Advertisement

Mechanical-based therapies may reduce pain and disability in some patients with knee osteoarthritis: A systematic review with meta-analysis

  • Sofia Oliveira
    Correspondence
    Corresponding author at: Center for MicroElectroMechanical Systems (CMEMS‑UMINHO), University of Minho, Azurém Campus, 4800‑058 Guimarães, Portugal.
    Affiliations
    Center for MicroElectroMechanical Systems (CMEMS‑UMINHO), University of Minho, Azurém Campus, 4800‑058 Guimarães, Portugal

    LABBELS – Associate Laboratory, Braga, Guimarães, Portugal
    Search for articles by this author
  • Renato Andrade
    Affiliations
    Clínica Espregueira - FIFA Medical Centre of Excellence, Porto, Portugal

    Dom Henrique Research Centre, Porto, Portugal

    Porto Biomechanics Laboratory (LABIOMEP), Faculty of Sports, University of Porto, Porto, Portugal
    Search for articles by this author
  • Cristina Valente
    Affiliations
    Clínica Espregueira - FIFA Medical Centre of Excellence, Porto, Portugal

    Dom Henrique Research Centre, Porto, Portugal
    Search for articles by this author
  • João Espregueira-Mendes
    Affiliations
    Clínica Espregueira - FIFA Medical Centre of Excellence, Porto, Portugal

    Dom Henrique Research Centre, Porto, Portugal

    ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal

    3B’s Research Group‑Biomaterials, Biodegradables and Biomimetics, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, University of Minho, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, Barco, 4805‑017 Guimarães, Portugal

    School of Medicine, University of Minho, Braga, Portugal
    Search for articles by this author
  • Filipe Silva
    Affiliations
    Center for MicroElectroMechanical Systems (CMEMS‑UMINHO), University of Minho, Azurém Campus, 4800‑058 Guimarães, Portugal

    LABBELS – Associate Laboratory, Braga, Guimarães, Portugal
    Search for articles by this author
  • Betina B. Hinckel
    Affiliations
    Department of Orthopaedic Surgery, William Beaumont Hospital, Royal Oak, MI, USA
    Search for articles by this author
  • Óscar Carvalho
    Affiliations
    Center for MicroElectroMechanical Systems (CMEMS‑UMINHO), University of Minho, Azurém Campus, 4800‑058 Guimarães, Portugal

    LABBELS – Associate Laboratory, Braga, Guimarães, Portugal
    Search for articles by this author
  • Ana Leal
    Affiliations
    Center for MicroElectroMechanical Systems (CMEMS‑UMINHO), University of Minho, Azurém Campus, 4800‑058 Guimarães, Portugal

    LABBELS – Associate Laboratory, Braga, Guimarães, Portugal

    Dom Henrique Research Centre, Porto, Portugal
    Search for articles by this author
Open AccessPublished:June 03, 2022DOI:https://doi.org/10.1016/j.knee.2022.05.005

      Highlights

      • Meta-analyses presented very-low certainty of evidence.
      • All studies were judged to have risk of bias in one or more domains.
      • 15 of 42 (38%) pooled comparisons were superior in mechanical-based therapies.
      • These therapies may be cautiously applied in some patients with knee OA.

      Abstract

      Background

      Mechanical-based therapies are not yet recommended to manage osteoarthritis (OA). This systematic review and meta-analysis aim to assess the effects of passive mechanical-based therapies (isolated or combined with other therapies) on patients with knee OA compared to placebo, other isolated or combined interventions.

      Methods

      Pubmed, Cochrane, Web of Science and EMBASE were searched up to December 2020. We included randomized and non-randomized trials using therapeutic ultrasound, phonophoresis, extracorporeal shockwave therapy (ESWT) and vibration (single or combined with other therapies) compared to placebo, and/or other physical therapies groups. Biochemical, patient-reported, physical and imaging outcome measures were retrieved. We judged risk of bias using the RoB2 tool for randomized studies, the ROBINS-I tool for non-randomized studies, and the GRADE to interpret certainty of results.

      Results

      We included 77 clinical studies. Ultrasound and ESWT statistically improved pain and disability comparing to placebo (combined or not with other therapies), and when added to other therapies versus other therapies alone. Ultrasound was statistically inferior to phonophoresis (combined or not with other therapies) in reducing pain and disability for specific therapeutic gels and/or combined therapies. Vibration plus exercise statistically improved pain relief and function versus exercise alone. All meta-analyses showed very-low certainty of evidence, with 15 of 42 (38%) pooled comparisons being statistically significant (weak to large effect).

      Conclusions

      Despite the inconsistent evidence with very-low certainty, the potential benefits of passive mechanical-based therapies should not be disregard and cautiously recommended that clinicians might use them in some patients with knee OA.

      Keywords

      1. Introduction

      Knee osteoarthritis (OA) is a highly prevalent joint degenerative disease and one of the main causes of disability; with a global prevalence of 22.9% and affecting approximately 654 million individuals [
      • Cui A.
      • Li H.
      • Wang D.
      • Zhong J.
      • Chen Y.
      • Lu H.
      Global, regional prevalence, incidence and risk factors of knee osteoarthritis in population-based studies.
      ]. OA has a significant clinical and economic impact worldwide, involving a considerable amount of healthcare resources including costs from pharmacological treatments, rehabilitation and time off-work [
      • Chen A.
      • Gupte C.
      • Akhtar K.
      • Smith P.
      • Cobb J.
      The global economic cost of osteoarthritis: how the UK compares.
      ].
      Non-operative treatment is the first-line of treatment to treat knee OA, and mechanical-based treatments (exercises-based physiotherapy and weight loss) are commonly used for pain and joint function improvement [
      • Charlesworth J.
      • Fitzpatrick J.
      • Kanthi N.
      • Perera P.
      • Orchard J.
      Osteoarthritis- a systematic review of long-term safety implications for osteoarthritis of the knee.
      ]. There is a growing interest in mechanical-based therapies, such as ultrasound or phonophoresis (use of ultrasound along with topical gels or drugs to enhance their delivery), extracorporeal shockwave therapy (ESWT) and vibration [
      • Collins N.J.
      • Hart H.F.
      • Mills K.A.G.
      Osteoarthritis year in review 2018: rehabilitation and outcomes.
      ,
      • Kolasinski S.L.
      • Neogi T.
      • Hochberg M.C.
      • Oatis C.
      • Guyatt G.
      • Block J.
      • et al.
      2019 American college of rheumatology/arthritis foundation guideline for the management of osteoarthritis of the hand, hip, and knee.
      ], however, according to OA management guidelines, they are not yet recommended in clinical practice [
      • Kolasinski S.L.
      • Neogi T.
      • Hochberg M.C.
      • Oatis C.
      • Guyatt G.
      • Block J.
      • et al.
      2019 American college of rheumatology/arthritis foundation guideline for the management of osteoarthritis of the hand, hip, and knee.
      ,
      • Geenen R.
      • Overman C.L.
      • Christensen R.
      • Åsenlöf P.
      • Capela S.
      • Huisinga K.L.
      • et al.
      EULAR recommendations for the health professional’s approach to pain management in inflammatory arthritis and osteoarthritis.
      ,
      • McAlindon T.E.
      • Bannuru R.R.
      • Sullivan M.C.
      • Arden N.K.
      • Berenbaum F.
      • Bierma-Zeinstra S.M.
      • et al.
      OARSI guidelines for the non-surgical management of knee osteoarthritis.
      ]. Before being widely implemented in the clinical setting, it is paramount to understand their potential role on the management of OA.
      Previous systematic reviews with meta-analysis have investigated the effects of therapeutic ultrasound [
      • Wu Y.
      • Zhu S.
      • Lv Z.
      • Kan S.
      • Wu Q.
      • Song W.
      • et al.
      Effects of therapeutic ultrasound for knee osteoarthritis : a systematic review and meta-analysis.
      ,
      • Zhang C.
      • Xie Y.
      • Luo X.
      • Ji Q.
      • Lu C.
      • He C.
      • et al.
      Effects of therapeutic ultrasound on pain, physical functions and safety outcomes in patients with knee osteoarthritis: A systematic review and meta-analysis.
      ,
      • Loyola-Sánchez A.
      • Richardson J.
      • Macintyre N.J.
      Efficacy of ultrasound therapy for the management of knee osteoarthritis : a systematic review with meta-analysis.
      ], ESWT [
      • Wang Y.C.
      • Huang H.T.
      • Huang P.J.
      • Liu Z.M.
      • Shih C.L.
      Efficacy and safety of extracorporeal shockwave therapy for treatment of knee osteoarthritis: a systematic review and meta-analysis.
      ,
      • Li T.
      • Ma J.
      • Zhao T.
      • Gao F.
      • Sun W.
      Application and efficacy of extracorporeal shockwave treatment for knee osteoarthritis: A systematic review and meta-analysis.
      ] and vibration [
      • Li X.
      • Wang X.Q.
      • Chen B.L.
      • Huang L.Y.
      • Liu Y.
      Whole-body vibration exercise for knee osteoarthritis: a systematic review and meta-analysis.
      ,
      • Zafar H.
      • Alghadir A.
      • Anwer S.
      • Al-Eisa E.
      Therapeutic effects of whole-body vibration training in knee osteoarthritis: a systematic review and meta-analysis.
      ,
      • Anwer S.
      • Alghadir A.
      • Zafar H.
      • Al-Eisa E.
      Effect of whole body vibration training on quadriceps muscle strength in individuals with knee osteoarthritis: A systematic review and meta-analysis.
      ] on patient-centered and physical outcomes measures. Most of these meta-analyses did not perform subgroup, sensitivity, publication bias analyses, as well as did not provide recommendations based on the certainty of evidence. Our aim is to perform a systematic review with meta-analysis that compares the aforementioned passive mechanical-based treatments to control, placebo, other therapies and/or in combination with other interventions, employing more rigorous procedures which were not applied in the previous referred systematic reviews. The purpose of the review was to summarize the characteristics of mechanical-based interventions; and to evaluate the effect of mechanical-based interventions in patients with knee OA.

      2. Methods

      This systematic review with meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement [
      • Page M.J.
      • McKenzie J.E.
      • Bossuyt P.M.
      • Boutron I.
      • Hoffmann T.C.
      • Mulrow C.D.
      • et al.
      statement: An updated guideline for reporting systematic reviews.
      ], and implemented under the guidance of Prisma in Exercise, Rehabilitation, Sport medicine and Sports science (PERSiST) [
      • Ardern C.L.
      • Büttner F.
      • Andrade R.
      • Weir A.
      • Ashe M.C.
      • Holden S.
      • et al.
      Implementing the 27 PRISMA 2020 Statement items for systematic reviews in the sport and exercise medicine, musculoskeletal rehabilitation and sports science fields : the PERSiST (implementing Prisma in Exercise, Rehabilitation, Sport medicine and Spor.
      ]. The protocol of the current review was prospectively registered at Open Science Framework (OSF: qdr6e) [

      Oliveira S, Andrade R, Valente C, Espregueira-mendes J, Silva F, Hinckel BB, et al. Effects of mechanical stimulation on knee cartilage for osteoarthritis treatment : protocol for a systematic review with meta-analysis. 2021.

      ].

      2.1 Data sources and searches

      We conducted a comprehensive electronic database search on Pubmed, Cochrane, Web of Science and EMBASE to identify clinical studies that analysed the effect of passive mechanical-based treatments on individuals with knee OA. The search strategy presented in supplemental Appendix S1 was applied from database inception to December 18, 2020. The reference list of the most relevant original studies and reviews were also retrieved to identify other potential eligible studies.
      All records were exported to an Excel® file (Microsoft Office®) and duplicated studies were removed using the software filter. Manual verification was performed to check for any missing duplicate records. Two authors (S.O. and R.A.) screened all titles and abstracts independently, followed by evaluation of the full texts for eligibility. Three other reviewers (B.B.H., A.L. and O.C.) were consulted in case of disagreement.

      2.2 Study selection

      The eligibility criteria for the systematic review was framed according to the Participants, Intervention, Comparison, Outcomes and Study Design (PICOS) approach [
      • Methley A.M.
      • Campbell S.
      • Chew-Graham C.
      • McNally R.
      • Cheraghi-Sohi S.P.I.C.O.
      PICOS and SPIDER: A comparison study of specificity and sensitivity in three search tools for qualitative systematic reviews.
      ]. Only studies written in the English language were included.

      2.2.1 Participants

      We included individuals of both genders diagnosed with unilateral and/or bilateral knee OA, confirmed by imaging examination using the Kellgren–Lawrence grading system.

      2.2.2 Intervention

      We included studies that evaluated passive mechanical-based treatments for knee OA, the ones including therapeutic ultrasound and phonophoresis, ESWT and vibration, alone or in combination with other therapies. Studies including ultrasound only for diagnosis or as support for other therapies (i.e., ultrasound-guided) were excluded. Studies evaluating active mechanical-based treatments, such as exercises and manual therapy, were not considered.

      2.2.3 Comparison

      We included studies that compared the patients subjected to mechanical-based treatments with placebo, control (without intervention) and/or with other physical therapies.

      2.2.4 Outcomes

      We included any outcomes related to biochemical, clinical and imaging outcomes.

      2.2.5 Study design

      We included randomized and non-randomized clinical comparative studies. We excluded conference proceedings, reviews or meta-analysis, case studies and expert opinions.

      2.3 Data extraction and quality assessment

      All data related to study characteristics and outcomes from the included studies were extracted by one author (S.O.) and subsequently reviewed by four other authors (R.A., B.B.H., A.L. and O.C.). We retrieved data on study characteristics (year, study design), population characteristics (sample number, age, percentage of male/female, height, weight, body mass index [BMI], OA grade and respective classification criteria, and duration of symptoms) and interventions definition (definition used for intervention and comparisons groups). Intervention parameters were obtained depending on the intervention (e.g., operating mode, frequency, acceleration, amplitude, duty cycle, pulse duration, power density, energy density, number of pulses, stimulation time, treatment duration, stimulated area and the number of stimulated points). Measured variables and outcomes were collected and categorized into four different domains: biochemical (inflammation, cartilage degradation markers); patient-reported outcome measures (pain intensity, disability and quality of life); physical examination outcome measures (gait performance, knee range of motion, muscle strength); and imaging outcomes (cartilage and synovial thickness, muscle morphology).
      Median, 25% and 75% percentiles, minimum and maximum values were calculated for each intervention parameter. Corresponding authors were contacted for additional data when needed. Missing raw data were also computed using the methods suggested by Cochrane Handbook [
      • Higgins J.
      • Thomas J.
      • Chandler J.
      • Cumpston M.
      • Tianjing L.
      • Page M.
      • et al.
      Cochrane handbook for systematic reviews of interventions.
      ]. Weighted pooled means and standard deviations (SD) were calculated.
      The risk of bias of the randomized studies was judged using the revised Cochrane risk-of-bias (RoB2) tool version 2 [
      • Sterne J.A.C.
      • Savović J.
      • Page M.J.
      • Elbers R.G.
      • Blencowe N.S.
      • Boutron I.
      • et al.
      RoB 2: A revised tool for assessing risk of bias in randomised trials.
      ]. This tool assesses five distinct bias domains: i) randomization, ii) deviations from intended interventions, iii) missing outcome data, iv) measurement of outcomes and v) selection of the reported result. Each of these domains were appraised and scored as “low risk”, “some concerns” and “high risk” of bias. The overall risk of bias judgement was based on the bias appraisal from the five domains.
      The risk of bias of non-randomized studies was judged using the revised Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool version 1 [
      • Sterne J.A.
      • Hernán M.A.
      • Reeves B.C.
      • Savović J.
      • Berkman N.D.
      • Viswanathan M.
      • et al.
      ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions.
      ]. This tool assesses seven distinct bias domains: i) confounding, ii) selection of patients, iii) classification of interventions, iv) deviations from intended interventions, v) missing outcome data, vi) measurement of outcomes, viii) selection of the reported result. Each of these bias domains were appraised and scored as “low risk”, “moderate risk”, “serious risk”, “critical risk” and “no information”. The overall risk of bias judgement was based on the bias appraisal from the seven domains.
      The risk of financial bias, due to industry funding and/or conflict of interest from the authors of the study, was also judged in all studies as an additional bias criterion.
      Three independent authors (S.O., R.A. and C.V.) appraised the risk of bias of all included studies and disagreements were resolved by consensus.

      2.4 Data synthesis and analysis

      Quantitative syntheses were conducted on RStudio 3.3.1 software (RStudio, Boston, MA, USA), using the “dmetar”, “meta” and “metafor” packages. Meta-analyses were conducted when there were three or more homogenous studies investigating the same intervention groups and reporting the same outcomes. Outcomes that were not eligible for meta-analysis were reported by narrative synthesis.
      We used a random-effects model due to the small sample sizes and variations in study methods and control populations. Continuous outcomes were expressed as standardized mean differences (SMDs) with 95% confidence intervals (CI). The SMDs magnitude were interpreted as large (≥0.8), moderate (0.5–0.79) and weak (0.2–0.49) [
      • Cohen J.
      Statistical power analysis for the behavioral sciences.
      ]. The level of statistical heterogeneity was established using I-squared (I2) statistics. We interpreted the statistical heterogeneity as not important (<50%), moderate (50–75%) and high (>75%) [
      • Higgins J.P.T.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      ]. All meta-analyses were first stratified according to the type of intervention, and then by outcome metric, intervention type and follow-up - post-treatment evaluation time (immediately after treatment) and short-term evaluation (<13 weeks). Subgroup analyses were performed for each intervention according to the comparison group (type of exercises, type of therapeutic gels and other therapies). All main analyses were performed using the mean changes from baseline to follow-up, using a coefficient correlation of 0.5 to calculate the SD of the mean change. Sensitivity analyses were then conducted by calculating with coefficient correlation values of 0.3, 0.5 and 0.7. Additional sensitivity analyses were conducted by removing (1) studies with partial and/or total overlapping population, (2) studies with different characteristics, and (3) studies which SD values were calculated from p-values for differences in means, according to Cochrane handbook methods [
      • Higgins J.
      • Thomas J.
      • Chandler J.
      • Cumpston M.
      • Tianjing L.
      • Page M.
      • et al.
      Cochrane handbook for systematic reviews of interventions.
      ]. A minimum of two studies were required to remain after study removal to perform the sensitive analysis. Leave-one-out analysis and Baujat plots were conducted to evaluate the effect of any single study in the pooled SMD or heterogeneity. Publication bias was assessed by a funnel plot symmetry. We also carried out the trim-and-fill analysis to compute the publication bias corrected SMD and assess if it had an effect on the pooled outcome (either under- or over-estimated). Meta-regression analysis was conducted for each intervention according to stimulation parameters (i.e., number of sessions, power and energy density, frequency, stimulation time, number of pulses, amplitude), percentage of females and OA grade.

      2.4.1 Certainty of evidence

      The recommendations based on the strength of evidence were summarized using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach [

      Schünemann H, Brozek J, Guyatt G, Oxman A, editors. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013. Available from guidelinedevelopment.org/handbook.; n.d.

      ]. The certainty of evidence was graded as high, moderate, low or very low certainty, being downgraded due to risk of bias [
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.
      • Kunz R.
      • Brozek J.
      • Alonso-Coello P.
      • et al.
      GRADE guidelines: 4. Rating the quality of evidence - Study limitations (risk of bias).
      ], inconsistency [
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • Woodcock J.
      • Brozek J.
      • Helfand M.
      • et al.
      GRADE guidelines: 7. Rating the quality of evidence - Inconsistency.
      ], imprecision [
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • Brozek J.
      • Alonso-Coello P.
      • Rind D.
      • et al.
      GRADE guidelines 6. Rating the quality of evidence - Imprecision.
      ], indirectness [
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • Woodcock J.
      • Brozek J.
      • Helfand M.
      • et al.
      GRADE guidelines: 8. Rating the quality of evidence - Indirectness.
      ], or publication bias [
      • Guyatt G.H.
      • Oxman A.D.
      • Montori V.
      • Vist G.
      • Kunz R.
      • Brozek J.
      • et al.
      GRADE guidelines: 5. Rating the quality of evidence - Publication bias.
      ]. Three authors (S.O., R.A. and C.V.) performed the GRADE appraisal.

      3. Results

      3.1 Search results and studies characteristics

      The initial database and hand search generated a total of 10,689 records, of which 821 full texts were screened to assess their eligibility, from which 77 studies met the eligibility criteria and were included in this study (Figure 1). A total of 69 studies were randomized [
      • Yeğin T.
      • Altan L.
      • Kasapoğlu A.M.
      The effect of therapeutic ultrasound on pain and physical function in patients with knee osteoarthritis.
      ,
      • Durmus D.
      • Unal M.
      The effect of capsaicin phonophoresis in knee osteoarthritis and can it be utilized early in primary care? : A randomized-controlled trial.
      ,
      • Ozgönenel L.
      • Aytekin E.
      • Durmuşoglu G.
      A double-blind trial of clinical effects of therapeutic ultrasound in knee osteoarthritis.
      ,
      • Luksurapan W.
      • Boonhong J.
      Effects of phonophoresis of piroxicam and ultrasound on symptomatic knee osteoarthritis.
      ,
      • Ulus Y.
      • Tander B.
      • Akyol Y.
      • Durmus D.
      • Buyukakıncak O.
      • Gul U.
      • et al.
      Therapeutic ultrasound versus sham ultrasound for the management of patients with knee osteoarthritis: a randomized double-blind controlled clinical study.
      ,
      • Yang P.
      • Li D.
      • Zhang S.
      • Wu Q.
      • Tang J.
      • Huang L.
      • et al.
      Efficacy of ultrasound in the treatment of osteoarthritis of the knee.
      ,
      • Sangtong K.
      • Chupinijrobkob C.
      • Putthakumnerd W.
      • Kuptniratsaikul V.
      Does adding transcutaneous electrical nerve stimulation to therapeutic ultrasound affect pain or function in people with osteoarthritis of the knee? A randomized controlled trial.
      ,
      • Ozgonenel L.
      • Okur S.C.Ç.
      • Dogan Y.P.
      • Caglar N.S.
      • Özgönenel L.
      • Okur S.C.Ç.
      • et al.
      Effectiveness of therapeutic ultrasound on clinical parameters and ultrasonographic cartilage thickness in knee osteoarthritis: a double-blind trial.
      ,
      • Kapci Yildiz S.
      • Ünlü Özkan F.
      • Aktaş İ.
      • Şilte A.D.
      • Yilmaz Kaysin M.
      • Bilgin B.N.
      The effectiveness of ultrasound treatment for the management of knee osteoarthritis: A randomized, placebo-controlled, double-blind study.
      ,
      • Toopchizadeh V.
      • Javadi R.
      • Sadat B.E.
      Therapeutic efficacy of dexamethasone phonophoresis on symptomatic knee osteoarthritis in elderly women.
      ,
      • Alfredo P.P.
      • Junior W.S.
      • Casarotto R.A.
      Efficacy of continuous and pulsed therapeutic ultrasound combined with exercises for knee osteoarthritis: a randomized controlled trial.
      ,
      • 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.
      ,
      • Pinkaew D.
      • Kiattisin K.
      • Wonglangka K.
      • Awoot P.
      Phonophoresis of Phyllanthus amarus nanoparticle gel improves functional capacity in individuals with knee osteoarthritis: A randomized controlled trial.
      ,
      • Huang M.-H.
      • Lin Y.-S.
      • Lee C.-L.
      • Yang R.-C.
      Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis.
      ,
      • Draper D.O.
      • Klyve D.
      • Ortiz R.
      • Best T.M.
      Effect of low-intensity long-duration ultrasound on the symptomatic relief of knee osteoarthritis: a randomized, placebo-controlled double-blind study.
      ,
      • Cakir S.
      • Hepguler S.
      • Ozturk C.
      • Korkmaz M.
      • Isleten B.
      • Atamaz F.C.
      Efficacy of therapeutic ultrasound for the management of knee osteoarthritis.
      ,
      • Devrimsel G.
      • Metin Y.
      • Serdaroglu B.M.
      Short-term effects of neuromuscular electrical stimulation and ultrasound therapies on muscle architecture and functional capacity in knee osteoarthritis: a randomized study.
      ,
      • Jia L.
      • Wang Y.
      • Chen J.
      • Chen W.
      Efficacy of focused low-intensity pulsed ultrasound therapy for the management of knee osteoarthritis: a randomized, double blind, placebo-controlled trial.
      ,
      • Mascarin N.C.
      • Vancini R.L.
      • Andrade M.L.D.S.
      • Magalhães E. de P.
      • de Lira C.A.B.
      • Coimbra I.B.
      Effects of kinesiotherapy, ultrasound and electrotherapy in management of bilateral knee osteoarthritis: prospective clinical trial.
      ,
      • Pinkaew D.
      • Kiattisin K.
      • Tocharus J.
      • Jumnongprakhon P.
      • Awoot P.
      • Decha P.
      • et al.
      Phonopheresis associated with nanoparticle gel from phyllanthus amarus relieves pain by reducing oxidative stress and proinflammatory markers in adults with knee osteoarthritis.
      ,
      • Pinkaew D.
      • Kiattisin K.
      • Wonglangka K.
      • Awoot P.
      Improved WOMAC score following treatment with nanoparticle phyllanthus amarus phonophoresis gel for knee osteoarthritis.
      ,
      • Karakaş A.
      • Dilek B.
      • Şahin M.A.
      • Ellidokuz H.
      • Şenocak Ö.
      The effectiveness of pulsed ultrasound treatment on pain, function, synovial sac thickness and femoral cartilage thickness in patients with knee osteoarthritis: a randomized, double-blind clinical, controlled study.
      ,
      • Kozanoglu E.
      • Basaran S.
      • Guzel R.
      • Guler-Uysal F.
      Short term efficacy of ibuprofen phonophoresis versus continuous ultrasound therapy in knee osteoarthritis.
      ,
      • Monisha R.
      • Manikumar M.
      • Krishnakumar A.
      Evaluating the effectiveness of phonophoresis by piroxicam and dimethyl sulfoxide for women’s with osteoarthritis knee joint.
      ,
      • Tascioglu F.
      • Kuzgun S.
      • Armagan O.
      • Ogutler G.
      Short-term effectiveness of ultrasound therapy in knee osteoarthritis.
      ,
      • Rayegani S.M.
      • Bahrami M.H.
      • Elyaspour D.
      • Saeedi M.
      • Sanjari H.
      Therapeutic effects of low level laser therapy (LLLT) in knee osteoarthritis, compared to therapeutic ultrasound.
      ,

      Loyola-sánchez A, Richardson J, Beattie KA, Otero-fuentes C, A AL, Richardson J, et al. Effect of low-intensity pulsed ultrasound on the cartilage repair in people with mild to moderate knee osteoarthritis: a double-blinded, randomized, placebo-controlled pilot study. Arch Phys Med Rehabil 2012;93:35–42. https://doi.org/10.1016/j.apmr.2011.07.196.

      ,
      • Kim E.-D.
      • Won Y.H.
      • Park S.-H.
      • Seo J.-H.
      • Kim D.-S.
      • Ko M.-H.
      • et al.
      Efficacy and safety of a stimulator using low-intensity pulsed ultrasound combined with transcutaneous electrical nerve stimulation in patients with painful knee osteoarthritis.
      ,
      • Boyaci A.
      • Tutoglu A.
      • Boyaci N.
      • Aridici R.
      • Koca I.
      Comparison of the efficacy of ketoprofen phonophoresis, ultrasound, and short-wave diathermy in knee osteoarthritis.
      ,
      • Abdalbary S.A.
      Ultrasound with mineral water or aqua gel to reduce pain and improve the WOMAC of knee osteoarthritis.
      ,
      • Coskun Benlidayi I.
      • Gokcen N.
      • Basaran S.
      Comparative short-term effectiveness of ibuprofen gel and cream phonophoresis in patients with knee osteoarthritis.
      ,
      • Nakhostin-Roohi B.
      • Khoshkhahesh F.
      • Bohlooli S.
      Effect of virgin olive oil versus piroxicam phonophoresis on exercise-induced anterior knee pain.
      ,
      • Zhao J.
      • Wang Q.
      • Wu J.
      • Shi X.
      • Qi Q.
      • Zheng H.
      • et al.
      Therapeutic effects of low-frequency phonophoresis with a Chinese herbal medicine versus sodium diclofenac for treatment of knee osteoarthritis: a double-blind, randomized, placebo-controlled clinical trial.
      ,
      • Said Ahmed M.A.
      • Saweeres E.S.B.
      • Abdelkader N.A.
      • Abdelmajeed S.F.
      • Fares A.R.
      • Ahmed M.A.S.
      • et al.
      Improved pain and function in knee osteoarthritis with dexamethasone phonophoresis: A randomized controlled trial.
      ,
      • Sedhom M.
      Efficacy of kinesio-taping versus phonophoresis on knee osteoarthritis: an experimental study.
      ,
      • Imamura M.
      • Alamino S.
      • Hsing W.T.
      • Alfieri F.M.
      • Schmitz C.
      • Battistella L.R.
      Radial extracorporeal shock wave therapy for disabling pain due to severe primary knee osteoarthritis.
      ,
      • Zhao Z.
      • Jing R.
      • Shi Z.
      • Zhao B.
      • Ai Q.
      • Xing G.
      Efficacy of extracorporeal shockwave therapy for knee osteoarthritis: a randomized controlled trial.
      ,
      • Ediz L.
      • Özgökçe M.
      Effectiveness of extracorporeal shock wave therapy to treat primary medial knee osteoarthritis with and without bone marrow edema in elderly patients.
      ,

      Elerian AE, Ewidea TMA. Effect of shock wave therapyversus corticosteroid injection in management of knee osteoarthritis. Int J Physiother 2016;3. https://doi.org/10.15621/ijphy/2016/v3i2/94906.

      ,
      • Zhong Z.
      • Liu B.
      • Liu G.
      • Chen J.
      • Li Y.
      • Chen J.
      • et al.
      A randomized controlled trial on the effects of low-dose extracorporeal shockwave therapy in patients with knee osteoarthritis.
      ,
      • Mishel M.
      • Shenouda S.S.
      Efficacy of extracorporeal shock wave therapy versus mobilization with movement on pain, disability and range of motion in patients with knee osteoarthritis.
      ,
      • Lizis P.
      • Kobza W.
      • Manko G.
      • Para B.
      The influence of extracorporeal shockwave therapy and kinesiotherapy on health status in females with knee osteoarthritis: a randomized controlled trial.
      ,
      • Lizis P.
      • Kobza W.
      • Manko G.
      Extracorporeal shockwave therapy is more effective than ultrasound on osteoarthritis of the knee: a pilot randomized controlled trial.
      ,
      • Uysal A.
      • Yildizgoren M.T.
      • Guler H.
      • Turhanoglu A.D.
      Effects of radial extracorporeal shock wave therapy on clinical variables and isokinetic performance in patients with knee osteoarthritis: a prospective, randomized, single-blind and controlled trial.
      ,
      • Hammam R.F.
      • Kamel R.M.
      • Draz A.H.
      • Azzam A.A.
      • Abu El Kasem S.T.
      Comparison of the effects between low- versus medium-energy radial extracorporeal shock wave therapy on knee osteoarthritis: A randomised controlled trial.
      ,
      • Usman Z.
      • Maharaj S.S.
      • Kaka B.
      Effects of combination therapy and infrared radiation on pain, physical function, and quality of life in subjects with knee osteoarthritis: A randomized controlled study.
      ,
      • Ammar T.
      Shock wave therapy versus interferential therapy in knee osteoarthritis.
      ,
      • Lee J.-K.
      • Lee B.-Y.
      • Shin W.-Y.
      • An M.-J.
      • Jung K.-I.
      • Yoon S.-R.
      Effect of extracorporeal shockwave therapy versus intra-articular injections of hyaluronic acid for the treatment of knee osteoarthritis.
      ,
      • Günaydin Ö.E.
      • Bayrakci T.V.
      Comparison of the added effects of kinesio taping and extracorporeal shockwave therapy to exercise alone in knee osteoarthritis.
      ,
      • Kim J.-H.
      • Kim J.-Y.
      • Choi C.-M.
      • Lee J.-K.
      • Kee H.-S.
      • Jung K.-I.
      • et al.
      The dose-related effects of extracorporeal shock wave therapy for knee osteoarthritis.
      ,
      • Eftekharsadat B.
      • Jahanjoo F.
      • Toopchizadeh V.
      • Heidari F.
      • Ahmadi R.
      • Babaei-Ghazani A.
      Extracorporeal shockwave therapy and physiotherapy in patients with moderate knee osteoarthritis.
      ,
      • Tossige-Gomes R.
      • Avelar N.C.P.
      • Simão A.P.
      • Neves C.D.C.
      • Brito-Melo G.E.A.
      • Coimbra C.C.
      • et al.
      Whole-body vibration decreases the proliferative response of TCD4+ cells in elderly individuals with knee osteoarthritis.
      ,
      • Simao A.P.
      • Mendonca V.A.
      • Avelar N.C.P.
      • Fonseca S.F.D.
      • Santos J.M.
      • Oliveira A.C.C.
      • et al.
      Whole body vibration training on muscle strength and brain-derived neurotrophic factor levels in elderly woman with knee osteoarthritis: A randomized clinical trial study.
      ,
      • Park Y.G.
      • Kwon B.S.
      • Park J.W.
      • Cha D.Y.
      • Nam K.Y.
      • Sim K.B.
      • et al.
      Therapeutic effect of whole body vibration on chronic knee osteoarthritis.
      ,
      • Abbasi E.
      • Kahrizi S.
      • Razi M.
      • Faghihzadeh S.
      The effect of whole-body vibration training on the lower extremity muscles’ electromyographic activities in patients with knee osteoarthritis.
      ,
      • Avelar N.C.P.
      • Simão A.P.
      • Tossige-Gomes R.
      • Neves C.D.C.
      • Rocha-Vieira E.
      • Coimbra C.C.C.C.
      • et al.
      The effect of adding whole-body vibration to squat training on the functional performance and self-report of disease status in elderly patients with knee osteoarthritis: a randomized, controlled clinical study.
      ,
      • Yildiriim M.A.
      • Uçar D.
      • Öneş K.
      Comparison of therapeutic duration of therapeutic ultrasound in patients with knee osteoarthritis.
      ,
      • Benedetti M.G.
      • Boccia G.
      • Cavazzuti L.
      • Magnani E.
      • Mariani E.
      • Rainoldi A.
      • et al.
      Localized muscle vibration reverses quadriceps muscle hypotrophy and improves physical function: A clinical and electrophysiological study.
      ,
      • Wang P.
      • Yang L.
      • Liu C.
      • Wei X.
      • Yang X.
      • Zhou Y.
      • et al.
      Effects of Whole Body Vibration Exercise associated with Quadriceps Resistance Exercise on functioning and quality of life in patients with knee osteoarthritis: A randomized controlled trial.
      ,
      • Wang P.
      • Yang L.
      • Li H.
      • Lei Z.
      • Yang X.
      • Liu C.
      • et al.
      Effects of whole-body vibration training with quadriceps strengthening exercise on functioning and gait parameters in patients with medial compartment knee osteoarthritis: a randomised controlled preliminary study.
      ,
      • Rabini A.
      • De Sire A.
      • Marzetti E.
      • Gimigliano R.
      • Ferriero G.
      • Piazzini D.B.
      • et al.
      Effects of focal muscle vibration on physical functioning in patients with knee osteoarthritis: a randomized controlled trial.
      ,
      • Trans T.
      • Aaboe J.
      • Henriksen M.
      • Christensen R.
      • Bliddal H.
      • Lund H.
      Effect of whole body vibration exercise on muscle strength and proprioception in females with knee osteoarthritis.
      ,
      • Lai Z.
      • Lee S.
      • Hu X.
      • Wang L.
      Effect of adding whole-body vibration training to squat training on physical function and muscle strength in individuals with knee osteoarthritis.
      ,
      • Simão A.P.
      • Avelar N.C.
      • Tossige-Gomes R.
      • Neves C.D.
      • Mendonça V.A.
      • Miranda A.S.
      • et al.
      Functional performance and inflammatory cytokines after squat exercises and whole-body vibration in elderly individuals with knee osteoarthritis.
      ,
      • Bokaeian H.R.
      • Bakhtiary A.H.
      • Mirmohammadkhani M.
      • Moghimi J.
      The effect of adding whole body vibration training to strengthening training in the treatment of knee osteoarthritis: A randomized clinical trial.
      ,
      • Yoon J.
      • Kanamori A.
      • Fujii K.
      • Isoda H.
      • Okura T.
      Evaluation of maslinic acid with whole-body vibration training in elderly women with knee osteoarthritis.
      ,
      • Akinbo S.
      • Owoeye O.
      • Adesegun S.
      Comparison of the therapeutic efficacy of diclofenac sodium and methyl salicylate phonophoresis in the management of knee osteoarthritis.
      ,
      • Oktayoglu P.
      • Gur A.
      • Yardimeden I.
      • Caglayan M.
      • Cevik F.
      • Bozkurt M.
      • et al.
      Comparison of the efficacy of phonophoresis and conventional ultrasound therapy in patients with primary knee osteoarthritis.
      ,
      • Külcü D.G.
      • Gülşen G.
      • Altunok E.Ç.
      Short-term efficacy of pulsed electromagnetic field therapy on pain and functional level in knee osteoarthritis: A randomized controlled study.
      ] and 8 were non-randomized [
      • Liu S.-C.
      • Qiao X.-F.
      • Tang Q.-X.
      • Li X.-G.
      • Yang J.-H.
      • Wang T.-Q.
      • et al.
      Therapeutic efficacy of extracorporeal shock wave combined with hyaluronic acid on knee osteoarthritis.
      ,
      • Lee J.H.
      • Lee S.
      • Choi S.
      • Choi Y.H.
      • Lee K.
      The effects of extracorporeal shock wave therapy on the pain and function of patients with degenerative knee arthritis.
      ,

      Li W, Pan Y, Yang Q, Guo Z-G, Yue Q, Meng Q-G. Extracorporeal shockwave therapy for the treatment of knee osteoarthritis. Med (United States) 2018;97. https://doi.org/10.1097/MD.0000000000011418.

      ,
      • El-sakka S.S.
      • Hussein M.I.
      • El-barbary A.M.
      • Rehan F.S.
      The effect of shock wave therapy as a new modality for treatment of primary knee osteoarthritis.
      ,
      • Xu Y.
      • Wu K.
      • Liu Y.
      • Geng H.
      • Zhang H.
      • Liu S.
      • et al.
      The effect of extracorporeal shock wave therapy on the treatment of moderate to severe knee osteoarthritis and cartilage lesion.
      ,
      • Moura-Fernandes M.C.
      • Moreira-Marconi E.
      • de Meirelles A.G.
      • de Oliveira A.P.
      • Silva A.R.
      • de Souza L.F.
      • et al.
      Effect of the combined intervention with passive whole-body vibration and auriculotherapy on the quality of life of individuals with knee osteoarthritis assessed by the WHOQOL-Bref: A multi-arm clinical trial.
      ,
      • Tsuji S.
      • Kobayashi A.
      • Tomita T.
      • Hamada M.
      • Sugamoto K.
      • Yoshikawa H.
      Quantitative index for deciding whether to administer preventive anticoagulant therapy in osteoarthritis patients undergoing total knee arthroplasty.
      ,
      • Lievens P.
      • Van de Voorde J.
      The influence of cycloidal vibrations on the knee joint mobility of osteoarthritic patients.
      ] clinical trials. Eleven studies [
      • Ozgönenel L.
      • Aytekin E.
      • Durmuşoglu G.
      A double-blind trial of clinical effects of therapeutic ultrasound in knee osteoarthritis.
      ,
      • Ozgonenel L.
      • Okur S.C.Ç.
      • Dogan Y.P.
      • Caglar N.S.
      • Özgönenel L.
      • Okur S.C.Ç.
      • et al.
      Effectiveness of therapeutic ultrasound on clinical parameters and ultrasonographic cartilage thickness in knee osteoarthritis: a double-blind trial.
      ,
      • 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.
      ,
      • Pinkaew D.
      • Kiattisin K.
      • Wonglangka K.
      • Awoot P.
      Phonophoresis of Phyllanthus amarus nanoparticle gel improves functional capacity in individuals with knee osteoarthritis: A randomized controlled trial.
      ,
      • Huang M.-H.
      • Lin Y.-S.
      • Lee C.-L.
      • Yang R.-C.
      Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis.
      ,
      • Pinkaew D.
      • Kiattisin K.
      • Tocharus J.
      • Jumnongprakhon P.
      • Awoot P.
      • Decha P.
      • et al.
      Phonopheresis associated with nanoparticle gel from phyllanthus amarus relieves pain by reducing oxidative stress and proinflammatory markers in adults with knee osteoarthritis.
      ,
      • Pinkaew D.
      • Kiattisin K.
      • Wonglangka K.
      • Awoot P.
      Improved WOMAC score following treatment with nanoparticle phyllanthus amarus phonophoresis gel for knee osteoarthritis.
      ,
      • Lizis P.
      • Kobza W.
      • Manko G.
      • Para B.
      The influence of extracorporeal shockwave therapy and kinesiotherapy on health status in females with knee osteoarthritis: a randomized controlled trial.
      ,
      • Lizis P.
      • Kobza W.
      • Manko G.
      Extracorporeal shockwave therapy is more effective than ultrasound on osteoarthritis of the knee: a pilot randomized controlled trial.
      ,
      • Avelar N.C.P.
      • Simão A.P.
      • Tossige-Gomes R.
      • Neves C.D.C.
      • Rocha-Vieira E.
      • Coimbra C.C.C.C.
      • et al.
      The effect of adding whole-body vibration to squat training on the functional performance and self-report of disease status in elderly patients with knee osteoarthritis: a randomized, controlled clinical study.
      ,
      • Simão A.P.
      • Avelar N.C.
      • Tossige-Gomes R.
      • Neves C.D.
      • Mendonça V.A.
      • Miranda A.S.
      • et al.
      Functional performance and inflammatory cytokines after squat exercises and whole-body vibration in elderly individuals with knee osteoarthritis.
      ] showed partially overlapping population.
      Figure thumbnail gr1
      Figure 1PRISMA 2020 flowchart of included and excluded studies.
      A total of 4798 participants were included with a weighted mean age of 60 ± 7.3 years old; 77% females. When reported, most patients displayed grade II and III (Kellgren–Lawrence grading system) and symptoms persistence for a median of 4.5 years (2.8–6.0). The population characteristics is displayed on supplemental Table S1 and the demographic data of each study is present on supplemental Tables S2 to S4.

      3.2 Risk of bias

      Most of the randomized clinical studies were judged as high risk of bias (70%, k = 48), with twenty studies showed some concerns (29%), and only one study (1%) had low risk of bias (Figure 2). More than one-third of the studies (36%, k = 25) were judged with high or unclear risk of randomization bias arising from the lack of information regarding allocation concealment. Bias due to deviation from intended interventions and measurement of the outcomes was observed in most studies (65%, k = 45) and about 28% of the studies (k = 19) were judged high or unclear risk of bias owing to missing data. Almost all studies (94%, k = 65) presented some concerns to high risk of selective reporting bias.
      Figure thumbnail gr2
      Figure 2Risk of bias plot for ROB-2 tool. Traffic lights and weight summary plots for randomized clinical studies.
      Seven non-randomized studies presented serious risk of bias, while one study had critical risk of bias due to selective reporting (Figure 3). Bias due to confounding was found in five studies (63%) since most studies did not report the OA grade of the participants. High risk of selection bias, due to participant selection, was judged to be present in half of the studies (50%, k = 4) since those studies did not present any information whether all the eligible participants were selected for the clinical trial. Seventy five percent of the studies (k = 6) were judged with serious risk of bias caused by the classification of interventions because important parameters, such as stimulation time, were not reported. Six studies (75%) were judged with no information due to missing data. Bias due to deviations from intended interventions was detected in only one study (12%), with moderate risk, while five other studies (63%) did not provide any information. Two studies (25%) were judged with serious risk of detection bias because the measurement of outcomes was not blinded.
      Figure thumbnail gr3
      Figure 3Risk of bias plot for ROBIS-I tool. Traffic lights and weight summary plots for nonrandomized clinical studies.
      Considering the risk of financial bias (Supplemental Figure S1), most of the studies stated no conflict of interests (77%, k = 59), others did not provide any information and, thus, were judged with unclear risk of bias (22%, k = 17). Only one study showed high risk of financial bias (1%).

      3.3 Frequency of interventions

      From the 77 included studies, 42 studies used ultrasound and/or phonophoresis [
      • Yeğin T.
      • Altan L.
      • Kasapoğlu A.M.
      The effect of therapeutic ultrasound on pain and physical function in patients with knee osteoarthritis.
      ,
      • Durmus D.
      • Unal M.
      The effect of capsaicin phonophoresis in knee osteoarthritis and can it be utilized early in primary care? : A randomized-controlled trial.
      ,
      • Ozgönenel L.
      • Aytekin E.
      • Durmuşoglu G.
      A double-blind trial of clinical effects of therapeutic ultrasound in knee osteoarthritis.
      ,
      • Luksurapan W.
      • Boonhong J.
      Effects of phonophoresis of piroxicam and ultrasound on symptomatic knee osteoarthritis.
      ,
      • Ulus Y.
      • Tander B.
      • Akyol Y.
      • Durmus D.
      • Buyukakıncak O.
      • Gul U.
      • et al.
      Therapeutic ultrasound versus sham ultrasound for the management of patients with knee osteoarthritis: a randomized double-blind controlled clinical study.
      ,
      • Yang P.
      • Li D.
      • Zhang S.
      • Wu Q.
      • Tang J.
      • Huang L.
      • et al.
      Efficacy of ultrasound in the treatment of osteoarthritis of the knee.
      ,
      • Sangtong K.
      • Chupinijrobkob C.
      • Putthakumnerd W.
      • Kuptniratsaikul V.
      Does adding transcutaneous electrical nerve stimulation to therapeutic ultrasound affect pain or function in people with osteoarthritis of the knee? A randomized controlled trial.
      ,
      • Ozgonenel L.
      • Okur S.C.Ç.
      • Dogan Y.P.
      • Caglar N.S.
      • Özgönenel L.
      • Okur S.C.Ç.
      • et al.
      Effectiveness of therapeutic ultrasound on clinical parameters and ultrasonographic cartilage thickness in knee osteoarthritis: a double-blind trial.
      ,
      • Kapci Yildiz S.
      • Ünlü Özkan F.
      • Aktaş İ.
      • Şilte A.D.
      • Yilmaz Kaysin M.
      • Bilgin B.N.
      The effectiveness of ultrasound treatment for the management of knee osteoarthritis: A randomized, placebo-controlled, double-blind study.
      ,
      • Toopchizadeh V.
      • Javadi R.
      • Sadat B.E.
      Therapeutic efficacy of dexamethasone phonophoresis on symptomatic knee osteoarthritis in elderly women.
      ,
      • Alfredo P.P.
      • Junior W.S.
      • Casarotto R.A.
      Efficacy of continuous and pulsed therapeutic ultrasound combined with exercises for knee osteoarthritis: a randomized controlled trial.
      ,
      • 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.
      ,
      • Pinkaew D.
      • Kiattisin K.
      • Wonglangka K.
      • Awoot P.
      Phonophoresis of Phyllanthus amarus nanoparticle gel improves functional capacity in individuals with knee osteoarthritis: A randomized controlled trial.
      ,
      • Huang M.-H.
      • Lin Y.-S.
      • Lee C.-L.
      • Yang R.-C.
      Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis.
      ,
      • Draper D.O.
      • Klyve D.
      • Ortiz R.
      • Best T.M.
      Effect of low-intensity long-duration ultrasound on the symptomatic relief of knee osteoarthritis: a randomized, placebo-controlled double-blind study.
      ,
      • Cakir S.
      • Hepguler S.
      • Ozturk C.
      • Korkmaz M.
      • Isleten B.
      • Atamaz F.C.
      Efficacy of therapeutic ultrasound for the management of knee osteoarthritis.
      ,
      • Devrimsel G.
      • Metin Y.
      • Serdaroglu B.M.
      Short-term effects of neuromuscular electrical stimulation and ultrasound therapies on muscle architecture and functional capacity in knee osteoarthritis: a randomized study.
      ,
      • Jia L.
      • Wang Y.
      • Chen J.
      • Chen W.
      Efficacy of focused low-intensity pulsed ultrasound therapy for the management of knee osteoarthritis: a randomized, double blind, placebo-controlled trial.
      ,
      • Mascarin N.C.
      • Vancini R.L.
      • Andrade M.L.D.S.
      • Magalhães E. de P.
      • de Lira C.A.B.
      • Coimbra I.B.
      Effects of kinesiotherapy, ultrasound and electrotherapy in management of bilateral knee osteoarthritis: prospective clinical trial.
      ,
      • Pinkaew D.
      • Kiattisin K.
      • Tocharus J.
      • Jumnongprakhon P.
      • Awoot P.
      • Decha P.
      • et al.
      Phonopheresis associated with nanoparticle gel from phyllanthus amarus relieves pain by reducing oxidative stress and proinflammatory markers in adults with knee osteoarthritis.
      ,
      • Pinkaew D.
      • Kiattisin K.
      • Wonglangka K.
      • Awoot P.
      Improved WOMAC score following treatment with nanoparticle phyllanthus amarus phonophoresis gel for knee osteoarthritis.
      ,
      • Karakaş A.
      • Dilek B.
      • Şahin M.A.
      • Ellidokuz H.
      • Şenocak Ö.
      The effectiveness of pulsed ultrasound treatment on pain, function, synovial sac thickness and femoral cartilage thickness in patients with knee osteoarthritis: a randomized, double-blind clinical, controlled study.
      ,
      • Kozanoglu E.
      • Basaran S.
      • Guzel R.
      • Guler-Uysal F.
      Short term efficacy of ibuprofen phonophoresis versus continuous ultrasound therapy in knee osteoarthritis.
      ,
      • Monisha R.
      • Manikumar M.
      • Krishnakumar A.
      Evaluating the effectiveness of phonophoresis by piroxicam and dimethyl sulfoxide for women’s with osteoarthritis knee joint.
      ,
      • Tascioglu F.
      • Kuzgun S.
      • Armagan O.
      • Ogutler G.
      Short-term effectiveness of ultrasound therapy in knee osteoarthritis.
      ,
      • Rayegani S.M.
      • Bahrami M.H.
      • Elyaspour D.
      • Saeedi M.
      • Sanjari H.
      Therapeutic effects of low level laser therapy (LLLT) in knee osteoarthritis, compared to therapeutic ultrasound.
      ,

      Loyola-sánchez A, Richardson J, Beattie KA, Otero-fuentes C, A AL, Richardson J, et al. Effect of low-intensity pulsed ultrasound on the cartilage repair in people with mild to moderate knee osteoarthritis: a double-blinded, randomized, placebo-controlled pilot study. Arch Phys Med Rehabil 2012;93:35–42. https://doi.org/10.1016/j.apmr.2011.07.196.

      ,
      • Kim E.-D.
      • Won Y.H.
      • Park S.-H.
      • Seo J.-H.
      • Kim D.-S.
      • Ko M.-H.
      • et al.
      Efficacy and safety of a stimulator using low-intensity pulsed ultrasound combined with transcutaneous electrical nerve stimulation in patients with painful knee osteoarthritis.
      ,
      • Boyaci A.
      • Tutoglu A.
      • Boyaci N.
      • Aridici R.
      • Koca I.
      Comparison of the efficacy of ketoprofen phonophoresis, ultrasound, and short-wave diathermy in knee osteoarthritis.
      ,
      • Abdalbary S.A.
      Ultrasound with mineral water or aqua gel to reduce pain and improve the WOMAC of knee osteoarthritis.
      ,
      • Coskun Benlidayi I.
      • Gokcen N.
      • Basaran S.
      Comparative short-term effectiveness of ibuprofen gel and cream phonophoresis in patients with knee osteoarthritis.
      ,
      • Nakhostin-Roohi B.
      • Khoshkhahesh F.
      • Bohlooli S.
      Effect of virgin olive oil versus piroxicam phonophoresis on exercise-induced anterior knee pain.
      ,
      • Zhao J.
      • Wang Q.
      • Wu J.
      • Shi X.
      • Qi Q.
      • Zheng H.
      • et al.
      Therapeutic effects of low-frequency phonophoresis with a Chinese herbal medicine versus sodium diclofenac for treatment of knee osteoarthritis: a double-blind, randomized, placebo-controlled clinical trial.
      ,
      • Said Ahmed M.A.
      • Saweeres E.S.B.
      • Abdelkader N.A.
      • Abdelmajeed S.F.
      • Fares A.R.
      • Ahmed M.A.S.
      • et al.
      Improved pain and function in knee osteoarthritis with dexamethasone phonophoresis: A randomized controlled trial.
      ,
      • Sedhom M.
      Efficacy of kinesio-taping versus phonophoresis on knee osteoarthritis: an experimental study.
      ,
      • Lizis P.
      • Kobza W.
      • Manko G.
      Extracorporeal shockwave therapy is more effective than ultrasound on osteoarthritis of the knee: a pilot randomized controlled trial.
      ,
      • Usman Z.
      • Maharaj S.S.
      • Kaka B.
      Effects of combination therapy and infrared radiation on pain, physical function, and quality of life in subjects with knee osteoarthritis: A randomized controlled study.
      ,
      • Yildiriim M.A.
      • Uçar D.
      • Öneş K.
      Comparison of therapeutic duration of therapeutic ultrasound in patients with knee osteoarthritis.
      ,
      • Akinbo S.
      • Owoeye O.
      • Adesegun S.
      Comparison of the therapeutic efficacy of diclofenac sodium and methyl salicylate phonophoresis in the management of knee osteoarthritis.
      ,
      • Oktayoglu P.
      • Gur A.
      • Yardimeden I.
      • Caglayan M.
      • Cevik F.
      • Bozkurt M.
      • et al.
      Comparison of the efficacy of phonophoresis and conventional ultrasound therapy in patients with primary knee osteoarthritis.
      ,
      • Külcü D.G.
      • Gülşen G.
      • Altunok E.Ç.
      Short-term efficacy of pulsed electromagnetic field therapy on pain and functional level in knee osteoarthritis: A randomized controlled study.
      ,
      • El-sakka S.S.
      • Hussein M.I.
      • El-barbary A.M.
      • Rehan F.S.
      The effect of shock wave therapy as a new modality for treatment of primary knee osteoarthritis.
      ], 20 studies applied ESWT [
      • Imamura M.
      • Alamino S.
      • Hsing W.T.
      • Alfieri F.M.
      • Schmitz C.
      • Battistella L.R.
      Radial extracorporeal shock wave therapy for disabling pain due to severe primary knee osteoarthritis.
      ,
      • Zhao Z.
      • Jing R.
      • Shi Z.
      • Zhao B.
      • Ai Q.
      • Xing G.
      Efficacy of extracorporeal shockwave therapy for knee osteoarthritis: a randomized controlled trial.
      ,
      • Ediz L.
      • Özgökçe M.
      Effectiveness of extracorporeal shock wave therapy to treat primary medial knee osteoarthritis with and without bone marrow edema in elderly patients.
      ,

      Elerian AE, Ewidea TMA. Effect of shock wave therapyversus corticosteroid injection in management of knee osteoarthritis. Int J Physiother 2016;3. https://doi.org/10.15621/ijphy/2016/v3i2/94906.

      ,
      • Zhong Z.
      • Liu B.
      • Liu G.
      • Chen J.
      • Li Y.
      • Chen J.
      • et al.
      A randomized controlled trial on the effects of low-dose extracorporeal shockwave therapy in patients with knee osteoarthritis.
      ,
      • Mishel M.
      • Shenouda S.S.
      Efficacy of extracorporeal shock wave therapy versus mobilization with movement on pain, disability and range of motion in patients with knee osteoarthritis.
      ,
      • Lizis P.
      • Kobza W.
      • Manko G.
      • Para B.
      The influence of extracorporeal shockwave therapy and kinesiotherapy on health status in females with knee osteoarthritis: a randomized controlled trial.
      ,
      • Lizis P.
      • Kobza W.
      • Manko G.
      Extracorporeal shockwave therapy is more effective than ultrasound on osteoarthritis of the knee: a pilot randomized controlled trial.
      ,
      • Uysal A.
      • Yildizgoren M.T.
      • Guler H.
      • Turhanoglu A.D.
      Effects of radial extracorporeal shock wave therapy on clinical variables and isokinetic performance in patients with knee osteoarthritis: a prospective, randomized, single-blind and controlled trial.
      ,
      • Hammam R.F.
      • Kamel R.M.
      • Draz A.H.
      • Azzam A.A.
      • Abu El Kasem S.T.
      Comparison of the effects between low- versus medium-energy radial extracorporeal shock wave therapy on knee osteoarthritis: A randomised controlled trial.
      ,
      • Ammar T.
      Shock wave therapy versus interferential therapy in knee osteoarthritis.
      ,
      • Lee J.-K.
      • Lee B.-Y.
      • Shin W.-Y.
      • An M.-J.
      • Jung K.-I.
      • Yoon S.-R.
      Effect of extracorporeal shockwave therapy versus intra-articular injections of hyaluronic acid for the treatment of knee osteoarthritis.
      ,
      • Günaydin Ö.E.
      • Bayrakci T.V.
      Comparison of the added effects of kinesio taping and extracorporeal shockwave therapy to exercise alone in knee osteoarthritis.
      ,
      • Kim J.-H.
      • Kim J.-Y.
      • Choi C.-M.
      • Lee J.-K.
      • Kee H.-S.
      • Jung K.-I.
      • et al.
      The dose-related effects of extracorporeal shock wave therapy for knee osteoarthritis.
      ,
      • Eftekharsadat B.
      • Jahanjoo F.
      • Toopchizadeh V.
      • Heidari F.
      • Ahmadi R.
      • Babaei-Ghazani A.
      Extracorporeal shockwave therapy and physiotherapy in patients with moderate knee osteoarthritis.
      ,
      • Liu S.-C.
      • Qiao X.-F.
      • Tang Q.-X.
      • Li X.-G.
      • Yang J.-H.
      • Wang T.-Q.
      • et al.
      Therapeutic efficacy of extracorporeal shock wave combined with hyaluronic acid on knee osteoarthritis.
      ,
      • Lee J.H.
      • Lee S.
      • Choi S.
      • Choi Y.H.
      • Lee K.
      The effects of extracorporeal shock wave therapy on the pain and function of patients with degenerative knee arthritis.
      ,

      Li W, Pan Y, Yang Q, Guo Z-G, Yue Q, Meng Q-G. Extracorporeal shockwave therapy for the treatment of knee osteoarthritis. Med (United States) 2018;97. https://doi.org/10.1097/MD.0000000000011418.

      ,
      • El-sakka S.S.
      • Hussein M.I.
      • El-barbary A.M.
      • Rehan F.S.
      The effect of shock wave therapy as a new modality for treatment of primary knee osteoarthritis.
      ,
      • Xu Y.
      • Wu K.
      • Liu Y.
      • Geng H.
      • Zhang H.
      • Liu S.
      • et al.
      The effect of extracorporeal shock wave therapy on the treatment of moderate to severe knee osteoarthritis and cartilage lesion.
      ] and 17 studies applied vibration [
      • Tossige-Gomes R.
      • Avelar N.C.P.
      • Simão A.P.
      • Neves C.D.C.
      • Brito-Melo G.E.A.
      • Coimbra C.C.
      • et al.
      Whole-body vibration decreases the proliferative response of TCD4+ cells in elderly individuals with knee osteoarthritis.
      ,
      • Simao A.P.
      • Mendonca V.A.
      • Avelar N.C.P.
      • Fonseca S.F.D.
      • Santos J.M.
      • Oliveira A.C.C.
      • et al.
      Whole body vibration training on muscle strength and brain-derived neurotrophic factor levels in elderly woman with knee osteoarthritis: A randomized clinical trial study.
      ,
      • Park Y.G.
      • Kwon B.S.
      • Park J.W.
      • Cha D.Y.
      • Nam K.Y.
      • Sim K.B.
      • et al.
      Therapeutic effect of whole body vibration on chronic knee osteoarthritis.
      ,
      • Abbasi E.
      • Kahrizi S.
      • Razi M.
      • Faghihzadeh S.
      The effect of whole-body vibration training on the lower extremity muscles’ electromyographic activities in patients with knee osteoarthritis.
      ,
      • Avelar N.C.P.
      • Simão A.P.
      • Tossige-Gomes R.
      • Neves C.D.C.
      • Rocha-Vieira E.
      • Coimbra C.C.C.C.
      • et al.
      The effect of adding whole-body vibration to squat training on the functional performance and self-report of disease status in elderly patients with knee osteoarthritis: a randomized, controlled clinical study.
      ,
      • Benedetti M.G.
      • Boccia G.
      • Cavazzuti L.
      • Magnani E.
      • Mariani E.
      • Rainoldi A.
      • et al.
      Localized muscle vibration reverses quadriceps muscle hypotrophy and improves physical function: A clinical and electrophysiological study.
      ,
      • Wang P.
      • Yang L.
      • Liu C.
      • Wei X.
      • Yang X.
      • Zhou Y.
      • et al.
      Effects of Whole Body Vibration Exercise associated with Quadriceps Resistance Exercise on functioning and quality of life in patients with knee osteoarthritis: A randomized controlled trial.
      ,
      • Wang P.
      • Yang L.
      • Li H.
      • Lei Z.
      • Yang X.
      • Liu C.
      • et al.
      Effects of whole-body vibration training with quadriceps strengthening exercise on functioning and gait parameters in patients with medial compartment knee osteoarthritis: a randomised controlled preliminary study.
      ,
      • Rabini A.
      • De Sire A.
      • Marzetti E.
      • Gimigliano R.
      • Ferriero G.
      • Piazzini D.B.
      • et al.
      Effects of focal muscle vibration on physical functioning in patients with knee osteoarthritis: a randomized controlled trial.
      ,
      • Trans T.
      • Aaboe J.
      • Henriksen M.
      • Christensen R.
      • Bliddal H.
      • Lund H.
      Effect of whole body vibration exercise on muscle strength and proprioception in females with knee osteoarthritis.
      ,
      • Lai Z.
      • Lee S.
      • Hu X.
      • Wang L.
      Effect of adding whole-body vibration training to squat training on physical function and muscle strength in individuals with knee osteoarthritis.
      ,
      • Simão A.P.
      • Avelar N.C.
      • Tossige-Gomes R.
      • Neves C.D.
      • Mendonça V.A.
      • Miranda A.S.
      • et al.
      Functional performance and inflammatory cytokines after squat exercises and whole-body vibration in elderly individuals with knee osteoarthritis.
      ,
      • Bokaeian H.R.
      • Bakhtiary A.H.
      • Mirmohammadkhani M.
      • Moghimi J.
      The effect of adding whole body vibration training to strengthening training in the treatment of knee osteoarthritis: A randomized clinical trial.
      ,
      • Yoon J.
      • Kanamori A.
      • Fujii K.
      • Isoda H.
      • Okura T.
      Evaluation of maslinic acid with whole-body vibration training in elderly women with knee osteoarthritis.
      ,
      • Moura-Fernandes M.C.
      • Moreira-Marconi E.
      • de Meirelles A.G.
      • de Oliveira A.P.
      • Silva A.R.
      • de Souza L.F.
      • et al.
      Effect of the combined intervention with passive whole-body vibration and auriculotherapy on the quality of life of individuals with knee osteoarthritis assessed by the WHOQOL-Bref: A multi-arm clinical trial.
      ,
      • Tsuji S.
      • Kobayashi A.
      • Tomita T.
      • Hamada M.
      • Sugamoto K.
      • Yoshikawa H.
      Quantitative index for deciding whether to administer preventive anticoagulant therapy in osteoarthritis patients undergoing total knee arthroplasty.
      ,
      • Lievens P.
      • Van de Voorde J.
      The influence of cycloidal vibrations on the knee joint mobility of osteoarthritic patients.
      ]. Two studies [
      • Lizis P.
      • Kobza W.
      • Manko G.
      Extracorporeal shockwave therapy is more effective than ultrasound on osteoarthritis of the knee: a pilot randomized controlled trial.
      ,
      • El-sakka S.S.
      • Hussein M.I.
      • El-barbary A.M.
      • Rehan F.S.
      The effect of shock wave therapy as a new modality for treatment of primary knee osteoarthritis.
      ] compared ultrasound with ESWT.

      3.4 Ultrasound and phonophoresis

      Placebo (k = 6) and phonophoresis (k = 6) were the most used comparison groups for ultrasound, while phonophoresis was compared to placebo (k = 1) and compared with different therapeutic gels (k = 3). Both interventions were often combined with other therapies (supplemental Table S5). Most of the studies (79%, k = 33) used ultrasound and phonophoresis as continuous (supplemental Table S6), with median resonance frequency of 1 MHz (range, 0.04 to 3.00) at a median power density of 1 W/cm2 (range, 0.1 to 2.5) for a median stimulation time of 9.5 min (range, 3 to 240) and a median number of sessions of 10 (range, 9 to 80). Supplemental Table S7 shows the intervention parameters of ultrasound and phonophoresis used in each study.
      Twenty-five studies [
      • Yeğin T.
      • Altan L.
      • Kasapoğlu A.M.
      The effect of therapeutic ultrasound on pain and physical function in patients with knee osteoarthritis.
      ,
      • Ozgönenel L.
      • Aytekin E.
      • Durmuşoglu G.
      A double-blind trial of clinical effects of therapeutic ultrasound in knee osteoarthritis.
      ,
      • Luksurapan W.
      • Boonhong J.
      Effects of phonophoresis of piroxicam and ultrasound on symptomatic knee osteoarthritis.
      ,
      • Ulus Y.
      • Tander B.
      • Akyol Y.
      • Durmus D.
      • Buyukakıncak O.
      • Gul U.
      • et al.
      Therapeutic ultrasound versus sham ultrasound for the management of patients with knee osteoarthritis: a randomized double-blind controlled clinical study.
      ,
      • Kapci Yildiz S.
      • Ünlü Özkan F.
      • Aktaş İ.
      • Şilte A.D.
      • Yilmaz Kaysin M.
      • Bilgin B.N.
      The effectiveness of ultrasound treatment for the management of knee osteoarthritis: A randomized, placebo-controlled, double-blind study.
      ,
      • Toopchizadeh V.
      • Javadi R.
      • Sadat B.E.
      Therapeutic efficacy of dexamethasone phonophoresis on symptomatic knee osteoarthritis in elderly women.
      ,
      • Alfredo P.P.
      • Junior W.S.
      • Casarotto R.A.
      Efficacy of continuous and pulsed therapeutic ultrasound combined with exercises for knee osteoarthritis: a randomized controlled trial.
      ,
      • 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.
      ,
      • Pinkaew D.
      • Kiattisin K.
      • Wonglangka K.
      • Awoot P.
      Phonophoresis of Phyllanthus amarus nanoparticle gel improves functional capacity in individuals with knee osteoarthritis: A randomized controlled trial.
      ,
      • Draper D.O.
      • Klyve D.
      • Ortiz R.
      • Best T.M.
      Effect of low-intensity long-duration ultrasound on the symptomatic relief of knee osteoarthritis: a randomized, placebo-controlled double-blind study.
      ,
      • Cakir S.
      • Hepguler S.
      • Ozturk C.
      • Korkmaz M.
      • Isleten B.
      • Atamaz F.C.
      Efficacy of therapeutic ultrasound for the management of knee osteoarthritis.
      ,
      • Devrimsel G.
      • Metin Y.
      • Serdaroglu B.M.
      Short-term effects of neuromuscular electrical stimulation and ultrasound therapies on muscle architecture and functional capacity in knee osteoarthritis: a randomized study.
      ,
      • Jia L.
      • Wang Y.
      • Chen J.
      • Chen W.
      Efficacy of focused low-intensity pulsed ultrasound therapy for the management of knee osteoarthritis: a randomized, double blind, placebo-controlled trial.
      ,
      • Mascarin N.C.
      • Vancini R.L.
      • Andrade M.L.D.S.
      • Magalhães E. de P.
      • de Lira C.A.B.
      • Coimbra I.B.
      Effects of kinesiotherapy, ultrasound and electrotherapy in management of bilateral knee osteoarthritis: prospective clinical trial.
      ,
      • Karakaş A.
      • Dilek B.
      • Şahin M.A.
      • Ellidokuz H.
      • Şenocak Ö.
      The effectiveness of pulsed ultrasound treatment on pain, function, synovial sac thickness and femoral cartilage thickness in patients with knee osteoarthritis: a randomized, double-blind clinical, controlled study.
      ,
      • Kozanoglu E.
      • Basaran S.
      • Guzel R.
      • Guler-Uysal F.
      Short term efficacy of ibuprofen phonophoresis versus continuous ultrasound therapy in knee osteoarthritis.
      ,
      • Tascioglu F.
      • Kuzgun S.
      • Armagan O.
      • Ogutler G.
      Short-term effectiveness of ultrasound therapy in knee osteoarthritis.
      ,

      Loyola-sánchez A, Richardson J, Beattie KA, Otero-fuentes C, A AL, Richardson J, et al. Effect of low-intensity pulsed ultrasound on the cartilage repair in people with mild to moderate knee osteoarthritis: a double-blinded, randomized, placebo-controlled pilot study. Arch Phys Med Rehabil 2012;93:35–42. https://doi.org/10.1016/j.apmr.2011.07.196.

      ,
      • Kim E.-D.
      • Won Y.H.
      • Park S.-H.
      • Seo J.-H.
      • Kim D.-S.
      • Ko M.-H.
      • et al.
      Efficacy and safety of a stimulator using low-intensity pulsed ultrasound combined with transcutaneous electrical nerve stimulation in patients with painful knee osteoarthritis.
      ,
      • Boyaci A.
      • Tutoglu A.
      • Boyaci N.
      • Aridici R.
      • Koca I.
      Comparison of the efficacy of ketoprofen phonophoresis, ultrasound, and short-wave diathermy in knee osteoarthritis.
      ,
      • Said Ahmed M.A.
      • Saweeres E.S.B.
      • Abdelkader N.A.
      • Abdelmajeed S.F.
      • Fares A.R.
      • Ahmed M.A.S.
      • et al.
      Improved pain and function in knee osteoarthritis with dexamethasone phonophoresis: A randomized controlled trial.
      ,
      • Usman Z.
      • Maharaj S.S.
      • Kaka B.
      Effects of combination therapy and infrared radiation on pain, physical function, and quality of life in subjects with knee osteoarthritis: A randomized controlled study.
      ,
      • Akinbo S.
      • Owoeye O.
      • Adesegun S.
      Comparison of the therapeutic efficacy of diclofenac sodium and methyl salicylate phonophoresis in the management of knee osteoarthritis.
      ,
      • Oktayoglu P.
      • Gur A.
      • Yardimeden I.
      • Caglayan M.
      • Cevik F.
      • Bozkurt M.
      • et al.
      Comparison of the efficacy of phonophoresis and conventional ultrasound therapy in patients with primary knee osteoarthritis.
      ,
      • El-sakka S.S.
      • Hussein M.I.
      • El-barbary A.M.
      • Rehan F.S.
      The effect of shock wave therapy as a new modality for treatment of primary knee osteoarthritis.
      ] with ultrasound and/or phonophoresis interventions were included in the meta-analyses (Table 1). Six out of twenty-three (26%) meta-analyses showed the superiority of ultrasound over other therapies, whereas phonophoresis was superior to ultrasound in one meta-analysis (4%). All meta-analyses were judged as very-low certainty of evidence. Forest plots are available in supplemental Figure S2.
      Table 1Quantitative meta-analysis results for each outcome measure of ultrasound and phonophoresis interventions.
      OutcomeInterventionControlSubgroupMain findingsGRADESupplemental Figure S1
      k, nI2, P valueSMD (95% CI)
      Pain at rest

      After treatment
      USPlaceboOVERALL4, 29342.0%, 0.14−0.43 (−0.87 to 0.00)⊕◯◯◯

      [*, ¶, &]
      1.1
      WOMAC Pain

      After treatment
      USPlaceboOVERALL4, 2380%, 0.64−0.47 (−0.79 to −0.14)⊕◯◯◯

      [*, ¶, &]
      1.2
      WOMAC Function

      After treatment
      USPlaceboOVERALL4, 2380%, 0.83−0.46 (−0.70 to −0.23)⊕◯◯◯

      [*, ¶, &]
      1.3
      WOMAC Stiffness

      After treatment
      USPlaceboOVERALL4, 23819.8%, 0.29−0.36 (−0.83 to 0.10)⊕◯◯◯

      [*, ¶, &]
      1.4
      WOMAC Total

      After treatment
      USPlaceboOVERALL4, 2580%, 0.53−0.42 (−0.76 to −0.09)⊕◯◯◯

      [*, ¶, &]
      1.5
      Pain at rest

      After treatment
      USPPPhyllanthus amarus1, 40NA3.03 (2.10 to 3.97)⊕◯◯◯

      [*, ¶¶, §§, ƚ, &]
      1.6
      Diclofenac1, 40NA0.34 (−0.29 to 0.96)
      Piroxicam1, 46NA0.93 (0.32 to 1.54)
      OVERALL3, 11691.8%, <0.0011.40 (−2.08 to 4.88)
      Pain at rest

      After treatment
      US + Other therapies

      PP + Other therapies

      Dexamethasone2, 10073.3%, 0.020.95 (−0.87 to 2.76)⊕◯◯◯

      [*, ¶, §, ƚ ƚ]
      1.7 & 1.8
      Ibuprofen1, 60NA0.09 (−0.42 to 0.60)
      ketoprofen1, 66NA0.39 (−0.10 to 0.87)
      Ex & Hot packs1, 5640.7%, 0.190.56 (−4.25 to 5.36)
      Hot packs2, 1260%, 0.410.24 (−1.63 to 2.12)
      Ex & TENS1, 44NA1.64 (0.95 to 2.33)
      OVERALL4, 22673.0%, 0.0050.63 (−0.17 to 1.42)
      WOMAC Pain

      After treatment
      US + Other therapies

      PP + Other therapies

      Diclofenac1, 26NA1.59 (0.69 to 2.49)⊕◯◯◯

      [*, ¶, §§, ƚ ƚ]
      1.9 & 1.10
      Methyl salicylate1, 26NA0.26 (−0.52 to 1.03)
      Dexamethasone2, 10080.8%, 0.0050.45 (−1.61 to 2.51)
      Ibuprofen1, 60NA−0.24 (−0.74 to 0.27)
      Ketoprofen1, 66NA0.29 (−0.20 to 0.78)
      Ex2, 5279.2%, 0.030.90 (−7.54 to 9.34)
      Ex & Hot packs1, 560%, 0.62−0.05 (−1.84 to 1.75)
      Hot packs2, 12653.6%, 0.140.03 (−3.31 to 3.37)
      Ex & TENS1, 44NA1.36 (0.70 to 2.02)
      OVERALL5, 27874.5%, <0.0010.43 (−0.23 to 1.09)
      WOMAC Function

      After treatment
      US + Other therapiesPP + Other therapiesDiclofenac1, 26NA2.07 (1.08 to 3.05)⊕◯◯◯

      [*, ¶, §§, ƚ ƚ, &]
      1.11 & 1.12
      Methyl salicylate1, 26NA0.26 (−0.52 to 1.03)
      Dexamethasone2, 10058.2%, 0.090.82 (−0.61 to 2.25)
      Ibuprofen1, 60NA−0.31 (−0.82 to 0.20)
      Ketoprofen1, 66NA0.39 (−0.10 to 0.88)
      Ex2, 5287.5%, 0.0051.13 (−10.34 to 12.61)
      Ex & Hot packs1, 560%, 0.910.46 (0.07 to 0.85)
      Hot packs2, 12673.8%, 0.050.04 (−4.42 to 4.51)
      Ex & TENS1, 44NA1.44 (0.77 to 2.11)
      OVERALL5, 27878.3%, <0.0010.64 (−0.09 to 1.36)
      WOMAC Stiffness

      After treatment
      US + Other therapiesPP + Other therapiesDiclofenac1, 26NA0.64 (−0.15 to 1.43)⊕◯◯◯

      [*, ¶, §§, ƚ ƚ, &&]
      1.13 & 1.14
      Methyl salicylate1, 26NA0.34 (−0.44 to 1.12)
      Dexamethasone2, 1000%, 0.521.02 (0.25 to 1.80)
      Ibuprofen1, 60NA−0.33 (−0.84 to 0.18)
      Ketoprofen1, 66NA0.29 (−0.20 to 0.77)
      Ex2, 520%, 0.590.49 (−1.43 to 2.40)
      Ex & Hot packs1, 560%, 0.500.85 (−1.67 to 3.36)
      Hot packs2, 12666.2%, 0.09−0.01 (−3.94 to 3.91)
      Ex & TENS1, 44NA1.26 (0.61 to 1.92)
      OVERALL5, 27866.4%, 0.0070.52 (0.01 to 1.02)
      WOMAC Total

      After treatment
      US + Other therapiesPP + Other therapiesDiclofenac1, 26NA2.29 (1.26 to 3.31)⊕◯◯◯

      [*, ¶, §§, ƚ ƚ, &]
      1.15 & 1.16
      Methyl salicylate1, 26NA0.37 (−0.41 to 1.15)
      Dexamethasone2, 10071.6%, 0.030.90 (−0.85 to 2.66)
      Ibuprofen1, 60NA−0.34 (−0.85 to 0.17)
      Ketoprofen1, 66NA0.38 (−0.10 to 0.87)
      Ex2, 5288.2%, 0.0041.30 (−10.86 to 13.45)
      Ex & Hot packs1, 560%, 0.930.48 (0.15 to 0.80)
      Hot packs2, 12675.2%, 0.040.03 (−4.56 to 4.61)
      Ex & TENS1, 44NA1.69 (0.99 to 2.39)
      OVERALL5, 27882.1%, <0.0010.72 (−0.10 to 1.53)
      Lequesne Pain

      After treatment
      US + Other therapiesPlacebo + Other therapiesEx1, 900%, 0.76−0.95 (−1.85 to −0.05)⊕◯◯◯

      [*, ¶, ƚ ƚ]
      1.17
      Diclofenac1, 106NA−0.75 (−1.15 to −0.36)
      Interferential current & Hot packs1, 40NA−0.19 (−0.81 to 0.43)
      OVERALL3, 23622.3%, 0.28−0.71 (−1.25 to −0.16)
      Pain at rest

      After treatment
      US + Other therapiesPlacebo + Other therapiesEx1, 1350%, 0.63−0.36 (−0.89 to 0.17)⊕◯◯◯

      [*, ¶, ƚ ƚ, &]
      Interferential current & Hot packs1, 40NA−0.41 (−1.04; 0.21)1.18
      OVERALL3, 1750%, 0.81−0.38 (−0.66 to −0.10)
      Pain at activity

      After treatment
      US + Other therapiesPlacebo + Other therapiesEx3, 22533.4%, 0.20−0.26 (−0.76 to 0.25)⊕◯◯◯

      [*, ¶, §, ƚ ƚ, &&]
      1.19
      Diclofenac1, 106NA−0.96 (−1.37 to −0.56)
      Interferential current & Hot packs1, 40NA−0.03 (−0.65 to 0.59)
      OVERALL5, 37162.5%, 0.01−0.35 (−0.78 to 0.07)
      WOMAC Pain

      After treatment
      US + Other therapiesPlacebo + Other therapiesEx2, 1350%, 0.56−0.30 (−0.92 to 0.31)⊕◯◯◯

      [*, ¶, ƚ ƚ, &]
      Interferential current & Hot packs1, 40NA−0.59 (−1.22 to 0.04)1.20
      OVERALL3, 1750%, 0.61−0.37 (−0.77 to 0.02)
      WOMAC Function

      After treatment
      US + Other therapiesPlacebo + Other therapiesEx2, 1350%, 0.65−0.14 (−0.65 to 0.37)⊕◯◯◯

      [*, ¶, ƚ ƚ, &]
      Interferential current & Hot packs1, 40NA−0.29 (−0.92 to 0.33)1.21
      OVERALL3, 1750%, 0.79−0.17 (−0.47 to 0.12)
      WOMAC Total

      After treatment
      US + Other therapiesPlacebo + Other therapiesEx1, 75NA−0.28 (−0.73 to 0.18)⊕◯◯◯

      [*, ¶, ƚ ƚ, &&]
      1.22
      Diclofenac1, 106NA−0.75 (−1.15 to −0.36)
      Interferential current & Hot packs1, 40NA−0.44 (−1.07 to 0.18)
      OVERALL3, 22120.3%, 0.28−0.52 (−1.17 to 0.13)
      Pain at rest

      After treatment
      US + Other therapiesOther therapiesEx + Hot packs1, 70NA−0.83 (−1.32 to −0.34)⊕◯◯◯

      [*, ¶, §§, ƚ ƚ, &]
      1.23
      TENS1, 38NA−1.92 (−2.70 to −1.13)
      Ex + IR radiation1, 60NA−1.38 (−1.94 to −0.81)
      Ex1, 800%, 0.56−0.27 (−1.92 to 1.38)
      OVERALL4, 24877.0%, 0.002−0.91 (−1.79 to −0.04)
      Pain at rest

      After treatment
      US + Ex or Hot packsOther therapies + Ex or Hot packsKinesio taping1, 23NA3.90 (2.38 to 5.43)⊕◯

      [*, ¶¶, §§, ƚ ƚ, &]
      1.24
      TENS2, 7795.9%, <0.001−0.27 (−21.55 to 21.01)
      ESWT1, 30NA0.66 (−0.08 to 1.40)
      OVERALL3, 13095.7%, <0.0010.96 (−2.84 to 4.75)
      WOMAC Pain

      After treatment
      US + Ex or Hot packsOther therapies + Ex or Hot packsKinesio taping1, 23NA0.76 (−0.16 to 1.68)⊕◯◯◯

      [¶¶, §, ƚ ƚ, &]
      1.25
      TENS2, 7784.6%, 0.010.16 (−9.96 to 10.27)
      OVERALL2, 10080.7%, 0.0060.32 (−1.87 to 2.50)
      WOMAC Function

      After treatment
      US + Ex or Hot packsOther therapies + Ex or Hot packsKinesio taping1, 23NA0.28 (−0.61 to 1.18)⊕◯◯◯

      [¶¶, ƚ ƚ, &]
      TENS2, 7756.2%, 0.16−0.16 (−5.68 to 5.37)1.26
      OVERALL2, 10044.8%, 0.16−0.06 (−1.33 to 1.21)
      WOMAC Stiffness

      After treatment
      US + Ex or Hot packsOther therapies + Ex or Hot packsKinesio taping1, 23NA0.10 (−0.79 to 0.99)⊕◯◯◯

      [¶¶, ƚ ƚ, &]
      TENS2, 7772.7%, 0.06−0.12 (−7.34 to 7.11)1.27
      OVERALL2, 10055.5%, 0.11−0.10 (−1.56 to 1.36)
      6 min Walk

      After treatment
      US + Ex or Hot packsOther therapies + Ex or Hot packsKinesio taping1, 23NA−0.19 (−1.08 to 0.70)⊕◯

      [*, ¶, ƚ ƚ, &]
      1.28
      TENS1, 17NA0.22 (−0.83 to 1.26)
      ESWT1, 30NA−0.21 (−0.93 to 0.51)
      OVERALL2, 700%, 0.79−0.11 (−0.64 to 0.43)
      US: Ultrasound; PP: Phonophoresis; Ex: Exercise; IR: Infrared; TENS: Transcutaneous electrical nerve stimulation; ESWT: Extracorporeal Shockwave Therapy; NA: Not applicable.
      * – serious study limitations due to risk of bias;
      ** – very serious study limitations due to risk of bias; ¶ – serious imprecision due to wide 95% CIs (cross the 0.5 or −0.5 SMD);¶¶ – very serious imprecision due to very wide 95% CIs (cross both the −0.5 & 0.5 SMD);§ – serious inconsistency due to substantial & significant heterogeneity &/or 95% CI do not overlap;§§ – very serious inconsistency due to substantial & significant heterogeneity & 95% CI do overlap with at least 2 studies;
      ƚ – serious indirectness due to indirect comparisons;
      ƚƚ – very serious indirectness due to indirect comparisons & differences in intervention;& – serious publication bias (studies added &/or asymmetric funnel plots);
      && – very serious publication bias (studies added, asymmetric funnel plots & different pooled effects).
      Ultrasound was statistically significantly superior to placebo in WOMAC pain (SMD = −0.47, 95% CI −0.79 to −0.14, weak effect), function (SMD = −0.46, 95% CI −0.70 to −0.23, weak effect), total score (SMD = −0.42, 95% CI to −0.76 to −0.09, weak effect), Lequesne pain (SMD = −0.71, 95% CI −1.25 to −0.16, moderate effect) and pain at rest (SMD = −0.38, 95% CI −0.66 to −0.10, weak effect), regardless the combination with other therapies. Pain at activity (SMD = −0.96, 95% CI −1.37 to −0.56, large effect), WOMAC total (SMD = −0.75, 95% CI −1.15 to −0.36, moderate effect) and Lequesne pain (SMD = −0.75, 95% CI −1.15 to −0.36, moderate effect) showed statistically significant improvements with ultrasound plus diclofenac versus placebo plus diclofenac. By adding ultrasound to other therapies, the pain at rest (SMD = −0.91, 95% CI −1.79 to −0.04, large effect) was statistically significantly reduced compared to other therapies alone, except when compared to exercises alone. By contrast, ultrasound with exercise plus hot packs was statistically inferior to kinesio taping combined with exercise plus hot packs in decreasing the pain at rest (SMD = 3.90, 95% CI 2.38 to 5.43, large effect).
      Ultrasound was statistically significantly inferior to phonophoresis for pain at rest when phyllanthus amarus gel (SMD = 3.03, 95% CI 2.10 to 3.97, large effect) or piroxicam (SMD = 0.93, 95% CI 0.32 to 1.54, large effect) were used during phonophoresis. However, when combining all types of gel, the overall pooled effect was not statistically significant. Combining ultrasound or phonophoresis with exercise and TENS, ultrasound was statistically inferior to phonophoresis in significantly improving the pain at rest (SMD = 1.64, 95% 0.95 to 2.33, large effect), WOMAC pain (SMD = 1.36, 95% CI 0.70 to 2.02, large effect), function (SMD = 1.44, 95% CI 0.77 to 2.11, large effect), stiffness (SMD = 1.26, 95% CI 0.61 to 1.92, large effect) and total score (SMD = 1.69, 95% CI 0.99 to 2.39, large effect). Combined with exercise plus hot packs, ultrasound was also statistically inferior to phonophoresis for WOMAC function (SMD = 0.46, 95% CI 0.07 to 0.85, weak effect) and total score (SMD = 0.48, 95% CI 0.15 to 0.80, weak effect). The application of diclofenac or dexamethasone gels during phonophoresis promoted statistically significant improvements in WOMAC index (moderate to large effect). However, the overall pooled effect for WOMAC stiffness outcome was the only one that changed significantly (moderate effect).

      3.5 Extracorporeal shockwave therapy

      The ESWT was more commonly compared to other therapies (k = 7) and combined with exercises (k = 5), while only two studies comparing the ESWT to placebo (supplemental Table S5). Nearly half of the studies (45%, k = 9) used radial ESWT (supplemental Table S6). ESWT was applied with a median frequency of 8 Hz (range, 4 to 16) with a median number of 2,000 pulses (range, 1,000 to 4,000) at a median energy density of 0.178 mJ/mm2 (range, 0.020 to 4.000), completing a median number of 4.5 sessions (range, 3 to 12). Supplemental Table S8 shows the ESWT parameters for each study.
      Twelve studies [
      • Imamura M.
      • Alamino S.
      • Hsing W.T.
      • Alfieri F.M.
      • Schmitz C.
      • Battistella L.R.
      Radial extracorporeal shock wave therapy for disabling pain due to severe primary knee osteoarthritis.
      ,
      • Ediz L.
      • Özgökçe M.
      Effectiveness of extracorporeal shock wave therapy to treat primary medial knee osteoarthritis with and without bone marrow edema in elderly patients.
      ,

      Elerian AE, Ewidea TMA. Effect of shock wave therapyversus corticosteroid injection in management of knee osteoarthritis. Int J Physiother 2016;3. https://doi.org/10.15621/ijphy/2016/v3i2/94906.

      ,
      • Zhong Z.
      • Liu B.
      • Liu G.
      • Chen J.
      • Li Y.
      • Chen J.
      • et al.
      A randomized controlled trial on the effects of low-dose extracorporeal shockwave therapy in patients with knee osteoarthritis.
      ,
      • Mishel M.
      • Shenouda S.S.
      Efficacy of extracorporeal shock wave therapy versus mobilization with movement on pain, disability and range of motion in patients with knee osteoarthritis.
      ,
      • Lizis P.
      • Kobza W.
      • Manko G.
      • Para B.
      The influence of extracorporeal shockwave therapy and kinesiotherapy on health status in females with knee osteoarthritis: a randomized controlled trial.
      ,
      • Lizis P.
      • Kobza W.
      • Manko G.
      Extracorporeal shockwave therapy is more effective than ultrasound on osteoarthritis of the knee: a pilot randomized controlled trial.
      ,
      • Uysal A.
      • Yildizgoren M.T.
      • Guler H.
      • Turhanoglu A.D.
      Effects of radial extracorporeal shock wave therapy on clinical variables and isokinetic performance in patients with knee osteoarthritis: a prospective, randomized, single-blind and controlled trial.
      ,
      • Hammam R.F.
      • Kamel R.M.
      • Draz A.H.
      • Azzam A.A.
      • Abu El Kasem S.T.
      Comparison of the effects between low- versus medium-energy radial extracorporeal shock wave therapy on knee osteoarthritis: A randomised controlled trial.
      ,
      • Ammar T.
      Shock wave therapy versus interferential therapy in knee osteoarthritis.
      ,
      • Lee J.-K.
      • Lee B.-Y.
      • Shin W.-Y.
      • An M.-J.
      • Jung K.-I.
      • Yoon S.-R.
      Effect of extracorporeal shockwave therapy versus intra-articular injections of hyaluronic acid for the treatment of knee osteoarthritis.
      ,
      • Eftekharsadat B.
      • Jahanjoo F.
      • Toopchizadeh V.
      • Heidari F.
      • Ahmadi R.
      • Babaei-Ghazani A.
      Extracorporeal shockwave therapy and physiotherapy in patients with moderate knee osteoarthritis.
      ] assessing the effects of ESWT were included in the meta-analysis (Table 2). Five out of eleven (45%) meta-analyses showed the superiority of ESWT over other therapies. All meta-analyses were judged as very-low certainty of evidence. The ESWT was consistently superior to other therapies in the improvement of pain at rest (SMD = −1.20, 95% CI −2.32 to −0.09, large effect) and WOMAC total (SMD = −2.46, 95% CI −3.42 to −1.51, large effect) outcomes, except when compared to ultrasound. ESWT combined with exercise statistically significantly reduced pain at rest versus interferential current plus exercise (SMD = −1.67, 95% CI −2.61 to −0.74, large effect). ESWT plus standard of care (i.e., heat packs, interference current therapy and ultrasound) was statistically superior to placebo plus usual care in significantly decreasing pain at rest (SMD = −0.69, 95% CI, −1.09 to −0.29, moderate effect), WOMAC pain (SMD = −0.68, 95% CI −1.08 to −0.29, moderate effect) and function (SMD = −0.66, 95% CI −1.05 to −0.26, moderate effect). The combination of ESWT with TENS also reduced the WOMAC pain (SMD = −0.64, 95% CI −1.11 to −0.17, moderate effect) and function (SMD = −0.80, 95% CI −1.28 to −0.32, moderate effect) as compared to placebo plus TENS. ESWT plus hot packs statistically significantly decreased WOMAC pain (SMD = −0.65, 95% CI −1.05 to −0.26, moderate effect) versus placebo plus hot packs. At short follow-up, adding ESWT to exercise, hot packs or standard of care, statistically improved the WOMAC pain (SMD = −1.01, 95% CI −1.70 to −0.33, large effect) and function (SMD = −1.06, 95% CI −1.99 to −0.13, large effect) scores. WOMAC stiffness (SMD = −1.00, 95% CI −1.53 to −0.47, large effect) was only statistically improved after ESWT plus exercise compared to placebo plus exercise. Forest plots are available in supplemental Figure S3.
      Table 2Quantitative meta−analysis results for each outcome measure of extracorporeal shockwave intervention.
      OutcomeInterventionControlSubgroupMain findingsGRADESupplemental Figure S2
      k, nI2, P valueSMD (95% CI)
      Pain at rest

      After treatment
      ESWTOther therapiesHA injection1, 40NA−1.58 (−2.30 to −0.86)⊕◯◯◯

      [*, ¶, §, ƚ ƚ, &&]
      2.1
      Ultrasound1, 60NA−0.57 (−1.20 to 0.06)
      Usual care1, 20NA−2.20 (−3.36 to −1.04)
      Kinesio taping1, 60NA−0.83 (−1.47 to −0.18)
      OVERALL4, 18065.0%, 0.04−1.20 (−2.32 to −0.09)
      WOMAC Total

      After treatment
      ESWTOther therapiesHA injection1, 40NA−2.88 (−3.79 to −1.97)⊕◯◯◯

      [*, ¶¶, ƚ ƚ]
      2.2
      Usual care1, 20NA−2.34 (−3.54 to −1.15)
      Kinesio taping1, 60NA−2.18 (−2.98 to −1.38)
      OVERALL3, 1200%, 0.51−2.46 (−3.42 to −1.51)
      Pain at rest

      After treatment
      ESWT + ExOther therapies + ExManual therapy1, 30NA−0.14 (−0.85 to 0.58)⊕◯◯◯

      [*, ¶¶, §§, ƚ ƚ, &]
      2.3
      Kinesio taping1, 40NA0.19 (−0.44 to 0.81)
      Interferential current1, 25NA−1.67 (−2.61 to −0.74)
      Usual care1, 50NA0.09 (−0.47 to 0.64)
      OVERALL4, 14575.0%, 0.007−0.33 (−1.66 to 1.00)
      Pain at rest

      After treatment
      ESWT + Other therapiesPlacebo + Other therapiesEx2, 10814%, 0.28−1.37 (−6.37 to 3.63)⊕◯◯◯

      [*, ¶, §, ƚ ƚ, &]
      2.4
      Usual care1, 104NA−0.69 (−1.09 to −0.29)
      TENS1, 73NA−0.23 (−0.69 to 0.23)
      OVERALL4, 28563.0%, 0.04−0.81 (−1.79 to 0.17)
      WOMAC Pain

      After treatment
      ESWT + Other therapiesPlacebo + Other therapiesHot packs1, 105NA−0.65 (−1.05 to −0.26)⊕◯◯◯

      [*, ¶¶, ƚ ƚ]
      2.5
      Usual care1, 104NA−0.68 (−1.08 to −0.29)
      TENS1, 73NA−0.64 (−1.11 to −0.17)
      OVERALL3, 2820%, 0.99−0.66 (−0.72 to −0.60)
      WOMAC Function

      After treatment
      ESWT + Other therapiesPlacebo + Other therapiesHot packs1, 105NA−0.21 (−0.59 to 0.17)⊕◯◯◯

      [*, ¶, ƚ ƚ, &]
      2.6
      Usual care1, 104NA−0.66 (−1.05 to −0.26)
      TENS1, 73NA−0.80 (−1.28 to −0.32)
      OVERALL3,28253.0%, 0.12−0.54 (−1.59 to 0.07)
      WOMAC Stiffness

      After treatment
      ESWT + Other therapiesPlacebo + Other therapiesHot packs1, 105NA0.00 (−0.38 to 0.38)⊕◯◯◯

      [*, ¶, ƚ ƚ, &]
      2.7
      Usual care1, 104NA−0.18 (−0.56 to 0.21)
      TENS1, 73NA−0.22 (−0.68 to 0.24)
      OVERALL3, 2820%, 0.72−0.12 (−0.42 to 0.17)
      WOMAC Pain

      Short follow−up
      ESWT + Other therapiesPlacebo + Other therapiesEx1, 63NA−1.28 (−1.82 to −0.73)⊕◯◯◯

      [*, ¶, ƚ ƚ, &]
      2.8
      Hot packs1, 105NA−0.74 (−1.13 to −0.34)
      Usual care1, 104NA−1.12 (−1.53 to −0.70)
      OVERALL3, 27232.7%, 0.23−1.01 (−1.70 to −0.33)
      WOMAC Function

      Short follow−up
      ESWT + Other therapiesPlacebo + Other therapiesEx1, 63NA−1.32 (−1.87 to −0.77)⊕◯◯◯

      [*, ¶, ƚ ƚ, &]
      Hot packs1, 105NA−0.66 (−1.06 to −0.27)2.9
      Usual care1, 104NA−1.27 (-1.69 to −0.85)
      OVERALL3, 27264.7%, 0.06−1.06 (−1.99 to −0.13)
      WOMAC Stiffness

      Short follow−up
      ESWT + Other therapiesPlacebo + Other therapiesEx1, 63NA−1.00 (−1.53 to −0.47)⊕◯◯◯

      [*, ¶¶, §, ƚ ƚ, &]
      2.10
      Hot packs1, 105NA0.01 (−0.37 to 0.39)
      Usual care1, 104NA−0.34 (−0.73 to 0.04)
      OVERALL3, 27278.4%, 0.01−0.42 (−1.67 to 0.83)
      Pain at rest

      After treatment
      ESWT + ExExOVERALL3, 11853.4%, 0.12−0.91 (−2.21 to 0.38)⊕◯◯◯

      [*, ¶, ƚ ƚ, &]
      2.11
      ESWT: Extracorporeal Shockwave Therapy; HA: Hyaluronic Acid; Ex: Exercise; TENS: Transcutaneous electrical nerve stimulation; NA: Not applicable.
      * – serious study limitations due to risk of bias;
      ** – very serious study limitations due to risk of bias; ¶ – serious imprecision due to wide 95% CIs (cross the 0.5 or −0.5 SMD);¶¶ – very serious imprecision due to very wide 95% CIs (cross both the −0.5 & 0.5 SMD);§ – serious inconsistency due to substantial & significant heterogeneity &/or 95% CI do not overlap;§§ – very serious inconsistency due to substantial & significant heterogeneity & 95% CI do overlap with at least 2 studies;
      ƚ – serious indirectness due to indirect comparisons;
      ƚƚ – very serious indirectness due to indirect comparisons & differences in intervention;& – serious publication bias (studies added &/or asymmetric funnel plots);
      && – very serious publication bias (studies added, asymmetric funnel plots & different pooled effects).

      3.6 Vibration

      Nearly half of the studies explored the vibration in combination with exercises (k = 7). Placebo, control and other therapies were also used as comparisons groups to vibration (supplemental Table S5). Vertical vibration was the most commonly mode employed (65%, k = 11) targeting the whole body (supplemental Table S6). A median frequency of 35 Hz (range, 5 to 150) with a median amplitude of 3.5 mm (range, 0.2 to 7.5) for a median duration of 20 min (range, 9 to 50) and a median number of 24 sessions (range, 9 to 120) were used. Supplemental Table S9 reports the vibration parameters for each study.
      Seven studies [
      • Park Y.G.
      • Kwon B.S.
      • Park J.W.
      • Cha D.Y.
      • Nam K.Y.
      • Sim K.B.
      • et al.
      Therapeutic effect of whole body vibration on chronic knee osteoarthritis.
      ,
      • Avelar N.C.P.
      • Simão A.P.
      • Tossige-Gomes R.
      • Neves C.D.C.
      • Rocha-Vieira E.
      • Coimbra C.C.C.C.
      • et al.
      The effect of adding whole-body vibration to squat training on the functional performance and self-report of disease status in elderly patients with knee osteoarthritis: a randomized, controlled clinical study.
      ,
      • Wang P.
      • Yang L.
      • Liu C.
      • Wei X.
      • Yang X.
      • Zhou Y.
      • et al.
      Effects of Whole Body Vibration Exercise associated with Quadriceps Resistance Exercise on functioning and quality of life in patients with knee osteoarthritis: A randomized controlled trial.
      ,
      • Wang P.
      • Yang L.
      • Li H.
      • Lei Z.
      • Yang X.
      • Liu C.
      • et al.
      Effects of whole-body vibration training with quadriceps strengthening exercise on functioning and gait parameters in patients with medial compartment knee osteoarthritis: a randomised controlled preliminary study.
      ,
      • Lai Z.
      • Lee S.
      • Hu X.
      • Wang L.
      Effect of adding whole-body vibration training to squat training on physical function and muscle strength in individuals with knee osteoarthritis.
      ,
      • Simão A.P.
      • Avelar N.C.
      • Tossige-Gomes R.
      • Neves C.D.
      • Mendonça V.A.
      • Miranda A.S.
      • et al.
      Functional performance and inflammatory cytokines after squat exercises and whole-body vibration in elderly individuals with knee osteoarthritis.
      ,
      • Tsuji S.
      • Kobayashi A.
      • Tomita T.
      • Hamada M.
      • Sugamoto K.
      • Yoshikawa H.
      Quantitative index for deciding whether to administer preventive anticoagulant therapy in osteoarthritis patients undergoing total knee arthroplasty.
      ] applying vibration plus exercise were included in the meta-analysis (Table 3). Three out of eight (38%) meta-analyses showed the superiority of vibration over other therapies. All meta-analyses were judged as very-low certainty of evidence. Vibration with exercise was superior to exercise alone in statistically improving pain at rest (SMD = −0.46, 95% CI −0.68 to −0.25, weak effect), WOMAC function (SMD = −0.43, 95% CI −0.56 to −0.29, weak effect) and timed up and go test (SMD = −0.80, 95% CI −1.14 to −0.46, large effect). Forest plots are available in supplemental Figure S4.
      Table 3Quantitative meta−analysis results for each outcome measure of vibration intervention.
      OutcomeInterventionControlSubgroupMain findingsGRADESupplemental Figure S3
      k, nI2, P valueSMD (95% CI)
      Pain at rest

      After treatment
      Vibration + ExExHome-based1, 36NA−0.42 (−1.08 to 0.24)⊕◯◯◯

      [*, ¶, ƚ ƚ]
      3.1
      Squat1, 41NA−0.40 (−1.02 to 0.22)
      Quadriceps1, 39NA−0.56 (−1.20 to 0.08)
      OVERALL3, 1160%, 0.93−0.46 (−0.68 to −0.25)
      WOMAC Pain

      After treatment
      Vibration + ExExSquat1, 21NA−0.42 (−1.29 to 0.45)⊕◯◯◯

      [*, ¶, ƚ ƚ, &&]
      Quadriceps2, 13847.9%, 0.17−0.59 (−3.89 to 2.72)3.2
      OVERALL3, 1596.0%, 0.35−0.57 (−1.31 to 0.16)
      WOMAC Function

      After treatment
      Vibration + ExExSquat1, 21NA−0.32 (−1.18 to 0.55)⊕◯◯◯

      [*, ¶, ƚ ƚ]
      Quadriceps2, 1380%, 0.96−0.44 (−0.55 to −0.34)3.3
      OVERALL3, 1590%, 0.96−0.43 (−0.56 to −0.29)
      WOMAC Stiffness

      After treatment
      Vibration + ExExSquat1, 21NA−0.23 (−1.09 to 0.63)⊕◯◯◯

      [*, ¶¶, §, ƚ ƚ, &]
      Quadriceps2, 13889.4%, 0.002−0.10 (−7.63 to 7.43)3.4
      OVERALL3, 15979.0%, 0.009−0.15 (−1.70 to 1.39)
      6 min Walk

      After treatment
      Vibration + ExExSquat2, 620%, 0.81−0.11 (−0.87 to 0.66)⊕◯◯◯

      [*, ¶¶, §§, ƚ ƚ, &]
      Quadriceps2, 13895.3%, <0.00012.00 (−14.21 to 18.21)3.5
      OVERALL4, 20092%, <0.00010.95 (−1.58 to 3.48)
      TUG

      After treatment
      Vibration + ExExHome-based1, 38NA−1.03 (−1.81 to −0.24)⊕◯

      [*, ¶, ƚ ƚ, &]
      3.6
      Squat2, 620%, 0.80−0.60 (−1.43 to 0.24)
      Quadriceps2, 13849.2%, 0.16−0.83 (−4.24 to 2.58)
      OVERALL5, 2380%, 0.53−0.80 (−1.14 to −0.46)
      Muscle strength extensors

      After treatment
      Vibration + ExExHome-based2, 7494.5%, <0.0011.45 (−15.21 to 18.10)⊕◯

      [*, ¶¶, §§, ƚ ƚ, &]
      3.7
      Squat2, 8083.5%, 0.010.68 (−6.69 to 8.06)
      Quadriceps1, 99NA0.22 (−0.18 to 0.61)
      OVERALL5, 25387.2%, <0.00010.87 (−0.53 to 2.26)
      Muscle strength flexors

      After treatment
      Vibration + ExExHome-based1, 38NA0.44 (−0.31 to 1.20)⊕◯

      [*, ¶¶, ƚ ƚ]
      3.8
      Squat2, 800%, 0.35−0.58 (−3.28 to 2.12)
      Quadriceps1, 99NA−0.15 (−0.54 to 0.25)
      OVERALL3, 21753%, 0.09−0.23 (−1.01 to 0.54)
      Ex: Exercise; NA: Not applicable.
      * – serious study limitations due to risk of bias;
      ** – very serious study limitations due to risk of bias; ¶ – serious imprecision due to wide 95% CIs (cross the 0.5 or −0.5 SMD); ¶¶ – very serious imprecision due to very wide 95% CIs (cross both the −0.5 & 0.5 SMD);§ – serious inconsistency due to substantial & significant heterogeneity &/or 95% CI do not overlap;§§ – very serious inconsistency due to substantial & significant heterogeneity & 95% CI do overlap with at least 2 studies;
      ƚ – serious indirectness due to indirect comparisons;
      ƚƚ – very serious indirectness due to indirect comparisons & differences in intervention;& – serious publication bias (studies added &/or asymmetric funnel plots);
      && – very serious publication bias (studies added, asymmetric funnel plots & different pooled effects).

      3.7 Sensitivity analysis, publication bias and meta-regression

      More than half of the meta-analyses (52%) displayed moderate to high heterogeneity. After excluding the study with the highest contribution to the pooled heterogeneity in the leave-one-out analysis, 19% of the meta-analyses remained with moderate to high heterogeneity, while 64% of the meta-analyses showed an I2 of 0%. By analysing the Baujat statistics, the most influencing study contributed between 0.01 to 29.64 of the pooled heterogeneity and generated an influence on the pooled effect size ranging from 0.01 to 26.11 (supplemental Table S10). The leave-one-out analyses for the highest and lowest effect size revealed that only 17% of the meta-analyses significantly changed in pooled effect after excluding the study with the lowest effect (supplemental Table S11). The baujat and leave-one-out analyses plots are available in OSF repository [

      Oliveira S, Andrade R, Valente C, Espregueira-mendes J, Silva F, Hinckel BB, et al. Effects of mechanical stimulation on knee cartilage for osteoarthritis treatment : protocol for a systematic review with meta-analysis. 2021.

      ].
      The sensitivity analysis for the studies with coefficient correlation value of 0.3 demonstrated that only one of 44 meta-analyses changed the pooled effect, while calculating the improvement with a coefficient correlation value of 0.7, seven of 44 meta-analyses varied significantly (supplemental Table S12). These differences were only observed in the subgroups analyses and not in the overall pooled meta-analysis. The forest plots for the sensitivity analysis are available in OSF repository [

      Oliveira S, Andrade R, Valente C, Espregueira-mendes J, Silva F, Hinckel BB, et al. Effects of mechanical stimulation on knee cartilage for osteoarthritis treatment : protocol for a systematic review with meta-analysis. 2021.

      ]. By removing studies with specific characteristics and/or with partial overlapping population, there were significant alterations in the pooled effect in four of 18 meta-analyses (supplemental Table S13).
      Publication bias was detected in 74% of the meta-analyses owing to funnel plot asymmetry. The trim-and-fill analyses corrected the pooled effect for publication bias, indicating that two of 44 meta-analyses changed the SMDs to non-significative, while three of 44 meta-analyses changed to significative (supplemental Table S11).
      Meta-regression was implemented to assess the influence of potential covariates in the pooled effect size (supplemental Table S14). For the meta-analyses comparing ultrasound to placebo (combining or not with other therapies), the number of sessions, power density, stimulation time and percentage of females influenced the pooled effect size for pain at rest, WOMAC stiffness and Lequesne pain. Comparing ultrasound plus other therapies versus other therapies alone, the percentage of females induced significant effects on the pooled effect size for pain at rest. The number of pulses and energy density were significant covariates that led to significant differences on pain at rest when adding exercise to ESWT. Percentage of females affected also the 6-minute walk distance when comparing vibration plus exercise to only exercise. The meta-regression plots are available in OSF repository [

      Oliveira S, Andrade R, Valente C, Espregueira-mendes J, Silva F, Hinckel BB, et al. Effects of mechanical stimulation on knee cartilage for osteoarthritis treatment : protocol for a systematic review with meta-analysis. 2021.

      ].

      3.8 Narrative synthesis

      The biochemical outcomes were only assessed in the studies (k = 5) applying ultrasound, phonophoresis and vibration (supplemental Table S15), revealing that ultrasound did not affect the inflammation and antioxidant markers, but vibration reduced the cartilage degradation markers content (supplemental Appendix S2). Patient-reported and physical examination outcome measures were reported for all intervention studies (supplemental Table S15), but the improvement as compared to comparison groups was inconsistent and conflicting across studies (supplemental Appendix S2). The imaging outcomes were only analysed in the studies (k = 5) applying ultrasound and ESWT (supplemental Table S15), but no significant improvement was reported following those interventions (supplemental Appendix S2).

      4. Discussion

      The main findings of our systematic review with meta-analysis are that mechanical-based treatments may significantly reduce pain intensity and disability in some of the patients with knee OA with weak to large effects, although with very-low certainty of evidence.
      Despite the statistically significant effects, our findings should be interpreted with some caution. Most of the meta-analyses displayed moderate to high heterogeneity (<50%), small sample sizes (<400), the subgroups analyses were performed with small number of studies and the certainty of evidence was very low for all meta-analyses. Some quantitative syntheses exhibited imprecise results with studies presenting pooled SMD effects size crossing both the −0.5 and 0.5 of the 95% CIs. Meta-regression demonstrated that some intervention parameters and percentage of females influenced the pooled effect size. Interestingly, no effect was observed for OA grade which may be due to the lack of studies reporting the OA grade. There were, though, a small number of studies in the meta-regression analyses, limiting these conclusions. The narrative synthesis also presented inconsistent and conflicting results, which may be also explained by the small sample size of the studies.
      Ultrasound statistically significantly improved the pain and WOMAC outcomes versus placebo, combined or not with other therapies, potentiating, particularly, the effects of diclofenac in comparison to placebo plus diclofenac. Ultrasound plus other therapies significantly improved the pain at rest versus other therapies alone, while it did not induce statistically significant improvements versus other therapies when combined with exercise or hot packs. Prior systematic reviews with meta-analysis have also showed that ultrasound reduced the patient́s pain and improved physical performance, but those meta-analyses only considered the comparison group placebo, exercises and no intervention as one [
      • Wu Y.
      • Zhu S.
      • Lv Z.
      • Kan S.
      • Wu Q.
      • Song W.
      • et al.
      Effects of therapeutic ultrasound for knee osteoarthritis : a systematic review and meta-analysis.
      ,
      • Zhang C.
      • Xie Y.
      • Luo X.
      • Ji Q.
      • Lu C.
      • He C.
      • et al.
      Effects of therapeutic ultrasound on pain, physical functions and safety outcomes in patients with knee osteoarthritis: A systematic review and meta-analysis.
      ,
      • Loyola-Sánchez A.
      • Richardson J.
      • Macintyre N.J.
      Efficacy of ultrasound therapy for the management of knee osteoarthritis : a systematic review with meta-analysis.
      ]. We conducted meticulous meta-analyses for each control group to establish more reliable comparisons, which confirmed that ultrasound was superior to placebo and may be combined with other therapies to improve the OA symptoms.
      Ultrasound and phonophoresis were compared in only one systematic review [
      • Wu Y.
      • Zhu S.
      • Lv Z.
      • Kan S.
      • Wu Q.
      • Song W.
      • et al.
      Effects of therapeutic ultrasound for knee osteoarthritis : a systematic review and meta-analysis.
      ], revealing that phonophoresis promoted pain relief in comparison to ultrasound, but did not result in functional improvements [
      • Wu Y.
      • Zhu S.
      • Lv Z.
      • Kan S.
      • Wu Q.
      • Song W.
      • et al.
      Effects of therapeutic ultrasound for knee osteoarthritis : a systematic review and meta-analysis.
      ]. Our meta-analyses showed that when comparing ultrasound versus phonophoresis, both in adjunct to other therapies, phonophoresis led to statistically significant effects on pain intensity and WOMAC subscales, but those effects were only observed in the subgroup analyses according to the type of combined intervention or therapeutic gel used. On the other hand, only one of six meta-analyses showed statistically significant effects of phonophoresis in reducing WOMAC stiffness versus ultrasound. This suggests that the type of gel or the combined therapy strongly affected the clinical outcomes of phonophoresis when compared to ultrasound.
      ESWT statistically improved the pain at rest and WOMAC total score with large effects versus other physical therapies such as kinesio taping, intra-articular injection or standard of care. Several systematic reviews with meta-analysis [
      • Wang Y.C.
      • Huang H.T.
      • Huang P.J.
      • Liu Z.M.
      • Shih C.L.
      Efficacy and safety of extracorporeal shockwave therapy for treatment of knee osteoarthritis: a systematic review and meta-analysis.
      ,
      • Li T.
      • Ma J.
      • Zhao T.
      • Gao F.
      • Sun W.
      Application and efficacy of extracorporeal shockwave treatment for knee osteoarthritis: A systematic review and meta-analysis.
      ,
      • Ma H.
      • Zhang W.
      • Shi J.
      • Zhou D.
      • Wang J.
      The efficacy and safety of extracorporeal shockwave therapy in knee osteoarthritis: A systematic review and meta-analysis.
      ,
      • Avendaño-Coy J.
      • Comino-Suárez N.
      • Grande-Muñoz J.
      • Avendaño-López C.
      • Gómez-Soriano J.
      Extracorporeal shockwave therapy improves pain and function in subjects with knee osteoarthritis: A systematic review and meta-analysis of randomized clinical trials.
      ,
      • Chen L.
      • Ye L.
      • Liu H.
      • Yang P.
      • Yang B.
      Extracorporeal shock wave therapy for the treatment of osteoarthritis: a systematic review and meta-analysis.
      ] indicated that ESWT was superior to placebo and to other physical therapies, being in line with our findings. We also studied the effects of ESWT in combination with other therapies. ESWT plus other physical therapies resulted in statistically significant effects in combination with exercise, standard of care, TENS or hot packs versus placebo plus those therapies after treatment or at short-term follow-up, suggesting its potential use in combination with other therapies to improve the pain and disability outcomes.
      Our meta-analyses displayed statistically significant effects in improving pain intensity, WOMAC function and time up and go test following vibration plus exercise versus exercise, which is in agreement with two previous systematic reviews with meta-analysis [
      • Zafar H.
      • Alghadir A.
      • Anwer S.
      • Al-Eisa E.
      Therapeutic effects of whole-body vibration training in knee osteoarthritis: a systematic review and meta-analysis.
      ,
      • Wang P.
      • Yang X.
      • Yang Y.
      • Yang L.
      • Zhou Y.
      • Liu C.
      • et al.
      Effects of whole body vibration on pain, stiffness and physical functions in patients with knee osteoarthritis: a systematic review and meta-analysis.
      ], while other systematic review with meta-analysis [
      • Li X.
      • Wang X.-Q.
      • Chen B.-L.
      • Huang L.-Y.
      • Liu Y.
      Whole-body vibration exercise for knee osteoarthritis: a systematic review and meta-analysis.
      ] did not report any difference after vibration. Our results indicate a potential benefit of adding vibration to exercise in improving pain, disability and functional performance.
      The stimulation parameters influence deeply the level of improvement in the outcome measures, being extremely relevant the understanding of the dosages applied in these clinical studies. One trial demonstrated that ultrasound for 8 minutes were superior than for 4 minutes [
      • Yildiriim M.A.
      • Uçar D.
      • Öneş K.
      Comparison of therapeutic duration of therapeutic ultrasound in patients with knee osteoarthritis.
      ]. ESWT at low energy dosages (0.02–0.04 mJ/mm2) was superior in improving the outcomes as compared to medium doses (0.093–0.178 mJ/mm2) [
      • Hammam R.F.
      • Kamel R.M.
      • Draz A.H.
      • Azzam A.A.
      • Abu El Kasem S.T.
      Comparison of the effects between low- versus medium-energy radial extracorporeal shock wave therapy on knee osteoarthritis: A randomised controlled trial.
      ,
      • Kim J.-H.
      • Kim J.-Y.
      • Choi C.-M.
      • Lee J.-K.
      • Kee H.-S.
      • Jung K.-I.
      • et al.
      The dose-related effects of extracorporeal shock wave therapy for knee osteoarthritis.
      ]. Most of studies did not fully report all stimulation parameters, precluding further conclusions on the influence of stimulation dosage. We have also not performed subgroup analysis by intervention parameters as it would often result in carrying those analyses with only one study.
      The inconsistent results reported in our review can be elucidated by the design of clinical trials and the intervention parameters. Most of the randomized or non-randomized studies displayed high and serious risk of bias, respectively, mainly due to lack of information about the methodology employed in the clinical trials and intervention parameters, missing data and selective reporting. These results highlight the need to implement more rigorous and transparent methodology in future clinical trials. The intervention parameters may also induce conflicting results and contribute to the heterogeneity of the meta-analyses where studies differed slightly in duration, intensity, operating mode and frequency of interventions. Our meta-regression results for ultrasound studies indicate that the pooled effect size increased with higher number of sessions and stimulation time and lower intensities. The studies applying ESWT versus other therapies showed significant effect size when analysing as covariates the number of pulses and energy density (or intensity), suggesting that lower energy density and lower number of pulses resulted in higher contribution to pooled effect sizes. Vibration studies did not show any impact on the effect size for any intervention parameters.
      Some limitations of our systematic review with meta-analysis must be acknowledged. There were some deviations to the protocol, whose justifications can be found in detail in the supplemental Appendix S3. The majority of meta-analyses assessed the effects only after treatment due to the lack studies with follow-up time points, with only three meta-analyses focusing on short follow-up and none for mid- and long-term follow-up. Some studies were not included in the meta-analyses due to missing data, and partial or total overlapping samples, but we might have missed other potential studies with overlapping population. We contacted the authors of the included trials for missing data, but most of them did not provide any information. There were also other possible meta-analyses that could be conducted, but the available studies were not homogeneous or in enough number. These limitations hampered us to perform further quantitative comparisons among the intervention studies and to assess their long-term effects. Other limitation is using combination of therapies in the meta-analyses. Despite statistically significant effects were observed, it is not possible to ascertain if the effects arose from the isolated addition of the mechanical-based intervention or from the combination of both therapies.
      In one single systematic review with meta-analysis, three mechanical-based therapies were analysed (isolated or combined with other therapies) compared to placebo, other therapies and combination of therapies; in terms of pain, disability and function outcomes, evidencing also the range of parameters used. This comprehensive review summarizes and highlights the effects of using such therapies in knee OA management, which information is of utmost importance for patients and to guide clinicians and physiotherapists for clinical reasoned decisions. These interventions are not currently recommended to treat knee OA due to low-quality evidence of the available clinical trials [
      • Kolasinski S.L.
      • Neogi T.
      • Hochberg M.C.
      • Oatis C.
      • Guyatt G.
      • Block J.
      • et al.
      2019 American college of rheumatology/arthritis foundation guideline for the management of osteoarthritis of the hand, hip, and knee.
      ,
      • Geenen R.
      • Overman C.L.
      • Christensen R.
      • Åsenlöf P.
      • Capela S.
      • Huisinga K.L.
      • et al.
      EULAR recommendations for the health professional’s approach to pain management in inflammatory arthritis and osteoarthritis.
      ,
      • McAlindon T.E.
      • Bannuru R.R.
      • Sullivan M.C.
      • Arden N.K.
      • Berenbaum F.
      • Bierma-Zeinstra S.M.
      • et al.
      OARSI guidelines for the non-surgical management of knee osteoarthritis.
      ]. Our findings confirm the statistically significant effects of using these passive therapies to reduce OA symptoms, but this evidence is limited by the very-low certainty of its effects, whose clinical relevance was not investigated. Clinicians and researchers should evaluate the use of these interventions in long-term to give a whole picture of their potential effects in knee OA management, since patients desire therapies that provide them longstanding pain relief and disability improvements. Further clinical trials should be committed in following rigorous and high-quality methodologies and to adhere to the Consolidated, Standard of Reporting Trials (CONSORT), as many included studies did not fully comply to the CONSORT guidelines [
      • Schulz K.F.
      • Altman D.G.
      • Moher D.
      CONSORT 2010 Statement: Updated guidelines for reporting parallel group randomised trials.
      ]. Clinicians and researchers must clearly provide the stimulation parameters that are critical for the intervention reproducibility (e.g., number of sessions, stimulation time, intensity, frequency) and to reliably compare studies. This fact underlines the need for further homogeneous studies with extractable data and information fully described to achieve more meaningful and relevant conclusions about the effects of the passive mechanical-based therapies on pain, disability and physical performance of patients with knee OA. In the advent of future homogeneous studies that compare these therapies to each other or to homogenous control groups, further analysis can be made using a network meta-analysis framework.

      5. Conclusions

      Although the statistically significant effects are based on very-low certainty, the potential benefits of using passive mechanical-based therapies, in combination or not with other physical therapies, should not be disregard. Therefore, we may cautiously recommend that clinicians might use them in specific clinical situations to reduce pain and disability in patients with knee OA.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      We would like to acknowledge the Fundação para a Ciência e Tecnologia (FCT) for the funding through the references: UIDB/04436/2020, UIDP/04436/2020, Stimcart -PTDC/EME-EME/4520/2021 and the PhD fellowship grant UI/BD/150951/2021.

      Authors' contribution

      All authors were involved both in the idealization of the systematic review and preparation of the protocol and manuscript. S.O. and R.A. were involved in the databases searches and data extraction. S.O. performed the data synthesis and organization in coordination with R.A., B.B.H., A.L. and O.C. S.O., R.A. and C.V. appraised the risk of bias of the studies included in the systematic review and summarized the certainty of recommendation using GRADE. S.O., R.A. and C.V. performed the meta-analysis. B.B.H., F.S.S. and J.EM. guided and provided advice during all steps of the development of the systematic review. All authors contributed to drafting and approving the final manuscript prior to submission to the peer-reviewed journal.

      Systematic review registration

      This systematic review with meta-analysis was prospectively registered at Open Science Framework (https://osf.io/qdr6e)

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

      References

        • Cui A.
        • Li H.
        • Wang D.
        • Zhong J.
        • Chen Y.
        • Lu H.
        Global, regional prevalence, incidence and risk factors of knee osteoarthritis in population-based studies.
        EClinicalMedicine. 2020; 29–30100587https://doi.org/10.1016/j.eclinm.2020.100587
        • Chen A.
        • Gupte C.
        • Akhtar K.
        • Smith P.
        • Cobb J.
        The global economic cost of osteoarthritis: how the UK compares.
        Arthritis. 2012; 2012: 1-6https://doi.org/10.1155/2012/698709
        • Charlesworth J.
        • Fitzpatrick J.
        • Kanthi N.
        • Perera P.
        • Orchard J.
        Osteoarthritis- a systematic review of long-term safety implications for osteoarthritis of the knee.
        BMC Musculoskelet Disord. 2019; 20: 1-12https://doi.org/10.1186/s12891-019-2525-0
        • Collins N.J.
        • Hart H.F.
        • Mills K.A.G.
        Osteoarthritis year in review 2018: rehabilitation and outcomes.
        Osteoarthr Cartil. 2019; 27: 378-391https://doi.org/10.1016/j.joca.2018.11.010
        • Kolasinski S.L.
        • Neogi T.
        • Hochberg M.C.
        • Oatis C.
        • Guyatt G.
        • Block J.
        • et al.
        2019 American college of rheumatology/arthritis foundation guideline for the management of osteoarthritis of the hand, hip, and knee.
        Arthritis Rheumatol. 2020; 72: 220-233https://doi.org/10.1002/art.41142
        • Geenen R.
        • Overman C.L.
        • Christensen R.
        • Åsenlöf P.
        • Capela S.
        • Huisinga K.L.
        • et al.
        EULAR recommendations for the health professional’s approach to pain management in inflammatory arthritis and osteoarthritis.
        Ann Rheum Dis. 2018; 77: 797-807https://doi.org/10.1136/annrheumdis-2017-212662
        • McAlindon T.E.
        • Bannuru R.R.
        • Sullivan M.C.
        • Arden N.K.
        • Berenbaum F.
        • Bierma-Zeinstra S.M.
        • et al.
        OARSI guidelines for the non-surgical management of knee osteoarthritis.
        Osteoarthr Cartil. 2014; 22: 363-388https://doi.org/10.1016/j.joca.2014.01.003
        • Wu Y.
        • Zhu S.
        • Lv Z.
        • Kan S.
        • Wu Q.
        • Song W.
        • et al.
        Effects of therapeutic ultrasound for knee osteoarthritis : a systematic review and meta-analysis.
        Clin Rehabil. 2019; 33: 1-13https://doi.org/10.1177/02692155198664
        • Zhang C.
        • Xie Y.
        • Luo X.
        • Ji Q.
        • Lu C.
        • He C.
        • et al.
        Effects of therapeutic ultrasound on pain, physical functions and safety outcomes in patients with knee osteoarthritis: A systematic review and meta-analysis.
        Clin Rehabil. 2016; 30: 960-971https://doi.org/10.1177/0269215515609415
        • Loyola-Sánchez A.
        • Richardson J.
        • Macintyre N.J.
        Efficacy of ultrasound therapy for the management of knee osteoarthritis : a systematic review with meta-analysis.
        Osteoarthr Cartil. 2010; 18: 1117-1126https://doi.org/10.1016/j.joca.2010.06.010
        • Wang Y.C.
        • Huang H.T.
        • Huang P.J.
        • Liu Z.M.
        • Shih C.L.
        Efficacy and safety of extracorporeal shockwave therapy for treatment of knee osteoarthritis: a systematic review and meta-analysis.
        Pain Med. 2020; 21: 822-835https://doi.org/10.1093/pm/pnz262
        • Li T.
        • Ma J.
        • Zhao T.
        • Gao F.
        • Sun W.
        Application and efficacy of extracorporeal shockwave treatment for knee osteoarthritis: A systematic review and meta-analysis.
        Exp Ther Med. 2019; : 2843-2850https://doi.org/10.3892/etm.2019.7897
        • Li X.
        • Wang X.Q.
        • Chen B.L.
        • Huang L.Y.
        • Liu Y.
        Whole-body vibration exercise for knee osteoarthritis: a systematic review and meta-analysis.
        Evidence-Based Complement Altern Med. 2015; 2015: 1-11https://doi.org/10.1155/2015/758147
        • Zafar H.
        • Alghadir A.
        • Anwer S.
        • Al-Eisa E.
        Therapeutic effects of whole-body vibration training in knee osteoarthritis: a systematic review and meta-analysis.
        Arch Phys Med Rehabil. 2015; 96: 1525-1532https://doi.org/10.1016/j.apmr.2015.03.010
        • Anwer S.
        • Alghadir A.
        • Zafar H.
        • Al-Eisa E.
        Effect of whole body vibration training on quadriceps muscle strength in individuals with knee osteoarthritis: A systematic review and meta-analysis.
        Physiotherapy. 2016; 102: 145-151https://doi.org/10.1016/j.physio.2015.10.004
        • Page M.J.
        • McKenzie J.E.
        • Bossuyt P.M.
        • Boutron I.
        • Hoffmann T.C.
        • Mulrow C.D.
        • et al.
        statement: An updated guideline for reporting systematic reviews.
        BMJ. 2020; 2021: 372https://doi.org/10.1136/bmj.n71
        • Ardern C.L.
        • Büttner F.
        • Andrade R.
        • Weir A.
        • Ashe M.C.
        • Holden S.
        • et al.
        Implementing the 27 PRISMA 2020 Statement items for systematic reviews in the sport and exercise medicine, musculoskeletal rehabilitation and sports science fields : the PERSiST (implementing Prisma in Exercise, Rehabilitation, Sport medicine and Spor.
        Br J Sports Med. 2021; : 1-21https://doi.org/10.1136/bjsports-2021-103987
      1. Oliveira S, Andrade R, Valente C, Espregueira-mendes J, Silva F, Hinckel BB, et al. Effects of mechanical stimulation on knee cartilage for osteoarthritis treatment : protocol for a systematic review with meta-analysis. 2021.

        • Methley A.M.
        • Campbell S.
        • Chew-Graham C.
        • McNally R.
        • Cheraghi-Sohi S.P.I.C.O.
        PICOS and SPIDER: A comparison study of specificity and sensitivity in three search tools for qualitative systematic reviews.
        BMC Health Serv Res. 2014; 14https://doi.org/10.1186/s12913-014-0579-0
        • Higgins J.
        • Thomas J.
        • Chandler J.
        • Cumpston M.
        • Tianjing L.
        • Page M.
        • et al.
        Cochrane handbook for systematic reviews of interventions.
        Wiley & Sons, 2019
        • Sterne J.A.C.
        • Savović J.
        • Page M.J.
        • Elbers R.G.
        • Blencowe N.S.
        • Boutron I.
        • et al.
        RoB 2: A revised tool for assessing risk of bias in randomised trials.
        BMJ. 2019; 366: 1-8https://doi.org/10.1136/bmj.l4898
        • Sterne J.A.
        • Hernán M.A.
        • Reeves B.C.
        • Savović J.
        • Berkman N.D.
        • Viswanathan M.
        • et al.
        ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions.
        BMJ. 2016; 355: 4-10https://doi.org/10.1136/bmj.i4919
        • Cohen J.
        Statistical power analysis for the behavioral sciences.
        Academic Press, 1989
        • Higgins J.P.T.
        • Thompson S.G.
        • Deeks J.J.
        • Altman D.G.
        Measuring inconsistency in meta-analyses.
        BMJ. 2003; 327: 557-560https://doi.org/10.1136/bmj.327.7414.557
      2. Schünemann H, Brozek J, Guyatt G, Oxman A, editors. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013. Available from guidelinedevelopment.org/handbook.; n.d.

        • Guyatt G.H.
        • Oxman A.D.
        • Vist G.
        • Kunz R.
        • Brozek J.
        • Alonso-Coello P.
        • et al.
        GRADE guidelines: 4. Rating the quality of evidence - Study limitations (risk of bias).
        J Clin Epidemiol. 2011; 64: 407-415https://doi.org/10.1016/j.jclinepi.2010.07.017
        • Guyatt G.H.
        • Oxman A.D.
        • Kunz R.
        • Woodcock J.
        • Brozek J.
        • Helfand M.
        • et al.
        GRADE guidelines: 7. Rating the quality of evidence - Inconsistency.
        J Clin Epidemiol. 2011; 64: 1294-1302https://doi.org/10.1016/j.jclinepi.2011.03.017
        • Guyatt G.H.
        • Oxman A.D.
        • Kunz R.
        • Brozek J.
        • Alonso-Coello P.
        • Rind D.
        • et al.
        GRADE guidelines 6. Rating the quality of evidence - Imprecision.
        J Clin Epidemiol. 2011; 64: 1283-1293https://doi.org/10.1016/j.jclinepi.2011.01.012
        • Guyatt G.H.
        • Oxman A.D.
        • Kunz R.
        • Woodcock J.
        • Brozek J.
        • Helfand M.
        • et al.
        GRADE guidelines: 8. Rating the quality of evidence - Indirectness.
        J Clin Epidemiol. 2011; 64: 1303-1310https://doi.org/10.1016/j.jclinepi.2011.04.014
        • Guyatt G.H.
        • Oxman A.D.
        • Montori V.
        • Vist G.
        • Kunz R.
        • Brozek J.
        • et al.
        GRADE guidelines: 5. Rating the quality of evidence - Publication bias.
        J Clin Epidemiol. 2011; 64: 1277-1282https://doi.org/10.1016/j.jclinepi.2011.01.011
        • Yeğin T.
        • Altan L.
        • Kasapoğlu A.M.
        The effect of therapeutic ultrasound on pain and physical function in patients with knee osteoarthritis.
        Ultrasound Med Biol. 2017; 43: 187-194https://doi.org/10.1016/j.ultrasmedbio.2016.08.035
        • Durmus D.
        • Unal M.
        The effect of capsaicin phonophoresis in knee osteoarthritis and can it be utilized early in primary care? : A randomized-controlled trial.
        KONURALP TIP Derg. 2016; 8: 173-180
        • Ozgönenel L.
        • Aytekin E.
        • Durmuşoglu G.
        A double-blind trial of clinical effects of therapeutic ultrasound in knee osteoarthritis.
        Ultrasound Med Biol. 2009; 35: 44-49https://doi.org/10.1016/j.ultrasmedbio.2008.07.009
        • Luksurapan W.
        • Boonhong J.
        Effects of phonophoresis of piroxicam and ultrasound on symptomatic knee osteoarthritis.
        Arch Phys Med Rehabil. 2013; 94: 250-255
        • Ulus Y.
        • Tander B.
        • Akyol Y.
        • Durmus D.
        • Buyukakıncak O.
        • Gul U.
        • et al.
        Therapeutic ultrasound versus sham ultrasound for the management of patients with knee osteoarthritis: a randomized double-blind controlled clinical study.
        Int J Rheum Dis. 2012; 15: 197-206https://doi.org/10.1111/j.1756-185X.2012.01709.x
        • Yang P.
        • Li D.
        • Zhang S.
        • Wu Q.
        • Tang J.
        • Huang L.
        • et al.
        Efficacy of ultrasound in the treatment of osteoarthritis of the knee.
        Orthop Surg. 2011; 3: 181-187https://doi.org/10.1111/j.1757-7861.2011.00144.x
        • Sangtong K.
        • Chupinijrobkob C.
        • Putthakumnerd W.
        • Kuptniratsaikul V.
        Does adding transcutaneous electrical nerve stimulation to therapeutic ultrasound affect pain or function in people with osteoarthritis of the knee? A randomized controlled trial.
        Clin Rehabil. 2019; 33: 1197-1205https://doi.org/10.1177/0269215519838017
        • Ozgonenel L.
        • Okur S.C.Ç.
        • Dogan Y.P.
        • Caglar N.S.
        • Özgönenel L.
        • Okur S.C.Ç.
        • et al.
        Effectiveness of therapeutic ultrasound on clinical parameters and ultrasonographic cartilage thickness in knee osteoarthritis: a double-blind trial.
        J Med Ultrasound. 2018; 26: 194-199https://doi.org/10.4103/JMU.JMU_21_18
        • Kapci Yildiz S.
        • Ünlü Özkan F.
        • Aktaş İ.
        • Şilte A.D.
        • Yilmaz Kaysin M.
        • Bilgin B.N.
        The effectiveness of ultrasound treatment for the management of knee osteoarthritis: A randomized, placebo-controlled, double-blind study.
        Turkish J Med Sci. 2015; 45: 1187-1191https://doi.org/10.3906/sag-1408-81
        • Toopchizadeh V.
        • Javadi R.
        • Sadat B.E.
        Therapeutic efficacy of dexamethasone phonophoresis on symptomatic knee osteoarthritis in elderly women.
        Int J Women’s Heal Reprod Sci. 2014; 2: 168-177https://doi.org/10.15296/ijwhr.2014.25
        • Alfredo P.P.
        • Junior W.S.
        • Casarotto R.A.
        Efficacy of continuous and pulsed therapeutic ultrasound combined with exercises for knee osteoarthritis: a randomized controlled trial.
        Clin Rehabil. 2020; 34: 480-490https://doi.org/10.1177/0269215520903786
        • 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.
        Arthritis Rheum. 2005; 53: 812-820https://doi.org/10.1002/art.21590
        • Pinkaew D.
        • Kiattisin K.
        • Wonglangka K.
        • Awoot P.
        Phonophoresis of Phyllanthus amarus nanoparticle gel improves functional capacity in individuals with knee osteoarthritis: A randomized controlled trial.
        J Bodyw Mov Ther. 2020; 24: 15-18https://doi.org/10.1016/j.jbmt.2019.04.013
        • Huang M.-H.
        • Lin Y.-S.
        • Lee C.-L.
        • Yang R.-C.
        Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis.
        Arch Phys Med Rehabil. 2005; 86: 1545-1551https://doi.org/10.1016/j.apmr.2005.02.007
        • Draper D.O.
        • Klyve D.
        • Ortiz R.
        • Best T.M.
        Effect of low-intensity long-duration ultrasound on the symptomatic relief of knee osteoarthritis: a randomized, placebo-controlled double-blind study.
        J Orthop Surg Res. 2018; 13: 257https://doi.org/10.1186/s13018-018-0965-0
        • Cakir S.
        • Hepguler S.
        • Ozturk C.
        • Korkmaz M.
        • Isleten B.
        • Atamaz F.C.
        Efficacy of therapeutic ultrasound for the management of knee osteoarthritis.
        Am J Phys Med Rehabil. 2014; 93: 405-412https://doi.org/10.1097/PHM.0000000000000033
        • Devrimsel G.
        • Metin Y.
        • Serdaroglu B.M.
        Short-term effects of neuromuscular electrical stimulation and ultrasound therapies on muscle architecture and functional capacity in knee osteoarthritis: a randomized study.
        Clin Rehabil. 2019; 33: 418-427https://doi.org/10.1177/0269215518817807
        • Jia L.
        • Wang Y.
        • Chen J.
        • Chen W.
        Efficacy of focused low-intensity pulsed ultrasound therapy for the management of knee osteoarthritis: a randomized, double blind, placebo-controlled trial.
        Sci Rep. 2016; 6: 35453https://doi.org/10.1038/srep35453
        • Mascarin N.C.
        • Vancini R.L.
        • Andrade M.L.D.S.
        • Magalhães E. de P.
        • de Lira C.A.B.
        • Coimbra I.B.
        Effects of kinesiotherapy, ultrasound and electrotherapy in management of bilateral knee osteoarthritis: prospective clinical trial.
        BMC Musculoskelet Disord. 2012; 13: 182https://doi.org/10.1186/1471-2474-13-182
        • Pinkaew D.
        • Kiattisin K.
        • Tocharus J.
        • Jumnongprakhon P.
        • Awoot P.
        • Decha P.
        • et al.
        Phonopheresis associated with nanoparticle gel from phyllanthus amarus relieves pain by reducing oxidative stress and proinflammatory markers in adults with knee osteoarthritis.
        Chin J Integr Med. 2019; 25: 691-695https://doi.org/10.1007/s11655-019-3202-8
        • Pinkaew D.
        • Kiattisin K.
        • Wonglangka K.
        • Awoot P.
        Improved WOMAC score following treatment with nanoparticle phyllanthus amarus phonophoresis gel for knee osteoarthritis.
        Indian J Public Heal Res Dev. 2019; 10: 1623-1628https://doi.org/10.37506/v10/i12/2019/ijphrd/192093
        • Karakaş A.
        • Dilek B.
        • Şahin M.A.
        • Ellidokuz H.
        • Şenocak Ö.
        The effectiveness of pulsed ultrasound treatment on pain, function, synovial sac thickness and femoral cartilage thickness in patients with knee osteoarthritis: a randomized, double-blind clinical, controlled study.
        Clin Rehabil. 2020; 34: 1474-1484https://doi.org/10.1177/0269215520942953
        • Kozanoglu E.
        • Basaran S.
        • Guzel R.
        • Guler-Uysal F.
        Short term efficacy of ibuprofen phonophoresis versus continuous ultrasound therapy in knee osteoarthritis.
        Swiss Med Wkly. 2003; 133: 333-338
        • Monisha R.
        • Manikumar M.
        • Krishnakumar A.
        Evaluating the effectiveness of phonophoresis by piroxicam and dimethyl sulfoxide for women’s with osteoarthritis knee joint.
        Asian J Pharm Clin Res. 2018; 11: 329-331https://doi.org/10.22159/ajpcr.2018.v11i6.24615
        • Tascioglu F.
        • Kuzgun S.
        • Armagan O.
        • Ogutler G.
        Short-term effectiveness of ultrasound therapy in knee osteoarthritis.
        J Int Med Res. 2010; 38: 1233-1242https://doi.org/10.1177/147323001003800404
        • Rayegani S.M.
        • Bahrami M.H.
        • Elyaspour D.
        • Saeedi M.
        • Sanjari H.
        Therapeutic effects of low level laser therapy (LLLT) in knee osteoarthritis, compared to therapeutic ultrasound.
        J Lasers Med Sci. 2012; 3: 71-74https://doi.org/10.22037/2010.v3i2.2830
      3. Loyola-sánchez A, Richardson J, Beattie KA, Otero-fuentes C, A AL, Richardson J, et al. Effect of low-intensity pulsed ultrasound on the cartilage repair in people with mild to moderate knee osteoarthritis: a double-blinded, randomized, placebo-controlled pilot study. Arch Phys Med Rehabil 2012;93:35–42. https://doi.org/10.1016/j.apmr.2011.07.196.

        • Kim E.-D.
        • Won Y.H.
        • Park S.-H.
        • Seo J.-H.
        • Kim D.-S.
        • Ko M.-H.
        • et al.
        Efficacy and safety of a stimulator using low-intensity pulsed ultrasound combined with transcutaneous electrical nerve stimulation in patients with painful knee osteoarthritis.
        Pain Res Manag. 2019; 2019: 7964897https://doi.org/10.1155/2019/7964897
        • Boyaci A.
        • Tutoglu A.
        • Boyaci N.
        • Aridici R.
        • Koca I.
        Comparison of the efficacy of ketoprofen phonophoresis, ultrasound, and short-wave diathermy in knee osteoarthritis.
        Rheumatol Int. 2013; 33: 2811-2818https://doi.org/10.1007/s00296-013-2815-z
        • Abdalbary S.A.
        Ultrasound with mineral water or aqua gel to reduce pain and improve the WOMAC of knee osteoarthritis.
        Futur Sci OA. 2016; (2:FSO110)https://doi.org/10.4155/fsoa-2016-0003
        • Coskun Benlidayi I.
        • Gokcen N.
        • Basaran S.
        Comparative short-term effectiveness of ibuprofen gel and cream phonophoresis in patients with knee osteoarthritis.
        Rheumatol Int. 2018; 38: 1927-1932https://doi.org/10.1007/s00296-018-4099-9
        • Nakhostin-Roohi B.
        • Khoshkhahesh F.
        • Bohlooli S.
        Effect of virgin olive oil versus piroxicam phonophoresis on exercise-induced anterior knee pain.
        Avicenna J Phytomedicine. 2016; 6: 535-541
        • Zhao J.
        • Wang Q.
        • Wu J.
        • Shi X.
        • Qi Q.
        • Zheng H.
        • et al.
        Therapeutic effects of low-frequency phonophoresis with a Chinese herbal medicine versus sodium diclofenac for treatment of knee osteoarthritis: a double-blind, randomized, placebo-controlled clinical trial.
        J Tradit Chinese Med. 2016; 36: 613-617