Treatment of knee osteoarthritis with acupuncture combined with Chinese herbal medicine: a systematic review and meta-analysis

Introduction

Osteoarthritis (OA) is a chronic degenerative disease that affects approximately 10% of men and 18% of women worldwide. The incidence of OA is increasing annually, along with increased aging. About 60–65% of people over 60 years of age suffer from symptomatic OA, of which 80% of patients present with symptoms including joint stiffness and limited range of motion, which seriously affects the quality of life of the victims (1,2). Even worse, an increasing proportion of young adults have also suffered from OA. OA is a heterogeneous disease caused by multiple factors and characterized by progressive decomposition of articular cartilage. It is commonly believed that knee osteoarthritis (KOA) results from a result of multiple pathogenic factors, such as age, sex, body quality, trauma and genetics, abnormal mechanical load, insufficient nutrition supply and genetic inducement, as well as metabolic factors and infrapatellar fat pad. and is characterized by joint pain and dysfunction with progressive intraarticular and subchondral bone injury, synovitis, osteophyte formation and reduced joint cava. As the prevalence of OA is rising, the treatment requirements on this disease also increase (3).

The current treatments of KOA mainly include non-steroidal anti-inflammatory drugs (NSAIDs), chondroitin, hyaluronic acid, surgical therapy, traditional Chinese medicine, acupuncture/massage, and exercise therapy. Weight reduction and muscle strength training around the knee joint may also help. Among them, the combination of acupuncture with Chinese herbal medicine (CHM) is highly effective, with few side effects. Also, it is simple and affordable (4,5).

A previous meta-analysis had investigated the efficacy and safety of this strategy, but with low literature quality, small sample size, and a limited number of response assessment indicators (6). As more relevant articles have been published in recent years, an updated meta-analysis with high-quality articles is warranted to provide accurate, reliable, and multifaceted evidence to evaluate the clinical efficacy of the combination in treating KOA. We present the following article in accordance with the PRISMA reporting checklist (available at https://dx.doi.org/10.21037/apm-21-2565).

Methods

Literature search strategy

Computer-based search

A computer-based search was performed by three researchers.

Databases

The Chinese databases included CNKI, Wanfang, VIP, and China Biomedical Literature (CBM) database; and English databases included PubMed, EMBASE, and Cochrane Library.

Search words

The search words included, “acupuncture”, “electroacupuncture”, “traditional Chinese medicine treatment”, “knee osteoarthritis”, “osteoarthritis of the knee”, “knee joint osteoarthritis”, and “KOA”, in Chinese and English, respectively.

Time period

The period between searches was from the month the databases were created to May 2021.

Search strategy

The search method of combining subject terms with free-text synonyms was used. An example of searching in PubMed is shown in Table 1.

Inclusion and exclusion criteria

Inclusion criteria

The inclusion criteria included: (I) the included patients met the diagnostic criteria of KOA; (II) published randomized controlled trials, with clearly-defined baseline data; (III) whether blinding is used or not; (IV) the combination group included patients who had received the combination of acupuncture with CHM alone, while the control group included patients who had undergone other treatment methods different from the combination of acupuncture and CHM; (V) the outcome measures included any of the following indicators: overall response rate (ORR), Visual Analogue Scale (VAS) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and Lysholm score. All the outcomes measures were reliable.

Exclusion criteria

The exclusion criteria included: (I) articles with poorly-defined diagnostic criteria, efficacy indicators, and/or descriptions; (II) articles with incorrect trial design or statistical methods; (III) reviews, dissertations, conference proceedings, and nursing records; (IV) basic experiments; (V) case reports and anecdotal evidence; (VI) expert experience; (VII) unpublished articles or overlapping publications; (VIII) articles with obvious errors or incomplete data; (IX) the original full-text is not available; and (X) literature where acupuncture and CHM are used as adjuvant therapy.

Data extraction

The search, inclusion, and exclusion of the literature were performed by two well-trained and qualified medical practitioners who had clinical experience in rheumatology and acupuncture, and the initial articles were screened after verification. The data extraction of the initial articles was then performed independently by two investigators and checked by a third investigator. In case of disagreement, the third investigator and the principal investigator negotiated to make a final decision. If there were missing data in the literature, the corresponding author was contacted via email or phone call to obtain such data. The extracted data mainly included: (I) basic information about the included articles: first author and year of publication, etc.; (II) information about the included subjects: number and ages of subjects in the combination group and the control groups, etc.; (III) study designs: types of design, interventions, and details, etc.; and (IV) outcome indicators and outcome measures: ORR, WOMAC score, VAS score, and Lysholm knee function score, etc.

Assessment of literature quality

The bias risk of the included studies was assessed using the Cochrane Bias Risk tool from the Handbook of the Cochrane Collaboration for Systematic Intervention Reviews, version 5.1.0 (https://www.cochrane.org/), which assesses the following seven domains: (I) allocation of the randomization sequence (selection bias); (II) allocation concealment (selection bias); (III) blinding of the participants and the team involved (performance bias); (IV) blinding of outcome evaluators (detection bias); (V) incomplete outcomes (attrition bias); (VI) report of selective outcome (publication bias); and (VII) other sources of bias.

The methodological quality of the literature was evaluated according to the Jadad score by two independent researchers with a valid Good Clinical Practice (GCP) certificate, and checked by a third investigator. In case of disagreement, the third investigator and the principal investigator negotiated to make a final decision. Points were awarded as follows: (I) randomization: 1 point was given if randomization was mentioned; additional 1 point was given if appropriate randomization was used; (II) double blinding: 1 point was given if double blinding was mentioned; additional 1 point was given if the method of double blinding was appropriate; and (III) withdrawals and dropouts: 1 point was given for a clear description of withdrawals and dropouts. Articles were rated as low-quality if scored 0–2 points, and as high-quality if scored 3–5 points.

Outcome measures

The primary outcome measure was ORR, and the secondary outcome measures included VAS score, WOMAC score, and Lysholm score.

Statistical analysis

Meta-analysis was performed using RevMan software (version 5.3; Cochrane Collaboration). Both fixed- and random-effects models were used. Heterogeneity was quantified by I² statistics. I²<50% suggested no heterogeneity, and the data were pooled using the fixed-effects model; I²>50% suggested the presence of heterogeneity among the studies, and the random-effects meta-analysis was employed. If more than 10 studies were included for a specific outcome measure, the presence of morbidity bias was analyzed using inverted funnel plots. The odds ratio (OR) was used as the effect measure for binary variables, and the mean difference (MD) was used for measures with the same unit and measurement method. A 95% confidence interval (CI) was given, and a P value of <0.05 was considered statistically significant.

Results

Literature search and screening

A flow chart of the study selection process is shown in Figure 1.

Figure 1 Literature search & screening flowchart.

Basic features of the included studies

The basic features of the included 33 studies are summarized in Table 2. There is no English literature.

Quality of the included articles

The included articles’ biases were assessed using the relevant tools in the Cochrane Handbook for Systematic Reviews of Interventions. A bar graph showing the assessment results is shown in Figure 2, and a pooled graph is shown in Figure 3.

Figure 2 Bar chart for bias risks of the included studies.

Figure 3 Bias risk assessment of the included studies. +, low risk; ?, unknown; −, high-risk.

Outcome measures

ORR

ORR was calculated in 31 articles (Figure 4). The heterogeneity among studies was low (P=0.03; I²=36%), so the fixed-effects model was used [OR =5.41 and its 95% CI was (4.38, 6.68); Z=15.66; P<0.00001]. Meta-analysis showed that the combination group had a higher ORR than the control group. In particular, acupuncture combined with orally administered CHM had significantly higher clinical efficacy compared with other treatment methods. The funnel plot is shown in Figure 5. The plot shows only slight asymmetry, indicating a possible minor publication bias.

Figure 4 Forest plot of the meta-analysis of ORR. ORR, overall response rate.

Figure 5 Funnel plot of the meta-analysis of ORR. ORR, overall response rate; OR, odds ratio; SE, standard error.

VAS score after treatment

VAS score was mentioned in 3 articles (Figure 6). The heterogeneity among studies was high (P<0.00001; I²=98%), so the random-effects model was used [MD =−1.86 and its 95% CI was (−2.44, −1.29); Z=6.37; P<0.00001]. Meta-analysis showed that the combination group had a larger decrease in VAS score after treatment than the control group. In particular, acupuncture combined with orally administered CHM had significantly higher VAS score improvement than other treatment methods. Thus, the combination could dramatically alleviate the pain symptoms.

Figure 6 Forest plot of meta-analysis of VAS score after treatment. VAS, Visual Analogue Scale.

WOMAC score after treatment

WOMAC score was mentioned in 3 articles (Figure 7). The heterogeneity among studies was high (P<0.00001; I²=100%), so the random-effects model was used [MD =−13.05 and its 95% CI was (−21.70, −4.41); Z=2.96; P=0.003]. Meta-analysis showed that the combination group had a larger decrease in WOMAC score after treatment than the control group. In particular, acupuncture combined with orally administered CHM had a significantly higher decrease in WOMAC score compared with other treatment methods. Thus, the combination could effectively relieve knee pain and stiffness in KOA patients and improve their daily living difficulties.

Figure 7 Forest plot of meta-analysis of WOMAC score after treatment. WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.

Lysholm score after treatment

Lysholm score was mentioned in 2 articles (Figure 8). The heterogeneity among studies was high (P=0.007; I²=86%), so the random-effects model was used [MD =10.47 and its 95% CI was (5.21, 15.72); Z=3.91; P<0.0001]. Meta-analysis showed that the combination group had a higher Lysholm score after treatment than the control group. In particular, acupuncture combined with orally administered CHM significantly increased the Lysholm score compared with other treatment methods. Thus, the combination could effectively relieve knee pain, stiffness, and swelling in KOA patients, and improve the quality of life.

Figure 8 Forest plot of meta-analysis of Lysholm score after treatment.

Adverse reactions

Adverse reactions were mentioned in two studies (Figure 9). In one study, the incidence of adverse reactions was 1.92% (mild swelling of the lower extremities in one case) and 3.85% (diarrhea in one case and dizziness in one case), respectively, in the control group and the combination group, showing no significant difference (P>0.05). In another study, two patients in the combination group experienced mild gastrointestinal discomfort and abdominal distension, which disappeared after stopping the CHM. Three patients showed gastrointestinal reactions in the control group, manifested as nausea, vomiting, abdominal pain, and constipation, which resolved after stopping the CHM. There were no significant changes in the findings of routine blood tests, routine urine tests, and liver/kidney function tests before and after treatment in both groups.

Figure 9 Forest plot of adverse reactions.

Discussion

KOA is a common degenerative disease of the knee joint, with the main symptoms being knee stiffness, pain, and movement disorders. Currently, the commonly used Western medical treatments, including Western drugs or surgery, still cannot cure KOA and are often associated with adverse effects (40). Therefore, the role of TCM in treating KOA has been increasingly recognized, particularly the combination of acupuncture with orally administered CHM. The clinical efficacy of acupuncture has long been demonstrated. When used in combination with liver- and kidney-tonifying drugs, wind-, cold-, and dampness-dispelling drugs, and blood circulation-activating drugs, acupuncture can alleviate KOA and reduce its recurrence. It also helps increase the patient’s quality of life and improve the economic/psychological burden of patients and their families.

The acupuncture points mentioned in the literature included neixiyan, waixiyan, zusanli, xuehai, liangqiu, yinlingquan, yanglingquan, weizhong, and ashi point, which are around the knee joint. Acupuncture at these points helps alleviate knee pain and regulate qi and blood. Acupuncture can enhance muscle strength, adjust soft tissue tension around the knee, improve joint stress, eliminate swelling and relieve pain. And promote local blood circulation, accelerate metabolism, benefit the absorption of inflammatory substances in the joint, enable the damaged tissue to repair, relieve the resting pain of the knee joint, swelling, pain from up and down stairs, stiffness and the improvement of joint mobility. The TCM orally administered Radix Angelicae Pubescentis, parasite scurrula, Radix Cyathulae, Poria, Radix Saposhnikoviae, Rhizoma Ligustici Chuanxiong, Radix Codonopsis, Radix Angelicae Sinensis, Radix Paeoniae Alba, Radix Rehmanniae Preparata, Radix Aconiti Preparata, and Eupolyphaga Seu Steleophaga. They were mainly liver- and kidney-tonifying drugs and blood circulation-activating drugs. It has modern pharmacological effects such as anti-inflammatory, analgesia, expanding blood vessels, improving circulation and regulating immune functions. The Chinese herbs with the actions of activating blood flow and removing blood stasis, and strengthening the muscles and bones were applied to the affected sites and irradiation by the spectrograp can promote the local absorption of medicines. Herbs with the effects of activating blood flow and removing blood stasis can ameliorate hemodynamical state, promote the microcirculation and improve the hypercoagulability to relieve blood stasis. Moreover, the herbs effective to nourish the kidney and strengthen effective to bones, activate blood flow and remove blood stasis can inhibit chrondral degeneration and promote the auto-reparation of the cartilagines TCM. Thus, they can exert very well effects in treating and preventing the KOA. The combination treats the disease via both oral and topical approaches, and from local and systemic perspectives. Strengthening the tendons, bones, and joints relieves knee pain and improve the quality of life in KOA patients.

Here we systematically evaluated the efficacy of the combination in treating KOA. A meta-analysis was conducted on the retrieved studies. Data were extracted from studies without significant heterogeneity and pooled with appropriate statistical methods to draw comprehensive conclusions, which to a certain extent can yield more reliable clinical data. The results suggested that the combination could effectively increase the ORR and reduce disease recurrence. However, most of the included articles were of low quality, as they failed to strictly follow the requirements of randomized control trials (e.g., blinding), and some of them were biased. The limitations of our current analysis are summarized as follows: (I) due to insufficient relevant foreign language literature, the included articles were all small-sample, single-center randomized controlled trials published in China, which could lead to selection bias; (II) most of the studies did not mention allocation concealment and blinding, which may have some influence on the results due to the risk of bias; (III) the duration of treatment, follow-up time, and specific acupuncture points/CHM varied among different studies, so there was statistical heterogeneity; (IV) while the vast majority of randomized controlled trials focusing on the combination of acupuncture and CHM in treating KOA were included in our current analysis, only a few studies on the combinations with warm acupuncture, small needle knife, and Western medicine were retrieved for comparisons, which may result in a certain risk of bias; and (V) the three indicators, including WOMAC score, VAS score, and Lysholm score, were adopted in only a small number of studies used, and were highly heterogeneous among these studies due to differences in treatment course, interventions in control group, and grouping protocols, which undermined the reliability of the results (41,42).

Limitations and heterogeneity

The limitations of meta-analysis: 33 studies were included, mostly randomized methods and random assignment, some had only overall efficiency, too-old or self-contained efficacy criteria; most literature lacked long-term follow-up data to evaluate patients’ disease recurrence, long-term survival quality and specific adverse effects. Evaluation indicators were limited, the outcome indicators only analyzed efficiency, VAS, WOMAC score and Lysholm joint function score, such as HSS score, Inflammatory factor and adverse events were not included in the analysis. On systematic review, the article has some bias in systematic review, selection bias, incomplete or not objective; in research level, there may be publication bias, positive results are easy to publish, negative results are not acceptable, in outcome level, researchers have reporting bias, Selective reports of favorable results.

The article on the source of heterogeneity to consider the following points: acupuncture selected acupoints are different: far away Near selection points, with the evidence selection points, meridian syndrome differentiation selection points and viscera syndrome differentiation selection points, etc.

The oral CHMs selected in the literature are also different, including tonifying the liver and kidney, strengthening tendons and bones, promoting blood circulation and dredging collaterals, regulating qi and so on, which will also cause some heterogeneity.

In conclusion, the combination of acupuncture with CHM has significant efficacy in treating KOA, with remarkable therapeutic effects in improving ORR, increasing Lysholm score, and lowering VAS score and WOMAC score. With a high clinical value, it may be a preferred treatment for KOA. However, as the currently available studies still had many limitations, the conclusions of our analysis still need to be further validated in more multicenter, large-sample randomized controlled trials at home and abroad. Based on our findings, future studies may increase their quality by optimizing research protocols and increasing sample sizes. In addition, the clinical value of the combination of acupuncture with CHM in treating KOA has been demonstrated, and the underlying mechanism may be a research priority (43).

Acknowledgments

Funding: This study was supported by Hubei University of Chinese Medicine “Youth Program” (2020ZZX029) and Hubei University of Chinese Medicine Doctoral Research Start-Up Fund.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://dx.doi.org/10.21037/apm-21-2565

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/apm-21-2565). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: J. Chapnick)