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Resúmenes Epistemonikos
Medwave 2017 Nov-Dic;17(9):e7109 doi: 10.5867/medwave.2017.09.7109
¿Es el ultrasonido de onda pulsátil una alternativa en el tratamiento de la artrosis?
Is pulsed ultrasound an alternative for osteoarthritis?
Joaquín Ananías, Diego Ubilla, Sebastián Irarrázaval, Luis Ortiz-Muñoz
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Abstract

INTRODUCTION
Many osteoarthritis patients persist symptomatic despite nonsurgical treatment. Pulsed ultrasound might be a viable alternative for such cases, but its real clinical relevance remains unclear.

METHODS
A literature review was conducted in Epistemonikos, the largest database for sys-tematic reviews in health that compiles multiple sources, including MEDLINE, EMBASE, and Cochrane, among others. Relevant data were extracted, and infor-mation from the primary studies was reanalyzed. A subsequent meta-analysis was conducted, and summary of findings tables were constructed using the GRADE methodology.

RESULTS AND CONCLUSIONS
Six systematic reviews including eight randomized trials were identified. In conclusion, it is not clear whether pulsed ultrasound improves functionality, and it might slightly decrease pain but the certainty of the evidence is low.


 
Problem

Osteoarthritis is a highly prevalent disease worldwide and a frequent cause of medical consultation for both, primary care and specialists. The persistence of pain despite nonsurgical treatment is one reason for such consults, and no clearly established alternatives exist for pain management.

Pulsed ultrasound corresponds to the use of sound waves in order to relieve pain or disability. For this purpose, it can direct the beam with a transducer over the area to be treated and it is interrupted in the form of pulsations, allowing higher intensities in order to have a greater effect.

There is no precise information about side effects of the use of therapeutic ultrasound, possibly because they do not exist, or they are very infrequent and related to the use in supra physiological intensities.

Methods

To answer the question, we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others, to identify systematic reviews and their included primary studies. We extracted data from the identified reviews and reanalyzed data from primary studies included in those reviews. With this information, we generated a structured summary denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos) using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies when it is possible, a summary of findings table following the GRADE approach and a table of other considerations for decision-making. 

Key messages

  • Pulsed ultrasound could lead to a small decrease in pain in osteoarthritis, but the certainty of the evidence is low.
  • It is not clear if the use of pulsed ultrasound produces an improvement in functionality in patients with osteoarthritis, because the certainty of the evi-dence is very low.
About the body of evidence for this question

What is the evidence.
See evidence matrix  in Epistemonikos later

We found six systematic reviews [1],[2],[3],[4],[5],[6] including eight studies overall, corresponding to randomized controlled trials [7],[8],[9],[10],[11],[12],[13],[14].

What types of patients were included*

All of the trials focused on osteoarthritis of the knee.

Average body mass index (BMI) ranged between 28.75 and 32.2 in four trials [7],[8],[11],[14] and four did not report it [9],[10],[12],[13]. Average age of the participants ranged between 57 and 65 years in the different trials. 

The proportion of women was between 33 and 100% in the different trials.

What types of interventions were included*

All of the trials used pulsed ultrasound.

One trial used ultrasound with a frequency of 1 MHz and potency of 1.5 W/cm2 in sessions of twelve minutes each, for two weeks (10 sessions in total) [7].

One trial used ultrasound with a frequency of 1 MHz and potency of 1.5 W/cm2 in sessions of fifteen minutes each, for eight weeks (24 sessions in total) [9].

One trial used ultrasound with a frequency of 1 MHz and potency of 2.5 W/cm2 in sessions of fifteen minutes each, three times a week for eight weeks (24 sessions in total) [10].

One trial used ultrasound with a frequency of 1 MHz and potency of 0.2 W/cm2 in sessions of nine and a half minutes each, for eight weeks (24 sessions in total) [11].

One trial used ultrasound with a frequency of 2.5 MHz in sessions of fifteen minutes each, for eight weeks (24 sessions in total) [13].

One trial used ultrasound with a frequency of 1 MHz and potency of 2 W/cm2 in sessions of five minutes each, for two weeks (10 sessions in total) [14].

Two trials did not describe the frequency or the power of the pulsed ultrasound, or the amount of sessions or the duration of them [8],[12].

Two trials associated isokinetic exercises to the pulsed ultrasound [9],[10]. 

Four trials compared against placebo or standard therapy [10],[11],[12],[13]

Four trials compared against placebo and against continued wave ultrasound [7],[8],[9],[14].

What types of outcomes
were measured

The outcomes, as classified in the identified systematic reviews, were as follows: effect on the intensity of pain (analyzed as a decrease or improvement) according to visual analogue scale; knee osteoarthritis severity index established by Lequesne; and sub-scale of physical functionality established by the Western Ontario and McMaster Universities Arthritis Index (WOMAC).

The average follow-up of the trials was 16 weeks with a range between 2 and 52 weeks.

* The information about primary studies is extracted from the systematic reviews identified, unless otherwise specified.

Summary of Findings

The information on the effects of pulsed ultrasound was based on three randomized trials that included 200 patients [8],[9],[10]. The remaining trials were not included in the meta-analysis as none of the identified systematic reviews extracted sufficient trial data. The three evaluated trials reported improvement in pain measured with visual analogue scale, and functionality by Lequesne knee osteoarthritis severity index. The summary of findings is as follows:

  • Pulsed ultrasound could lead to a small decrease in pain in osteoarthritis, but the certainty of the evidence is low.
  • It is not clear if the use of pulsed ultrasound produces an improvement in functionality in patients with osteoarthritis, because the certainty of the evidence is very low.

Visit the following link to access the interactive version of this table (Interactive Summary of Findings - iSoF)

Other considerations for decision-making

To whom this evidence does and does not apply

  • While the intention of this summary was to include osteoarthritis in general, considering all of the possible affected joints, the trials that were found focused specifically on osteoarthritis of the knee.
  • In absence of direct evidence for other joints, we believe that extrapolating the conclusions of this summary could lead to error since the effect of ultrasound depends on the target tissue, and there are other joints deeper(surrounded by more soft tissue) such as hip and shoulder, in which we could assumed a lower intensity of ultrasound and therefore a lesser effect.
  • It is important to emphasize that different primary studies evaluating pulsatile ultrasound used different frequencies and intensities, with different application times and total treatment duration. It is not possible with the existing data to make judgments about the effectiveness of some specific type of pulsatile wave ultrasound.
About the outcomes included in this summary
  • The outcomes included in this summary are those considered critical for decision-making by the authors of this summary. Furthermore, we conducted a search of the Core Outcome Measures in Effectiveness Trials (COMET) Initiative, finding one relevant article [15] that indicated, through a consensus, the following as the most relevant outcomes: joint pain, functionality, quality of life in relation to health, work situation, mortality, reoperation, hospital readmission, and overall satisfaction with the results of the treatment.
Balance between benefits and risks, and certainty of the evidence
  • Although the observed effect over pain is statistically significant, the magnitude of the effect was below the minimally important difference reported in the literature [16]. In the case of functionality by Lequesne index, according to the literature [17] the difference presented in the meta-analysis would be clinically significant, but the certainty of the evidence is very low.
  • In terms of safety, adverse effects have not been described in any of the trials included in this summary, therefore we expanded the search to ultrasound in general. One study described the intention of monitoring the incidence of adverse events associated to the use of continued wave ultrasound and reported absence of major complications [18]. Another study reported absence of adverse events during and after the application of continued wave ultrasound [19].
Resource considerations
  • Although pulsed ultrasound is a widely available therapy and at a cost generally accessible to the majority of the population, it implies a significant amount of time to attend the multiple sessions that are needed.
  • Considering the scarce benefit reported, even when the existing evidence shows no adverse effects, the balance between costs and benefits is not favorable.
What would patients and their doctors think about this intervention
  • Faced with the evidence presented in this summary, most patients and clinicians should lean against the use of this intervention.
  • However, without clearly effective therapeutic alternatives, variation could exist in the clinical decisions made by patients and individual clinicians. 

Differences between this summary and other sources

  • The reviews included in this summary differ among each other. One review [1] concluded pulsed ultrasound would be better than placebo on pain reduction and functionality improvement, without associated adverse effects. Another review [2] reported pulsed ultrasound could be beneficial in decreasing pain, but it mentions treatment duration as a limitation because it must be defined patient by patient. Four reviews [3],[4],[5],[7] concluded ultrasound could be beneficial in decreasing pain and improving functionality in patients with knee osteoarthritis, but given that the available evidence has methodological limitations and is difficult to compare, new studies of better quality are required. Finally, another review [6] determines ultrasound is ineffective for decreasing pain in knee osteoarthritis because the evidence has low certainty or it is controversial.
  • The conclusions of this summary agree with the main international guidelines for osteoarthritis: The Osteoarthritis Research Society International (OARSI) [20] indicates it is uncertain whether therapeutic ultrasound for the treatment of knee osteoarthritis is useful and it is not recommended for the treatment of knee osteoarthritis or multiple joints. The American Academy of Orthopedic Surgeons (AAOS) [21] concludes that given the inconsistency of the findings for multiple physical therapies, including therapeutic ultrasound, they cannot make a recommendation in favor or against its use in patients with symptomatic knee osteoarthritis.
Could this evidence change in the future?
  • The probability that the conclusions of this summary change with future trials is high, due to the low and very low certainty of the existing evidence.
  • We identify at least four ongoing trials [22],[23],[24],[25] in the International Clinical Trials Registry Platform of the World Health Organization, which could provide relevant information.
  • New reviews, especially if they manage to obtain additional information from existing trials, could provide more reliable results. However, we did not identify ongoing reviews in the PROSPERO database.
How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.

Follow the link to access the interactive version: Pulsed ultrasound versus placebo for osteoarthritis

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier.

After creating an account in Epistemonikos, users will be able to save the matrixes and to receive automated notifications any time new evidence potentially relevant for the question appears.

This article is part of the Epistemonikos Evidence Synthesis project. It is elaborated with a pre-established methodology, following rigorous methodological standards and internal peer review process. Each of these articles corresponds to a summary, denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos), whose main objective is to synthesize the body of evidence for a specific question, with a friendly format to clinical professionals. Its main resources are based on the evidence matrix of Epistemonikos and analysis of results using GRADE methodology. Further details of the methods for developing this FRISBEE are described here (http://dx.doi.org/10.5867/medwave.2014.06.5997)

Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).

Potential conflicts of interest

The authors do not have relevant interests to declare.

Licencia Creative Commons Esta obra de Medwave está bajo una licencia Creative Commons Atribución-NoComercial 3.0 Unported. Esta licencia permite el uso, distribución y reproducción del artículo en cualquier medio, siempre y cuando se otorgue el crédito correspondiente al autor del artículo y al medio en que se publica, en este caso, Medwave.

 

INTRODUCTION
Many osteoarthritis patients persist symptomatic despite nonsurgical treatment. Pulsed ultrasound might be a viable alternative for such cases, but its real clinical relevance remains unclear.

METHODS
A literature review was conducted in Epistemonikos, the largest database for sys-tematic reviews in health that compiles multiple sources, including MEDLINE, EMBASE, and Cochrane, among others. Relevant data were extracted, and infor-mation from the primary studies was reanalyzed. A subsequent meta-analysis was conducted, and summary of findings tables were constructed using the GRADE methodology.

RESULTS AND CONCLUSIONS
Six systematic reviews including eight randomized trials were identified. In conclusion, it is not clear whether pulsed ultrasound improves functionality, and it might slightly decrease pain but the certainty of the evidence is low.

Autores: Joaquín Ananías[1,2], Diego Ubilla[1,2], Sebastián Irarrázaval[2,3], Luis Ortiz-Muñoz[2,4]

Filiación:
[1] Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[2] Proyecto Epistemonikos, Santiago, Chile
[3] Departamento de Traumatología y Ortopedia, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[4] Centro Evidencia UC, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

E-mail: ortizkine@gmail.com

Correspondencia a:
[1] Centro Evidencia UC
Pontificia Universidad Católica de Chile
Centro de Innovación UC Anacleto Angelini
Avda.Vicuña Mackenna 4860
Macul
Santiago
Chile

Citación: Ananías J, Ubilla D, Irarrázaval S, Ortiz-Muñoz L. Is pulsed ultrasound an alternative for osteoarthritis?. Medwave 2017 Nov-Dic;17(9):e7109 doi: 10.5867/medwave.2017.09.7109

Fecha de envío: 27/11/2017

Fecha de aceptación: 20/12/2017

Fecha de publicación: 26/12/2017

Origen: Este artículo es producto del Epistemonikos Evidence Synthesis Project de la Fundación Epistemonikos, en colaboración con Medwave para su publicación.

Tipo de revisión: Con revisión por pares sin ciego por parte del equipo metodológico del Epistemonikos Evidence Synthesis Project.

Ficha PubMed

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  1. Zeng C, Li H, Yang T, Deng ZH, Yang Y, Zhang Y, Ding X, Lei GH. Effectiveness of continuous and pulsed ultrasound for the management of knee osteoarthritis: a systematic review and network meta-analysis. Osteoarthritis Cartilage. 2014 Aug;22(8):1090-9. | CrossRef | PubMed |
  2. Zhang C, Xie Y, Luo X, Ji Q, Lu C, He C, Wang P. Effects of therapeutic ultrasound on pain, physical functions and safety outcomes in patients with knee osteoarthritis: a systematic review and me-ta-analysis. Clin Rehabil. 2016 Oct;30(10):960-971. | PubMed |
  3. Loyola-Sánchez A, Richardson J, MacIntyre NJ. Efficacy of ultrasound therapy for the manage-ment of knee osteoarthritis: a systematic review with meta-analysis. Osteoarthritis Cartilage. 2010 Sep;18(9):1117-26. | CrossRef | PubMed |
  4. Rutjes AW, Nüesch E, Sterchi R, Jüni P. Therapeutic ultrasound for osteoarthritis of the knee or hip. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD003132. | CrossRef | PubMed |
  5. Ibarra Cornejo, José L , Fernández Lara, María José , Eugenin Vergara, David A , Beltrán Maldona-do, Eduardo A. Physical agents’ effectiveness in the pain treatment in knee arthrosis: a system-atic review. Revista Médica Electrónica. 2015. | Link |
  6. Rodriguez EI , Ramírez LC. Pulsed therapeutic ultrasound in the treatment of persons with knee osteoarthritis. Revista Salud UIS. 2015. | CrossRef |
  7. Cakir S, Hepguler S, Ozturk C, Korkmaz M, Isleten B, Atamaz FC. Efficacy of therapeutic ultra-sound for the management of knee osteoarthritis: a randomized, controlled, and double-blind study. Am J Phys Med Rehabil. 2014 May;93(5):405-12. | CrossRef | PubMed |
  8. Cetin N, Aytar A, Atalay A, Akman MN. Comparing hot pack, short-wave diathermy, ultrasound, and TENS on isokinetic strength, pain, and functional status of women with osteoarthritic knees: a single-blind, randomized, controlled trial. Am J Phys Med Rehabil. 2008 Jun;87(6):443-51. | CrossRef | PubMed |
  9. Huang MH, Lin YS, Lee CL, Yang RC. Use of ultrasound to increase effectiveness of isokinetic ex-ercise for knee osteoarthritis. Arch Phys Med Rehabil. 2005 Aug;86(8):1545-51. | PubMed |
  10. Huang MH, Yang RC, Lee CL, Chen TW, Wang MC. Preliminary results of integrated therapy for patients with knee osteoarthritis. Arthritis Rheum. 2005 Dec 15;53(6):812-20. | PubMed |
  11. Loyola-Sánchez A, Richardson J, Beattie KA, Otero-Fuentes C, Adachi JD, MacIntyre NJ. 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 Jan;93(1):35-42. | CrossRef | PubMed |
  12. Yang PF, Li D, Zhang SM, Wu Q, Tang J, Huang LK, Liu W, Xu XD, Chen SR. Efficacy of ultrasound in the treatment of osteoarthritis of the knee. Orthop Surg. 2011 Aug;3(3):181-7. | CrossRef | PubMed |
  13. Huang M , Chen T , Weng M , Wang Y. Effects of Pulse Sonication on Functional Status of Patients with Knee Osteoarthritis. International Society of Physical and Rehabilitation Medicine. 2001. | Link |
  14. Tascioglu, F , Kuzgun, S , Armagan, O , Ogutler, G. Short-Term Effectiveness of Ultrasound Thera-py in Knee Osteoarthritis.The Journal of International Medical research. 2010. | CrossRef |
  15. COMET Initiative. Defining an International Standard Set of Outcome Measures for Patients With Hip or Knee Osteoarthritis: Consensus of the International Consortium for Health Outcomes Measurement Hip and Knee Osteoarthritis Working Group. Arthritis Care and Research. 2016;68(11):1631-39 | CrossRef |
  16. Tubach F, Ravaud P, Baron G, Falissard B, Logeart I, Bellamy N, Bombardier C, Felson D, Hochberg M, van der Heijde D, Dougados M. Evaluation of clinically relevant changes in patient reported outcomes in knee and hip osteoarthritis: the minimal clinically important improvement. Ann Rheum Dis. 2005 Jan;64(1):29-33.
  17. E. Eberle and B. Ottillinger. Clinically relevant change and clinically relevant difference in knee osteoarthritis. Journal of the Osteoarthritis Research Society International. 1999.
  18. Falconer J, Hayes KW, Chang RW. Effect of ultrasound on mobility in osteoarthritis of the knee. A randomized clinical trial. Arthritis Care Res. 1992 Mar;5(1):29-35. | PubMed |
  19. Ozgönenel L, Aytekin E, Durmuşoglu G. A double-blind trial of clinical effects of therapeutic ultra-sound in knee osteoarthritis. Ultrasound Med Biol. 2009 Jan;35(1):44-9. | CrossRef | PubMed |
  20. McAlindon TE, Bannuru RR, Sullivan MC, Arden NK, Berenbaum F, Bierma-Zeinstra SM, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Carti-lage. 2014 Mar;22(3):363-88.
  21. Brown GA. AAOS clinical practice guideline: treatment of osteoarthritis of the knee: evidence-based guideline, 2nd edition. J Am Acad Orthop Surg. 2013 Sep;21(9):577-9.
  22. Xing Wu. Low intensity pulsed ultrasound(LIPUS) combined with sodium hyaluronate(SH) for the treatment of moderate knee Osteoarthritis. | Link |
  23. Chen Wen-zhi, Jia Lang. Efficacy and safety of low intensity pulsed ultrasound for knee osteoar-thritis: a prospective, randomized controlled trial protocol. | Link |
  24. Norma J MacIntyre. Randomized Trial in knee Osteoarthritis Using Low Intensity Ultrasound - Evaluating Feasibility. | Link |
  25. Adalberto Loyola-Sanchez, Julie Richardson, Karen Beattie. The Effects of Low Intensity Ultra-sound on Medial Tibial Cartilage Morphology in Patients With Mild or Moderate Knee Osteoar-thritis: A Double Blind, Randomized Placebo-controlled Study. | Link |
Zeng C, Li H, Yang T, Deng ZH, Yang Y, Zhang Y, Ding X, Lei GH. Effectiveness of continuous and pulsed ultrasound for the management of knee osteoarthritis: a systematic review and network meta-analysis. Osteoarthritis Cartilage. 2014 Aug;22(8):1090-9. | CrossRef | PubMed |

Zhang C, Xie Y, Luo X, Ji Q, Lu C, He C, Wang P. Effects of therapeutic ultrasound on pain, physical functions and safety outcomes in patients with knee osteoarthritis: a systematic review and me-ta-analysis. Clin Rehabil. 2016 Oct;30(10):960-971. | PubMed |

Loyola-Sánchez A, Richardson J, MacIntyre NJ. Efficacy of ultrasound therapy for the manage-ment of knee osteoarthritis: a systematic review with meta-analysis. Osteoarthritis Cartilage. 2010 Sep;18(9):1117-26. | CrossRef | PubMed |

Rutjes AW, Nüesch E, Sterchi R, Jüni P. Therapeutic ultrasound for osteoarthritis of the knee or hip. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD003132. | CrossRef | PubMed |

Ibarra Cornejo, José L , Fernández Lara, María José , Eugenin Vergara, David A , Beltrán Maldona-do, Eduardo A. Physical agents’ effectiveness in the pain treatment in knee arthrosis: a system-atic review. Revista Médica Electrónica. 2015. | Link |

Rodriguez EI , Ramírez LC. Pulsed therapeutic ultrasound in the treatment of persons with knee osteoarthritis. Revista Salud UIS. 2015. | CrossRef |

Cakir S, Hepguler S, Ozturk C, Korkmaz M, Isleten B, Atamaz FC. Efficacy of therapeutic ultra-sound for the management of knee osteoarthritis: a randomized, controlled, and double-blind study. Am J Phys Med Rehabil. 2014 May;93(5):405-12. | CrossRef | PubMed |

Cetin N, Aytar A, Atalay A, Akman MN. Comparing hot pack, short-wave diathermy, ultrasound, and TENS on isokinetic strength, pain, and functional status of women with osteoarthritic knees: a single-blind, randomized, controlled trial. Am J Phys Med Rehabil. 2008 Jun;87(6):443-51. | CrossRef | PubMed |

Huang MH, Lin YS, Lee CL, Yang RC. Use of ultrasound to increase effectiveness of isokinetic ex-ercise for knee osteoarthritis. Arch Phys Med Rehabil. 2005 Aug;86(8):1545-51. | PubMed |

Huang MH, Yang RC, Lee CL, Chen TW, Wang MC. Preliminary results of integrated therapy for patients with knee osteoarthritis. Arthritis Rheum. 2005 Dec 15;53(6):812-20. | PubMed |

Loyola-Sánchez A, Richardson J, Beattie KA, Otero-Fuentes C, Adachi JD, MacIntyre NJ. 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 Jan;93(1):35-42. | CrossRef | PubMed |

Yang PF, Li D, Zhang SM, Wu Q, Tang J, Huang LK, Liu W, Xu XD, Chen SR. Efficacy of ultrasound in the treatment of osteoarthritis of the knee. Orthop Surg. 2011 Aug;3(3):181-7. | CrossRef | PubMed |

Huang M , Chen T , Weng M , Wang Y. Effects of Pulse Sonication on Functional Status of Patients with Knee Osteoarthritis. International Society of Physical and Rehabilitation Medicine. 2001. | Link |

Tascioglu, F , Kuzgun, S , Armagan, O , Ogutler, G. Short-Term Effectiveness of Ultrasound Thera-py in Knee Osteoarthritis.The Journal of International Medical research. 2010. | CrossRef |

COMET Initiative. Defining an International Standard Set of Outcome Measures for Patients With Hip or Knee Osteoarthritis: Consensus of the International Consortium for Health Outcomes Measurement Hip and Knee Osteoarthritis Working Group. Arthritis Care and Research. 2016;68(11):1631-39 | CrossRef |

Tubach F, Ravaud P, Baron G, Falissard B, Logeart I, Bellamy N, Bombardier C, Felson D, Hochberg M, van der Heijde D, Dougados M. Evaluation of clinically relevant changes in patient reported outcomes in knee and hip osteoarthritis: the minimal clinically important improvement. Ann Rheum Dis. 2005 Jan;64(1):29-33.

E. Eberle and B. Ottillinger. Clinically relevant change and clinically relevant difference in knee osteoarthritis. Journal of the Osteoarthritis Research Society International. 1999.

Falconer J, Hayes KW, Chang RW. Effect of ultrasound on mobility in osteoarthritis of the knee. A randomized clinical trial. Arthritis Care Res. 1992 Mar;5(1):29-35. | PubMed |

Ozgönenel L, Aytekin E, Durmuşoglu G. A double-blind trial of clinical effects of therapeutic ultra-sound in knee osteoarthritis. Ultrasound Med Biol. 2009 Jan;35(1):44-9. | CrossRef | PubMed |

McAlindon TE, Bannuru RR, Sullivan MC, Arden NK, Berenbaum F, Bierma-Zeinstra SM, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Carti-lage. 2014 Mar;22(3):363-88.

Brown GA. AAOS clinical practice guideline: treatment of osteoarthritis of the knee: evidence-based guideline, 2nd edition. J Am Acad Orthop Surg. 2013 Sep;21(9):577-9.

Xing Wu. Low intensity pulsed ultrasound(LIPUS) combined with sodium hyaluronate(SH) for the treatment of moderate knee Osteoarthritis. | Link |

Chen Wen-zhi, Jia Lang. Efficacy and safety of low intensity pulsed ultrasound for knee osteoar-thritis: a prospective, randomized controlled trial protocol. | Link |

Norma J MacIntyre. Randomized Trial in knee Osteoarthritis Using Low Intensity Ultrasound - Evaluating Feasibility. | Link |

Adalberto Loyola-Sanchez, Julie Richardson, Karen Beattie. The Effects of Low Intensity Ultra-sound on Medial Tibial Cartilage Morphology in Patients With Mild or Moderate Knee Osteoar-thritis: A Double Blind, Randomized Placebo-controlled Study. | Link |