The efficiency and safety of alendronate versus teriparatide for treatment glucocorticoid-induced osteoporosis: A meta-analysis and systematic review of randomized controlled trials.

BACKGROUND: Glucocorticoid-induced osteoporosis (GIOP) is the most common secondary osteoporosis, alendronate (ALE) and teriparatide (TPTD) are widely used in the treatment of GIOP. However, which of these two drugs has a better curative effect needs the support of evidence-based medicine.
METHODS: We searched PubMed, Embase, Cochrane Library, Web of Science, and Google Scholar for randomized controlled trials of ALE and TPTD in the treatment of glucocorticoid-induced osteoporosis until February 2022. These patients included in the study took glucocorticoid doses greater than 7.5 mg/d for more than 3 months before treatment with ALE and TPTD. The risk ratio (RR) and its 95% confidence interval (CI) are used as the influence index of discontinuous data, and the standardized mean difference (SMD) and its 95% CI are used as the influence index of continuous data.
RESULTS: A total of 4102 patients were enrolled in all 5 studies that met the admission criteria. We found that compared with ALE, TPTD could reduce the rate of new vertebral fracture (RR = 0.13, 95% CI: 0.05-0.34, P<0.00001). TPTD increased LS bone mineral density (BMD) (0.53, 95% CI 0.42-0.64, P<0.00001), TH BMD (0.17, 95% CI 0.05-0.28, P = 0.004) and FN BMD (0.17, 95% CI 0.05-0.29, P = 0.006) compared to ALE. However, there was no significant difference in the incidence of non-vertebral fracture and adverse events between the two groups.
CONCLUSIONS: Compared with ALE, TPTD is an effective drug to reduce vertebral fracture risk in patients with GIOP. Furthermore, long-term use of TPTD can increase the bone mineral density of LS, FN, and TH.

Introduction

Glucocorticoids are widely used in the treatment of rheumatic and autoimmune-related diseases (rheumatoid arthritis, systemic lupus erythematosus, polymyositis, vasculitis), inflammatory bowel disease, nephrotic syndrome, interstitial pneumonia, severe infection, shock, and so on. However, glucocorticoids cause severe side effects on bones, which makes GIOP the most common secondary osteoporosis [1]. In patients who receive long-term glucocorticoid treatment, 30–50% may have fractures, especially the lumbar spine (LS) femoral neck (FN), and total hip (TH) [2]. Taking 2.5 mg of oral prednisone daily increases the risk of fractures, and when the dose is greater than 7.5 mg (dosage equivalent to daily endogenous glucocorticoid production), the risk increases 5 times [3]. In addition, the risk of fractures increases significantly with the increasing dose of glucocorticoids and the prolongation of time [4].

The mechanism of GIOP can be summarized as follows: glucocorticoids reduce the number of osteoblasts and inhibit their function, stimulate the production of osteoclasts and increase their activity, thereby hindering bone growth and development. Glucocorticoid mainly interferes with bone formation by up-regulating peroxisome proliferator-activated receptor γ receptor 2 (PPARγ2) and affecting the Wnt/β-catenin signaling pathway. The former is beneficial to the differentiation of pluripotent precursor cells into adipocytes, resulting in a reduction in the number of osteoblasts. The latter is due to increased expression of sclerostin, inhibits Wnt signaling, resulting in reduced differentiation of osteoclast precursors into mature osteoblasts and increases apoptosis of osteoblasts and osteocytes [5].

The pathogenesis of GIOP is multifactorial, with both glucocorticoids’ direct effects on osteocytes and indirect effects on multiple neuroendocrine and metabolic pathways.

The latter is mainly manifested by hypogonadism, decreased physical activity, increased calcium loss from the kidneys and intestines, and decreased production of growth hormone, insulin-like growth factor 1 (IGF1), and IGF1 binding protein (IGF-BP) [6]. In addition, excessive use of glucocorticoids can adversely affect bones and muscles, causing bone and muscle atrophy and weakness, and increasing the risk of falls and fractures [7].

Bisphosphonate is a synthetic pyrophosphate analog, which can inhibit osteoclast activity, inhibit bone resorption and increase bone mineral density in patients treated with glucocorticoid. It has been proved to be an effective method for the prevention and treatment of GIOP. ALE is bisphosphate that can effectively increase the BMD of the LS, FN, and TH. It has been widely used to prevent and treat GIOP [8]. TPTD, as a parathyroid hormone analog, can effectively induce pre-osteoblasts to differentiate into osteoblasts, improve osteoblasts’ activity, stimulate pre-existing osteoblasts to form new bone, and reduce osteoblasts apoptosis [9].

The meta-analysis previously published did not focus on the specific disease of glucocorticoid-induced osteoporosis, nor two specific drugs, nor did it discuss the spines that exert drug effects at the micro-level such as bone metabolism indicators, nor did it pay more attention to the main adverse reactions of drugs. The main purpose of this systematic review and meta-analysis is to compare the safety and effectiveness of TPTD and ALE and to provide a new idea for the clinical treatment of GIOP.

Methods

This study is reported by PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Please refer to S1 file for detailed table contents.

Search strategy and selection criteria

We searched PubMed, Embase, Cochrane Library, Web of Science, and Google databases for randomized controlled trials of ALE and TPTD in the treatment of glucocorticoid-induced osteoporosis until February 2022. In the retrieval process, we use keywords and Medical Subject Headings (MESH) terms to search the database. Search strategy is as follows: ("alendronate"[MeSH Terms] AND "teriparatide"[MeSH Terms]) AND ((("glucocorticoid "[MeSH Terms]) AND "osteoporosis"[MeSH Terms) OR "glucocorticoid-induced osteoporosis "[All Fields] OR "GIOP "[All Fields]])). In this meta-analysis, all data are extracted from previously published studies, so patient consent and ethical approval are not required. Specific literature search strategies can refer to S2 File.

Study inclusion and exclusion criteria

The inclusion criteria are as follows: (1)Patients were at least 21 years old; (2) Patients had taken prednisone or its equivalent at a dosage of ≥5 mg/day for≥3 months before screening; (3) Patients were required to have an LS or TH BMD T score of ≤−2.0 or ≤−1.0 plus at least one fragility fracture while taking glucocorticoids; (4) Studies’ language was English; (5) Studies were RCTs.

The exclusion criteria are as follows:(1) Primary osteoporosis (including postmenopausal osteoporosis, senile osteoporosis, and idiopathic osteoporosis) and other secondary osteoporosis caused by non-glucocorticoid; (2) The type of articles was review, meta-analysis, and other non-RCT; (3) The content and outcome are not the incidences of vertebral fracture and the change of BMD.

Data extraction and quality assessment

ZML, YZ, DZ, XQG, and ZBS were responsible for the literature No. 11–14, including extraction of relevant content in this article, including major and minor outcomes. ZML was also responsible for collecting and integrating the data extracted by the five authors.

The primary outcome of this study was the incidence of vertebral fracture and non-vertebral fracture, while the secondary outcome was the mean percent changes from baseline to 6,12,18 months in the ALE and TPTD groups in the lumbar spine(LS) bone mineral density (BMD), the mean percent changes from baseline to 18 months in the two groups in the BMD of the femoral neck (FN) and total hip (TH), the incidence of 5 adverse events with the highest incidence, and changes in bone formation and resorption markers in both groups. In this paper, two researchers independently conducted the literature search, screening, data extraction, and heterogeneity analysis. If there is any objection, we will reach an agreement after discussion, complete the preliminary search according to the established search strategy, and read the abstract and full text to exclude studies that do not meet the inclusion criteria.

Data synthesis and analysis

All data are summarized using mean and standard deviation (SD). We use risk ratio (RR) with a 95% confidence interval (CI) as the effective index of discontinuous data and standardized mean difference (SMD) as the effective index of continuous data. We use I2 to evaluate heterogeneity between studies, and if I2 ≥ 50% is considered to be high heterogeneity, a random effect model is used, otherwise, a fixed-effect model is used. All of the above analysis was done through Review Manager version 5.3. Egger linear regression test and funnel plot were performed using Stata 16.0 to estimate publication bias. Specific data processing processes and code can refer to S2 File.

Results

Search results and study characteristics

Of the 62 articles initially searched, 30were excluded because of content and outcome irrelevant, 15were excluded because of repetition, and17 were excluded because of non-RCTs. A total of 4102patients were included in the 5 studies [10-14] that met the inclusion criteria of this article ().

We counted the baseline characteristics of these studies, including the studies’ first author and year of publication, the number of patients in each study, the dose and duration of glucocorticoids taken, and gender, age, menopause (female), and BMD or T-score of the LS and FN before taking the drug (

Risk of bias in the included studies

All studies are randomized controlled trials but do not explain the random sequence generation process, and some of them have reporting biases (

Risk of bias assessment of each included study.

(A) Risk of bias graph. (B) Risk of bias summary.

The Egger linear regression test and funnel plot were used to measure the percent change in LS BMD at 18 months. The funnel plot does have certain asymmetry, but each study is within a 95% confidence interval, and the Egger linear regression test P = 0.07 > 0.05, which shows that publication bias is not statistically significant, but the number of studies included in this study is limited, and the interpretation of the results should be more cautious ().

Incidence of vertebral and non-vertebral fractures

We found that compared with ALE, TPTD could significantly reduce the rate of new vertebral fracture (RR = 0.13, 95% CI: 0.05–0.34, P<0.00001), but there was no significant difference between the two in terms of non-vertebral fractures (RR = 1.28, 95% CI: 0.81–2.02, P = 0.29) (Figs

Mean percent change from baseline in the BMD at the LS, FN, TH

We first analyzed the percentage change of LS BMD at 6, 12, and 18 months. The results showed that compared with ALE, TPTD could increase LS BMD from baseline to 6 months (0.30, 95% CI 0.19–0.42, P<0.00001), 12 months (0.48, 95% CI 0.36–0.60, P<0.00001) and 18 months (0.53, 95% CI 0.42–0.64, P<0.00001) (

Compared with ALE, TPTD increased the BMD of FN from baseline to 18 months (0.17, 95% CI 0.05–0.29, P = 0.006); and increased the BMD of TH from baseline to 18 months (0.17, 95% CI 0.05–0.28, P = 0.004) (Figs

We further analyzed that the longer the time of taking TPTD within a certain period, the more obvious the increase of LS BMD, and the LS BMD at 18 months was significantly higher than that at 6 months and 12 months. In addition, TPTD had different effects on different parts bone tissue. After taking TPTD for 18 months, the increase of BMD of LS was higher than that of FN and TH.

Percent change in markers of bone formation and resorption

Two studies have reported bone metabolic markers, of which N-terminal propeptide of type I collagen (PINP) is a marker of bone formation and C-telopeptide of type I collagen (CTX) is a marker of bone resorption. In patients taking TPTD, both PINP and CTX increased compared to the baseline, began to rise at 1 month, peaked at 6 months, and decreased slowly at 18 months. However, in patients taking ALE, both PINP and CTX decreased from the baseline, began to decline at 1 month, reached the lowest level at 6 months, and increased slowly at 18 months (Figs

Adverse events

A total of 3 studies reported the incidence of adverse reactions to the two drugs, we selected 5 high-incidence adverse events for research. The results showed that, overall, there was no significant difference in the incidence of adverse reactions between the two groups (RR = 1.00, 95% CI: 0.89–1.12, P = 0.58). Patients taking TPTD had a higher incidence of nausea than ALE (RR = 1.68, 95% CI: 1.19–2.36, P = 0.003). In contrast, patients taking ALE had a higher incidence of dyspepsia (RR = 0.51, 95% CI: 0.31–0.83, P = 0.007) and urinary tract infections (RR = 0.69, 95% CI: 0.48–0.99, P = 0.04) than TPTD (

Discussion

Through meta-analysis and systematic review of 5 randomized controlled trials, we found that compared with ALE, TPTD can effectively increase the BMD of LS, FN, and TH, and the incidence of vertebral fracture was lower. However, there was no significant difference in the incidence of non-vertebral fracture and adverse reactions between the two groups.

Consistent with the results of this article, Ya-Kang Wang et al. [15] conducted a meta-analysis of ALE for GIOP and found that ALE can significantly increase the BMD of the LS and FN. Similarly, Chun-Lin Liu et al. [9] conducted a meta-analysis of bisphosphonates and TPTD for osteoporosis and found that TPTD can significantly increase the BMD of LS, TH, and FN, especially GIOP; and compared with bisphosphonates, TPTD cannot reduce the incidence of non-vertebral fractures.

Another meta-analysis showed that ALE, as a second-generation bisphosphonate, could significantly increase the BMD of LS, TH, and FN, and the incidence of gastrointestinal adverse reactions was very low, but could not reduce the incidence of vertebral and non-vertebral fractures [16]. But our study shows that TPTD is more effective than ALE in reducing the incidence of vertebral fractures, which reflects the unique advantages of TPTD.

Because of the high price and gastrointestinal adverse reactions, TPTD is used as a second-line drug, but the results show that compared with ALE, it can effectively reduce the incidence of vertebral fracture, and there is no significant difference in adverse reactions. In addition, TPTD also has its unique advantages, as a synthetic metabolic agent, it is significantly better than bisphosphonate in preventing glucocorticoid-induced bone loss and fracture, and can reduce the adverse reactions of glucocorticoids, which is consistent with the results of this study. However, the guidelines do not yet use TPTD as a first-line drug [2].

Through meta-analysis and systematic evaluation of five randomized controlled trials, the main outcomes were as follows: Compared with ALE, patients taking TPTD had a lower incidence of vertebral fracture; secondary outcomes: similarly, patients taking TPTD improved the BMD of LS, FN, and TH compared to those taking ALE, and the BMD of LS, FN, and TH gradually increased with the prolongation of dosing time. There was no statistical difference between the two drugs in the incidence of non-vertebral fractures and adverse reactions.

Ya-Kang Wang et al. [15] conducted a meta-analysis on the efficacy of ALE in the treatment of GIOP and found that ALE could significantly improve the BMD of LS and FN. After 12 months of medication, the BMD of LS increased without significant gastrointestinal adverse reactions. The results of these studies are consistent with this study. In addition, they also found that the fracture risk of patients who took ALE for 12 months did not change significantly, but our study found that ALE could reduce the incidence of vertebral fractures.

Chun-Lin Liu et al. [9] compared the efficacy of bisphosphonates and TPTD in the treatment of osteoporosis and found that TPTD could significantly increase the BMD of LS, TH, and FN in osteoporosis patients, especially GIOP. In addition, there was no difference in the effect of TPTD on the incidence of non-vertebral fractures when compared to bisphosphonates. The results of this study are consistent with our study.

Shun-Li Kan et al. [16] performed a meta-analysis on the efficacy of ALE in preventing GIOP in rheumatic patients and found that ALE could increase the BMD of LS, TH, and trochanter, which were consistent with the results of our study. There were no significant differences in the incidence of gastrointestinal adverse reactions and vertebral and non-vertebral fractures, in contrast, our study found that both TPTD and ALE were found to reduce the incidence of vertebral fractures. Compared with the previously published meta-analysis, this study differs in that it focuses mainly on glucocorticoid-induced osteoporosis rather than on osteoporosis in general. In our study, two of the two anti-osteoporosis drugs were selected to compare the efficacy and safety of GIOP, so it was more targeted. The main outcome of this study was the incidence of vertebral fracture, which was also more targeted. In addition, this study also had unique features that previous studies did not have. In our study, bone metabolism indexes were innovatively taken as evaluation indexes of drug efficacy, so that the mechanism of drug action can be explored from a microscopic perspective. In this study, the main adverse reactions of drugs were also used as evaluation indicators, instead of focusing on gastrointestinal reactions as in the previous study.

Limitations

However, there are still some shortcomings in our study. First, whether the female subjects are postmenopausal or not may have an impact on the efficacy of drug treatment, but the women included in this study include both menopausal and non-menopausal women. Second, all the patients included in this study were given long-term additional calcium and vitamin D supplementation, which also had a certain impact on the efficacy of drug treatment. Third, the longest study included in this article is only 36 months, and the long-term efficacy of the drug needs to be further explored.

Conclusion

In general, compared with ALE, TPTD can reduce the incidence of vertebral fracture, increase the BMD of LS, FN, and TH, and increase the bone metabolic markers. However, there was no significant difference in the incidence of non-vertebral fracture and main adverse reactions between the two groups.

PRISMA_2020_checklist.

(PDF)

Click here for additional data file.

Specific literature search strategies, data processing procedures and codes.

(ZIP)

Click here for additional data file.

17 Feb 2022

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Wisit Cheungpasitporn, MD

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Thank you for stating the following financial disclosure:

"This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors."

At this time, please address the following queries:

a) Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution.

b) State what role the funders took in the study. If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

c) If any authors received a salary from any of your funders, please state which authors and which funders.

d) If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.”

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

3. Thank you for stating the following in your Competing Interests section:

"All other authors have no conflicts of interest."

Please complete your Competing Interests on the online submission form to state any Competing Interests. If you have no competing interests, please state "The authors have declared that no competing interests exist.", as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now

This information should be included in your cover letter; we will change the online submission form on your behalf.

4. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability.

Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.

Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

[Note: HTML markup is below. Please do not edit.]

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: Partly

**********

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

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: No

Reviewer #2: Yes

**********

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: No

Reviewer #2: No

**********

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 comprehensive summary of their systematic review and meta-analysis of the efficiency and safety of alendronate versus teriparatide for treatment glucocorticoid-induced osteoporosis: A meta-analysis and systematic review of randomized controlled trials. They presented that teriparatide is an effective drug to reduce the risk of vertebral fracture in patients with GIOP. Furthermore, long-term use of teriparatide can increase the bone mineral density of lumbar spine, femoral neck, and total hip. This review is interesting. However, there are some concerns that need to be addressed.

1. Grey literature: If the authors performed the search using specific gray literature, please provide the name of such database. Overall, I have concerns about the reproducibility of the meta-analysis. There are some key flaws that may affect the summary effect estimate. Since search limited, unpublished studies were not included, I worry that this summary effect estimate will shrink or be nullified if grey literature, unpublished studies are found. The authors may only be able to say that their meta-analysis resolves discrepancies between published studies. I am hesitant because there are too many examples of unpublished data nullifying significant effects in meta-analyses. If the authors conduct a thorough search for unpublished data, this comment becomes irrelevant. Please add this information in supplementary.

2. The protocol registration was absent. Prospective registration of systematic reviews promotes transparency, helps reduce potential for bias and serves to avoid unintended duplication of reviews.

3. In "Methods" part, the independent investigators who extracted data and evaluated quality of each study should be clarify.

4. I wonder if the search strategies have been developed with the help of a librarian or experienced reviewers in the field. Generally, if the search yield is too low, systematic reviewers would need to modify the search term to ensure that it well cover most of the related papers. This could be done by in the PICO such as Control and Outcome; employ a free text rather than thesaurus search terms. I think the keywords for the outcome domain were not comprehensive enough to capture all potential synonyms of the outcomes of interested in this study, and therefore would be best not to limit the search with these terms. An example of the search strategies used for a particular database would show a transparency in this step (I don’t think the keywords presented is sufficient as an example of a search strategies as recommended in PRISMA).

5. The date of the literature was March 2021. In accordance with guidelines, the literature search should be performed until six months before the submission of the manuscript for publication. If the manuscript is accepted for publication, it is already outdated. In addition, the author should describe exact date and duration of the literature search in both abstract and main manuscript.

6. How authors dealt with missing data. Did you receive all answers from authors of the studies or make some imputation? In general, if the study did not report the data of the primary or secondary outcomes measures, the authors should contact via email to provide this information. Have you considered to contact authors via researchers’ network ResearchGate (https://www.researchgate.net/), Academia (https://www.academia.edu/), Loop (https://loop.frontiersin.org/) or Quora (https://es.quora.com/)? Nowadays these platforms are very useful and efficient canals to contact authors.

7. The authors should demonstrate both statistics and visualization. In addition, I suggest plot the funnel and contour-enhanced funnel in the graphic and not only the studies for better interpretation. Besides, it is necessary to present the p value for this analysis.

9. Finally, since I am not a native English user, I did not check for typo and grammatical errors thoroughly. This should be done by an appropriate language reviewer.

Reviewer #2: My comments and suggestions.

1. The statement in Introduction "Taking 2.5mg of oral prednisone increases the risk of fractures and when the dose is greater than 7.5mg, the risk increases by 5 times". Do you mean to say "the risk of fractures increased by 5 times with a dose of 7.5mg compared to 2.5mg"? This statement has to be fixed.

2. In the same statement - "the approximate physical number of endogenous glucocorticoids" is not clear. I would suggest changing to something like "dosage equivalent to daily endogenous glucocorticoid production".

3. Repetitive statements/conclusion: "The dose and duration of glucocorticoids have a significant effect on the occurrence of fractures. The daily average dose of glucocorticoids seems to be more predictive of the risk of fracture risk than cumulative doses." gets repeated 2 lines later as "In addition, the risk of fractures increases significantly with the increasing dose of glucocorticoids and the prolongation of time". Please avoid repetitions of the same fact.

4. Repetitive statements: "Long-term treatment and high-dose of glucocorticoids will cause osteoporotic fractures in 30-50% of adult patients". This statement is repetitive and was used 4 lines above under "In patients who receive long-term glucocorticoid treatment, 30-50% may have fractures, especially the lumbar spine (LS) femoral neck (FN) and total hip (TH)". Please avoid repetitions of the same fact.

5. I believe the mechanism of GIOP and pathogenesis is discussed in great detail but it does not relate to this paper at all. I would recommend shortening the pathogenesis/mechanism part in introduction. Otherwise consider adding a statement as to how the pathogenesis/mechanism is relevant to your paper.

6. In Introduction, page 6, the authors talk about bisphosphonates. "it has been proved to be an effective method for prevention and treatment of GIOP". Recommend removing "method". I would suggest changing it to "It has been shown to be effective for prevention and treatment of GIOP"

7. Same paragraph, page 6. "ALE is a kind of bisphosphonate". Remove kind of. It should be "ALE is a bisphosphonate"

8. What is the purpose of this statement "Decreased osteogenesis is the main pathogenesis of GIOP and glucocorticoids can significantly inhibit osteoblasts activity"?. You have a already discussed the mechanism/pathogenesis in the previous paragraph. its repetitive.

9. I recommend that the the authors discuss in the introduction on what's lacking in the current literature which prompted them to do this meta-analysis.

10. I see at least 2 meta-analysis on the same topic with very similar results. The authors mention these studies in their discussion. However they fail to add how is their study different from these other meta-analyses and how does their meta-analyses contribute to the current literature. I would recommend expanding more as discussion is very short.

10. Under discussion, authors talk about mechanism of ALE. Again, they discuss the mechanism of action of bisphosphonates under introduction. I would recommend removing this in the discussion or add a statement as to how is it relevant to your study. Because, the authors randomly state the mechanism of ALE during the discussion and then revert back to talking about prior meta-analyses results. There is no continuity.

11. The discussion should be well structured - I would recommend talking summarizing their results in the first paragraph. Then talk about prior studies that have compared these 2 drugs and summarize their results. Then talk about how this study is different/unique when compared to previous studies and what does it add to the literature. Then mention your strengths/limitations. I do not see a reason as to why mechanism of ALE and TPTD have been mentioned again in discussion when they already been mentioned in Introduction. Discussion NEEDS to be expanded.

12. Under study inclusion and exclusion criteria: "Patients were required to have a LS or TH

BMD T score of ≤−2.0 or ≤−1.0 plus at least one fragility fracture while taking glucocorticoids". According to standard definitions, Osteoporosis is defined as patients with BMD T score of ≤−2.5. Osteopenia is T score between -2.5 to -1.0. Why was -2.0 chosen here as the inclusion criteria and not -2.5?

13. Under results "MEAN PERCENT CHANGE FROM BASELINE IN THE BMD AT THE LS, FN, TH)". Authors have repeated the same results twice. "We further analyzed that the longer the time of taking TPTD within a certain period of time, the more obvious the 15 increase of LS BMD, and the LS BMD at 18 months was significantly higher than that at 6 months and 12 months. And the effect of TPTD on bone tissue was also different. For example, after taking TPTD for 18 months, the increase of BMD of LS was higher than that of FN and TH." The next line is repetition of this statement. "We found that the longer the time of taking TPTD within a certain period of time, the more obvious the increase of LS BMD. The LS BMD at 18 months was significantly higher than that at 6 months and 12 months. In addition, TPTD had different effects on different parts’ bone tissue. After taking TPTD for 18 months, the increase of bone mineral density of LS was higher than that of FN and TH."

**********

6. 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: Yes: Wisit Kaewput

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

14 Mar 2022

Relevant files have been uploaded

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

1 Apr 2022

3 Apr 2022

We have uploaded it in file form.

Submitted filename: Response to Reviewers - 2.docx

Click here for additional data file.

14 Apr 2022

The efficiency and safety of alendronate versus teriparatide for treatment glucocorticoid-induced osteoporosis: A meta-analysis and systematic review of randomized controlled trials

PONE-D-22-00100R2

Dear Dr. Fei Yin,

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.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Wisit Cheungpasitporn, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

It appears that all comments have been appropriately responded to. I recommend publication.

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

**********

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

**********

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

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

**********

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

**********

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 addressed all my previous concerns and significantly improved quality of the manuscript. I have no additional comment.

Reviewer #2: No further comments. All the comments have been addressed by the authors extensively. I thank them for editing the article.

**********

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: Yes: Wisit Kaewput

Reviewer #2: No

19 Apr 2022

PONE-D-22-00100R2

The efficiency and safety of alendronate versus teriparatide for treatment glucocorticoid-induced osteoporosis: A meta-analysis and systematic review of randomized controlled trials

Dear Dr. Yin:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Wisit Cheungpasitporn

Academic Editor

PLOS ONE

Table 1

Baseline characteristics.

Comparison	N	GC dose(mg/d)b	GC duration(m)	Age(y)	Sex (M/F)	Postmenopause n(%)	LS BMD(gm/cm2)/ T-score	PINP (ug/l)	CTX(pmol/l)
Benito R. Losada 2008 d
alendronate	32	7.5±1.7	5.3±2.9	54.9±4.5	5/27	NM	0.8 ±0.05	NM	NM
teriparatide	29	8.8±1.9	2.7±3.2	52.5 ±5.0	5/24	NM	0.8 ±0.05	NM	NM
Alan L. Burshell 2009 d
alendronate	77	8.0	16.8	60.6±2.5	17/60	50(64.9)	−2.7±0.1	39.7±4.5	3570.8±616.6
teriparatide	80	7.5	14.4	56.1±2.6	13/67	41(51.3)	−2.5±0.1	44.5±4.8	3585.0±643.2
Jean-Pierre 2009 d
alendronate	192	10.1±0.7	5.1 ± 0.5	57.1±1.0	NM	NM	0.85±0.01	NM	NM
teriparatide	195	9.4±0.4	5.2 ± 0.6	55.8±1.0	NM	NM	0.85±0.01	NM	NM
B. L. Langdahl 2009 d
alendronate
Postmenopausal	143	7.3	26.4	62.1±1.2	0/143	143(100)	−2.7±0.1	39.0±4.7	3844.8±580.5
Premenopausal	30	10.0	10.8	35.8±2.1	0/30	0	−2.6±0.2	43.0±3.6	2670.0±217.6
Men	41	10.0	25.2	59.7±1.9	41/0	0	−2.3±0.2	36.5±9.6	4173.8±977.4
teriparatide
Postmenopausal	134	7	31.2	61.9±1.2	0/134	134(100)	−2.7±0.1	47.3±6.4	4030.8±606.5
Premenopausal	37	8	21.6	40.0±1.9	0/37	0	−2.4±0.2	34.8±4.2	2331.0±602.0
Men	42	10	27.6	55.5±1.9	42/0	0	−2.3±0.2	36.3±8.0	3236.0±837.8
Kenneth G. Saag 2009 d
alendronate	214	≥5	24	57.3±14.0	41/173	143 (66.8)	0.864±0.014	39.5±4.0	3604.0±540.1
teriparatide	214	≥5	27.6	56.1±13.4	42/172	134 (62.6)	0.863±0.014	41.0±5.1	3384.5±486.4

aAll patients received supplements of calcium (1000 mg/d) and vitamin D (800 IU/d).

b prednisone or equivalent.

cvalues are mean±SD.

dvalues are mean±SE.

BMD = bone mineral density.

LS = lumbar spine.

PINP = N-terminal propeptide of type I collagen.

CTX = C-telopeptide of type I collagen.

GC = glucocorticoid.

M = male.

F = female.

NM = not mentioned.