are causes of   the secondary osteoporosis and it should be mentioned that there are also   other conditions leading to osteoporosis in this regard which are not mentioned here.

Thank   you for the suggestion. We have modified the 2nd paragraph of Introduction to   describe the types of male osteoporosis and its risk factors.

“Male osteoporosis can be classified into   primary and secondary osteoporosis. The cause of primary male osteoporosis is   age-related bone loss (senile osteoporosis)   or unknown (idiopathic osteoporosis). Secondary male osteoporosis is caused   by lifestyles, medical conditions or medications harmful to the bone. Some of   the lifestyle behaviours contributing to male osteoporosis are excessive   consumption of alcohol and caffeinated beverages, cigarette-smoking and   physical inactivity. Male osteoporosis can occur secondary to other diseases,   such as hypogonadism, gastrointestinal disease, hyperparathyroidism and   thyrotoxicosis. Prolonged use for medications, such as glucocorticoids,   antineoplastic agents and anticonvulsants, will also cause osteoporosis”

Another   question is that while reading the text I had the impression that authors   have suggested that smoking cessation would lead to osteoporosis which is not   true. Smoking is the risk factor.

Thank   you for the comment. We acknowledge that smoking the risk factor of male   osteoporosis. This has been clearly established at the start of section 6: “Cigarette   smoking is recognized as an independent risk factor for bone loss and   fracture”

We   also want to alert the readers that the   negative impact of smoking on bone is   not easily reversible. Thus, towards the end of the 1^st paragraph   in section 6, we mentioned that

“The adverse effects of smoking on bone cannot be easily reversed even after   cessation. This is illustrated by another animal, whereby the skeletal   negative impacts of nicotine (intraperitoneal, 7 mg/kg/6 days a week, 2   months) could not be reversed after cessation for two months…”

The   conclusion needs to be rewritten. For instance   the first line the concerns for using T3 is an important concern and so could   have a dedicated section to be discussed. So most of the conclusion would be   directed to that section and then the authors need to provide a more   descriptive conclusion for their article. Adding a limitation section   mentioning lack of information   regarding T3 in different aspects would also be helpful

Thank   you for the comments.

We   have rearranged the “Conclusion and Perspectives” into three new sections.

‘Section   10 - Perspectives on the use of T3’ discussed practical issues on the   development and use of T3 as bone health supplements.

‘Section   11 - Limitations’ discussed some important aspects of fragility fracture not   reviewed in this paper.

‘Section   12 – Conclusion’ is the descriptive conclusion for this review.