BMJ Open. Complementary medicine. COMPLEMENTARY MEDICINE, Herbal medicine < THERAPEUTICS, RHEUMATOLOGY

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1 The Evidence of Chinese herbal medicine Duhuo Jisheng Decoction for knee osteoarthritis: a systematic review of randomised clinical trials Journal: Manuscript ID: bmjopen-0-00 Article Type: Research Date Submitted by the Author: 0-Jun-0 Complete List of Authors: Zhang, Wenming; Fujian University of Traditional Chinese Medicine, Academy of Integrative Medicine Wang, Shangquan; Wangjing Hospital, China Academy of Chinese Medical Sciences, Department of General Orthopedics Zhang, Ranxing; Wangjing Hospital, China Academy of Chinese Medical Sciences, Clinical laboratory Zhang, Yuanyuan; Fujian University of Traditional Chinese Medicine, Academy of Integrative Medicine Li, Xinjian; Fujian University of Traditional Chinese Medicine, Academy of Integrative Medicine Lin, Yanping; Fujian University of Traditional Chinese Medicine, Academy of Integrative Medicine wei, xu; Wangjing Hospital, China Academy of Chinese Medical Sciences, Scientific Research <b>primary Subject Heading</b>: Complementary medicine Secondary Subject Heading: Complementary medicine, Evidence based practice Keywords: COMPLEMENTARY MEDICINE, Herbal medicine < THERAPEUTICS, RHEUMATOLOGY : first published as 0./bmjopen-0-00 on January 0. Downloaded from on February 0 by guest. Protected by copyright.

2 Page of Research The Evidence of Chinese herbal medicine Duhuo Jisheng Decoction for knee osteoarthritis: a systematic review of randomised clinical trials Wenming Zhang, Shangquan Wang, Ranxing Zhang, Yuanyuan Zhang, Xinjian Li, Yanping Lin, Xu Wei Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, No. Qiuyang Road, Minhou Shangjie, Fuzhou, Fujian 00, P. R. China Department of General Orthopedics, Wangjing Hospital, China Academy of Chinese Medical Sciences, Huajiadi Street, Chaoyang District, Beijing 000, P. R. China Clinical laboratory, Wangjing Hospital, China Academy of Chinese Medical Sciences, Huajiadi Street, Chaoyang District, Beijing 000, P. R. China Department of Scientific Research, Wangjing Hospital, China Academy of Chinese Medical Sciences, Huajiadi Street, Chaoyang District, Beijing 000, P. R. China Correspondence to Dr Yanping Lin; lyp@.com; Dr Xu Wei; weixu.00@.com ABSTRACT Objectives: Duhuo Jisheng decoction (DJD) was considered beneficial for knee osteoarthritis (KOA) related symptoms control in some Asia countries. This review was to assess the evidence from randomised clinical trials and quantify the effects of DJD on KOA. Designs: Seven electronic databases were searched up to April, 0. Randomised clinical trials investigating treatment of KOA in which DJD was used either as a monotherapy or in combination with conventional therapy versus no intervention, placebo or conventional therapy were enrolled. The risk of bias was evaluated using the Cochrane Collaboration tool. We estimated the mean difference (MD) or - : first published as 0./bmjopen-0-00 on January 0. Downloaded from on February 0 by guest. Protected by copyright.

3 Page of standardized mean difference (SMD) and % confidence interval according to inter-study heterogeneity. Results: Fifteen studies with 0 participants were identified. The quality of studies presented high risk of bias. Meta-analysis from studies demonstrated that DJD combined with conventional western medicine, such as glucosamine, diacerein, and meloxicam could be selected for improving physical function (MD:. [.,.]; I = %; P < ). The results from studies showed that DJD plus conventional therapy including diacerein or sodium hyaluronate injection was beneficial for relieving pain (SMD: 0. [0., 0.]; I = 0%; P < ). It was recommended that DJD should be practiced at least for weeks. The most common adverse effect was gastrointestinal symptoms including nausea and diarrhea in the limited trials. Conclusions: DJD combined with conventional western medicine or other therapy appears to have some benefits for KOA. However, the evidence on the effectiveness and the safety of DJD is insufficient because of the limited trials and low methodological quality. Therefore, practitioners should be cautious when applying DJD in the daily practice. Strengths and limitations of this study This study is the first systematic review to provide an objective assessment of DJD for the management of KOA by integrating different outcome measures from randomised controlled trials. The included trials were on the basis of evidence which has a high risk of bias and low quality. The effectiveness and safety of DJD and combination therapy for KOA is uncertain because of the limited number of included trials and methodological limitations. INTRODUCTION Knee osteoarthritis (KOA) is a major cause of pain and motor dysfunction, with an estimated prevalence between % and % in the general population throughout the world. Also, patients with KOA usually have poorer quality of life or activities of daily living compared with healthy people. Age, overweight, trauma to joint due to repetiting movements in particular squatting and kneeling, type diabetes are common risk factors of KOA. In some Asian countries, the increasingly epidemiological data have - : first published as 0./bmjopen-0-00 on January 0. Downloaded from on February 0 by guest. Protected by copyright.

4 Page of indicated that the high prevalence of KOA has constituted an important health topic with intense medical care expenditures, particularly for those over 0 years of age. - In light of this situation, how to effectively manage the degenerative joint disease of knee remains an extremely important issue till now. The main objectives in the management of KOA were to alleviate pain, educate the patients about their disease, restore function, slow down the progression of the disease, and maintain health-related quality of life. Based on existing treatment guidelines, the Osteoarthritis Research Society International (OARSI) set up a committee to complete systematic review of current evidence that eventually developed recommendations for the treatment of KOA. However, there was ongoing debate for treatment options in the daily practice. Glucosamine and viscosupplementation, for instance, the evidences were somewhat inconclusive due to lack of sufficient studies designing placebo as comparator, evaluation of hard outcome, long-term pharmacoeconomic and safety evaluation. In contrast, non-pharmacological treatments, such as exercise, self-management and education, stress reduction provided symptom relief with few side effects. 0 Besides that, alternative treatments such as herbal preparations, acupuncture, moxibustion, massage, and tai chi were being investigated for their efficacy in randomised controlled trials. Nowadays, many clinicians do not hesitate to recommend herbs, herbal products to their patients for the effective treatment of several chronic diseases. Recently, researchers have discovered that Chinese herbal medicine, - a kind of complementary and alternative therapy, may alleviate the symptoms of KOA. Duhuo Jisheng decoction (DJD), a Chinese herbal recipe consisting of fifteen commonly used herbs: Doubleteeth Pubesscent Angelica Root (Duhuo, Radix Angelicae Pubescentis), Chinese Taxillus Twig (Sangjisheng, Herba Taxilli), Largeleaf Gentian Root (Qinjiao, Radix Gentianae Macrophyllae), Divaricate Saposhnikovia Root (Fangfeng, Radix Saposhnikoviae), Manchurian Wild Ginger (Xinxi, Herba Asari), Szechwan Lovage Rhizome (Chuanxiong, Rhizoma Chuanxiong), Angelica Root (Danggui, Radix Angelicae Sinensis), Rehmannia (Dihuang, Radix Rehmanniae Glutinosae), White Peony Root (BaiShao, Radix Paeoniae Alba), Cinnamon Bark (Rougui, Cortex Cinnamomi), Sclerotium of Tuckahoe (Fuling, Poria), Eucommia Bark (Duzhong, Cortex Eucommiae), Achyranthes Root (Niuxi, Radix Achyranthis Bidentatae), Ginseng Root (Renshen, Panax Ginseng), Licorice root (Gancao, Radix Glycyrrhizae). DJD is documented in Bei Ji Qian Jin Yao Fang, a famous medical books as far back as the Tang Dynasty. 0 According to the theory of the traditional Chinese medicine (TCM), DJD can be mainly used to treat arthralgia syndrome, with the effects of eliminating stagnation and removing blood stasis, nourishing the liver and kidney, invigorating Qi and blood. With the development of modern biology techniques, - : first published as 0./bmjopen-0-00 on January 0. Downloaded from on February 0 by guest. Protected by copyright.

5 Page of researches on the mechanism of DJD showed that the decoction could promote chondrocyte proliferation and inhibit the apoptosis of sodium nitroprussiate-induced chondrocyte, the expression of vascular endothelial growth factor (VEGF) and hypoxia inducible factor-α (HIF-α). - In addition, the compounds in the DJD proved to be potential synergy and polypharmacology in the treatment of osteoarthritis through computational approaches. In recent years, a number of published clinical studies of DJD have reported the effectiveness ranging from case series and randomised controlled trials and showed that DJD could contribute to KOA-related symptoms control. -0 On the other side, the clinical safety of DJD has been described in some studies with small sample sizes or limited durations. Nevertheless, until now, few studies have systematically examined the effectiveness and safety of DJD treatment for KOA according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). So the aim of the present study is to evaluate the beneficial and harmful effects of DJD for KOA from randomised controlled trials. METHODS Database and Search Strategies Seven databases including PubMed ( 0), EMBASE (0 0), Cochrane Central Register of Controlled Trials (CENTRAL, 0), China National Knowledge Infrastructure (CNKI, 0), Chinese Scientific Journal Database (VIP, 0), Wanfang data ( 0), Chinese Biomedical Literature Database (CBM, 0) were electronically searched up to April, 0. The reference list of retrieved papers was also searched. The search terms were used individually or combined: Duhuo Jisheng, knee osteoarthritis, knee arthritis, osteoarthritis of knee joint, knee joint osseous arthritis, clinical trial and randomised controlled trial. To increase the search sensitivity, no date and language limits were included. No restrictions on population characteristics were imposed. Study selection Types of studies Randomised controlled trials on the use of DJD for the treatment of KOA were included. Quasi-randomised controlled trials were not enrolled. Multiple publications reporting the same groups of participants were - : first published as 0./bmjopen-0-00 on January 0. Downloaded from on February 0 by guest. Protected by copyright.

6 Page of excluded. Types of participants The diagnosis of study participants were in accordance with the recognized criteria of knee osteoarthritis, such as the guideline established by American College of Rheumatology in. Participants were excluded if they had rheumatoid arthritis, ankylosing arthritis, joint tuberculosis, purulent arthritis, allergic arthritis, Kashin-Beck disease, or Podagra. Types of interventions In the randomised controlled trials, the treatment group was oral Duhuo Jisheng decoction or pill, modified Duhuo Jisheng decoction used alone or combined with conventional treatments regardless of dose, preparation formulation and duration. According to the principle of the similarity of TCM formula, the key herbs in the modified Duhuo Jisheng decoction should include Doubleteeth Pubesscent Angelica Root (Duhuo, Radix Angelicae Pubescentis), Largeleaf Gentian Root (Qinjiao, Radix Gentianae Macrophyllae), Divaricate Saposhnikovia Root (Fangfeng, Radix Saposhnikoviae), Manchurian Wild Ginger (Xinxi, Herba Asari), Cinnamon Bark (Rougui, Cortex Cinnamomi). Types of controls The control group was no treatment, placebo, or conventional therapies. Conventional treatments were used based on the guideline issued by the Osteoarthritis Research Society International (OARSI). Types of outcomes The primary outcome was measured by VAS scores (visual analogue scale), total WOMAC scores (Western Ontario and MacMaster universities arthritis index), total Lequesne scores (Lequesne functional index), total Lysholm scores (Lysholm knee score scale) or analogous pain scales. The secondary outcome was adverse drug reaction (ADR) or adverse event. Two authors (Zhang YY and Li XJ) conducted the literature searching and study selection. Discrepancies regarding to whether to include or exclude a study were resolved by consensus with a third investigator (Lin YP). - : first published as 0./bmjopen-0-00 on January 0. Downloaded from on February 0 by guest. Protected by copyright.

7 Page of Data Extraction Data abstraction included the first author names, year of publication, sample size, diagnosis criteria, age and sex of the participants, details of the intervention and control, treatment duration, follow up, and outcome measurement for each study. Two authors (Wang SQ and Wei X) conducted data extraction independently according to predefined criteria. Methodological quality assessment Two authors (Zhang WM and Zhang RX) assessed the methodological quality of each trial independently according to the standards advised by the Cochrane handbook. Disagreement, if any, was resolved by discussion and reached consensus through a third party (Lin YP). The risk of bias was evaluated for each study by assessing the randomization process, the treatment allocation concealment, blinding of participants and personnel, blinding of outcome assessment, the completeness of the data, and the reporting of results and other bias. When inadequate information was presented in the trial and we were unable to explicitly judge "yes" or "no", the item was judged as "unclear". Across studies, the risk of bias was considered by using one of the three answers: high, low, unclear. Data Synthesis Data analysis was carried out with RevMan software (version.) provided by Cochrane Collaboration. Given the characteristics of extracted data in the review, continuous outcomes were expressed as mean difference (MD) with % confidence intervals (CI). For VAS scores, however, standardized mean difference (SMD) was used because the studies included in our meta-analysis assessed the outcome based on different scales (e.g., VAS 0-0 and VAS 0-00). Pooled-effect estimate were calculated using random-effect model if substantial heterogeneity existed (I > 0%), whereas the fixed-effect model was used to analyse data that were not significantly heterogeneous. Publication bias would be analyzed by funnel plot analysis if sufficient studies (n 0) were found. RESULTS Description of Included Trials Among identified studies and additional studies, studies were eligible for data extraction - : first published as 0./bmjopen-0-00 on January 0. Downloaded from on February 0 by guest. Protected by copyright.

8 Page of according to the inclusion and exclusion criteria. 0 - The flow diagram for screening the trials is described in figure. One study was conducted in Thailand, 0 the other studies in China. - Identification Screening Eligibility Included Study Characteristics Records identified through electronic search (n=) Records after duplicates removed (n=) Records screened (n=) Full-text articles assessed for eligibility (n=) Studies included in the systematic review (n=) Additional records through other sources (n=) Figure PRISMA 00 flow diagram. Records excluded (n=0) Full-text articles excluded, with reasons (n=) Not RCTs design (n=) Incorrect intervention (n=) Not recognized control (n=) inappropriate clinical outcome assessment (n=) No data for extraction (n=) Essential characteristics of the studies are described in table. All the studies including patients from the treatment group and controls were recruited into this systematic review. Four different diagnostic criteria of KOA were used in the included trials: trials used American college of rheumatology guidelines for the medical management of osteoarthritis (ACR criteria-), trial used 00 Chinese medical association guidelines for the diagnosis and treatment of osteoarthritis (CMA criteria-00), trial used American rheumatism association criteria for the classification and reporting of osteoarthritis (ARA criteria-), trial used 00 Chinese medical association guidelines for the diagnosis and treatment of osteoarthritis (CMA criteria-00), trial did not - : first published as 0./bmjopen-0-00 on January 0. Downloaded from on February 0 by guest. Protected by copyright.

9 Page of report the specific diagnostic criteria. The average age of patients enrolled in the review ranged from. to years, female participants accounting for up to.0%. All studies used Duhuo Jisheng decoction, except for one study which used Duhuo Jisheng wan (Duhuo Jisheng pill). 0 Among the included clinical trials, trials compared Duhuo Jisheng wan (DJW) or DJD alone with conventional western medicine including diclofenac, 0 glucosamine, meloxicam, 0 and celecoxib. Ten trials compared the combination of DJW or DJD and conventional treatments with conventional treatments, such as sodium hyaluronate, knee arthroscopic surgery and rehabilitation training, glucosamine, and diacerein, Meloxicam and glucosamine. 0 The total duration of treatment ranged from to weeks, and the follow up completed in trials ranging from weeks to months. Various outcomes were compared between the groups (table ). Risk of Bias in Included Trials Methodological quality of included studies is described in table. The risk of bias was unclear for one study 0 and high for studies. - Only one study used random number table, trials reported patients registration order as random method, other trials did not provide detailed information regarding random sequence generation. Concealment of allocation, blinding of participants and personnel, outcome assessment could be achievable in a randomised, double-blind, double-dummy, controlled trial. 0 However, the majority of trials did not report the concrete details about allocation concealment and blinding of outcome assessors. In this review, blinding of participants and personnel was still difficult. - Incomplete outcome data and other bias were low risk in studies Selective reporting could not be judged in all the studies because of the insufficient information provided. Outcome measurements In order to provide more accurate effectiveness of the treatments, we evaluate the effect according to various outcome scales and the type of interventions. A change in total Lequesne scores, total Lysholm scores, total WOMAC scores, and VAS scores was reported in the trials. Considering the different interventions, it could be divided into subgroups including DJD versus conventional western medicine, DJD plus conventional therapies versus conventional therapies. The summarized results of included trials are listed in table. - : first published as 0./bmjopen-0-00 on January 0. Downloaded from on February 0 by guest. Protected by copyright.

10 Page of Total Lequesne scores studies compared DJD (DJW) with conventional western medicine, diclofenac, 0 glucosamine, respectively. Random effect model was used in the analysis. The pooled effects from studies (n = 0 vs. ) showed statistical heterogeneity (I = %) and no significant difference between treatment and control group (MD:. [-.,.]; P = 0.0). Total Lysholm scores Among studies [0-,, -], studies compared DJD with comparators of meloxicam, 0 glucosamine, and celecoxib; studies assessed the effect of the combination of DJD with knee arthroscopic surgery and rehabilitation training, or Sodium hyaluronate injection. The pooled effects from studies (n = vs. ) identified no significant effect of DJD compared with conventional western medicine (MD:. [-0.,.]; P = 0.0) with high heterogeneity (I = %). Similarly, the pooled effects from studies (n = vs. ) showed no significant effect of DJD and conventional therapy (MD: -0. [-.,.]; P = 0.) with no heterogeneity (I = 0%). Total WOMAC scores All studies compared DJD plus conventional western medicine with conventional western medicine, including glucosamine, diacerein, meloxicam and glucosamine. 0 The result indicated a high heterogeneity among the studies (I = %). A meta-analysis (n = vs. ) of the trials identified a significant effect of DJD and conventional western medicine compared with conventional western medicine alone (MD:. [.,.]; P < ). VAS scores When it comes to VAS scores, studies evaluated the effects of DJD compared with conventional western medicine, including diclofenac, 0 meloxicam, 0 and glucosamine. Meta-analysis (n = vs. ) exhibited no significant improvement between the groups (SMD: 0. [-.,.]; P = 0.) with high heterogeneity (I = %). In addition, studies reported the combined effect of DJD and conventional therapy which covered sodium hyaluronate injection, diacerein. Meta-analysis (n = vs. ) demonstrated a significant improvement between the groups (SMD: 0. [0., 0.]; P < ) with no heterogeneity (I = 0%). - : first published as 0./bmjopen-0-00 on January 0. Downloaded from on February 0 by guest. Protected by copyright.

11 Page 0 of Adverse Effect 0 0 Adverse effect was reported in studies and was not mentioned in the other studies. Common adverse events occurring in the DJW were raised blood pressure (%), central nervous system symptoms including dizziness, somnolence and drowsiness (%), and gastrointestinal symptoms including nausea/vomiting, dyspepsia, diarrhea and constipation (%). 0 No adverse drug reaction (ADR) of DJD was found in the study by Yu et al. Another study reported the adverse effect of DJD alone and the incidence of nausea, loss of appetite, diarrhea was high (0%). But none of the adverse effects were serious in the DJD groups. The remaining studies observed adverse effect of DJD plus conventional therapy when compared with conventional therapy. Both two studies observed two cases of diarrhea and nausea, and one of the trials also reported one case of dizziness. Two participants experienced gastrointestinal symptoms and had to withdraw from the trial. Additionally, no significant abnormality was seen in the blood routine 0 examination, liver and renal function from the other studies. Funnel plot analysis According to the different intervention and outcome measurement, funnel plot analysis could not be completed because of the small number of included studies (less than 0) in the meta-analysis : first published as 0./bmjopen-0-00 on January 0. Downloaded from on February 0 by guest. Protected by copyright.

12 Page of Table Basic characteristics of the included studies First author (year) Teekachunhatean, 00 [0] Sample size (T/C) 00 (00/00) Yu, 00 [] (/) Cao, 0 [] 00 (0/0) Gu, 0 [0] 0 (0/0) Li, 0 [] (/) Yu, 0 [] (/) Diagnosis Population Duration of Treatment Comparison Follow up criteria characteristics treatment T: mean age (. years) ACR criteria- ACR criteria- ACR criteria- ACR criteria- ARA criteria- ACR criteria- M/F (/ cases) C: mean age (. years) M/F (/ cases) T: mean age ( years) M/F (/ cases) C: mean age ( years) M/F (/ cases) T: mean age (. years) M/F (/ cases) C: mean age (. years) M/F (/ cases) T: mean age (. years) M/F (/ cases) C: mean age (. years) M/F (/ cases) T: mean age (. years) M/F (/ cases) C: mean age (. years) M/F (/ cases) T: mean age (. years) M/F (/ cases) C: mean age (. years) Diclofenac DJW weeks None mg/time, PO, Tid DJD DJD+C DJD DJD DJD+C Glucosamine 0. g/time, PO, Tid Sodium hyaluronate ml/time, intra-articular injection Once per week Meloxicam. mg/time, Qd Glucosamine 0. g/time, PO, Bid M/F (0/ cases) - weeks weeks weeks None weeks None weeks None Outcome assessment Lequesne VAS AE Lequesne ADR VAS ADR Lysholm VAS Lysholm VAS ADR Glucosamine weeks weeks WOMAC pills/time, PO, Tid : first published as 0./bmjopen-0-00 on January 0. Downloaded from on February 0 by guest. Protected by copyright.

13 Page of Table (Continued) First author (year) Sample size (T/C) Zhang, 0 [] 0 (0/0) Diagnosis criteria ACR Population characteristics Treatment criteria- 0 Zheng, 0 [] 0 (0/0) NA 0 Zhong, 0 [] (/) Dong, 0 [] 0 (0/0) 0 Huang, 0 [] 0 (/) Jiang, 0 [] 0 (0/0) 0 CMA criteria-00 ACR criteria- ACR criteria- ACR criteria- on February 0 by guest. Protected by copyright. T: mean age ( years) M/F (/ cases) C: mean age ( years) M/F (/ cases) T: mean age (. years) M/F (/ cases) C: mean age (. years) M/F (/ cases) T: mean age (0 years) M/F (0/ cases) C: mean age ( years) M/F (/ cases) T: mean age (. years) M/F (/ cases) C: mean age (. years) M/F (/ cases) T: mean age (. years) M/F (/ cases) C: mean age (. years) M/F (/0 cases) T: mean age (. years) M/F (/ cases) C: mean age (. years) M/F (/ cases) DJD+C DJD DJD+C DJD+C DJD+C DJD+C Diacerein Comparison 0 mg/time, PO, Bid Celecoxib 0. g/time, PO, Qd Glucosamine pills/time, PO, Tid Knee arthroscopic surgery +Rehabilitation training Sodium hyaluronate 0 mg/time, intra-articular injection Once per week Meloxicam. mg/time, PO, Bid +Glucosamine 0. g/time, PO, Bid - Duration of treatment Follow up weeks None Outcome assessment WOMAC VAS ADR weeks None Lysholm weeks None WOMAC weeks months Lysholm T: weeks C: weeks weeks weeks None Lysholm VAS WOMAC : first published as 0./bmjopen-0-00 on January 0. Downloaded from ADR

14 Page of Table (Continued) Sample First author size (year) (T/C) 0Wang, 0 [] 00 (0/0) Zhou, 0 [0] 0 (0/0) 0 Zhou, 0 [] 0 (0/0) 0 0 Diagnosis criteria Population characteristics Treatment ACR criteria- ACR criteria- CMA criteria-00 T: mean age (. years) M/F (/ cases) C: mean age (. years) M/F (/ cases) T: mean age (NA) M/F (NA) C: mean age (NA) M/F (NA) T: mean age ( years) M/F (/ cases) C: mean age (. years) M/F (/ cases) T, treatment group; C, control group; M, male; F, female; NA, not reported DJD+C DJD+C DJD+C Comparison Glucosamine pills/time, PO, Tid Meloxicam mg/time, PO, Bid +Glucosamine. g/time, PO, Bid Glucosamine 0. g/time, PO, Bid ACR, American college of rheumatology; CMA, Chinese medical association; ARA, American rheumatism association Duration of treatment Follow up Outcome assessment weeks None WOMAC weeks None weeks None DJD, Duhuo Jisheng decoction; DJW, Duhuo Jisheng wan (Duhuo Jisheng pill); Tid, three times a day; Bid, twice a day; Qd, once a day; PO, oral administration WOMAC, Western Ontario and MacMaster universities arthritis index; VAS, visual analogue scale; Lequesne, Lequesne functional index; Lysholm, Lysholm knee score scale ADR, adverse drug reaction; AE, adverse event on February 0 by guest. Protected by copyright. - WOMAC ADR WOMAC ADR : first published as 0./bmjopen-0-00 on January 0. Downloaded from

15 Page of Table Risk of bias assessment in included studies based on the Cochrane handbook Blinding of Blinding of Random sequence Concealment incomplete selective Other Risk of Included studies participants and outcome generation of allocation outcome data reporting bias bias personnel assessment Teekachunhatean, 00? ? + Unclear 0[0] Yu, 00 []??? +? + High Cao, 0 [] random number table????? High Gu, 0 [0]??? +? + High Li, 0 [] registration order? +? + High Yu, 0 [] 0??? +? + High Zhang, 0 []?????? High Zheng, 0 [] registration order???? High Zhong, 0 []?????? High Dong, 0 []??? +? + High Huang, 0 []??? +? + High 0 Jiang, 0 []?????? High Wang, 0 []?????? High Zhou, 0 [0]?????? High Zhou, 0 [] registration order? +? + High +, low risk of bias;, high risk of bias;?, unclear risk of bias on February 0 by guest. Protected by copyright. : first published as 0./bmjopen-0-00 on January 0. Downloaded from

16 Page of Table Summarized results of direct comparisons Clinical outcomes Number of studies Number of subjects MD (% CI) Total Lequesne scores DJD (DJW) vs. Diclofenac vs. -0. [-0., -0.] DJD vs. Glucosamine vs..00 [.,.] Meta-analysis (DJD with conventional western medicine) 0 vs.. [-.,.] Total Lysholm scores DJD vs. Meloxicam 0 vs. 0. [-.,.] DJD vs. Glucosamine vs..0 [.,.] DJD vs. Celecoxib 0 vs. 0.0 [.,.] Meta-analysis (DJD with conventional western medicine) vs.. [-0.,.] DJD+ KAS+ RT vs. KAS+ RT 0 vs [-.,.] DJD+ Sodium hyaluronate vs. Sodium hyaluronate vs. -0. [-.,.] Meta-analysis (DJD plus conventional therapy with conventional therapy) vs. -0. [-.,.] Total WOMAC scores DJD+ Glucosamine vs. Glucosamine vs..0 [.,.] DJD+ Diacerein vs. Diacerein 0 vs. 0.0 [.,.] DJD+ Glucosamine vs. Glucosamine vs..0 [.,.] DJD+ Meloxicam+ Glucosamine vs. Meloxicam+ Glucosamine 0 vs. 0.0 [-.0,.0] DJD+ Meloxicam+ Glucosamine vs. Meloxicam+ Glucosamine 0 vs. 0.0 [.,.] DJD+ Glucosamine vs. Glucosamine 0 vs. 0. [-.,.] DJD+ Glucosamine vs. Glucosamine vs..0 [.0,.0] Meta-analysis (DJD plus conventional western medicine with conventional western medicine) vs.. [.,.] - : first published as 0./bmjopen-0-00 on January 0. Downloaded from on February 0 by guest. Protected by copyright.

17 Page of Table (Continued) Clinical outcomes Number of studies Number of subjects SMD (% CI) VAS scores DJD (DJW) vs. Diclofenac vs. -.0 [-.0, -0.] DJD vs. Meloxicam 0 vs. 0. [0.,.] DJD vs. Glucosamine vs. 0. [0.,.] Meta-analysis (DJD with conventional western medicine) vs. 0. [-.,.] DJD+ Sodium hyaluronate vs. Sodium hyaluronate 0 vs [0.0, 0.] DJD+ Diacerein vs. Diacerein 0 vs [0.,.] DJD+ Sodium hyaluronate vs. Sodium hyaluronate vs. 0. [0.,.0] Meta-analysis (DJD plus conventional therapy with conventional therapy) vs. 0. [0., 0.] Lequesne, Lequesne functional index; Lysholm, Lysholm knee score scale; WOMAC, Western Ontario and MacMaster universities arthritis index; VAS, visual analogue scale; DJD, Duhuo Jisheng decoction; DJW, Duhuo Jisheng wan (Duhuo Jisheng pill); KAS, knee arthroscopic surgery; RT, Rehabilitation training - : first published as 0./bmjopen-0-00 on January 0. Downloaded from on February 0 by guest. Protected by copyright.

18 Page of DISCUSSION Summary of evidence As an adjunctive treatment method to KOA, Chinese herbal medicine has been used in the clinical practice for many years. - DJD is a popular TCM formula for the treatment of arthralgia and functional disorder in patients with KOA. This review compared effectiveness and safety of DJD (DJW) with conventional treatment, DJD plus conventional treatment with conventional treatment for the management of KOA. In a conclusion, this study demonstrated that DJD (duration ranging to weeks) combined with conventional western medicine, such as glucosamine, diacerein, and meloxicam could be selected for improving physical function of KOA associated with total WOMAC scores (n = vs. ; MD:. [.,.]; I = %; P < ). Also, DJD (duration ranging to weeks) plus conventional therapy including diacerein or sodium hyaluronate injection was beneficial for relieving pain of KOA (n = vs. ; SMD: 0. [0., 0.]; I = 0%; P < ). For the other two outcome scales, total Lequesne scores and Lysholm scores, there were no significant difference between the treatment and control group. The result of meta-analysis indicated that DJD alone versus conventional western medicine exhibited no significant improvement in VAS scores. On the other side, the information on the safety of DJD or comprehensive therapies including DJD was insufficient in few studies. Based on the limited data, whether the adverse effect of DJD alone or the combination of DJD with conventional therapy, the most common gastrointestinal symptoms including 0 nausea and diarrhea were found in trials. This study is the first systematic review to provide an objective assessment of DJD for the management of KOA by integrating different outcome measures from randomised controlled trials. All the comparators conformed to the recommendations in the clinical practice guidelines. A detailed subgroup analysis based on different comparisons revealed clinical outcome of KOA from scales regarding DJD. Limitations One limitation in this review was that the results are on the basis of evidence which has a high risk of bias and low quality. All included studies declared randomisation, but only one study described concrete random method. Three studies used registration order of patients visit as the method of random sequence generation, which is considered inappropriate and not recommended. Only one placebo-controlled trial in the form of a pill implemented allocation concealment and double-blind. 0 In addition, the lack of a placebo control was of critical concern and is common problem confronted by TCM - : first published as 0./bmjopen-0-00 on January 0. Downloaded from on February 0 by guest. Protected by copyright.

19 Page of research as a whole. There was no comparator of placebo in the previous studies. Therefore, placebo effect was still not completely eliminated. Nevertheless, it is difficult to prepare a placebo that has the same colour, taste and flavour as a Chinese herbal decoction. Blinding of outcome assessor was unclear in the most of the enrolled studies. Seven studies do not explicitly describe the drop-outs and withdrawals. The protocol in every research was not public or visible, so selective reporting was difficult to be judged. A further limitation was the decision to pool the results of the trials that put DJD and DJW together and did not consider the duration of treatment between the groups. In the first place, the efficacy of the similar drug composition but not identical dosage forms might be different in clinical practice. In the second place, the various duration of treatments from to weeks was provided, which might have influenced the pooled effects of the review to some extent. Besides that, long-term effect (more than one year) could not found in the current study. What is more, we just paid attention to the functional and pain scales assessed by the total scores or VAS scores. However, the sub-items in the scales such as joint stiffness and swelling were not considered. Quality of life was always applied to the evaluation of KOA, - but the design in the included trials was rarely seen as well. Implications for practice Based on our investigation, DJD combined with conventional western medicine seems to be efficacious for improving physical function (total WOMAC scores) in people with KOA. In the meantime, DJD plus conventional therapy including diacerein or sodium hyaluronate injection may have positive effect on reducing pain (VAS scores). And it is recommended that DJD should be practiced at least for weeks. However, the current findings are supported by the low quality evidence and we draw no comprehensive or final conclusions about the effectiveness and safety of the treatments. Moreover, the severity of KOA patients was not reported in most studies. As to whether different severity of KOA can be treated by this integrative medicine method, it is necessary to obtain more high quality of evidence. Implications for research The trials with high methodological quality and adequate power are needed to further identify the effectiveness and safety of DJD or DJD plus conventional treatments. Rigorous methods of design, measurement, evaluation (DME) following the Cochrane Handbook should be applied. Clinical trials registries should be encouraged to provide the details of the protocols treating KOA. Specifically, - : first published as 0./bmjopen-0-00 on January 0. Downloaded from on February 0 by guest. Protected by copyright.

20 Page of placebo-controlled clinical trials are essential, although it is not enough for Chinese herbal decoction. Furthermore, Careful consideration of the interventions respond to different KOA severity is required to seek optimal subgroups which provide greater benefits than harm. Outcome measures should include the evaluation of sub-items in the internationally recognized scales, quality of life and long-term effect should be assessed as well. CONCLUSIONS Overall, DJD combined with conventional western medicine or other therapy appears to have some benefits in improving physical function and decreasing pain for KOA. The safety of DJD and combination therapies is uncertain because of the limited number of included trials. The methodological limitations reduce the confidence in the effect estimates in the present systematic review. Therefore, future studies should overcome the limitations to more precisely assess the effectiveness and safety of DJD. Randomised controlled trials, for instance, should be strictly required in study design and reporting according to the Consolidated Standards of Reporting Trials (CONSORT). Acknowledgements The authors would like to thank Hao Y from World Journal of Acupuncture-moxibustion for revising the English language of this paper. Contributors All the authors made substantial contributions and approved the final version. Zhang WM, Wang SQ and Zhang RX contributed equally to this paper. Zhang WM, Lin YP and Wei X conceived the idea for the study; Zhang YY and Li XJ completed the literature searching and study selection; Wang SQ and Wei X conducted data extraction; Zhang WM and Zhang RX evaluated the methodological quality; Zhang WM, Wang SQ and Zhang RX conducted the meta-analysis and wrote the first draft of the article. Funding This work was supported by grants from National Natural Science Foundation of China (grant No. ). Competing interests The authors declare that they have no conflict of interests. The funders had no role in the paper. Provenance and peer review Not commissioned; externally peer reviewed. Data sharing statement No additional data are available. REFERRNCES - : first published as 0./bmjopen-0-00 on January 0. Downloaded from on February 0 by guest. Protected by copyright.

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