Evaluation of the Therapeutic Effect of Traditional Chinese Medicine on Osteoarthritis: A Systematic Review and Meta-Analysis

Background Osteoarthritis (OA) is a common degenerative disease of bone and joint characterized by the damage of articular cartilage and hypertonia, which often occurs in the middle-aged and elderly. Traditional Chinese medicine (TCM) therapy, including acupuncture (ACU), oral administration, and external use of traditional Chinese medicines (TCMs), can significantly improve the therapeutic effect on OA and reduce the occurrence of side effects. We provide a latest meta-analysis on the treatment of OA with TCM. Materials and Methods In the electronic database, appropriate articles without language restrictions on keywords were selected until August 1, 2019. All trajectories are screened according to certain criteria. The quality of qualified research was also assessed. We have made a detailed record of the results of the measurement. Meta-analysis was carried out with Revman 5.3 software. Results Forty-four articles involving 4014 patients (2012 cases in the experimental group and 2002 cases in the control group) with OA were selected. This article focuses on the study of the treatment of OA by using the general mode of TCM. The quality evaluation included in the study was evaluated independently according to the Cochrane intervention system evaluation manual. In this meta-analysis, 68.18% of the literature correctly described the conditions for the generation of random assignment sequences, only 6.82% of the literature correctly mentioned the hidden details of allocation, and all studies mentioned randomly assigned participants. Compared with Western medicine, the total effective rate (TER) of OA treatment in TCM was significantly increased and the recurrence rate (RR) was significantly decreased (P < 0.00001). In addition, the experimental group was also superior to the control group in terms of the indicators of joint activity function, inflammatory factor content, and various indicators affecting bone metabolism. It can be showed by the network analysis diagram that Aconiti Radix, Achyranthis Bidentatae Radix, and other TCMs can inhibit inflammatory stimulation and relieve the pain symptoms of patients with OA. ACU at Yinlingquan, Xiyan, and other acupoints can effectively improve the clinical symptoms of patients with OA. Conclusion TCM therapy in treatment of patients with OA could effectively restore joint function, enhance the TER, and reduce RR. However, the results of this study should be handled with care due to the limitations existing. Some rigorous randomized controlled trials (RCTs) are needed to confirm these findings.


Introduction
Osteoarthritis (OA) is a chronic degenerative joint disease, which occurs frequently in the elderly, and OA is one of the diseases that lead to disability in the world [1]. e effect of this disease is significant in the knee, hip, and hands [2]. At this stage, the concept of OA has been further developed. OA is considered to be an entire joint disease, including changes in the articular cartilage, subcartilage bone, ligaments, capsule, and synovium, resulting in functional joint injury [3], resulting in joint pain and physical disability [4], thus impairing the quality of life of patients with OA.
OA is considered to be the main cause of chronic pain in clinics. e pain symptoms associated with OA lead to the decrease of physical fitness and behavior ability [5]. In the world today, the trials of pain and disability caused by OA are interdisciplinary, involving surgical treatment, drugs, and physiotherapy [6]. However, the cost of physiotherapy is important for patients, and the evidence that physiotherapy is effective in treating OA patients is not clear [7]. Although hip and knee replacement has become a routine treatment for end-stage arthritis, the risk of surgery is high, including the mortality rate caused by surgery and the failure rate of reoperation due to failed implants. Also, the cost of operation also has significant cost effectiveness [8]. e main goal of drug therapy is not only to control joint pain but also to avoid the toxic effects of treatment [9]. Nonsteroidal anti-inflammatory drugs and anesthetic painkillers are commonly used in drug therapy. However, taking these drugs may also cause gastrointestinal damage, heart and kidney load, and other side effects [10].
At present, there are no nonspecific, safe, and effective drugs and methods in clinical treatment [9], so there is an urgent need to seek a breakthrough from traditional Chinese medicine (TCM). From ancient times to the present, the use of traditional Chinese medicines (TCMs) and all kinds of TCM therapy has played an inestimable role in the treatment of OA of which experience and therapeutic effects have been tested and refined in Asian countries in the past few thousand years. OA belongs to the category of Gu Bi in TCM. In ancient times, medical saints studied OA and recorded its pathogenesis and treatment in many TCM medical works, such as "Inner Classic of the Yellow Emperor" and "Treatise on Febrile and Miscellaneous Diseases." e most important thing is to record the excellent results of TCM in the treatment of OA [11]. e treatment of OA with TCM includes internal and external use of TCMs, acupuncture (ACU), massage manipulation and Tai Chi exercise, and other therapies. Various studies have shown that the use of TCMs has analgesic and anti-inflammatory effects on the treatment of OA. ACU is one of the most common complementary and alternative medical therapies in medicine and is also a popular therapy for relieving pain and treating dysfunction related to musculoskeletal conditions. e therapeutic effect of ACU will remain unchanged with the passage of time [12]. e use of a massage technique can effectively reduce the pain of each joint and achieve the purpose of supplementary treatment. Tai Chi exercise can improve the physical and mental health of patients and effectively relieve psychological depression symptoms caused by OA pain.
is article mainly introduces the therapeutic effects of oral administration of TCMs (OATCM), external use of TCMs (EUTCM), and ACU on OA.
Here, we provide a novel and comprehensive meta analysis with detailed information for the efficacy of TCM including TCMs and ACU on patients with OA ( Figure 1).

Methods and Program
As Dr. zou et al., 2019 [13], have done a lot of solid data retrieval work using various databases, their data mining and processing methods are worth learning and using for reference. erefore, we followed the methods of Dr. Zou et al., 2019.
2.1. Literature Retrieval Strategy. Keywords "Osteoarthritis (OA)" [Title/Abstract] AND "Traditional Chinese medicine (TCM)" OR "Acupuncture (ACU)" [Title/Abstract] AND "Clinical" [Title/Abstract] were used as search items in electronic databases including Pubmed, Wanfang, CNKI, CBM, and VIP. Articles published before August 1, 2019, were checked without language restrictions in order to obtain a comprehensive search. All relevant articles were downloaded into Endnote software (version X9, omson Reuters, Inc., New York, NY, United States) for exploring further. Duplicate records were removed. A full-text review was performed while the title/abstract were thought to be thematic. e job mentioned above was executed by three investigators independently. Conflicts were resolved by the consensus and discussion.

Inclusion and Exclusion Criteria.
According to the suggestions of medical experts, we designed the inclusion criteria as follows: (1) Patients in RCTs were diagnosed with OA by diagnostic criteria of knee osteoarthritis (DCKO), guidelines for the diagnosis and treatment of osteoarthritis (GDTO) version 2007, guiding principles for clinical research of new drugs of traditional Chinese medicine (GPCRNDTCM), clinical guideline of new drugs for traditional Chinese medicine (CGNDTCM), diagnosis and treatment scheme of traditional Chinese medicine for 95 diseases in 22 specialties (DTSTCM95D22S), criteria for diagnosis and therapeutic effect of diseases and syndromes of traditional Chinese medicine (CDTEDSTCM), or diagnostic criteria of therapeutic effect of traditional Chinese medicine on knee osteoarthritis (DCTETCMKO). (2) All trials mentioned were described as RCTs. (3) Patients in the most of the experimental groups received TCM therapy, whereas patients in the most of the control groups received Western medicine therapy. (4) Outcome measurements of each study must have included a minimum of one of the following indices: total effective rate (TER), Western Ontario and McMaster University osteoarthritis index (WOMAC), visual analogue scale (VAS), interleukin (IL)-1, IL-6, tumor necrosis factor-α (TNF-α), syndrome score of traditional Chinese medicine (SSTCM), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), matrix metalloproteinases-3 (MMP-3), insulin-like growth factor-1 (IGF-1), bone morphogenetic protein-7 (BMP-7), receptor activator of nuclear factor-κ B ligand (RANKL), bone gla protein (BGP), osteoprotegerin (OPG), fibroblast growth factor-2 (FGF-2), angiopoietin I (Ang I), vascular endothelial growth factor (VEGF), recurrence rate (RR), swelling score (SS), superoxide dismutase (SOD), transforming growth factor-β (TGF-β), Lysholm, and Lequesne. e exclusion criterion was designed as follows: (1) Articles such as reviews, animal trials, case report, and comments were thought to be unrelated to the topic. (2) Trials were not RCTs, or diagnostic criteria in the statement were ambiguous. (3) e intervention of OA patients was not based on TCM treatment.

Data Extraction and Quality Assessment.
Information on qualified studies, including authors, methods, sample size, interventions, and result measurements is obtained. e quality of the included study was independently evaluated by three researchers according to the Cochrane Handbook for Systematic Reviews of Interventions, and different opinions were resolved by consensus. Quality assessment includes random sequence generation (selection bias), allocation concealment (selection bias), blindness of participants and personnel (performance bias), blindness of result evaluation (detection bias), incomplete result data (attrition bias), selective reporting (reporting bias), and other deviations.
ere are three levels of judgment each semester. e "low risk" of the deviation indicates that the description of the method or procedure is appropriate, the "high risk" indicates that the description of the method or procedure is insufficient or incorrect, and the "unclear risk" indicates that the description of the method and/or procedure is insufficient.

Data
Analysis. Data analysis was performed using Review Manager 5.3 (Cochrane Collaboration). Outcome measures such as TER and RR were regarded as dichotomous variables and presented as the odds ratio (OR) with 95% confidence intervals (95% CI), contents of inflammatory cytokines (IL-1, IL-6, TNF-α, MMP-3, and TGF-β), indexes of scoring (SSTCM, VAS, WOMAC, Lysholm, SS, and Lequesne), and levels of bone metabolism (IGF-1, OPG, BGP, FGF-2, RANKL, and BMP-7), and factors of ESR and CRP were continuous variables that presented as the mean difference (MD) with 95% CI. P statistics and I 2 tests were applied to assess heterogeneity among studies. A fixed-effect model was used to analyze data with low heterogeneity (P > 0.1 and I 2 ≤ 50%), and data with high heterogeneity (P < 0.1 or I 2 > 50%) were estimated using the random-effects model. Potential publication bias was revealed by funnel plots.

Characteristics of the Eligible Studies.
A total of 7836 studies were identified through database retrieval, of which 4260 were deleted due to duplication. Of the remaining 3575 studies, 3487 were excluded due to substandard topics. After that, there were still 88 articles to be further examined in full.

Pain Research and Management
Forty-four studies were excluded from this procedure because of unclear diagnosis in 8 articles, inappropriate interventions in 21 studies, and single-arm design in 15 studies. Forty-four studies  were included in quantitative synthesis finally ( Figure 2).
Meta-analysis was performed on 4014 OA patients (2012 in the experimental group and 2002 in the control group). e age of the patients ranged from 40 to 80 years, and there was no obvious difference in terms of age and sex between the two groups (Table 1). Trials were conducted between 2000 and 2019; all were RCTs with a comparison between TCM therapy only and Western medicine therapy or with a comparison between a combination of TCM therapy and Western medicine therapy. e usual regimens of TCM therapy were OATCM, EUTCM, and the ACU. In the EUTCM, it can be divided into the methods of traditional Chinese medicine iontophoresis (TCMI), hot compress of TCMs, and fumigation of TCMs. e usual regimens of Western medicine therapy were sodium hyaluronate (SH), arthroscopic debridement (AD), and Western medicine capsules.
irty studies reported that the duration of treatment lasted for 2 to 4 weeks. ree trials reported a follow-up ranging from 3 to 6 months ( Table 2). e TCMs and ACU involved in each article were integrated. e prescriptions handed down from ancient times to today, including the OATCM and EUTCM group, were sorted out (Table S1). e acupoint involved in the ACU group articles were also integrated (Table S2). At the same time, we provided the corresponding international code for acupoint (Table S3).

Quality of Included Trials Assessment.
According to the Cochrane risk of deviation estimation, all trials in the literature mentioned the random allocation of participants, and 30 trials [14, 16-18, 20, 21, 23-26, 28, 29, 32-34, 38-46, 51-53, 55-57] described the conditions for the generation of random allocation sequences. Detailed information on allocation concealment and blinding of participants of majority studies was mentioned in 3 trials [45,56,57]. Blinding of outcome assessment of all studies was reported in 1 trial [56]. Forty-two studies [14-36, 38-50, 52 -57] were considered to have a lower risk of wear bias due to the availability of complete data.

TER of TCM erapy vs. Western Medicine erapy.
e standard of clinical efficacy reported in the included trials was divided into four grades including clinical recovery, marked effect, effectiveness, and invalidation. TER referred to the percentage of patients who were evaluated to recovery, marked effect, and effectiveness.

Influence on Other Indices of TCM erapy vs. Western
Medicine erapy. In this meta-analysis, we summarized 5 and less articles related to the same index and summarized the results in the supplemental files. OATCM therapy can significantly reduce SS (P < 0.0001) and Lequesne Pain Research and Management (P < 0.00001) levels in self-activity indicators of patients with OA. Also, EUTCM therapy can also reduce Lequesne (P < 0.0001), but the therapeutic effect of SS (P � 0.27) has no statistical significance (Table S4). Associated inflammatory factors include TGF-β and IL-6. OATCM treatment could significantly increase the level of TGF-β (P < 0.00001), but had no statistical significance in reducing IL-6 (P � 0.12). Both EUTCM therapy and ACU therapy can significantly increase TGF-β and decrease IL-6 levels (P < 0.001) (Table S5). Among the indicators related to bone balance, ACU therapy can significantly increase the level of BGP and FGF-2 and reduce RANKL (P < 0.001), but there is no statistical significance for the improvement of IGF-1 (P � 0.24) and OPG (P � 0.62). OATCM therapy can significantly reduce BMP-7 (P < 0.00001) (Table S6). ACU therapy can significantly reduce the levels of Ang I and VEGF (P < 0.00001) in the collected studies (Table S7). OATCM and EUTCM therapy can effectively reduce the RR and increase SOD (P < 0.00001) (Table S8). A forest plot illustrating the results of the analysis of ESR and CRP  indicators is shown in Figure S1. Both OATCM and ACU therapy can effectively reduce ESR and CRP (P < 0.00001).
In addition, EUTCM therapy can significantly reduce ESR (P � 0.09), but there is no statistical significance for CRP (P � 0.15).

Network Relationship Diagram between Acupoints and
Corresponding Indexes. e 21 acupoints and 19 related indexes were imported into Cytoscape 3.7.1 software, and the network analysis of the interaction between acupoints and corresponding indexes in ACU treatment of OA was drawn, Figure 7(a), through the module analysis of the main graph using the eagle algorithm through ClusterViz plug-in Cytoscape, and three main relational subgraphs were obtained. Figure 7(a) shows the overall relationship between acupoints and indicators. Figure 7(b) shows the interaction between Yinlingquan (ST9) and Xuehai (SP10) acupoints and inflammatory factors, which have major therapeutic effects. Figure 7(c) mainly shows the effects of acupoint Yanglingquan (GB34), Liangqiu (ST34), Xiyan (EX-LE4), Zusanli (ST36), and Heding (EX-LE2) on FGF-2, OPG, and BGP of the bone metabolism indexes. Figure 7(d) shows the effect of acupoints such as Xiyangguan (GB33), Weizhong (BL40), and Ashi on the level of TER, WOMAC, and VAS. After ACU treatment, the indexes have been well improved, and the symptoms of OA have been significantly improved (Figure 7).

Network Relationship Diagram between TCMs and Corresponding Indexes.
e 113 TCMs and 17 related indexes were imported into Cytoscape 3.7.1 software, and the network analysis diagram of the interaction between TCMs      and indicators interaction in the treatment of OA was drawn, as shown in Figure 8(a). en, through ClusterViz plug-in Cytoscape, the module analysis of the main graph is carried out by using EAGLE algorithm to get five main relational subgraphs. Figure 8(a) shows the relationship between TCMs and indicators. Figure 8(        3.6. Publication Bias. Publication bias was expressed by a funnel plot. In this study, funnel plots of TCM therapy vs. Western medicine therapy on TER, VAS, WOMAC, and IL-1 were applied. e plot is basically symmetrical except that there is some bias due to different usage methods of TCMs in the EUTCM group, which indicates that there is no obvious publication bias (Figures 9(a)-9(d)).

Discussion
OA is a degenerative disease that causes pain, stiffness, and decline in body function [6]. With the combined effects of ageing and increasing obesity in the global population, along with increasing numbers of joint injuries, the occurrence of diseases such as OA is becoming more prevalent, with worldwide estimates suggesting that 250 million people are currently affected [58]. At this stage, there are great risks for the various diagnosis and treatment effects of Western medicine, and there is a lack of high-quality data on the benefits and hazards of adverse drug reactions [59]. Current treatments for OA are inadequate [60]. In the theory of TCM, OA belongs to the category of osteoarthralgia, which has been recorded in various literature. e Chinese medicine is through the classification of the causes of OA, symptomatic administration, and the use of appropriate methods of treatment [34]. In the treatment of OA, the use of TCM has few side effects and remarkable curative effects. In contemporary development, the treatment of TCM will be more and more popular among the public. e results of this meta-analysis show that the treatment of TCM has a significant TER for OA and could reduce the RR. Moreover, there were significant differences in WOMAC (P < 0.00001), VAS (P < 0.00001), IL-1 (P < 0.00001), TNF-α (P < 0.00001), BGP (P � 0.007), and  other indicator factors in patients with OA treated by TCM. It could regulate the expression of inflammatory factors, improve the synthesis and invasion of reactive oxygen species on chondrocytes collagen, reduce cartilage damage, block bone destruction, balance bone absorption and bone metabolism, reduce pain in patients, and promote the body's self-activity function [61][62][63][64]. ACU is an effective physiotherapy for the treatment of OA with few side effects [65]. e compatibility of multiple acupoints focuses on dispelling wind and activating collaterals, eliminating arthralgia, and relieving pain [66]. Combined with the usual treatment of OA and the acupoints summed up by the network pharmacological map, it can be concluded that Yinlingquan (ST9), Xiyan (EX-LE4), Weizhong (BL40), Xuehai (SP10), Yanglingquan (GB34), and Zusanli (ST36) have a great effect on the treatment of OA. According to the analysis of the relationship between TCMs and the index network, Aconiti Radix, Achyranthis Bidentatae Radix, Typhonii Rhizoma, Persicae Semen, and Chuanxiong Rhizoma are very effective in the treatment of OA. e use of these TCMs and acupoints can not only significantly reduce inflammatory factors but also reduce pain and improve the quality of life of patients.
After a comprehensive analysis of the included literature, it was found that there were some limitations: 1. Although the 44 included studies were all RCTs, most of them did not describe the allocation scheme and allocation concealment in detail, which may lead to selection bias and implementation bias. 2. In this included experiment, all the studies were in Chinese, which may make the data collection incomplete and, thus, may have a biased effect on the analysis results. 3. e literature included in this paper lacks uniformity in reference standards for total efficiency and does not strictly distinguish their differences, which may affect the reliability of the results. erefore, it is suggested that the criteria of clinical efficacy should be unified in future studies. 4. ere are deviations in the quality and objectivity of the literature in the selection of research. In addition, the clinical risk assessment and report of the included literature are not clear, which may have a certain impact on the demonstration strength of TCM efficacy. 5. e indicators included in this meta-analysis have some heterogeneity, which may have an impact on the accuracy and objectivity of the results. erefore, in the future systematic review and meta-analysis, more large samples and high-quality RCTs should be included. It is also hoped that the later RCTs can clarify the specific methods of randomized trials, and more rigorous clinical trials can be conducted to improve the reliability of the clinical effects of TCM.
Compared with other articles, this meta-analysis adopted a more systematic literature retrieval method and included a large sample size. It also contained more comprehensive outcome measures, making this meta-analysis more complete and reliable. With the help of the network relationship construction model in network pharmacology, network analysis was conducted on all TCMs, acupoints, and corresponding indicators involved in this meta-analysis, so as to find the most core relationship between TCM diagnosis and treatment of OA.

Conclusions
e use of various treatments of TCM can significantly improve the level of TER and reduce the occurrence of RR in the later stage of treatment. ese effects are mediated by a combination of several mechanisms. is method of treatment with TCM can reduce pain, improve their ability to move, and improve their living standards by reducing the level of VAS, WOMAC, SSTCM, SS, and Lequesne and increasing the level of Lysholm. TCM therapy can reduce inflammation and exert anti-inflammatory effects by reducing the levels of IL-1, IL-6, TNF-α, MMP-3, ESR, and CRP and increasing TGF-β. TCM therapy can increase BGP, FGF-2, IGF-1, and OPG and reduce BMP-7 and RANKL levels to improve bone metabolism in order to achieve the balance of bone metabolism. e TCM therapy can also reduce the levels of VEGF and Ang I, reduce cartilage injury, and restore vascular endothelial function. e effect of TCM therapy can also increase the level of SOD and reduce the existence of reactive oxygen species. e net analysis of ACU and index showed that ACU at local acupoints such as Yinlingxue, Xuehai, and Yanglingquan can reduce inflammatory indexes, reduce cartilage damage, balance bone metabolism, reduce WOMAC, and improve TER. e network analysis chart of TCMs and index showed that TCMs can effectively reduce WOMAC through the inhibition of IL-1 and MMP-3 and improve the effect of TER and so on. However, our findings must be handled with care because of the small size and low quality of the clinical trial samples cited. Other rigorous and large-scale RCTs are needed to confirm these results.

Data Availability
e data used to support the findings of this study are included within the supplementary information files and the article Conflicts of Interest e authors declare that they have no conflicts of interest.

Authors' Contributions
All authors contributed to the study conception and design. Material preparation and data collection were performed by Lin Wang, Xiao-fei Zhang, and Xue zhang. Yu-wei Duan and Zhi-chao Wang analyzed the data. e first draft of the manuscript was written by Lin Wang. All authors commented on previous versions of the manuscript and amended the paper. All authors read and approved the final manuscript. Lin Wang, Xiao-fei Zhang, and Xue zhang contributed equally to this work. 20 Pain Research and Management