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Efficacy of ultrasound therapy for the management of knee osteoarthritis: a systematic review with meta-analysis

Open ArchivePublished:July 15, 2010DOI:https://doi.org/10.1016/j.joca.2010.06.010

      Summary

      Objective

      To assess the efficacy of ultrasound therapy (US) for decreasing pain and improving physical function, patient-perception of disease severity, and cartilage repair in people with knee osteoarthritis (OA).

      Methods

      We conducted a systematic review (to February 2009) without language limits in MEDLINE, EMBASE, Cochrane Library, LILACS, MEDCARIB, CINAHL, PEDro, SPORT-discus, REHABDATA, and World Health Organization Clinical Trial Registry. We included randomized controlled trials of people with knee OA comparing the outcomes of interest for those receiving US with those receiving no US. Two reviewers independently selected studies, extracted relevant data and assessed quality. Pooled analyses were conducted using inverse-variance random effects models.

      Main results

      Six small trials (378 patients) were included. US improves pain [Standardized Mean Difference (SMD) (95% confidence interval (CI))=−0.49 (−0.79, −0.18), P=0.002], and tends to improve self-reported physical function [SMD (CI)=−0.54 (−1.19, 0.12), P=0.11] along with walking performance [SMD (CI)=0.81 (−0.09, 1.72), P=0.08]. Results from two trials (128 patients), conducted by the same group, show a positive effect of US on pain [SMD (CI)=−0.77 (−1.15, −0.39), P<0.001], self-reported physical function [SMD (CI)=−1.25 (−1.69, −0.81), P<0.001], and walking performance [SMD (CI)=1.47 (1.06, 1.88), P<0.001] at 10 months after the intervention concluded. Heterogeneity observed between studies regarding the effect of US on pain was explained by US dose, mode and intensity. The quality of evidence supporting these effect estimates was rated as low.

      Conclusions

      US could be efficacious for decreasing pain and may improve physical function in patients with knee OA. The findings of this review should be confirmed using methodologically rigorous and adequately powered clinical trials.

      Keywords

      Introduction

      Knee osteoarthritis (OA) is the most common presentation of OA, with an estimated prevalence between 12% and 35% in the general population
      • Pop T.
      • Szczygielska D.
      • Druzbicki M.
      Epidemiology and cost of conservative treatment of patients with degenerative joint disease of the hip and knee.
      • Quintana J.M.
      • Arostegui I.
      • Escobar A.
      • Azkarate J.
      • Goenaga J.I.
      • Lafuente I.
      Prevalence of knee and hip osteoarthritis and the appropriateness of joint replacement in an older population.
      and is considered the leading cause of musculoskeletal disability in the elderly population worldwide
      • Zhang Y.
      • Jordan J.M.
      Epidemiology of osteoarthritis.
      . Physiotherapy is recommended for the management of painful knee OA
      • Zhang W.
      • Moskowitz R.W.
      • Nuki G.
      • Abramson S.
      • Altman R.D.
      • Arden N.
      • et al.
      OARSI recommendations for the management of hip and knee osteoarthritis, part II: OARSI evidence-based, expert consensus guidelines.
      and ultrasound therapy (US) is one of the most common physical agents used within physiotherapy practice in several countries
      • Bélanger A.Y.
      Ultrasound.
      . US is based on the application of high frequency sound waves to the tissues of the body in order to obtain mechanical or thermal effects
      • Baker K.G.
      • Robertson V.J.
      • Duck F.A.
      A review of therapeutic ultrasound: biophysical effects.
      . These effects aim to enhance soft tissue healing, decrease the inflammatory response, increase blood flow, increase metabolic activity, and decrease pain
      • Baker K.G.
      • Robertson V.J.
      • Duck F.A.
      A review of therapeutic ultrasound: biophysical effects.
      . Moreover, there is some evidence that ultrasonic energy stimulates the repair of joint cartilage in animal models of cartilage injury
      • Cook S.D.
      • Salkeld S.L.
      • Patron L.P.
      • Doughty E.S.
      • Jones D.G.
      The effect of low-intensity pulsed ultrasound on autologous osteochondral plugs in a canine model.
      • Huang M.H.
      • Ding H.J.
      • Chai C.Y.
      • Huang Y.F.
      • Yang R.C.
      Effects of sonication on articular cartilage in experimental osteoarthritis.
      • Singh K.I.
      • Sobti V.K.
      • Roy K.S.
      Gross and histomorphological effects of therapeutic ultrasound (1 watt/cm2) in experimental acute traumatic arthritis in donkeys.
      . Therefore, US could be an effective intervention in the management of pain and disability in people with knee OA.
      The Osteoarthritis Research Society International (OARSI) struck a committee to complete a systematic review of existing treatment guidelines (2007) in order to develop recommendations for the management of knee and hip OA
      • Zhang W.
      • Moskowitz R.W.
      • Nuki G.
      • Abramson S.
      • Altman R.D.
      • Arden N.
      • et al.
      OARSI recommendations for the management of hip and knee osteoarthritis, part II: OARSI evidence-based, expert consensus guidelines.
      . Ultrasound was not identified as a core treatment modality based on the results of a systematic review published in 2001 by the Cochrane Collaboration
      • Welch V.
      • Brosseau L.
      • Peterson J.
      • Shea B.
      • Tugwell P.
      • Wells G.
      Therapeutic ultrasound for osteoarthritis of the knee.
      . The Cochrane systematic review included studies available prior to June 2000
      • Welch V.
      • Brosseau L.
      • Peterson J.
      • Shea B.
      • Tugwell P.
      • Wells G.
      Therapeutic ultrasound for osteoarthritis of the knee.
      while more recent trials evaluating the effectiveness of US in the management of knee OA were not reviewed. Since there is a need for effective conservative treatment options for people with knee OA, it is important to confirm or change current clinical practice guidelines based on best available evidence. Therefore, the objective of this systematic review and meta-analysis was to determine the efficacy of US in decreasing pain and improving physical function in people with knee OA. Further, we extended the scope of previous systematic reviews on the topic by evaluating the efficacy of US on patient-perception of disease severity, and cartilage repair. We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) recommendations
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • Mulrow C.
      • Gotzsche P.C.
      • Ioannidis J.P.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
      in the creation of this manuscript.

      Methods

      Search strategy

      The Cochrane Central Register of Controlled Trials (fourth Quarter 2008), MEDLINE (1950 to January week 4, 2009), MEDLINE Daily Update (Feb 5, 2009), MEDLINE In Process & Other non-indexed citations (February 5, 2009), EMBASE (1980–2009 week 6), LILACS (February 6, 2009), MEDCARIB (February 6, 2009), CINAHL (February 8, 2009), pre CINAHL (February 8, 2009), PEDro (last updated February 2, 2009), AMED (1985 to January 2009), SPORTdiscus (1830 to February 9, 2009), REHABDATA (1956 to February 9, 2009), and World Health Organization Clinical Trial Registry (February 8, 2009) databases were searched by one of the authors (AL). In addition, published literature with restricted distribution was searched through the ISI Web of Knowledge, Papers First, Proceedings First, and ProQuest for Dissertations and Theses. Authors of an unpublished study reported as a conference proceeding in the Proceedings First database were contacted via e-mail. A detailed example of the full electronic search strategy for Ovid MEDLINE is provided in Appendix A. Briefly, the following medical subject headings (MeSH) were used: Osteoarthritis, Arthritis, Ultrasonic Therapy, Ultrasonics, Sonication, Diathermy, Cartilage, and Wound Healing; keywords were osteoarthritis, arthritis experimental, ultrasound therapy, low intensity pulsed ultrasound, low intensity ultrasound, and cartilage repair. To increase the search sensitivity, no date, language, or design limits were included. Duplicates were removed after all databases were searched.

      Study selection and eligibility criteria

      Two reviewers (AL, JR) independently screened all citations obtained and retrieved all parallel group randomized controlled trials involving patients with knee OA that compared US with placebo or no intervention. Trials that compared US in combination with another intervention to which the comparison group was exposed were also included. Studies were excluded from the review if phonophoresis was the only ultrasonic intervention, US was combined with another intervention not provided to the comparison group, and samples included subjects having other diagnoses and results for the subjects with knee OA were not reported separately. Cohen’s unweighted Kappa (κ) was used to measure agreement between reviewers
      • Cohen J.A.
      A coefficient of agreement for nominal scales.
      . Observed agreement was fair (κ=0.57)
      • Orwin R.G.
      Evaluating coding decisions.
      . Disagreement was solved by consensus including a third reviewer (NM). Colleagues translated non-English articles (n=9) written in their first language (a physical therapist, an engineer, an occupational therapist, a rheumatologist, and a physiatrist).

      Data extraction and management

      Two reviewers, using a pre-tested data collection form, followed a double extraction method. The reviewers independently extracted data related to the study population (clinical setting, diagnostic criteria, joint involvement, sex, age and OA severity), study design, US intervention (device, frequency, mode, intensity and dose), co-interventions, outcomes (pain, physical function, participant’s perception of disease severity, and cartilage repair), and the monitoring/reporting of adverse events. The US dose was calculated using the following formula
      • Bélanger A.Y.
      Ultrasound.
      :
      Energy(J/cm2)=(Averagetemporalintensity)(Time)(Effectiveradiatingarea)Treatedsurfacearea


      We defined cartilage repair as all measures that directly or indirectly assess the cartilage formation–degradation process (i.e., imaging, arthroscopy, fluid biomarkers). Primary authors were contacted in the case of missing data or unclear reporting. A physiatrist with expertise in OA and US (AL) and a physical therapist with expertise in research methodology and OA (NM) reviewed the papers and extracted the data.

      Risk of bias and quality assessment

      The risk of bias was assessed for each study by evaluating the rigor of the randomization process, the treatment allocation concealment, the blinding process, the completeness of the data, and the reporting of results following the Cochrane Collaboration recommendations
      • Higgins J.P.T.
      • Altman D.G.
      Chapter 8: assessing risk of bias in included studies.
      . To judge the completeness of the data as adequate, a dropout rate of less than 15% was required.
      Given the objective of this systematic review, we identified randomization, treatment allocation concealment, blinding, and completeness of data as key domains for establishing risk of bias. For each included study, risk of bias was determined to be low when all key domains were performed adequately, unclear when one or more key domains were not clearly described, and high when one or more key domains were inadequate. Across studies, the risk of bias was considered low if all studies had low risk, unclear when more than 75% of the studies had unclear or low risk and less than 25% of the studies had high risk of bias, and high when more than 25% of the studies had high risk of bias. Observed agreement was fair (κ=0.56)
      • Orwin R.G.
      Evaluating coding decisions.
      and disagreement was resolved by consensus and inclusion of a third reviewer, who is a physical therapist with research methodology expertise (JR).
      The quality of the evidence for each outcome was determined by considering the risk of bias, the heterogeneity of the findings, the use of surrogate measurements for outcome assessment, and the precision of the effect estimates as recommended by the Grading of Recommendations, Assessment Development and Evaluation (GRADE) working group
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • Kunz R.
      • Falck-Ytter Y.
      • Alonso-Coello P.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      .

      Statistical analyses

      An inverse-variance random effects model
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      was used to calculate pooled standardized mean differences (SMDs) using Review Manager (RevMan [computer program] Version 5.0 Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008, Oxford, UK). The SMD is a ratio between the differences observed between groups and the standard deviation (SD) of the outcomes among participants (Hedges’ adjusted g). The 95% confidence interval (CI) was calculated and a Z test was performed with significance set at P<0.05. Heterogeneity among studies was assessed with a χ2 test with significance set at P<0.10 and an inconsistency test (I2) which represents the percentage variability in the effect estimates that is due to heterogeneity rather than chance. Inconsistency (I2)>40% was considered significantly high
      • Higgins J.P.T.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      .
      Two studies
      • Huang M.
      • Lin Y.
      • Lee C.
      • Yang R.
      Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis.
      • Huang M.
      • Chen T.
      • Weng M.
      • Wang Y.
      reported different subgroups of US, so the means and SDs of these subgroups were pooled using the following formulas
      • Mendenhall W.
      • Beaver R.J.
      • Beaver B.M.
      Introduction to Probability and Statistics.
      :
      Meanpooled=(X1×n1)(X2×n2)(X3×n3)(X×n)n1+n2+n3+n


      SDpooled=(s12×n11)+(s22×n21)+(s32×n31)+(sn2×n1)(n11)+(n21)+(n31)+(n1)


      where X=mean for each group, SD=standard deviation, s2=variance, and n=number of participants in that group.
      Three studies
      • Huang M.
      • Lin Y.
      • Lee C.
      • Yang R.
      Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis.
      • Huang M.
      • Chen T.
      • Weng M.
      • Wang Y.
      • Huang M.H.
      • Yang R.C.
      • Lee C.L.
      • Chen T.W.
      • Wang M.C.
      Preliminary results of integrated therapy for patients with knee osteoarthritis.
      reported the results of pain outcomes by knee rather than by patient. Therefore, we included the number of patients (n=35 instead of n=70) in each group during the pooled analysis, in order to account for the intercorrelation of measurements taken from the knees of the same patient.
      In order to express the effect estimates as percentage change relative to the control groups, the SMDs were back transformed to mean differences (MD) using SDs reported in observational studies
      • Villanueva I.
      • del Mar Guzman M.
      • Javier Toyos F.
      • Ariza-Ariza R.
      • Navarro F.
      Relative efficiency and validity properties of a visual analogue vs a categorical scaled version of the western ontario and McMaster universities osteoarthritis (WOMAC) index: Spanish versions.
      • Huang M.H.
      • Lin Y.S.
      • Yang R.C.
      • Lee C.L.
      A comparison of various therapeutic exercises on the functional status of patients with knee osteoarthritis.
      (Appendix B). Heterogeneity was explored through subgroup analyses following a priori hypotheses that considered factors such as disease severity, US mode/intensity/dose, co-interventions, number of sessions provided, and methodological adequacy.

      Results

      Twenty-three studies, out of 1119 citations identified, fulfilled the inclusion criteria and were retrieved for full text review (see Fig. 1). Of these, only six studies were included and considered in the final analysis. The remaining 17 studies were excluded because the samples included persons with diagnoses other than knee OA
      • Esmat N.
      Treatment of arthrosis deformans by simultaneous application of interferential current and ultrasonic waves.
      • Sabadyshin R.A.
      • Rudyk B.I.
      • Fil’chagin N.M.
      • Svarcova J.
      • Zvarova J.
      • Kouba A.
      • Trnavsky K.
      Does physiotherapy affect the pain in activated arthrosis?.
      ; compared US with short wave diathermy
      • Bansil C.K.
      • Joshi J.B.
      Effectiveness of shortwave diathermy and ultrasound in the treatment of osteo-arthritis of the knee joint.
      • Jan M.H.
      • Lai J.S.
      The effects of physiotherapy on osteoarthritic knees of females.
      • Kalpakcioglu B.A.
      • Cakmak B.
      • Bahadir C.
      Comparison of ultrasound and short wave diathermy therapy in knee osteoarthritis.
      , diadynamic currents/magnetotherapy
      • Lisinski P.
      • Zapalski W.
      • Stryla W.
      Physical agents for pain management in patients with gonarthrosis.
      , or phonophoresis
      • Kozanoglu E.
      • Basaran S.
      • Guzel R.
      • Guler-Uysal F.
      Short term efficacy of ibuprofen phonophoresis versus continuous ultrasound therapy in knee osteoarthritis.
      , without a control group with similar exposure; compared different frequencies/modes of US
      • Golubenko T.A.
      • Griffin J.E.
      • Echternach J.L.
      • Bowmaker K.L.
      Results of frequency differences in ultrasonic therapy.
      • Winterfeld H.J.
      • Conradi E.
      Clinical comparison of the effect of ultrasound using direct and alternating current in the treatment of gonarthrosis.
      , or used US in combination with other physical modalities
      • Grigor’eva V.D.
      • Fedorova N.E.
      • Kiselev V.I.
      without a control group; four articles were case series reports
      • Bernau A.
      • Kruppa G.
      • Scala D.A.
      • Trinchieri P.
      • Schwartz F.F.
      Ultrasonics in osteoarthritis.
      • Soren A.
      Treatment of musculoskeletal disorders with ultrasound.
      ; and one study was performed in vitro
      • Ryaby J.T.
      • Cai F.F.
      • Culley P.L.
      • Kaufman J.J.
      • Lippiello L.
      .

      Description of included studies

      The six small, English-language, randomized controlled trials
      • Huang M.
      • Lin Y.
      • Lee C.
      • Yang R.
      Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis.
      • Huang M.
      • Chen T.
      • Weng M.
      • Wang Y.
      • Huang M.H.
      • Yang R.C.
      • Lee C.L.
      • Chen T.W.
      • Wang M.C.
      Preliminary results of integrated therapy for patients with knee osteoarthritis.
      • Cetin N.
      • Aytar A.
      • Atalay A.
      • Akman M.N.
      Comparing hot pack, short-wave diathermy, ultrasound, and TENS on isokinetic strength, pain, and functional status of women with osteoarthritic knees: a single-blind, randomized, controlled trial.
      • Falconer J.
      • Hayes K.W.
      • Chang R.W.
      Effect of ultrasound on mobility in osteoarthritis of the knee. A randomized clinical trial.
      • Ozgonenel L.
      • Aytekin E.
      • Durmusoglu G.
      A double-blind trial of clinical effects of therapeutic ultrasound in knee osteoarthritis.
      included in this review are summarized in Table I. In one study
      • Huang M.
      • Chen T.
      • Weng M.
      • Wang Y.
      , unpublished data were provided by the primary author. All trials included people with knee OA who met the American College of Rheumatology diagnostic criteria
      • Altman R.
      • Asch E.
      • Bloch D.
      • Bole G.
      • Borenstein D.
      • Brandt K.
      • et al.
      Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and therapeutic criteria committee of the american rheumatism association.
      and the mean age of participants was over 53 years. All trials delivered ultrasonic energy at a frequency of 1 MHz. For the study by Falconer et al.
      • Falconer J.
      • Hayes K.W.
      • Chang R.W.
      Effect of ultrasound on mobility in osteoarthritis of the knee. A randomized clinical trial.
      , tabulated results were extracted. Five studies reported sufficient information for the dose calculation
      • Huang M.
      • Lin Y.
      • Lee C.
      • Yang R.
      Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis.
      • Huang M.
      • Chen T.
      • Weng M.
      • Wang Y.
      • Huang M.H.
      • Yang R.C.
      • Lee C.L.
      • Chen T.W.
      • Wang M.C.
      Preliminary results of integrated therapy for patients with knee osteoarthritis.
      • Falconer J.
      • Hayes K.W.
      • Chang R.W.
      Effect of ultrasound on mobility in osteoarthritis of the knee. A randomized clinical trial.
      • Ozgonenel L.
      • Aytekin E.
      • Durmusoglu G.
      A double-blind trial of clinical effects of therapeutic ultrasound in knee osteoarthritis.
      . Three trials
      • Huang M.
      • Lin Y.
      • Lee C.
      • Yang R.
      Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis.
      • Huang M.
      • Chen T.
      • Weng M.
      • Wang Y.
      • Huang M.H.
      • Yang R.C.
      • Lee C.L.
      • Chen T.W.
      • Wang M.C.
      Preliminary results of integrated therapy for patients with knee osteoarthritis.
      conducted by the same group reported a peak intensity value followed by the statement: “The intensity of sonication was adjusted to the level at which the patient felt a warm sensation or a mild sting”. It can be inferred from this statement that the output intensity was modified for each US application and the calculated dose would be inaccurate. Communication with the primary author confirmed that the intensity output was fixed and only the speed of the sound head varied during the US application. Thus, US dose could be calculated.
      Table ISummary of included randomized controlled trials evaluating the effectiveness of US in people with knee OA
      SourceCharacteristics of subjectsIntervention groupComparison groupOutcomesFollow-upRisk of bias
      Cetin et al.
      • Cetin N.
      • Aytar A.
      • Atalay A.
      • Akman M.N.
      Comparing hot pack, short-wave diathermy, ultrasound, and TENS on isokinetic strength, pain, and functional status of women with osteoarthritic knees: a single-blind, randomized, controlled trial.
      (Turkey)
      100% Women with mild to severe bilateral knee OA; ∼58 (8) years.n
      Sample size of subjects whose data were included in the present meta−analysis.
      =18

      Sonopulus 590 US device, continuous mode, 1.5 W/cm2 intensity, 180 J/cm2 dose
      Treated surface area was not reported and US dose was calculated using a value of 25cm2 reported in 1 similar trial17.
      , 24 ten-min sessions in 8 weeks.

      Also: standardized warm up, isokinetic exercises, and hotpack.
      n
      Sample size of subjects whose data were included in the present meta−analysis.
      =17

      Standardized warm up, isokinetic exercises and hotpack.
      Same number of sessions and period of time as in the intervention group.
      Pain-VAS
      Visual Analogue Scale (VAS) from 0cm (no pain) to 10cm (most intense pain).


      Physical function-LSI
      LSI scale from 0 (better) to 26 (worst).


      Walking speed-time to walk 50 m in seconds)
      8 WeeksHigh
      Falconer et al.
      • Falconer J.
      • Hayes K.W.
      • Chang R.W.
      Effect of ultrasound on mobility in osteoarthritis of the knee. A randomized clinical trial.
      (USA)
      ∼72% Women with severity not specified; ∼67.5 (11) years.n
      Sample size of subjects whose data were included in the present meta−analysis.
      =34

      Chattanooga Intellect 200 US device, continuous mode
      The ultrasonic mode was not reported, we assumed it was continuous based on the way the intensity of the energy was delivered (“from 0W/cm2 to maximal tolerable dose not exceeding 2.5W/cm2 ”).
      , 1.7 W/cm2 intensity, 26 J/cm2 dose, 12 twelve-min sessions in 4–6 weeks.
      n
      Sample size of subjects whose data were included in the present meta−analysis.
      =35

      Sham US (start button not pushed).
      Treated surface area was not reported and US dose was calculated using a value of 25cm2 reported in 1 similar trial17.
      Pain-VAS

      Walking speed-50 ft walk time (converted to m/min)
      4–6 WeeksHigh
      Huang et al.
      • Huang M.
      • Chen T.
      • Weng M.
      • Wang Y.
      (Taiwan)
      ∼33% Women with mild to severe bilateral knee OA; ∼60 (9) years.n
      Sample size of subjects whose data were included in the present meta−analysis.
      =30

      Sonopulus 590 US device; pulsed mode (duty cycle: 25%), 2.5 W/cm2 intensity, 112 J/cm2 dose, 24 fifteen-min sessions in 8 weeks.
      n
      Sample size of subjects whose data were included in the present meta−analysis.
      =30

      Sham US.
      Treated surface area was not reported and US dose was calculated using a value of 25cm2 reported in 1 similar trial17.
      Pain-VAS
      Visual Analogue Scale (VAS) from 0cm (no pain) to 10cm (most intense pain).


      Physical function-LSI
      LSI scale from 0 (better) to 26 (worst).


      Walking speed-50 ft walk time (converted to m/min)

      Arthritis Severity Index=ratio of 99mTechnetium uptake
      99mTechnetium uptake was measured by bone scan (TOSHIBA GCA-90 γ-camera) 3h after administrating the radioisotope.
      knee/99mTechnetium uptake middle third ipsilateral femur
      8 WeeksUnclear
      Huang et al.
      • Huang M.
      • Lin Y.
      • Lee C.
      • Yang R.
      Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis.
      (Taiwan)
      ∼81% Women with mild knee OA; ∼62 (17) years.Group 1: n
      Sample size of subjects whose data were included in the present meta−analysis.
      =27; Continuous mode, 1.5 W/cm2 intensity, 270 J/cm2 dose.

      Group 2: n
      Sample size of subjects whose data were included in the present meta−analysis.
      =30; Pulsed mode (duty cycle: 25%), 2.5 W/cm2 intensity, 112.5 J/cm2 dose.

      Both groups used a Sonopulus 590 US device, 24 fifteen-min sessions in 8 weeks.

      Also: standardized warm up, isokinetic exercises and hotpack (home exercise program following 8 weeks).
      n
      Sample size of subjects whose data were included in the present meta−analysis.
      =25

      Standardized warm up, isokinetic exercises and hotpack
      Treated surface area was not reported and US dose was calculated using a value of 25cm2 reported in 1 similar trial17.
      (home exercise program following 8 weeks).
      Pain-VAS
      Visual Analogue Scale (VAS) from 0cm (no pain) to 10cm (most intense pain).


      Physical function-LSI
      LSI scale from 0 (better) to 26 (worst).


      Walking speed-50 ft walk time (converted to m/min)
      8 Weeks and 12 monthsHigh
      Huang et al.
      • Huang M.H.
      • Yang R.C.
      • Lee C.L.
      • Chen T.W.
      • Wang M.C.
      Preliminary results of integrated therapy for patients with knee osteoarthritis.
      (Taiwan)
      ∼81% Female with mild knee OA, ∼65 (13) years.n
      Sample size of subjects whose data were included in the present meta−analysis.
      =32

      Sonopulus 590 US device, pulsed mode (duty cycle: 25%), 2.5 W/cm2 intensity, 112 J/cm2 dose, 24 fifteen-min sessions in 8 weeks.

      Also: standardized warm up, isokinetic exercises and hotpack (home exercise program following 8 weeks).
      n
      Sample size of subjects whose data were included in the present meta−analysis.
      =30

      Standardized warm up, isokinetic exercises and hotpack
      Treated surface area was not reported and US dose was calculated using a value of 25cm2 reported in 1 similar trial17.
      (home exercise program following 8 weeks).
      Pain-VAS
      Visual Analogue Scale (VAS) from 0cm (no pain) to 10cm (most intense pain).


      Physical function-LSI
      LSI scale from 0 (better) to 26 (worst).


      Walking speed-50 ft walk time (converted to m/min)
      8 Weeks and 12 monthsHigh
      Ozgonenel et al.
      • Ozgonenel L.
      • Aytekin E.
      • Durmusoglu G.
      A double-blind trial of clinical effects of therapeutic ultrasound in knee osteoarthritis.
      (Turkey)
      ∼80% Women with mild to moderate knee OA; ∼55 (7.5) years.n
      Sample size of subjects whose data were included in the present meta−analysis.
      =34

      Peterson .250 US device, continuous mode, 1 W/cm2 intensity, 150.72 J/cm2 dose, 10 five-min sessions in 2 weeks.
      n
      Sample size of subjects whose data were included in the present meta−analysis.
      =31

      Sham US (applicator disconnected from device).
      Treated surface area was not reported and US dose was calculated using a value of 25cm2 reported in 1 similar trial17.
      Pain-VAS
      Visual Analogue Scale (VAS) from 0cm (no pain) to 10cm (most intense pain).


      Physical function-WOMAC
      Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function subscale from 0 (better) to 68 (worst).


      Walking speed-time to walk 50 m (seconds)
      2 WeeksHigh
      Sample size of subjects whose data were included in the present meta−analysis.
      Treated surface area was not reported and US dose was calculated using a value of 25 cm2 reported in 1 similar trial
      • Huang M.
      • Lin Y.
      • Lee C.
      • Yang R.
      Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis.
      .
      Visual Analogue Scale (VAS) from 0 cm (no pain) to 10 cm (most intense pain).
      § LSI scale from 0 (better) to 26 (worst).
      Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function subscale from 0 (better) to 68 (worst).
      The ultrasonic mode was not reported, we assumed it was continuous based on the way the intensity of the energy was delivered (“from 0 W/cm2 to maximal tolerable dose not exceeding 2.5 W/cm2 ”).
      # 99mTechnetium uptake was measured by bone scan (TOSHIBA GCA-90 γ-camera) 3 h after administrating the radioisotope.
      ∗∗ Same number of sessions and period of time as in the intervention group.
      One trial
      • Falconer J.
      • Hayes K.W.
      • Chang R.W.
      Effect of ultrasound on mobility in osteoarthritis of the knee. A randomized clinical trial.
      did not report the mode of US, however the author confirmed the use of continuous US (personal communication). For the trial by Cetin et al.
      • Cetin N.
      • Aytar A.
      • Atalay A.
      • Akman M.N.
      Comparing hot pack, short-wave diathermy, ultrasound, and TENS on isokinetic strength, pain, and functional status of women with osteoarthritic knees: a single-blind, randomized, controlled trial.
      , the therapeutic dose was calculated using the size of the treated surface area (25 cm2) reported in a trial that used the same US device
      • Huang M.
      • Lin Y.
      • Lee C.
      • Yang R.
      Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis.
      . Only two trials
      • Huang M.
      • Lin Y.
      • Lee C.
      • Yang R.
      Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis.
      • Huang M.H.
      • Yang R.C.
      • Lee C.L.
      • Chen T.W.
      • Wang M.C.
      Preliminary results of integrated therapy for patients with knee osteoarthritis.
      , which were conducted by the same research group, reported outcomes of pain and physical function at 12 months (10 months after completing the interventions) and this information was analyzed separately.

      Risk of bias and quality assessment

      The risk of bias was unclear for one study
      • Huang M.
      • Chen T.
      • Weng M.
      • Wang Y.
      and high for five studies
      • Huang M.
      • Lin Y.
      • Lee C.
      • Yang R.
      Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis.
      • Huang M.H.
      • Yang R.C.
      • Lee C.L.
      • Chen T.W.
      • Wang M.C.
      Preliminary results of integrated therapy for patients with knee osteoarthritis.
      • Cetin N.
      • Aytar A.
      • Atalay A.
      • Akman M.N.
      Comparing hot pack, short-wave diathermy, ultrasound, and TENS on isokinetic strength, pain, and functional status of women with osteoarthritic knees: a single-blind, randomized, controlled trial.
      • Falconer J.
      • Hayes K.W.
      • Chang R.W.
      Effect of ultrasound on mobility in osteoarthritis of the knee. A randomized clinical trial.
      • Ozgonenel L.
      • Aytekin E.
      • Durmusoglu G.
      A double-blind trial of clinical effects of therapeutic ultrasound in knee osteoarthritis.
      (Table II). Thus, the evidence included in this review has a high risk of bias overall.
      Table IIRisk of bias assessment of the included randomized controlled trials
      TrialsKey domainsReporting of outcomes completeRisk of bias
      Group allocation concealmentRandomizationBlinding of treatment providerBlinding of participantsCompleteness of data
      Cetin et al.
      • Cetin N.
      • Aytar A.
      • Atalay A.
      • Akman M.N.
      Comparing hot pack, short-wave diathermy, ultrasound, and TENS on isokinetic strength, pain, and functional status of women with osteoarthritic knees: a single-blind, randomized, controlled trial.
      UnclearUnclearNoNoYesYesHigh
      Falconer et al.
      • Falconer J.
      • Hayes K.W.
      • Chang R.W.
      Effect of ultrasound on mobility in osteoarthritis of the knee. A randomized clinical trial.
      UnclearUnclearNoYesYesNo-final walking performance not reported by groupHigh
      Huang et al.
      • Huang M.
      • Chen T.
      • Weng M.
      • Wang Y.
      UnclearUnclearUnclearUnclearYesYesUnclear
      Huang et al.
      • Huang M.
      • Lin Y.
      • Lee C.
      • Yang R.
      Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis.
      NoNoNoNoYes (8 weeks)

      No (12 months)
      YesHigh
      Huang et al.
      • Huang M.H.
      • Yang R.C.
      • Lee C.L.
      • Chen T.W.
      • Wang M.C.
      Preliminary results of integrated therapy for patients with knee osteoarthritis.
      NoNoNoNoYesYesHigh
      Ozgonenel et al.
      • Ozgonenel L.
      • Aytekin E.
      • Durmusoglu G.
      A double-blind trial of clinical effects of therapeutic ultrasound in knee osteoarthritis.
      UnclearUnclearNoYesYesYesHigh
      The quality of evidence is low for pain and physical function outcomes because of the high risk of bias (Table II), and the heterogeneity observed in results across trials [I2=51–92%, Fig. 2, Fig. 3, Fig. 4] (Appendix B). The quality of evidence is considered low for cartilage repair because the only trial
      • Huang M.
      • Chen T.
      • Weng M.
      • Wang Y.
      that reported this outcome had an unclear risk of bias (Table II) and used a surrogate measure (99mTechnetium uptake) to assess cartilage status (Appendix B).
      Figure thumbnail gr2
      Fig. 2Meta-analyses of ultrasound effect on pain (cm-VAS). A: SMDs at the end of the intervention. B: Mode/intensity and dose subgroup analysis. C: SMDs at 12 months (10 months after completing US).
      Figure thumbnail gr3
      Fig. 3Meta-analyses of ultrasound effect on self-reported physical function (LSI scores and WOMAC physical function subscale scores). A: SMDs at the end of the intervention. B: SMDs of LSI scores at 12 months (10 months after completing US).
      Figure thumbnail gr4
      Fig. 4Meta-analyses of ultrasound effect on walking performance (time to walk 50 m in minutes and walking speed in m/min). A: SMDs at the end of the intervention. B: SMDs of walking speed (m/min) at 12 months (10 months after completing US).

      Effect of US on pain

      All included trials assessed pain using a Visual Analog Scale (VAS) measured in centimeters. Overall, the application of US resulted in decreased pain [SMD (CI)=−0.49 (−0.79, −0.18), P=0.002] [Fig. 2(A)]. However, high heterogeneity was found (χ2=10.26, P=0.07, I2=51%), therefore predefined subgroup analyses were conducted. Ultrasound mode, intensity, and therapeutic dose completely explained the inconsistency between the groups [Fig. 2(B)]. In all subgroups, effect estimates favored US therapy; however, the differences were statistically significant only in the low intensity/pulsed US and US dose<150 J/cm2 subgroups [SMD (CI)=−0.85 (−1.16, −0.54)]. Overall, trials
      • Huang M.
      • Lin Y.
      • Lee C.
      • Yang R.
      Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis.
      • Huang M.H.
      • Yang R.C.
      • Lee C.L.
      • Chen T.W.
      • Wang M.C.
      Preliminary results of integrated therapy for patients with knee osteoarthritis.
      that reported VAS at 12 months (10 months after completing the interventions) favored US [SMD (CI)=−0.77 (−1.15, −0.39), P<0.001] [Fig. 2(C)].

      Effect of US on physical function

      Self-reported physical function

      Five studies included self-reported physical function measurements: four used the Lequesne Severity Index (LSI) score
      • Huang M.
      • Lin Y.
      • Lee C.
      • Yang R.
      Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis.
      • Huang M.
      • Chen T.
      • Weng M.
      • Wang Y.
      • Huang M.H.
      • Yang R.C.
      • Lee C.L.
      • Chen T.W.
      • Wang M.C.
      Preliminary results of integrated therapy for patients with knee osteoarthritis.
      • Cetin N.
      • Aytar A.
      • Atalay A.
      • Akman M.N.
      Comparing hot pack, short-wave diathermy, ultrasound, and TENS on isokinetic strength, pain, and functional status of women with osteoarthritic knees: a single-blind, randomized, controlled trial.
      ; one used the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function subscale score
      • Ozgonenel L.
      • Aytekin E.
      • Durmusoglu G.
      A double-blind trial of clinical effects of therapeutic ultrasound in knee osteoarthritis.
      (Table I). The effect estimate observed favored the US intervention, however the difference between groups was not statistically significant [SMD (CI)=−0.54 (−1.19, 0.12), P=0.11] [Fig. 3(A)]. Heterogeneity was high (χ2=29.11, P<0.001, I2=86%), and predefined subgroup analyses were performed. Inconsistency was not explained satisfactorily by any of the subgroup analyses performed. Data pooled from two trials
      • Huang M.
      • Lin Y.
      • Lee C.
      • Yang R.
      Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis.
      • Huang M.H.
      • Yang R.C.
      • Lee C.L.
      • Chen T.W.
      • Wang M.C.
      Preliminary results of integrated therapy for patients with knee osteoarthritis.
      showed an improvement at 12 months (10 months after completing the interventions) in the self-reported physical function of people who received US [SMD (CI)=−1.25 (−1.69, −0.81), P<0.001] [Fig. 3(B)].

      Walking performance

      Five studies reported walking performance: two studies measured the time taken to walk 50 m in minutes
      • Cetin N.
      • Aytar A.
      • Atalay A.
      • Akman M.N.
      Comparing hot pack, short-wave diathermy, ultrasound, and TENS on isokinetic strength, pain, and functional status of women with osteoarthritic knees: a single-blind, randomized, controlled trial.
      • Ozgonenel L.
      • Aytekin E.
      • Durmusoglu G.
      A double-blind trial of clinical effects of therapeutic ultrasound in knee osteoarthritis.
      ; three studies measured walking speed (m/min)
      • Huang M.
      • Lin Y.
      • Lee C.
      • Yang R.
      Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis.
      • Huang M.
      • Chen T.
      • Weng M.
      • Wang Y.
      • Huang M.H.
      • Yang R.C.
      • Lee C.L.
      • Chen T.W.
      • Wang M.C.
      Preliminary results of integrated therapy for patients with knee osteoarthritis.
      (Table I). There was no significant improvement in the walking performance in the US group [SMD (CI)=0.81 (−0.09, 1.72), P=0.08] [Fig. 4(A)]. High heterogeneity was observed (χ2=52.2, P<0.001, I2=92%), and the subgroup analyses did not explain this inconsistency. Pooling the results of two studies
      • Huang M.
      • Lin Y.
      • Lee C.
      • Yang R.
      Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis.
      • Huang M.H.
      • Yang R.C.
      • Lee C.L.
      • Chen T.W.
      • Wang M.C.
      Preliminary results of integrated therapy for patients with knee osteoarthritis.
      , by the same research group, showed that walking speed at 12 months (10 months after completing the interventions) was improved in the US group [SMD (CI)=1.47 (1.06, 1.88), P<0.001] [Fig. 4(B)].

      Effect of US on patient-perception of disease severity

      No studies were identified which reported an outcome related to patient-perception of disease severity.

      Effect of US on cartilage repair

      Only one study
      • Huang M.
      • Chen T.
      • Weng M.
      • Wang Y.
      reported an outcome related to knee joint structure. The authors measured 99mTechnetium uptake on bone scans in order to determine an ‘index of arthritis severity’, 99mTechnetium uptake in the knee divided by the 99mTechnetium uptake in the middle third of the ipsilateral femur. The authors validated this outcome measure on animal models of cartilage injury
      • Huang M.H.
      • Ding H.J.
      • Yang C.C.
      • Chai C.Y.
      • Yang R.C.
      The early evaluation of induced osteoarthritis in rats with 99Tcm-pertechnetate scans.
      . The results of this study showed a significant decrease in the ‘index of arthritis severity’ measured after an 8 week US intervention for patients in the lowest and middle tertile for baseline measures of ‘index of arthritis severity’ [MD (CI)=0.8 (0.32, 1.28), P<0.001 and 1.8 (0.85, 2.75), P<0.001, respectively] but not for those in the highest tertile at baseline [MD (CI)=0.10 (−1.06, 1.26), P=0.87]. We considered this outcome an indirect measurement of cartilage status/repair. Our search did not yield any trial reporting a direct measurement of cartilage repair.

      Adverse events

      One study
      • Falconer J.
      • Hayes K.W.
      • Chang R.W.
      Effect of ultrasound on mobility in osteoarthritis of the knee. A randomized clinical trial.
      described the intention to monitor the incidence of adverse events related to the application of US and reported the absence of major complications. Another study
      • Ozgonenel L.
      • Aytekin E.
      • Durmusoglu G.
      A double-blind trial of clinical effects of therapeutic ultrasound in knee osteoarthritis.
      reported that no adverse events occurred either during or after the interventions. Since the number of adverse events reported in these two trials was zero, and adverse events were not reported in the rest of the included trials, an estimate of US safety could not be calculated.

      Discussion

      This systematic review provides a meta-analysis of the efficacy of US for decreasing pain and improving physical function in people with knee OA. New evidence was found (Table I) which shows that US can reduce pain by 21%, compared to a control group (Appendix B). The clinical importance of this finding can be appreciated in terms of the number of patients it is necessary to treat in order to observe improvement in pain in one patient. To calculate the number needed to treat (NNT), we used the formula proposed by Chinn et al.
      • Chinn S.
      A simple method for converting an odds ratio to effect size for use in meta-analysis.
      . The SMD was transformed to an odds ratio and the proportion of subjects in the control group that will experience improvement in pain (29%) was determined from a prospective study involving a comparable patient sample
      • Peters T.J.
      • Sanders C.
      • Dieppe P.
      • Donovan J.
      Factors associated with change in pain and disability over time: a community-based prospective observational study of hip and knee osteoarthritis.
      . Using this approach, the NNT is 7. It also seems that US applied using low intensity (<1 W/cm2), pulsed mode, and a therapeutic dose<150 J/cm2 could be more effective at reducing pain than US applied using high intensity (≥1 W/cm2), continuous mode and a therapeutic dose>150 J/cm2. In general, a non-significant positive effect (19.68% lower Lequesne Severity Index (LSI) score than the control group) was observed on physical function with the use of US (Appendix B). Based on the findings from two trials by one research group
      • Huang M.
      • Lin Y.
      • Lee C.
      • Yang R.
      Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis.
      • Huang M.H.
      • Yang R.C.
      • Lee C.L.
      • Chen T.W.
      • Wang M.C.
      Preliminary results of integrated therapy for patients with knee osteoarthritis.
      , beneficial effects may last for 10 months after the US treatment is completed [Fig. 2, Fig. 3, Fig. 4].
      Limited evidence found in this review prevents conclusive statements regarding dose effects and the effectiveness of US on cartilage repair. Our findings which suggest a threshold US dosage for pain reduction in persons with knee OA are consistent with previous findings that higher US doses are less effective for tissue repair in humans
      • Byl N.N.
      • McKenzie A.
      • Wong T.
      • West J.
      • Hunt T.K.
      Incisional wound healing: a controlled study of low and high dose ultrasound.
      and even harmful for the growth plate of rabbits
      • Lyon R.
      • Liu X.C.
      • Meier J.
      The effects of therapeutic vs. high-intensity ultrasound on the rabbit growth plate.
      . Only one small trial with unclear risk of bias assessed the cartilage repair process. This study used an indirect measurement of cartilage status in people with knee OA and reported that low intensity pulsed US may help to enhance the cartilage repair process on this population. These findings together with animal studies which permit direct measurement of cartilage tissue response to US
      • Cook S.D.
      • Salkeld S.L.
      • Patron L.P.
      • Doughty E.S.
      • Jones D.G.
      The effect of low-intensity pulsed ultrasound on autologous osteochondral plugs in a canine model.
      • Huang M.H.
      • Ding H.J.
      • Chai C.Y.
      • Huang Y.F.
      • Yang R.C.
      Effects of sonication on articular cartilage in experimental osteoarthritis.
      • Singh K.I.
      • Sobti V.K.
      • Roy K.S.
      Gross and histomorphological effects of therapeutic ultrasound (1 watt/cm2) in experimental acute traumatic arthritis in donkeys.
      are consistent with the “mechanotransduction theory”. This theory proposes that mechanical stimuli increase the chondrocyte production of proteoglycans and anti-inflammatory proteins
      • Choi B.H.
      • Choi M.H.
      • Kwak M.G.
      • Min B.H.
      • Woo Z.H.
      • Park S.R.
      Mechanotransduction pathways of low-intensity ultrasound in C-28/I2 human chondrocyte cell line.
      . Further studies are warranted to determine if low dose pulsed US is optimal for pain relief and stimulation of cartilage repair.
      Our findings suggest that US delivered using a pulsed mode and at low intensities have a pronounced effect on pain reduction. In theory, the thermal effect of US is proposed to reduce pain
      • Baker K.G.
      • Robertson V.J.
      • Duck F.A.
      A review of therapeutic ultrasound: biophysical effects.
      . The thermal effect is achieved by applying high intensity US in a continuous mode to heat the nerve fibers which attenuates nociception
      • Bélanger A.Y.
      Ultrasound.
      . However, our findings suggest a non-thermal mechanism for pain reduction which may be related to a threshold dose effect, as stated previously, or attenuation of the nociceptive signals via mechanical stimuli. Nevertheless, the limited number and quality of the trials included in the subgroup analyses limit further inferences.
      None of the subgroup analyses that we conducted explained the heterogeneity observed for physical function and walking performance outcomes. Heterogeneity was reduced for self-reported physical function (I2 reduced from 86% to 30%) and walking performance (I2 reduced from 94% to 0%) when groups with a similar severity of knee OA were compared and the US group was favoured. However, these subgroups were comprised of subjects with mild disease severity (Altman II), so it is unclear if these observations are related to the comparison of homogeneous groups or to the mild disease severity. Thus, consideration of disease status may be important when assessing the effects of US in the knee OA population.
      The main results of this review support the findings of a recently updated Cochrane review
      • Rutjes A.W.S.
      • Nüesch E.
      • Sterchi R.
      • Jüni P.
      Therapeutic ultrasound for osteoarthritis of the knee or hip.
      . However some differences warrant comment. The authors of the Cochrane review assumed that the US provided in the study by Falconer et al.
      • Falconer J.
      • Hayes K.W.
      • Chang R.W.
      Effect of ultrasound on mobility in osteoarthritis of the knee. A randomized clinical trial.
      was pulsed. For the current review, however, the authors confirmed that it was continuous. Our search yielded one unpublished trial
      • Huang M.
      • Chen T.
      • Weng M.
      • Wang Y.
      related to our objective to evaluate the effectiveness of US on cartilage repair. This trial was not considered in the updated Cochrane review. Finally, we decided to analyze the data from two trials
      • Huang M.
      • Lin Y.
      • Lee C.
      • Yang R.
      Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis.
      • Huang M.H.
      • Yang R.C.
      • Lee C.L.
      • Chen T.W.
      • Wang M.C.
      Preliminary results of integrated therapy for patients with knee osteoarthritis.
      that reported outcomes at 12 months (10 months after the interventions were completed) to explore the longer term US effects. These long-term effects were not considered in the updated Cochrane review. Despite these differences, our results are compatible.
      A limitation of our review is that the findings are based on evidence which has a high risk of bias and low quality. When we synthesized only the trials that adequately blinded the participants
      • Falconer J.
      • Hayes K.W.
      • Chang R.W.
      Effect of ultrasound on mobility in osteoarthritis of the knee. A randomized clinical trial.
      • Ozgonenel L.
      • Aytekin E.
      • Durmusoglu G.
      A double-blind trial of clinical effects of therapeutic ultrasound in knee osteoarthritis.
      the effect size decreased considerably and was no longer statistically significant [SMD (CI)=−0.24 (−0.63, 0.14)]. This suggests that the effect sizes for pain found in this review could be partly inflated by the methodological limitations of the included studies.
      A further limitation is the decision to pool the results of the studies that compared US and placebo with studies that included co-interventions. We assume that no interaction between US and the isokinetic exercises occurred, however we cannot test this assumption. It is well known that exercise is beneficial in relieving pain and improving physical function for people with knee OA
      • Fransen M.
      • McConnell S.
      Exercise for osteoarthritis of the knee.
      . Therefore, a positive interaction between US and exercise cannot be ruled out. Finally, because of the limited number of small trials identified, the risk of publication bias could not be determined. Hence, the possibility exists that only positive trials were published while negative trials were not. Overall, the methodological limitations described reduce the confidence in the effect estimates observed in the present meta-analyses.

      Implications for practice

      US (10–24 sessions) appears to be efficacious for decreasing pain, and may improve physical function in patients with knee OA. It is possible that the mode, intensity, and dose of US all influence the effect on pain. It is also possible that pain reduction may be sustained for 10 months after US is discontinued. However, these results are currently supported by low quality evidence and definitive trials are needed.

      Implications for research

      Trials that are methodologically rigorous and adequately powered are needed to confirm the effectiveness of US to reduce pain, and improve physical function in people with knee OA. Outcome measures in trials should include cartilage repair and patient-perception of knee OA severity to provide insight into potential synergistic action mechanisms. Careful consideration of ultrasound prescription and disease stage is required to assess the optimal therapeutic parameters and the subgroup(s) of people who will benefit most. Long-term effects of the US intervention should be assessed as well. Finally, the mechanism by which therapeutic ultrasound reduces pain in knee OA needs to be explored further.

      Author contributions

      All authors made substantial contributions to the conceptualization, design, data collection, analysis, interpretation, drafting and revisions; and approved the final version.

      Conflict of interest

      None of the authors has any financial and personal relationships with other people or organizations that could potentially and inappropriately influence this work and its conclusions.

      Acknowledgement

      Role of funding sources: AL was supported by the Consejo Nacional de Ciencia y Tecnologia (CONACYT) of Mexico scholarship (number 209621 ), and by a McMaster University School of Graduate Studies International Excellence Award . These sponsors had no involvement in the design, conduct or publication of this study.

      Appendix A. Medical Subject Headings and keyword search strategy performed in Ovid MEDLINE (1950 to January week 4, 2009)

      Tabled 1
      1Exp Osteoarthritis/
      2Osteoarthritis.mp.
      3Exp Arthritis, Experimental/
      4Exp Arthritis/
      5Arthritis experimental.mp.
      6Exp Wound Healing/
      7Ultrasonic Therapy/
      8Exp Ultrasonics/
      9Ultrasound therapy.mp.
      10Ultrasonic therapy.mp.
      11Exp Sonication/
      12Sonication.mp.
      13Low intensity pulsed ultrasound.mp.
      14Low intensity ultrasound.mp.
      15Exp Diathermy/
      16Cartilage, Articular/
      17Exp Cartilage/
      18Cartilage repair.mp.
      196 or 1 or 18 or 3 or 16 or 17 or 2 or 5
      2011 or 7 or 9 or 12 or 15 or 14 or 8 or 10 or 13
      2220 and 19

      Appendix B. Summary of findings and quality of evidence assessment

      Tabled 1
      OutcomesControl group meanUltrasound group mean with respect to the control group (CI)Relative change
      Relativechange(%)=(MeandifferenceFinalcontrolmean)×100.
      (CI)
      Quality of the evidence
      We considered that the probability of having a “publication bias” in this review is low.
      ,
      GRADE Working Group grades of evidence15. 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.
      Comments
      Pain

      VAS from 0 (no pain) to 10 (intense pain)

      Follow up: 2–8 weeks
      3.95
      The final score mean for the control groups was calculated by pooling the means and standard errors through a generic inverse-variance method.
      0.84 Lower (1.2–0.48 lower)21% Lower (30%, 12%)LowHigh risk of bias of the included studies and considerable results’ heterogeneity.
      Follow-up: 12 months
      All patients included in these studies had mild knee OA (Altman Grade II) and completed a home-exercise program after 2 months of treatment/sham US.
      3.95
      The final score mean for the control groups was calculated by pooling the means and standard errors through a generic inverse-variance method.
      1.22 Lower (1.62–0.82 lower)30% Lower (40%, 20%)LowBlinding issues and lack of completeness in the follow-up data (<85% of participants) detected.
      Physical function

      LSI scale from 0 (better) to 26 (worst)

      Follow-up: 2–8 weeks
      5.65
      The final score mean for the control groups was calculated by pooling the means and standard errors through a generic inverse-variance method.
      1.11
      MD were calculated through a back transformation of the SMD using the SD reported in Villanueva et al.21 [Lequesne severity index=2.06] and Huang et al.22 [walking speed 5.73].
      Lower (2.45 lower to 0.24 higher)

      Mild severity (grade II) subgroup=2.7
      MD were calculated through a back transformation of the SMD using the SD reported in Villanueva et al.21 [Lequesne severity index=2.06] and Huang et al.22 [walking speed 5.73].
      lower (4.03–1.38 lower)
      19.68% Lower (89.32% lower to 8% higher)

      47% Lower (71%, 24%)
      LowHigh risk of bias of the included studies and considerable results’ heterogeneity.
      Follow-up: 12 months
      All patients included in these studies had mild knee OA (Altman Grade II) and completed a home-exercise program after 2 months of treatment/sham US.


      LSI
      5.65
      The final score mean for the control groups was calculated by pooling the means and standard errors through a generic inverse-variance method.
      2.07
      MD were calculated through a back transformation of the SMD using the SD reported in Villanueva et al.21 [Lequesne severity index=2.06] and Huang et al.22 [walking speed 5.73].
      Lower (2.91–1.22 lower)
      36% Lower (51%, 21%)Low
      Walking performance

      Walking speed (m/min)

      Follow-up: 2–8 weeks
      82.47
      The final score mean for the control groups was calculated by pooling the means and standard errors through a generic inverse-variance method.
      4.64
      MD were calculated through a back transformation of the SMD using the SD reported in Villanueva et al.21 [Lequesne severity index=2.06] and Huang et al.22 [walking speed 5.73].
      Higher (0.5 lower to 9.85 higher)

      Mild severity (grade II) subgroup=11.17
      MD were calculated through a back transformation of the SMD using the SD reported in Villanueva et al.21 [Lequesne severity index=2.06] and Huang et al.22 [walking speed 5.73].
      higher (14.32–8.07 higher)
      5% Higher (0.6% lower to 12% higher)

      13% Higher (17%, 10%)
      LowHigh risk of bias of the included studies and considerable results’ heterogeneity.
      Follow-up: 12 months
      All patients included in these studies had mild knee OA (Altman Grade II) and completed a home-exercise program after 2 months of treatment/sham US.


      Walking speed (m/min)
      82.47
      The final score mean for the control groups was calculated by pooling the means and standard errors through a generic inverse-variance method.
      10.89
      MD were calculated through a back transformation of the SMD using the SD reported in Villanueva et al.21 [Lequesne severity index=2.06] and Huang et al.22 [walking speed 5.73].
      Higher (7.07–14.71 higher)
      13% Higher (8%, 18%)Low
      Cartilage repair

      Follow-up: 8 weeks

      Arthritis Severity Index (smaller values mean less severity)
      4.91.8 Lower (2.47–1.13 lower)36% Lower (50%, 23%)LowHigh risk of bias and indirectness of the outcome measure (we consider bone scan as a surrogate measurement of cartilage repair).
      We considered that the probability of having a “publication bias” in this review is low.
      GRADE Working Group grades of evidence
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      . 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.
      The final score mean for the control groups was calculated by pooling the means and standard errors through a generic inverse-variance method.
      § All patients included in these studies had mild knee OA (Altman Grade II) and completed a home-exercise program after 2 months of treatment/sham US.
      Relativechange(%)=(MeandifferenceFinalcontrolmean)×100.
      MD were calculated through a back transformation of the SMD using the SD reported in Villanueva et al.
      • Villanueva I.
      • del Mar Guzman M.
      • Javier Toyos F.
      • Ariza-Ariza R.
      • Navarro F.
      Relative efficiency and validity properties of a visual analogue vs a categorical scaled version of the western ontario and McMaster universities osteoarthritis (WOMAC) index: Spanish versions.
      [Lequesne severity index=2.06] and Huang et al.
      • Huang M.H.
      • Lin Y.S.
      • Yang R.C.
      • Lee C.L.
      A comparison of various therapeutic exercises on the functional status of patients with knee osteoarthritis.
      [walking speed 5.73].

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