Association between sarcopenia and osteoarthritis: A protocol for meta-analysis.

BACKGROUND: Sarcopenia, a relatively new syndrome referring to the age-related decline of muscle strength and degenerative loss of skeletal muscle mass and function, often resulting in frailty, disability, and mortality. Osteoarthritis, as a prevalent joint degenerative disease, is affecting over 250 million patients worldwide, and it is the fifth leading cause of disability. Despite the high prevalence of osteoarthritis, there are still lack of efficient treatment potions in clinics, partially due to the heterogeneous and complexity of osteoarthritis pathology. Previous studies revealed the association between sarcopenia and osteoarthritis, but the conclusions remain controversial and the prevalence of sarcopenia within osteoarthritis patients still needs to be elucidated. To identify the current evidence on the prevalence of sarcopenia and its association with osteoarthritis across studies, we performed this systematic review and meta-analysis that would help us to further confirm the association between these two diseases. METHODS AND ANALYSIS: Electronic sources including PubMed, Embase, and Web of Science will be searched systematically following appropriate strategies to identify relevant studies from inception up to 28 February 2022 with no language restriction. Two investigators will evaluate the preselected studies independently for inclusion, data extraction and quality assessment using a standardized protocol. Meta-analysis will be performed to pool the estimated effect using studies assessing an association between sarcopenia and osteoarthritis. Subgroup analyses will also be performed when data are sufficient. Heterogeneity and publication bias of included studies will be investigated. PROSPERO REGISTRATION NUMBER: CRD42020155694.

Introduction

With global population aging and increased longevity, aging and age-related diseases have become substantial burden and inevitable challenges worldwide. Sarcopenia, defined as an age-related muscle mass decline and muscle strength loss, results in reduced mobility, function and quality of life, and thus greatly increasing healthcare expenditures [1]. Although sarcopenia is a relatively new syndrome which was first described in the 1980s [2], it has become a common condition with an estimated prevalence from 12.9% to 40.4% with various diagnostic criteria [3, 4]. Sarcopenia is not only simply recognized as an age-related syndrome but also found to be correlated with increased risk of fall/fracture [5, 6], functional decline [7], multiple chronic diseases [8-10], loss of independence [11-13], frailty and mortality [14]. Sarcopenia is becoming a critical public health burden compounded by an expanding elderly population, being reported that the direct cost for medical spending due to sarcopenia was around $18.5 billion (i.e., 1.5% of the total health care spending) [15] for the year of 2000 in the United States, and since then, the economic burden of this progressive and generalized skeletal muscular disorder has grown substantially [16].

Osteoarthritis, the most common degenerative joint disease, is a leading contributor of physical disability nowadays [17, 18]. Since osteoarthritis has brought a severe impact on both individuals and the society as a whole, a comprehensive understanding of the underlying mechanism and potential risk factors of osteoarthritis has a significant importance [19]. Multiple types of risk factors have been identified to be correlated with pathogenesis of osteoarthritis [20], among which muscle weakness is considered as one of the major ones [21, 22]. For the various recommended intervention measures of osteoarthritis, functional exercise and muscle strength exercise have been drawing growing attention. Previous studies have suggested that there appears to be a bidirectional relationship between muscle weakness and osteoarthritis, muscle weakness might be a contributor to osteoarthritis progression and vice versa. On the one hand, as the atrophy or weakness of periarticular muscles would lead to the development, progression and severity of osteoarthritis, patients with osteoarthritis would adapt their lifestyle to sedentary and inactivity to avoid joint pain and stiffness [23-26]. Subsequently, sedentary and physical inactivity would in turn reduces energy expenditure and results in muscle wasting, thus would lower the joint-protective ability [27]. On the other hand, pain and stiffness of osteoarthritis joints cause physical inactivity, which would lead to adipose tissue gains and overweight development in these patients. The pressure of increased load further exacerbates the progression of osteoarthritis, and it is the combination of these factors that is considered to create and perpetuate a vicious cycle between muscle weakness and osteoarthritis [28, 29].

Yet, few studies considered muscle weakness or atrophy as a disease (i.e., sarcopenia) and the relationship between sarcopenia and osteoarthritis has remained ambiguous and no strong consensus has been reached [30]. Some suggested that sarcopenia was likely to positively correlate with osteoarthritis [31-34], and other studies did not support this observation [35, 36]. One of the plausible reason could be the definition of sarcopenia has been progressing and updating for decades, but full agreement on the involved variables and cutoff points has not reached yet [3], and this may lead to different prevalence rates. Furthermore, different anatomical location of osteoarthritis may exhibit different associations with sarcopenia. One study found that sarcopenia was associated with osteoarthritis at the hip and lower limbs [34], while another study reported that sarcopenia was independently associated with knee osteoarthritis and inversely associated with lumbar spine osteoarthritis [33]. One approach to synthesis existing knowledge is to identify consistencies across studies through a meta-analysis, but to our knowledge, no such study has systematically reviewed current evidence on the association between sarcopenia and osteoarthritis.

Therefore, this meta-analysis study aims to identify the association between sarcopenia and osteoarthritis more comprehensively. The results of this study will further our knowledge on whether sarcopenia and osteoarthritis are associated at different targeted joints, thereby enabling the development of preventive and therapeutic strategies for both sarcopenia and osteoarthritis.

Methods

Study design

This meta-analysis protocol has been registered with the international prospective register of systematic reviews PROSPERO network (registration number: CRD42020155694). The consent of this protocol is developed based on the Preferred Reporting Items for Systematic Review and Meta-Analyses Protocols (PRISMA-P) 2015 Statement Guidelines (S1 Appendix) [37].

Eligibility criteria

The initially-retrieved studies will be evaluated for inclusion according to the following inclusion criteria: (1) observational studies including cohort studies, cross-sectional studies or case-control studies that focus on the prevalence of sarcopenia in patients with and without osteoarthritis, (2) diagnosis of sarcopenia using any definition criteria (e.g., low appendicular muscle mass criteria, or the European Working Group on Sarcopenia in Older People [EWGSOP] criteria including low handgrip strength and/or low walking speed in combination with low muscle mass), and (3) the age of included subjects are ≥60 years. Studies will be excluded if they are: (1) lack of reporting on study outcomes and (2) duplicate publications.

Information sources

Three electronic databases (i.e., PubMed, Web of Science, and Embase) will be searched with appropriate search strategies from inception up to February 2022 from each platform or database. In addition, reference lists of the included literature and relevant systematic reviews will also be browsed to identify the eligible studies.

Search strategy

The search will be carried out by combining keywords terms or medical subject heading terms (MESH) for eligible studies from the databases mentioned above. The same search terms will be adapted based on the specific requirements of different syntax rules. The electronic search strategy is listed in Tables 1–3.

Table 1

Draft of search strategy to be used using PubMed electronic database.

Number	Search terms
1	“osteoarthritis”[Mesh]
2	osteoarthriti*[Title/Abstract]
3	osteoarthro*[Title/Abstract]
4	gonarthriti*[Title/Abstract]
5	coxarthriti*[Title/Abstract]
6	coxarthro*[Title/Abstract]
7	osteo?arthritis[Title/Abstract]
8	gonarthro*[Title/Abstract]
9	OR/1-8
10	“sarcopenia”[Mesh]
11	“muscle weakness”[Mesh]
12	sarcopen*[Title/Abstract]
13	“muscle mass”[Title/Abstract]
14	“muscle volume”[Title/Abstract]
15	“muscle quality”[Title/Abstract]
16	“muscle size”[Title/Abstract]
17	“lean mass”[Title/Abstract]
18	“muscle strength”[Title/Abstract]
19	“grip strength”[Title/Abstract]
20	“gripping strength”[Title/Abstract]
21	“hand strength”[Title/Abstract]
22	“holding power”[Title/Abstract]
23	“grip dynamometer”[Title/Abstract]
24	handgrip[Title/Abstract]
25	“muscular atrophy”[Title/Abstract]
26	“muscle atrophy”[Title/Abstract]
27	“muscular dystrophy”[Title/Abstract]
28	“muscle dystrophy”[Title/Abstract]
29	“physical function”[Title/Abstract]
30	“muscle weakness”[Title/Abstract]
31	OR/10-30
32	9 AND 31

Table 3

Draft of search strategy to be used using Web of Science electronic database.

Number	Search terms
1	TS = (osteoarthriti* OR osteoarthro* OR gonarthriti* OR gonarthro*OR coxarthriti* OR coxarthro* OR osteo*arthritis)
2	TS = (sarcopen* OR “muscle weakness” OR “muscle atrophy” OR “muscle mass” OR “muscle volume” OR “muscle quality” OR “muscle size” OR “lean mass” OR “muscle strength” OR “grip strength” OR “gripping strength” OR “hand strength” OR “holding power” OR “grip dynamometer” OR handgrip OR “muscular atrophy” OR “muscular dystrophy” OR “muscle dystrophy” OR “physical function” OR “muscle weakness”)
3	1 AND 2

Study selection

Two investigators will screen the title and abstract of each retrieved study independently to identify eligible studies after removing duplicates. Full text will be reviewed according to the inclusion and exclusion criteria if the eligibility of studies is uncertain. Discussion will be made by consulting a third investigator for any disagreements between the two investigators. Studies will not be restricted on the language and publication date. Study selection will be documented and summarized based on the PRISMA flow diagram.

Data extraction

After systematic literature search is carried out, two investigators will screen the the included studies independently and extract the following data from in a standardized format: name of the author(s), year of publication, study design, setting of the study, data sources, study period, sample size, age range of the participants, sex distribution, prevalence of sarcopenia in patients with and without osteoarthritis. The effect sizes (i.e., odds ratio [OR], relative risk [RR] or hazard ratio [HR]) will be directly extracted or calculated on the basis of the relevant data in the original study as far as possible. If any data of interest is not available, we will contact the author(s) of the concerned study to obtain the supplemental data to the best extent. Any disagreements in data extraction will be consulting a third investigator to reach a consensus.

Quality assessment

Two investigators will evaluated the quality of included studies independently according to the Newcastle-Ottawa Quality Scale (NOS) [38]. The NOS scale is a validated scale for non-randomized studies in meta-analysis that evaluates the risk of bias with broad perspectives: (1) the selection of the study groups; (2) the comparability of the groups; and (3) the ascertainment of either the exposure or outcome of interest for case-control or prospective/ retrospective cohort studies, respectively [39]. For the cross-sectional studies, an adapted form of NOS will be used to evaluates the risk of bias [40, 41]. Studies with more than five stars will be considered as high methodological quality. In case of any discrepancies, a consensus will be reached through a discussion, with the assistance of a third reviewer when necessary. Studies with a high risk of bias (e.g., small-sample or low-quality studies) will be excluded and the reasons for their exclusion will be noted.

Data analysis

All data will be statistical analyzed using the statistical software Review Manager 5.3 software. The study characteristics will be summarized in narrative texts and baseline tables. Specifically, effect sizes (the pooled OR, RR or HR) and corresponding 95% CIs will be calculated respectively. Statistical heterogeneity between the studies will be evaluated with I2 values, for highly heterogeneous studies (>50%) a random-effects model will be used. A fixed-effects model will be applied to perform data pooling when the level of heterogeneity is not significant. The meta-analysis is set to a statistical significance as p value < 0.05. When data are sufficient, this study will also perform subgroup analyses stratified by obesity (obesity and non-obesity) and different joints (hip, knee and hand).

Assessment of publication bias

The publication bias among various studies will be assessed using the visual examination of funnel plot and Egger’s test if ten or more studies are available. Asymmetric funnel plot may imply possible publication bias, small-study effects, or other factors. If asymmetry is caused by small-study effects, we will conduct sensitivity analysis by excluding these studies to explore how this affects the results and conclusions of the meta-analysis.

Sensitivity analysis

Sensitivity analysis will be performed to test the robustness of pooled results regarding study characteristics and methodological quality by removing some of the small-sample or low-quality studies. If heterogeneity exists, sensitivity analysis will be re-run while removing poor quality data in a step-by-step wise.

Discussion

As sarcopenia is a relatively new disorder with high incidence and prevalence in elderly population, it has seriously affected the health of the elderly throughout the world. It has been postulated that sarcopenia and osteoarthritis may be co-existing conditions [42]. But the pathophysiological mechanisms associated with sarcopenia and osteoarthritis are unclear. Plausible factors might include ageing, disuse and inflammation. Yet, the relevance of these findings has not been established. To explore the relationship between these two prevailing diseases, it is of great significance to conduct a meta-analysis to determine the impact of sarcopenia on osteoarthritis.

So far, there have been several studies on the correlation between sarcopenia and osteoarthritis. Of them, four studies suggested that sarcopenia was likely to positively correlate with osteoarthritis [31-34], and two studies showed that obesity and sarcopenic obesity, but not sarcopenia, were associated with osteoarthritis [35, 36]. In addition, one study found that sarcopenia was associated with osteoarthritis at the hip and lower limbs [34], while another study reported that sarcopenia was independently associated with knee osteoarthritis and inversely associated with lumbar spine osteoarthritis [33]. However, due to the variation in diagnostic criteria and classification of sarcopenia, the association between sarcopenia and osteoarthritis is still inconclusive [32, 35]. Previous studies analyzed sarcopenia by adopting different diagnosis standards and in relation to different weight-bearing joints osteoarthritis, which could be a possible reason why the literature findings were inconsistent. An earlier cross-sectional study discussed the associations between low skeletal muscle mass and radiographic osteoarthritis of the hip, lumbar and knee joints, and the results showed that the skeletal muscle mass exhibited different associations with different joints [33]. Sarcopenia, as a disease affecting the whole body, may not only influence the knee joints but also other joints. According to the diagnostic criteria given by EWGSOP [1], sarcopenia can be diagnosed by the tests of muscle strength (usually based on grip strength), muscle mass (usually based on dual-energy X-ray absorptiometry or bioelectrical impedance analysis) and muscle function (usually based on gait speed, short physical performance battery, or time-up-and-go tests), which involve multiple joints of the body including hand, hip, and knee.

Nevertheless, sarcopenia, as well as sarcopenic obesity, have both been recognized as leading contributors of increased disability and mortality [14, 43]. Given that the effect of obesity towards osteoarthritis in previous studies, we will further perform subgroup and sensitivity analyses focusing on obesity or sarcopenic obesity as well. Previously, obesity, which is often represented by an increased body mass index (BMI) or body weight, was generally considered as a major risk factor of osteoarthritis [44]. However, in view of that the ratio of muscle mass over fat mass is changing constantly with the aging process [45-47], conventional anthropometric indicators, such as BMI and weight, may not be able to fully represent adiposity [48]. Recently, sarcopenia and sarcopenic obesity have been reported to be associated with a number of diseases including osteoarthritis [10, 29, 49]. Thus, subgroup and sensitivity analyses of sarcopenia, sarcopenic obesity and obesity will be conducted to better illustrate the relationship of these disorders.

The outcome of this meta-analysis may address an association between sarcopenia and osteoarthritis that is of pivotal importance to understanding the underlying mechanisms. The results from this study are also likely to inform healthcare a better decision-making treatment decision and to maximize the benefits of prevent and control osteoarthritis progression for limiting sarcopenia risk.

(DOCX)

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13 May 2022

11 Jun 2022

Dear Editor,

Thank you for the opportunity to submit a revision of our research paper, “Prevalence of sarcopenia and its association with osteoarthritis: a protocol for meta-analysis” [PONE-D-22-07545] for consideration for publication in PLOS ONE.

We provide a point-by-point response to the Editors’ and Reviewers’ comments. We hope that our responses are satisfactory and that the changes we have made in the text reflect our responsiveness to the comments and suggestions.

We look forward to your further assessment of this revised paper and thank you again for your consideration of our manuscript for publication in your journal.

Yours sincerely,

Hui Li, MD, PhD

Department of Orthopaedics, Xiangya Hospital, Central South University

lihui1988@csu.edu.cn

Academic Editor

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Response: Per the editor’s comment, we have updated the format accordingly throughout the revised manuscript.

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"This work was supported by the National Natural Science Foundation of China (81930071, 81902265, 82072502), and the Youth Science Foundation of Xiangya Hospital (2021Q14). No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Funding section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

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

Response: We are sorry for the confusion. We have updated the funding statement in cover letter and remove the funding information in manuscript. Please change the online submission on our behalf.

Action: “Funding statement H.L. is funded by the National Natural Science Foundation of China (81902265), and Y.W. is funded by the Youth Science Foundation of Xiangya Hospital (2021Q14). No funding bodies had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.” (Line 17-21 in Cover letter).

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

Response: Per the editor’s comment, we have updated the Data Availability statement in Cover letter.

Action: “Data Availability statement All relevant data are within the article and its Supporting information files.” (Detailedly, retrieval and storage of study records, abstracts and full-text articles will be performed using EndNote 20. Subsequently, extracted data will be tabulated and upload as a Supporting information file.) (Line 23-27 in Cover letter)

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Response: Per the editor’s comment, we have updated the name of supporting information file and its in-text citation accordingly.

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Response: Per the editor’s comment, we have checked the reference list and confirmed it is complete and correct. All cited papers have not been retracted.

Review #1:

Comment 1: Manuscript by Wang et al involves the description of protocol to find a relevance between sarcopenia and osteoarthritis. It could be a powerful tool to cumulate and show their relationship. Manuscript is well written. Protocol includes multiple databases which is beneficial and avoid publication biasness. Results of meta-analysis could be affected by quality of included studies. For example, there could be effect of small study (study using small sample size than study with large sample size) on the heterogeneity of results. Author should include the quality assessment for such studies. Format of references should be consistent.

Response: We appreciate the reviewer’s positive comments of our manuscript.

First of all, quality assessment was conducted using Newcastle-Ottawa Quality Assessment Scale (NOS) and studies with an NOS score ≥ 5 were considered high quality. If there are low quality studies, data synthesis will be performed carefully. Sensitivity analyses excluding those studies with low quality will be conducted when necessary.

Secondly, if there are ten or more studies in the meta-analysis, we will perform funnel plots and Egger’s regression test to investigate publication bias according to the Cochrane Handbook (REF: Page MJ, Higgins JPT, Sterne JAC. Chapter 13: Assessing risk of bias due to missing results in a synthesis. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Cochrane, 2022. Available from www.training.cochrane.org/handbook.). If asymmetric funnel plot is suggested by a visual assessment, we will perform exploratory analyses to investigate it and to investigate whether asymmetry is the result of publication bias, small-study effects, or other factors. If it is likely that asymmetry is caused by small-study effects, we will conduct sensitivity analysis by excluding these studies to explore how this affects the results and conclusions of the meta-analysis.

Finally, we have checked the reference list and confirmed it is complete and correct.

Action: “Studies with a high risk of bias (e.g., small-sample or low-quality studies) will be excluded and the reasons for their exclusion will be noted.” (Line 166-167)

“Asymmetric funnel plot may imply possible publication bias, small-study effects, or other factors. If asymmetry is caused by small-study effects, we will conduct sensitivity analysis by excluding these studies to explore how this affects the results and conclusions of the meta-analysis.” (Line 184-187)

Review #2:

Comment 1: The protocol is well written in a good scientific way, but a linguistic revision and rephrasing are needed to correct as:

- in Page8, line 42: " two investigators will be evaluate" replace by " two investigators will evaluate"

- page11, line 70: " To be correlate with" replace by " to be correlated".

Response: We appreciate the reviewer’s comments and have corrected these errors accordingly.

Action: “Two investigators will evaluate the preselected studies independently for inclusion, data extraction and quality assessment using a standardized protocol.” (Line 34-36)

“Multiple types of risk factors have been identified to be correlated with pathogenesis of osteoarthritis [20],…” (Line 62-63)

Comment 2: The title:

"Prevalence of sarcopenia and its association with osteoarthritis", the aim of the study and the included studies are focusing on the association between osteoarthritis and sarcopenia, so delete the prevalence from the title. The prevalence is only could be estimated from the cross-sectional study and not from the case control and cohort study.

Response: We appreciate the reviewer’s comments and have changed the title accordingly.

Action: “Association between sarcopenia and osteoarthritis: a protocol for meta-analysis” (Line 1)

Comment 3: Introduction:

At the end of the introduction "Therefore, this meta-analysis study aims to estimate the pooled prevalence of sarcopenia and to identify its association with osteoarthritis more comprehensively".

The aim is not clear here and not matched with methods and the planned analysis, please concentrate on the association between the sarcopenia and osteoarthritis as you explained through all the protocol sections.

Revise the protocol from the title and afterwords to maintain the integrity between all sections.

Response: We appreciate the reviewer’s comments and have revised the protocol accordingly.

Action: “Association between sarcopenia and osteoarthritis: a protocol for meta-analysis” (Line 1)

“Meta-analysis will be performed to pool the estimated effect using studies assessing an association between sarcopenia and osteoarthritis. Subgroup analyses will also be performed when data are sufficient.” (Line 36-38)

“…, but to our knowledge, no such study has systematically reviewed current evidence on the association between sarcopenia and osteoarthritis.” (Line 94-95)

“Therefore, this meta-analysis study aims to identify the association between sarcopenia and osteoarthritis more comprehensively.” (Line 97-98)

Comment 4: Methods

In general all items were covered in eligibility criteria: please justify the selected age (>60 years old)

Response: We appreciate the reviewer’s comment. Sarcopenia is defined as age-related loss of skeletal muscle mass plus loss of muscle strength and/or reduced physical performance. And the age cutoff points were set as 60 or 65 years old, according to consensus of European Working Group on Sarcopenia in Older People (EWGSOP) and Asian Working Group for Sarcopenia (AWGS) [1, 2]. Although there are several mechanisms that may be involved in the onset and progression of sarcopenia, we would like to focus on the primary etiology (age-related sarcopenia). Furthermore, it has been shown that the incidence of osteoarthritis increases rapidly between the ages of 50 years and 75 years, which is unlikely to have biased our meta-analyses [3].

1． Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, et al. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing. 2010;39(4):412-23. Epub 20100413. doi: 10.1093/ageing/afq034.

2． Chen LK, Woo J, Assantachai P, Auyeung TW, Chou MY, Iijima K, et al. Asian Working Group for Sarcopenia: 2019 Consensus Update on Sarcopenia Diagnosis and Treatment. J Am Med Dir Assoc. 2020;21(3):300-7 e2. Epub 20200204. doi: 10.1016/j.jamda.2019.12.012.

3． Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet. 2019;393(10182):1745-59. doi: 10.1016/S0140-6736(19)30417-9.

Comment 5: Discussion:

On page 17, from line 210 and after: This is a section discussing few studies will be included in the studies, but it's better to include them with the other studies at the end of the study.

Response: We appreciate the reviewer’s comment. As requested, discussion was adjusted and rephrased.

Action: So far, there have been several studies on the correlation between sarcopenia and osteoarthritis. Of them, four studies suggested that sarcopenia was likely to positively correlate with osteoarthritis [31-34], and two studies showed that obesity and sarcopenic obesity, but not sarcopenia, were associated with osteoarthritis [35, 36]. In addition, one study found that sarcopenia was associated with osteoarthritis at the hip and lower limbs [34], while another study reported that sarcopenia was independently associated with knee osteoarthritis and inversely associated with lumbar spine osteoarthritis [33]. However, due to the variation in diagnostic criteria and classification of sarcopenia, the association between sarcopenia and osteoarthritis is still inconclusive [32, 35]. Previous studies analyzed sarcopenia by adopting different diagnosis standards and in relation to different weight-bearing joints osteoarthritis, which could be a possible reason why the literature findings were inconsistent. An earlier cross-sectional study discussed the associations between low skeletal muscle mass and radiographic osteoarthritis of the hip, lumbar and knee joints, and the results showed that the skeletal muscle mass exhibited different associations with different joints [33]. Sarcopenia, as a disease affecting the whole body, may not only influence the knee joints but also other joints. According to the diagnostic criteria given by EWGSOP [1], sarcopenia can be diagnosed by the tests of muscle strength (usually based on grip strength), muscle mass (usually based on dual-energy X-ray absorptiometry or bioelectrical impedance analysis) and muscle function (usually based on gait speed, short physical performance battery, or time-up-and-go tests), which involve multiple joints of the body including hand, hip, and knee. (Line 206-227)

Comment 6: Include the subgroup analysis about the relation with adiposity and obesity in the methods section. Also the same regarding the association with osteoarthritis in different joints.

Response: We appreciate the reviewer’s insightful comment and have added the corresponding content in the revised manuscript.

Action: “When data are sufficient, this study will also perform subgroup analyses stratified by obesity (sarcopenia, sarcopenic obesity and obesity) and different joints (hip, knee and hand).” (Line 177-179)

Submitted filename: Response to Reviewers.docx

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18 Jul 2022

Association between sarcopenia and osteoarthritis: a protocol for meta-analysis

PONE-D-22-07545R1

Dear Dr. Li,

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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Osama Farouk

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Yes

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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 and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have fully addressed my concerns. After assessment of responses on academic editor and other reviewer comments, the authors replied well to majority of the comments. I think the revised protocol manuscript is ready for publication.

Reviewer #2: Dear authors

Thank you for the done revisions, I think it's now ready for publication.

I wish it will be an interesting study.

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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.

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Reviewer #1: No

Reviewer #2: No

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26 Jul 2022

PONE-D-22-07545R1

Association between sarcopenia and osteoarthritis: a protocol for meta-analysis

Dear Dr. Li:

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. Osama Farouk

Academic Editor

PLOS ONE

Table 2

Draft of search strategy to be used using Embase electronic database.

Number	Search terms
1	‘osteoarthritis’/exp
2	osteoarthriti*:ti,ab,kw
3	osteoarthro*:ti,ab,kw
4	gonarthriti*:ti,ab,kw
5	gonarthro*:ti,ab,kw
6	coxarthriti*:ti,ab,kw
7	coxarthro*:ti,ab,kw
8	osteo*arthritis:ti,ab,kw
9	OR/1-8
10	‘sarcopenia’/exp
11	‘muscle weakness’/exp
12	sarcopen*:ti,ab,kw
13	‘muscle mass’:ti,ab,kw
14	‘muscle volume’:ti,ab,kw
15	‘muscle quality’:ti,ab,kw
16	‘muscle size’:ti,ab,kw
17	‘lean mass’:ti,ab,kw
18	‘muscle strength’:ti,ab,kw
19	‘grip strength’:ti,ab,kw
20	‘gripping strength’:ti,ab,kw
21	‘hand strength’:ti,ab,kw
22	‘holding power’:ti,ab,kw
23	‘grip dynamometer’:ti,ab,kw
24	handgrip:ti,ab,kw
25	‘muscular atrophy’:ti,ab,kw
26	‘muscle atrophy’:ti,ab,kw
27	‘muscular dystrophy’:ti,ab,kw
28	‘muscle dystrophy’:ti,ab,kw
29	‘physical function’:ti,ab,kw
30	‘muscle weakness’:ti,ab,kw
31	OR/10-30
32	9 AND 31