Efficacy of therapeutic ultrasound vs sham ultrasound on pain and physical function in people with knee osteoarthritis: A meta-analysis of randomized controlled trials

Table 1 Example search strategy: Strategy used to search the OVID Medline electronic database (January 1, 2009 to September 5 2013)

1	Exp Osteoarthritis/
2	osteoarthr$.ti,ab,sh.
3	gonarthr$.ti,ab,sh.
4	coxarthr$.ti,ab,sh.
5	arthr$.ti,ab.
6	[(knee$ or hip$ or joint$) adj3 (pain$ or ach$ or discomfort$)].ti,ab.
7	[(knee$ or hip$ or joint$) adj3 stiff$].ti,ab.
8	Exp Ultrasonic Therapy/
9	Exp Ultrasonography/
10	us.fs.
11	(ultrasound$ or ultrasonic$).tw.
12	short wave therapy.tw.
13	ultrasonograph$.tw.
14	randomized controlled trial.pt.
15	controlled clinical trial.pt.
16	randomized controlled trial.sh.
17	random allocation.sh.
18	double blind method.sh.
19	single blind method.sh.
20	clinical trial.pt.
21	Exp Clinical Trial/
22	(clin$ adj25 trial$).ti,ab.
23	[(singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)].ti,ab.
24	placebos.sh.
25	placebo$.ti,ab.
26	random$.ti,ab.
27	research design.sh.
28	comparative study.sh.
29	exp evaluation studies/
30	follow up studies.sh.
31	prospective studies.sh.
32	(control$ or prospectiv$ or volunteer$).ti,ab.
33	1 or 2 or 3 or 4 or 5 or 6 or 7
34	8 or 9 or 10 or 11 or 12 or 13
35	14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32
36	33 and 34 and 35
37	animal/
38	animal/ and human/
39	37 not 38
40	36 not 39
41	Limit 40 to yr = ”2009-Current”

Table 2 Criteria used to classify risk of bias in trials according to components of methodological quality

Random sequence generation
Low risk	Referring to a random number table; Using a computer random number generator; Coin tossing; Shuffling cards or envelopes; Throwing dice; Drawing of lots
High risk	Sequence generated by odd or even date of birth; Sequence generated by some rule based on date (or day) of admission; Sequence generated by some rule based on hospital or clinic record number; Allocation by judgment of the clinician; Allocation by preference of the participant; Allocation based on the results of a laboratory test or a series of tests; Allocation by availability of the intervention
Unclear	Insufficient information
Allocation concealment
Low risk	Central allocation (including telephone, web-based); Sequentially numbered, opaque, sealed envelopes; An equivalent method was used to conceal allocation
High risk	Using an open random allocation schedule (e.g., a list of random numbers); Assignment envelopes were used without appropriate safeguards (e.g., if envelopes were unsealed or nonopaque or not sequentially numbered); Alternation or rotation; Date of birth; Case record number; Any other explicitly unconcealed procedure
Unclear	Insufficient information
Blinding of each of: participant, care provider, outcome assessor
Low risk	Unlikely that the blinding could have been broken
High risk	Likely that the blinding could have been broken
Unclear	Insufficient information
Completeness of outcome data collection
Low risk	No missing outcome data; Reasons for missing outcome data unlikely to be related to true outcome; Missing outcome data balanced in numbers across all groups, with similar reasons for missing data across groups; Missing data have been imputed using appropriate methods; For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size
High risk	Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; "As-treated" analysis done with substantial departure of the intervention received from that assigned at randomization. Potentially inappropriate application of simple imputation. For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size
Unclear	Insufficient information
Completeness of outcome reporting
Low risk	The study protocol is available and all of the study’s pre-specified outcomes that are of interest in the review have been reported in the pre-specified way; The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified
High risk	Not all of the study’s pre-specified primary outcomes have been reported; One or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g., subscales) that were not pre-specified; One or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis; The study report fails to include results for a key outcome that would be expected to have been reported for such a study
Unclear	Insufficient information
Other potential sources
Low risk	The study appears to be free of other sources of bias
High risk	There is at least one important risk of bias. For example, the study had a potential source of bias related to the specific study design used or has been claimed to be fraudulent, or has some other problem
Unclear	Insufficient information

Table 3 Characteristics of the studies selected for full text review

	Falconer et al[18]	Ozgönenel et al[19]	Tascioglu et al[20]	Yang et al[21]	Loyola-Sánchez et al[22]	Ulus et al[23]
Trial registry number	Not available	Not available	Not available	Not available	NTC00931749	Not available
Trial duration	4-6 wk (12 sessions 2-3 x/wk)	2 wk (10 sessions 5 x/wk)	2 wk (10 sessions 5x/wk)	5 d (5 sessions); + 1 mo follow up	8 wk (24 sessions 3 x/wk)	3 wk (15 sessions 5 x/wk)
Sample size	Randomized: 74; analyzed: 69 (35 CG)	Randomized: 67; analyzed: 65 (31 CG)	Randomized: 90; analyzed: 82 (27 CG)	Randomized and analyzed: 87 (100 knees; 50 CG)	Randomized: 27; analyzed: 25 (13 CG)	Randomized: 42; analyzed: 40 (20 CG)
Sample characteristics (Mean SD/n reported)	Age approximately 67.5 (11) yr; 50 F; All restricted knee ROM ≥ 6 mo; 8 knee joint replacement; 51 bilateral OA	Age approximately 55 (7.5) yr; 54 F; Newly diagnosed; 31 mild OA, 36 moderate OA	Age approximately 60 (3) yr; 56 F; Disease duration 6.5 yr; 48 mild OA, 34 moderate OA	Age 58.3 yr; 72 F; Disease duration 2.8 yr	Age approximately 61.8 (10) yr; 21 F; 8 had mild OA, 19 had moderate OA; 24 bilateral OA	Age approximately 60.5 (9.5) yr; 34 F; disease duration 8.9(8.7) yr; 17 mild OA, 23 moderate OA; all bilateral OA
Ultrasound device	Chattanooga Intellect 200	Peterson .250	Sonopuls 434	NERCUM	Chattanooga Intellect Mobile	Sonopuls 434
Application protocol	12 min; 1 MHz; intensity: 1.7 W/cm2, continuous mode (n = 34)	5 min; 1 MHz; intensity 1 W/cm2; continuous mode (n = 34)	5 min; 1 MHz; intensity 1 W/cm2, continuous mode (n = 27); pulsed (duty cycle 20%, n = 28)	No details: 15min treatment model then 20min rehabilitation model (n = 50 knees)	9.5 min; 1MHz; intensity 1 W/cm2; pulsed mode (duty cycle 20%, n = 12)	10 min; 1 MHz; intensity 1 W/cm2; continuous mode (n = 20)
Sham Application	Start button not pushed	Applicator disconnected from back of device	No output delivered	No output delivered	Ceramic crystal removed from soundhead	No output delivered and applicator disconnected from back of device
Application site	Knee flexed or extended per most restricted motion; treated surface area 100 cm2	Patellofemoral and tibiofemoral borders; treated surface area 25 cm2	Antero-medial and lateral parts of extended knee; treated surface area 60 cm2	Knee extended; 4 soundheads fixed on joint line; treated surface area not reported	Knee flexed to 90°; Soundhead fixed at antero-medial joint line. treated surface area 5 cm2	Antero-medial and lateral parts of extended knee; treated surface area 60 cm2
Dosage	26 J/cm2	150.7 J/cm2	196.3 J/cm2 39.3 J/cm2	Unable to calculate	114 J/cm2	196.3 J/cm2
Concurrent treatment	Stretching, joint mobilizations, exercises (ROM, bridging, isometric quads, home program)	none	none	none	None reported; use of analgesics not reported	Hotpacks (20 min); IFC (10 min); exercises (isometric quads); analgesics except during physio
Outcomes included in meta-analysis	Pain – 10 cm VAS	Pain on movement in past wk – 10 cm VAS WOMAC LK 3.1 Physical Function subscale Walking speed [time (s) to walk 50 m]	Pain on movement in past wk – 10 cm VAS Walking speed [time (s) to walk 20 m]	none	Pain following walking test – 11 point NRS WOMAC LK 3.1 Physical Function subscale Distance (m) walked in 6 min	Pain on activity – 10 cm VAS WOMAC LK 3.1 Physical Function subscale Walking speed [time (s) to walk 50 m]
Funding source	Non-profit	Not reported	Not reported	NERCUM, institutional	Government	Unfunded
Comments	Trial author confirmed mode was continuous; pain data extracted from graphs; request for pain and walking data was unsuccessful		Treated surface area not reported; estimated to be 3x the sound head size (based on parts of knee treated)	Attempts to contact authors for pain and physical function data that could be pooled were unsuccessful	1 of the 2 reviewers co-authored the trial; outcomes pooled in this review were secondary outcomes in trial	Treated surface area not reported; estimated to be 3x the sound head size (based on parts of knee treated)

OA: Knee osteoarthritis; CG: Control group; F: Female; NERCUM: National Engineering Research Centre of Ultrasound Medicine; ROM: Range of motion; IFC: Interferential current electrotherapy; VAS: Horizontal visual analogue scale (10 = worst pain); NRS: Numeric rating scale (10 = worst pain); WOMAC LK 3.1: Western Ontario and McMaster Universities Osteoarthritis Index (Likert scale version) self-report questionnaire physical function subscale (68 = worst limitation).

Table 4 Methodological quality assessment of the randomized sham-controlled trials

Ref.	Random Sequence Generation	Allocation Concealment	Blinding of Participant	Blinding of Care Provider	Blinding of Assessor	Data Collection Complete	Complete Outcome Reporting	Free of Other Potential Bias	Risk of Bias1
Falconer et al[18]	Unclear	Unclear	Yes	No	Yes	Yes	No	Yes	High
Ozgönenel et al[19]	Unclear	Unclear	Yes	No	Yes	Unclear	Yes	Yes	High
Tascioglu et al[20]	Unclear	Unclear	Yes	No	Yes	Unclear	Yes	Yes	High
Yang et al[21]	Unclear	Unclear	Unclear	Unclear	Unclear	Yes	No	No	High
Loyola-Sánchez et al[22]	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Low
Ulus et al[23]	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes	High

¹Overall risk of bias for each study assessed as Low if has a Yes answer for ALL the items or as High if has NO or Unclear answer for one or more items.

Table 5 Summary of findings

Outcomes	Difference1 in ultrasound group mean relative to the control group mean (95%CI)	No of Participants and knees (studies)	Strength of the body of evidence2	Inconsistency (I2)	Outcome specific risk of bias
Pain VAS; NRS Follow-up: 2-8 wk	0.39 standard deviations lower [-0.70-(-0.08)]	281 (5 studies)	Low	36%	High risk of bias of the included studies, imprecision due to small sample size and wide CI
Self-reported physical function WOMAC® LK 3.1 Physical function; Follow-up: 2-8 wk	2.49 points lower (-0.55-0.14)	130 (3 studies)	Very low	0%	High risk of bias of the included studies, imprecision due to very small sample size and wide CI
Walking performance 50 m walk speed (s); 20 m walk speed (s); 6MWT (m) Follow-up: 2-8 wks	0.11 standard deviations lower (-0.59-0.37)	212 (4 studies)	Very low	64%	High risk of bias in the included studies, imprecision due to small sample size and wide CI, inconsistent

¹Standardized mean difference reported for pain and walking performance; Mean difference reported for self-reported physical function outcomes;

²GRADE Working Group grades of evidence, High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. VAS: Horizontal 10 cm visual analogue scale for pain (maximum score = 10, lower score is better); NRS: Pain with movement numeric rating scale (maximum score = 10, lower score is better); WOMAC LK 3.1 Physical function: Likert Scale version of the Western Ontario and McMaster Osteoarthritis Index physical function subscale (maximum score = 80, lower score is better); 6MWT: 6 min walk test (distance measured in metres, higher score is better).