Efficacy of core muscle strengthening training around the knee compared to oral nonsteroidal anti-inflammatory drugs in early-stage knee osteoarthritis patients: protocol for a randomized controlled trial

Efficacy of core muscle strengthening training around the knee compared to oral nonsteroidal anti-inflammatory drugs in early-stage knee osteoarthritis patients: protocol for a randomized controlled trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy of core muscle strengthening training around the knee compared to oral nonsteroidal anti-inflammatory drugs in early-stage knee osteoarthritis patients: protocol for a randomized controlled trial Chen Wei, Xiang Wang, Yizhe Xiong, Wuwei Song, Xiaoyu Guo, Jiacheng Yu, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5915635/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Dec, 2025 Read the published version in Trials → Version 1 posted 5 You are reading this latest preprint version Abstract Background Knee osteoarthritis (KOA) is a prevalent condition characterized by a high incidence and disability rate, making early intervention particularly critical. It is essential to focus on addressing the underlying disease rather than solely alleviating symptoms through pharmacological treatments. The Osteoarthritis Research Society International recommends non-pharmacological therapies as the primary intervention strategy, with physical therapy identified as the principal method. Current rehabilitation training programs often present challenges, including prolonged treatment durations, complex procedures, and the necessity for medical supervision. Preliminary clinical observations suggest that core muscle strengthening training around the knee (CMSTK) may effectively reduce pain, enhance mobility, improve quality of life, and avoid the aforementioned limitations. Nevertheless, further high-quality research with larger sample sizes is required to validate its efficacy conclusively. Methods This study is a 12-week single-blind randomized controlled trial. 100 early-stage knee osteoarthritis (EKOA) patients will be recruited and randomly divided into CMSTK group and oral nonsteroidal anti-inflammatory drugs group. Outcome assessments will be conducted before allocation and at 2, 4, 8, and 12 weeks after allocation. Comprehensive efficacy will be evaluated by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Data collectors and statisticians will be blinded, and participants will be asked not to reveal their allocation to assessors. Discussion This study aims to investigate the specific efficacy of CMSTK for the treatment of EKOA. The findings of this research will enhance the therapeutic approaches for early intervention in KOA, offer a scientific foundation for enabling patients with EKOA to engage in self-directed exercise, and contribute to the alleviation of social, medical, and economic burdens associated with the condition. Trail registration Chinese Clinical Trials Registry ChiCTR2400089758. Prospectively registered on 14 September 2024. Early-stage knee osteoarthritis Physical therapy Oral nonsteroidal anti-inflammatory drugs Protocol Comprehensive efficacy Figures Figure 1 Background Knee osteoarthritis (KOA) is a chronic degenerative joint disease characterized by progressive cartilage deterioration in the knee joint, narrowing of the joint space, abnormal remodeling of subchondral bone, and the osteophyte formation at joint edges. It is manifested by symptoms such as knee pain, swelling, limited range of motion (ROM) in flexion and extension, muscular atrophy, and internal and external knee valgus [ 1 , 2 ]. An epidemiologic study indicated that the prevalence of KOA is 18% [ 3 ], with a significant increase in prevalence associated with advancing age [ 4 ]. Another epidemiologic study in the United States revealed that KOA is the second leading cause of disability among individuals over 50 years of age [ 5 ]. In 2018, there were more than 14 million symptomatic KOA patients in the United States, with individuals under 65 years of age accounting for over half of the total cases [ 6 ]. This trend suggests that KOA is increasingly affecting younger populations. Consequently, the high prevalence and disability rate associated with KOA not only severely impact the quality of life for patients but also contribute to emotional disorders such as anxiety, depression, and insomnia as the disease progresses. Additionally, KOA imposes a significant medical and economic burden on society. Given the aging global population, the trend of KOA affecting younger individuals, and the rising incidence of KOA each year, researches focused on the prevention, delay, and early intervention of KOA have become the center of attention [ 7 ]. There is currently no effective treatment for KOA in modern medicine, and most available treatments focus primarily on pain relief. While oral nonsteroidal anti-inflammatory drugs (NSAIDs) can alleviate pain, they do not alter the natural progression of KOA or address the underlying causes of the disease. Furthermore, long-term use of NSAIDs may lead to gastrointestinal complications, cardiovascular events, and damage to hepatic and renal function. Intra-articular injections carry a risk of infection and their benefits remain uncertain, while surgical interventions can be traumatic, costly, and less acceptable to patients [ 8 ][ 9 ]. In addition to symptomatic medications, there are also disease-modifying osteoarthritis drugs (DMOADs), including extracellular matrix-degrading enzyme inhibitors, cartilage regeneration agents, and drugs targeting subchondral bone remodeling. However, the efficacy of most DMOADs is still uncertain, and there is a notable lack of evidence from clinical trials to support their use [ 10 ][ 11 ][ 12 ][ 13 ]. Studies have demonstrated that therapies such as massage, exercise, and sports are effective in increasing metabolism, generating heat, enhancing blood flow, improving local circulation, strengthening core muscle, and enhancing joint mobility [ 14 ][ 15 ][ 16 ]. Among these, aerobic exercise is the most effective for alleviating pain and improving athletic performance [ 17 ]. The Osteoarthritis Research Society International (OARSI) recommends non-surgical treatments as a fundamental intervention in the management of KOA in the 2019 guildline [ 18 ]. Current exercise prescriptions for KOA primarily include aerobic walking, strength training, joint mobility training, and neuromuscular training. However, many of these exercise prescriptions are complex, time-consuming, and cumbersome, with some processes being repetitive and prone to low patient compliance and non-standard movements, which can adversely affect treatment efficacy. Furthermore, most rehabilitation prescriptions necessitate that patients visit hospitals with the assistance of doctors or rehabilitation therapists, which can be a significant burden for patients. Telerehabilitation [ 19 ] may be a viable solution; however, in some remote areas, information and communication technology is underdeveloped, and many older individuals do not utilize electronic devices or the Internet. Consequently, simplifying the training process and the facilitating of the implementation are crucial for enhancing patient compliance, autonomy and enthusiasm. After reviewing both domestic and international rehabilitation training protocols and relevant foundational research literature, we developed an exercise prescription focused on core muscle strengthening training around the knee (CMSTK) [ 20 ][ 21 ][ 22 ][ 23 ][ 24 ]. Our findings indicate that this approach effectively alleviates pain, improves joint mobility, and enhances the quality of daily life and work for patients with early-stage knee osteoarthritis (EKOA) in recent clinical applications. Notably, we have also observed satisfactory outcomes in patients with middle and advanced KOA, including significant reductions in pain and increased walking distance. Some researchers have noted that while muscle strengthing training enhances quadriceps strength, relieves knee pain and improves range of motion in KOA patients, the biomechanical relationship between KOA and quadriceps remains unclear [ 25 ]. Methods Aim The main purpose of this study is to investigate the specific efficacy of the exercise prescription for the treatment of EKOA by comparing the effects of CMSTK and oral NSAIDs on pain, range of motion, quality of life, and muscle quality in patients with EKOA. The findings of this study will be discussed to guide clinical practice, enhance treatment strategies, facilitate patient self-management, improve compliance, and ultimately optimize outcomes for individuals with EKOA while potentially delaying the progression of the disease. Study design This study is a 12-week single-blind randomized controlled trial. The protocol was designed following the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT). This trial will be conducted in both outpatient and inpatient departments of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, and the assessment and collection of data will be conducted in the hospital by data collectors who are blinded to trial group assignment. Participants and setting We will recruit 100 participants at Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, in East China. The protocol has been approved by the Ethics Committee of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (ethical approval number: 2024-1506-089-01). Diagnostic criteria Referring to the diagnostic criteria of “Guideline for diagnosis and non-surgical treatment of early-stage knee osteoarthritis (2024 edition)” [26]: 1. Recurrent knee pain for more than 1 month. 2. Age ≥40 years. 3. Morning stiffness ≤30 minutes; pain during squatting and going up and down stairs. 4. Bone friction sound (or sensation) and joint space pressure pain during activity. 5. X-ray in standing position shows no obvious changes in the joints, or there are bone encumbrances and / or suspected narrowing of the joint space. 6. MRI shows the presence of limited or diffuse cartilage damage (range ≤75%), or subchondral bone marrow edema in any region (range ≥25%). EKOA can be diagnosed by meeting the diagnostic criteria 1 + 2 + 3 + 4 + 5 or 1 + 6. Inclusion criteria 1. Meet the diagnostic criteria of EKOA. 2. Age 40–70 years old. 3. Patients with 30mm≤ Visual Analogue Scale (VAS) ≤70mm while walking. 4. Voluntarily participate in this study and sign the informed consent. Exclusion criteria 1. Patients with serious diseases of the heart, liver, kidney, blood system, etc. 2. Patients with joint inflammatory diseases such as rheumatoid arthritis, gouty arthritis, ankylosing spondylitis and other diseases affecting lower extremity function. 3. Patients during pregnancy, lactation, or pregnancy preparation. 4. Patients with any surgery in the corresponding knee joint 6 months prior to study inclusion. 5. Patients who are allergic to Celecoxib or contraindicated in it. 6. Patients with any intra-articular injections in the corresponding knee joint 3 months prior to study inclusion. 7. Patients with regular lower limb training or rehabilitation treatment 1 months prior to study inclusion. Participants who meet any of the above criteria will not be able to participate in this study. Randomization and allocation Block randomization will be used. The randomization sequence will be created using SPSS 26.0 statistical software and patients will be stratified with a 1:1 allocation ratio using random block sizes of 2, 4, and 6. Then, according to the result of block randomization, the corresponding test envelope which will be given to the investigator who do not know the result is obtained. Blinding Trial participants, data collectors and statisticians are blinded to trial group assignment until the completion of this trail. Participant timeline Table 1 shows the assessments at each timepoint following the SPIRIT 2013 statement [27]. Figure 1 demonstrates the flow chart of the trial. Treatment group The treatment group receives CMSTK which is divided into two parts for 4 weeks. The initial exercises will be conducted under the supervision and guidance of a doctor. 1. Patients take a supine position where their lower limbs are naturally straight, with the foot in dorsal extension. A pillow or folded towel is placed under the thigh on the affected side. Patients then apply vertical downward pressure on it with back muscles of their thigh (hamstrings), and maintain this position and strength for 10–15 seconds before slowly relaxing. After a 3-second rest, patients repeat the previous set of actions; this constitutes one group. Each session consists of 10–15 groups, performed twice a day. 2. Patients take a supine position where their lower limbs are naturally straight, with the foot in dorsal extension. A pillow or folded towel is placed in the popliteal fossa of the affected knee, ensuring that the knee joint remains static. Patients are then instructed to actively contract the anterior thigh muscles (quadriceps) and maintain this position and strength for 10–15 seconds before slowly relaxing. After a 3-second rest, patients repeat the previous set of actions; this constitutes one group. Each session consists of 10–15 groups, performed twice a day. The number and duration of groups per day should be gradually increased based on the patients’ tolerance. Feelings of soreness and distension in the thigh are normal reactions following training. We publish daily training programs and tasks via WeChat and request that patients check in each day, either by submitting photos or videos. If elderly patients are unfamiliar with using electronic devices or the internet, we will encourage them to engage in active exercise via phone calls. Control group The control group receives Celecoxib capsules (produced by Pfizer Pharmaceuticals LLC, specification: 200mg / capsule, pharmaceutical product registration certificate number: National Medical Products Administration (NMPA) approval number J20120063) with a dosage of 200mg / day, to relieve symptoms of KOA for 4 weeks [28]. Health education and self-management Both groups were given health education. If the body mass index (BMI) >25 kg/m 2 , the investigators will remind the participants to control their weight and deliver information about weight management and healthy diet [29]. If the patients are experiencing significant anxiety regarding their condition, we will patiently explain the mechanisms of the pain, the progression of the disease, and the importance of actively participating in their treatment. Additionally, we will provide the latest guidelines and clinical studies to bolster the patients’ confidence in their management of KOA. We also offer patients lifestyle guidance, which includes avoiding excessive kneeling and squatting [30], prolonged high-intensity exercise, and sedentary behavior [31]. Remedy medication Remedy medication (oral acetaminophen at a maximum dosage of 1000 mg/day [28]), will be administered if patients experience severe pain during the study. Data collectors will record that in detail on the case report form (CRF). Outcome assessments Outcomes will be measured before allocation (t 0 ) and at 2 (t 1 ), 4 (t 2 ), 8 (t 3 ), and 12 (t 4 ) weeks after allocation. Basic information including sex, age, course and affected side will be conducted before allocation. All participants will be assessed by researchers blinded to group tasks. Primary outcome measures The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) will be utilized to evaluate knee pain, stiffness, and physical function during the week prior to the assessment. The WOMAC consists of 24 items divided into three subscales: lower extremity pain (5 items), stiffness (2 items), and physical function (17 items). Each item is rated on a Likert scale from 0 (no symptoms) to 4 (extremely severe), resulting in a total score that ranges from 0 to 96. Higher scores indicate more severe symptoms [32]. The reliability and validity of the WOMAC total score and subscales have been confirmed [33]. Secondary outcome measures VAS VAS is one of the sensitive and reliable methods for pain measurement [34] and it will be utilized to evaluate the average level of knee pain during the week prior to the assessment. 36-Item Short Form Survey (SF-36) SF-36 includes 8 dimensions: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health, comprising a total of 36 questions. The overall score ranges from 0 to 100, with a higher score indicating a better quality of life [35]. Each dimension will be separately analyzed, and physical component score (PCS) and mental component score (MCS) scores will be analyzed at last to evaluate physical and mental health of EKOA patients [36]. SF-36 will not be assessed 2 weeks after the allocation. ROM in flexion and extension tests ROM in flexion and extension tests will be conducted at the Baltimore Therapeutic Equipment (BTE) Primus RS system on both knees. Isometric muscle strength tests Isometric muscle strength tests for assessing the quality of muscle around the knee will also be conducted at the BTE Primus RS system on both knees. Comprehensive efficacy evaluation (total effective rate) Comprehensive efficacy will be calculated using the WOMAC score, following the method of nimodipine. The efficacy index = (WOMAC score before allocation - WOMAC score at 12 weeks after allocation) / WOMAC score before allocation × 100% [37]. The specific judgment is as follows: Cured: Efficacy index ≥95% Apparently effective: 75%≤ efficacy index <95% Effective: 30%≤ efficacy index <75% Ineffective: efficacy index <30% Total effective rate = (cured + apparently effective + effective) / number of patients × 100% Safety measure Participants will be monitored for any adverse events during the trail, which will be recorded on the CRF. All adverse events will be followed up until normal. Patient satisfaction with the efficacy of treatment Patient satisfaction involves extremely satisfied, satisfied, average, dissatisfied, and extremely dissatisfied and will be conducted at each follow-up. Sample size The calculation of sample size was carried out according to the calculation requirements of the sample size of noninferiority experiments [38]. This was based on the variation of WOMAC of previous studies on physical training and oral NSAIDs in the treatment of KOA. The difference in WOMAC scores between the two groups after treatment was 8 [39]. Non-inferiority threshold was set to 3.825 [40]. The sampling ratio for the treatment and control groups was 1:1. We set α to 0.05, test power 1 - β to 80%, dropout rate to 20%. The sample size calculation was then conducted using G*Power 3.1.9.7 software. A total of 100 participants is required for the calculation. We finally calculated a sample size of 50 subjects per group. Statistical analysis Statistical analysis will be performed using the IBM SPSS statistics software (version 26.0). The p value <0.05 will be considered statistically significant. For categorical variables (e.g., sex, total effective rate and affected side), Fisher’s exact test or the chi-square test will be used to determine if there is a significant difference in distribution between the two groups. For continuous variables (e.g., age and course), the rank sum test, t test, or variance analysis will be utilized. The follow-up data of two groups (e.g., WOMAC, VAS, ROM, SF-36 and Isometric muscle strength) will be statistically analyzed using repeated measures ANOVA if they conformed to normal distribution and chi-square, and if not, the rank sum test will be used. Data collection and monitoring Data will be recorded by trained data collectors in the hospital and collected with a CRF. In accordance with Good Clinical Practice (GCP) monitoring guidelines, routine compliance monitoring will be implemented by the data monitoring committee who will be responsible for the data management and quality control, which consists of the hospital and the institute. Discussion KOA is a widespread condition that has a high prevalence and causes significant disability, resulting in considerable medical and economic strain on society. Therefore, early intervention in KOA to prevent its progression from early to advanced stages is crucial. In comparison to symptomatic medications, non-surgical treatments recommended by OARSI as the primary approach for managing KOA in the 2019 guideline show significant promise in treating the condition. This study aims to investigate the specific efficacy of the exercise prescription (CMSTK) for the treatment of EKOA. In contrast to prior researches, this study involves the recruitment of patients diagnosed with EKOA as participants. The CMSTK facilitates home-based exercise, thereby reducing the time and financial burden associated with traveling to healthcare facilities. Furthermore, CMSTK has been optimized based on professional rehabilitation training protocols, significantly minimizing both the duration and complexity of the exercises which will enhance patient compliance, autonomy and enthusiasm. This approach ensures that virtually all patients are capable of independently performing subsequent exercises following initial training instruction. The primary objective is to strengthen the core muscle groups directionally, thereby enhancing overall stability of the knee joint. The study is subject to several limitations. First, the single-blinded design may introduce potential bias from the researchers involved. We aim to reduce the influence of researchers' guidance or suggestions in the patient assessment process during the experimental phase by employing researchers who are blind to the group assignments. Second, supervising and managing patient training presents significant challenges, making it difficult to ascertain whether patients are genuinely participating in exercise. This difficulty persists despite our implementation of daily check-in requirements, the involvement of family members for oversight, and the utilization of training task cards. Patients will be educated about the natural progression of KOA, the late-stage symptoms, the impact on their daily activities, and the significance of ongoing exercise as a therapeutic intervention for KOA upon their allocation. Additionally, we will implement a system of regular reminders via WeChat or telephone to reinforce this information in the future. Finally, this study is limited to 12 weeks of follow-up, and longer-term outcomes are not evaluated. Similarly, the duration of treatment in this study is limited to a period of four weeks, and the effects of extended treatment durations are not assessed. Trial status Recruitment began on 20 September 2024, and the approximate date for the completion of recruitment will be 30 March 2025. The current protocol is the version 2 dated 8 May 2024. Abbreviations KOA: Knee osteoarthritis ROM: Range of motion NSAIDs: Nonsteroidal anti-inflammatory drugs DMOADs: Disease-modifying osteoarthritis drugs OARSI: Osteoarthritis Research Society International CMSTK: Core muscle strengthening training around the knee EKOA: early-stage knee osteoarthritis SPIRIT: Standard Protocol Items: Recommendations for Interventional Trials VAS: Visual Analogue Scale NMPA: National Medical Products Administration BMI: Body mass index CRF: Case report form WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index SF-36: 36-Item Short Form Survey PCS: Physical component score MCS: Mental component score BTE: Baltimore Therapeutic Equipment GCP: Good Clinical Practice Declarations Ethics declarations Ethics approval and consent to participate The trial will be conducted in accordance with the Declaration of Helsinki. The protocol has been approved by the Ethics Committee of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine on 15 May, 2024 (ethical approval number: 2024-1506-089-01). All participating patients will provide written informed consent. Consent for publication This manuscript does not contain individual personal data from patients. Competing interests The authors declare that they have no competing interests. Availability of data and materials Not applicable. Funding This research was funded by the National Natural science Foundation of China (project approval number: 82374488) and Program for 2020 Shanghai Science and Technology Committee ‘Science and Technology Innovation Action Plan’ (project approval number: 22Y21920200). The funders do not have a role in collection, analyzation, and interpretation of data, or in writing of the manuscript. Authors’ information Authors and Affiliations Shi’s Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China Chen Wei, Xiang Wang, Yizhe Xiong, Wuwei Song, Xiaoyu Guo, Jiacheng Yu, Wenyu Jiang, Yuhao Zhao, Zhenlin Yang, Zishan Sun, Rui Huang & Yongkang Sun Contributions CW, XW and YX designed the trial. CW and YZ drafted the manuscript. WS, XG, JY and WJ are responsible for data collection and statistical processing. ZY, ZS, RH and YS are responsible for the follow-up and supervision of patients. The authors read and approved the final manuscript. Corresponding author Correspondence to Xiang Wang. Acknowledgements The authors are grateful for colleagues from Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine in providing critical comments on study design, invaluable guidance and support throughout the trial. Plans to give access to the full protocol, participant level-data and statistical code The study protocol is publicly available on the website Chictr.org.cn with registration number: ChiCTR2400089758. The trial datasets generated or analyzed during the current study during the study are not publicly available. Trial results The trial results will be presented in scientific conferences at a national or international level, and also submitted for publication in academic journals that are reviewed by experts in the field. References Jiang W, Chen H, Lin Y, Cheng K, Zhou D, Chen R, et al. Mechanical stress abnormalities promote chondrocyte senescence - The pathogenesis of knee osteoarthritis. Biomed Pharmacother. 2023 Nov;167:115552. doi: 10.1016/j.biopha.2023.115552. Mohajer B, Dolatshahi M, Moradi K, Najafzadeh N, Eng J, Zikria B, et al. Role of Thigh Muscle Changes in Knee Osteoarthritis Outcomes: Osteoarthritis Initiative Data. 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Roos EM, Klässbo M, Lohmander LS. WOMAC osteoarthritis index. Reliability, validity, and responsiveness in patients with arthroscopically assessed osteoarthritis. Western Ontario and MacMaster Universities. Scand J Rheumatol. 1999;28(4):210-5. doi: 10.1080/03009749950155562. Piaggio G, Elbourne DR, Altman DG, Pocock SJ, Evans SJ; CONSORT Group. Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement. JAMA. 2006 Mar 8;295(10):1152-60. doi: 10.1001/jama.295.10.1152. Zhijie Y, Jianfeng C, Yafeng Z. Efficacy of muscle meridian manipulation in the treatment of knee osteoarthritis. Jiangsu Medical Journal. 2014 Nov;40(21):2590-2. Guo J, Peng C, Hu Z, Guo L, Dai R, Li Y. Effect of Wu Qin Xi exercises on pain and function in people with knee osteoarthritis: A systematic review and meta-analysis. Front Med (Lausanne). 2022 Nov 7;9:979207. doi: 10.3389/fmed.2022.979207. Supplementary Files SupplementaryMaterial1.SPIRITchecklist.docx Supplementary Information Supplementary Material 1. SPIRIT checklist. SupplementaryMaterial2.Modelconsentform.docx Supplementary Material 2. Model consent form. Cite Share Download PDF Status: Published Journal Publication published 01 Dec, 2025 Read the published version in Trials → Version 1 posted Reviewers agreed at journal 04 Apr, 2025 Reviewers invited by journal 04 Apr, 2025 Editor invited by journal 16 Feb, 2025 Editor assigned by journal 02 Feb, 2025 First submitted to journal 27 Jan, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5915635","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":438258682,"identity":"ad42d16b-a421-4203-8851-e106882d5933","order_by":0,"name":"Chen Wei","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2klEQVRIiWNgGAWjYBACfvb245//VNjU9zMzHyBOi2TPmTQGnjNpjDPb2RKI02JwI8GMgbftMOOGfh4DIl12IyHtgQRbGrMBM8/HG28Y7OR0GwjoYOx5eNzAgMeGzZyZd7PlHIZkY7MDBLQwsyckSCRIpPFYNvNuk+ZhOJC4jZAWNoYEA4kDBoclDA7zPCNOCw9HgplkQ8JhA6AWNuK0SPCcSTZmOJCWINnMZmw5x4AIv9gfbz/4mPGfTQI//+GHN95U2MkR1IJmJbFRg6SFVB2jYBSMglEwIgAAZGpArAQCafUAAAAASUVORK5CYII=","orcid":"https://orcid.org/0009-0005-2484-0738","institution":"Shuguang Hospital","correspondingAuthor":true,"prefix":"","firstName":"Chen","middleName":"","lastName":"Wei","suffix":""},{"id":438258683,"identity":"dd755dac-417f-4764-8ebc-535fb5d22d4d","order_by":1,"name":"Xiang Wang","email":"","orcid":"https://orcid.org/0000-0002-1748-1942","institution":"Shuguang 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Yu","email":"","orcid":"","institution":"Shuguang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jiacheng","middleName":"","lastName":"Yu","suffix":""},{"id":438258688,"identity":"8668f2d6-0d5f-489b-b3e0-f8454515bd30","order_by":6,"name":"Wenyu Jiang","email":"","orcid":"","institution":"Shuguang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wenyu","middleName":"","lastName":"Jiang","suffix":""},{"id":438258689,"identity":"850c9189-1185-48b0-a79a-ad226c01c899","order_by":7,"name":"Yuhao Zhao","email":"","orcid":"","institution":"Shuguang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuhao","middleName":"","lastName":"Zhao","suffix":""},{"id":438258690,"identity":"4ccf2739-22ed-4a39-87db-780e8cfee60f","order_by":8,"name":"Zhenlin Yang","email":"","orcid":"","institution":"Shuguang 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02:10:00","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5915635/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5915635/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-025-08996-3","type":"published","date":"2025-12-01T15:57:24+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82557984,"identity":"9a45a13c-8970-416c-8864-693dcb1eb561","added_by":"auto","created_at":"2025-05-13 01:19:59","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":46778,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow chart of the trail\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5915635/v1/025b8d07ac38fdf9073cfd8d.jpg"},{"id":97724970,"identity":"e9c1e0dd-1569-4bae-ae06-7b9dea4f9fa9","added_by":"auto","created_at":"2025-12-08 16:13:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1002811,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5915635/v1/489f1f52-2fd1-40ec-8d08-4bd1c65d9e28.pdf"},{"id":82559403,"identity":"2e1b93b2-fb73-44ae-9617-657d808c7621","added_by":"auto","created_at":"2025-05-13 01:27:59","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":28642,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSupplementary Material 1. SPIRIT checklist.\u003c/p\u003e","description":"","filename":"SupplementaryMaterial1.SPIRITchecklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-5915635/v1/d76187e2209202bbcb95df42.docx"},{"id":82560510,"identity":"62102016-cabd-46a3-9137-970541dc4f8b","added_by":"auto","created_at":"2025-05-13 01:35:59","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":26322,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Material 2. Model consent form.\u003c/p\u003e","description":"","filename":"SupplementaryMaterial2.Modelconsentform.docx","url":"https://assets-eu.researchsquare.com/files/rs-5915635/v1/b437c47ac52c7fb64ee42303.docx"}],"financialInterests":"","formattedTitle":"Efficacy of core muscle strengthening training around the knee compared to oral nonsteroidal anti-inflammatory drugs in early-stage knee osteoarthritis patients: protocol for a randomized controlled trial","fulltext":[{"header":"Background","content":"\u003cp\u003eKnee osteoarthritis (KOA) is a chronic degenerative joint disease characterized by progressive cartilage deterioration in the knee joint, narrowing of the joint space, abnormal remodeling of subchondral bone, and the osteophyte formation at joint edges. It is manifested by symptoms such as knee pain, swelling, limited range of motion (ROM) in flexion and extension, muscular atrophy, and internal and external knee valgus [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. An epidemiologic study indicated that the prevalence of KOA is 18% [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], with a significant increase in prevalence associated with advancing age [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Another epidemiologic study in the United States revealed that KOA is the second leading cause of disability among individuals over 50 years of age [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In 2018, there were more than 14\u0026nbsp;million symptomatic KOA patients in the United States, with individuals under 65 years of age accounting for over half of the total cases [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. This trend suggests that KOA is increasingly affecting younger populations. Consequently, the high prevalence and disability rate associated with KOA not only severely impact the quality of life for patients but also contribute to emotional disorders such as anxiety, depression, and insomnia as the disease progresses. Additionally, KOA imposes a significant medical and economic burden on society. Given the aging global population, the trend of KOA affecting younger individuals, and the rising incidence of KOA each year, researches focused on the prevention, delay, and early intervention of KOA have become the center of attention [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere is currently no effective treatment for KOA in modern medicine, and most available treatments focus primarily on pain relief. While oral nonsteroidal anti-inflammatory drugs (NSAIDs) can alleviate pain, they do not alter the natural progression of KOA or address the underlying causes of the disease. Furthermore, long-term use of NSAIDs may lead to gastrointestinal complications, cardiovascular events, and damage to hepatic and renal function. Intra-articular injections carry a risk of infection and their benefits remain uncertain, while surgical interventions can be traumatic, costly, and less acceptable to patients [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e][\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In addition to symptomatic medications, there are also disease-modifying osteoarthritis drugs (DMOADs), including extracellular matrix-degrading enzyme inhibitors, cartilage regeneration agents, and drugs targeting subchondral bone remodeling. However, the efficacy of most DMOADs is still uncertain, and there is a notable lack of evidence from clinical trials to support their use [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e][\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e][\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e][\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eStudies have demonstrated that therapies such as massage, exercise, and sports are effective in increasing metabolism, generating heat, enhancing blood flow, improving local circulation, strengthening core muscle, and enhancing joint mobility [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e][\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e][\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Among these, aerobic exercise is the most effective for alleviating pain and improving athletic performance [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The Osteoarthritis Research Society International (OARSI) recommends non-surgical treatments as a fundamental intervention in the management of KOA in the 2019 guildline [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Current exercise prescriptions for KOA primarily include aerobic walking, strength training, joint mobility training, and neuromuscular training. However, many of these exercise prescriptions are complex, time-consuming, and cumbersome, with some processes being repetitive and prone to low patient compliance and non-standard movements, which can adversely affect treatment efficacy. Furthermore, most rehabilitation prescriptions necessitate that patients visit hospitals with the assistance of doctors or rehabilitation therapists, which can be a significant burden for patients. Telerehabilitation [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] may be a viable solution; however, in some remote areas, information and communication technology is underdeveloped, and many older individuals do not utilize electronic devices or the Internet. Consequently, simplifying the training process and the facilitating of the implementation are crucial for enhancing patient compliance, autonomy and enthusiasm. After reviewing both domestic and international rehabilitation training protocols and relevant foundational research literature, we developed an exercise prescription focused on core muscle strengthening training around the knee (CMSTK) [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e][\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e][\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e][\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e][\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Our findings indicate that this approach effectively alleviates pain, improves joint mobility, and enhances the quality of daily life and work for patients with early-stage knee osteoarthritis (EKOA) in recent clinical applications. Notably, we have also observed satisfactory outcomes in patients with middle and advanced KOA, including significant reductions in pain and increased walking distance. Some researchers have noted that while muscle strengthing training enhances quadriceps strength, relieves knee pain and improves range of motion in KOA patients, the biomechanical relationship between KOA and quadriceps remains unclear [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eAim\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe main purpose of this study is to investigate the specific efficacy of the exercise prescription for the treatment of EKOA by comparing the effects of CMSTK and oral NSAIDs on pain, range of motion, quality of life, and muscle quality in patients with EKOA. The findings of this study will be discussed to guide clinical practice, enhance treatment strategies, facilitate patient self-management, improve compliance, and ultimately optimize outcomes for individuals with EKOA while potentially delaying the progression of the disease.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is a 12-week single-blind randomized controlled trial. The protocol was designed following the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT). This trial will be conducted in both outpatient and inpatient departments of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, and the assessment and collection of data will be conducted in the hospital by data collectors who are blinded to trial group assignment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipants and setting\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe will recruit 100 participants at Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, in East China. The protocol has been approved by the Ethics Committee of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (ethical approval number: 2024-1506-089-01).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiagnostic criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eReferring to the diagnostic criteria of “Guideline for diagnosis and non-surgical treatment of early-stage knee osteoarthritis (2024 edition)” [26]:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e1. Recurrent knee pain for more than 1 month.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2. Age ≥40 years.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3. Morning stiffness ≤30 minutes; pain during squatting and going up and down stairs.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e4. Bone friction sound (or sensation) and joint space pressure pain during activity.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e5. X-ray in standing position shows no obvious changes in the joints, or there are bone encumbrances and / or suspected narrowing of the joint space.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e6. MRI shows the presence of limited or diffuse cartilage damage (range ≤75%), or subchondral bone marrow edema in any region (range ≥25%).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEKOA can be diagnosed by meeting the diagnostic criteria 1 + 2 + 3 + 4 + 5 or 1 + 6.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1. Meet the diagnostic criteria of EKOA.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2. Age 40–70 years old.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3. Patients with 30mm≤ Visual Analogue Scale (VAS) ≤70mm while walking.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e4. Voluntarily participate in this study and sign the informed consent.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1. Patients with serious diseases of the heart, liver, kidney, blood system, etc.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2. Patients with joint inflammatory diseases such as rheumatoid arthritis, gouty arthritis, ankylosing spondylitis and other diseases affecting lower extremity function.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3. Patients during pregnancy, lactation, or pregnancy preparation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e4. Patients with any surgery in the corresponding knee joint 6 months prior to study inclusion.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e5. Patients who are allergic to Celecoxib or contraindicated in it.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e6. Patients with any intra-articular injections in the corresponding knee joint 3 months prior to study inclusion.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e7. Patients with regular lower limb training or rehabilitation treatment 1 months prior to study inclusion.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eParticipants who meet any of the above criteria will not be able to participate in this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRandomization and allocation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBlock randomization will be used. The randomization sequence will be created using SPSS 26.0 statistical software and patients will be stratified with a 1:1 allocation ratio using random block sizes of 2, 4, and 6. Then, according to the result of block randomization, the corresponding test envelope which will be given to the investigator who do not know the result is obtained.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBlinding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTrial participants, data collectors and statisticians are blinded to trial group assignment until the completion of this trail.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipant timeline\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 1 shows the assessments at each timepoint following the SPIRIT 2013 statement [27]. Figure 1 demonstrates the flow chart of the trial.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cimg 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\" width=\"691\" height=\"847\"\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe treatment group receives CMSTK which is divided into two parts for 4 weeks. The initial exercises will be conducted under the supervision and guidance of a doctor.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e1. Patients take a supine position where their lower limbs are naturally straight, with the foot in dorsal extension. A pillow or folded towel is placed under the thigh on the affected side. Patients then apply vertical downward pressure on it with back muscles of their thigh (hamstrings), and maintain this position and strength for 10–15 seconds before slowly relaxing. After a 3-second rest, patients repeat the previous set of actions; this constitutes one group. Each session consists of 10–15 groups, performed twice a day.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2. Patients take a supine position where their lower limbs are naturally straight, with the foot in dorsal extension. A pillow or folded towel is placed in the popliteal fossa of the affected knee, ensuring that the knee joint remains static. Patients are then instructed to actively contract the anterior thigh muscles (quadriceps) and maintain this position and strength for 10–15 seconds before slowly relaxing. After a 3-second rest, patients repeat the previous set of actions; this constitutes one group. Each session consists of 10–15 groups, performed twice a day.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe number and duration of groups per day should be gradually increased based on the patients’ tolerance. Feelings of soreness and distension in the thigh are normal reactions following training. We publish daily training programs and tasks via WeChat and request that patients check in each day, either by submitting photos or videos. If elderly patients are unfamiliar with using electronic devices or the internet, we will encourage them to engage in active exercise via phone calls.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eControl group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe control group receives Celecoxib capsules (produced by Pfizer Pharmaceuticals LLC, specification: 200mg / capsule, pharmaceutical product registration certificate number: National Medical Products Administration (NMPA) approval number J20120063) with a dosage of 200mg / day, to relieve symptoms of KOA for 4 weeks [28].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHealth education and self-management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBoth groups were given health education. If the body mass index (BMI) \u0026gt;25 kg/m\u003csup\u003e2\u003c/sup\u003e, the investigators will remind the participants to control their weight and deliver information about weight management and healthy diet [29]. If the patients are experiencing significant anxiety regarding their condition, we will patiently explain the mechanisms of the pain, the progression of the disease, and the importance of actively participating in their treatment. Additionally, we will provide the latest guidelines and clinical studies to bolster the patients’ confidence in their management of KOA. We also offer patients lifestyle guidance, which includes avoiding excessive kneeling and squatting [30], prolonged high-intensity exercise, and sedentary behavior [31].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRemedy medication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRemedy medication (oral acetaminophen at a maximum dosage of 1000 mg/day [28]), will be administered if patients experience severe pain during the study. Data collectors will record that in detail on the case report form (CRF).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome assessments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOutcomes will be measured before allocation (t\u003csub\u003e0\u003c/sub\u003e) and at 2 (t\u003csub\u003e1\u003c/sub\u003e), 4 (t\u003csub\u003e2\u003c/sub\u003e), 8 (t\u003csub\u003e3\u003c/sub\u003e), and 12 (t\u003csub\u003e4\u003c/sub\u003e) weeks after allocation. Basic information including sex, age, course and affected side will be conducted before allocation. All participants will be assessed by researchers blinded to group tasks.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary outcome measures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) will be utilized to evaluate knee pain, stiffness, and physical function during the week prior to the assessment. The WOMAC consists of 24 items divided into three subscales: lower extremity pain (5 items), stiffness (2 items), and physical function (17 items). Each item is rated on a Likert scale from 0 (no symptoms) to 4 (extremely severe), resulting in a total score that ranges from 0 to 96. Higher scores indicate more severe symptoms [32]. The reliability and validity of the WOMAC total score and subscales have been confirmed [33].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary outcome measures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eVAS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eVAS is one of the sensitive and reliable methods for pain measurement [34] and it will be utilized to evaluate the average level of knee pain during the week prior to the assessment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e36-Item Short Form Survey (SF-36)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSF-36 includes 8 dimensions: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health, comprising a total of 36 questions. The overall score ranges from 0 to 100, with a higher score indicating a better quality of life [35]. Each dimension will be separately analyzed, and physical component score (PCS) and mental component score (MCS) scores will be analyzed at last to evaluate physical and mental health of EKOA patients [36]. SF-36 will not be assessed 2 weeks after the allocation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eROM in flexion and extension tests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eROM in flexion and extension tests will be conducted at the Baltimore Therapeutic Equipment (BTE) Primus RS system on both knees.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIsometric muscle strength tests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIsometric muscle strength tests for assessing the quality of muscle around the knee will also be conducted at the BTE Primus RS system on both knees.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComprehensive efficacy evaluation (total effective rate)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eComprehensive efficacy will be calculated using the WOMAC score, following the method of nimodipine. The efficacy index = (WOMAC score before allocation - WOMAC score at 12 weeks after allocation) / WOMAC score before allocation × 100% [37]. The specific judgment is as follows:\u003c/p\u003e\n\u003cp\u003eCured: Efficacy index ≥95%\u003c/p\u003e\n\u003cp\u003eApparently effective: 75%≤ efficacy index \u0026lt;95%\u003c/p\u003e\n\u003cp\u003eEffective: 30%≤ efficacy index \u0026lt;75%\u003c/p\u003e\n\u003cp\u003eIneffective: efficacy index \u0026lt;30%\u003c/p\u003e\n\u003cp\u003eTotal effective rate = (cured + apparently effective + effective) / number of patients × 100%\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety measure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants will be monitored for any adverse events during the trail, which will be recorded on the CRF. All adverse events will be followed up until normal.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient satisfaction with the efficacy of treatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatient satisfaction involves extremely satisfied, satisfied, average, dissatisfied, and extremely dissatisfied and will be conducted at each follow-up.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe calculation of sample size was carried out according to the calculation requirements of the sample size of noninferiority experiments [38]. This was based on the variation of WOMAC of previous studies on physical training and oral NSAIDs in the treatment of KOA. The difference in WOMAC scores between the two groups after treatment was 8 [39]. Non-inferiority threshold was set to 3.825 [40]. The sampling ratio for the treatment and control groups was 1:1. We set α to 0.05, test power 1 - β to 80%, dropout rate to 20%. The sample size calculation was then conducted using G*Power 3.1.9.7 software. A total of 100 participants is required for the calculation. We finally calculated a sample size of 50 subjects per group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analysis will be performed using the IBM SPSS statistics software (version 26.0). The p value \u0026lt;0.05 will be considered statistically significant. For categorical variables (e.g., sex, total effective rate and affected side), Fisher’s exact test or the chi-square test will be used to determine if there is a significant difference in distribution between the two groups. For continuous variables (e.g., age and course), the rank sum test, t test, or variance analysis will be utilized. The follow-up data of two groups (e.g., WOMAC, VAS, ROM, SF-36 and Isometric muscle strength) will be statistically analyzed using repeated measures ANOVA if they conformed to normal distribution and chi-square, and if not, the rank sum test will be used.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection and monitoring\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData will be recorded by trained data collectors in the hospital and collected with a CRF. In accordance with Good Clinical Practice (GCP) monitoring guidelines, routine compliance monitoring will be implemented by the data monitoring committee who will be responsible for the data management and quality control, which consists of the hospital and the institute.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eKOA is a widespread condition that has a high prevalence and causes significant disability, resulting in considerable medical and economic strain on society. Therefore, early intervention in KOA to prevent its progression from early to advanced stages is crucial. In comparison to symptomatic medications, non-surgical treatments recommended by OARSI as the primary approach for managing KOA in the 2019 guideline show significant promise in treating the condition. This study aims to investigate the specific efficacy of the exercise prescription (CMSTK) for the treatment of EKOA. In contrast to prior researches, this study involves the recruitment of patients diagnosed with EKOA as participants. The CMSTK facilitates home-based exercise, thereby reducing the time and financial burden associated with traveling to healthcare facilities. Furthermore, CMSTK has been optimized based on professional rehabilitation training protocols, significantly minimizing both the duration and complexity of the exercises which will enhance patient compliance, autonomy and enthusiasm. This approach ensures that virtually all patients are capable of independently performing subsequent exercises following initial training instruction. The primary objective is to strengthen the core muscle groups directionally, thereby enhancing overall stability of the knee joint.\u003c/p\u003e \u003cp\u003eThe study is subject to several limitations. First, the single-blinded design may introduce potential bias from the researchers involved. We aim to reduce the influence of researchers' guidance or suggestions in the patient assessment process during the experimental phase by employing researchers who are blind to the group assignments. Second, supervising and managing patient training presents significant challenges, making it difficult to ascertain whether patients are genuinely participating in exercise. This difficulty persists despite our implementation of daily check-in requirements, the involvement of family members for oversight, and the utilization of training task cards. Patients will be educated about the natural progression of KOA, the late-stage symptoms, the impact on their daily activities, and the significance of ongoing exercise as a therapeutic intervention for KOA upon their allocation. Additionally, we will implement a system of regular reminders via WeChat or telephone to reinforce this information in the future. Finally, this study is limited to 12 weeks of follow-up, and longer-term outcomes are not evaluated. Similarly, the duration of treatment in this study is limited to a period of four weeks, and the effects of extended treatment durations are not assessed.\u003c/p\u003e \u003cdiv id=\"Sec28\" class=\"Section2\"\u003e \u003ch2\u003eTrial status\u003c/h2\u003e \u003cp\u003eRecruitment began on 20 September 2024, and the approximate date for the completion of recruitment will be 30 March 2025. The current protocol is the version 2 dated 8 May 2024.\u003c/p\u003e \u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eKOA:\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eKnee osteoarthritis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eROM:\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eRange of motion\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eNSAIDs:\u003c/em\u003e\u003c/strong\u003e Nonsteroidal anti-inflammatory drugs\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eDMOADs:\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eDisease-modifying osteoarthritis drugs\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eOARSI:\u003c/em\u003e\u003c/strong\u003e Osteoarthritis Research Society International\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCMSTK:\u003c/em\u003e\u003c/strong\u003e Core muscle strengthening training around the knee\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEKOA:\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eearly-stage knee osteoarthritis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSPIRIT:\u003c/em\u003e\u003c/strong\u003e Standard Protocol Items: Recommendations for Interventional Trials\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eVAS:\u003c/em\u003e\u003c/strong\u003e Visual Analogue Scale\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eNMPA:\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eNational Medical Products Administration\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eBMI:\u003c/em\u003e\u003c/strong\u003e Body mass index\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCRF:\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eCase report form\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eWOMAC:\u003c/em\u003e\u003c/strong\u003e Western Ontario and McMaster Universities Osteoarthritis Index\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSF-36:\u003c/em\u003e\u003c/strong\u003e 36-Item Short Form Survey\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePCS:\u003c/em\u003e\u003c/strong\u003e Physical component score\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eMCS:\u003c/em\u003e\u003c/strong\u003e Mental component score\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eBTE:\u003c/em\u003e\u003c/strong\u003e Baltimore Therapeutic Equipment\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eGCP:\u003c/em\u003e\u003c/strong\u003e Good Clinical Practice\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial will be conducted in accordance with the Declaration of Helsinki. The protocol has been approved by the Ethics Committee of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine on 15 May, 2024 (ethical approval number: 2024-1506-089-01). All participating patients will provide written informed consent.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis manuscript does not contain individual personal data from patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was funded by the National Natural science Foundation of China (project approval number: 82374488) and Program for 2020 Shanghai Science and Technology Committee ‘Science and Technology Innovation Action Plan’ (project approval number: 22Y21920200). The funders do not have a role in collection, analyzation, and interpretation of data, or in writing of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors and Affiliations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eShi’s Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China\u003c/p\u003e\n\u003cp\u003eChen Wei, Xiang Wang, Yizhe Xiong, Wuwei Song, Xiaoyu Guo, Jiacheng Yu, Wenyu Jiang, Yuhao Zhao, Zhenlin Yang, Zishan Sun, Rui Huang \u0026amp; Yongkang Sun\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCW, XW and YX designed the trial. CW and YZ drafted the manuscript. WS, XG, JY and WJ are responsible for data collection and statistical processing. ZY, ZS, RH and YS are responsible for the follow-up and supervision of patients. The authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorresponding author\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrespondence to Xiang Wang.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful for colleagues from Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine in providing critical comments on study design, invaluable guidance and support throughout the trial.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to give access to the full protocol, participant level-data and statistical code\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol is publicly available on the website Chictr.org.cn with registration number: ChiCTR2400089758. The trial datasets generated or analyzed during the current study during the study are not publicly available.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial results\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial results will be presented in scientific conferences at a national or international level, and also submitted for publication in academic journals that are reviewed by experts in the field.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eJiang W, Chen H, Lin Y, Cheng K, Zhou D, Chen R, et al. Mechanical stress abnormalities promote chondrocyte senescence - The pathogenesis of knee osteoarthritis. Biomed Pharmacother. 2023 Nov;167:115552. doi: 10.1016/j.biopha.2023.115552.\u003c/li\u003e\n\u003cli\u003eMohajer B, Dolatshahi M, Moradi K, Najafzadeh N, Eng J, Zikria B, et al. Role of Thigh Muscle Changes in Knee Osteoarthritis Outcomes: Osteoarthritis Initiative Data. Radiology. 2022 Oct;305(1):169-178. doi: 10.1148/radiol.212771.\u003c/li\u003e\n\u003cli\u003eShengyu W, Yuan L, Shuqing T. Analysis of influential factors of knee osteoarthritis in middle-aged and old people. China Medical Herald. 2021 Nov;18(27):80-83.\u003c/li\u003e\n\u003cli\u003eHeidari B. Knee osteoarthritis prevalence, risk factors, pathogenesis and features: Part I. Caspian J Intern Med. 2011 Spring;2(2):205-12.\u003c/li\u003e\n\u003cli\u003eArden N, Nevitt MC. Osteoarthritis: epidemiology. Best Pract Res Clin Rheumatol. 2006 Feb;20(1):3-25. doi: 10.1016/j.berh.2005.09.007.\u003c/li\u003e\n\u003cli\u003eMinnig MCC, Golightly YM, Nelson AE. Epidemiology of osteoarthritis: literature update 2022-2023. Curr Opin Rheumatol. 2024 Mar 1;36(2):108-112. doi: 10.1097/BOR.0000000000000985.\u003c/li\u003e\n\u003cli\u003eMichael JW, Schl\u0026uuml;ter-Brust KU, Eysel P. The epidemiology, etiology, diagnosis, and treatment of osteoarthritis of the knee. 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Nat Rev Rheumatol. 2020 Dec;16(12):673-688. doi: 10.1038/s41584-020-00518-6. \u003c/li\u003e\n\u003cli\u003eSiddiq MAB, Oo WM, Hunter DJ. New therapeutic strategies in osteoarthritis. Joint Bone Spine. 2024 Dec;91(6):105739. doi: 10.1016/j.jbspin.2024.105739. \u003c/li\u003e\n\u003cli\u003eSuri S, Walsh DA. Osteochondral alterations in osteoarthritis. Bone. 2012 Aug;51(2):204-11. doi: 10.1016/j.bone.2011.10.010.\u003c/li\u003e\n\u003cli\u003eIslam MU, Nayab M, Ansari AN. Effect of dry cupping versus soft and prolonged massage in the management of knee osteoarthritis - a randomized controlled clinical trial. J Complement Integr Med. 2021 Mar 31;18(4):797-804. doi: 10.1515/jcim-2020-0350.\u003c/li\u003e\n\u003cli\u003ePerlman AI, Ali A, Njike VY, Hom D, Davidi A, Gould-Fogerite S, et al. Massage therapy for osteoarthritis of the knee: a randomized dose-finding trial. PLoS One. 2012;7(2):e30248. doi: 10.1371/journal.pone.0030248.\u003c/li\u003e\n\u003cli\u003ePerlman AI, Sabina A, Williams AL, Njike VY, Katz DL. Massage therapy for osteoarthritis of the knee: a randomized controlled trial. Arch Intern Med. 2006 Dec 11-25;166(22):2533-8. doi: 10.1001/archinte.166.22.2533.\u003c/li\u003e\n\u003cli\u003eGoh SL, Persson MSM, Stocks J, Hou Y, Welton NJ, Lin J, et al. Relative Efficacy of Different Exercises for Pain, Function, Performance and Quality of Life in Knee and Hip Osteoarthritis: Systematic Review and Network Meta-Analysis. Sports Med. 2019 May;49(5):743-761. doi: 10.1007/s40279-019-01082-0.\u003c/li\u003e\n\u003cli\u003eBannuru RR, Osani MC, Vaysbrot EE, Arden NK, Bennell K, Bierma-Zeinstra SMA, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage. 2019 Nov;27(11):1578-1589. doi: 10.1016/j.joca.2019.06.011.\u003c/li\u003e\n\u003cli\u003eBurns RB, Crislip D, Daviou P, Temkin A, Vesmarovich S, Anshutz J, et al. Using telerehabilitation to support assistive technology. Assist Technol. 1998;10(2):126-33. doi: 10.1080/10400435.1998.10131970.\u003c/li\u003e\n\u003cli\u003eSegal NA, Torner JC, Felson D, Niu J, Sharma L, Lewis CE, et al. Effect of thigh strength on incident radiographic and symptomatic knee osteoarthritis in a longitudinal cohort. Arthritis Rheum. 2009 Sep 15;61(9):1210-7. doi: 10.1002/art.24541.\u003c/li\u003e\n\u003cli\u003eMo L, Jiang B, Mei T, Zhou D. Exercise Therapy for Knee Osteoarthritis: A Systematic Review and Network Meta-analysis. Orthop J Sports Med. 2023 Jun 5;11(5):23259671231172773. doi: 10.1177/23259671231172773.\u003c/li\u003e\n\u003cli\u003eBobes \u0026Aacute;lvarez C, Issa-Khozouz Santamar\u0026iacute;a P, Fern\u0026aacute;ndez-Mat\u0026iacute;as R, Pecos-Mart\u0026iacute;n D, Achalandabaso-Ochoa A, Fern\u0026aacute;ndez-Carnero S, et al. Comparison of Blood Flow Restriction Training versus Non-Occlusive Training in Patients with Anterior Cruciate Ligament Reconstruction or Knee Osteoarthritis: A Systematic Review. J Clin Med. 2020 Dec 27;10(1):68. doi: 10.3390/jcm10010068.\u003c/li\u003e\n\u003cli\u003eSi J, Sun L, Li Z, Zhu W, Yin W, Peng L. Effectiveness of home-based exercise interventions on pain, physical function and quality of life in individuals with knee osteoarthritis: a systematic review and meta-analysis. J Orthop Surg Res. 2023 Jul 17;18(1):503. doi: 10.1186/s13018-023-04004-z.\u003c/li\u003e\n\u003cli\u003eMao Y, Qiu B, Wang W, Zhou P, Ou Z. Efficacy of home-based exercise in the treatment of pain and disability at the hip and knee in patients with osteoarthritis: a systematic review and meta-analysis. BMC Musculoskelet Disord. 2024 Jun 26;25(1):499. doi: 10.1186/s12891-024-07585-w.\u003c/li\u003e\n\u003cli\u003eDeVita P, Aaboe J, Bartholdy C, Leonardis JM, Bliddal H, Henriksen M. Quadriceps-strengthening exercise and quadriceps and knee biomechanics during walking in knee osteoarthritis: A two-centre randomized controlled trial. Clin Biomech (Bristol). 2018 Nov;59:199-206. doi: 10.1016/j.clinbiomech.2018.09.016.\u003c/li\u003e\n\u003cli\u003eOsteoarthrosis Committee of Chinese Aging Well Association. [Guideline for diagnosis and non-surgical treatment of early-stage knee osteoarthritis (2024 edition)]. Zhonghua Yi Xue Za Zhi. 2024 Aug 13;104(31):2895-2909. Chinese. doi: 10.3760/cma.j.cn112137-20240503-01035. \u003c/li\u003e\n\u003cli\u003eChan AW, Tetzlaff JM, Altman DG, Laupacis A, G\u0026oslash;tzsche PC, Krleža-Jerić K, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013 Feb 5;158(3):200-7. doi: 10.7326/0003-4819-158-3-201302050-00583.\u003c/li\u003e\n\u003cli\u003eClegg DO, Reda DJ, Harris CL, Klein MA, O\u0026apos;Dell JR, Hooper MM, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006 Feb 23;354(8):795-808. doi: 10.1056/NEJMoa052771.\u003c/li\u003e\n\u003cli\u003eToivanen AT, Heli\u0026ouml;vaara M, Impivaara O, Arokoski JP, Knekt P, Lauren H, et al. Obesity, physically demanding work and traumatic knee injury are major risk factors for knee osteoarthritis--a population-based study with a follow-up of 22 years. Rheumatology (Oxford). 2010 Feb;49(2):308-14. doi: 10.1093/rheumatology/kep388.\u003c/li\u003e\n\u003cli\u003eJianbing C, Qianyun Y, Xiaofeng Z. Risk factors for knee osteoarthritis: a meta-analysis. Journal of Jinan University(Natural Science \u0026amp; Medicine Edition). 2023 Aug;44(4):406-415.\u003c/li\u003e\n\u003cli\u003eAlentorn-Geli E, Samuelsson K, Musahl V, Green CL, Bhandari M, Karlsson J. The Association of Recreational and Competitive Running With Hip and Knee Osteoarthritis: A Systematic Review and Meta-analysis. J Orthop Sports Phys Ther. 2017 Jun;47(6):373-390. doi: 10.2519/jospt.2017.7137.\u003c/li\u003e\n\u003cli\u003eFaucher M, Poiraudeau S, Lefevre-Colau MM, Rannou F, Fermanian J, Revel M. Assessment of the test-retest reliability and construct validity of a modified WOMAC index in knee osteoarthritis. Joint Bone Spine. 2004 Mar;71(2):121-7. doi: 10.1016/S1297-319X(03)00112-X.\u003c/li\u003e\n\u003cli\u003eBellamy N, Campbell J, Hill J, Band P. A comparative study of telephone versus onsite completion of the WOMAC 3.0 osteoarthritis index. J Rheumatol. 2002 Apr;29(4):783-6.\u003c/li\u003e\n\u003cli\u003eFrench T, Hewlett S, Kirwan J, Sanderson T. Different wording of the Patient Global Visual Analogue Scale (PG-VAS) affects rheumatoid arthritis patients\u0026apos; scoring and the overall Disease Activity Score (DAS28): a cross-sectional study. Musculoskeletal Care. 2013 Dec;11(4):229-37. doi: 10.1002/msc.1046.\u003c/li\u003e\n\u003cli\u003eWare JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992 Jun;30(6):473-83.\u003c/li\u003e\n\u003cli\u003eLaucis NC, Hays RD, Bhattacharyya T. Scoring the SF-36 in Orthopaedics: A Brief Guide. J Bone Joint Surg Am. 2015 Oct 7;97(19):1628-34. doi: 10.2106/JBJS.O.00030.\u003c/li\u003e\n\u003cli\u003eRoos EM, Kl\u0026auml;ssbo M, Lohmander LS. WOMAC osteoarthritis index. Reliability, validity, and responsiveness in patients with arthroscopically assessed osteoarthritis. Western Ontario and MacMaster Universities. Scand J Rheumatol. 1999;28(4):210-5. doi: 10.1080/03009749950155562.\u003c/li\u003e\n\u003cli\u003ePiaggio G, Elbourne DR, Altman DG, Pocock SJ, Evans SJ; CONSORT Group. Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement. JAMA. 2006 Mar 8;295(10):1152-60. doi: 10.1001/jama.295.10.1152.\u003c/li\u003e\n\u003cli\u003eZhijie Y, Jianfeng C, Yafeng Z. Efficacy of muscle meridian manipulation in the treatment of knee osteoarthritis. Jiangsu Medical Journal. 2014 Nov;40(21):2590-2.\u003c/li\u003e\n\u003cli\u003eGuo J, Peng C, Hu Z, Guo L, Dai R, Li Y. Effect of Wu Qin Xi exercises on pain and function in people with knee osteoarthritis: A systematic review and meta-analysis. Front Med (Lausanne). 2022 Nov 7;9:979207. doi: 10.3389/fmed.2022.979207.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Early-stage knee osteoarthritis, Physical therapy, Oral nonsteroidal anti-inflammatory drugs, Protocol, Comprehensive efficacy","lastPublishedDoi":"10.21203/rs.3.rs-5915635/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5915635/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eKnee osteoarthritis (KOA) is a prevalent condition characterized by a high incidence and disability rate, making early intervention particularly critical. It is essential to focus on addressing the underlying disease rather than solely alleviating symptoms through pharmacological treatments. The Osteoarthritis Research Society International recommends non-pharmacological therapies as the primary intervention strategy, with physical therapy identified as the principal method. Current rehabilitation training programs often present challenges, including prolonged treatment durations, complex procedures, and the necessity for medical supervision. Preliminary clinical observations suggest that core muscle strengthening training around the knee (CMSTK) may effectively reduce pain, enhance mobility, improve quality of life, and avoid the aforementioned limitations. Nevertheless, further high-quality research with larger sample sizes is required to validate its efficacy conclusively.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis study is a 12-week single-blind randomized controlled trial. 100 early-stage knee osteoarthritis (EKOA) patients will be recruited and randomly divided into CMSTK group and oral nonsteroidal anti-inflammatory drugs group. Outcome assessments will be conducted before allocation and at 2, 4, 8, and 12 weeks after allocation. Comprehensive efficacy will be evaluated by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Data collectors and statisticians will be blinded, and participants will be asked not to reveal their allocation to assessors.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eThis study aims to investigate the specific efficacy of CMSTK for the treatment of EKOA. The findings of this research will enhance the therapeutic approaches for early intervention in KOA, offer a scientific foundation for enabling patients with EKOA to engage in self-directed exercise, and contribute to the alleviation of social, medical, and economic burdens associated with the condition.\u003c/p\u003e\u003ch2\u003eTrail registration\u003c/h2\u003e \u003cp\u003eChinese Clinical Trials Registry ChiCTR2400089758. 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