Valgus Knee Braces May Have No Long-term Effect on Pain Improvement and Functional Activity in Patients With Knee Osteoarthritis: A Meta-analysis of Randomized Trials


 Background:KOA as a high incidence of old age seriously affects the quality of life of the elderly. The valgus knee bracesareaimportantphysical therapy for KOA, but its specific effect is not clear.This meta-analysisis to systematically evaluate the effectiveness of valgus knee braces on pain and function improvement in patients with knee osteoarthritis (KOA).Methods :A meta-analysis of clinical randomized controlled trials(RCTs) on pain and functional changes in patients with KOA after using valgus knee braces. The search period is from the self-built database to May 2020, and the search range is PubMed, Embase, and Web of Science databases. First, two authors independently screened the literature, formulated inclusion criteria and exclusion criteria, and determined the included literature. The researchers then extracted the interventions and outcome indicators of included literature, and assessed the risk of bias through Cochrane Handbook 5.0.1. Finally, Revman5.3 was used for data analysis.Results :A total of 10 articles were included in this study, including 739 patients. 8 articles related to the Visual Analogue Scale (VAS) pain score, the results showed that RR = -0.29, 95% CI [-0.73, 0.15], P = 0.20; There were 4 articles on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function score, the results showed that RR = -0.15, 95% CI [-0.41,0.11], P = 0.26; Two articles related to the impact of Knee Injury and Osteoarthritis Outcome Score (KOOS) score, the results showed that RR = 0.58, 95% CI [-4.25, 5.42], P = 0.81; 3articles were related to KOOS activities of daily living (KOOS-ADL) score, the results showed that RR = 0.04, 95% CI [-0.62,0.69], P = 0.91.These results indicated that the valgus knee braces have no statistically significant in pain and functional activity improvement of patients with KOA. The subgroup analysis showed that the follow-up time was the source of the heterogeneity of the VAS pain score. Conclusion :The current evidence suggests that valgus knee braces may not effectively improve pain symptom and functional activity in KOA patients in the long-term, but only benefit KOA patients in the short-term.


Introduction
Osteoarthritis (OA) is a common degenerative joint disease [1], which is one of the main causes of disability. The incidence of osteoarthritis increases with age. As the global population ages, it will have a huge social burden [2]. Knee osteoarthritis (KOA) accounts for 83% of the total burden of OA [3]. The incidence of KOA can reach up to 44%, and women are higher than men [4][5]. Early KOA advocates conservative treatment, mostly through oral analgesics, articular injection drugs, physical therapy, and other treatment methods [6][7][8], but these methods did not effectively treat KOA. In late KOA, total knee replacement(TKR) is often used. Although TKR can achieve good result, there are many complications such as aseptic loosening of the prosthesis, fractures around the prosthesis, and infection around the prosthesis. What is even more frustrating is that TKR will face the problem of revision [9]. Therefore, there is an urgent need for a conservative therapy for effective treatment of KOA, while ensuring the quality of life of patients, as long as possible to delay the time of TKR and reduce the revision rate.
The valgus knee braces can theoretically effectively correct the lower limb force lines, improve the pain and function of KOA patients by changing the biomechanical axis, and then delay the surgery, which is more cost-effective [10][11][12][13]. Kirkley et al [14] con rmed that valgus knee braces can effectively improve the pain symptom and joint mobility of KOA patients. While Hunter et al [15] found that valgus knee braces can improve the pain symptom of KOA patients, but they can not elevate the function of joint mobility. It is not di cult to nd that the treatment effect of valgus knee braces on KOA is not accurate, and the previous systematic review published by Brouwer et al [16] also con rmed this. Previous studies lacked high-quality clinical randomized controlled trials (RCTs), so conclusions may be biased. Therefore, this study intends to incorporate RCTs for systematic review and meta-analysis to clarify the effectiveness and safety of valgus knee braces in the treatment of knee osteoarthritis, and provide a theoretical basis for future clinical decisions.

Search Strategy
PubMed, Embase, and Web of Science databases were searched by computer. The search period was from a self-built database to May 2020. To supplement the literature, manually enter the references included in the study if necessary. The search terms include "Osteoarthritis", "knee", "brace OR bracing OR Valgus brace OR Unloader brace".

Inclusion Criteria
RCTs of using valgus knee braces to treat KOA; In RCTs, the experimental group was given valgus knee braces treatment, and the control group was given non-bracing and other conservative treatments. The age, sex, race, nationality, and course of disease in the included studies are not limited; RCTs have one or more of the following outcome indicators: WOMAC function score (Western Ontario and McMaster Universities Osteoarthritis Index, WOMAC); VAS pain score (Visual Analog Scale, VAS); KOOS pain score (knee injury and osteo arthritis outcome score, KOOS); KOOS-ADL score (KOOS-Activi ties of Daily Living, KOOS-ADL).

Exclusion Criteria
Non-clinical randomized controlled trials; The conference included literature, reviews, and published the same research literature repeatedly in different languages; The outcome indicators data in RCTs cannot be used.

Data extraction
Two researchers screened the literature separately, including the rst step of screening after browsing the titles and abstracts of the literature, as well as reading the full text and determining whether it was nally included. After the data were included, the two researchers checked each other. If the opinions were not uniform, the third researcher should judge whether they were included. The relevant information extracted includes: (1) Basic information of the literature, including title, year, rst author, course of treatment, etc.

quality assessment
The bias risk of the included studies was evaluated according to the Cochrane Handbook 5.0.1 RCT bias risk assessment tool. The quality of the literature is assessed by judging whether the included literature is a random method, whether there is allocation concealment, whether the blind method is used, whether the result data is complete, and whether the research results are selectively reported. Each result is divided into low risk, unclear, and high risk. The quality of the methodology was evaluated by two researchers, and if there were different opinions, the third researcher would participate in the discussion and resolved.

Statistical analysis
Revman5.3 software was used for data analysis. Heterogeneity analysis: The heterogeneity of the research results was tested by χ². The size of heterogeneity is judged by I². When I² <50%, a xed-effect model should be used; when I²> 50%, a subgroup analysis of the causes of heterogeneity may be performed; When the difference between the two studies was not statistically signi cant, a randomeffects model can be used for analysis. When P <0.05, it means that the difference of the research results was statistically signi cant.

Literature Search Study Characteristics
A total of 739 patients were included in the 10 studies, including 412 patients in the experimental group and 414 patients in the control group. The minimum sample size was 10 and the maximum sample size was 86. Table 1 showed the detailed characteristics and main conclusions of all studies. Table 2 summarized the intervention measures for each study and the results of the outcome indicators.

Subgroup Analysis
As can be seen from the above results, there were two outcome indicators with high heterogeneity, which were VAS pain score and KOOS-ADL score.However, it is considered that the KOOS-ADL score was included in fewer studies, the VAS score had the value of subgroup analysis. Through analysis of 8 studies that reported the impact of valgus knee braces on VAS scores of KOA patients, it was found that the follow-up time of these 8 studies was very different, so we conducted a subgroup analysis of followup time. In the process of subgroup analysis, it was found that the calculation method of VAS score in Thoumie's [20] study is very different from other studies. After using or excluding this study, the heterogeneity had changed greatly. Therefore, the subgroup analysis excluded the Thoumie's [20] study.
The results of the subgroup analysis of the follow-up time were shown in Table 3 and Figure 8. When the follow-up time was greater than 52weeks: only one study was included, there was no results of the heterogeneity; when the follow-up time was less than 24weeks, the heterogeneity was I 2 = 35%; when the follow-up time was between 24-48 weeks, the heterogeneity was I 2 = 7%; the results showed that the follow-up time was the source of the heterogeneity of the VAS score.

Adverse Reactions
None of the 10 articles included in this study reported adverse reactions.

Discussion
At present, most of the conservative treatment methods for knee osteoarthritis (KOA) are from weight control, exercise, physical therapy (including traditional Chinese medicine acupuncture, laser therapy, electromagnetic therapy, etc.), oral analgesics, and joint cavity injection drugs [26,27]. More and more studies have begun to pay attention to the changes in the force of the knee joint space. The change of the force will cause the abnormality of the lower limb force lines, which will affect the progress of KOA. The valgus knee braces can theoretically change the direction of the force of the knee joint space, further improve symptoms and functions, and delay the progress of KOA accordingly. However, the clinical e cacy of valgus knee braces in the treatment of KOA is not clear, and even different studies have concluded the opposite [15][16][17][18][19][20][21][22][23][24][25][28][29][30][31][32][33][34][35][36][37]. Therefore, to clarify its e cacy, this study included 10 studies for meta-analysis.
Meta-analysis results showed that valgus knee braces did not improve the VAS pain score (P = 0.29), WOMAC function score (P = 0.26), KOOS score (P = 0.81) and KOOS-ADL score (P = 0.91). These results indicate that valgus knee braces cannot improve the pain, activity function, and quality of the daily life of KOA patients.
Besides, due to the high heterogeneity of the VAS pain score, we conducted a subgroup analysis of the follow-up time. The results showed that when the follow-up time was less than 24weeks, valgus knee braces can improve the VAS pain score of KOA patients (P = 0.03); Negative results were obtained when the follow-up time was between 24 and 48 weeks (P = 0.17), which means that valgus knee braces could not improve the pain symptoms of KOA patients; when the follow-up time was greater than 48weeks, the result was P = 0.0001. But the VAS pain score of the experimental group in the included study was greater than that of the control group, so it still showed that valgus knee braces cannot improve or even increase the pain symptoms of KOA patients. By analyzing the results of the subgroup analysis, we can think that valgus knee braces can have an effect on the pain of KOA patients in the short-term, but it cannot improve the pain symptoms of the knee in the long-term. The results of Duivenvoorden et al. [34] further corroborated the conclusions of this study. They conducted a secondary analysis of randomized controlled trial data in 80 patients with KOA, and found no biomechanical arguments to support the use of valgus knee braces. Although the meta-analysis results of Moyer et al. [37] showed that valgus knee braces can improve pain and function in patients with KOA, we can nd after analysis of the results that most of the follow-up time included in this study was short-term follow-up. Except for the follow-up time of one study was 52weeks, and the follow-up time of the remaining included studies were all 24weeks or less, so it can only explain the role of valgus knee braces in the short-term, and cannot cover its long-term e cacy. Although our study only includes 10 studies and 739 patients, there are 6 studies with a followup time of more than 24 weeks. It can also explain to a certain extent that valgus knee braces may only be bene cial to patients with KOA in the short-term, but cannot maintain its therapeutic effect for a long time.
We analyze the results of this study that are different from others. The reasons why valgus knee braces cannot improve pain symptoms and joint mobility for a long time may be as follows: 1)The patient's compliance with valgus knee braces as a treatment is poor. According to reports [39], the patients use valgus knee braces no more than 4 hours a day, so the effectiveness of valgus knee braces may be underestimated in the long-term.2) Studies have found that [40] when a patient is using a valgus knee brace, the support of valgus knee brace will make the patient subconsciously believe that the knee joint on the brace side is injured and biases to use the limb on the other side. The movement of the knee joint on the brace side will be reduced, which will affect the improvement of the stiffness of the knee joint and the recovery of the activity function, and further affect the improvement of the pain symptoms.
3) The valgus knee braces mainly provide a valgus moment of force. Studies have shown that [41] the use of valgus knee braces reduced the external knee adduction moment, but not the external exion moment and free moment which are also important in the development of KOA. This may also be one of the reasons that the valgus knee braces are effective in the short-term and ineffective in the long-term.4) Creep [42] means that the deformation will increase with time under constant load. The valgus knee braces will produce creep during long-term use. Therefore, the reason why the long-term treatment effect of the valgus knee braces is not ideal may be related to the creep of the material.Therefore, only by solving the above problems can valgus knee braces play the greatest role for KOA patients.
The limitations of this study are as follows: 1)In this study, because of the small number of RCTs included, the publication bias was not detected through the funnel chart, so there may be a publication bias;2) The valgus knee braces used in the experimental group of RCTs included in this study are produced by different manufacturers, and the intervention measures of the control group are not the same, which may be biased due to large clinical heterogeneity;3) Although this study searched PubMed, Embase and Web of Science databases, not all relevant studies were included;4) The RCTs included in this study (Muller [23] only) did not provide complete outcome indicator data, which led us to use statistical methods to determine the outcome indicators data based on the information provided, but after we excluded this study, the results were not affected.

Conclusion
In summary, the current evidence shows that valgus knee braces cannot effectively improve the pain symptoms and knee mobility of KOA patients in the long-term, and are only bene cial to KOA patients in the short-term. Limited by the number and quality of included studies, more high-quality clinical RCTs with longer follow-up time need to be included in meta-analysis to verify the above conclusions.  Subgroup analysis of VAS pain score