Research ArticleAre Kidney-Tonifying and Blood-Activating Medicinal HerbsBetter than NSAIDs for Knee Osteoarthritis? A SystematicReview and Meta-Analysis

Hetao Huang ,1 Jianke Pan,2 Weiyi Yang ,2 Yanhong Han ,1 Minghui Luo,2

Haodong Liang,3 Lingfeng Zeng,2 Guihong Liang ,2 Jiongtong Lin ,1 and Jun Liu 1

1Second School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, China2Department of Orthopaedics, Second Affiliated Hospital of Guangzhou University of Chinese Medicine,Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, China3Guangzhou Hospital of Traditional Chinese Medicine, Guangzhou 510130, China

Correspondence should be addressed to Jun Liu; liujun.gdtcm@hotmail.com

Received 25 June 2019; Revised 19 September 2019; Accepted 25 September 2019; Published 25 November 2019

Academic Editor: Lorna Suen

Copyright © 2019 Hetao Huang et al. 'is is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objective. To compare the efficacy and safety of kidney-tonifying and blood-activating medicinal herbs (KTBAMs) and non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of knee osteoarthritis (KOA). Methods. Randomized controlledtrials (RCTs) from online databases that compared the efficacy of KTBAMs and NSAIDs in the treatment of KOA were retrieved.'e main outcomes included the evaluation of functional outcomes, pain, and adverse effects. 'e Cochrane risk-of-bias (ROB)tool was used to assess methodological quality. Results. A total of 38 RCTs (3994 participants) were included in our meta-analysis.We found that KTBAMs had a significantly higher total effective rate (P< 0.00001, risk ratio (RR)� 1.08, confidence interval(CI)� 1.05 to 1.11, I2 � 4%) and a lower gastrointestinal adverse reaction rate (P< 0.00001, RR� 0.36, CI� 0.24 to 0.53, I2 � 33%)than NSAIDs. KTBAMs showed greater improvements in the Knee Society Scale (KSS) scores (mean difference (MD)� 7.17, 95%CI 0.71 to 13.64, P � 0.03). Regarding the visual analog scale (VAS) scores, WOMAC scores, and Lequence scores, there were nosignificant differences between the KTBAM group and the NSAID group. 'e GRADE quality level of this systematic reviewindicated that the very low-quality evidence showed that KTBAMs had a higher total effective rate, while the moderate-qualityevidence showed that the adverse reactions of KTBAMs were lower and the KSS scores were higher. Low-quality evidence showedno significant differences in improving VAS scores, WOMAC scores, or Lequence scores. Conclusion. KTBAMs were superior toNSAIDs in terms of a higher total effective rate, a lower adverse reaction rate, and a higher KSS score. 'ere were no significantdifferences between KTBAMs and NSAIDs in improving VAS scores, WOMAC scores, and Lequence scores of patients withKOA. 'erefore, KTBAMs may be an alternative effective method for treating KOA. However, high-quality, well-designed RCTswith long-term follow-up are still required.

1. Introduction

Knee osteoarthritis (KOA) is one of the most commonchronic muscular diseases in old people [1]. 'e mainmanifestations of KOA are pain and dysfunction in theknees, which affect quality of life and lead to a high rate ofdisability in elderly individuals. 'e approximate prevalenceof KOA in the general population throughout the world is12%–35% [2]. KOA has a heavy socioeconomic burden in

developed countries. Recently, KOA has become one of theglobal burden diseases. In some Asian countries, the highprevalence of KOA has increased medical care expendituresand attracted much government attention [3].

'e main objectives in the management of KOA havebeen to alleviate pain, educate patients about their disease,restore function, slow down the progression of disease, andmaintain a health-related quality of life [4]. Traditionally, themanagement of end-stage KOA for relieving pain and

HindawiEvidence-Based Complementary and Alternative MedicineVolume 2019, Article ID 9094515, 19 pageshttps://doi.org/10.1155/2019/9094515

improving function has been knee arthroplasty [1]. Con-servative approaches address early stages of the disease, suchas oral NSAIDs, hyaluronic injection, and self-management,but the clinical results may not satisfy patients. In light ofthis situation, alternative treatments such as herbal prepa-rations [5], acupuncture [6], moxibustion [7], massage [8],and tai-chi [9] have been investigated for their efficacy inrandomized controlled trials (RCTs) and have drawnattention.

As an alternative therapy, Chinese herbal medicine(CHM) or herbal products have been used and recom-mended by many clinicians. 'ese have been indicated tohelp alleviate KOA symptoms and reduce costs [10–13].KTBAMs are one type of Chinese herbal recipe consisting ofherbals that can “tonify kidney” and “activate blood” basedon traditional Chinese theory. Research on the mechanismof some recipes of KTBAMs have shown their effectivenessin promoting chondrocyte proliferation, inhibiting sodiumnitroprussiate-induced chondrocyte apoptosis, and regu-lating the expression of vascular endothelial growth factor(VEGF) and hypoxia-inducible factor-1α (HIF-1α) [14–18].Recently, researchers have reported that KTBAMs can helpcontrol KOA-related symptoms and have been widely usedin many Asian countries [19]. NSAIDs are the most popularmedicine because of their promising effect for KOA, al-though they are accompanied by high costs and many re-lated side effects [20]. KTBAMs, alone or combined withconventional pharmaceutical drugs, have also been com-monly used for the clinical management of KOA. Someresearchers [21, 22] have published systematic reviews of theefficacy and safety of traditional Chinese medicine pre-scriptions in the treatment of KOA. However, most of thesystematic reviews have been based on intervention mea-sures that include “traditional Chinese medicine,” but thereis no systematic review of a specific kind of traditionalChinese medicine. In particular, no study has systematicallyexamined the effectiveness and safety of KTBAMs for KOAaccording to the Preferred Reporting Items for Systematicreviews and Meta-Analyses (PRISMA) until now. To assistclinical practice and possibly to reduce the heavy burden ofKOA patients, it is important to systematically review thecurrent evidence of KTBAMs compared with NSAIDS.'us, we performed a meta-analysis of RCTs to assess theevidence for the efficacy and safety of KTBAMs for KOA incomparison with NSAIDs.

In the previous systematic reviews of the efficacy andsafety of traditional Chinese medicine prescriptions in thetreatment of KOA, the included studies compared differentprescriptions with different efficacies and mechanisms ofaction, and there was a high level of clinical heterogeneityamong the studies [23, 24]. In contrast, in the present study,the interventions were strictly limited to KTBAMs, and thecontrol measures were limited to NSAIDs. To some extent,the bias caused by heterogeneous sources and drugs withdifferent mechanisms of action was reduced, and the resultsof this study have higher clinical significance. In addition,our study incorporated additional and updated clinical re-search reports, which complemented and updated theprevious systematic reviews. In conclusion, it is necessary to

study the efficacy and safety of KTBAMs in the treatment ofKOA.

2. Materials and Methods

2.1. Literature Search. Seven databases, including PubMed,EMBASE, Cochrane Central Register of Controlled Trials,China National Knowledge Infrastructure, Chinese Scien-tific Journal Database, Wanfang Data and Chinese Bio-medical Literature Database, were investigated from theirinception through August 2019. 'e reference lists of re-trieved papers were also studied. 'e following search termswere used individually or in combination.'emesh terms inthis paper are as follows: “osteoarthritis, knee,” “Anti-In-flammatory Agents, Non-Steroidal,” and the entry terms areas follows: “Bushen,” “Kidney-tonifying,” “Blood-activat-ing,” “arthritis,” “osteoarthritis,” “knee osteoarthritis,” “kneearthritis,” and “osteoarthritis of knee joint.” To increase thesearch range, no date and no language limits were imposed.Additionally, no restrictions on population characteristicswere imposed.'e specific search strategies for PubMed andEMBASE searches are shown in the Supplemental Table.

2.2. StudySelection. Two reviewers (HTH and JKP) screenedthe abstracts of all retrieved titles and decided whether thepaper contained potentially relevant data. Disagreementswere discussed with another author (JL). 'e eligibilitycriteria for this meta-analysis were RCTs comparingKTBAMs with NSAIDs for the treatment of KOA.

'e inclusion criteria were as follows: (a) patients werediagnosed with KOA. 'e diagnosis of participants was inaccordance with the recognized criteria for KOA, such as theguidelines established by the American College of Rheu-matology in 1995. (b) 'e treatment group was treated witha KTBAM (the traditional Chinese medicine prescriptionmust have contained both a recognized CHM with kidney-tonifying effects and a CHM with blood-activating effects).'e control group was treated with NSAIDs. In addition, thetreatment duration was required to be at least 2 weeks, morethan 10 subjects were assessed in each group, and theoriginal data were available. (c) 'e types of study includedRCTs that were not limited based on concealment, blindingmethods, and allocation schemes, and the language waslimited to Chinese and English. 'e sex, age, and source ofthe subjects were not limited.

'e exclusion criteria were as follows: (a) multiplepublications reporting on the same groups of participantswere excluded to reduce overlapping data; (b) participantswere excluded if they had rheumatoid arthritis, ankylosingarthritis, joint tuberculosis, purulent arthritis, allergic ar-thritis, Kashin–Beck disease, or podagra; (c) case reports,letters, editorials, and nonhuman studies were excluded; and(d) studies from which the relevant data could not beextracted were excluded.

2.3. Data Extraction. Data extraction included the firstauthor’s name, year of publication, sample size, diagnosticcriteria, age and sex of the participants, details of the

2 Evidence-Based Complementary and Alternative Medicine

intervention and control conditions, treatment duration,and outcome measurements for each study. Two authors(HTH and WYY) independently conducted the data ex-traction according to predefined criteria. Any uncertaintywas resolved through discussion with another author (JL).'e reasons for exclusion were recorded. 'e data wereextracted from the included RCTs to a predefined Excel table(Microsoft Corp, Redmond, WA) and cross-checked by thetwo reviewers (HTH and WYY)

2.4. Risk of Bias and Quality Assessment. Two authors (HTHand HDL) independently assessed the methodologicalquality of each trial according to the standards advised by theCochrane Handbook [25]. Disagreements, if any, were re-solved by discussion and reached consensus through a thirdreviewer (JKP). 'e risk of bias was evaluated for each studyby assessing the randomization process, the treatment al-location concealment, the blinding of participants andpersonnel, the blinding of outcome assessment, the com-pleteness of the data, the reporting of results, and otherbiases. Selective reporting bias was judged according to thepublished protocols for the registered clinical trials that werecontained on the Chinese clinical trial registry (http://www.chictr.org) and international clinical trial registry of the USNational Institutes of Health (http://clinicaltrials.gov)websites. We compared the outcome measures between thestudy protocol and the final published trial.

2.5. Data Analysis. Data analysis was carried out usingReview Manager software (V.5.3) provided by the CochraneCollaboration. Given the characteristics of the extracted datain the review, continuous outcomes were expressed as themean differences (MDs) with 95% confidence intervals(CIs). Differences in categorical variables were expressed asrisk ratio (RR) values and 95% CIs. Heterogeneity wasassessed by means of I2 statistics. I2≥ 50% represented highheterogeneity. A standardized mean difference (SMD) wasused when the studies included in the meta-analysis assessedthe outcome based on different scales (e.g., visual analogscale (VAS) 0-10 and VAS 0-100). Initially, a fixed-effectmodel would be used to compare the outcomes, unless theheterogeneity tests indicated that the I2 statistic ≥50% andsubstantial heterogeneity existed between studies; in thiscase, the reasons for this heterogeneity would be searched forand a random-effect model would be used for comparison.'e subgroup analysis was undertaken according to pre-specified criteria to investigate heterogeneous results or todetermine the effect of prespecified criteria on the pooledestimate. We assumed that clinical differences would mainlyoriginate from the treatment duration and the dosage andfrequency of NSAIDs; therefore, subgroups were dividedbased on these factors. Publication bias was analyzed byfunnel plot analysis if sufficient studies (n≥ 10) were found.

2.6. GRADE the Evidence. 'e GRADE system was used toevaluate the quality of the evidence for each outcome [25].GRADE-pro GDT Online Tools (available on https://

gradepro.org/) were used to evaluate the evidence re-garding the included outcomes. Initially, RCTs were con-sidered to be of high confidence in estimating an effect, andobservational studies were considered to be of low confi-dence in estimating an effect. 'e reasons that may decreasethe level of confidence included risk of bias, inconsistency,indirectness, imprecision, and publication bias. 'e reasonsthat may increase the level of confidence included a largeeffect, dose response, and accounting for all plausible re-sidual confounding and bias. 'e GRADE evidence wasdivided into the following categories: (1) high-quality evi-dence, which indicated that further research was unlikely tochange the confidence in the estimate of the effect; (2)moderate-quality evidence, which indicated that furtherresearch was likely to have an important impact on theconfidence in the estimate of the effect and may change theestimate; (3) low-quality evidence, which indicated thatfurther research was likely to have an important impact onconfidence in the estimate of the effect and was likely tochange the estimate; and (4) very low-quality evidence,which indicated that we were very uncertain about theresults.

3. Results

3.1. Description of Included Studies. 'e results of searchingstrategies are shown in Figure 1. In total, 3685 records wereobtained through database searches, and 252 potentiallyrelevant articles were identified after screening the titles andabstracts. According to the selection criteria, 214 articleswere excluded. Finally, 38 RCTs [19, 26–62] were included inthe review. One study was conducted in 'ailand [19], andthe other studies were conducted in China. 'e language ofthe enrolled trials included English and Chinese.

'e essential characteristics of the 38 studies [19, 26–62]are described in Table 1. All the studies, including 2012 patientsfrom the treatment group and 1982 individuals in the controlgroup, were recruited into this systematic review. Two differentdiagnostic criteria of KOA were used in most of the includedtrials: 19 studies [19, 30, 36–38, 41, 42, 44–54, 58] used the 1995American College of Rheumatology Guidelines for 'eMedical Management of Osteoarthritis (ACR criteria-1995)and 15 studies [26, 27, 31, 33–35, 39, 40, 43, 55–57, 60–62] usedthe 2007 Chinese Medical Association Guidelines for 'eDiagnosis and Treatment of Osteoarthritis (CMA criteria-2007). One study [28] used the Guiding Principles for ClinicalResearch of New Chinese Medicine, two studies [29, 32] re-ferred to the Criteria for the Diagnosis and 'erapeutic Effectof Diseases and Syndromes in Traditional Chinese Medicine,and only one study [59] did not explicitly mention diagnosticcriteria. 'e two sets of criteria for KOA in China were ba-sically the same and consistent with the criteria in America anddepend mostly on a diagnosis of clinical manifestations and aknee joint X-ray. 'e patients enrolled in the review rangedfrom 48 to 65 years of age.

In total, 3994 participants were involved in the 38 RCTs;nine studies [29, 37, 39, 41, 45, 52, 53, 58, 59] did not provideinformation on the participants’ sex; the remaining 29 RCTs[19, 26–28, 30–36, 40, 42–44, 46–51, 54–57, 60–62] included

Evidence-Based Complementary and Alternative Medicine 3

Records identified in PubMed, EMBASE, and Cochrane database searches

(n = 3658)

Scre

enin

g In

clude

d El

igib

ility

Id

entif

icat

ion

Records after duplicates removed (n = 1516)

Records screened (n = 1516)

Records excluded by identified titles or abstracts

(n = 1264)

Full-text articles assessed for eligibility (n = 252)

214 articles were excluded with the following reasons:

(i)(ii)

(iii)(iv)

Non-RCTs (n = 16) Duplicate reports (n = 25) Inapproprite intervention (n = 127) Data not extractable (n = 46)

Studies included in qualitative synthesis (n = 38)

Studies included in quantitative synthesis (meta-analysis)

(n = 38)

Figure 1: Flow chart showing study identi�cation, review, and selection.

Table 1: Basic characteristics of the included studies.

First author, year,country

Samplesize (T/C)

Age,mean± SD(year)

Sex(M/F)

Treatment group Control groupTreatmentsession(week)

Outcomeassessment

Teekachunhatean S,2004, �ailand [19]

200(100/100)

T:62.66± 9.46

C:62.38± 8.22

T:22/78C:

19/81

Duhuo jishengpills

Diclofenac 25mg/time,PO, TID 4 LES, VS, AE

Su ZF, 2016, China[26] 59 (30/29) T: 58.9

C: 57.1

T: 8/22

C: 9/20

Kangguzengsheng pills

Celecoxib, 200mg/time,PO, QD 4 TER, WS, VS

Niu QW, 2016, China[27]

210(105/105)

T:59.88± 2.41

C:58.64± 2.32

T:45/60C:

44/61

Jingwu gutongcapsule

Diclofenac sodium tablet,100mg/time, PO, QD 4 KS, VS

Lv G, 2016, China [28] 91 (46/45)

T:54.39± 5.24

C:55.08± 4.5

T:20/26C:

21/24

Qubi tang Diacerein, 50mg/time, PO,BID 12 TER, AE

Zhang GL, 2016,China [29] 88 (44/44) NA NA Cangxi tongbi

tangEtodolac tablet, 400mg/

time, PO, QD 5 TER, VS

4 Evidence-Based Complementary and Alternative Medicine

Table 1: Continued.

First author, year,country

Samplesize (T/C)

Age,mean± SD(year)

Sex(M/F)

Treatment group Control groupTreatmentsession(week)

Outcomeassessment

Bo Y, 2016, China [30] 80 (40/40) T: 51.2C: 49.8

T: 19/21C:

17/23

Shugan zishentang

Meloxicam, 7.5mg/time,PO, QD 8 TER, CCR,

WS, AE

Zhang XL, 2016,China [31]

286(142/144)

T: 55± 7C: 56± 8

T: 31/105C:35/105

Zhuanggu guanjiepills + placebo

Celecoxib, 200mg/time,PO, QD+placebo 4 TER, CCR,

WS, AE

Li YP, 2015, China[32] 86 (45/41) T: 54.5± 6.2

C: 53.8± 6.3

T: 19/26C:

12/29

Huoxue tongluobushen fang

Meloxicam, 7.5mg/time,PO, QD 4 TER, AE

Zhu XY, 2014, China[33] 70 (35/35)

T:51.79± 7.01

C:48.62± 7.51

T: 12/21C:

15/19

Long bie capsule Diacerein, 50mg/time, PO,QD 4 AE

Xu WL, 2014, China[34] 60 (30/30)

T: 55.6± 9.3C:

52.5± 11.4

T: 11/19

C: 9/21

Long bie capsule Celecoxib, 200mg/time,PO, QD 4 WS, AE

Sun Y, 2014, China[35]

100(50/50)

T:48.25± 5.87

C:49.26± 5.15

T: 15/35C:

16/34

Zeng ye run jietang

Meloxicam, 7.5mg/time,PO, QD 8 TER, CCR,

LES, AE

Zhang JQ, 2014, China[36] 71 (35/36)

T:60.45± 6.53

C:62.14± 8.14

T: 9/26

C: 7/29

Bushen huoxuefang

Celecoxib, 200mg/time,PO, QD 12 TER, CCR,

LYS, VS, AE

Yang HR, 2014, China[37]

200(100/100)

T: 65C: 64 NA Jia wei yang he

tangLoxoprofen sodium,60mg/time, PO, BID 8 KS

Zhou HJ, 2012, China[38] 78 (43/35)

T:53.61± 6.37

C:54.18± 6.13

T: 17/26C:

14/21

Shufu Jiangudecoction

Celecoxib, 200mg/time,PO, QD 8 TER, CCR,

LYS, VS

Xu YS, 2013, China[39] 68 (34/34)

T:59.17± 12.17

C:62.72± 11.64

NA Bushen huoxuefang

Celecoxib, 200mg/time,PO, BID 6 WS

Lu M, 2012, China[40]

240(120/120)

T:52.93± 14.22

C:54.01± 15.35

T:55/65C:

50/70

Tenghuang Jiangutablet Celecoxib 4 TER, CCR,

WS, AE

Sun SL, 2012, China[41] 48 (24/24) T: 62.75

C: 65.75 NA Qi teng tang Meloxicam, 7.5mg/time,PO, QD 4 TER, LES, AE

Fan XH, 2012, China[42]

152(76//76)

T: 50.6± 8.2C: 49.8± 7.6

T:29/47C:

35/41

Jiawei DangguiSini Tang

Celecoxib, 200mg/time,PO, QD 8 TER, CCR,

WS, VS

Ji MH, 2010, China[43] 40 (20/20)

T:50.75± 2.12

C:51.02± 1.54

T: 9/11

C: 9/11

Buahen huoxuetongluo fang Celecoxib 4 LES, KS

Yu CG, 2009, China[44]

200(100/100)

T: NA; 44/46C: NA; 52/48

T:44/46C:

52/48

Bushen huayutang

Fenbid capsule 200mg/time, PO, QD 4 TER, LES

Evidence-Based Complementary and Alternative Medicine 5

Table 1: Continued.

First author, year,country

Samplesize (T/C)

Age,mean± SD(year)

Sex(M/F)

Treatment group Control groupTreatmentsession(week)

Outcomeassessment

Yang B, 2009, China[45] 60 (30/30) NA NA Bushen huoxue

medicinalCelecoxib, 200mg/time,

PO, QD 4 TER, CCR

Guo YJ, 2010, China[46]

160 (82/78)

T: 63.93C: 61.83

T:34/48C:

32/46

Quyu Tongbidecoction

Diclofenac tablet, 75mg/time, PO, BID 2 TER

Huang BQ, 2009,China [47] 60 (32/28)

T: 50.2± 87C:

51.1± 10.2

T: 6/26C:

11/17

Bushen zhuanggufang

Meloxicam, 15mg/time,PO, QD 5 TER, CCR,

AE

Wu JX, 2009, China[48] 40 (21/19) T: 56.5

C: 57.3

T: 4/17

C: 3/16

Duhuo jishengdecoction Celecoxib 4 LES, KS

Zhao L, 2008, China[49] 50 (25/25)

T:63.09± 7.65

C:62.65± 10.8

T: 2/20

C: 4/19

Bushen huoxuemedicinal Celecoxib 4 VS

Li M, 2007, China [50] 120 (60/60)

T: 57.6C: 55.2

T:28/32C:

27/33

Gu shu tang Fenbid capsule, 300mg/time, PO, BID 4 TER, CCR

Ye JX, 2005, China[51]

152 (80/72)

T:59.2± 17.6

C:57.5± 15.3

T:35/45C:

31/41

Guanjietong tablet Ibuprofen capsule, 300mg/time, PO, QD 4 TER, CCR

Li YM, 2005, China[52] 60 (30/30) T: 58.4

C: 57.2 NA Bushen huoxuejianxi fang

Diclofenac tablet, 50mg/time, PO, BID 4 TER, AE

Wang PM, 2005,China [53] 40 (20/20)

T:59.85± 10.29C: 60.1± 9.5

NA Xining fang Diclofenac tablet, 75mg/time, PO, QD 4 WS, VS, AE

Li ZW, 2010, China[54] 96 (48/48) T: 52.4± 7.6

C: 53.2± 8.5

T:25/23C:

22/26

Bushen huayutang

Diclofenac sodium tablet,75mg/time, PO, BID 8 TER, WS

Wang HD, 2017,China [55] 48 (24/24) T: 56.2± 8.6

C: 55.7± 8.9

T: 14/10C:15/9

Bushen huoxuetang

Loxoprofen sodium,60mg/time, PO, TID 12 TER

Chen N, 2017, China[56] 90 (45/45) T: 45.51

C: 45.19

T: 6/39

C: 6/39

Bushen qiangjincapsule

Celecoxib, 200mg/time,PO, QD 4 VS, WS, LES,

TER, AE

Zheng T, 2019, China[57]

100 (50/50)

T:63.26± 4.72

C:63.12± 4.93

T:27/23C:

24/26

Bushen huoxuefang

Celecoxib, 100mg/time,PO, BID 4 VS, WS, TER,

AE

Li MX, 2017, China[58] 60 (30/30)

T:57.33± 1.59

C:60.07± 1.61

NA Bushen huoxuefang

Diacerein, 50mg/time, PO,QD 4 TER

Wang Z, 2017, China[59]

144 (72/72) NA NA Bushen huoxue

tongluo fangCelecoxib, 100mg/time,

PO, QD 12 TER, VS, LYS

Yuan JJ, 2017, China[60] 70 (35/35)

T:48.30± 5.60

C:41.20± 4.80

T: 18/17C:

15/20

Bushen huoxuetang

Celecoxib, 200mg/time,PO, QD 12 VS, KS

6 Evidence-Based Complementary and Alternative Medicine

1192 male participants and 2006 female participants. 'eRCTs recruited people with durations of treatment thatvaried from 2 weeks to 12 weeks. Only five studies[19, 33, 39, 49, 60] reported baseline severity of KOA with aKellgren–Lawrence X-ray of the participants. 'e otherstudies did not provide information on baseline diseaseseverity, but all reported baseline balance measures.

All studies investigated oral KTBAMs, including multi-ingredient CHM, and the top 20 forms used based on fre-quency are listed (Table 2). 'e preparation forms of themulti-ingredient CHM formulas were decoctions in 28studies [28–30, 32, 35–39, 41–50, 52–55, 57–60, 62], tabletsin two studies [40, 51], capsules in five studies[27, 33, 34, 56, 61], and pills in the others [19, 26, 31]. Allstudies used KTBAMs compared with NSAIDs. Among theincluded trials, KTBAMS were compared with meloxicam insix studies [30, 32, 35, 41, 47, 62], with celecoxib in 17 studies[26, 31, 34, 36, 38–40, 42, 43, 45, 48, 49, 56, 57, 59–61], withdiacerein in three studies [28, 33, 58], with diclofenac in sixstudies [19, 27, 46, 52–54], with loxoprofen in two studies[37, 55], with fenbid in two studies [44, 50], and withibuprofen [51] or etodolac [29] in the remaining studies.

All studies provided treatment of equal duration in theintervention and control groups. 'e treatment durationswere 2 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, and 12weeks. Only one study [31] had a posttreatment follow-upphase of 4 weeks. Ten studies [19, 31, 38–40, 48, 56, 58, 60, 62]reported dropouts during the treatment phase with reasonsprovided. None of the dropouts were due to serious adverseevents (AEs). Studies were considered to have no dropoutswhen they reported equal numbers.

3.2. Quality Assessment. Sixteen studies [28, 29, 33, 34,39, 40, 42, 48, 49, 53, 55, 56, 58, 60–62] used a randomnumber table and were evaluated as low risk. 'e others[19, 30, 32, 35–38, 41, 43–47, 50–52, 54, 57, 59] hadunclear risk for not providing detailed information re-garding random sequence generation. 'ree studies[26, 27, 31] were assessed as high risk because theygenerated the sequence according to the order in whichthe patients attended the clinic. For allocation conceal-ment, one study [58] was at low risk for using allocationconcealment, and other studies were at unclear risk

because they lacked the relevant information. Two studies[19, 29] were assessed as having low risk for blinding ofparticipants and personnel because placebo controlgroups were established. Other studies [26–28, 30–62]were assessed as having a high risk for blinding partici-pants and personnel because of the absence of placebocontrols. One study [19] was at low risk for the blinding ofoutcome assessors; other studies [26–62] were at unclearrisk because they provided no such information. Tenstudies [19, 31, 38–40, 48, 56, 58, 60, 62] were at high riskfor incomplete outcome data because they did not includedropouts in their posttreatment data analysis. 'e otherstudies [26–30, 32–37, 41–47, 49–55, 57, 59, 61] were atlow risk. All studies had a low risk for selective outcomereporting because their methods matched the results andhad an unclear risk for other biases (Figure 2). 'e resultsof the GRADE analysis are presented in Figure 3.

3.3. Outcomes. 'e primary outcomes of this meta-analysiswere “total effective rate” and “adverse effects,” and thesecondary outcomes were “VAS scores,” “WOMAC scores,”“Lequence scores,” and “KSS scores.”

3.3.1. Total Effective Rate. 'e evaluation of the total ef-fective rate was based on the Guiding Principles for ClinicalResearch of New Chinese Medicine formulated by the StateFood and Drug Administration of China [63]. 'e effectiverate was graded into 4 categories: (1) Clinically controlled:pain and other symptoms disappeared, joint activity wasnormal, integral decreased ≥95%, and X-ray was normal. (2)Significantly improved: pain and other symptoms dis-appeared, joint movement was not limited, integral de-creased ≥70% and <95%, and X-ray showed a markedimprovement. (3) Improved: pain and other symptoms werebasically eliminated, joint movement was slightly limited,integral decreased ≥30% and <70%, and X-ray showedimprovement. (4) Ineffective: symptoms such as pain andjoint activity did not improve significantly, integral de-creased <30%, and X-ray did not change. 'e effective ratewas calculated as follows: (total pretreatment score − totalposttreatment score)/total pretreatment score× 100%. 'etotal effective rate was calculated as follows: (number of

Table 1: Continued.

First author, year,country

Samplesize (T/C)

Age,mean± SD(year)

Sex(M/F)

Treatment group Control groupTreatmentsession(week)

Outcomeassessment

Pan JK, 2017, China[61] 80 (40/40)

T:64.53± 6.47

C:64.55± 5.57

T: 6/34

C: 5/35

Longbie capsule Celecoxib, 200mg/time,PO, QD 4 TER, VS,

LES, AE

Xing QJ, 2018, China[62]

137 (69/68)

T: 51.0± 8.0C: 53.0± 9.0

T: 31/38C:

32/36

Yiqi huayubushen fang

Meloxicam, 7.5mg/time,PO, QD 6 TER, VS, WS,

AE

Note: TER: total effective rate; CCR: clinical control rate; WS: WOMAC scale; LES: Lequence score; KS: KSS score; LYS: Lysholm score; VS: VAS scale; AE:gastrointestinal adverse reactions; NA: not available; T/C: treatment group/control group; M/F: male/female; SD: standard deviation.

Evidence-Based Complementary and Alternative Medicine 7

clinically controlled + number of significantly impro-ved + number of improved)/total number of cases× 100%.

'e review found that the total effective rates were re-ported in 27 studies [26, 28–32, 35, 36, 38, 40, 42, 45, 46,50–52, 55–59, 61, 62], and the post-follow-up effectiveness inthese 27 studies and the total sample were analyzed in arandom-effect model (Figure 4). KTBAMs were significantlymore effective than NSAIDs (n� 2784, RR� 1.09, 95% CI1.05 to 1.14, P< 0.00001; I2 � 64%) at the end of the treat-ment phase. Considering that 2 weeks, 4 weeks, 5 weeks, 6weeks, 8 weeks, and 12 weeks were commonly used treat-ment durations, a subgroup meta-analysis according to thetreatment duration was conducted. 'e effectiveness of oralKTBAMs in the studies with 4 weeks of treatment(RR� 1.08, 95% CI 1.01 to 1.16, P � 0.03) was consistentwith that of the studies with 8 weeks of treatment (RR� 1.11,95% CI 1.05 to 1.18, P � 0.0004), as well as the overall effectof all studies.

3.3.2. Adverse Effects. A total of 17 studies [19, 28, 30, 32–36,40, 41, 47, 52, 53, 56, 57, 61, 62] reported adverse effects(Figure 5) but these were not mentioned in the other studies.Commonly seen AEs were gastrointestinal symptoms (in-cluding nausea/vomiting, dyspepsia, diarrhea, and con-stipation). Increased blood pressure and central nervoussystem symptoms were also reported. No abnormalities werereported in the routine blood examinations or in liver andrenal function. However, adverse drug reactions were notreported, and none of the adverse effects were serious ineither group.

All studies were pooled into meta-analyses. KTBAMsdemonstrated a lower rate of occurrence of AEs (RR� 0.36,95% CI 0.24 to 0.53, P< 0.00001, with low heterogeneity,I2 � 33%). Similarly, subgroup analyses of 4 weeks(RR � 0.43, 95% CI 0.27 to 0.67, P � 0.0002), 8 weeks(RR � 0.19, 95% CI 0.06 to 0.62, P � 0.006), and 12 weeks(RR � 0.17, 95% CI 0.04 to 0.72, P � 0.02) were consistentwith the pooled effect. 'e results at 5 weeks (RR� 0.18,95% CI 0.01 to 3.51) and 6 weeks (RR � 1.97, 95% CI 0.18 to21.23) indicated no significant differences between thegroups.

3.3.3. VAS Scores. For the VAS scores, twelve studies[26, 27, 29, 36, 38, 42, 49, 53, 57, 59–61] evaluated the effectsof KTBAMs compared with conventional NSAIDs (Fig-ure 6). Data from one study [19] were excluded because theassessments of the VAS scores included pain and stiffness,which was different from the other studies. 'e mean dif-ferences in VAS scores were not significantly different be-tween the KTBAM group and the NSAID group after 4weeks (MD� 0.21, 95% CI − 1.07 to 0.56, P � 0.63), 6 weeks(MD� − 0.26, 95% CI − 0.76 to 0.24, P � 0.31), and 8 weeks(MD� − 0.20, 95% CI − 0.87 to 0.21, P � 0.48), as well as forthe overall effect across all studies (MD� − 0.41, 95% CI− 0.89 to 0.06, P< 0.09, with high heterogeneity, I2 � 96).However, the KTBAM group seemed to have an advantageover the NSAID group in the comparison of VAS scores after5 weeks (MD� − 1.23, 95% CI − 1.40 to − 1.06, P< 0.00001)and 12 weeks (MD� − 0.78, 95% CI − 1.17 to − 0.39,P< 0.0001) of treatment.

Table 2: Top 20 Chinese herbs and efficacy based on frequency of usage in the 38 study prescriptions.

English name Latin name Chinese Pinyin name Frequency of usageKidney-tonifying herbsAchyranthes Root Radix achyranthis bidentatae Niuxi 24Prepared Radix Rehmanniae Radix rehmanniae preparata Shudihuang 18Malaytea Scurfpea Fruit Fructus psoraleae Buguzhi 14Eucommia bark Cortex eucommia Duzhong 13Chinese Taxillus Twig Herba taxilli Sangjisheng 13Drynaria Fortunei Rhizoma drynariae Gusuibu 13Epimedium herb Herba epimedii Yinyanghuo 10Common Macrocarpium Fruit Fructus corni Shanzhuyu 7Prepared common Monkshood Daughter Root Radix Aconiti Lateralis Preparata Fuzi 7Blood-activating herbsAchyranthes Root Radix achyranthis bidentatae Niuxi 24Chinese Angelica Radix angelicae sinensis Danggui 20Suberect Spatholobus Stem Caulis spatholobi Jixueteng 14Danshen Root Radix salviae miltiorrhizae Danshen 11Szechwan Lovage Rhizome Rhizoma chuanxiong Chuanxiong 10Pain reliefDoubleteeth Pubescent Angelica Root Radix angelicae pubescentis Duhuo 10Clematis Root Radix clematidis Weilingxian 10White Peony Root Radix paeoniae alba Baishao 9Common Flowering Quince Fruit Fructus chaenomelis Mugua 9OthersLicorice Root Radix glycyrrhizae Gancao 16Astragalus Radix astragalus Huangqi 10Wolfiporia Extensa Poria cocos Fuling 7

8 Evidence-Based Complementary and Alternative Medicine

Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Incomplete outcome data (attrition bias)

Selective reporting (reporting bias)

Other biases

Low risk of bias

Unclear risk of bias

High risk of bias

25 50(%)

0 10075

(a)

Bo Y, 2016

Chen N, 2017

Fan XH, 2012

Guo YJ, 2010

Huang BQ, 2009

Ji MH, 2010

Li M, 2007

Li MX, 2017

Li YM, 2005

Li YP, 2015

Li ZW, 2010

Lu M, 2012

Lv G, 2016

Niu QW, 2016

Pan JK, 2017

Sun SL, 2012

Sun Y, 2014

Su ZF, 2016

Teekachunhatean S, 2004

Wang HD, 2017

Wang PM, 2005

Wang Z, 2017

Wu JX, 2009

Xing QJ, 2018

Xu WL, 2014

Xu YS, 2013

Yang B, 2009

Yang HR, 2014

Ye JX, 2005

Yuan JJ, 2017

Yu CG, 2009

Zhang GL, 2016

Zhang JQ, 2014

Zhang XL, 2016

Zhao L, 2008

Zheng T, 2019

Zhou HJ, 2012

Zhu XY, 2014

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Figure 2: Risk of bias assessment. Note: (a) Risk of bias graph: review authors’ judgments about each risk of bias item presented aspercentages across all included studies. (b). Risk of bias summary: review authors’ judgments about each risk of bias item for each includedstudy (“+” indicates a low risk of bias, “− ” indicates a high risk of bias, and “?” indicates an unclear or unknown risk of bias).

Evidence-Based Complementary and Alternative Medicine 9

3.3.4. WOMAC Scores. Ten studies [26, 30, 34, 39, 40, 42, 53,54, 56, 57] measuredWOMAC scores to evaluate the e£cacyof treatment (Figure 7). Of these, all ten studies were pooledand analyzed, with 538 participants in the KTBAM groupand 537 in the NSAID group. �e aggregated result in therandom-e¤ect model showed a signi�cant di¤erence(MD� − 3.78, 95% CI − 7.61 to 0.04, P � 0.05) betweenKTBAMs and NSAIDs on WOMAC scores with hetero-geneity (I2� 97%). �e subgroup analyses based on treat-ment durations of 2 weeks, 4 weeks, and 6 weeks wereconsistent with the pooled result (2 weeks: MD� 0.31, 95%CI − 0.90 to 1.52, P � 0.62; 4 weeks: MD� − 2.31, 95% CI− 8.28 to 3.66, P � 0.45; 6 weeks: MD� 0.77, 95% CI − 2.46 to4.00, P � 0.64). For comparison, the 8-week duration oftreatment included only two studies [42, 54] and showed afavor toward NSAIDs (MD� − 10.13, 95% CI − 15.34 to− 4.91, P � 0.0001). Two studies used diclofenac [53, 54] as acomparison, one study used meloxicam [30], and theremaining used celecoxib [26, 34, 39, 40, 42, 56, 57]. In thesubgroup analysis based on type of NSAID, the meta-analysis results for these groups were consistent with theoverall meta-analysis results and suggested a high level ofheterogeneity.

3.3.5. Lequence Scores. Lequence scores were reported by eightstudies [19, 35, 41, 43, 44, 48, 56, 61] (Figure 8) as an outcome toassess the e£cacy of treatment. �e pooled results of the meta-analysis suggested no preference for KTBAMs or NSAIDs(n� 798; MD� − 0.29, 95% CI − 1.05 to 0.46, P � 0.44,I2� 85%). A subgroup analysis was performed based on treat-ment duration, and the result for this group (4 weeks) (7 studies;n� 698, MD� − 0.07, 95% CI − 0.80 to 0.65, I2� 79%, P � 0.84)was consistent with the pooled e¤ect. For the eight-week group,NSAIDs were more e¤ective than KTBAMs (1 study; n� 100,MD� − 1.65, 95% CI − 2.33 to − 0.97, P< 0.00001).

3.3.6. KSS Scores. Five studies [27, 37, 43, 48, 60] reportedKnee Society Scale (KSS) scores (Figure 9), with 316 par-ticipants in the KTBAM group and 314 participants in theNSAID group. �e mean di¤erence in KSS scores showed asigni�cant di¤erence between the KTBAM group and theNSAID group (MD� 7.17, 95% CI 0.71 to 13.64, P � 0.03)with high heterogeneity (I2� 94%), consistent with thesubgroup analysis of 8 weeks and 12 weeks. However, theKTBAM group showed no signi�cant di¤erence in im-proving KSS scores after 4 weeks (MD� 5.80, 95% CI − 5.88

Summary of findings:

Kidney-tonifying and blood-activating medicinal herbs compared to NSAIDs for knee osteoarthritis

Patient or population: knee osteoarthritisSetting:Intervention: kidney tonifying and blood-activating medicinal (KTBAM)Comparison: NSAIDs

Outcomes

Anticipated absolute effects∗(95% CI)Relative effect

(95% CI)No. of participants

(studies)

Certainty ofthe evidence

(GRADE)Comments

Risk with NSAIDsRisk with kidney-

tonifying and blood-activating medicinal

Total effective rate (TER) 842 per 1,000 868 per 1,000(859 to 868)

RR 1.03(1.02 to 1.03)

2812(27 RCTs) Very lowa,b,c

Adverse effects (AE) 106 per 1,000 38 per 1,000(26 to 56)

RR 0.36(0.24 to 0.53)

1609(17 RCTs) Moderatea,b

VAS scores (VAS) The mean VAS scorewas 0

MD 0.41 lower(0.89 lower to 0.06

higher)- 1356

(12 RCTs) Lowa,b,d

WOMAC scores (WOMAC) The mean WOMACscore was 0

MD 3.78 lower(7.61 lower to 0.04

higher)- 1075

(10 RCTs) Lowa,b,d

Lequence scores (Lequence) The mean Lequencescore was 0

MD 0.29 lower(1.05 lower to 0.46

higher)- 798

(8 RCTs) Lowa,b,d

KSS scores (KSS) The mean KSS scorewas 0

MD 7.17 higher(0.71 higher to 13.64

higher)- 630

(5 RCTs) Moderatea,b,d

∗The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; RR: risk ratio; MD: mean difference

GRADE Working Group grades of evidenceHigh certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

aRandom sequence generation, allocation concealment, blinding of participants and investigators, and incomplete outcome dataExplanations

bDifferent interventionscThe funnel plot is not asymmetricdGreater heterogeneity (P > 50%)

Figure 3: Grade of evidence evaluation based on GRADE Working Group.

10 Evidence-Based Complementary and Alternative Medicine

to 17.48, P � 0.33). Considering the variety of NSAIDs andthe similar mechanisms of action of the different drugs, nosubgroup of NSAID type could be conducted.

3.4. Publication Bias. Funnel plots were performed for thecomparison of KTBAMs and NSAIDs in total effective rate.'e results suggested that there was potential bias in the

Risk ratioM-H, random, 95% CI

Risk ratioM-H, random, 95% CI

0.5 0.7 1 1.5 2NSAIDS KTBAM

Test for subgroup differences: chi2= 6.33, df = 5 (P = 0.28); I 2 = 21.0%

Study or subgroupExperimental

Events TotalControl

Events Total

1.1.1. 2 weeks

Heterogeneity: not applicable Test for overall effect: Z = 0.42 (P = 0.67)

Total events 73 71

Guo YJ, 2010 0.98 [0.88, 1.08]73 82 71 78 4.6Subtotal (95% CI) 0.98 [0.88, 1.08]82 78 4.6

Heterogeneity: tau2 = 0.01; chi2 = 54.49, df = 14 (P < 0.00001 ); I 2 = 74%Test for overall effect: Z = 2.12 (P = 0.03)

1.1.2. 4 weeks

Total events 769 673

Chen N, 2017 1.00 [0.90, 1.12]42 45 42 45 4.4Li M, 2007 1.04 [0.92, 1.17]55 60 53 60 4.2Li MX, 2017 1.04 [0.92, 1.16]29 30 28 30 4.2Li YM, 2005 1.08 [0.86, 1.36]26 30 24 30 2.2Li YP, 2015 1.29 [1.04, 1.60]41 45 29 41 2.4Lu M, 2012 1.11 [1.03, 1.19]115 118 102 116 5.3Pan JK, 2017 1.03 [0.90, 1.18]37 40 36 40 3.8Su ZF, 2016 0.93 [0.78, 1.11]26 30 27 29 3.1Sun SL, 2012 0.86 [0.68, 1.10]19 24 22 24 2.1Yang B, 2009 1.04 [0.86, 1.25]27 30 26 30 2.9Ye JX, 2005 1.15 [1.01, 1.32]73 80 57 72 3.8Yu CG, 2009 1.88 [1.56, 2.28]98 100 52 100 2.8Zhang GL, 2016 1.02 [0.92, 1.14]42 44 41 44 4.6Zhang XL, 2016 1.06 [0.90, 1.24]99 142 95 144 3.3Zheng T, 2019 1.03 [0.84, 1.26]40 50 39 50 2.6

Subtotal (95% CI) 1.08 [1.01, 1.16]868 855 51.4

1.1.3. 5 weeks

Heterogeneity: not applicable Test for overall effect: Z = 1.80 (P = 0.07)

Total events 29 20

Huang BQ, 2009 1.27 [0.98, 1.64]29 32 20 28 1.9Subtotal (95% CI) 1.27 [0.98, 1.64]32 28 1.9

1.1.4. 6 weeks

Heterogeneity: not applicable Test for overall effect: Z = 1.33 (P = 0.19)

Total events 66 61

Xing QJ, 2018 1.07 [0.97, 1.17]66 69 61 68 4.8Subtotal (95% CI) 1.07 [0.97, 1.17]69 68 4.8

1.1.5. 8 weeks

Heterogeneity: tau2 = 0.00; chi2 = 6.89, df = 5 (P = 0.23); I 2 = 27%Test for overall effect: Z = 3.54 (P = 0.0004)

Total events 371 330

Bo Y, 2016 1.10 [0.87, 1.38]33 40 30 40 2.2Fan XH, 2012 1.08 [0.97, 1.20]71 76 66 76 4.5Li ZW, 2010 1.29 [1.10, 1.51]48 48 37 48 3.3Sun Y, 2014 1.20 [1.04, 1.37]49 50 41 50 3.8Zhang GL, 2016 1.06 [0.99, 1.14]129 136 125 140 5.4Zhou HJ, 2012 1.08 [0.94, 1.23]41 43 31 35 3.8

Subtotal (95% CI) 1.11 [1.05, 1.18]393 389 23.0

1.1.6. 12 weeks

Heterogeneity: tau2 = 0.01; chi2 = 10.77, df = 3 (P = 0.01); I 2 = 72%Test for overall effect: Z = 1.75 (P = 0.08)

Total events 170 151

Lv G, 2016 1.23 [1.04, 1.45]44 46 35 45 3.1Wang HD, 2017 1.47 [1.05, 2.05]22 24 15 24 1.3Wang Z, 2017 1.04 [0.97, 1.13]70 72 67 72 5.3Zhang JQ, 2014 1.03 [0.93, 1.13]34 35 34 36 4.7

Subtotal (95% Cl) 1.12 [0.99, 1.27]177 177 14.4

Heterogeneity: tau2 = 0.01; chi2 = 75.91, df = 27 (P < 0.00001 ); I 2 = 64%Test for overall effect: Z = 4.08 (P < 0.0001)

Total events 1478 1306 Total (95% CI) 1.09 [1.05, 1.14]1621 1595 100.0

Weight(%)

Figure 4: Forest plot of the effect of KTBAMs versus NSAIDs on the total effective rate.

Evidence-Based Complementary and Alternative Medicine 11

analysis, and either a publication bias or a low-quality small-sample test may have been the main reasons (Figure 10).

4. Discussion

Traditional Chinese medicine has been widely used inclinical practice in China as an alternative approach forKOA. Previous studies have demonstrated the efficacy ofherbal medicines, such as Duhuo Jisheng decoction (DJD)

[64, 65]. Based on traditional Chinese medicine theory,tonifying kidney and activating blood is one of the mostcommon approaches for KOA. DJD is a formula for thetreatment of arthralgia and functional disorders by tonifyingkidney and eliminating dampness. Our study compared theefficacy and safety of KTBAMs and NSAIDs for KOA from38 RCTs.

A previous study of a related topic had serious meth-odological flaws (such as lacking a protocol and containing a

Experimental Risk ratioM-H, fixed, 95% CI

4.1.1. 4 weeksChen N, 2017Li YM, 2005Li YP, 2015Lu M, 2012Pan JK, 2017Sun SL, 2012Teekachunhatean S, 2004Wang PM, 2005Xu WL, 2014Zheng T, 2019Zhu XY, 2014

Subtotal (95% CI)Total eventsHeterogeneity: chi2 = 18.31, df = 10 (P = 0.05); I2 = 45%Test for overall effect: Z = 3.66 (P = 0.0002)

4.1.2. 5 weeksHuang BQ, 2009

Subtotal (95% CI)Total eventsHeterogeneity: not applicableTest for overall effect: Z = 1.14 (P = 0.26)

4.1.3. 6 weeksXing QJ, 2018

Subtotal (95% CI)Total eventsHeterogeneity: not applicableTest for overall effect: Z = 0.56 (P = 0.58)

4.1.4. 8 weeksBo Y, 2016Sun Y, 2014

Subtotal (95% CI) 90Total eventsHeterogeneity: chi2 = 0.29, df = 1 (P = 0.59); I2 = 0%Test for overall effect: Z = 2.74 (P = 0.006)

4.1.5. 12 weeksLv G, 2016Zhang JQ, 2014

Subtotal (95% CI)Total eventsHeterogeneity: chi2 = 0.25, df = 1 (P = 0.62); I2 = 0%Test for over all effect: Z = 2.40 (P = 0.02)

Total (95% CI)

Risk ratioM-H, fixed, 95% CI

0.32 [0.03, 2.94]0.14 [0.01, 2.65]0.30 [0.09, 1.05]0.09 [0.01, 1.63]1.33 [0.32, 5.58]0.20 [0.01, 3.96]2.20 [0.79, 6.10]0.17 [0.04, 0.65]0.20 [0.01, 4.00]0.14 [0.02, 1.12]0.14 [0.01, 2.67]0.43 [0.27, 0.67]

0.18 [0.01, 3.51]0.18 [0.01, 3.51]

1.97 [0.18, 21.23]1.97 [0.18, 21.23]

0.13 [0.02, 0.95]0.25 [0.06, 1.12]0.19 [0.06, 0.62]

0.12 [0.02, 0.94]0.26 [0.03, 2.19]0.17 [0.04, 0.72]

0.36 [0.24, 0.53]

0.002 0.1 1 10 500KTBAM NSAIDs

Total eventsHeterogeneity: chi2 = 23.98, df = 16 (P = 0.09); I2 = 33%Test for overall effect: Z = 5.15 (P < 0.00001)Test for subgroup differences: chi2 = 4.90, df = 4 (P = 0.30); I2 = 18.4%

Study or subgroup

103040

112010

22

0

0

2

2

12

3

2

29

Events

443045

1204024

10020305035

538

3232

6969

1

1

4050

4635

11

81

810

TotalControl

54

3395325

12273

2

2

88

16

84

12

85

Events

423041

1204024

10020305035

532

2828

6868

405090

453681

799

Total

3.53.9

10.66.23.42.85.6

13.52.87.93.9

64.3

3.03.0

1.11.1

9.09.0

18.0

9.14.4

13.6

100.0

Weight(%)

Figure 5: Forest plot of the safety of KTBAMs versus NSAIDs based on adverse events (AEs).

12 Evidence-Based Complementary and Alternative Medicine

noncomprehensive literature search) that existed in anotherpreviously published review [66], but the �ndings wereconsistent with the results of our study. However, we in-cluded 16 additional studies, including one conducted in�ailand, compared with the reviews that included onlystudies in mainland China.We did not evaluate the clinicallycontrolled rate in our research because its de�nitions variedacross studies making it di£cult to obtain an objective result.Additionally, we assumed that the dosage and frequency oforal NSAIDs play a signi�cant role in functional im-provement and pain control, although no signi�cant dif-ferences were found based on limited data. Overall, weprovided a more reliable result in this review.

�e meta-analysis indicated that KTBAMs were e¤ectivefor KOA as follows: (1) 4 weeks of treatment and 8 weeks oftreatment with KTBAMs had a higher total e¤ective ratethan NSAIDs with the very low-quality evidence; (2) themoderate-quality evidence showed that the adverse re-actions from the KTBAMs were lower and the KSS scores

were higher; and (3) KTBAMs were neither superior norinferior to NSAIDs with regards to the VAS scores,WOMAC scores, and Lequence scores based on low-qualityevidence. �e results of the meta-analysis were inconsistent.Previous research with DJD showed that it can be mainlyused to treat arthralgia syndrome, with the e¤ects ofeliminating stagnation, removing blood stasis, nourishingthe liver and kidney, and invigorating the Qi and blood [19].As one of the decoctions of KTBAMs, DJD can improvephysical function and decrease the pain associated with KOAwhen combined with conventional Western medicine orother therapies [67]. One reasonmay be that KTBAMs couldproduce add-on e¤ects when combined with other therapies.Another reason was the complex combinations of herbs andvariations in the dosage forms. Lacking detailed informationabout the severity of KOA in most studies could have af-fected the results. �e long-term e¤ects of KTBAMs couldnot be evaluated because of the lack of rigorous reporting offollow-up assessments. Di¤erent dosages of Chinese

ExperimentalSD Total MeanMean

Study or subgroupSD Total

Weight(%) IV, random, 95% CI

Control IV, random, 95% CI

Mean difference Mean difference

2.03 0.87 105 4.13 0.95 105 7.4%2.35 0.62 40 2.4 0.55 40 7.4%1.79 0.96 30 1.56 0.77 29 7.1%

3.1.1. 4 weeksNiu QW, 2016Pan JK, 2017Su ZF, 2016Wang PM, 2005 5.4 20 4.9 0.9 20 6.8%

3.74 0.95 35 4.34 0.94 35 7.1%3.63 0.61 25 2.83 0.59 25 7.3%

Yuan JJ, 2017Zhao L, 2008Zheng T, 2019 3.25 0.84 50 3.44 0.97 50 7.3%

Subtotal (95% Cl) 305 304 50.4%

–2.10 [–2.35, –1.85]–0.05 [–0.31, 0.21]0.23 [–0.21, 0.67]0.50 [–0.09, 1.09]

–0.60 [–1.04, –0.16]0.80 [0.47, 1.13]

–0.19 [–0.55, 0.17]–0.21[–1.07, 0.65]

Heterogeneity: tau2 = 1.30; chi2 = 256.99, df = 6 (P < 0.00001); I2 = 98%Test for overall effect: Z = 0.48 (P = 0.63)

3.1.2. 5 weeks Zhang GL, 2016 4.18 0.41 44 5.41 0.41 44 7.5% –1.23 [–1.40, –1.06]

Subtotal (95% Cl) 44 44 7.5% –1.23 [–1.40, –1.06]Heterogeneity: not applicableTest for overall effect: Z = 14.07 (P < 0.00001)

3.1.3. 6 weeks Wang Z, 2017 3.63 1.52 72 3.89 1.53 72 7.0% –0.26 [–0.76, 0.24]

72 72 7.0% –0.26 [–0.76, 0.24]Subtotal (95% Cl)Heterogeneity: not applicableTest for overall effect: Z = 1.02 (P = 0.31)

3.1.4. 8 weeks Fan XH, 2012 2.8 0.9 76 2.7 0.7 7.4% 0.10 [–0.16, 0.36]

1.7 1.1 43 2.3 1.5 6.8%Zhou HJ, 2012 Subtotal (95% Cl) 119

7635

111 14.2%–0.60 [–1.20, –0.00]–0.20 [–0.87, 0.48]

Heterogeneity: tau2 = 0.19; chi2 = 4.47, df = 1 (P = 0.03); I2 = 78%Test for overall effect: Z = 0.57 (P = 0.57)

3.1.5. 12 weeks 72Wang Z, 2017 1.17 1.1 1.75 1.5 72 7.1%

Yuan JJ, 2017 1.94 0.97 35 3.11 1.16 35 7.0%Zhang JQ, 2014 1.17 1.1 35 1.75 1.5 36 6.7%

Subtotal (95% Cl) 142 143 20.9%

–0.58 [–1.01, –0.15]–1.17 [–1.67, –0.67]–0.58 [–1.19, 0.03]–0.78 [–1.17, –0.39]

Heterogeneity: tau2 = 0.05; chi2 = 3.57, df = 2 (P = 0.17); I2 = 44%Test for overall effect: Z = 3.90 (P < 0.0001)

Total (95% Cl) 674682 100.0% –0.41 [–0.89, 0.06]

–2 2–1 0 1KTBAM NSAIDs

Heterogeneity: tau2 = 0.77; chi2 = 346.69, df = 13 (P < 0.00001); I2 = 96% Test for overall effect: Z = 1.71 (P = 0.09) Test for subgroup differences: chi2 = 25.26, df = 4 (P < 0.0001); I2 = 84.2%

Figure 6: Forest plot of the e¤ect of KTBAMs versus NSAIDs on VAS scores.

Evidence-Based Complementary and Alternative Medicine 13

medicine and varied components of the prescriptions, in-cluding the use of other types of herbs, may have been apotential bias that in©uenced our results.

In our research, changes in some measures between thetwo groups were signi�cantly di¤erent after 8 weeks oftreatment, but no di¤erences were observed before 8 weeks.

10.410.4

0.31 [–0.90, 1.52]0.31 [–0.90, 1.52]

6.1.1. 2 weeksChen N, 2017

Subtotal (95% CI)Heterogeneity: not applicableTest for overall effect: Z = 0.50 (P = 0.62)

10.4 -0.58 [–1.60, 0.44]10.1 –15.20 [–17.34, –13.06]5.78.0

6.1.2. 4 weeksChen N, 2017Lu M, 2012Su ZF, 2016Wang PM, 2005Xu WL, 2014 10.0

2.37 [–8.55, 13.29]2.45 [–4.20, 9.10]0.26 [–2.17, 2.69]

9.8 –0.58 [–3.57, 2.41]Zheng T, 2019Subtotal (95% CI) 54.0Heterogeneity: tau2 = 49.32; chi2 = 158.83, df = 5 (P < 0.00001); I2 = 97%Test for overall effect: Z = 0.76 (P = 0.45)

9.79.7

0.77 [–2.46, 4.00]0.77 (–2.46, 4.00]

6.1.3. 6 weeksXu YS, 2013

Subtotal (95% CI)

Heterogeneity: not applicableTest for overall effect: Z = 0.47 (P = 0.64)

6.1.4. 8 weeksBo Y, 2016 5.7Fan XH, 2012 10.0

–8.88 [–19.62, 1.86]–7.20 [–9.85, –4.55]

Li ZW, 2010 –13.40 [–15.53, –11.27]Subtotal (95% CI) 25.9Heterogeneity: tau2 = 15.28; chi2 = 12.91, df = 2 (P = 0.002); I2 = 85%Test for overall effect: Z = 3.81 (P = 0.0001)

Total (95% CI) 100.0 –3.78 [–7.61, 0.04]

–20 20–10NSAIDs

Heterogeneity: tau2 = 36.36; chi2 = 296.31, df = 10 (P < 0.00001 ); I2 = 97%Test for overall effect: Z = 1.94 (P = 0.05)Test for subgroup differences: chi2= 15.43, df = 3 (P = 0.001 ); I2 = 80.6%

Study or subgroup Experimental Control Mean differnceIV, random, 95% CITotal

Weight(%)

Mean differnceIV, random, 95% CI

26.78

22.5816.3 34.4734.5513.02 17.69

68.5120.6 26.3

Mean

16.43

10.1–10.13 [–15.34, –4.91]

537

45

4512029203050

294

3434

7648

40

164

45

–2.31 [–8.28, 3.66]

4545

12030203050

295

3434

4076

164

538

Total

48

457.6

4.75

22.237.4 4.9

SD

6.16

2.9

2.54

23.71 11.61

7.43

26.47

23.16

32.132.1

12.76

15.66

77.3927.839.7

Mean

18.27

31.5

2.96

9.2

9.77

7.37

26.69.25.7

SD

7.824.87

2.41

18.89

0 10KTBAM

Figure 7: Forest plot of the e¤ect of KTBAMs versus NSAIDs on WOMAC scores.

7.1.1. 4 weeks Chen N, 2017 Ji MH, 2010 Pan JK, 2017 Sun SL, 2012 Teekachunhatean S, 2004Wu JX, 2009 Yu CG, 2009

Subtotal (95% CI) Heterogeneity: tau2 = 0.66; chi2= 28.53, df = 6 (P < 0.0001 ); I2 = 79% Test for overall effect: Z = 0.20 (P = 0.84)

7.1.2. 8 weeks Sun Y, 2014

Subtotal (95% CI) Heterogeneity: not applicable Test for overall effect: Z = 4.76 (P < 0.00001)

Total (95% CI)

0 2 4NSAIDs KTBAM

Heterogeneity: tau2 = 0.90; chi2 = 45.88, df = 7 (P < 0.00001 ); I2 = 85% Test for overall effect: Z = 0.76 (P = 0.44) Test for subgroup differences: chi2 = 9.71, df = 1 (P = 0.002); I2 = 89.7%

Study or subgroup Experimental

7.135.3

7.438.338.925.313.75

6.82

Mean

1.52.791.011.24.62.8

4.01

1.64

SD

6.624.397.9

7.958.644.396.18

8.47

Mean

1.373.421.151.023.833.043.92

1.82

SD

45204024

10021

100350

5050

400

TotalControl Mean differnce

45204024

10019

100348

5050

398

Total

14.97.9

15.514.811.88.4

12.285.5

14.514.5

100.0

Weight(%)

0.51 [–0.08, 1.10]0.91 [–1.02, 2.84]

–0.47 [–0.94, 0.00]0.38 [–0.25, 1.01]0.28 [–0.89, 1.45]0.92 [–0.90, 2.74]

–2.43 [–3.53, –1.33]–0.07 [–0.80, 0.65]

–1.65 [–2.33, –0.97]–1.65 [–2.33, –0.97]

–0.29 [–1.05, 0.46]

Mean differnceIV, random, 95% CI IV, random, 95% CI

–2–4

Figure 8: Forest plot of the e¤ect of KTBAMs versus NSAIDs on Lequence scores.

14 Evidence-Based Complementary and Alternative Medicine

�erefore, we supposed that the e£cacy of NSAIDs wassigni�cantly more stable and reliable than that of KTBAMs(with respect to WOMAC scores, Lequence functional indexscores, and KSS scores). �e reason why NSAIDs were morereliable may be due to the possibility that KTBAMs mayexert their e¤ects via several probable mechanisms from thepharmacodynamic point of view [19], and these mechanismsmight have in©uenced drug concentrations and the sub-sequent drug e¤ects. As an ancient traditional treatment,KTBAM therapy has developed over thousands of years inChina. In the earliest published Chinese medical work,“Inner Classic of the Yellow Emperor” (475 B.C.–221 B.C.),KTBAM therapy was frequently reported as having

bene�cial outcomes. Despite the lack of knowledge about thebiological mechanisms by which Chinese herbal therapyworks for knee osteoarthritis, the multitarget therapeutice¤ect of traditional Chinese medicine has been recognizedby many researchers. Some animal experimental studieshave indicated that Chinese herbs decreased the levels ofnitric oxide in the serum, synovium, and joint cartilage inosteoarthritic rabbits [68]. Another study showed that Du-Huo-Ji-Sheng decoction (a KTBAM compound) exertedsigni�cant therapeutic e¤ects in osteoarthritic rabbits,probably through inhibiting the expression of VEGF andhypoxia-inducible factor-1α [15]. Yaotongning capsules (aKTBAM compound) promoted proliferation and glycos-aminoglycan synthesis in IL-1β-induced chondrocytes andmay have potential activity in treating chondrocyte de-generation caused by osteoarthritis [69, 70]. A study hasfound that kidney-tonifying and blood-activating Chineseherbs may suppress the expression of interferon regulatoryfactor 7 (IRF-7) by regulating the TLR4/MyD88 signalingpathway, resulting in less secretion of interleukin 6 (IL-6)and matrix metallopeptidase 13 (MMP-13), which alleviatesin©ammation and delays cartilage destruction [71]. Anotherstudy reported the e¤ects of low, medium, and high doses ofBushen Huoxue recipe on knee arthritis in rats. It had beenfound that the pathological changes of knee arthritis in thelow-, medium-, and high-dosage groups were graduallyalleviated, although the detailed mechanism of action wasunknown [72].

KTBAMs had fewer AEs than NSAIDs. �e mostcommon AEs were gastrointestinal symptoms, which weresimilar in the two groups and required no medical in-tervention. NSAIDs are among the most widely prescribeddrugs. Debilitating diseases such as rheumatoid arthritis andosteoarthritis are commonly managed by NSAIDs.

8.1.1. 4 weeksJi MH, 2010Niu QW, 2016Wu JX, 2009Yuan JJ, 2017

Subtotal (95% CI)Heterogeneity: tau2 = 123.23; chi2 = 63.23, df = 3 (P < 0.00001 ); I2 = 95%Test for overall effect: Z = 0.97 (P = 0.33)

8.1.2. 8 weeksYang HR, 2014

Subtotal (95% CI)Heterogeneity: Not applicableTest for overall effect: Z = 6.69 (P < 0.00001)

8.1.3. 12 weeksYuan JJ, 2017

Subtotal (95% CI)Heterogeneity: not applicableTest for overall effect: Z = 3.82 (P = 0.0001)

Total (95% CI) 314

–20 20–10 0 10NSAIDs KTBAM

Heterogeneity: tau2 = 53.76; chi2 = 82.02, df = 5 (P < 0.00001 ); I2 = 94%Test for overall effect: Z = 2.18 (P = 0.03)Test for subgroup differences: chi2 = 1.35, df = 2 (P = 0.51; I2 = 0%

Study or subgroup

172.987.55172.966.92

152.85

82.2

19.8513.2719.845.82

5.01

6.04

201052135

181

100100

3535

316

177.0566.44

177.0561.11

146.6

72.97

20.178.87

20.187.01

7.13

13.37

201051935

179

100100

3535

11.619.311.619.461.9

19.919.9

18.218.2

100.0

–4.15 [–16.55, 8.25]21.11 [18.06, 24.16]–4.15 [–16.57, 8.27]

5.81 [2.79, 8.83]5.80 [–5.88, 17.48]

6.25 [4.42, 8.08]6.25 [4.42, 8.08]

9.23 [4.50, 13.96]9.23 [4.50, 13.96]

7.17 [0.71, 13.64]

ExperimentalMean SD Total Mean SD Total

Control Mean differnceWeight(%)

Mean differnceIV, random, 95% CI IV, random, 95% CI

Figure 9: Forest plot of the e¤ect of KTBAMs versus NSAIDs on KSS scores.

SE (l

og[R

R])

0

0.05

0.1

0.15

0.20.7 0.85 1 1.2 1.5

RR

Subgroups2 weeks4 weeks6 weeks

8 weeks12 weeks

Figure 10: Funnel plot of the total e¤ective rate comparison be-tween KTBAMs and NSAIDs.

Evidence-Based Complementary and Alternative Medicine 15

However, the pharmacological mechanism of NSAIDs isoften associated with the presence of gastrointestinal sideeffects [73, 74]. NSAIDs are recognized as the most commondrugs involved in hypersensitivity drug reactions [75–78].Until recently, antibiotics, particularly betalactams, wereconsidered the most important inducers of this hypersen-sitivity [79–81], but NSAIDs are now the leading contributor[77]. However, the present study found that KTBAMs had alower incidence of adverse reactions thanNSAIDs. KTBAMsare mostly natural botanical drugs. Compared with someAristolochiaceae plants, KTBAMs have less toxic side effects.From the point of view of recognizing and treating diseasesin traditional Chinese medicine, the Yin and Yang in har-monious balance indicate health, whereas imbalances toeither side indicate unhealthiness, which may result indiseases. CHM is a form of natural plant medicine thatmainly treats diseases by adjusting the balance of Yin andYang and has fewer adverse reactions than Western med-ications [82]. 'is suggests that KTBAMs are safe for themanagement of KOA. However, whether other potentialAEs would occur with longer follow-ups was not clear.

'e strengths of this review are as follows. First, this isthe only study that included patients from different coun-tries in the evaluation of the efficacy and safety of a particulartype of CHM for KOA based on the theory of traditionalChinese medicine. Second, this study included 38 studiesRCTs with 3994 participants, and subgroup analyses wereperformed for the different treatment durations and types ofNSAIDs, therefore obtaining detailed results. Finally, anintention-to-treat approach was adopted in this meta-analysis to address dropouts; this makes the efficacy resultsmore conservative.

Based on our study, KTBAMs may be an effective andsafe alternative treatment in people with KOA when com-pared with NSAIDs. Additionally, we recommend thatKTBAMs be used for less than 8 weeks. However, the qualityof the trials included in our research was low; therefore, nofirm conclusions could be drawn. Furthermore, the variedcomposition of the KTBAMs in the formula in these trialsand whether these differences play an important role in theefficacy of KTBAMs should be considered. Moreover, moststudies did not report the severity of KOA. It is difficult tomake a definite conclusion regarding on which patients,based on the level of KOA severity, these findings apply.

Future research should consider including a placebocontrol, using uniform diagnostic criteria, and using out-come measures according to international guidelines. Moretrials with well-designed and unified outcome measure-ments following the Cochrane Handbook should be con-ducted. Baseline disease severity and AEs should be reportedin more detail, and follow-up periods should be used toconfirm the long-term effects.

5. Limitations

Some limitations of our review downgraded the certainty ofthese results. First, these RCTs were found mostly in theChinese literature, with the exception of one in 'ailand,and the results were based on evidence with a high risk of

bias and low quality; in accordance with the GRADE ap-proach, the overall quality of evidence was limited (rangingfrom “moderate” to “very low”) due to some serious or veryserious limitations. Second, although the outcome measuresused in most of these studies are consistent with in-ternational guidelines, some of the included studies did notformally report these measures, and the outcome mea-surements were varied, which led to difficulty in the in-terpretation of the trials’ results.'ird, results for the efficacyand safety of KTBAMs versus placebo were not availablefrom this review because only one of the included studiesused a placebo control; therefore, placebo effects were notcompletely eliminated. Fourth, the long-term effects ofKTBAMs remain uncertain because of the lack of outcomemeasures used in the follow-up phase. Finally, the hetero-geneity across studies was high, mainly owing to themethodological flaws and the use of different medications.

6. Conclusion

KTBAMs appear to be as effective as NSAIDs and seem tohave an add-on effect to NSAIDs for the treatment of KOA.Additionally, KTBAMs appeared safe for KOA patientsbecause of the lower rate of occurrence of AEs than NSAIDs,but NSAIDs appeared to have a more reliable effect thanKTBAMs after 8 weeks of treatment. However, the meth-odological limitations reduced the confidence in the effectestimates in this research. More high-quality RCTs withunified measurements and guidelines are needed in thefuture to precisely assess the effectiveness and safety ofKTBAMs.

Conflicts of Interest

'e authors declare that there are no conflicts of interestregarding the publication of this paper.

Authors’ Contributions

HTH and JL contributed to the conception and design of thestudy. JKP, WYY, YHH, HDL, MHL, and LFZ contributedto the analysis and interpretation of data. HTH and GHLparticipated in the quality assessment. HTH and YHHcontributed to the drafting of the article. All authors readand approved the final manuscript.

Acknowledgments

'e authors would like to thank Li Y and Chen Y from theChinese Cochrane Centre for courses on evidence-basedclinic and improving search strategies. 'is study wassupported by grants from National Natural Science Foun-dation of China (No. 81873314, No. 81974574), the ChinaPostdoctoral Science Foundation (No. 2018M633036), theMedical Science Research Foundation of GuangdongProvince (No. B2019091), the Project of Guangdong Pro-vincial Department of Finance (No. [2014]157, No. [2018]8),Key Scientific Research Platforms and Research Projects ofUniversities in Guangdong Province (No. 2018KQNCX041),and the Science and Technology Research Project of

16 Evidence-Based Complementary and Alternative Medicine

Guangdong Provincial Hospital of Chinese Medicine (No.YN2019ML08, YK2013B2N19, and YN2015MS15).

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