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Therapeutic ultrasound for osteoarthritis of the knee or hip

(Review)

Rutjes AWS, Nesch E, Sterchi R, Jni P

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2010, Issue 1http://www.thecochranelibrary.com

Therapeutic ultrasound for osteoarthritis of the knee or hip (Review)

Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .6BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .8RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

19DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .24CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Any type of therapeutic ultrasound versus control, Outcome 1 Pain. . . . . . . . 36Analysis 1.2. Comparison 1 Any type of therapeutic ultrasound versus control, Outcome 2 Function. . . . . . . 37Analysis 1.3. Comparison 1 Any type of therapeutic ultrasound versus control, Outcome 3 Number of patients experiencing

any adverse event. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37Analysis 1.4. Comparison 1 Any type of therapeutic ultrasound versus control, Outcome 4 Number of patients withdrawn

or dropped out due to adverse events. . . . . . . . . . . . . . . . . . . . . . . . . . 38Analysis 1.5. Comparison 1 Any type of therapeutic ultrasound versus control, Outcome 5 Number of patients experiencing

any serious adverse event. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3838APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .42INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iTherapeutic ultrasound for osteoarthritis of the knee or hip (Review)



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[Intervention Review]

Therapeutic ultrasound for osteoarthritis of the knee or hip

Anne WS Rutjes1, Eveline Nesch1, Rebekka Sterchi1, Peter Jni1

1Division of Clinical Epidemiology and Biostatistics, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland

Contact address: Anne WS Rutjes, Division of Clinical Epidemiology and Biostatistics, Institute of Social and Preventive Medicine,University of Bern, Finkenhubelweg 11, Bern, 3012, Switzerland. [email protected]. [email protected].

Editorial group: Cochrane Musculoskeletal Group.Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 1, 2010.Review content assessed as up-to-date: 22 July 2009.

Citation: Rutjes AWS, Nesch E, Sterchi R, Jni P. Therapeutic ultrasound for osteoarthritis of the knee or hip. Cochrane Databaseof Systematic Reviews2010, Issue 1. Art. No.: CD003132. DOI: 10.1002/14651858.CD003132.pub2.


A B S T R A C T

Background

Osteoarthritis is the most common form of joint disease and the leading cause of pain and physical disability in the elderly. Therapeuticultrasound is one of several physical therapy modalities suggested for the management of pain and loss of function due to osteoarthritis(OA).

Objectives

To compare therapeutic ultrasound with sham or no specific intervention in terms of effects on pain and function safety outcomes inpatients with knee or hip OA.

Search strategy

We updated the search in CENTRAL, CINAHL, EMBASE, MEDLINE and PEDro up to 23 July 2009, checked conference proceed-ings, reference lists, and contacted authors.

Selection criteria

Studies were included if they were randomised or quasi-randomised controlled trials that compared therapeutic ultrasound with a shamintervention or no intervention in patients with osteoarthritis of the knee or hip.

Data collection and analysis

Two independent review authors extracted data using standardized forms. Investigators were contacted to obtain missing outcomeinformation. Standardised mean differences (SMDs) were calculated for pain and function, relative risks for safety outcomes. Trialswere combined using inverse-variance random-effects meta-analysis.

Main results

Compared to the previous version of the review, four additional trials were identified resulting in the inclusion of five small sized trialsin a total of 341 patients with knee OA. No trial included patients with hip OA. Two evaluated pulsed ultrasound, two continuous andone evaluated both pulsed and continuous ultrasound as the active treatment. The methodological quality and the quality of reportingwas poor and a high degree of heterogeneity among the trials was revealed for function (88%). For pain, there was an effect in favourof ultrasound therapy, which corresponded to a difference in pain scores between ultrasound and control of -1.2 cm on a 10-cm VAS(95% CI -1.9 to -0.6 cm). For function, we found a trend in favour of ultrasound, which corresponded to a difference in functionscores of -1.3 units on a standardised WOMAC disability scale ranging from 0 to 10 (95% CI -3.0 to 0.3). Safety was evaluated in twotrials including up to 136 patients; no adverse event, serious adverse event or withdrawals due to adverse events occurred in either trial.

1Therapeutic ultrasound for osteoarthritis of the knee or hip (Review)

mailto:[email protected]:[email protected]:[email protected]:[email protected]


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Authors conclusions

In contrast to the previous version of this review, our results suggest that therapeutic ultrasound may be beneficial for patients withosteoarthritis of the knee. Because of the low quality of the evidence, we are uncertain about the magnitude of the effects on pain reliefand function, however. Therapeutic ultrasound is widely used for its potential benefits on both knee pain and function, which may beclinically relevant. Appropriately designed trials of adequate power are therefore warranted.

P L A I N L A N G U A G E S U M M A R Y

Therapeutic ultrasound for osteoarthritis

This summary of a Cochrane review presents what we know from research about the effect of therapeutic ultrasound on knee or hiposteoarthritis. The previous version of this review concluded that therapeutic ultrasound had no benefit over fake therapeutic ultrasoundin pain relief and functional status.

The updated review shows that in people with osteoarthritis,

-Therapeutic ultrasound may be beneficial for people with osteoarthritis of the knee.

-Therapeutic ultrasound may improve your physical function but this finding could be the result of chance.

- We are uncertain about the magnitude of effects on pain relief or the ability to use your knee, because of the low quality of theevidence.

-Therapeutic ultrasound may not have any side effects: no side effects were reported, but we do not have precise information aboutside effects. This is particularly true for rare but serious side effects.

There are no studies that address the benefits of therapeutic ultrasound in people with hip osteoarthritis.

What is osteoarthritis and what is therapeutic ultrasound?

Osteoarthritis is a disease of the joints, such as your knee or hip. When the joint loses cartilage, the bone grows to try and repair thedamage. Instead of making things better, however, the bone grows abnormally and makes things worse. For example, the bone canbecome misshapen and make the joint painful and unstable. This can affect your physical function or ability to use your knee.

Therapeutic ultrasound means using sound waves to try and relieve pain or disability. Your doctor or physiotherapist will use a round-headed wand or probe on the skin of the painful area. Ultrasound gel is used on the wand and on your skin to make it more comfortableand help the sound waves reach the affected area.

Best estimate of what happens to people with osteoarthritis who have had therapeutic ultrasound for a duration of 2-8 weeks:

Pain

-People who used therapeutic ultrasound had an improvement in their pain of about 3 on a scale from 0 (no pain) to 10 (extreme pain)after using it up to 2 months.

-People who used a fake therapeutic ultrasound had an improvement in their pain of about 2 on a scale from 0 to 10 after using it upto 2 months.

Another way of saying this is:

- 37 people out of 100 who use therapeutic ultrasound respond to treatment (37%).

- 31 people out of 100 who use fake therapeutic ultrasound respond to treatment (31%).

- 6 more people respond to treatment with therapeutic ultrasound than with fake therapeutic ultrasound (difference of 6%).




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S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Therapeutic ultrasound compared with sham or no specific intervention for patients with knee or hip osteoarthritis

Patient or population: Patients with knee osteoarthritis (none of the trials included patients with hip osteoarthritis)

Settings: Private physical therapy practice in USA (1 trial) and medical university hospital outpatient clinic in Taiwan (2 trials), and outpatient clrehabilitation in Turkey (2 trials)

Intervention: Therapeutic ultrasound

Comparison: Sham or no specific intervention

Outcomes Illustrative comparative risks* (95% CI) Relative effect

(95% CI)

No of Participants

(studies)

Quality

(GRADE

Assumed risk Corresponding risk

Sham or no specific in-

tervention

Therapeutic ultrasound

PainVAS pain scales

Follow-up: 2 to 8 weeks

-1.8 cm change on 10cm VAS1

29% improvement

-3.0 cm change( -1.2 cm, -1.9 to -0.6

cm)2

50% improvement

( 21%, 10% to 32%)3

SMD -0.49 (-0.76 to -0.23)

320(5)

++OOlow4

Function

Various validated function

scales

Follow-up: 2 to 8 weeks

-1.2 units on WOMAC

(range 0 to 10)1

21% improvement

-2.6 units on WOMAC

( -1.3, -3.0 to 0.3)6

46% improvement

( 25%, -5% to 54%)7

SMD -0.64 (-1.42 to

0.14)

251

(4)

++OO

low8

Number of patients ex-

periencing any adverse

event

Follow-up: 2 weeks

150 per 1000 patient-

years1See comment not estimable 67

(1)

++OO

low9

Number of patients who

withdrew because of ad-

verse events

Follow-up: 2 weeks

17 per 1000 patient-years1

See comment not estimable 67

(1)

++OO

low9

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heCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
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9 Downgraded (2 levels) because of: small sample size, due to absence of events, no relative risk could be calculated, 1 out of 5 studies

reported this outcome, possibly leading

to selective outcome reporting bias.10 Downgraded (2 levels) because of: small sample size, due to absence of events, no relative risk could be calculated, 2 out of 5 studies

reported this outcome, possibly leading to selective outcome reporting bias.

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B A C K G R O U N D

Osteoarthritis (OA) is an age related condition, occurring morefrequently in women than in men. Its prevalence, causal associa-tions and outcomes vary markedly according to the joint site af-fected (Jni 2006). OA is characterized by focal areas of loss ofarticular cartilage in synovial joints, accompanied by subchondralbone changes, osteophyte formation at the joint margins, thicken-ing of the joint capsule and mild synovitis (Solomon 1997). Theobjectives of management of knee and hip OA are to relieve painand to maintain or improve function.

Therapeutic ultrasound is one of many physical therapy modali-ties and can be used as part of an overall rehabilitation program(Rand 2007). Therapeutic ultrasound consists of high frequency

vibrations (Hartley 1993; Nelson 1999)thatcanbepulsedorcon-tinuous. Pulsed ultrasound produces non-thermal effects and isgenerally recommended for acute pain and inflammation. Con-tinuous ultrasound generates thermal effects (Rand 2007). Ther-apeutic ultrasound that penetrates deeply enough to increase col-lagen elasticity may be useful in the early stages of a flexibilityprogram (Hicks 1990).

The 2008 OARSI recommendations for the management of hipand knee OA state that the optimal management of OA re-quires a combination of non-pharmacological and pharmacologi-cal modalities, including physical therapy (Zhang 2008), but doesnot specifically mention ultrasound as treatment adjunct. Only 1out of 5 existing guidelines considering ultrasound actually rec-ommended its use, but the recommendation was not based onevidence from randomised trials.

O B J E C T I V E S

We set out to compare therapeutic ultrasound with sham or nospecific intervention in terms of effects on pain and function andsafety outcomes in patients with knee or hip OA and to explorewhether potential variation between trials could be explained bycharacteristics of the ultrasound, by biases affecting individual tri-als or by publication bias.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomised or quasi randomised controlled trials with a controlgroup receiving a sham intervention or no intervention.

Types of participants

At least 75% of patients with clinically and/or radiologically con-firmed osteoarthritis of the knee or hip.

Types of interventions

Any type of continuous or pulsed therapeutic ultrasound.Phonophoresis (the use of ultrasound to enhance the deliveryof topically applied drugs) or extracorporeal ultrasonic treatment(derivative of lithotripsy, the mechanical breaking up of renalstones with sound waves) were not considered. Eligible controlinterventions were placebo or a non-intervention control (usualcare). Concurrent therapy was accepted providing it was provided

to both, experimental and control groups.

Types of outcome measures

Main outcomes

Main outcomes were pain and function, as currently recom-mended for osteoarthritis trials (Altman 1996; Pham 2004). Ifdata on more than one pain scale were provided for a trial, wereferred to a previously described hierarchy of pain-related out-comes (Jni 2006; Reichenbach 2007) and extracted only data on

the pain scale that was highest on this hierarchy:1. Global pain2. Pain on walking3. WOMAC osteoarthritis index pain subscore4. Composite pain scores other than WOMAC5. Pain on activities other than walking6. Rest pain or pain during the night7. WOMAC global algofunctional score8. Lequesne osteoarthritis index global score9. Other algofunctional scale10. Patients global assessment11. Physicians global assessmentIf data on more than one function scale were provided for a trial,

we extracted data according to hierarchy presented below.1. Global disability score2. Walking disability3. WOMAC disability subscore4. Composite disability scores other than WOMAC5. Disability other than walking6. WOMAC global scale7. Lequesne osteoarthritis index global score8. Other algofunctional scale9. Patients global assessment10. Physicians global assessmentIf pain or function outcomes were reported at several time-points,we extracted the estimate at the end of the treatment period.




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Secondary outcomes

Secondary outcomes were the number of patients experiencingany adverse event, patients who were withdrawn or dropped outbecause of adverse events, and patients experiencing any seriousadverse events between randomisation and end of follow-up. Se-rious adverse events were defined as events resulting in hospital-isation, prolongation of hospitalisation, persistent or significantdisability, congenital abnormality/birth defect of offspring, life-threatening events or death.

Search methods for identification of studies

Electronic searches

We searched electronic databases of CENTRAL through TheCochrane Library (http://mrw.interscience.wiley.com/cochrane/), MEDLINE and EMBASE through the Ovid platform(www.ovid.com), CINAHL through EBSCOhost, PhysiotherapyEvidence Database (PEDro, http://www.pedro.org.au/), all fromimplementation to July 23,2009using a combination of keywordsand text words related to ultrasound combined with keywordsand text words related to osteoarthritis and a validated filter forcontrolled clinical trials (Dickersin 1994). The search strategy ispresented in Appendix 1 and Appendix 2.

Searching other resources

We manually searched conference proceedings, used Science Ci-tation Index to retrieve reports citing relevant articles, contactedcontent experts and trialists and screened reference lists of all ob-tained articles, including related reviews. Finally, we searched sev-eral clinicaltrial registries(www.clinicaltrials.gov, www.controlled-trials.com, www.actr.org.au, www.umin.ac.jp/ctr) to identify on-going trials. The last update of the manual search was on February02, 2009.

Data collection and analysis

Selection of studies

Two review authors independently evaluated all titlesand abstractsfor eligibility. Disagreements were resolved by discussion. We ap-plied no language restrictions. If multiple reports described thesame trial, we considered all.

Data extraction and management

Two review authors (AR and EN or RS) extracted trial informa-tion independently using a standardised, piloted data extractionform accompanied by a codebook. Disagreements were resolved

by discussion. We extracted the characteristics of the therapeutic

application, including type of device, head size of the probe, anyspecific skin or probe preparation, the frequency and duration oftreatment and the total number of sessions. Other data extractedincluded the type of control intervention used, patient character-istics (gender, average age, duration of symptoms, type of joint),characteristics of pain, function, and safety outcomes, design, trialsize, trial duration (defined as time from randomisation until endof follow-up), type andsource of financialsupport andpublicationstatus. When necessary, means and measures of dispersion wereapproximated from figures in the reports. For crossover trials, weextracted data from the first period only. Whenever possible, weused results froman intention-to-treat analysis. If effectsizes couldnot be calculated, we contacted the authors for additional data.

Assessment of risk of bias in included studies

Two review authors (AR and EN or RS) independently assessedrandomisation, blinding and adequacy of analyses (Jni 2001).Disagreements were resolved by consensus. Two components ofrandomisation were assessed: generation of allocation sequencesand concealment of allocation. Generation of sequences was con-sidered adequate if it resulted in an unpredictable allocation sched-ule; mechanisms considered adequate included random-numbertables, computer-generated random numbers, minimisation, cointossing, shuffling of cards, and drawing of lots. Trials using an un-predictable allocationsequence wereconsideredrandomised; trialsusing potentially predictable allocation mechanisms, suchas alter-nation or the allocation of patients according to date of birth, wereconsidered quasi-randomised.Allocation concealment wasconsid-ered adequate, if the investigators responsible for patient selectionwere unable to suspect beforeallocation which treatmentwas next;methods considered adequate included central randomisation andsequentially numbered, sealed, opaque envelopes. Blinding of pa-tients was considered adequate if a sham intervention was usedthat was identical in appearance to the experimental intervention.Handling of incomplete outcome data was considered adequate ifall randomised patients were included in the analysis (intention-to-treat principle). Finally, we used GRADE to describe the qual-ity of the overall body of evidence (Guyatt 2008; Higgins 2008),defined as the extent of confidence into the estimated treatmentbenefits and harms.

Data synthesis

Continuous outcomes were summarized using standardized meandifferences (SMD), with the differences in mean values at theend of treatment across treatment groups divided by the pooledstandard deviation. If differences in mean values at the end ofthe treatment were unavailable, differences in mean changes wereused. If some of the required data were unavailable, we used ap-proximations as previously described (Reichenbach 2007). Huang




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2005 B had two experimental groups, which were combined us-

ing weighted averages of the point estimates and pooled standarddeviations. In Huang 2005 Aand Huang 2005 B the units of ran-domisation were patients, whereas the units of analysis were knees.We therefore inflated the standard error with the square root ofthe ratio of number of knees divided by number of patients toaccount for the correlation of knees within patients. An SMD of-0.20 standard deviation units can be considered a small differ-ence between experimental and control group, an SMD of -0.50 amoderate, and -0.80 a large difference (Cohen, 1988; Jni 2006).SMDs can also be interpreted in terms of the percent of overlap ofthe experimental groups scores with scores of the control group.An SMD of -0.20 indicates an overlap in the distributions of painor function scores in about 85% of cases, an SMD of -0.50 in

approximately 67%, and an SMD of -0.80 in about 53% of cases(Cohen, 1988;Jni 2006). Onthe basis of a median pooled SD of2.5 cm found in large-scale osteoarthritis trials that assessed painusing a 10 cm visual analogue scale (VAS) (Nesch 2009), SMDsof -0.20, -0.50 and -0.80 correspond to approximate differencesin pain scores between experimental and control groups of 0.5,1.25 and 2.0 cm on a 10 cm VAS. SMDs for function were backtransformed to a standardised WOMAC disability score (Bellamy1995) ranging from 0 to 10 on the basis of a median pooled SDof 2.1 units observed in large-scale osteoarthritis trials (Nesch2009). Binary outcomes were expressed as relative risks.We used standard inverse-variance random-effects meta-analysis (DerSimonian 1986) to combine trials. We quantified heterogene-

ity between trials using the I2 statistic (Higgins 2003), which de-scribes the percentage of variation across trials that is attributableto heterogeneity rather than to chance and the corresponding2

test. I2 values of 25%, 50% and 75% may be interpreted as low,moderate, and high between-trial heterogeneity, although the in-terpretation of I2 dependsonthesizeandnumberoftrialsincluded(Rcker 2008). The association between trial size and treatmenteffects was investigated in funnel plots, plotting effect sizes on thehorizontal axis against their standard errorson the vertical axis. Weassessed asymmetry by the Eggers test (Sterne 2001). For the mainanalysis on pain and function, we performed analyses stratifiedby the following trial characteristics: concealment of allocation,use of a sham intervention in the control group, blinding of pa-

tients, blinding of outcome assessors, analysis in accordance withthe intention-to-treat principle, trial size, difference in the use ofanalgesic co-interventions, use of concurrent treatment, specifictype of ultrasound therapy (pulsed versus continuous), durationof stimulation per session, total number of sessions, duration oftreatment period and source of funding. A cut-off of 200 patientswas used to distinguish between small and large trials; a sample

size of 100 patients per group will yield more than 80% power to

detect a small to moderate SMD of -0.40 at a two-sided P valueof 0.05. Then, we converted SMDs of pain intensity and func-tion to odds ratios (Chinn 2000) to derive numbers needed totreat (NNT) to cause one additional treatment response on painor function as compared with control, and numbers needed toharm (NNH) to cause one additional adverse outcome. We de-fined treatment response as a 50% improvement in scores ( Clegg2006), which corresponds to an average decrease of 1.2 standarddeviation units (Nesch 2009). With a median standardised painintensity at baseline of 2.4 standard deviation units and a medianstandardised decrease in pain scores of 0.72 standard deviationunits observed in large osteoarthritis trials (Nesch 2009), we cal-culated that a median of 31% of patients in the control group

would achieve an improvement of pain scores of 50% or more.This percentage was used as the control group response rate to cal-culate NNTs for treatment response on pain. Based on the medianstandardised WOMAC function score at baseline of 2.7 standarddeviation units and the median standardised decrease in functionscores of 0.58 standard deviation units (Nesch 2009), 26% ofpatients in the control group would achieve a reduction in func-tion of 50% or more. Again, this percentage was used as the con-trol group response rate to calculate NNTs for treatment responseon function. Median risks of 150 patients with adverse events per1000 patient-years, 4 patients with serious adverse eventsper 1000patient-years and 17 dropouts due to adverse events per 1000 pa-tient-years observed in placebo groups in large osteoarthritis trials

(Nesch 2009) were used to calculate NNHs for safety outcomes.Analyses were performed in RevMan version 5 (Nordic CochraneCentre, Cochrane Collaboration, Copenhagen) and STATA ver-sion 10.1 (StataCorp, College Station, Texas). All P values are two-sided.

R E S U L T S

Description of studies

See: Characteristicsofincludedstudies; Characteristicsofexcludedstudies; Characteristics of studies awaiting classification.We identified 2156 references to articles and considered 66 tobe potentially eligible (Figure 1). Five randomised trials in 341patients met our inclusion criteria. Two trials evaluated pulsedultrasound (Falconer 1992; Huang 2005 A), two continuous (Cetin 2008; zgnenel 2009) and one evaluated both pulsed andcontinuous ultrasound as the active treatment (Huang 2005 B).




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Figure 1. Flow chart

All trials used a parallel group design, in which three used asham intervention in the control group (Falconer 1992; Huang2005 B; zgnenel 2009). All but one trial (zgnenel 2009)provided standardised concurrent treatment in both experimentalandcontrol groups. Cetin2008used hotpacksand isokinetic exer-cise, Falconer 1992 isometric exercise, mobilising exercise, manualtherapy and joint protection, Huang 2005 Aand Huang 2005 Bisokinetic exercise and hot packs. In addition, instruction in dailyhome exercises were given in the trials byFalconer 1992; Huang2005 Aand Huang 2005 B. In the trial byzgnenel 2009, it

was unclear if concurrent treatment was given, with the authorsstating that no physiotherapy was prescribed prior to ultrasoundtreatment to either of the groups, but referring to their interven-tion as physiotherapy program. Therefore, we could not excludethat other physiotherapy modalities were provided in addition toultrasound treatment.Treatment param-eters were insufficiently described (see Characteristics of included

studies). All trials used ultrasound probes with direct skin contactat 1 MHz. 1 to 1.5 W/cm2 was the maximum intensity in trialsusing continuous ultrasound, 2.5 W/cm2 in trials using pulsedultrasound. Two trials explicitly stated the mean intensity, whichwas 1.5 W/cm2 in Cetin 2008 and 1.7 W/cm2 in Falconer 1992.The two trials by Huang and colleagues reported that intensitywas increased up to a level at which a warm sensation or a mildsting was felt, not exceeding 2.5 W/cm2. Only two trials reportedthe size of the probe used (Falconer 1992; zgnenel 2009).The duration of treatment per lesion was reported to be 3, 5 and5 minutes, the number of lesions treated per session four, threeand three, respectively in Falconer 1992; Huang 2005 A; andHuang 2005 B. From these data, we estimated that the durationof ultrasound treatment per session was 12, 15 and 15 minutesin these trials. Cetin 2008 and zgnenel 2009 described thatthe duration of ultrasound per session was 10 and 5 minutes,respectively. The median number of treatment sessions per weekwas 3 (range 2 to 5), the median length of the treatment period




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was 8 weeks (range 2 to 8).

All trials explicitly included patients with knee OA only, with thediagnosis based on clinical and/or radiographic evidence. The ma-jority of patients had a clinical severity requiring simple non-sur-gical treatments (Jni 2006). In one trial, 21 out of 40 patientshad severity grade III or IV according to Kellgren and Lawrence,however (Cetin 2008). In another trial, 8 out of 69 patients hadreceived total knee arthroplasty more than 6 months before thetrial started, and all patients in this study had chronic knee con-tractures (Falconer 1992). One trial reported the average diseaseduration, which was 7 years (Falconer 1992), two reported theaverage body mass index, which was 28 and 32 kg/m2 in Cetin2008 and zgnenel 2009, respectively.Five randomised trials were excluded because a concurrent ther-

apy was given in the ultrasound group, which was not given inthe control group: ultrasound therapy, exercise and hot packs ver-sus exercise in Ones 2006, treatment according to Dutch phys-iotherapy guideline versus behavioral graded activity in Veenhof2007, pulsed short wave diathermy, exercise and ultrasound ther-apy versus pulsed short wave diathermy with different parame-ters, exercise and ultrasound therapy in Tuzun 2003, ultrasoundtherapy, transcutaneous electrostimulation and exercise versus ex-ercise in Dincer 2008 and glucosamine sulfate, NSAID and ul-trasound therapy versus combined traditional Chinese medicineversus glucosamine sulfate, NSAID, ultrasound therapy and tra-ditional Chinese medicine in Qin 2008. Three randomised trialswere excluded because ultrasound was compared to active control

interventions: ultrasound therapy versus short wave diathermy orultrasound therapy with exercise or diathermy with exercise in Jan1991, ultrasound therapy with deep relief gel versus ultrasoundtherapy with standard gel in Yang 2005, ultrasound therapy ver-sus phonophoresis in Dafinova 1996 and Kozanoglu 2003, andultrasound therapy versus shortwave diathermy or galvanic elec-trostimulation in Bansil 1975, Kalpakcioglu 2006 and Svarcova1988. Bansil 1975 and Svarcova 1988 were included in the previ-ous version of this review. The Characteristics of excluded studiestable presents the main reasons for exclusion of other studies.

Risk of bias in included studies

Figure 2 summarises the methodological characteristics and source

of funding of included trials. No trial reported adequate sequence

generation or adequate concealment of allocation. Both trials by

Huang et al reported the use of sequentially numbered, sealed andopaque envelopes, but they reported that envelopes were sequen-tially numbered I to IV, likely to represent the four comparisongroups patients were allocated to in both of these trials. The en-velopes should have been numbered 1 to 140 and 1 to 120 tocover the numbers of patient randomised in Huang 2005 AandHuang 2005 B, respectively. As we had no evidence to suggestthat the envelopes were appropriately numbered in a sequentialmanner, random allocation could have been undermined. Twotrials were described as double-blind (Falconer 1992, zgnenel2009). Three trials used sham interventions, using identical de-vices in experimental and control groups (Falconer 1992, Huang2005 B, zgnenel 2009). In Falconer 1992, the sham device

was fully functional, dials were lit, audible beeps were given, butno energy was delivered to the tissue. In Huang 2005 B, the in-vestigators stated that the absence of a warm or stinging sensa-tion in the control group resulted in a failure of patient blind-ing. zgnenel 2009 stated that the probe was disconnected onthe back of a working ultrasound machine and the patient wasunable to determine whether the cable was disconnected or not.Only the sham device used in Falconer 1992 and zgnenel 20092009 were therefore considered to have adequate patient blinding.None of the trials was considered to have performed an intention-to-treat analysis for any of the primary outcomes of this review.Exclusions had explicitly occurred in all but two trials, with per-centages of exclusions ranging from 0% to 10% in experimental

groups and from0% to 17% incontrol groups. Intwo trials(Cetin2008; zgnenel 2009) it was unclear whether exclusions fromthe analysis had occurred. Three trials explicitly specified primaryoutcomes, although it was unclear whether these were specified apriori (Falconer 1992; Huang 2005 B; zgnenel 2009). OnlyFalconer 1992 and zgnenel 2009 reported a sample size calcu-lation. None of the trials had a sample size of approximately 200patients to achieve sufficient power for detecting a small to mod-erate SMD. Three trials were supported by a non-profit organisa-tion (Falconer 1992; Huang 2005 A; Huang 2005 B), one was alsosupported by a commercial body (Huang 2005 B). The source offunding was unclear in the the other two trials (see Characteristicsof included studies).




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Figure 2. Methodological characteristics and source of funding of included trials. (+) indicates low risk of

bias, (?) unclear and (-) a high risk of bias on a specific item.




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For the effectiveness outcomes pain and function, the quality of

the evidence (Guyatt 2008) was classified as low in view of the riskof bias in the included, predominantly small trials of questionablequality, the large heterogeneity between trials on function, the po-tential for selective reporting of function outcomes and the pos-sible indirectness of one trial (Summary of findings for the maincomparison). For the safety outcomes, the quality of the evidence(Guyatt 2008) was classified as low, again because of the predom-inantly small trials of questionable quality, the small number oftrials reporting the outcomes and the absence of events resultingin not estimable relative risks.

Effects of interventions

See: Summary of findings for the main comparison

Pain

Five trials (320 patients, 464 knees) contributed to the meta-anal-ysis of pain outcomes (Figure 3). The analysis suggested a SMDof -0.49 (95% CI -0.76 to -0.23), which corresponds to a differ-ence in pain scores of 1.2 cm on a 10-cm VAS between ultrasoundand control. Referring to a median pain intensity of 6.1 cm inplacebo groups at baseline, this corresponds to a difference of 21%improvement (95% CI 10% to 32%) between electrostimulationand control (Summary of findings for the main comparison). TheNNT to cause one additional treatment response on pain as com-pared to control was 6 (95% CI 5 to 12). An I2 of 26% indicateda low degree of of between-trial heterogeneity (P value for hetero-

geneity = 0.25). The funnel plot did not appear asymmetrical (Figure 4, P value for asymmetry = 0.23).

Figure 3. Forest plot of 5 trials comparing the effects of therapeutic ultrasound and control (sham or no

intervention) on knee pain. Values on x-axis denote standardised mean differences. Data relating to the 2

experimental arms in Huang 2005 B were pooled.




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Figure 4. Funnel plot for effects on knee pain.

Numbers on x-axis refer to standardised mean differences (SMDs), on y-axis to standard errors of SMDs.

Table 1 presents results from stratified analyses. There was littleevidence that estimates of SMD increased with the duration ofultrasound therapy applied per session (P value for trend = 0.15).There was no evidence to suggest that SMDs depended on thetype of ultrasound therapy used (P value for interaction = 0.48).SMDs did not seem to depend on type of control intervention,patient blinding, total number of sessions or treatment duration.The absence of sufficient (high quality) trials hampered the ex-ploration of associations of SMDs with other trial characteristics.In all trials it was unclear whether the provision of analgesic co-interventions was similar between groups, none hadused adequate

concealment of allocation, performed analyses according to theintention-to-treat principle or achieved a sample size of at least200 patients. Therefore, we could not evaluate the impact of thesecharacteristics.

Table 1. Results of stratified analyses of pain outcomes

Variable No. of trials No. of patients:experimental

No. of patients:control

Pain-intensity Heterogeneity P for interaction

n n n SMD (95% CI) I2 (%)




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FunctionFour trials (251patients)contributed to the meta-analyses of func-tion (Figure 5). The analysis suggested a SMD of -0.64 (95% CI-1.42 to 0.14, P value = 0.11), corresponding to a difference infunction scores of 1.3 units on a standardised WOMAC disabilityscale ranging from 0 to 10, favouring ultrasound therapy. Refer-ring to a median function score of 5.6 units in placebo groupsat baseline, this corresponds to a difference of 25% improvement(95% CI -5% to 54%) between electrostimulation and control(Summary of findings for the main comparison). The NNT tocause one additional treatment response on function as comparedto control was not calculated as differences were not statisticallysignificant. An I2 of 88% indicated a large degree of between-

trial heterogeneity (P value for heterogeneity < 0.001). On visualinspection, the variation could be explained by the trial of Cetin2008 that estimated an effect size favouring control, in contrast tothe other trials. The trial byHuang 2005 Areported an unrealisti-cally large effect in favour of ultrasound therapy. The funnel plotdid not appear asymmetrical (Figure 6, P value for asymmetry =0.93).

Figure 5. Forest plot of 3 trials comparing the effects of therapeutic ultrasound and control (sham or no

intervention) on function. Values on x-axis denote standardised mean differences. Data relating to the 2

experimental arms in Huang 2005 B were pooled.




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Figure 6. Funnel plot for effects on functioning of the knee.

Numbers on x-axis refer to standardised mean differences (SMDs), on y-axis to standard errors of SMDs.

Table 2 presents results from stratified analyses. There was littleevidence that estimates of SMD increased with the duration ofultrasound therapy applied per session (P value for trend = 0.16),but a positive interaction test suggested that SMDs were associatedwith the type of ultrasound therapy used, with more favourableeffects of pulsed ultrasound therapy (P value for interaction =0.005).The absence of sufficient high quality trials hampered theexploration of potential effects of all other treatment and designcharacteristics. Confidence intervals were either wide and tests ofinteraction not significant or the impact of several characteristicscould not be evaluated at all.

Table 2. Results of stratified analyses of function

Variable No. of trials No. of patients:experimental

No. of patients:control

Pain-intensity Heterogeneity P for interaction

n n n SMD (95% CI) I2 (%)

All trials 4 143 108 -0.64 (-1.42to0.14)

88%




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Table 2. Results of stratified analyses of function (Continued)

Total number ofsessions

0.70

10 1 34 33 -0.27 (-0.76 to0.22)

N/A

12 0

24 3 109 75 -0.76 (-1.83 to0.31)

91%

Durationof treatment pe-riod

0.70

2 weeks 1 34 33 -0.27 (-0.76 to0.22)

N/A

6 weeks 0

8 weeks 3 109 75 -0.76 (-1.83 to0.31)

94%

Commercialfunding

0.78

Yes 1 57 25 -0.90 (-1.39 to -0.41)

N/A

No or unclear 3 86 83 -0.54 (-1.65 to0.56)

91%

US: Ultrasound therapy; No.: number; N/A: not applicable; Huang 2005 B contributed to both strata, with the same 25 controlpatients displayed in each stratum; P-value from test for trend.

Safety

One trial contributed to the analysis of patients experiencing anyadverse event or being withdrawn or dropping out because of ad-verse events (zgnenel 2009). This trial reported that no ad-verse events or withdrawals or dropouts due to adverse events hadoccurred, neither in the experimental nor in the control group.Therefore, relative risks could not be estimated. Two trials (136patients) contributed to the meta-analysis of patients experienc-ing any serious adverse event (Falconer 1992; zgnenel 2009).Again, the relative risk could not be calculated since both reportsstated that no serious adverse events had occurred, neither in the

ultrasound nor in the control group. In general, there was no evi-dence to suggest that electrostimulation is unsafe.

D I S C U S S I O N

Summary of main results

Our systematic review of trials comparing any type of therapeuticultrasoundwith a shamor non-intervention control revealed a lackof adequately sized, methodologically sound and appropriately




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reported trials and a high degree of between trial heterogeneity for

one of the two main outcomes, which made the interpretation ofresultsdifficult.Overalleffectsizesforpainreliefandimprovementof function in patients with knee osteoarthritis seemed moderatelyin favour of ultrasound therapy. Only two trials reported safetyoutcomes;generally,thereisnoevidencetosuggestthatultrasoundtherapy is unsafe. In view of its mechanisms of action, ultrasoundtherapy is rather unlikely to cause serious adverse events but activesurveillance of harms with formal monitoring of potential adverseevents is clearly desirable.

Quality of the evidence

The methodological quality and the quality of reporting was poor.All trials were small sized, including 82 patients at most. None ofthe trials described generation of allocation sequences or conceal-ment of allocation, or reported whether primary outcomes werespecified a priori. None of the trials was analysed according tothe intention-to-treat principle, and only one trial described theoccurrence of adverse events or withdrawals and dropouts becauseof adverse events.

Potential biases in the review process

Our review is based on a broad literature search, and it seems un-

likely that we missed relevant trials (Egger 2003). Trial selectionand data extraction, including quality assessment, were done in-dependently by two authors to minimize bias, transcription errorsandothersourcesofobservervariation(Egger2001; Tendal 2009).Components used for quality assessment are validated and re-ported to be associated with bias (Jni 2001; Wood 2008; Nesch2009). As with any systematic review, our study is limited by thequality of included trials. As indicated above, trials generally suf-fered from poor methodological quality, inadequate reporting andsmall sample size. The low number of trials hampered our explo-ration of the potential effects of ultrasound modalities, subopti-mal design choices and type of funding. One trial showed an un-realistically large SMD for function (Huang 2005 A). Conversely,

Cetin 2008 reported a null effect for pain and a trend towards aharmful effectof ultrasoundfor function. The confidence intervalsof this trials effect size for pain overlapped with the confidenceintervals of all other trials, accordingly the estimated heterogeneitybetween trials was low. SMDs for function were discrepant, how-ever: whereas the effect size in zgnenel 2009 were just aboutcompatible withCetin2008,and Huang 2005 B, they were clearlyincompatible with Huang 2005 A. These discrepancies may bedue to differences in characteristics of the intervention, differencesin patient characteristics, bias or chance. The discrepancies areunlikely to be explained by the type of scale used, however: theLequesne algofunctional scale used by Cetin 2008 was also usedin Huang 2005 Aand Huang 2005 B, which showed a clearcut

benefit of ultrasound. If we had used walking speed data rather

than the Lequesne index as a measure of function, effect sizes inthe trials by Huang and colleagues would have been even moreextreme in favour of ultrasound (SMD -1.7, 95% CI -2.3 to -1.1 in Huang 2005 Aand -2.1, 95% CI -2.64 to -1.50 in Huang2005 B). Walking speed was also recorded in Falconer 1992, andalthough we were unable to obtain sufficient data to calculate theSMD for function, the reported results indicate that differencesbetween groups were likely to be small, non-significant and incontrast to Huang and colleagues results. The absence of signif-icance can not be explained by sample size alone, as the numberof patients in Falconer 1992 exceeded the numbers analysed inHuang 2005 A.

Agreements and disagreements with otherstudies or reviews

We are aware of 14 related reviews addressing the effectiveness ofultrasound therapy for knee or hip osteoarthritis (list available onrequest). Here we will focus mainly on the similarities with anddifferences to the previous version of this review (Welch 2001),which included three studies. We updated the search and usedstricter selection criteria, which resulted in four additional trials.In contrast to the review ofWelch 2001, we only included ran-domised trials. Welch and colleagues also included other designtypes and allowed active treatment in the control group. Here we

focused on sham or non-intervention controls and excluded twopreviously included studies (Bansil 1975; Svarcova 1988). In thisupdate, we performed a detailed quality assessment of componenttrials, followed by an exploration of sources of variation betweentrials, including concealment of allocation, blinding, intention-to-treat analysis, and characteristics of ultrasound therapy, whichwas not possible in the previous version, due to the low number oftrials identified. To analyse continuous data, Welch and colleaguesused weighted mean differences of the change from baseline scores,whereas we used SMDs of end of treatment scores. In addition,fixed effect models were used in the previous version unless therewas statistically significant heterogeneity between trials based on2 testing. Model selection based on the mechanistic application of

heterogeneity tests shouldbe avoided, however. Here,we used ran-dom effects models, which will generally be more conservative interms of the estimated precision, but will be more affected by smallstudy effectsthan a fixed effectmodel, which makes an explorationof sources of variation including different types of bias mandatory.Results from the previous and current version are therefore not di-rectly comparable.Welch 2001 concludedthatultrasoundtherapyappeared to have no benefit over placebo or short wave diathermyfor people with hipor knee OA. Ouroverall estimates forpain andfunction seemed moderate, favouring therapeutic ultrasound, butwe share concerns expressed byWelch 2001, who stated that con-clusions were limited by the poor reporting of the characteristicsof the device, the population, the stage of OA, therapeutic appli-




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cation of the ultrasound and overall low methodological quality

of the trials included.Srbely2008 recentlypublishedasystematicreviewevaluatingther-apeutic ultrasound in people with osteoarthritis. They includedfive reviews and nine original studies, including animal and nonrandomised studies, and refrained from statistically summarisingthe data. Nevertheless, the paper seems to give a complete overviewon the available evidence for therapeutic ultrasound. As in thepresent review, the authors acknowledged the low quality of evi-dence. They highlighted, however, that there is an accumulatingbody of research suggesting that ultrasound may have the poten-tial to provide significant benefits in the treatment and manage-ment of the osteoarthritic complex. Following this statements,wethink ultrasound should not be discarded as treatment adjunctive,

however, health specialist should be aware of the lack of soundevidence and be reluctant to give ultrasound therapy as a routineoption, until valid evidence supporting its use becomes available.Our ratings of methodological quality differ in some respect fromthose that can be found in PEDro (http://www.pedro.org.au/). Asan example, for both trials of Huang 2005 Aand Huang 2005B our ratings concerning generation of allocation sequences andconcealment of allocation differ. We rated these components asunclear, whereas PEDro assessors rated them as adequate. Thisdifference can not be explained by the definitions used, which aresimilar in our review and in PEDro. PEDro does not allow for acategory unclear, however, which may have driven the assessors togive credit to these two trials and classify randomisation methods

as adequate rather than inadequate in the absence of evidencesuggesting neither of the two mutually exclusive categories.

A U T H O R S C O N C L U S I O N S

Implications for practice

Despite the widespread use of therapeutic ultrasound in physicaltherapy, evidence of its clinical effectiveness in people with hip orknee OA is of poor quality and therefore inconclusive. The effectsof ultrasound therapy on both, knee pain and function, are po-tentially clinically relevant and deserve further clinical evaluation.

Implications for research

The current systematic review is inconclusive, hampered by theinclusion of only small trials of questionable quality. Adequatelysized randomised parallel-group trials in approximately 2 x 100patients with knee or hip osteoarthritis are necessary to determinewhether either continuous or pulsed ultrasound therapy is indeed

associated with a clinically relevant benefit on pain and function.A sample size of 2 x 100 patients will yield more than 80% powerto detect a small to moderate SMD of -0.40 at a two-sided P valueof 0.05. The trials should enrol patients without prior experienceof ultrasound therapy or evaluate success of blinding at the endof trial, use adequate concealment of allocation, experimental andsham interventions that are close to indistinguishable and an in-tention-to-treat analysis. Evaluation whether effects increase withlonger stimulation times per session or with type of ultrasound isrecommended.

A C K N O W L E D G E M E N T S

Vivian Welch, Lucie Brosseau, Joan Peterson, Beverley Shea, PeterTugwell and George A. Wells were authors on the original review.We thank the Cochrane Musculoskeletal editorial team for valu-able comments and Malcolm Sturdy for database support. Theauthors are grateful to Judith Falconer for providing additionalinformation concerning design and for trying to locate files of hertrial published in 1992.

R E F E R E N C E S

References to studies included in this review

Cetin 2008 {published data only}Cetin N, Aytar A, Atalay A, Akman MN. Comparing hot pack,short-wave diathermy, ultrasound, and TENS on isokineticstrength, pain, and functional status of women with osteoarthriticknees: a single-blind, randomized, controlled trial. American

Journal of Physical Medicine & Rehabilitation 2008;87:44351.

Falconer 1992 {published data only} Falconer J, Hayes KW, Change RW. Effect of ultrasound onmobility in osteoarthritis of the knee. Arthritis Care and Research1992;5(1):2935.

Huang 2005 A {published data only}Huang MH, Yang RC, Lee CL, Chen TW, Wang MC, HuangMH, et al.Preliminary results of integrated therapy for patients withknee osteoarthritis. Arthritis and rheumatism 2005;53:81220.

Huang 2005 B {published data only}Huang MH, Lin YS, Lee CL, Yang RC, Huang MH, Lin YS, etal.Use of ultrasound to increase effectiveness of isokinetic exercisefor knee osteoarthritis. Archives of Physical Medicine &Rehabilitation 2005;86:154551.

zgnenel 2009 {published data only}zgnenel L, Aytekin E, Durmuolu G. A double-blind trialof clinical effects of therapeutic ultrasound in knee osteoarthritis.Ultrasound in medicine & biology2009;35(1):449.




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References to studies excluded from this review

Antich 1986 {published data only}Antich TJ, Randall CC, Westbrook RA, Morrissey MC, BrewsterCE. Physical therapy treatment of knee extensor mechanismdisorders: comparison of four treatment modalities. The Journal ofOrthopaedic and Sports Physical Therapy1986;8:25559.

Bansil 1975 {published data only}Bansil CK, Joshi JB. Effectiveness of shortwave diathermy andultrasound in the treatment of osteoarthritis of the knee joint.

Medical journal of Zambia1975;9(5):1389.

Esmat 1975 {published data only}Esmat N. Treatment of arthrosis deformans by simultaneousapplication of interferential current and ultrasonic waves. The

Journal of the Egyptian Medical Association 1975;58:32833.

Jan 1991 {published data only}Jan MH, Lai JS. The effects of physiotherapy on osteoarthritic kneesof females. Journal Formosan Medical Association 1991;90:100813.

Jones 2004 {published data only}Jones JP, Bae YK. Ultrasonic imaging, characterization, andstimulation of acupuncture points. Journal of Alternative &Complementary Medicine. 2004; Vol. 10, issue 1:202-203 (O-9).

Lindahl 1952 {published data only}Lindahl O. Clinical effect of ultrasonic waves in chondromalacicand osteoarthritic changes in the knee. Rheumatism 1952;8(2):3637.

Machalett 1975 {published data only}

Machalett H. Questions of therapy and morbidity of the bonyframework and the locomotor apparatus in a rural practice.Zeitschrift fr rztliche Fortbildung1975;69:4345.

Svarcova 1988 {published data only}Svarcova J, Trnavsky K, Zvarova J. The influence of ultrasound,galvanic currents and shortwave diathermy on pain intensity inpatients with osteoarthritis. Scandinavian journal of rheumatology1988;Suppl. 67:8385.

Zielke 1987 {published data only}Zielke A. Physical therapy in degenerative diseases of the joints.

Zeitschrift fr die gesamte innere Medizin und ihre Grenzgebiete

1987;42:1058.

References to studies awaiting assessment

Kostadinov 1978 {published data only}Kostadinov D, Mihailov S, Kalaidjiev G. Kurortologiya i.Comparative investigations on gonarthrosis treatment with somephysical factors. [Bulgarian]. Fizioterapiya1978;15:16974.

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Bellamy 1995

Bellamy N. Outcome measurement in osteoarthritis clinical trials. JRheumatol1995;22(suppl.43):4951.

Chinn 2000Chinn S. A simple method for converting an odds ratio to effectsize for use in meta-analysis. Statistics in Medicine2000;19(22):312731.

Clegg 2006Clegg DO, Reda DJ, Harris CL, Klein MA, ODell JR, HooperMM, et al.Glucosamine, chondroitin sulfate, and the two incombination for painful knee osteoarthritis. New England Journalof Medicine2006;354(8):795808.

Cohen, 1988Cohen, J. (1988). Statistical power analysis for the behavioral sciences.

2nd Edition. Hillsdale, NJ: Lawrence Earlbaum Associates, 1988.Dafinova 1996

Dafinova Y, Boncheva I, Dikova M, Popov V, Lozanova M.Ultraphonophoretic application of voltaren emulgel in patientswith knee-joint osteoarthrosis [Bulgarian]. Fizikalna Kurortna iRekhabilitatsionna Meditsina1996;35(1):1820.

DerSimonian 1986DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlledclinical trials1986;7(3):17788. [PUBMED: 3802833]

Dickersin 1994Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies forsystematic reviews. BMJ1994;309(6964):128691.

Dincer 2008

Dincer U, Cakar E, Ozdemir B, Kiralp MZ, Dursun H.Comparison of effects of combined physical therapy program andexercise on corrupted balance functions in patient with kneebilateral osteoarthritis [Turkish]. Romatizma2008;23(1):913.

Egger 2001Egger M, Smith GD. Principles of and procedures for systematicreviews. In: Egger M, Smith GD, Altman DG editor(s). SystematicReviews in Health Care: Meta-Analyis in Context. London: BMJBooks, 2001:2342.

Egger 2003Egger M, Juni P, Bartlett C, Holenstein F, Sterne J. How importantare comprehensive literature searches and the assessment of trialquality in systematic reviews? Empirical study. Health technology

assessment (Winchester, England) 2003;7(1):176.Guyatt 2008

Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al.GRADE: an emerging consensus on rating quality ofevidence and strength of recommendations. BMJ2008;336(7650):9246.

Hartley 1993Hartley A. Therapeutic Ultrasound. Anne Hartley Agency. 2.Etobicoke, Ontario, Canada: Anne Hartley Agency, 1993.

Hicks 1990Hicks JE. Exercise in patients with inflammatory arthritis andconnective tissue disease. Rheumatic diseases clinics of North America1990;16(4):84570.




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Higgins 2003

Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuringinconsistency in meta-analyses. BMJ2003;327(7414):55760.

Higgins 2008Higgins JPT, Green S (eds). Cochrane Handbook for SystematicReviews of Interventions. Version 5.0.1 [updated September 2008].The Cochrane Collaboration, 2008. Available fromwww.cochranehandbook.org.

Jni 2001Jni P, Altman DG, Egger M. Systematic reviews in health care:Assessing the quality of controlled clinical trials. BMJ2001;323(7303):426. [PUBMED: 11440947]

Jni 2006Jni P, Reichenbach S, Dieppe P. Osteoarthritis: rational approachto treating the individual. Best practice & research. Clinicalrheumatology2006;20(4):72140.

Kalpakcioglu 2006Kalpakcioglu BA, Cakmak B, Bahadir C. Comparison of ultrasoundand short wave diathermy therapy in knee osteoarthritis [Turkish].Turkiye Fiziksel Tip ve Rehabilitasyon Dergisi2006;52(4):16873.

Kozanoglu 2003Kozanoglu E, Basaran S, Guzel R, Guler-Uysal F. Short termefficacy of ibuprofen phonophoresis versus continuous ultrasoundtherapy in knee osteoarthritis. Swiss Medical Weekly2003;133:3338.

Nelson 1999Nelson RM, Hayes KW, Currier DP. Clinical Electrotherapy. ThirdEdition. Appleton & Rouge, 1999.

Nesch 2009Nesch E, Trelle S, Reichenbach S, Rutjes AW, Brgi E, Scherer M,et al.The effects of the exclusion of patients from the analysis inrandomised controlled trials: meta-epidemiological study. BMJ2009;339:b3244.

Ones 2006Ones K, Tetik S, Tetik C, Ones N. The effects of heat onosteoarthritis of the knee. The Pain Clinic2006;18(1):6775.

Pham 2004Pham T, van der Heijde D, Altman RD, Anderson JJ, Bellamy N,Hochberg M, et al.OMERACT-OARSI initiative: OsteoarthritisResearch Society International set of responder criteria forosteoarthritis clinical trials revisited. Osteoarthritis Cartilage2004;12(5):38999.

Qin 2008Qin XY, Li XX, Berghea F, Suteanu S, Qin X-Y, Li X-X, etal.Comparative study on Chinese medicine and western medicinefor treatment of osteoarthritis of the knee in Caucasian patients.

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Rcker G, Schwarzer G, Carpenter JR, Schumacher M. Unduereliance on I2 in assessing heterogeneity may mislead. BMC medicalresearch methodology2008;8(1):79. [PUBMED: 19036172]

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Srbely 2008Srbely JZ. Ultrasound in the management of osteoarthritis: part I: areview of the current literature. Journal of the Canadian Chiropractic

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Sterne 2001Sterne JA, Egger M. Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis.

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Tuzun 2003Tuzun EH, Otman S, Kirdi N. Comparison of different methods ofpulsed shortwave diathermy in knee osteoarthritis. The Pain Clinic2003;15:42127.

Veenhof 2007Veenhof C, Chm, Dekker J, Koke AJA, Oostendorp RA, BijlsmaJWJ. Which patients with osteoarthritis of hip and/or knee benefit

most from behavioral graded activity?. International Journal ofBehavioral Medicine2007;14:8691.

Wood 2008Wood L, Egger M, Gluud LL, Schulz KF, Jni P, Altman DG, etal.Empirical evidence of bias in treatment effect estimates incontrolled trials with different interventions and outcomes: meta-epidemiological study. BMJ (Clinical research ed.) 2008;336(7644):6015. [PUBMED: 18316340]

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References to other published versions of this review

Welch 2001Welch V, Brosseau L, Peterson J, Shea B, Tugwell P, Wells G.Therapeutic ultrasound for osteoarthritis of the knee. CochraneDatabase of Systematic Reviews2001, Issue 3. [DOI: 10.1002/14651858.CD003132]




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Indicates the major publication for the study

C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Cetin 2008

Methods Randomised controlled trial5-arm parallel group designTrial duration: 8 weeks

No power calculation reportedFunding by non-profit organisation: no information provided

Participants 100 patients randomised*100 patients with knee OA reported at baselineStudy joints: 100 kneesNumber of females: 100 of 100 (100%)Average age: 60 yearsAverage BMI: 28 kg/m2Average disease duration: not reportedSeverity**: according to Kellgren and Lawrence: 3 patiens with grade I, 16 with II, 16with grade III, and 5 with grade IV

Interventions Experimental intervention: Ultrasound therapy + hot packs + isokinetic exercise, 3 timesper weekControl intervention: hot packs + isokinetic exercise, 3 times per weekDuration of treatment period: 8 weeksAnalgesics allowed, unclear whether intake was similar between groups.Device: Sonopuls 590 US (Enraf Nonius)Type: continuous USDuration of stimulation per session: 10 minutes, minutes pertreated region notreportedTotal sessions: 24Frequency: 1.00 MHzIntensity: 1.5 W/cm2Head size (cm2): not reported

Treated anatomical areas: around the knee, with lower extremity in maximal extensionArea treated per session: not reportedSkin preparation: not reported (direct contact)Safety precautions: not reported

Outcomes Extracted pain outcome: Pain on walking after 8 weeks (VAS), described as Knee painseverity after a 50-m walkExtracted function outcome: Lequesne OA index global score (Likert) after 8 weeksNo primary outcome reported

Notes *Only 2 arms (40 patients) qualified for inclusion in this review. In total, 100 patientswere equally randomised in 5 groups: 1) short wave diathermy + hot packs + isokinetic




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Cetin 2008 (Continued)

exercise, 2) transcutaneous electrical stimulation + hot packs + isokinetic exercise, 3)Ultrasound therapy + hot packs + isokinetic exercise, 4) hot packs + isokinetic exercise,5) isokinetic exercise.** numbers applicable to the 40 patients included in the review

Risk of bias

Item Authors judgement Description

Adequate sequence generation? Unclear No information provided.

Allocation concealment? Unclear No information provided.

Adequate blinding of patients? No No sham intervention.

Adequate blinding of physicians/physicaltherapists?

No For safety reasons, the treating health careprovider must be aware of the type of ul-trasound therapy given.

Adequate blinding of outcome assessors? Unclear Although the investigators wrote that Pa-tients were evaluated at baseline and at theend of the treatment sessionsby the physician, who was blinded with re-

gard to the type of treatment the patientswouldreceive, VAS andLequesnearelikelyto be self reported by patients, who werenot blinded.

Intention-to-treat analysis performed?Pain

Unclear No information provided.

Intention-to-treat analysis performed?Function


Funding by commercial organisationavoided?


Falconer 1992

Methods Randomised, double-blind trial2-arm parallel group designTrial duration: 14.6 weeksPower calculation reportedFunding by non-profit organisation: Arthritis Foundation, Arthritis Health Prof. Asso-ciation, NIAMS Grant number AM30692

Participants 74 patients randomisedNumber of patients with knee OA not reported at baseline




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Falconer 1992 (Continued)

Study joints analysed: 69Number of females: 50 of 69 (72%)Average age: 68 yearsAverage BMI: not reportedAverage disease duration: 6.95 years (US: 6.4, Control: 7.5)Severity: moderate knee OA, Altman grade II, 8 patients had history of total kneereplacement

Interventions Experimental intervention: ultrasound therapy, 2-3 times per weekControl intervention: sham ultrasound therapy, 2-3 times per weekConcurrent Treatment (30 minutes): passive stretch during cooling period, manual ther-

apy, active ROM and isometric strengthening exercises, instruction in daily home exer-cise, joint protection.Duration of treatment period: 6 weeksUnclear whether analgesics were allowed and the intake was assessedDevice: Sonopulus 590 (Enraf Nonius)Type: not reported, but in light of the maximal intensity reported, most likely pulsedultrasound therapyDuration of stimulation per session: 12 minutes, 3 minutes per treated regionTotal sessions: 12Frequency: 1.00 MHzIntensity: mean 1,7 W/cm2, increased to maximum tolerable dosage, at which warmthwithout pain was felt, not exceeding 2.5 W/cm2Head size (cm2): 10 (effective radiating surface 8.5)

Treated anatomical areas: anterior, posterior, medial, lateral, with lower extremity inmaximal flexion or extension, depending on which end range presented with the mostfunctional lossArea treated per session: 100cm2Skin preparation: aqueous gelSafety precautions: power increased in 0.1W/cm2 increments to a maximum of2.5W/cm2

Outcomes Extractedpain outcome: Global pain at 6 weeks, described as pain, measured on 10 cmVAS.Extracted function outcome*: Walking disability at 6 weeks, described as gait velocity.Primary outcome: Pain and active range of motion

Notes *not enough data presented to allow pooling, it was only stated that no significantdifferences were observed between the experimental and control group. Despite a greateffort, Dr. Falconer was unable to locate the original data file and to provide additionaldata.

Risk of bias


Adequate sequence generation? Unclear No information provided. In personalcommunication Dr Falconer indicated thatpermuted block randomisation was used.




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Falconer 1992 (Continued)

Allocation concealment? Unclear No information provided.

Adequate blinding of patients? Yes Sham device: identical in appearance, dialswere lit and audible beeps were given ateach sham increase in dosage. No energydelivered to tissue.



Adequate blinding of outcome assessors? Yes


No 34 out of 37 (92%) randomised to experi-mentaland 35outof 37(95%) randomisedto control group were analysed.


No Not applicable, trial did not contribute tofunction meta-analyses.



Huang 2005 A

Methods Randomised trial4-arm parallel group designTrial duration: 8 weeksNo power calculation reportedFunding by non-profit organisation: Supported by a project grant provided from theNational Science Council of Taiwan

Participants 140 patients randomised*140 patients with bilateral knee OA reported at baselineStudy joints: 280 knees for pain outcome

Number of females: 113 of 140 (81%)Average age: 65 yearsAverage BMI: not reportedAverage disease duration: not reported, ranging from 5 months to 12 yearsSeverity: moderate knee OA, Altman grade II

Interventions Experimentalintervention:Ultrasoundtherapy,isokineticexercise,hotpacks,threetimesper weekControl intervention: isokinetic exercise and hot packs, three times per weekDuration of treatment period: 8 weeksUnclear whether analgesics were allowed and the intake was assessedDevice: Sonopulus 590 (Enraf Nonius)Duration of stimulation persession: unclear, 5 minutes per treated to each treated region




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Huang 2005 A (Continued)

Total sessions: 24 plannedFrequency: 1.00 MHzIntensity: up to a level at which a warm sensation or a mild sting was felt, not exceeding2.5 W/cm2Head size (cm2): not reportedTreated anatomical areas: medial collateral ligament, anserine bursa, and the poplitealfossa tender points (5min/area), with lower extremity in 90 flexion for first 2 areas andmaximal extension for popliteal fossa pointsArea treated per session: 25cm2Skin prep: not reportedSafety precautions: none reported

Outcomes Extracted pain outcome: Pain on walking at 8 weeks, described as severity of kneepain while remaining in a weight-bearing position (walking or standing) for 5 minutes,measured on 10 cm VAS.Extracted function outcome: Lequesnes Index after 8 weeks, measured on 0 to 26 Likertscale.Primary outcome: not reported

Notes *2 arms (70 patients) were excluded from the review: no intervention arm (35 patients)and isokinetic exercise + pulsed ultrasound + intraarticular hyaluronan + hot packs arm(35 patients).

Risk of bias



Allocation concealment? Unclear Although authors wrote that they usedsequentially numbered opaque sealed en-velopes, we had no evidence to suggestthattheenvelopeswereappropriatelynum-bered in a sequential manner and randomallocation couldthereforehave been under-mined.

Quote: and randomly assigned to 4 groups(groups I-IV) by a secure system of opaquesealed envelopes that were sequentiallynumbered I-IV. The doctor who assignedthe patients was blinded to the treatmentthe patients would receive.With 140 patients randomised, the en-velopes should have been sequentiallynumbered 1-140 and not I to IV.

Adequate blinding of patients? No No sham intervention.




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Huang 2005 A (Continued)


No No sham intervention.

Adequate blinding of outcome assessors? Unclear Quote: All the evaluations were performedby the same physiatrists who were alsoblinded to the treatment the patients re-ceived. We scored unclear for both painand function, however, as a VAS was usedforpain,andLequesneforfunctionthatareusually scored by the patient, who was not

blinded.


No 64 out of 70 (91%) randomised to experi-mentaland 60outof 70(86%) randomisedto control group were analysed (analysis onknee level).


No 32 out of 35 (91%) randomised to experi-mentaland 30outof 35(86%) randomisedto control group were analysed (analysis onpatient level).

Funding by commercial organisation

avoided?


Huang 2005 B

Methods Randomised trial4-arm parallel group designTrial duration: 8 weeksNo power calculation reportedFunding by non-profit organisation: Supported by a project grant provided from theNational Science Council of Taiwan (grant number NSC-92-2314-B-037-067)

Participants 120 patients randomised*

120 patients with bilateral knee OA reported at baselineStudy joints: 240 knees for pain outcomeNumber of females: 97 of 120 (81%)Average age: 62 yearsAverage BMI: not reportedAverage disease duration: not reported, ranging from 6 months to 11 yearsSeverity: moderate knee OA, Altman grade II

Interventions Comparison 1:Experimental intervention: continuous ultrasound therapy, isokineticexercise, hot packs,three times per weekControl intervention: sham ultrasound therapy, isokinetic exercise and hot packs, threetimes per week




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Huang 2005 B (Continued)

Comparison 2:Experimental intervention: pulsed ultrasound therapy, isokinetic exercise, hot packs,three times per weekControl intervention: sham ultrasound therapy, isokinetic exercise and hot packs, threetimes per weekDuration of treatment period: 8 weeksUnclear whether analgesics were allowed and the intake was assessedDevice: Sonopulus 590 (Enraf Nonius)Duration of stimulation per session: unclear, 5 minutes per treated to eachtreated regionTotal sessions: 24 plannedFrequency: 1.00 MHz

Intensity: up to a level at which a warm sensation or a mild sting was felt, not exceeding2.5 W/cm2Head size (cm2): not reportedTreated anatomical areas: medial collateral ligament, anserine bursa, and the poplitealfossa tender points (5min/area), with lower extremity in 90 flexion for first 2 areas andmaximal extension for popliteal fossa pointsArea treated per session: 25cm2Skin prep: not reportedSafety precautions: none reported

Outcomes Extracted pain outcome: Pain on walking at 8 weeks, described as severity of knee painwhile remaining in a weight-bearing position (walking or standing) for 5 minutes in theparallel bars of the treadmill, measured on 10 cm VAS.

Extracted function outcome: Lequesnes Index after 8 weeks, measured on 0 to 26 Likertscale.Primary outcome: Change in ambulation speed and Lequesne index

Notes *1 arm (30 patients), in which no intervention was given, was excluded from the review

Risk of bias



Allocation concealment? Unclear Although authors wrote that they usedsequentially numbered opaque sealed en-velopes, we had no evidence to suggestthattheenvelopeswereappropriatelynum-bered in a sequential manner and randomallocation couldthereforehave been under-mined.Quote: they were randomly assigned to 4groups by a secure system of sequentiallynumbered I through IV opaque sealed en-velopes. The physician who assigned thepatients was blinded as to the treatmentthey would receive.




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Huang 2005 B (Continued)

With 120 patients randomised, the en-velopes should have been sequentiallynumbered 1-120 and not I to IV.

Adequate blinding of patients? No Sham intervention given in the controlgroup, but the investigators stated (...)however, the absence of a warmor stinging sensation for the treated pa-tients caused the failure of the sham US ap-plication.



Adequate blinding of outcome assessors? No For Pain: VAS is usually scored by patients,who were not blinded. For function: no in-formation provided.


No Comparison I: 54 out of 60 (90%) ran-domised to experimental and 50 out of 60(83%) randomised to control group wereanalysed.Comparison II: 60 out of 60 (100%) ran-

domised to experimental and 50 out of 60(83%) randomised to control group wereanalysed.Analyses performed on knee level.


No Comparison I: 27 out of 30 (90%) ran-domised to experimental and 25 out of 30(83%) randomised to control group wereanalysed.Comparison II: 30 out of 30 (100%) ran-domised to experimental and 25 out of 30(83%) randomised to control group wereanalysed.Analyses performed on patient level.


Unclear Treatment equipment supplied by Chat-tecx group, ATL ultrasound and Enraf No-nius.




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zgnenel 2009

Methods Randomised trial2-arm parallel group designTrial duration: 2 weeksPower calculation reportedFunding by non-profit organisation: No information provided

Participants 67 patients randomised67 patients with newly diagnosed knee OA reported at baselineStudy joints: 67 kneesNumber of females: 54 of 67 (81%)Average age: 55 years

Average BMI: 32 kg/m2Average disease duration: not reported, but all patients were newly diagnosed with OASeverity: knee pain and limitation on most days of the past 6 months and Kellgren-Lawrence score II (31 patients) to III (36 patients)

Interventions Experimental intervention: continuous ultrasound therapy, five times per weekControl intervention: sham ultrasound therapy, five times per weekDuration of treatment period: 2 weeksAnalgesics were not allowed, two patients were dropped out from the control group dueto analgesic intakeDevice: Petson .250 ultrasound equipmentDuration of stimulation per session: 5 minutesTotal sessions: 10

Frequency: 1.00 MHzIntensity: 1 W/cm2Head size: 4 cmTreated anatomical areas: patellofemoral and tibiofemoral borders of the target knee onboth the lateral and medial margins, avoiding the patellaArea treated per session: 25cm2

Skin prep: Aqueous gelSafety precautions: circular movements

Outcomes Extracted pain outcome: WOMAC pain subscale at 2 weeks, 2 days after end of lasttreatment, measured on 0 to 20 Likert scaleExtracted function outcome: WOMAC physical function subscale at 2 weeks, 2 daysafterend of last treatment, measured on 0 to 68 Likert scalePrimary outcome reported: knee pain on movement over the past week, measured on10 cm VAS

Notes

Risk of bias






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zgnenel 2009 (Continued)

Allocation concealment? Unclear Authors merely state that An independentresearcher not involved in the data assess-ment randomized the subjects..

Adequate blinding of patients? Yes Sham device: identical in appearance.Quotes: An applicator disconnected fromthe back to working ultrasound machine.Patient in position unable to see whetherthe cable was disconnected or not.

Adequate blinding of physicians/physicaltherapists? No For safety reasons, the treating health careprovider must be aware of the type of ul-trasound therapy given.

Adequate blinding of outcome assessors? Yes Quote: Both the therapeutic US and thesham US application were performed bythe same therapist and patients were as-sessed by three blinded researchers beforeand at the end of therapy program. Paina

Documents

US Cochrane.pdf