The Efficacy and Safety of Zhengqing Fengtongning for Knee Osteoarthritis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Background Zhengqing Fengtongning release tablet (ZQFTN) is a proprietary Chinese medicine preparation of sinomenine, the main active component of the traditional Chinese medicine (TCM) Sinomenium acutum. It is used in China as a complementary and alternative medicine (CAM) for knee osteoarthritis (KOA). The objective of this study was to evaluate the clinical efficacy and safety of ZQFTN in KOA treatment. Method Randomized controlled trials of ZQFTN in KOA treatment were searched in PubMed, Cochrane Library, China National Knowledge Infrastructure, Chinese Scientific Journals Database, and Wanfang database. Two reviewers independently conducted the screening, extracted the data, and assessed the methodological quality. Statistical analysis was performed using RevMan 5.3 software. Results Eighteen studies were assessed that included 1512 participants (757 in the treatment group and 755 in the control group). The results showed that compared with the control group, the Visual Analogue Scale (standardized mean difference (SMD) = −0.87, 95% confidence interval (CI): [−1.08, −0.66], P < 0.001), Western Ontario and Mc Master University (WOMAC) Osteoarthritis Index pain score (SMD = −0.67, 95% CI: [−0.88, −0.46], P < 0.001), WOMAC stiffness score (SMD = −0.53, 95% CI: [−0.86, −0.20], P=0.001), WOMAC function score (SMD = −0.76, 95% CI: [−0.97, −0.55], P < 0.001), serum interleukin-1β level (SMD = −4.36, 95% CI: [−6.41, −2.31], P < 0.001), and serum tumor necrosis factor-α level (SMD = −8.45, 95% CI: [−11.20, −5.69], P < 0.001) of the ZQFTN treatment group were lower, and the total effective rate was higher relative risk (RR = 1.15, 95% CI [1.07, 1.23], P < 0.001). There was no significant difference in the incidence of adverse reactions between the two groups (RR = 0.96, 95% CI: [0.69, 1.35], P=0.82). Conclusion ZQFTN can effectively relieve knee pain, morning stiffness, and daily activity function disorders, reduce the expression of inflammatory factors in serum, and improve the total clinical response rate without increasing the incidence of adverse reactions. Therefore, ZQFTN has considerable potential as a CAM for KOA. However, due to the limitation of the quality of the included studies, the strength of this conclusion is affected. In the next step, multicenter, large sample, high-quality randomized controlled studies are needed to further confirm the present conclusion.


Introduction
Knee osteoarthritis (KOA) is a degenerative disease that occurs in the knee joint, with chronic joint pain, swelling, stiffness, and dysfunction as the main manifestations. With the increase in life expectancy and aging of the global population, its incidence is increasing and the burden on countries around the world is consequently becoming greater [1]. At present, the drugs used to treat KOA mainly include analgesics, intraarticular corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and symptomatic slow acting drugs for osteoarthritis (SYSADOA) [2][3][4].
Although these drugs have certain effects on the pain and disease relief of osteoarthritis (OA) patients, they also increase the incidence of gastrointestinal ulcers and cardiovascular events, affecting their use by some patients [5]. erefore, the need for a safe and effective option for OA treatment has transferred the focus of research from conventional drugs to complementary and alternative medicines (CAMs). Over time, ever increasing evidence has shown that traditional Chinese medicine (TCM) therapies, including acupuncture, galbanum oil, sesame oil, and Qigong, have favorable therapeutic potential as CAMs in OA treatment [6][7][8][9].

Materials and Methods
e systematic review protocol was developed with guidance from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and is registered in PROSPERO (CRD42021284282).

Search Strategy.
Randomized controlled trials (RCTs) of ZQFTN in the treatment of KOA were searched in PubMed, Cochrane Library, China National Knowledge Infrastructure, Chinese Scientific Journals Database, and Wanfang database. e retrieval time is from a database construction to August 31, 2021. e retrieval strategy adopted the combination of subject words and free words. e key words were as follows: "Osteoarthritis" "knee osteoarthritis" "KOA" "Zhengqing Fengtongning release tablets" "Zhengqing Fengtongning" "Sinomenine," and "Sinomenium". e search strategy was as follows, taking PubMed as an example:

Exclusion Criteria.
e exclusion criteria were as follows: (1) Repeated publications (2) Full-text literature is not available (3) Studies with incomplete data and information 2.3. Literature Screening and Data Extraction. Two reviewers (Zeling Huang and Xiao Mao) searched the literature and screened it independently according to the inclusion and exclusion criteria. We used standard data extraction methods to extract data. e basic information, sample characteristics, intervention measures, outcome, and other data, which were included in the article, were extracted by two reviewers (Zeling Huang and Xiao Mao). In the case of any inconsistency occurring in the result, this was further discussed by the two researchers or scrutinized by the third reviewer (Zhenqiang Hong).

Quality Assessment of the Included Studies.
A bias risk assessment was conducted by two reviewers (Zeling Huang and Xiao Mao) based on the bias risk assessment tool recommended in the Cochrane manual [39,40]. e details that were assessed were as follows: (1) random sequence generation; (2) allocation concealment; (3) blinding of participants and personnel; (4) blinding of outcome assessment; (5) incomplete outcome data; (6) selective reporting; and (7) others. Make high risk, low risk, or unclear judgments for each item. Any disagreements were resolved by the third reviewer (Zhenqiang Hong). Denmark, 2014), was used to analyze the collected clinical research data. e enumeration data were evaluated using the relative risk (RR) and 95% confidence interval (CI), and the measurement data were combined using the standardized mean difference (SMD) and 95% CI. Analysis was performed using a fixed or random effects model according to the heterogeneity. e percentage of heterogeneity in the study was determined by the I 2 statistic; if the I 2 < 50%, the heterogeneity among the included studies was considered to be small and the fixed effect model was adopted. If I 2 ≥ 50%, the heterogeneity among the included studies was considered significant, and the random effect model was adopted [41]. Subgroup analysis was conducted according to different treatments in the treatment group, and sensitivity analysis was also used to analyze the sources of heterogeneity. A value P < 0.10 was considered to suggest statistical heterogeneity and prompted random effects modeling.

Characteristics of the Included Studies.
e study of all included papers was a single-center, randomized controlled trial undertaken in China. In total, there were 757 cases in the experimental group and 755 cases in the control group. Except for three studies [28,31,33] that did not indicate drug sources, ZQFTN in the other fifteen studies was all produced by Hunan Zhengqing Pharmaceutical Group Co., Ltd. (Huaihua, Hunan, China). e included studies on the ZQFTN dosage are not uniform. Six studies [25,26,28,34,37,38] defined ZQFTN alone as the experimental group, with a total of 209 patients, while the control group used SYSADOA, with a total of 209 patients. In seven studies [22,23,27,[31][32][33]35], ZQFTN combined with SYSADOA was defined as the experimental group, with 318 patients in total, and SYSADOA was used by the control group, with 315 patients in total. In three studies [21,24,29], ZQFTN combined with NSAIDs was defined as the experimental group, with a total of 145 patients, and NSAIDs were used by the control group, with a total of 146 patients. In two studies [30,36], 85 patients were treated with ZQFTN combined with sodium hyaluronate injection as the experimental group, and 85 patients were treated with sodium hyaluronate injection in the control group. e characteristics of the included studies are presented in Table 1.

Treatment Effects
e total effective rate is an important indicator for assessing the effect of treatment, which is mainly based on the changes in the patient's clinical symptoms before and after treatment. A total of seventeen of the included studies reported the total effective rate, but their criteria for judging the treatment effect included the WOMAC score, Lequesne index, and hospital for special surgery knee score. To enhance the strength of the results, we only performed meta-analysis on the six studies that used WOMAC scores to determine the total effective rate, involving a total of 534 patients, with 267 in the experimental group and 267 in the control group.
e results of heterogeneity analysis showed good homogeneity among the included studies (P � 0.46, I 2 � 0%), and the fixed effect model was used for analysis. e results showed that the total effective rate of the experimental group was higher than that of the control group (RR � 1.15, 95% CI: [1.07, 1.23], P < 0.001). e analysis was divided into three subgroups according to different treatment methods of the experimental group. e results of the subgroup analysis showed that the total effective rate of ZQFTN alone was equivalent to that of SYSADOA alone (MD � 1.13, 95% CI: [0.99, 1.28], P � 0.06). e total effective rate of ZQFTN combined with SYSADOA was higher than that of SYSADOA alone (RR � 1.18, 95% CI: [1.07, 1.30], P < 0.001). e total effective rate of ZQFTN combined with NSAIDs was equivalent to that of NSAIDs alone (RR � 1.06, 95% CI: [0.85, 1.33], P � 0.03) ( Figure 3).

VAS.
Four studies [30,31,35,38] reported a pain VAS after treatment, involving a total of 294 patients, 147 in the experimental group, and 147 in the control group. Heterogeneity analysis results showed good homogeneity among the included studies (P � 0.17, I 2 � 40%), and the fixed effect model was used for analysis. Results showed that the VAS of the experimental group was lower than that of the control group after treatment (SMD � −0.87, 95% CI:    (Figure 4).

WOMAC Function Score.
Four studies [23,26,28,31] reported the WOMAC function score after treatment, involving 366 patients (183 in the experimental group and 183 in the control group). Heterogeneity analysis showed good  (Figure 7).

Serum IL-1β
Level. Four studies [15,16,24,28] reported the serum IL-1β level after treatment, involving 368 patients (184 in the experimental group and 184 in the control group). e results of the heterogeneity analysis showed that there was significant heterogeneity among the included studies (P < 0.001, I 2 � 97%), and the random effect model was used to analyze the results. e results showed that the serum IL-1β level of the experimental group was lower than that of the control group after treatment (SMD � −4. 36 (Figure 8).

Publication Bias.
e inverted funnel plot of publication bias was generated with the adverse reactions as indicators, and the scatter point distribution of each study was asymmetric, suggesting the possibility of publication bias in this study ( Figure 11).

Discussion
Sinomenium acutum is the vine stem of the Asteraceae plant and Chinese Anseraceae plant among others. It is a TCM, which has the function of dispelling wind dampness, channelling channels and collaterals, and relieving urination, and is often used to treat rheumatoid arthritis, OA, and gout arthritis [42]. Sinomenine is an alkaloid extracted from Sinomenium acutum and is the main active ingredient of Sinomenium acutum. Experimental studies have found that sinomenine has clear anti-inflammatory and analgesic effects. Its anti-inflammatory effect mainly results from its selective inhibition of cyclooxygenase-2 activity, whereby capillary permeability is reduced by downregulating prostaglandin E synthesis, or preventing histamine-induced capillary permeability increase by inhibiting the release of various inflammatory mediators, thus blocking inflammatory infiltration and exudation. Sinomenine also has anticoagulation and antiembolism effects and reduces tissue damage [20]. Studies have shown that sinomenine can reduce synovial inflammation and cartilage degeneration by inhibiting the expression of inflammatory factors and chondrocyte apoptosis, thus delaying the progression of osteoarthritis [43]. ZQFTN as an oral preparation of  Evidence-Based Complementary and Alternative Medicine sinomenine has been used ever more frequently in the clinical treatment of OA.

Effectiveness of ZQFTN in Treating KOA.
rough a literature search, it was found that ZQFTN could be used as a complementary drug in combination with SYSADOA, NSAIDs, or sodium hyaluronate, or used alone as an alternative drug for KOA. e results showed that ZQFTN has good efficacy, but due to the influence of inconsistent treatment methods, insufficient sample size, and other factors, the conclusions were frequently unconvincing and the evidence basis was not strong. To determine the effectiveness of oral ZQFTN in KOA treatment, 18 RCTs were included in the present study, including 1512 KOA patients.
e results of the meta-analysis showed that ZQFTN could effectively relieve knee pain, morning stiffness, and daily activity disturbance. e VAS and WOMAC scores were lower than the control group, and the total clinical effectiveness rate was higher than the control group, indicating that ZQFTN had significant clinical efficacy as a CAM for KOA. e results of serum IL-1β and TNF-α showed that their respective levels in the experimental group were lower than those in the control group, suggesting that the mechanism of ZQFTN in treating KOA may be associated with its ability to reduce inflammation.

Safety of ZQFTN in Treating KOA.
Adverse events related to drug treatment were recorded in 15 studies, and meta-analysis results showed that there was no significant difference in the incidence of adverse reactions between the experimental and control groups. e reported adverse reactions were mainly gastrointestinal, including nausea and diarrhea, and allergic reactions, such as pruritus and rash, which were consistent with the adverse events recorded in the instructions of ZQFTN, SYSA-DOA, and NSAIDs. Eight studies monitored the changes of blood routine and liver and kidney functions during medication, including 737 KOA patients. e results showed that a total of five patients in the experimental groups displayed a slight increase in transaminases, while a further seven patients in control groups showed a slight increase in transaminases, which returned to normal after symptomatic treatment. ese results indicated that the use of ZQFTN did not increase the risk for adverse events and that it was safe as a CAM for KOA.

Limitations of the Study.
rough a comprehensive analysis of the included literature, the following problems were found to generally exist in this literature: (1) ere was no allocation concealment or blind method in all studies, and strict and careful experimental design was lacking. (2) e sample size of some of the literature was small, and the calculation basis of sample size was not given. (3) ere were differences in medication duration and dosage in the included studies, which were not conducive to the formation of standardized medication guidance. (

Conclusion
is study demonstrated that ZQFTN has high clinical efficacy and safety in the treatment of KOA and thus has considerable potential as a CAM for KOA. However, due to the limitation of the quality of included studies, the strength of this conclusion is affected. In the next step, multicenter, large sample, high-quality randomized controlled studies are needed to further confirm the present conclusion.

Data Availability
e table data used to support the findings of this study are included within the article. e figure data used to support the findings of this study are included within the figure files.

Conflicts of Interest
e authors declare that there are no conflicts of interest regarding the publication of this study.