Background: To investigate the efficacy of continuous and pulsed ultrasound (US) in the management ofknee osteoarthritis (OA).Design: This systematic review and network meta-analysis covered 12 trials in total. Electronic databasesincluding MEDLINE, Embase and Cochrane Library were searched through to identify randomizedcontrolled trials comparing the two modes of US with control interventions (sham or blank) or with eachother. Bayesian network meta-analysis was used to integrate both the direct and indirect evidences ontreatment effectiveness.Results: Pulsed US (PUS) is more effective in both pain relief and function improvement when comparedwith the control group; but for continuous US (CUS), there is only a significant difference in pain relief incomparison with the control group. In addition, no matter in terms of pain intensity or function at thelast follow-up time point, PUS always exhibited a greater probability of being the preferred mode.However, the evidence of heterogeneity and the limitation in sample size of some studies could be apotential threat to the validity of results.Conclusions: Our findings indicated that PUS, with a greater probability of being the preferred mode, ismore effective in both pain relief and function improvement when compared with the control group.However, CUS could only be considered as a pain relief treatment in the management of knee OA. Thefindings also confirmed that none of these modes is dangerous.Level of evidence: Level II, systematic review and network meta-analysis of randomized controlled trials.
Osteoarthritis (OA) is a progressive rheumatic disease, theincidence of which keeps rising with the growth of the ageingpopulation in many societies. About 9 million people suffer fromsymptomatic, radiographically confirmed knee OA in the USA1. Themain complaints of knee OA include: pain during body moving orweight bearing, stiffness, swelling, deformity and decreasedwalking time and distance. Therefore, the relevant therapiesgenerally aim to relieve pain, improve functionality and mitigate
G.-h. Lei, Department of Or-y, #87 Xiangya Road, Chang-
disability for enhancing the quality of life. As the prevalence of kneeOA increases2, the increasing rates of knee arthroplasty, which isthe only effective way of late phase, has made the identification ofeffective conservative treatments a high priority.
Therapeutic ultrasound (US), based on the application of soundwaves in tissues, is one of the most widely used physical agents inknee OA. There are two modes of US, continuous and pulsed.Continuous US (CUS) generates thermal effects by stimulating theprocess of tissue regeneration, changing cell membrane perme-ability and increasing intracellular calcium, while pulsed US (PUS)mainly produces non-thermal effects to increase tissue meta-bolism, enhance fibrous tissue extensibility and elevate painthreshold3e5. In the past few years, a rapidly growing interest intesting the effects of US has been observed, but no agreement wasreached yet; especially, there is no exact conclusion on whichmodality of US (continuous or pulsed) is more effective in painrelief and functionality improvement of knee OA.
C. Zeng et al. / Osteoarthritis and Cartilage 22 (2014) 1090e1099 1091
Recently, the Osteoarthritis Research Society International(OARSI) developed the guidelines (2014) for non-surgical man-agement of knee OA6, which is the most up-to-date guideline tillpresent. The recommendation level of US for knee-only OA wasuncertain based on the results of two systematic reviews7,8 pub-lished in 2010 and one randomized controlled trial (RCT)9 pub-lished in 2012. Although these two previous systematic reviewscovered several RCTs (one of them reported a statistically signifi-cant pain relief for knee OA7), evidencewas limited because only sixRCTs were available at that time. It is worth mentioning thatwhether the physical function was actually improved remains un-clear. Furthermore, the authors admitted that the small sample sizeand low quality of trials included in their mode subgroup analyses(continuous or pulsed) inhibited further inferences7.
Network meta-analysis has been recently developed to evaluatethe relative effectiveness of several interventions and synthesizeevidence across a network of randomized trials. The mainlystrength of network meta-analysis is to combine the direct (studiescompared PUS with CUS directly) and indirect estimates (studiescompared PUS with CUS via control group) and calculated a mixedeffect size as the weighted average of the direct evidence and theindirect evidence10. Comparing with traditional meta-analysis,network meta-analysis is able to offer information on compari-sons for which no trails exist. In our case, the application of indirectevidence can improve the precision of the direct estimate byshortening the width of the confidence intervals in contrast todirect estimates alone11.
Considering the accumulation of new trials, this paper intendedto conduct an up-to-date systematic review and Bayesian networkmeta-analysis covering all the available direct and indirect evi-dences on US effects in order to generate a unified and coherentanalysis for all RCTs12e15. The objective of this study was to assessthe effects of US (continuous or pulsed) on pain relief and functionimprovement for knee OA.
Materials and methods
Literature search
The electronic databases of Medline, Embase and Cochrane li-brary were searched through using a series of logic combination ofkeywords and text words related to OA, interested interventionsand randomized controlled trials (Appendix 1). The latest electronicsearch was conducted in February 2014 to identify the references ofthe retrieved papers and reviews. In addition, the following web-sites were searched through manually to identify unpublished andongoing studies: Current Controlled Trials (http://www.controlled-trials.com/), ClinicalTrials.gov (http://www.clinicaltrials.gov/)andthe World Health Organization International Clinical Trials Registry(http://apps.who.int/trialsearch/Default.aspx).
Study selection
Two researchers reviewed all the retrieved abstracts and fulltexts independently. Disagreements were resolved through dis-cussions and consultations to another researcher. Those papersmeeting the following criteria were included in the analysis: (1)randomized controlled trials; (2) patients with knee OA (3)studies containing at least two of the following eligible treat-ments: PUS, CUS and control group (blank or sham); (4) studiesreporting the pain or function outcomes of patients; (5) Englishliterature. On the other hand, the trials with unbalanced addi-tional modality (e.g., education or exercise) between groups wereexcluded.
Quality assessment
Two researchers evaluated the methodological quality sepa-rately. The modified oxford score16,17, a scale ranged from 0 to 7according to the descriptions of randomization, concealment allo-cation, blinding method and reporting of participant withdrawals,was used to measure the methodological quality of includedstudies.
Outcome measures
The primary goal of this study was to identify the effectivenessof pain management and function improvement by applying thePUS or CUS therapy respectively. The degree of pain intensity aftertreatment was used as the measure of pain management effect. If astudy reported multiple pain scales, the highest one on the hier-archy of pain scale related outcomes was selected, as described byJüni and colleagues18. The WOMAC function was the preferredmeasure for function. If a study did not measure or report theWOMAC function, WOMAC total, Lequesne Index or other func-tional measurement scales were used in the analysis instead. If astudy reported outcomes at multiple time points after treatment,only the data from the final follow-up time point was extracted foranalysis. The effect of painmanagement and function improvementwas expressed as the standard mean differences (SMD) betweendifferent treatment arms. A negative value of SMD indicates lowerpain intensity and better status of function after treatment.
Statistical analysis
The random effect Bayesian network meta-analysis was per-formed to compare the pain management and function improve-ment effect between different modes of US therapy for knee OA.The advantage of network meta-analysis is that it allows indirectcomparisons of interventions among primary trials. In this study,the random effect Bayesian network meta-analysis was performedusing WinBUGS software (version 1.4.3, MRC Biostatistics Unit,Cambridge, UK), R version 3.0.2 (The R Foundation for StatisticalComputing) and STATA software (version 11.0, StataCorp, CollegeStation, TX). The codes of random effect models for multi-arm trialswere available at http://www.mtm.uoi.gr/ (Appendix 2). ThreeMarkov chains ran simultaneously with different initial valueschosen arbitrarily. A total of 50,000 simulations were generated foreach of the three sets of initial values, and the first 10,000 simu-lations were discarded due to the burn-in period. The pooled effectsizes were reported from the median of the posterior distribution.The corresponding 95% credible intervals with the 2.5th and 97.5thpercentiles of the posterior distribution were used in this study,which could be interpreted in away similar to the conventional 95%confidence intervals. In order to estimate the network inconsis-tency between indirect and direct estimates in each closed loop, theabsolute difference between the direct and indirect treatment ef-fect estimates was calculated. Loops with the lower CI limit did notreach the zero line were considered to represent statistically sig-nificant inconsistency19. The fit of the model to data can bemeasured by calculating the posterior mean residual deviance. Ifthe mean of the residual deviance is similar to the number of datapoints of the model, it indicates that the model fits the dataadequately20. All treatments were then ranked based on the level ofeffectiveness according to their posterior probabilities (first best,second best, third best, etc.). The probability values were summa-rized and reported as the surface under the cumulative ranking(SUCRA)21. SUCRA is equal to 1 for the best treatment, and 0 for theworst treatment.
C. Zeng et al. / Osteoarthritis and Cartilage 22 (2014) 1090e10991092
The classic pairwise meta-analysis was also performed by usingSTATA software (version 11.0, StataCorp, College Station, TX). Theheterogeneity was tested by Q statistics (P � 0.05 was consideredheterogeneous) and I2 statistics, which measures the percentage ofthe total variation across various studies (I2 � 50% was consideredheterogeneous). To evaluate the publication bias, Begg's tests22
were performed, where a P value less than 0.5 was considered toreflect publication bias.
Results
Study selection and characteristics
Figure 1 showed the selection process of the included trials inthis study. A total of 1769 records were identified from the pre-liminary database and website search and 993 records wereselected after removing duplicates. Then 927 records excludedwithreasons and 66 full-text trials were evaluated for eligibility. Even-tually, 12 studies were included in this research9,23e33. The char-acteristics of the included studies were listed in Table I. Themethodological quality assessment (Table II) showed that threestudies belonged to low quality (score � 3), four belonged to me-dium quality (scored 4 or 5), and the rest belonged to high quality(scored 6 or 7). Data from eight studies involving a total of 525patients with knee OA was available for network meta-ana-lysis9,23e29. Figure 2 showed the network structure of the com-parisons for the primary outcomes.
Fig. 1. Flowchart for the sele
Pain intensity
The results of network meta-analysis and pairwise meta-analysis were reported in Table III. PUS achieved a significantlylower pain intensity compared to the control group (SMD: �0.59,95%CI: �0.89 to �0.26), and CUS achieved a significantly bettereffect of pain management compared to the control group(SMD: �0.41, 95%CI: �0.67 to �0.07). However, there was no sig-nificant difference between the PUS and CUS group in terms of painintensity after treatment (SMD: �0.18, 95%CI: �0.94 to 0.37). Noevidence of inconsistency between direct and indirect estimateswas found in this network meta-analysis. Evaluation of the good-ness of fit indicated adequate fit with a posterior mean residualdeviance of 20.07 (19 data points). The distribution of probability ofeach treatment for this outcome was shown in Fig. 3. PUS is mostlikely to be the best treatment (93%) compared to CUS (56%) and thecontrol group (0%). Pairwise meta-analysis showed nearly the sameresults (Table III). Significant evidence of heterogeneity was onlyobserved in the comparison between PUS and the control group(P ¼ 0.07, I2 ¼ 54%). There was no publication bias among variousstudies. The original pain outcomes of the studies which were notincluded in meta-analysis were reported in Appendix 3.
Function
Table III also showed the outcomes of networkmeta-analysis forfunction. It indicated that only the PUS therapy was significantlymore effective in terms of function improvement compared to the
ction of included trials.
Table ICharacteristics of the included studies
Study Groups Balance* N Age(years)
Gender(M/F)
MeanBMI
Parameters of intervention Interested outcome(pain/function)
Test timez
Loyola-S�anchez2012
G1: PUSG2: sham
None 1413
62.661.2
3/113/10
3430.4
9.5 min � 3 times � 8 weeks,20% duty cycle, 1 MHz,average temporal intensity:0.2 W/cm2, therapeuticdose: 112.5 J/cm2
VAS/WOMAC function 8 weeks
Ulus 2012 G1: CUSG2: sham
Hot pack,interferentialcurrent,exercise
2020
60.760.3
3/173/17
31.631.1
10 min � 5 times � 3 weeks,1 MHz, 1 W/cm2
VAS/WOMAC functionand LI
0 week
Tascioglu 2010 G1: CUSG2: PUSG3: sham
None 272827
59.761.460
10/177/219/18
3030.828.7
5 min � 5 times � 2 weeks,1 MHz, 2 W/cm2
VAS/WOMAC total 2 days
€Ozg€onenel 2009 G1: CUSG2: sham
None 34x33
53.656.2
6/287/26
None 5 min � 5 times � 2 weeks,1 MHz, 1 W/cm2
VAS/WOMAC function 2 days
Huang 2005a G1: PUSG2: blank
Exercise 3231
65y 27/113y None 5 min � 3 times � 8 weeks,1 MHz, 2.5 W/cm2
VAS/LI 0, 1 year
Huang 2005b G1: CUSG2: PUSG3: blank
Exercise,hot pack
485642
62y 23/97y None 5 min � 3 times � 8 weeks,1 MHz, continuous:1.5 W/cm2; pulsed: 2.5 W/cm2
VAS/LI 0, 1 year
Cetin 2008 G1: CUSG2: blank
Exercise,hot pack
20x20
57.661.1
OnlyFemales
29.827.7
10 min � 3 times � 8 weeks,1 MHz, 1.5 W/cm2
VAS/LI 0 week
Cakir 2013 G1: CUSG2: PUSG3: sham
Exercise 202020
56.958.257.1
6/144/163/17
27.930.929.5
12 min � 5 times � 2 weeks,CUS: 1 MHz, 1 W/cm2;PUS: 1 MHz, 1 W/cm2
BMI 30 min � 12 treatments(2e3 times per week over4e6 weeks); increments of0.1 W/cm2 to maximum 2.5 W/cm2
VAS/gait velocity 0, 12 weeks
Külcü 2009 G1: CUSG2: blank
None 1515
63.162
2/133/12
e 10 min � 5 sessions � 3 weeks;1 MHz, 1.5 W/cm2
VASWOMAC
0 week
Kapidzic 2011 G1: CUSG2: sham
Thermotherapyand exercises
4050
60y e e 5 min, 3 weeks, 0.8 W/cm2 Likert's scale/WOMACfunction and LI
0 week
W, watt; ms, microsecond; N, number of subjects; M, male; F, female; BMI, Body Mass Index; VAS, visual analogue scale (0e10); WOMAC function, function subscale ofWestern Ontario andMcMaster University Osteoarthritis Index (0e68);WOMAC total, Western Ontario andMcMaster University Osteoarthritis Index consists three subscales(pain, stiffness and functional status, 0e96); LI, Lequesne index (0e26).
* Usual cares which were balance between groups.y Only data for the whole trial is available.z 0 means at the end of the treatment.x Only data from the baseline is available.
C. Zeng et al. / Osteoarthritis and Cartilage 22 (2014) 1090e1099 1093
control group (SMD: �0.57, 95%CI: �1.12 to �0.01). There was nosignificant difference between CUS and the control group(SMD: �0.26, 95%CI: �0.79 to 0.28), and between PUS and CUS(SMD: �0.31, 95%CI: �0.94 to 0.37) in terms of function improve-ment. There was no evidence of inconsistency between the directand indirect evidences. The model had an adequate fit to data, witha posterior mean residual deviance of 19.64 (19 data points).Figure 4 displayed the distribution of probability of each treatmentranked at each of the three possible positions. According to theresult of the posterior probability values of rank, it was found thatPUS is most likely (98%) to be the best treatment for functionimprovement, followed by CUS (51%) and the control group (9%).The pairwise meta-analysis also ended up with similar results asthe network meta-analysis in terms of function. However, therewas significant heterogeneity between the two direct comparisons(PUS vs control: P¼ 0.00, I2¼ 83%; PUS vs CUS: P¼ 0.005, I2¼ 81%).Based on the P values of Beggs' test, publication bias did not existamong various studies. The functional results of the studiesexcluded from this network meta-analysis were reported inAppendix 3.
Adverse effects
There were only three trials that reported adverse effects. Twoof them claimed that no adverse effect related to the CUS
treatment was observed, and one study reported the adverse ef-fect of electric shock/stinging sensation related to the PUS treat-ment. However, there was no significant difference between theintervention and the control group in terms of the incidence ofadverse effect.
Discussion
This network meta-analysis reviewed two kinds of therapeuticUS (continuous or pulsed) in terms of pain relief and functionimprovement for patients with knee OA. It was found that PUS ismore effective in terms of both pain relief and function improve-ment when comparedwith the control group (blank and sham), butfor CUS, the significant difference only exists in pain relief incomparison with the control group. In addition, no matter in termsof pain intensity or function at the last follow-up time point, PUS ismost likely to be the preferred mode.
Recently, a provincial survey conducted in Canada indicatedthat a majority of physical therapists (85%) expressed interest inthe effectiveness of US in pain relief and physical function34.However, the recommendations mentioned in the current clinicalpractice guidelines have not arrived at any agreement whichagainst helping policy makers, service commissioners, and pro-viders to judge the efficacy of US therapy. One guideline rec-ommended US for OA management35; three guidelines were
Table IIMethodological evaluation of included studies
C. Zeng et al. / Osteoarthritis and Cartilage 22 (2014) 1090e10991094
against the use of US36e38; three guidelines, including the latestone, regarded US as an uncertain appropriate modality6,39,40;other four guidelines did not even mention about US as a treat-ment option41e44. Two reviews published in 2010 involving fiveand six randomized controlled trials respectively reached asimilar conclusion that therapeutic US might be beneficial (pain
CUS
PUS
control
5(224) 5(328)
6(286)
6(331)
3(147)
3(199)
Fig. 2. Structure of network formed by interventions and their direct comparisons. Thelines between treatment nodes indicate the direct comparisons made within ran-domized trials. The width of the lines is proportional to the number of trials comparingeach pair of treatments. Numbers represent numbers of trials (number of analyzedpatients) per comparison. Inside numbers are for pain outcome and outside numbersare for function outcome.
Table IIIResults of network meta-analysis and pairwise meta-analysis
Comparison Network meta-analysis,SMD (95%CI)
Pairwise meta-anSMD (95%CI)
PUS vs controlPain �0.59 (�0.89, �0.26) �0.55 (�0.90, �0Function �0.57 (�1.12, �0.01) �0.63 (�1.31, 0.0
PUS vs CUSPain �0.18 (�0.49, 0.17) �0.13 (�0.41, 0.1Function �0.31 (�0.94, 0.37) �0.33 (�1.10, 0.4
relief and function improvement) for patients with knee OA7,8.With the accumulation of evidences, especially for the mode(continuous or pulsed) subgroup, this network meta-analysisfurther supported that PUS could be the preferred mode interms of both pain relief and function improvement withoutsignificant adverse effects.
In vitro studies have supported the effects of PUS in inducingchondrocyte proliferation and matrix production in human artic-ular cartilage45e49. Meanwhile, based on a number of researchesestablishing animal models of cartilage injury, in vivo experimentsalso showed that low intensity PUS was beneficial to cartilagehealth50e55. Therewas also a study suggesting that PUSwith topicallidocaine gel could induce greater anaesthetic effects compared toCUS with topical lidocaine gel and lidocaine application alone56.The findings of these studies were consistent with the results ob-tained here. On the other hand, unlike the athermal mechanicaleffects generated by the application of PUS, CUS aims to generatethermal effects which could increase capillary permeability andtissue metabolism, enhance fibrous tissue extensibility, and espe-cially elevate the pain threshold5,57. Likewise, CUS was proved to bean effective way only in pain relief for patients with knee OA in thisstudy.
As far as we know, this is the first network meta-analysis ofUS for knee OA, which compiled evidences from both direct andindirect comparisons for evaluating the relative effectiveness inpain relief and function improvement. In addition, this studyovercame two limitations which were admitted in the previousclassical meta-analysis7. One is the effects of co-interventions(including education or exercise) which could be effective inpain relief and function improvement. The control group of thisstudy was limited to sham or blank control, and the additionalmodality was required to be balanced between groups in order toeliminate the potential impact of standard care. Under suchcircumstance, it is meaningful to conclude that US was effectiveas long as the results were significant. Otherwise, it is uncom-fortable to draw a definite conclusion whether US is beneficial ornot when the results were non-significant. The other limitationresolved is the powerful mode subgroup analysis which wasconducted in this network meta-analysis. Furthermore, Beggs'test suggested that publication bias was not observed among theincluded studies.
Nevertheless, the limitations of this study should not be ignored.Firstly, variations of US sessions, doses and differences in finalfollow-up time point might contribute to the significant evidence ofheterogeneity, particularly for the possible doseeresponse patternswhich could greatly affect the performance of US. However,because of the limited number of included trials and insufficientdescriptions of treatment parameters, this study could not exploreit in depth. Fortunately, no obvious evidence of inconsistency wasobserved in this network meta-analysis. Secondly, several included
alysis, Heterogeneity (P/I2) Publication bias(P value of Beggs' test)
.21) 0.07/54% 0.0866) 0.00/83% 0.462
.14) 0.21/30% 1.000
.00) 0.29/18% 1.000
5) 0.71/0% 1.0005) 0.005/81% 0.296
0.2
.4.6
.81
0.2
.4.6
.81
0.2
.4.6
.81
1 2 3 1 2 3
1 2 3
CUS PUS
control
Cum
ulat
ive
Prob
abil
itie
s
RankGraphs by Treatment
Fig. 3. Rankings for pain intensity. Graph displays distribution of probabilities for each treatment. X-axis represents the possible rank of each treatment (from the best rank to worseaccording to the outcomes), Y-axis represents the cumulative probability for each treatment to be the best option, among the best two options, among the best three options, and so on.
C. Zeng et al. / Osteoarthritis and Cartilage 22 (2014) 1090e1099 1095
studies measured the pain or function parameters too shortly afterall treatment courses. It is uncertain whether these effects maydiminish after a long time. Thirdly, the low level of methodologicalquality and the limitation in sample size of some studies could be apotential threat to the validity of results. Fourthly, this study onlyfocused on the effectiveness of pain relief and function improve-ment, it is difficult to measure other indices in this Bayesiannetwork meta-analysis.
Conclusion
Our findings indicated that PUS, with a greater probability ofbeing the preferred mode, is more effective in both pain relief and
0.2
.4.6
.81
0.2
.4.6
.81
1 2 3
1 2 3
CUS
control
Cum
ulat
ive
Prob
abil
itie
s
RaGraphs by Treatment
Fig. 4. Rankings for function. Graph displays distribution of probabilities for each treatmenaccording to the outcome), Y-axis represents the cumulative probability for each treatment to
function improvement when compared with the control group.However, CUS could only be considered as a pain relief treatment inthemanagement of knee OA. The findings also confirmed that noneof these modes is dangerous.
Contribution of authors
All authors had full access to all the data in the study and takeresponsibility for the integrity of the data and the accuracy of thedata analysis. CZ and GL contributed to the study concept anddesign and drafted the manuscript. HL, TY and ZD contributed todata collection. YY, YZ and XD contributed to preparation anddata analysis. GL contributed to revision of the manuscript. All
0.2
.4.6
.81
1 2 3
PUS
nk
t. X-axis represents the possible rank of each treatment (from the best rank to worsebe the best option, among the best two options, among the best three options, and so on.
C. Zeng et al. / Osteoarthritis and Cartilage 22 (2014) 1090e10991096
the authors contributed to the interpretation of the data andcritically reviewed the manuscript for publication.
Conflict of interestThe authors declare that they have no conflict of interest.
Acknowledgements
This work was supported by Hunan Provincial InnovationFoundation for Postgraduate, the Fundamental Research Fundsfor the Central Universities of Central South University, the Na-tional Natural Science Foundation of China (Nos. 81201420,81272034), the Provincial Science Foundation of Hunan (No.14JJ3032), the Scientific Research Project of the Development andReform Commission of Hunan Province (No. [2013]1199), theScientific Research Project of Science and Technology Office ofHunan Province (No. 2013SK2018), the Doctoral Scientific FundProject of the Ministry of Education of China (No.20120162110036).
Appendix 1. Search strategies for Pubmed, Ovid/MEDLINE,The Cochrane Library and Ovid/EMBASE database
Pubmed
1. osteoarthro*[tiab] or gonarthriti*[tiab] or gonarthro*[tiab] orcoxarthriti*[tiab] or coxarthro*[tiab] or osteo?arthritis[tiab]
2. (knee*[tiab] or joint*[tiab]) and (pain*[tiab] or discomfort*[tiab])
3. (knee*[tiab] or joint*[tiab]) and stiff*[tiab]4. 1 or 2 or 35. randomized[tiab]6. placebo[tiab]7. controlled[tiab]8. random*[tiab]9. trial*[tiab]
10. groups[tiab]11. ((singl*[tiab] or doubl*[tiab] or tripl*[tiab]) and (mask*[tiab]
or blind*[tiab]))12. Or/5-1113. Ultrasonography[tiab]14. Ultrasonic[tiab]15. ultrasound*[tiab] or ultrasonic*[tiab]16. short[tiab] and wave[tiab]17. ultrasonograph*[tiab]18. Ultraso*[tiab]19. Or 13-1820. 4 and 12 and 19
10. ((knee$ or joint$) adj3 (pain$ or ach$ or discomfort$)).ti,ab.11. ((knee$ or joint$) adj3 stiff$).ti,ab12. Or/1-1113. randomized controlled trial.pt.14. controlled clinical trial.pt.15. randomi?ed.ab.16. placebo.ab,tw.17. controlled.ti,ab18. randomly.ti,ab.19. trial.ti,ab.20. groups.ti,ab21. ((randomized controlled trials) or (random$ allocation) or
(double blind) or (single blind)).tw22. ((singl$ or doubl$ or tripl$) and (mask$ or blind$)).tw23. Or/13-2224. exp ultrasonography/25. exp Ultrasonic Therapy/26. (ultrasound$ or ultrasonic$).tw.27. short wave therapy.tw.28. ultrasonograph$.tw.29. Ultraso$.ti,ab,sh30. Or/24-2931. 12 and 23 and 30
The Cochrane Library
#1 (osteoarthritis* OR osteoarthro* OR gonarthriti* OR gonar-thro* OR coxarthriti* OR coxarthro* OR arthros* OR arthrot*OR ((knee* OR joint*) near/3 (pain* OR ach* OR discomfort*))OR ((knee*OR joint*) near/3 stiff*))
#2 MeSH descriptor Osteoarthritis explode all trees#3 #1 or #2#4 short wave therapy in Clinical Trials#5 ultrasonograph in Clinical Trials#6 (ultrasound* or ultrasonic*) in Clinical Trials#7MeSH descriptor Ultrasonography explode all trees#8 MeSH descriptor Short-Wave Therapy explode all trees#9 #4 or #5 or #6 or #7 or #8
10. ((knee$ or joint$) adj3 (pain$ or ach$ or discomfort$)).ti,ab.11. ((knee$ or joint$) adj3 stiff$).ti,ab12. Or/1-1113. randomized controlled trial.pt.14. controlled clinical trial.pt.
C. Zeng et al. / Osteoarthritis and Cartilage 22 (2014) 1090e1099 1097
15. randomi?ed.ab.16. placebo.ab,tw.17. controlled.ti,ab18. randomly.ti,ab.19. trial.ti,ab.20. groups.ti,ab21. ((randomized controlled trials) or (random$ allocation) or
(double blind) or (single blind)).tw22. ((singl$ or doubl$ or tripl$) and (mask$ or blind$)).tw23. Or/13-2224. exp ultrasonography/25. exp Ultrasonic Therapy/26. (ultrasound$ or ultrasonic$).tw.27. short wave therapy.tw.28. ultrasonograph$.tw.29. Ultraso$.ti,ab,sh30. Or/24-2931. 12 and 23 and 30
Appendix 2. WinBUGS codes of random effect models formulti-arm trials
Appendix 3. Results of the studies not included in the network meta-analysis
Study Groups Pain scale/function scale Outcome of pain Outcome of function
P < 0.0001 Median (range)G1: 11.5 (0e26)G2: 24 (18e30)
P < 0.0001
Kapidzic 2011 G1: CUSG2: placebo
Likert's scale/WOMACfunction and LI
Difference of beforeand after treatmentG1: 0.83 ± 0.51G2: 0.53 ± 0.40
P < 0.05 Difference of beforeand after treatmentG1: 0.61 ± 0.55G2: 0.38 ± 0.70
P < 0.05
NS: not significant, NR: not report.
C. Zeng et al. / Osteoarthritis and Cartilage 22 (2014) 1090e10991098
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