The Efficacy and Safety of Chinese Herbal Medicine in the Treatment of Knee Osteoarthritis: An Updated Systematic Review and Meta-Analysis of 56 Randomized Controlled Trials

Objective This systematic review and meta-analysis were performed to investigate the efficacy and safety of Chinese herbal medicine (CHM) in the treatment of knee osteoarthritis (KOA). Methods An electronic search was conducted in eight databases (PubMed, EMBASE, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database, Chinese VIP Database, and Wanfang Database) from inception until December 2019. The risk of bias assessment of the included RCTs was evaluated by Cochrane collaboration's tool. The inclusion criteria were RCTs that investigated the efficacy and safety of CHM in the treatment of KOA, with no restrictions on publication status or language. The exclusion criteria included nonrandomized or quasi-RCTs, no clear KOA diagnostic approach, combined Chinese medicinal herbs with other traditional Chinese medicine treatment modalities, and published using repeated data and missing data. We computed the relative risk (RR) and the standard mean difference (SMD) for dichotomous outcomes and continuous outcomes, respectively. When heterogeneity was detected or there was significant statistical heterogeneity (P < 0.05 or I2 > 50%), a random-effects model was employed, followed by further subgroup analysis and metaregression estimations to ascertain the origins of heterogeneity. Otherwise, we used a fixed-effects model (P ≥ 0.05 or I2 ≤ 50%). The primary outcome measures were visual analog score (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Lysholm score, and Lequesne index. Secondary outcome measures were the total clinical effective rate and adverse events. The meta-analysis was performed using the Stata 14.0 software. Results A total of 56 RCTs comprising 5350 patients met the inclusion criteria. This meta-analysis showed that application of CHM as adjuvant therapy or monotherapy for KOA can significantly decrease VAS, WOMAC, and the Lequesne index and improve the Lysholm score as well as the total effective rate. In addition, this treatment has fewer adverse effects, suggesting that CHM is generally safe and well tolerated among patients with KOA. Conclusion Our study offers supportive evidence that CHM, either adjuvant therapy or monotherapy, reduces the VAS, WOMAC, and Lequesne index and improves the Lysholm score and overall effective rate in patients with KOA. Additionally, CHM was well tolerated and safe in KOA patients. We found frequently used CHMs that might contribute to the formulation of a herbal formula that could be considered for further clinical use. However, given the heterogeneity and limited sample size in this study, larger multicenter and high-quality RCTs are needed to validate the benefits of CHM in the treatment of KOA.


Introduction
Knee osteoarthritis (KOA) is a multifactorial degenerative joint disorder characterized by changes in the structure of the joint tissues, including cartilage degeneration, subchondral bone restructuring, and synovial membrane inflamma-tion in the elderly [1]. KOA is more prevalent in older adults [2]. A previous study reported that approximately 12% of the aging population in the West suffered from KOA, and 25% of the population above 55 years old had a persistent knee pain episode [3]. According to current data, 9.3 million adults in the US are affected by KOA [4]. As the population ages, it is projected that the number of persons with KOA will increase [5,6]. Osteoarthritis was projected to become the fourth leading cause of disability by 2021 [7].
The primary management goals for KOA have been to alleviate pain, educate patients about the disease, rehabilitate, slow the progression of the disease, and maintain a healthy lifestyle [8]. However, effective therapeutic strategies for KOA disease modification are currently unavailable [9]. The current therapeutic options advanced in various evidence-based clinical guidelines include nonpharmacological therapies, weight loss, oral pharmacological medications, exercise, topical therapies, surgical treatments, and intra-articular therapies [10][11][12]. Notably, nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular hyaluronic acid or corticosteroids are the most frequently used in clinical practice [13][14][15]. Long-term use of NSAIDs and corticosteroids, on the other hand, has serious adverse effects [16]. Therefore, clinicians and patients are increasingly preferring to treat KOA using complementary as well as alternative medicine [17][18][19].
Chinese herbal medicine (CHM) has been used in various forms in the treatment of KOA, both in China and the rest of the world [20,21]. The adoption of CHM for treating pain disorders, including KOA, has been steadily increasing in Asian countries as well as across the globe [22]. In comparison to other herbal medicines, CHM contains distinct medicinal components that target specific biological processes associated with disease, which are dependent on the differentiation of specific symptoms [23,24]. According to a recent study, CHM actively reduces pain via analgesic, invigorating blood circulation, and anti-inflammatory effects [25].
CHM has long been regarded as a vital component in the treatment of KOA in China and is gaining popularity in other parts of the world. However, quantitative research evidence on its effects is currently limited. CHM's biological effect and potential interactions with other prescription medications have not yet been elucidated [26]. Two systematic reviews found that CMH is both safe and effective in the treatment of KOA [27,28]. However, due to the low quality of the methodology and the limited sample size in the included studies, there is a knowledge gap on the planned application of CHM in treating KOA. Recently, there has been an increase in the number of high-quality randomized controlled clinical trials (RCTs) on the safety and efficacy of CHM in the treatment of KOA. Therefore, we conducted a large sample size systematic review and meta-analysis of

Methods
We used the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) Statement to perform a systematic review and meta-analysis [30]. This study has been registered at http://www.researchregistry.com, and the study's unique identifying number (UIN) from the Research Registry is reviewregistry971. There are no protocols preregistered for this review. We did not collect any primary personal data; hence, we did not require ethical approval. 2.3. Literature Selection. The PRISMA flow diagram was used to select the trials that were included. We imported the literature results into the Endnote X7 software. Two independent authors initially screened the titles and abstracts of potentially eligible articles to remove duplications as well as RCTs that did not meet the inclusion criteria. Following that, we downloaded and reviewed the full texts of the remaining prospective studies. Any disagreements between the two authors were resolved through discussion with a third independent author.
2.4. Data Extraction. Two independent reviewers extracted the data, while a third independent reviewer checked for consistency. A standard form was used to collect the retrieved items, which included the following basic research information: the name(s) of the author(s), publication date, study design, diagnostic criteria, sample size, age, CHM and WCM intervention methods, gender, disease duration, and course of treatment. We retrieved the mean, standard deviation (SD), and the number of participants in each study for continuous outcomes. For dichotomous outcomes, we retrieved the total number of CHM and WCM events as well as the number of occurrences in each group. Where possible, we recomputed the data in other formats to allow for pooled analysis. Any disagreements that arose between these two reviewers were resolved through dialogue. We contacted the relevant authors of the included studies to provide us with any missing data and additional information.
2.5. Quality Assessment of Included Studies. Two independent authors used the Cochrane collaboration tool to assess the quality of methodology and risk of bias of the included RCT studies [31]. This Cochrane tool assesses the following parameters, randomization, subject blinding, allocation concealment, outcome evaluation blinding, selective outcome reporting, incomplete outcome data, and other bias, and categorizes studies as unclear, low, or high risk of bias for each item.
2.6. CHM Composition. We compiled a list of the major components of the CHM formulae. We determined the frequency of use of all Chinese medicinal herbs and estimated and discussed in detail those that were frequently used.

Statistical
Analysis. The Stata software (version 12.0; Stata-Corp, College Station, TX) was used to evaluate all of the data retrieved in this study for meta-analysis. When heterogeneity was detected or there was significant statistical heterogeneity (P < 0:05 or I 2 > 50%), a random-effects model was employed, followed by further subgroup analysis and metaregression estimations to ascertain the origins of heterogeneity. Otherwise, we used a fixed-effects model (P ≥ 0:05 or I 2 ≤ 50%). We conducted a sensitivity analysis by excluding individual studies one by one to determine the strength and stability of the pooled data. Besides, the effect of publication bias was examined using Begg's and Egger's tests. We computed the relative risk (RR) and the standard mean difference (SMD) for dichotomous outcomes and continuous outcomes, respectively. Finally, 56 articles  were included for analysis ( Figure 1).

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3.3.7. Publication Bias and Sensitivity Analysis. We examined the possibility of publication bias of the adverse effects in this meta-analysis using Begg's funnel plot and Egger's test ( Figure 10). As a result of the symmetrical shape of the funnel plots and the P values from Begg's and Egger's tests, there was evidence of notable publication bias for adverse events (P = 0:661 and P = 0:847, respectively).
To establish the influence of each included study on the pooled RRs for the effective rate and adverse effects and to validate the robustness of our findings, we performed a sensitivity analysis by excluding one study at a time and computing the pooled RRs for the rest of the RCTs. The results of the sensitivity analysis indicated that excluding each study individually had no discernible influence on the pooled RRs showing that the findings of this meta-analysis are comparatively robust (Figure 11).    .   (Table 4).

Discussion
4.1. Summary of Evidence. Herein, we updated a systematic review and meta-analysis on the efficacy and safety of CHM treatment in patients with KOA. A total of fifty-six highquality RCTs, including 5350 patients with KOA, were included in the analysis. Our primary findings indicated that using CHM as adjuvant therapy or monotherapy for KOA treatment reduced the VAS, WOMAC, and Lequesne index while improving the Lysholm score and overall effective rate. Additionally, we discovered that CHM adjuvant or monotherapy had fewer adverse effects than the controls, indicating that CHM was safe and effective in treating KOA. Therefore, we provide supporting evidence that, to a significant extent, CHM can potentially be recommended for use in KOA patients.

Comparison with Previous
Studies. Significant research demonstrates that the oral and topical use of CHM is both safe and effective in the treatment of KOA. A meta-analysis of 23 RCTs including 2362 patients demonstrated that CHM is both safe and effective in alleviating pain, restoring function, and promoting health in patients with KOA [28]. Another systematic review found that Duhuo Jisheng decoction (DJD) combined with Western medicine or sodium hyaluronate injection was effective in treating KOA [88]. However, the effectiveness and safety of DJD remain debatable due to a scarcity of clinical trials and a lack of methodological rigor. Additionally, a Cochrane review of two RCTs including 327 patients found that orally bioavailable avocado soybean unsaponifiables (ASU) significantly relieved the pain symptoms in hip-OA patients when compared to a placebo. Additionally, this review established that the use of ASU helped patients in reducing their use of NSAIDs [89]. However, a primary concern in these earlier investigations has been the limited sample size and low quality. Therefore, in the current systematic review, we included 56

Strengths.
The strengths of this meta-analysis study included a clearly defined research question, which minimized the bias in the selection of RCTs and improved the fidelity and consistency due to a precise research approach that we designed before the meta-analysis, an in-depth search of the literature, agreement between the two researchers on the entry data components, and quality control appraisal of all data. All of the studies included were RCTs with a significant propor-tion being of high quality. This assisted in overcoming the drawbacks associated with recall or selection bias in nonrandomized studies. Additionally, the total number of trials and the overall sample size were comparatively large (56 trials with 5350 patients). To ascertain the source of heterogeneity, we performed subgroup and metaregression analyses. Consequently, we found no evidence of publication bias in this meta-analysis, and sensitivity analysis revealed that the findings of this meta-analysis are comparatively robust.

4.4.
Limitations. This study has several limitations. First, although RCTs were included, the primary studies included had certain inherent and methodological limitations; specifically, only 42 of the trials supplied sufficient information on the randomization process. The remaining RCTs, on the other hand, reported the allocation concealment. KOA is a chronic condition requiring lifelong treatment. Long-term efficacy and safety studies are critical for determining a drug's therapeutic usefulness. However, the duration of therapy, in this case, was between two and twelve weeks. Therefore, we were unable to assess the long-term safety of CHM for treating KOA since the duration of treatment in the included studies was short, and no dropouts were revealed in a significant percentage of the included studies. Thirdly, the formula composition, dosage, administration approaches, and duration of CHM treatments varied significantly in the primary RCTs. This clinical heterogeneity has the potential to jeopardize the validity of our findings. Fourthly, a significant proportion of the included RCTs did not involve a formal pretrial sample size calculation. Inadequate sample size in RCTs appears to be one risk factor for overestimating intervention benefits. 4.6. Implications for Research. Here, we provide key concepts that are likely to stimulate further research in this field. Initiatives to increase the methodological quality of RCTs are urgently needed. We urge that in the future, recommendations such as the CONSORT Extension for Chinese Herbal Medicine Formulas 2017 [90], the CONSORT 2010 statement [91], and the protocols for designing RCTs to investigate CHM [92] be used to establish and report RCTs on CHM. Despite the finding that CHM therapy was reasonably safe for patients with KOA in the evaluated studies, further research is needed to corroborate the safety of CHM for KOA. Bian et al. [93] established a standard format for reporting adverse drug reactions (ADR) in CHM, which is likely to enhance ADR reporting. Clinical trials and studies with a longer follow-up time are recommended to provide a complete understanding of the long-term safety profile of CHM in patients with KOA. Recent advances in integrative medicine have enabled research to be conducted on disease-syndrome combinations. The effectiveness of TCM practice is contingent upon accurate syndrome differentiation. Therefore, an excellent distinction of disease symptoms is required for drug prescriptions [94]. Accurate syndrome differentiation of KOA should be performed during the evaluation of the safety and efficacy of CHM treatment. Individualized TCM prescriptions will give satisfactory treatment  24 Oxidative Medicine and Cellular Longevity for specific diseases. For example, a study by Bensoussan et al. [95] published in JAMA showed that using personalized CHM to treat irritable bowel syndrome was superior to common hypnotic prescriptions. Thus, in future clinic practice, a suitable selection of medications among the 17 most often used herbs is recommended based on syndrome-specific characteristics. This will improve the efficacy of CHM in the treatment of KOA.

Conclusion
Our systematic and meta-analysis study offers supportive evidence that CHM, either adjuvant therapy or monotherapy, reduces the VAS, WOMAC, and Lequesne index and improves the Lysholm score and overall effective rate in patients with KOA. Additionally, CHM was well tolerated and safe in KOA patients. We found frequently used CHMs that might contribute to the formulation of a herbal formula that could be considered for further clinical use. However, given the heterogeneity and limited sample size in this study, larger multicenter and high-quality RCTs are needed to validate the benefits of CHM in the treatment of KOA.

Data Availability
Previously reported data were used to support this study. These prior studies and datasets are cited at relevant places within the text as references .