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Efficacy of low frequency pulsed subsensory threshold electrical stimulation vs placebo on pain and physical function in people with knee osteoarthritis: systematic review with meta-analysis

  • A. Negm
    Correspondence
    Address correspondence and reprint requests to: A. Negm, School of Rehabilitation Sciences, McMaster University, IAHS 403/432, 1400 Main St. W., Hamilton, Ontario L8S 1C7, Canada. Tel: 1-905-525-9140x21166.
    Affiliations
    School of Rehabilitation Sciences, McMaster University, 1400 Main St. W., Hamilton, Ontario L8S 1C7, Canada
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  • A. Lorbergs
    Affiliations
    School of Rehabilitation Sciences, McMaster University, 1400 Main St. W., Hamilton, Ontario L8S 1C7, Canada
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  • N.J. MacIntyre
    Affiliations
    School of Rehabilitation Sciences, McMaster University, 1400 Main St. W., Hamilton, Ontario L8S 1C7, Canada
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      Summary

      Objective

      To determine if low frequency (≤100 Hz) pulsed subsensory threshold electrical stimulation produced either through pulsed electromagnetic field (PEMF) or pulsed electrical stimulation (PES) vs sham PEMF/PES intervention is effective in improving pain and physical function at treatment completion in adults with knee osteoarthritis (OA) blinded to treatment.

      Method

      The relevant studies were identified by searching eight electronic databases and hand search of the past systematic reviews on the same topic till April 5, 2012.
      We included randomized controlled trials (RCTs) of people with knee OA comparing the outcomes of interest for those receiving PEMF/PES with those receiving sham PEMF/PES. Two reviewers independently selected studies, extracted relevant data and assessed quality. Pooled analyses were conducted using inverse-variance random effects models and standardized mean difference (SMD) for the primary outcomes.

      Results

      Seven small trials (459 participants/knees) were included. PEMF/PES improves physical function (SMD = 0.22, 95% confidence interval (CI) = 0.04, 0.41, P = 0.02, I2 = 0%), and does not reduce pain (SMD = 0.08, 95% CI = −0.17, 0.32, P = 0.55, I2 = 43%). The strength of the body of evidence was low for physical function and very low for pain.

      Conclusion

      Current evidence of low and very low quality suggests that low frequency (≤100 Hz) pulsed subsensory threshold electrical stimulation produced either through PEMF/PES vs sham PEMF/PES is effective in improving physical function but not pain intensity at treatment completion in adults with knee OA blinded to treatment. Methodologically rigorous and adequately powered RCTs are needed to confirm the findings of this review.

      Keywords

      Introduction

      Osteoarthritis (OA) is a degenerative disorder of the articular cartilage associated with hypertrophic bone changes
      • Bennell K.L.
      • Hunter D.J.
      • Hinman R.S.
      Management of osteoarthritis of the knee.
      . It is the most common chronic joint disease and the leading cause of pain and disability among older adults around the world
      • Fransen M.
      • Bridgett L.
      • March L.
      • Hoy D.
      • Penserga E.
      • Brooks P.
      The epidemiology of osteoarthritis in Asia.
      . Knee OA has an immense public health impact due to the need for healthcare services particularly if surgical replacement of the knee joint is required
      • Quintana J.M.
      • Arostegui I.
      • Escobar A.
      • Azkarate J.
      • Goenaga J.I.
      • Lafuente I.
      Prevalence of knee and hip osteoarthritis and the appropriateness of joint replacement in an older population.
      . In 2000, 25 million people in North America had knee OA, and that number is expected to double by 2020 due to several factors including sedentary life style, increasing prevalence of obesity and population aging
      • Bartlett S.J.
      • Ling S.M.
      • Mayo N.
      • Scott S.
      • Bingham III, C.O.
      Identifying common trajectories of joint space narrowing over two years in knee osteoarthritis.
      .
      Effective, conservative interventions for relieving pain and improving physical function are needed for people with knee OA
      • Mann C.
      • Gooberman-Hill R.
      Health care provision for osteoarthritis: concordance between what patients would like and what health professionals think they should have.
      . Pulsed electromagnetic field (PEMF) and pulsed electrical stimulation (PES) are emerging non-pharmacologic conservative treatments of knee OA. Both treatments produce pulsed electric potentials below the sensory threshold either through an electromagnetic coil system (PEMF) or surface electrodes (PES) applied around the knee joint
      • Thawer H.A.
      Pulsed electromagnetic fields for osteogenesis and repair.
      • Trock D.H.
      Electromagnetic fields and magnets. Investigational treatment for musculoskeletal disorders.
      • Hulme J.
      • Robinson V.
      • DeBie R.
      • Wells G.
      • Judd M.
      • Tugwell P.
      Electromagnetic fields for the treatment of osteoarthritis.
      . These subsensory-threshold pulsed electric potentials stimulate intrinsic potentials
      • Schmidt-Rohlfing B.
      • Silny J.
      • Woodruff S.
      • Gavenis K.
      Effects of pulsed and sinusoid electromagnetic fields on human chondrocytes cultivated in a collagen matrix.
      , which alter the homoeostatic balance of cartilage matrix degradation and synthesis in favour of cartilage repair
      • Ciombor D.M.
      • Aaron R.K.
      • Wang S.
      • Simon B.
      Modification of osteoarthritis by pulsed electromagnetic field – a morphological study.
      . In cell culture and animal studies, electrical stimulation similar to that produced by PEMF/PES increases cartilage synthesis by down regulation of interleukin-1 (IL-1) and up regulation of transforming growth factor beta (TGFβ) which lead to increased aggrecan, type II collagen, and proteoglycan content in the cartilage matrix and enhanced chondrocyte proliferation
      • Wang W.
      • Wang Z.
      • Zhang G.
      • Clark C.C.
      • Brighton C.T.
      Up-regulation of chondrocyte matrix genes and products by electric fields.
      . In an animal model study, PES of less than 100 Hz has shown higher efficacy than frequencies of 150 Hz or more
      • McLeod K.J.
      • Rubin C.T.
      The effect of low-frequency electrical fields on osteogenesis.
      . Moreover, higher frequencies have been associated with harmful changes in bone tissue
      • Thawer H.A.
      Pulsed electromagnetic fields for osteogenesis and repair.
      .
      Previous systematic reviews have addressed the question of efficacy of PEMF and PES for knee OA management and reached contradicting conclusions
      • McCarthy C.J.
      • Callaghan M.J.
      • Oldham J.A.
      Pulsed electromagnetic energy treatment offers no clinical benefit in reducing the pain of knee osteoarthritis: a systematic review.
      • Vavken P.
      • Arrich F.
      • Schuhfried O.
      • Dorotka R.
      Effectiveness of pulsed electromagnetic field therapy in the management of osteoarthritis of the knee: a meta-analysis of randomized controlled trials.
      . McCarthy et al. (2006) pooled data from five randomized controlled trials (RCTs) (276 participants/knees) and concluded that PEMF and PES are not effective for knee OA pain or physical function
      • McCarthy C.J.
      • Callaghan M.J.
      • Oldham J.A.
      Pulsed electromagnetic energy treatment offers no clinical benefit in reducing the pain of knee osteoarthritis: a systematic review.
      ; Vavken et al. (2009) pooled data for nine RCTs (483 participants/knees) and concluded that PEMF and PES might improve physical function but not pain in the knee OA population at treatment completion
      • Vavken P.
      • Arrich F.
      • Schuhfried O.
      • Dorotka R.
      Effectiveness of pulsed electromagnetic field therapy in the management of osteoarthritis of the knee: a meta-analysis of randomized controlled trials.
      . A systematic review conducted by We et al. searched literature published to December 2011 to determine the efficacy of PEMF pooling data from 14 studies (930 participants/knees) reporting knee OA pain and physical function outcomes at 4, 8, 12, and 16 weeks
      • We S.R.
      • Koog Y.H.
      • Jeong K.I.
      • Wi H.
      Effects of Pulsed Electromagnetic Field on Knee Osteoarthritis: a Systematic Review.
      . Similar to the conclusions reported by Vavken et al. (2009), We et al. reported that physical function was improved at 8 weeks with active PEMF (five trials, 304 participants/knees; all interventions completed at 6 weeks) and pain was not significantly improved at any time point (maximum of 11 trials, 762 participants/knees (at 4 weeks) in which the intervention period was 2, 3, 4, or 6 weeks). However, the inclusion of trials in which pulsed subsensory threshold electrical stimulation was applied at higher frequencies than that expected to be biologically beneficial to participants with and without knee OA who were not blinded and/or not randomized to treatment leaves the question of efficacy unresolved.

      Objective

      The objective of this systematic review was to determine if low frequency (≤100 Hz) pulsed subsensory threshold electrical stimulation produced either through PEMF/PES vs sham PEMF/PES intervention is effective in improving pain and physical function at treatment completion in adults with knee OA blinded to treatment. Adverse events were the primary safety outcome. Secondary outcomes included patient global assessment, imaging-based knee joint status, health-related quality of life and physician global assessment.

      Methods

      The Cochrane Collaboration methodology was followed
      • Higgins J.P.T.
      • Green S.
      • Collaboration C.
      Cochrane Handbook for Systematic Reviews of Interventions.
      in the conduct of this review and PRISMA guidelines were followed for reporting the methods and results of this systematic review and meta-analysis
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • Mulrow C.
      • Gotzsche P.C.
      • Ioannidis J.P.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
      .

      Eligibility criteria and search strategy

      Studies were included if: (1) participants with clinically and/or radiological confirmed knee OA; (2) PEMF/PES frequency was ≤100 Hz; (3) Comparator is sham PEMF/PES; (4) primary outcome was pain and/or physical function; (5) the study design is RCT with blinded participants; (6) data for knee OA participants were reported independently pre- and post-treatment; and (7) participants were over 30 years of age. Studies were excluded if: (1) results were reported in another trial; (2) published data were insufficient for meta-analysis and corresponding authors did not respond to requests for further information; (3) co-interventions were applied to only one group; and (4) the trial was written in a language other than English.
      The relevant studies were identified by searching five electronic databases: MEDLINE, CINAHL, EMBASE, CENTRAL and AMED. The search strategy combined medical subject headings (MeSH) and text terms describing knee OA with terms describing PEMF/PES. The search was limited to English language, human, adult, and RCT. The keywords and MeSH used for each of the databases and the search results are shown in Appendix A. We searched three clinical trial registries to identify ongoing trials: Clinical Trials Registry, Current Controlled Trials and the World Health Organisation International Clinical Trials Registry Platform. Hand search of the past systematic reviews on the same topic was performed. The last search was run on April 5, 2012.

      Study selection

      The eligibility assessment of title and abstract of citations obtained from the search was performed by two independent reviewers (AN, AL) unblinded to author, journal and country. Any disagreement was resolved through consensus. After title and abstract screening for potentially eligible studies, two reviewers (AN, NM) checked the full text articles for eligibility independently and any disagreements were resolved through consensus. The agreement between the two reviewers was assessed by examining raw agreement and unweighted kappa (κ).

      Data extraction and management

      A data extraction form was developed for this review and pilot-tested independently on three randomly-selected studies by two reviewers (AN, NM) to ensure consistency in extraction. The extraction form was refined accordingly and data were extracted in duplicate. Six authors were contacted for further information, two authors responded and one provided numerical data that were presented graphically in the published paper
      • Fary R.E.
      • Carroll G.J.
      • Briffa T.G.
      • Briffa N.K.
      The effectiveness of pulsed electrical stimulation in the management of osteoarthritis of the knee: results of a double-blind, randomized, placebo-controlled, repeated-measures trial.
      . The extracted information included the characteristics of participants (age, gender, knee OA severity and method of diagnosis), PEMF/PES (the device, application and treatment protocol), and the type of outcome measures, baseline data, post-treatment data, and change means and standard deviations (SDs) or the information from which SD could be derived, such as standard error or confidence interval (CI). When a trial presented outcomes at more than one time point, data for all time points were extracted; however, only data acquired immediately post-treatment were used in the meta-analysis.

      Assessment of risk of bias for included studies

      Two reviewers (AN, NM) independently assessed risk of bias for each study according to the Cochrane Handbook (chapter 8) for eight domains: sequence generation, allocation concealment, blinding of participants and care givers, blinding of outcome assessors, completeness of outcome data, completeness of outcome reporting and the potential for other threats to the validity of the study
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • Mulrow C.
      • Gotzsche P.C.
      • Ioannidis J.P.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
      . Any disagreement regarding risk of bias was resolved by consensus. Risk of publication bias was examined using a funnel plot of each study's effect estimates for the primary outcomes against their standard error; no statistical test was performed.

      Data synthesis

      The outcomes in the included studies reported continuous data (mean and SD) and used different outcome measures for each outcome with the exception of patient and physician global assessments, therefore, standardized mean differences (SMDs) were used to estimate the treatment effect to facilitate comparisons across all outcomes. Change means and SDs were pooled to adjust for the baseline differences between groups in each study. Three studies
      • Özgüçlü E.
      • Cetin A.
      • Cetin M.
      • Calp E.
      Additional effect of pulsed electromagnetic field therapy on knee osteoarthritis treatment: a randomized, placebo-controlled study.
      • Ay S.
      • Evcik D.
      The effects of pulsed electromagnetic fields in the treatment of knee osteoarthritis: a randomized, placebo-controlled trial.
      • Thamsborg G.
      • Florescu A.
      • Oturai P.
      • Fallentin E.
      • Tritsaris K.
      • Dissing S.
      Treatment of knee osteoarthritis with pulsed electromagnetic fields: a randomized, double-blind, placebo-controlled study.
      reported post-treatment means and SDs. Therefore, change means and SDs were imputed as recommended by the Cochrane Handbook
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • Mulrow C.
      • Gotzsche P.C.
      • Ioannidis J.P.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
      . Relative risk (RR) and 95% CIs for the reported side effects were calculated.
      One study
      • Özgüçlü E.
      • Cetin A.
      • Cetin M.
      • Calp E.
      Additional effect of pulsed electromagnetic field therapy on knee osteoarthritis treatment: a randomized, placebo-controlled study.
      did not report post-treatment SDs for the outcomes (required to calculate change SD). Furthermore, calculating the SD from the study data was not possible since other important statistics (standard error, CI, or exact P-values) were not provided. Baseline SDs were used instead of post-treatment SDs based on the assumption that the intervention does not change the variability between groups
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • Mulrow C.
      • Gotzsche P.C.
      • Ioannidis J.P.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
      . SMDs were pooled and the inverse-variance random effects model was used considering the variability across studies
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • Mulrow C.
      • Gotzsche P.C.
      • Ioannidis J.P.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
      . Review Manager Version 5 was used for data analysis (http://ims.cochrane.org/revman). CIs at the 95% level (95% CI) were calculated for pooled estimates for each outcome and the Z test was used to determine the treatment effect. Statistical significance was considered at P < 0.05.

      Investigation of heterogeneity and subgroup analysis

      Heterogeneity among the included studies was measured using the chi-squared test (χ2). For χ2 values with P < 0.1, heterogeneity was considered to be significantly high. The I2 was used to assess the inconsistency between the pooled studies. The I2 of <60% was considered to be acceptable for pooling the data across the studies
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • Mulrow C.
      • Gotzsche P.C.
      • Ioannidis J.P.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
      .
      The pulsed subsensory threshold electrical stimulation types, treatment duration and source of funding were hypothesized to generate heterogeneity across the studies. Therefore subgroup analyses were planned a priori for the different types of pulsed subsensory threshold electrical stimulation (PES and PEMF), treatment durations (<12 weeks and ≥12 weeks) and source of funding (non-industry and industry).

      Grading of evidence

      Two reviewers (AN, NM) graded the strength of the body of evidence that emerged from this review using the Gradepro program
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • Kunz R.
      • Falck-Ytter Y.
      • Alonso-Coello P.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      . Five domains were assessed: risk of bias, inconsistency of the results, indirectness of the outcome, imprecision of the results and publication bias.

      Sensitivity analysis

      To ensure the robustness of the pooled outcomes, post-hoc sensitivity analyses were conducted by repeating the meta-analyses after removing data from each of the three studies for which the change SD was imputed
      • Özgüçlü E.
      • Cetin A.
      • Cetin M.
      • Calp E.
      Additional effect of pulsed electromagnetic field therapy on knee osteoarthritis treatment: a randomized, placebo-controlled study.
      • Ay S.
      • Evcik D.
      The effects of pulsed electromagnetic fields in the treatment of knee osteoarthritis: a randomized, placebo-controlled trial.
      • Thamsborg G.
      • Florescu A.
      • Oturai P.
      • Fallentin E.
      • Tritsaris K.
      • Dissing S.
      Treatment of knee osteoarthritis with pulsed electromagnetic fields: a randomized, double-blind, placebo-controlled study.
      .

      Results

      Figure 1 shows the flow diagram for identification of eligible trials. After title and abstract screening, 11 studies were retrieved for full text review. Seven studies met the eligibility criteria. The raw agreement between the reviewers in identifying the full text studies for inclusion in this review was 100% (κ = 1).
      Figure thumbnail gr1
      Fig. 1Flow diagram for identification of eligible trials evaluating the effect of PEMF/PES.

      Description of included studies

      Seven parallel group randomized placebo controlled studies published between 1994 and 2011 were included. Two trials were conducted in USA
      • Garland D.
      • Holt P.
      • Harrington J.T.
      • Caldwell J.
      • Zizic T.
      • Cholewczynski J.
      A 3-month, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a highly optimized, capacitively coupled, pulsed electrical stimulator in patients with osteoarthritis of the knee.
      • Trock D.H.
      • Bollet A.J.
      • Markoll R.
      The effect of pulsed electromagnetic fields in the treatment of osteoarthritis of the knee and cervical spine. Report of randomized, double blind, placebo controlled trials.
      , two in Turkey
      • Özgüçlü E.
      • Cetin A.
      • Cetin M.
      • Calp E.
      Additional effect of pulsed electromagnetic field therapy on knee osteoarthritis treatment: a randomized, placebo-controlled study.
      • Ay S.
      • Evcik D.
      The effects of pulsed electromagnetic fields in the treatment of knee osteoarthritis: a randomized, placebo-controlled trial.
      , and one in each of Denmark
      • Thamsborg G.
      • Florescu A.
      • Oturai P.
      • Fallentin E.
      • Tritsaris K.
      • Dissing S.
      Treatment of knee osteoarthritis with pulsed electromagnetic fields: a randomized, double-blind, placebo-controlled study.
      , Australia
      • Fary R.E.
      • Carroll G.J.
      • Briffa T.G.
      • Briffa N.K.
      The effectiveness of pulsed electrical stimulation in the management of osteoarthritis of the knee: results of a double-blind, randomized, placebo-controlled, repeated-measures trial.
      and the UK
      • Pipitone N.
      • Scott D.L.
      Magnetic pulse treatment for knee osteoarthritis: a randomised, double-blind, placebo-controlled study.
      . The duration of the intervention varied from 2 to 26 weeks and the frequency of PEMF/PES ranged from 5 to 100 Hz. The control groups in all the studies used sham devices. In total, the studies included 459 participants with an average age of 63.7 years and with greater proportion of females compared to males. The description and characteristics of the included studies are summarized in Table I.
      Table ICharacteristics of participants and interventions in the included studies
      StudySample size

      (N)
      Age, y (mean (SD))Female (%)Intervention
      PEMF/PESControlPEMF/PESControlPEMF/PESControlTypeFrequency (Hz)Total exposure (Hs × Session/Week)Duration (Weeks)
      Trock et al.
      • Trock D.H.
      • Bollet A.J.
      • Markoll R.
      The effect of pulsed electromagnetic fields in the treatment of osteoarthritis of the knee and cervical spine. Report of randomized, double blind, placebo controlled trials.
      404469.2 (11.5)65.8 (11.7)6970.5PEMF5–120.5 × 3-54–6
      Pipitone and Scott
      • Pipitone N.
      • Scott D.L.
      Magnetic pulse treatment for knee osteoarthritis: a randomised, double-blind, placebo-controlled study.
      343562643520PEMF3–200.5 × 76
      Thamsborg et al.
      • Thamsborg G.
      • Florescu A.
      • Oturai P.
      • Fallentin E.
      • Tritsaris K.
      • Dissing S.
      Treatment of knee osteoarthritis with pulsed electromagnetic fields: a randomized, double-blind, placebo-controlled study.
      424160.4 (8.7)59.6 (8.6)47.660.9PEMF502 × 56
      Garland et al.
      • Garland D.
      • Holt P.
      • Harrington J.T.
      • Caldwell J.
      • Zizic T.
      • Cholewczynski J.
      A 3-month, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a highly optimized, capacitively coupled, pulsed electrical stimulator in patients with osteoarthritis of the knee.
      391964.3 (10.2)69.9 (11.4)69.257.9PES1007 × 712
      Ay and Evcik
      • Ay S.
      • Evcik D.
      The effects of pulsed electromagnetic fields in the treatment of knee osteoarthritis: a randomized, placebo-controlled trial.
      302558.9 (8.8)57.7 (6.5)7076PEMF500.5 × 53
      Özgüçlü et al.
      • Özgüçlü E.
      • Cetin A.
      • Cetin M.
      • Calp E.
      Additional effect of pulsed electromagnetic field therapy on knee osteoarthritis treatment: a randomized, placebo-controlled study.
      202060.6 (7.7)62.2 (8.2)NRNRPEMF500.5 × 52
      Fary et al.
      • Fary R.E.
      • Carroll G.J.
      • Briffa T.G.
      • Briffa N.K.
      The effectiveness of pulsed electrical stimulation in the management of osteoarthritis of the knee: results of a double-blind, randomized, placebo-controlled, repeated-measures trial.
      343670.7 (8.9)68.9 (11.4)5044PES1007 × 726
      NR, Not reported.

      Description of excluded studies

      After the full-text eligibility assessment, four studies were excluded
      • Zizic T.M.
      • Hoffman K.C.
      • Holt P.A.
      • Hungerford D.S.
      • O'Dell J.R.
      • Jacobs M.A.
      • et al.
      The treatment of osteoarthritis of the knee with pulsed electrical stimulation.
      • Jacobson J.I.
      • Gorman R.
      • Yamanashi W.S.
      • Saxena B.B.
      • Clayton L.
      Low-amplitude, extremely low frequency magnetic fields for the treatment of osteoarthritic knees: a double-blind clinical study.
      • Nicolakis P.
      • Kollmitzer J.
      • Crevenna R.
      • Bittner C.
      • Erdogmus C.B.
      • Nicolakis J.
      Pulsed magnetic field therapy for osteoarthritis of the knee – a double-blind sham-controlled trial.
      • Trock D.H.
      • Bollet A.J.
      • Dyer Jr., R.H.
      • Fielding L.P.
      • Miner W.K.
      • Markoll R.
      A double-blind trial of the clinical effects of pulsed electromagnetic fields in osteoarthritis.
      for various reasons. The RCT by Zizic et al. (1995) was excluded because the SDs or other important statistics (standard error, CI, or exact P-values) were not provided
      • Trock D.H.
      • Bollet A.J.
      • Markoll R.
      The effect of pulsed electromagnetic fields in the treatment of osteoarthritis of the knee and cervical spine. Report of randomized, double blind, placebo controlled trials.
      . In the trial by Jacobson et al. (2001), radiological or clinical criteria for diagnosing knee OA was not reported and SDs for means were not provided for the intervention and placebo groups
      • Jacobson J.I.
      • Gorman R.
      • Yamanashi W.S.
      • Saxena B.B.
      • Clayton L.
      Low-amplitude, extremely low frequency magnetic fields for the treatment of osteoarthritic knees: a double-blind clinical study.
      . Nicolakis et al. (2002) used PEMF but with frequencies exceeding 100 Hz
      • Nicolakis P.
      • Kollmitzer J.
      • Crevenna R.
      • Bittner C.
      • Erdogmus C.B.
      • Nicolakis J.
      Pulsed magnetic field therapy for osteoarthritis of the knee – a double-blind sham-controlled trial.
      . Lastly, Trock et al. (1993) included five participants with hand OA, one participant with ankle OA and 21 participants with knee OA and the results for knee OA participants were not presented separately
      • Trock D.H.
      • Bollet A.J.
      • Dyer Jr., R.H.
      • Fielding L.P.
      • Miner W.K.
      • Markoll R.
      A double-blind trial of the clinical effects of pulsed electromagnetic fields in osteoarthritis.
      . We contacted these authors to get the required information to include these studies but they did not reply.

      Risk of bias in the included studies

      Table II summarizes the risk of bias assessment for the seven included studies. The overall methodological quality assessment indicated that risk of bias was low in one study
      • Fary R.E.
      • Carroll G.J.
      • Briffa T.G.
      • Briffa N.K.
      The effectiveness of pulsed electrical stimulation in the management of osteoarthritis of the knee: results of a double-blind, randomized, placebo-controlled, repeated-measures trial.
      , unclear in another
      • Thamsborg G.
      • Florescu A.
      • Oturai P.
      • Fallentin E.
      • Tritsaris K.
      • Dissing S.
      Treatment of knee osteoarthritis with pulsed electromagnetic fields: a randomized, double-blind, placebo-controlled study.
      and high in the other five studies
      • Garland D.
      • Holt P.
      • Harrington J.T.
      • Caldwell J.
      • Zizic T.
      • Cholewczynski J.
      A 3-month, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a highly optimized, capacitively coupled, pulsed electrical stimulator in patients with osteoarthritis of the knee.
      • Özgüçlü E.
      • Cetin A.
      • Cetin M.
      • Calp E.
      Additional effect of pulsed electromagnetic field therapy on knee osteoarthritis treatment: a randomized, placebo-controlled study.
      • Ay S.
      • Evcik D.
      The effects of pulsed electromagnetic fields in the treatment of knee osteoarthritis: a randomized, placebo-controlled trial.
      • Trock D.H.
      • Bollet A.J.
      • Markoll R.
      The effect of pulsed electromagnetic fields in the treatment of osteoarthritis of the knee and cervical spine. Report of randomized, double blind, placebo controlled trials.
      • Pipitone N.
      • Scott D.L.
      Magnetic pulse treatment for knee osteoarthritis: a randomised, double-blind, placebo-controlled study.
      . As a result, risk of bias across the studies is high. The raw agreement between the reviewers in evaluating the risk of bias domains was 89.5% (κ = 0.81). Publication bias was not detected in the funnel plots of the primary outcomes, since they are relatively symmetrical as shown in Fig. 2 for pain.
      Table IIMethodological quality of included studies
      TrialsRandom sequence generationKey domainsOverall risk of bias
      Allocation concealmentBlinding of participantBlinding of care providerBlinding of outcome assessorIncomplete outcome dataSelective reportingOther bias
      Trock et al.
      • Trock D.H.
      • Bollet A.J.
      • Markoll R.
      The effect of pulsed electromagnetic fields in the treatment of osteoarthritis of the knee and cervical spine. Report of randomized, double blind, placebo controlled trials.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      High
      Unclear if high or low risk of bias.
      Low
      Low risk of bias.
      High
      Unclear if high or low risk of bias.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      High
      Unclear if high or low risk of bias.
      Pipitone and Scott
      • Pipitone N.
      • Scott D.L.
      Magnetic pulse treatment for knee osteoarthritis: a randomised, double-blind, placebo-controlled study.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      High
      Unclear if high or low risk of bias.
      Low
      Low risk of bias.
      High
      Unclear if high or low risk of bias.
      Thamsbor et al.g
      • Thamsborg G.
      • Florescu A.
      • Oturai P.
      • Fallentin E.
      • Tritsaris K.
      • Dissing S.
      Treatment of knee osteoarthritis with pulsed electromagnetic fields: a randomized, double-blind, placebo-controlled study.
      Unclear
      High risk of bias.
      Unclear
      High risk of bias.
      Low
      Low risk of bias.
      Unclear
      High risk of bias.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      Unclear
      High risk of bias.
      Garland et al.
      • Garland D.
      • Holt P.
      • Harrington J.T.
      • Caldwell J.
      • Zizic T.
      • Cholewczynski J.
      A 3-month, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a highly optimized, capacitively coupled, pulsed electrical stimulator in patients with osteoarthritis of the knee.
      High
      Unclear if high or low risk of bias.
      High
      Unclear if high or low risk of bias.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      Unclear
      High risk of bias.
      High
      Unclear if high or low risk of bias.
      Ay and Evcik
      • Ay S.
      • Evcik D.
      The effects of pulsed electromagnetic fields in the treatment of knee osteoarthritis: a randomized, placebo-controlled trial.
      High
      Unclear if high or low risk of bias.
      Unclear
      High risk of bias.
      High
      Unclear if high or low risk of bias.
      High
      Unclear if high or low risk of bias.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      Unclear
      High risk of bias.
      High
      Unclear if high or low risk of bias.
      Özgüçlü et al.
      • Özgüçlü E.
      • Cetin A.
      • Cetin M.
      • Calp E.
      Additional effect of pulsed electromagnetic field therapy on knee osteoarthritis treatment: a randomized, placebo-controlled study.
      Low
      Low risk of bias.
      High
      Unclear if high or low risk of bias.
      Low
      Low risk of bias.
      High
      Unclear if high or low risk of bias.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      High
      Unclear if high or low risk of bias.
      Low
      Low risk of bias.
      High
      Unclear if high or low risk of bias.
      Fary et al.
      • Fary R.E.
      • Carroll G.J.
      • Briffa T.G.
      • Briffa N.K.
      The effectiveness of pulsed electrical stimulation in the management of osteoarthritis of the knee: results of a double-blind, randomized, placebo-controlled, repeated-measures trial.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      Low
      Low risk of bias.
      Low risk of bias.
      Unclear if high or low risk of bias.
      High risk of bias.
      Figure thumbnail gr2
      Fig. 2Funnel plot for the seven included studies for the pain outcome.

      Effects of interventions

      Table III demonstrates an overall summary of the effects of PEMF and PES on all outcomes of interest.
      Table IIISummary of Findings
      OutcomesSMD and RR (95% CI) compared to the control groupSample Size (no. of studies)Quality of the evidence
      GRADE Working Group grades of evidence, High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
      Inconsistency, I2
      |Inconsistency across studies; up to 40%, might not be important; 30–60%, may represent moderate heterogeneity; 50–90%, may represent substantial heterogeneity.
      Heterogeneity, χ2, P value
      Chi-square P value; <0.1, statistical significant heterogeneity; ≥0.1, non-significant heterogeneity.
      Outcome specific risk of bias
      Pain reduction

      VAS
      • Trock D.H.
      • Bollet A.J.
      • Markoll R.
      The effect of pulsed electromagnetic fields in the treatment of osteoarthritis of the knee and cervical spine. Report of randomized, double blind, placebo controlled trials.
      • Ay S.
      • Evcik D.
      The effects of pulsed electromagnetic fields in the treatment of knee osteoarthritis: a randomized, placebo-controlled trial.
      and WOMAC pain subscale
      • Garland D.
      • Holt P.
      • Harrington J.T.
      • Caldwell J.
      • Zizic T.
      • Cholewczynski J.
      A 3-month, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a highly optimized, capacitively coupled, pulsed electrical stimulator in patients with osteoarthritis of the knee.
      • Fary R.E.
      • Carroll G.J.
      • Briffa T.G.
      • Briffa N.K.
      The effectiveness of pulsed electrical stimulation in the management of osteoarthritis of the knee: results of a double-blind, randomized, placebo-controlled, repeated-measures trial.
      • Özgüçlü E.
      • Cetin A.
      • Cetin M.
      • Calp E.
      Additional effect of pulsed electromagnetic field therapy on knee osteoarthritis treatment: a randomized, placebo-controlled study.
      • Thamsborg G.
      • Florescu A.
      • Oturai P.
      • Fallentin E.
      • Tritsaris K.
      • Dissing S.
      Treatment of knee osteoarthritis with pulsed electromagnetic fields: a randomized, double-blind, placebo-controlled study.
      • Pipitone N.
      • Scott D.L.
      Magnetic pulse treatment for knee osteoarthritis: a randomised, double-blind, placebo-controlled study.


      Follow-up: 2–26 weeks
      0.08 SD higher (−0.17 to 0.32)459 (seven studies)Very low
      Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
      43%0.1High risk of bias of the included studies, high results' heterogeneity, small sample size and wide CI
      Physical function

      WOMAC physical function
      • Garland D.
      • Holt P.
      • Harrington J.T.
      • Caldwell J.
      • Zizic T.
      • Cholewczynski J.
      A 3-month, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a highly optimized, capacitively coupled, pulsed electrical stimulator in patients with osteoarthritis of the knee.
      • Fary R.E.
      • Carroll G.J.
      • Briffa T.G.
      • Briffa N.K.
      The effectiveness of pulsed electrical stimulation in the management of osteoarthritis of the knee: results of a double-blind, randomized, placebo-controlled, repeated-measures trial.
      • Özgüçlü E.
      • Cetin A.
      • Cetin M.
      • Calp E.
      Additional effect of pulsed electromagnetic field therapy on knee osteoarthritis treatment: a randomized, placebo-controlled study.
      • Thamsborg G.
      • Florescu A.
      • Oturai P.
      • Fallentin E.
      • Tritsaris K.
      • Dissing S.
      Treatment of knee osteoarthritis with pulsed electromagnetic fields: a randomized, double-blind, placebo-controlled study.
      • Pipitone N.
      • Scott D.L.
      Magnetic pulse treatment for knee osteoarthritis: a randomised, double-blind, placebo-controlled study.
      lequesne index
      • Ay S.
      • Evcik D.
      The effects of pulsed electromagnetic fields in the treatment of knee osteoarthritis: a randomized, placebo-controlled trial.
      ADL
      • Trock D.H.
      • Bollet A.J.
      • Markoll R.
      The effect of pulsed electromagnetic fields in the treatment of osteoarthritis of the knee and cervical spine. Report of randomized, double blind, placebo controlled trials.


      Follow-up: 2–26 weeks
      0.22 SD higher (0.04–0.41)456 (7 studies)Low
      Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
      0%0.45High risk of bias of the included studies, small sample size and wide CI
      Adverse event

      Skin rash
      • Garland D.
      • Holt P.
      • Harrington J.T.
      • Caldwell J.
      • Zizic T.
      • Cholewczynski J.
      A 3-month, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a highly optimized, capacitively coupled, pulsed electrical stimulator in patients with osteoarthritis of the knee.
      • Fary R.E.
      • Carroll G.J.
      • Briffa T.G.
      • Briffa N.K.
      The effectiveness of pulsed electrical stimulation in the management of osteoarthritis of the knee: results of a double-blind, randomized, placebo-controlled, repeated-measures trial.


      Follow-up: 12–26 weeks
      RR 0.96 (0.45–2.03)128 (2 studies)Very low
      Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
      0%0.78High risk of bias in the included studies, very small sample size and wide CI
      Patient global assessment

      VAS
      • Garland D.
      • Holt P.
      • Harrington J.T.
      • Caldwell J.
      • Zizic T.
      • Cholewczynski J.
      A 3-month, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a highly optimized, capacitively coupled, pulsed electrical stimulator in patients with osteoarthritis of the knee.
      • Fary R.E.
      • Carroll G.J.
      • Briffa T.G.
      • Briffa N.K.
      The effectiveness of pulsed electrical stimulation in the management of osteoarthritis of the knee: results of a double-blind, randomized, placebo-controlled, repeated-measures trial.
      • Trock D.H.
      • Bollet A.J.
      • Markoll R.
      The effect of pulsed electromagnetic fields in the treatment of osteoarthritis of the knee and cervical spine. Report of randomized, double blind, placebo controlled trials.


      Follow-up: 6–26 weeks
      0.26 SD higher (−0.14, 0.66)209 (3 studies)Very low
      Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
      61%0.08High risk of bias of the included studies, results' inconsistency, small sample size and wide CI
      Quality of life

      SF36
      • Fary R.E.
      • Carroll G.J.
      • Briffa T.G.
      • Briffa N.K.
      The effectiveness of pulsed electrical stimulation in the management of osteoarthritis of the knee: results of a double-blind, randomized, placebo-controlled, repeated-measures trial.
      and EQOL
      • Pipitone N.
      • Scott D.L.
      Magnetic pulse treatment for knee osteoarthritis: a randomised, double-blind, placebo-controlled study.


      Follow-up: 6–26 weeks
      Highly heterogeneous result139 (2 studies)Very low
      Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
      84%0.01High results' heterogeneity, small sample size and wide CI
      Physician global assessment

      VAS
      • Trock D.H.
      • Bollet A.J.
      • Markoll R.
      The effect of pulsed electromagnetic fields in the treatment of osteoarthritis of the knee and cervical spine. Report of randomized, double blind, placebo controlled trials.


      Follow-up: 6 weeks
      0.46 SD higher (0.02, 0.90)81 (1 study)Very low
      Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
      Only one study includedOnly one study includedHigh risk of incomplete data in the included study, very small sample size and wide CI
      VAS, Visual analogue scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index; ADL, Activity of daily life questionnaire; EQOL, Euro-quality of life questionnaire.
      GRADE Working Group grades of evidence, High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
      |Inconsistency across studies; up to 40%, might not be important; 30–60%, may represent moderate heterogeneity; 50–90%, may represent substantial heterogeneity.
      Chi-square P value; <0.1, statistical significant heterogeneity; ≥0.1, non-significant heterogeneity.
      § Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

      Primary outcomes

      In seven RCTs included for meta-analysis, pain was assessed in a total of 459 participants randomized to an active PEMF/PES group (n = 239) and a placebo PEMF/PES group (n = 220). No difference between groups was observed (SMD = 0.08, 95% CI: −0.17, 0.32, P = 0.55) as illustrated in Fig. 3. Overall, the strength of the body of evidence for the pain outcome was judged to be very low for reasons described in Table III.
      Figure thumbnail gr3
      Fig. 3Forest plot for meta-analysis of the effect of pulsed PEMF/PES compared to sham treatment on pain.
      Figure 4 illustrates the beneficial effect of PEMF/PES on physical function (SMD = 0.22, 95% CI: 0.04, 0.41, P = 0.02) in 456 of the participants with knee OA enrolled in the seven RCTs. See Table III for the summary of findings for this outcome including the rationale for judging the strength of the body of evidence as low.
      Figure thumbnail gr4
      Fig. 4Forest plot for meta-analysis of the effect of PEMF/PES compared to sham treatment on physical function.
      Heterogeneity due to pulsed subsensory threshold electrical stimulation types, treatment regimens and sources of funding was hypothesized to influence treatment effect. Five studies used PEMF devices and two studies used PES devices (see Table I). Treatment duration was ≥12 weeks in two studies and <12 weeks in five studies (see Table I). Three studies were funded by industry
      • Garland D.
      • Holt P.
      • Harrington J.T.
      • Caldwell J.
      • Zizic T.
      • Cholewczynski J.
      A 3-month, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a highly optimized, capacitively coupled, pulsed electrical stimulator in patients with osteoarthritis of the knee.
      • Trock D.H.
      • Bollet A.J.
      • Markoll R.
      The effect of pulsed electromagnetic fields in the treatment of osteoarthritis of the knee and cervical spine. Report of randomized, double blind, placebo controlled trials.
      • Pipitone N.
      • Scott D.L.
      Magnetic pulse treatment for knee osteoarthritis: a randomised, double-blind, placebo-controlled study.
      , two were federally funded
      • Fary R.E.
      • Carroll G.J.
      • Briffa T.G.
      • Briffa N.K.
      The effectiveness of pulsed electrical stimulation in the management of osteoarthritis of the knee: results of a double-blind, randomized, placebo-controlled, repeated-measures trial.
      • Thamsborg G.
      • Florescu A.
      • Oturai P.
      • Fallentin E.
      • Tritsaris K.
      • Dissing S.
      Treatment of knee osteoarthritis with pulsed electromagnetic fields: a randomized, double-blind, placebo-controlled study.
      and two studies did not report the source of funding
      • Özgüçlü E.
      • Cetin A.
      • Cetin M.
      • Calp E.
      Additional effect of pulsed electromagnetic field therapy on knee osteoarthritis treatment: a randomized, placebo-controlled study.
      • Ay S.
      • Evcik D.
      The effects of pulsed electromagnetic fields in the treatment of knee osteoarthritis: a randomized, placebo-controlled trial.
      . The results of subgroup analyses for pain and physical function outcomes are shown in Table IV.
      Table IVSummary of SMD, inconsistency (I2), and heterogeneity (χ2, P value) on subgroup analyses for pain and physical function outcomes
      Subgroup analysesPainPhysical function
      SMD (95% CI)I2
      Inconsistency across studies; up to 40%, might not be important; 30–60%, may represent moderate heterogeneity; 50–90%, may represent substantial heterogeneity.
      χ2, P value
      Chi-square P value; <0.1, statistical significant heterogeneity; ≥0.1, non-significant heterogeneity.
      SMD (95% CI)I2
      Inconsistency across studies; up to 40%, might not be important; 30–60%, may represent moderate heterogeneity; 50–90%, may represent substantial heterogeneity.
      χ2, P value
      Chi-square P value; <0.1, statistical significant heterogeneity; ≥0.1, non-significant heterogeneity.
      Type
      PEMF
      • Özgüçlü E.
      • Cetin A.
      • Cetin M.
      • Calp E.
      Additional effect of pulsed electromagnetic field therapy on knee osteoarthritis treatment: a randomized, placebo-controlled study.
      • Ay S.
      • Evcik D.
      The effects of pulsed electromagnetic fields in the treatment of knee osteoarthritis: a randomized, placebo-controlled trial.
      • Thamsborg G.
      • Florescu A.
      • Oturai P.
      • Fallentin E.
      • Tritsaris K.
      • Dissing S.
      Treatment of knee osteoarthritis with pulsed electromagnetic fields: a randomized, double-blind, placebo-controlled study.
      • Trock D.H.
      • Bollet A.J.
      • Markoll R.
      The effect of pulsed electromagnetic fields in the treatment of osteoarthritis of the knee and cervical spine. Report of randomized, double blind, placebo controlled trials.
      • Pipitone N.
      • Scott D.L.
      Magnetic pulse treatment for knee osteoarthritis: a randomised, double-blind, placebo-controlled study.
      0.08 (−0.19, 0.35)36%0.180.24 (0.02, 0.46)0%0.70
      PES
      • Garland D.
      • Holt P.
      • Harrington J.T.
      • Caldwell J.
      • Zizic T.
      • Cholewczynski J.
      A 3-month, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a highly optimized, capacitively coupled, pulsed electrical stimulator in patients with osteoarthritis of the knee.
      • Fary R.E.
      • Carroll G.J.
      • Briffa T.G.
      • Briffa N.K.
      The effectiveness of pulsed electrical stimulation in the management of osteoarthritis of the knee: results of a double-blind, randomized, placebo-controlled, repeated-measures trial.
      0.09 (−0.67, 0.85)77%0.040.21 (−0.47, 0.89)71%0.06
      Treatment duration
      ≥12 Weeks
      • Garland D.
      • Holt P.
      • Harrington J.T.
      • Caldwell J.
      • Zizic T.
      • Cholewczynski J.
      A 3-month, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a highly optimized, capacitively coupled, pulsed electrical stimulator in patients with osteoarthritis of the knee.
      • Fary R.E.
      • Carroll G.J.
      • Briffa T.G.
      • Briffa N.K.
      The effectiveness of pulsed electrical stimulation in the management of osteoarthritis of the knee: results of a double-blind, randomized, placebo-controlled, repeated-measures trial.
      0.09 (−0.67, 0.85)77%0.040.21 (−0.47, 0.89)71%0.06
      <12 Weeks
      • Özgüçlü E.
      • Cetin A.
      • Cetin M.
      • Calp E.
      Additional effect of pulsed electromagnetic field therapy on knee osteoarthritis treatment: a randomized, placebo-controlled study.
      • Ay S.
      • Evcik D.
      The effects of pulsed electromagnetic fields in the treatment of knee osteoarthritis: a randomized, placebo-controlled trial.
      • Thamsborg G.
      • Florescu A.
      • Oturai P.
      • Fallentin E.
      • Tritsaris K.
      • Dissing S.
      Treatment of knee osteoarthritis with pulsed electromagnetic fields: a randomized, double-blind, placebo-controlled study.
      • Trock D.H.
      • Bollet A.J.
      • Markoll R.
      The effect of pulsed electromagnetic fields in the treatment of osteoarthritis of the knee and cervical spine. Report of randomized, double blind, placebo controlled trials.
      • Pipitone N.
      • Scott D.L.
      Magnetic pulse treatment for knee osteoarthritis: a randomised, double-blind, placebo-controlled study.
      0.08 (−0.19, 0.35)36%0.180.24 (0.02, 0.46)0%0.70
      Funding
      Industry
      • Garland D.
      • Holt P.
      • Harrington J.T.
      • Caldwell J.
      • Zizic T.
      • Cholewczynski J.
      A 3-month, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a highly optimized, capacitively coupled, pulsed electrical stimulator in patients with osteoarthritis of the knee.
      • Trock D.H.
      • Bollet A.J.
      • Markoll R.
      The effect of pulsed electromagnetic fields in the treatment of osteoarthritis of the knee and cervical spine. Report of randomized, double blind, placebo controlled trials.
      • Pipitone N.
      • Scott D.L.
      Magnetic pulse treatment for knee osteoarthritis: a randomised, double-blind, placebo-controlled study.
      6.63 (−2.66, 15.91)74%0.023.65 (0.57, 6.73)33%0.23
      Non-industry
      • Fary R.E.
      • Carroll G.J.
      • Briffa T.G.
      • Briffa N.K.
      The effectiveness of pulsed electrical stimulation in the management of osteoarthritis of the knee: results of a double-blind, randomized, placebo-controlled, repeated-measures trial.
      • Özgüçlü E.
      • Cetin A.
      • Cetin M.
      • Calp E.
      Additional effect of pulsed electromagnetic field therapy on knee osteoarthritis treatment: a randomized, placebo-controlled study.
      • Ay S.
      • Evcik D.
      The effects of pulsed electromagnetic fields in the treatment of knee osteoarthritis: a randomized, placebo-controlled trial.
      • Thamsborg G.
      • Florescu A.
      • Oturai P.
      • Fallentin E.
      • Tritsaris K.
      • Dissing S.
      Treatment of knee osteoarthritis with pulsed electromagnetic fields: a randomized, double-blind, placebo-controlled study.
      −0.32 (−0.92, 0.28)0%0.470.37 (−1.20, 1.94)0%0.79
      Inconsistency across studies; up to 40%, might not be important; 30–60%, may represent moderate heterogeneity; 50–90%, may represent substantial heterogeneity.
      Chi-square P value; <0.1, statistical significant heterogeneity; ≥0.1, non-significant heterogeneity.

      Adverse events

      Four studies reported few, self-limited adverse events, such as temporary increase in knee pain, foot numbness and paraesthesia, and sensation of warmth. The risk ratio was calculated for mild knee skin rash that was reported two studies (RR = 0.96, 95% CI: 0.45, 2.03, P = 0.91) and is shown in Fig. 5. There was no difference between the experimental and placebo groups in terms of skin rash; however, the strength of this body of evidence was very low as described in Table III.
      Figure thumbnail gr5
      Fig. 5Forest plot for meta-analysis of the effect of PEMF/PES compared to sham treatment on adverse events (skin rash).

      Secondary outcomes

      No RCT reported imaging-based knee joint status outcomes. Table III summarizes the pooled estimates of effects on health-related quality of life and physician global assessment. Figure 6 shows the pooled estimate for effect on patient global assessment reported in three trials (209 participants/knees). As summarized in Table III, precision of the estimate is low (95% CI: −4.39, 18.77) and inconsistency is high.
      Figure thumbnail gr6
      Fig. 6Forest plot for meta-analysis of the effect of PEMF/PES compared to sham treatment on patient global assessment.

      Sensitivity analyses

      The pooled estimates were unchanged by the removal of each study in which change SDs was imputed
      • Özgüçlü E.
      • Cetin A.
      • Cetin M.
      • Calp E.
      Additional effect of pulsed electromagnetic field therapy on knee osteoarthritis treatment: a randomized, placebo-controlled study.
      • Ay S.
      • Evcik D.
      The effects of pulsed electromagnetic fields in the treatment of knee osteoarthritis: a randomized, placebo-controlled trial.
      • Thamsborg G.
      • Florescu A.
      • Oturai P.
      • Fallentin E.
      • Tritsaris K.
      • Dissing S.
      Treatment of knee osteoarthritis with pulsed electromagnetic fields: a randomized, double-blind, placebo-controlled study.
      .

      Quality of evidence

      The strength of the body of evidence was assessed using the criteria recommended by the GRADE Working Group
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • Kunz R.
      • Falck-Ytter Y.
      • Alonso-Coello P.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      . The strength of the body of evidence of all outcomes was reduced by high risk of bias, small sample size (imprecision) and inconsistency of the results (high I2 value). The strength of the body of evidence is low for physical function and very low for the other outcomes.

      Discussion

      The main finding of this systematic review and meta-analysis is that PEMF/PES treatment improves physical function but does not decrease pain significantly in people with knee OA. Heterogeneity was not a significant problem for pain or physical function outcomes and subgroup analyses show that the effect estimates are similar regardless of the type of pulsed subsensory threshold electrical stimulation (PEMF and PES) and length of treatment (<12 and ≥12 weeks). The effect sizes for pain and physical function outcomes in the three studies funded by industry were larger and more inconsistent compared to the four studies that were not funded by industry. The strength of the body of evidence is low for physical function indicating that further research is very likely to have an important impact on our confidence in the effect estimate and is likely to change the estimate. The very low strength of the body of evidence regarding the effect on pain creates great uncertainty about the estimate and future research is expected to change the estimated effect.
      The proposed mechanism of action of PEMF and PES is to enhance articular cartilage regeneration
      • Ciombor D.M.
      • Aaron R.K.
      • Wang S.
      • Simon B.
      Modification of osteoarthritis by pulsed electromagnetic field – a morphological study.
      . Because articular cartilage is poorly innervated and vascularized, it follows that this intervention may not decrease knee OA pain. Pain is perceived due to stimulation of unmyelinated and small myelinated nerve fibres in the joint and surrounding tissues such as the joint capsule, ligaments, synovium, bone and the outer edge of the menisci
      • Felson D.T.
      The sources of pain in knee osteoarthritis.
      . Moreover, central sensitization (hyperexcitability of neurones in the central nervous system) has been observed in people with chronic pain due to knee OA
      • Imamura M.
      • Imamura S.T.
      • Kaziyama H.H.
      • Targino R.A.
      • Hsing W.T.
      • de Souza L.P.
      • et al.
      Impact of nervous system hyperalgesia on pain, disability, and quality of life in patients with knee osteoarthritis: a controlled analysis.
      . Chronic pain is a multidimensional problem
      • Davidson M.A.
      • Tripp D.A.
      • Fabrigar L.R.
      • Davidson P.R.
      Chronic pain assessment: a seven-factor model.
      resulting in changes in brain areas active in sensorimotor function, affect and cognition
      • Felson D.T.
      The sources of pain in knee osteoarthritis.
      . Even if future research demonstrates that PEMF/PES have a small effect on pain, this effect may be of minimal clinical significance without a corresponding intervention that addresses changes in the central nervous system.
      All reported adverse events were mild and self-limited. Skin rash was the most frequently reported adverse event and rates were similar for both the active and sham PEMF/PES stimulation groups. The two studies that reported skin rash used PES devices and the longest treatment session (7 h daily). Therefore, skin rash may be a problem for people using the PES device or may be related to the duration of contact between the electrodes and the skin. As a result, caution is warranted when applying the PES device to the knee of people prone to skin irritation. Overall, low frequency PEMF/PES appears to be safe for use in people with knee OA.
      Few studies reported on our secondary outcomes of interest. Patient global assessment was reported in three studies and there was no difference between groups. Only two studies reported health-related quality of life and the pooled studies were highly heterogeneous (Table III). Physician global assessment was reported in a single study that showed the effectiveness of PEMF/PES in improving this outcome. However, we have to interpret the improvement in physician global assessment with caution because the study was small and of low quality (Table III). No study reported imaging-based knee joint status outcomes. High quality studies are needed to evaluate the effectiveness of PEMF/PES on knee joint status, physician global assessment; patient global assessment and health-related quality of life.
      Follow-up rates across the included studies ranged from 75% to 100% and studies reported compliance rates varying from 63% to 75%. These rates for follow-up and compliance suggest that PEMF/PES has acceptable tolerability in the knee OA population. Considering that three of the included studies used self-applied devices, PEMF/PES may be a useful self-management tool for people with knee OA to improve physical function.
      Our findings confirm and extend those reported in the meta-analysis conducted by Vavken et al. (2009)
      • Vavken P.
      • Arrich F.
      • Schuhfried O.
      • Dorotka R.
      Effectiveness of pulsed electromagnetic field therapy in the management of osteoarthritis of the knee: a meta-analysis of randomized controlled trials.
      and We et al. (2012)
      • We S.R.
      • Koog Y.H.
      • Jeong K.I.
      • Wi H.
      Effects of Pulsed Electromagnetic Field on Knee Osteoarthritis: a Systematic Review.
      . Our review includes data for an additional 128 participants/knees that were not reported in the other reviews. Moreover, our study had important differences in methodology that provide greater confidence in the estimates of effect. The review by Vavken et al. (2009) included high and low frequency PEMF/PES and we excluded studies that used high frequency PEMF and did not report outcomes for participants with knee OA separate from those with hand and ankle OA. Vavken et al. (2009) used the end point clinical scores and weighted mean difference to combine scores of different scales in their statistical analysis, which is inappropriate. We used the change mean to balance any differences in baseline values between the study groups and SMD to combine scores of different scales. We et al. (2012) included trials administering either high or low frequency PEMF and did not perform subgroup analysis based on frequency. Sixteen sensitivity analyses were reported to determine efficacy on pain at 4 weeks (0–2 weeks prior to completion of the intervention) and 8 weeks (2 weeks following completion of the intervention). It is unclear if these analyses were planned a priori
      • Sun X.
      • Briel M.
      • Walter S.D.
      • Guyatt G.H.
      Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses.
      . Two of low frequency PEMF trials included in the review by We et al.
      • We S.R.
      • Koog Y.H.
      • Jeong K.I.
      • Wi H.
      Effects of Pulsed Electromagnetic Field on Knee Osteoarthritis: a Systematic Review.
      were excluded from our systematic review because of our eligibility criteria (lack of participant blinding and English language limit). Despite these differences, the main results regarding efficacy of PEMF/PES on physical function, but not pain, are consistent.
      The methodological rigour adopted in the review process is the main strength of this meta-synthesis. For example, a comprehensive search strategy and duplicate assessment of eligibility, extraction of data, assessment of risk of bias and judgement of the strength of the body of evidence were conducted. A data extraction form was developed and piloted for consistency between the two reviewers extracting data from the studies. In contrast to the overall risk of bias, six of the included studies had a low risk of bias due to blinding of participants and all seven included studies had low risk of bias due to blinding of outcome assessors. This is critical to the validity of the estimated effects on outcomes since lack of blinding is likely to inflate the effect size
      • Schulz K.F.
      • Chalmers I.
      • Altman D.G.
      The landscape and lexicon of blinding in randomized trials.
      . These factors are strengths in our review; we hypothesize that inclusion of future larger trials will increase the confidence that PEMF/PES is effective for improving physical function and a small effect on pain may emerge.
      Limitations need to be considered in interpreting the results of our review. At the level of the included trials, there is variability in treatment duration, number of sessions, treatment setting (where the treatment was provided and by whom), frequency, reported units and other parameters of PEMF/PES. Furthermore, no trials reported dose parameters at the skin surface. Therefore, we are unable to determine the therapeutic window or recommend a specific treatment protocol for administrating PEMF/PES. The small number and size of trials precluded focussing inclusion criteria further. Five of the seven included trials had a high risk of bias. Few to no studies collected data related to our secondary outcomes of interest. To examine the proposed mechanism of PEMF/PES on enhancing cartilage regeneration, future studies need to include outcome measures that detect cartilage metabolism or change in morphology. At the review level, our literature search was limited to the English language which may have excluded relevant literature and bias the results. Some studies were excluded from our review due to missing methodological and statistical details; therefore, we urge future publications of RCTs to follow the CONSORT statement reporting guidelines for non-pharmacologic treatments
      • Boutron I.
      • Moher D.
      • Altman D.G.
      • Schulz K.F.
      • Ravaud P.
      • CONSORT G.
      Methods and processes of the CONSORT group: example of an extension for trials assessing nonpharmacologic treatments.
      .

      Conclusion

      Our results suggest that low frequency (≤100 Hz) pulsed subsensory threshold electrical stimulation produced either through PEMF/PES vs sham PEMF/PES is effective in improving physical function but not pain intensity at treatment completion in adults with knee OA blinded to treatment. We cannot give a conclusion about the effect of this treatment on the secondary outcomes due to the small numbers of studies that reported them. PEMF/PES is associated with few, self-limited adverse events such as skin rash. More studies are needed to confirm and extend the findings of this systematic review.

      Author contributions

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

      Conflict of interest

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

      Appendix A.

      Search strategies

      Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) <1946 to week 1 April 2012>
      • 1
        exp Electric Stimulation Therapy/or Pulsed electrical stimulation treatment.mp. (52016)
      • 2
        electromagnetics.mp. or exp Electromagnetic Phenomena/ (308044)
      • 3
        electromagnetic$.tw. (18146)
      • 4
        exp electric stimulation therapy/ (52016)
      • 5
        electrical stimulation.tw. (34065)
      • 6
        exp Electromagnetic Phenomena/or exp Electric Stimulation Therapy/or exp Electromagnetic Fields/or pulsed electromagnetic.mp. or exp Magnetic Field Therapy/ (363141)
      • 7
        osteoarthritis.mp. or exp Osteoarthritis/or exp Osteoarthritis, Knee/ (47206)
      • 8
        Knee osteoarthritis.mp. or exp Osteoarthritis, Knee/ (8830)
      • 9
        exp Osteoarthritis/or gonarthrosis.mp. or exp Osteoarthritis, Knee/ (38215)
      • 10
        1 or 2 or 3 or 4 or 5 or 6 (401885)
      • 11
        7 or 8 or 9 (47510)
      • 12
        10 and 11 (414)
      • 13
        limit 12 to (english language and humans and randomized controlled trial) (78)
      Database: Embase <1974 to 2012 April>
      • 1
        Electric Stimulation Therapy.mp. or exp electrostimulation therapy/ (147605)
      • 2
        Electromagnetics.mp. or exp electromagnetic field/ (15534)
      • 3
        Electromagnetic Phenomena.mp. or exp electromagnetic field/ (15496)
      • 4
        Electromagnetic.mp. or exp electromagnetic field/ (28950)
      • 5
        electric stimulation therapy.mp. or exp electrostimulation therapy/ (147605)
      • 6
        Electrical stimulation.mp. or exp electrostimulation/ (89918)
      • 7
        exp pulsed electric field/or exp electromagnetic field/or exp electrostimulation therapy/or pulsed electromagnetic.mp. (162787)
      • 8
        [limit 15 to (human and english language and randomized controlled trial and english)] (0)
      • 9
        Electric Stimulation Therapy.mp. or exp electrostimulation therapy/ (147605)
      • 10
        Electromagnetics.mp. or exp electromagnetic field/ (15534)
      • 11
        Electromagnetic Phenomena.mp. or exp electromagnetic field/ (15496)
      • 12
        Electromagnetic.mp. or exp electromagnetic field/ (28950)
      • 13
        electric stimulation therapy.mp. or exp electrostimulation therapy/ (147605)
      • 14
        Electrical stimulation.mp. or exp electrostimulation/ (89918)
      • 15
        exp pulsed electric field/or exp electromagnetic field/or exp electrostimulation therapy/or pulsed electromagnetic.mp. (162787)
      • 16
        Magnetic Field Therapy.mp. or exp magnetotherapy/ (638)
      • 17
        exp electromagnetic field/or exp electrostimulation/or exp electrostimulation therapy/or Pulsed electrical stimulation treatment.mp. (223854)
      • 18
        exp knee osteoarthritis/or Osteoarthritis.mp. or exp osteoarthritis/ (76544)
      • 19
        Knee osteoarthritis.mp. or exp knee osteoarthritis/ (13867)
      • 20
        gonarthrosis.mp. or exp knee osteoarthritis/ (13885)
      • 21
        9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 (250541)
      • 22
        18 or 19 or 20 (76774)
      • 23
        21 and 22 (1007)
      • 24
        limit 23 to (human and english language and randomized controlled trial and english) (137)
      Database: AMED (Allied and Complementary Medicine) <1985 to April 2012>
      • 1
        exp Electric Stimulation Therapy/or Pulsed electrical stimulation treatment.mp. (0)
      • 2
        electromagnetics.mp. or exp Electromagnetic Phenomena/ (190)
      • 3
        electromagnetic$.tw. (712)
      • 4
        exp electric stimulation therapy/ (0)
      • 5
        electrical stimulation.tw. (1363)
      • 6
        exp Electromagnetic Phenomena/or exp Electric Stimulation Therapy/or exp Electromagnetic Fields/or pulsed electromagnetic.mp. or exp Magnetic Field Therapy/ (221)
      • 7
        osteoarthritis.mp. or exp Osteoarthritis/or exp Osteoarthritis, Knee/ (2205)
      • 8
        Knee osteoarthritis.mp. or exp Osteoarthritis, Knee/ (595)
      • 9
        exp Osteoarthritis/or gonarthrosis.mp. or exp Osteoarthritis, Knee/ (1612)
      • 10
        1 or 2 or 3 or 4 or 5 or 6 (2063)
      • 11
        7 or 8 or 9 (2227)
      • 12
        10 and 11 (26)
      • 13
        limit 12 to (english language and humans and randomized controlled trial) [Limit not valid; records were retained] (25)
      Database: CINAHL (EBSCOHost Search engine) (up to April 2012)
      • S14
        S11 and S12 Limiters – English Language; Human; Randomized Controlled Trial; Publication Type: Randomized Controlled Trial; Language: English
      • S13
        S11 and S126
      • S12
        S1 or S2 or S3 or S4 or S5 or S6 or S7 or S1045
      • S11
        (MH “Osteoarthritis, Knee”) OR “Knee osteoarthritis”8521
      • S10
        (MH “Magnet Therapy”) OR “Magnetic Field Therapy”1952
      • S9
        (MH “Electrophoresis, Gel, Pulsed-Field”) OR (MH “Electromagnetic Fields”) OR (MH “Electromagnetics+”) OR “pulsed electromagnetic field”632
      • S8
        (MH “Electrophoresis, Gel, Pulsed-Field”) OR (MH “Electromagnetic Fields”) OR (MH “Electromagnetics+”) OR “pulsed electromagnetic field”1674
      • S7
        (MH “Electrophoresis, Gel, Pulsed-Field”) OR (MH “Electromagnetic Fields”) OR (MH “Electromagnetics+”) OR “pulsed electromagnetic field”1674
      • S6
        (MH “Electromagnetic Fields”) OR (MH “Electromagnetics+”) OR (MH “Magnet Therapy”)1674
      • S5
        (MH “Electromagnetics+”) OR (MH “Electromagnetic Fields”) OR “Electromagnetic Phenomena”1812
      • S4
        (MH “Magnet Therapy”) OR (MH “Electric Stimulation+”) OR (MH “Electrical Stimulation, Functional”) OR (MH “Electrical Stimulation, Neuromuscular”) OR “Electric Stimulation Therapy”1226
      • S3
        (MH “Electromagnetics+”) OR “Electromagnetics” OR (MH “Electromagnetic Fields”) OR (MH “Bioelectromagnetic Applications”)6925
      • S2
        (MH “Electric Stimulation+”) OR (MH “Electrical Stimulation, Functional”) OR (MH “Electrical Stimulation, Neuromuscular”) OR “Pulsed electrical stimulation treatment”1246
      • S1
        (MH “Magnet Therapy”) OR (MH “Electric Stimulation+”) OR (MH “Electrical Stimulation, Functional”) OR (MH “Electrical Stimulation, Neuromuscular”) OR “Electric Stimulation Therapy”6383
      Database: Cochrane Central Register of Controlled Trials (up to April 2012)
      • #1
        knee osteoarthritis:ti,ab,kw in Trials2265
      • #2
        pulsed electromagnetic field:ti,ab,kw in Trials
      • #3
        pulsed electrical stimulation:ti,ab,kw in Trials
      • #4
        (#1 AND (#2 OR #3))29

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