Authors: Serap Cakir, MD Simin Hepguler, MD Cihat Ozturk, MD Murat Korkmaz, MD Banu Isleten, MD Funda Calis Atamaz, MD
Osteoarthritis
ORIGINAL RESEARCH ARTICLE
Affiliations: From the Department of Physical Medicine and Rehabilitation, Medical Faculty of Ege University, Izmir, Turkey.
Correspondence: All correspondence and requests for reprints should be addressed to: Funda Calis Atamaz, MD, Ege Universitesi Tip Fakultesi, Fiziksel Tıp ve Rehabilitasyon Anabilim Dali, Bornova, Izmir 35040, Turkey.
Efficacy of Therapeutic Ultrasound for the Management of Knee Osteoarthritis A Randomized, Controlled, and Double-Blind Study ABSTRACT
Disclosures: Equipment and financial support were provided by Ege University for this project. Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article.
0894-9115/14/9305-0405 American Journal of Physical Medicine & Rehabilitation Copyright * 2013 by Lippincott Williams & Wilkins DOI: 10.1097/PHM.0000000000000033
Cakir S, Hepguler S, Ozturk C, Korkmaz M, Isleten B, Atamaz FC: Efficacy of therapeutic ultrasound for the management of knee osteoarthritis: a randomized, controlled, and double-blind study. Am J Phys Med Rehabil 2014;93:405Y412.
Objective: The aim of this study was to compare whether the effectiveness of continuous ultrasound (US) was superior against pulsed US and against sham US in knee osteoarthritis.
Design: A randomized controlled study was carried out on 60 patients diagnosed with knee osteoarthritis according to American College of Rheumatology. The patients were randomized into the following three treatments: (1) continuous US (at a frequency of 1 MHz with intensity of 1 W/cm2), (2) pulse US (same frequency and intensity on 1:4 pulse ratio), and (3) sham US. All treatments were applied with 5-cm2 head US device five times a week for 2 weeks in addition to home exercise program including quadriceps isometric exercise, muscle strength exercises, and stretching exercises of the lower extremity muscles for at least three times per week. Assessments were performed at baseline, at the end of the treatment, and at the end of the treatments and at the sixth month using the following measurements: Western Ontario and McMaster University Osteoarthritis IndexYpain, stiffness, function, visual analog scaleYpain at rest, visual analog scaleYpain on movement, visual analog scaleYdisease severity, and 20-m walking time. Among these parameters, the Western Ontario and McMaster University Osteoarthritis IndexYpain was the primary outcome.
Results: All groups showed a significant improvement in all parameters in both following visits (P G 0.05). However, there was no significant difference between the groups. Although the mean reduction percent in Western Ontario and McMaster University Osteoarthritis IndexYpain was significantly higher in group I (continuous US) when compared to sham group (46.5% vs 28.9%, P G 0.05) at the end of the treatment, this result was not found in other pain parameters.
Conclusions: The present study demonstrated that all assessment parameters significantly improved in all groups without a significant difference. This result suggested that therapeutic US provided no additional benefit in improving pain and functions in addition to exercise training. Key Words: www.ajpmr.com
Osteoarthritis, Therapeutic Ultrasound, Thermal Therapy
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O
steoarthritis (OA) is a chronic degenerative disease of joints characterized by marginal osteophyte formation, subchondral bone changes and focal loss of articular cartilage.1 Although it may affect many joints, weight-bearing joints like knee joint are especially at risk for OA. Because it has been reported as being a major cause of significant morbidity and an extensive use of health-care resources in elderly population, its therapy is essential in the world-wide. According to recent guidelines, primary objective is to reduce of pain and to improve functional disability in the treatment of OA.2Y4 Thermal therapies are widely used in knee OA for these purposes since it is well known that heat increases tissue metabolism, collagen elasticity, capillary blood flow and decreases muscle spasms.5 Therapeutic ultrasound (US) is one of the thermal therapy modalities used in knee OA.5Y7 According to the results of the studies comparing the effects of therapeutic US with those of sham US, it could be effective for decreasing pain and improving physical functions in patients with knee OA. Therapeutic US can also be used for its non-thermal (chemical, biologic, mechanic) effects in a pulse mode.5,9,10 It is widely used by physical therapists for acute pain and inflammation of OA. Moreover, some authors reported that US delivered with a pulsed mode and with low intensity had more effects on pain improvement when it was compared with continuous US.10 However, there is limited scientific evidence to support the use of both modalities of US in patients with knee OA due to the inadequacies in the quality of and appropriateness of randomized controlled trials. Similarly, it cannot be concluded exactly which modality of US is the most effective in relieving the pain of knee OA without inflammation. In this study, it was aimed to compare the effectiveness of continuous US and pulsed US in the knee OA. At the same time, the effects of these modalities of US were compared with those of sham US in addition to exercise training.
MATERIALS AND METHODS Patients and Study Design The randomized, controlled, double-blind and factorial design study, the outpatients with knee pain for at least at 6 months least, diagnosed knee OA according to American College of Rheumatology, confirmed with radiologically in KellgrenYLawrence grades of 2 or 3,11 aged 40Y80 years were eligible. The patients who had an experience of any physical therapy agent, intra-articular corticosteroid therapy
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or chondroprotective agents during the 30 days prior to the study or viscosupplementation treatment within 6 months prior to the study were excluded. The patients were also excluded if they had a diagnosis of joint infection, neoplasm, diabetes mellitus, paresis, osteonecrosis, recent trauma, ascertained/suspected pregnancy or lactating and poor general health status. The other exclusion criteria were any history of contraindication of heat therapy or previous major surgery. The study was approved by the institutional review board at each center, and all participants provided written informed consent. During the therapy period and within 1 week before the treatment patients were not allowed to take non-steroidal antiinflammatory drugs (NSAIDs). Paracetamol use up to 2000 mg/day was allowed. Other drugs for systemic diseases were not stopped. Randomization was carried out by using covariate adaptive randomization with Frane method.12 The patients were randomized into following three treatments: I. continuous US, II. pulse US and III. sham US. All patients, investigators and analysts were blinded with the exception of the safety monitoring board member (SH), but this member did not assess the patients. All treatments were applied with 5 cm2 head US device for 5 times a week for 2 weeks by same device and same physiotherapist (Enraf Nonius Sonoplus 190). Continuous US was administered at a frequency of 1 MHz with intensity of 1 W/cm2. Pulse US was used for same frequency and intensity on 1:4 pulse ratios. These treatment parameters were chosen according to previous studies.13 The patients in the sham group received exactly the same treatment procedure as the treatment groups, except that the power switch was off. Each treatment was continued approximately 12 minutes over the painful area in the knee region with full contact in a supine position. All patients instructed to perform home exercise program including quadriceps isometric exercise, muscle strength exercises (chair lift and mini-squats exercises) and stretching exercises of the lower extremity muscles at least for 3 times per week. To ensure that exercises were learned properly, a complete set of premade exercise cards which have shown all exercises were also hand out. At the following visits, the patients were instructed to regularly perform their exercises.
Assessments Firstly, patients_ age, weight, body mass index (BMI), disease duration, current drug therapies
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were recorded. All assessments were carried out at baseline, at the end of the treatment and 6th months by the same physician who was unaware for the patient_s group of treatment. Primary outcome was Western Ontario and McMaster University Osteoarthritis Index (WOMAC)Ypain.14 In addition, 100 mm VAS was used in assessing knee pain at rest and knee pain on movement. The patients were also asked to assess their disease severity by using VAS. In addition, the following clinical parameters were used to assess the response to the treatment: WOMAC-stiffness, WOMAC-function, 20 meter walking time (sc).
Sample Size The treatment response was defined as a 40% improvement in WOMAC-pain scores, which corresponds to an average decrease of 8 points.15 The number of patients recruited was determined according to a power of 0.80, a P value of 0.05 and
30% dropout rate with paired t test. The needed patient number was 12 for each group.
Statistics Statistical analyses were performed with the 15.0 Statistical Package for the Social Sciences (SPSS). All the results were expressed as mean T SD (standard deviation). A P value below 0.05 was considered a statistical significance. The repeated measurements analysis of variance was used to evaluate over the time of observation for the clinical assessment parameters. Post Hoc test was Bonferroni test. Comparison analysis was carried out between treatment groups by One-way analysis of variance (ANOVA) test. In addition, standardized effect sizes (Cohen d) with 95% confidence intervals (95% CI) were calculated as a difference between mean scores divided by the pooled SD.16
FIGURE 1 Participant flowchart and assessment. www.ajpmr.com
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RESULTS Figure 1 summarizes the patient recruitment, participation and attrition during the study. No patient reported any complain leading to noncompliance. No patient received other therapy except the intake of paracetamol during follow-up. Fifty eight patients completed the study. One patient in group 1 could not attend follow-up visit at 6th month due to health problems not related knee pain. One patient in group 3 stated not enough time to attend as a reason at 6th month. As shown in Table 1, there were no significant differences among the groups at baseline. In the Table 2, the clinical characteristics related with pain are presented. All groups showed a significant improvement in all pain parameters in both following visits (P G 0.05). However, there was no significant difference among the groups. Although the mean reduction percent in WOMACpain was significantly higher in group I (continuous US) when compared to sham group (P G 0.05) after the treatment, this result was not found in other pain parameters. The Cohen d value was also 0.9 for sham group after the treatment while other treatment groups showed the Cohen d values higher than 1.0. Table 3 presents functional clinical parameters. A significant improvement of WOMAC- function was seen in all groups during the follow-up (P G 0.05) without any difference among the groups. The Cohen d values were also higher than 1.0 for all groups. When the patient_s judgment for her/his disease severity was measured on a VAS, this parameter was significantly decreased in all patients. There was no statistical significant difference among the groups. Moreover, the mean reduction percents from baseline for these parameters were similar in all patients.
In all groups, 20 meter walking times were significantly improved after the treatments (P G 0.05), although the mean reduction percents from baseline were not sufficient in clinically. The Cohen d values showed small effect sizes in this parameter. On the other hand, this improvement did not continue at 6th month.
DISCUSSION The present study demonstrated that all assessment parameters significantly improved in all groups without a significant difference. This result suggested that therapeutic US provided no additional benefit in improving pain and functions in addition to exercise training. Although therapeutic US is a frequently used modality in clinical practice of knee OA, the quality of the evidence based on randomized controlled studies is low due to considerable results_ heterogeneity, lack of blindness and insufficient follow-up.10,13 Moreover, there is no standardized application approach regarding its intensity, mode and therapeutic dose. Despite the sensory differences between treatment and sham groups, blinding represents an important, distinct aspect of randomized controlled trials and prevents bias. Indeed, in the review of studies in therapeutic US, it has been reported that the studies had high risk of bias.10,13 The inclusion of patients who had no experience of any physical therapy agent may allow blinding of the patients in such studies if a sham intervention is identical in appearance from the control intervention as reported previously.17 Based on this belief, we excluded the patients who had an experience of any physical therapy agent to achieve blinding. Another issue is short follow-up period of these studies because clinical evaluations were carried out
TABLE 1 Characteristics of the Patients at Baseline
Age (year, mean TSD) Sex * Women (%) Men (%) BMI (kg/m2, mean T SD) Duration (year, mean T SD) Side* Right (%) Left (%)
Group 1
Group 2
Group 3
(n = 20)
(n = 20)
(n = 20)
P Value
56.9 T 8.8
58.2 T 9.9
57.1 T 7.8
0.894
14 (70) 6 (30) 27.9 T 4.4 4.0 T 2.9
16 (80) 4 (20) 30.9 T 4.0 5.1 T 4.1
17 (85) 3 (15) 29.5 T 5.9 4.5 T 3.8
0.714
12 (60) 8 (40)
11 (55) 9 (45)
12 (60) 8 (40)
0.515
0.146 0.508
One way-ANOVA test, * Chi-square test. BMI: Body mass index.
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TABLE 2 The characteristics related with pain during the study Group 1- Continuous US
Group 2- Pulsed US
Group 3- Sham US
(n = 20)
(n = 20)
(n = 20)
Mean T SD WOMAC-pain At baseline l At end of treatment Mean difference 95% Cl Effect size (d) 6th month Mean difference 95% Cl Effect size (d) VAS-pain at rest At baseline l At end of treatment Mean difference 95% Cl Effect size (d) 6th month Mean difference 95% Cl Effect size (d) VAS-pain on movement At baseline l At end of treatment Mean difference 95% Cl Effect size (d) 6th month Mean difference 95% Cl Effect size (d)
15.9 T 4.3 8.5 T 4.5* 7.4 4.8 to 10.0 1.7 9.5 T 2.6*
%
46.5
40.3
2.1 to 10.7 1.8 57.9 T 20.2 28.3 T 18.2* 49.6 39.4 to 54.8 1.5 21.4 T 17.8* 36.5 22.7 to 50.3 1.9 75.5 T 18.3 37.0 T 23.0* 38.5 26.8 to 42.2 1.9 38.7 T 16.2* 36.8 26.8 to 42.0 2.1
51.1
63.0
51.0
48.7
Mean T SD 14.5 T 3.1 9.5 T 3.9* 5.0 2.4 to 7.6 1.4 11.3 T 2.2* 3.2 0.8 to 5.6 1.2 55.7 T 17.8 26.9 T 19.5* 28.8 17.8 to 39.8 1.5 20.2 T 14.1* 35.5 21.5 to 49.5 2.2 73.0 T 19.9 48.7 T 18.6* 24.3 18.4 to 28.2 1.3 37.5 T 24.1* 35.5 29.8 to 39.2 1.6
%
34.5
22.1
51.7
63.7
33.3
48.6
Mean T SD 14.9 T 4.3 10.6 T 4.8* 4.3 1.4 to 7.7 0.9 11.1 T 2.6* 3.8 1.1 to 6.5 1.1 53.6 T 19.1 27.8 T 21.9* 25.8 18.6 to 33.0 1.3 22.3 T 14.2* 31.3 14.9 to 47.7 1.9 72.2 T 21.8 39.4 T 27.2* 32.8 24.5 to 41.5 1.3 38.1 T 27.0* 34.1 28.6 to 39.4 1.4
%
Pl
28.9
0.029
25.5
0.069
48.1
0.781
58.4
0.485
45.4
0.082
47.2
0.578
* P G 0.05. repeated measurements analysis of variance. l One way ANOVA test for the reductions. %: Reduction in the baseline value. US: US. WOMAC: The Western Ontario and McMaster University Osteoarthritis Index. VAS: Visual analog scale.
only at baseline and at the end of the treatment. When it is compared with those of the studies about efficacy of US on knee OA,18Y21 it seems that we had sufficient follow-up period. Most importantly, the main problem which was reported the cause of low quality of the evidence in review of therapeutic US was results_ heterogeneity. The reason was that US treatment had been used different intensity, mode and therapeutic dose in various studies. For example, some authors reported that US delivered with a pulsed mode and with low intensity had more effects on pain improvement with non-thermal effects.10,13 In vitro studies support the useful effects of pulsed US with its anabolic effects on cartilage. It has been showed that it stimulated chondrocyte proliferation and matrix production in human articular cartilage.22,23 www.ajpmr.com
There are also the studies shown that it stimulated osteogenesis and fracture healing.24 On the other hand, therapeutic US is primarily used for its thermal effects. Deep heating with US can produce increased capillary permeability and tissue metabolism, enhancement of fibrous tissue extensibility and elevation of the pain threshold leading pain relief effect.6,25 So indeed, the studies used continuous US reported significant improvements in pain parameters.18,26 According to these results, it cannot be concluded exactly what is optimal dosage and mode for the most effect in relieving pain on the knee OA. Moreover, it is well known that the resultant tissue temperature following application of US will primarily depend on the extent of conduction into surrounding tissues and dissipation by blood Therapeutic Ultrasound for Knee Osteoarthritis
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TABLE 3 The results of the functional parameters Group 1- Continuous US
Group 2- Pulsed US
Group 3- Sham US
(n = 20)
(n = 20)
(n = 20)
Mean T SD WOMAC-function At baseline l At end of treatment Mean difference 95% Cl Effect size (d) 6th month Mean difference 95% Cl Effect size (d) 20 meter walking time (sc) At baseline l At end of treatment Mean difference 95% Cl Effect size (d) 6th month Mean difference 95% Cl Effect size (d) VAS-disease severity At baseline l At end of treatment Mean difference 95% Cl Effect size (d) 6th month Mean difference 95% Cl Effect size (d)
55.7 T 13.4 35.6 T 12.6* 20.1 17.8 to 22.4 1.5 32.6 T 11.3* 23.1 17.9 to 28.3 1.9 15.4 T 4.1 13.7 T 2.4* 1.7 1.1 to 2.3 0.5 15.1 T 1.9 0.3 j0.1 to 0.9 0.1 73.9 T 19.2 34.2 T 21.6* 39.7 34.1 to 45.3 1.9 30.0 T 11.6* 43.9 38.2 to 49.6 2.8
Mean T SD
%
52.4 T 11.9 37.2 T 12.6* 15.2 12.7 to 17.7 1.2 37.1 T 6.2* 15.3 12.1 to 18.5 1.6
36.1
41.5
15.5 T 2.5 14.3 T 2.3* 1.2 1.0 to 1.4 0.5 16.8 T 3.3 j1.3 j1.9 to 0.5 0.4
11.0
1.9
67.9 T 18.7 30.8 T 20.8* 37.1 32.5 to 41.7 1.9 32.5 T 10.7* 35.4 31.8 to 39.0 2.3
53.7
59.4
%
29.0
29.2
7.7
j8.3
54.6
52.1
Mean T SD 52.5 T 15.4 38.9 T 16.9* 13.6 11.0 to 16.2 0.8 35.5 T 8.1* 17.0 14.2 to 20.0 1.4 14.7 T 2.8 13.3 T 2.7* 1.4 0.9 to 1.9 0.5 15.1 T 2.4 j0.4 j0.9 to 0.1 0.2 68.4 T 20.5 33.5 T 27.7* 34.9 29.4 to 40.4 1.4 29.5 T 11.0* 38.9 31.2 to 46.6 2.4
%
Pl
25.9
0.057
32.4
0.067
9.5
0.124
j2.7
0.055
51.0
0.851
56.9
0.245
* P G 0.05. repeated measurements analysis of variance. l One way ANOVA test for reductions. %: Reduction in the baseline value. US: US. WOMAC: The Western Ontario and McMaster University Osteoarthritis Index. VAS: Visual analog scale.
perfusion.27 Since dissipation by blood perfusion is highly variable and poor in fatty tissue, higher doses of US may be used in obese patients to receive the same intensity at the target tissue. Considering this uncertainty of treatment parameters, we selected treatment parameters based on previous data.13 Then, we attempted to compare efficacy of pulse and continuous US in addition to exercise therapy. Our findings showed that pain was significantly decreased in both US groups without a difference. The parameters related with functions were also improved in both treatments. At the same time, we detected similar findings in sham group as a surprising finding. Because the patients in the sham group were given exercise training, we cannot conclude the effect of sham intervention on pain relief. Nevertheless, this finding suggested that neither pulsed US
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nor continuous US provided additional benefit in improving pain. In a similar study conducted by Tascioglu et al,19 pain relief with respect to VAS and WOMAC was significantly more in the group of US with pulsed mode. However, in that study, continuous mode of US was administered with intensity of 2 W/cm2 while we used 1 W/cm2. Considering the conclusion reported by Sanchez AL10 that US applied using low intensity and pulsed mode could be more effective, it can be explained why we did not find a significant difference between pulsed US and continuous US groups with 1 W/cm2 intensity in contrast to that study. Another statement can be addressed that exercise training was not prescribed in that study although it is well known that exercise reduces pain and improves function in patients with knee OA. In
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the study of Ulus et al,21 the authors concluded that the effect of US could be masked by the exercises because they could not find a difference between groups similar to our study. Pain already decreased up to 60% even at 6th month (Table 2) in our study. Then, we cannot state whether exercise had alone impact on this result and US provided no additional benefit in analgesia. However, in this stance, it should be discussed the effect of sham intervention on pain relief. Since many study found that the patients in the sham group showed significant improvement when compared with baseline values, the authors reported that the sham effect could be attributable to various factors such as age, diagnosis, study design, therapist and patient relationship or cultural differences.28 These factors may be contributed to pain relief in our sham group. Our study has several limitations. Firstly, we did not record the intake of paracetamol even through paracetamol use up to 2000 mg/day was allowed. The analgesic use was significantly higher in sham group although there was no difference with respect to improve pain parameters in previous data.29 Considering this data, it can be concluded that the intake of paracetamol may be higher in our sham group. Another limitation of the study could be the lack of a group consisting of US alone, because we cannot conclude whether US without exercise has similar effects on improvement for knee pain. Further trials may be needed to expose amount of paracetamol use in the patients, and to present solely the efficacy of US without exercise. Treatment parameters can be addressed as another limitation of the study. For example, pulse US is usually used in higher intensities then continuous one in contrast to our study. Ten almost daily sessions within 2 weeks may be discussed that it is much more than usually accepted. However, there is no standardized intervention for US as stated in the review of Rutjes et al.13 This result suggests that physician should consider the type of the patient population to be targeted in selecting treatment parameters. In conclusion, this randomized and controlled study which compared the effectiveness of continuous US, pulsed US and sham in addition to exercise training in the knee OA showed that all assessment parameters significantly improved in all groups without a significant difference. This result has to be confirmed by further well designed controlled studies. REFERENCES 1. Lawrence JS, Bremner JM, Bier F: Osteo-arthrosis. Prevalence in the population and relationship between symptoms and x-ray changes. Ann Rheum Dis 1966;25:1Y24 www.ajpmr.com
2. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines: Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. Arthritis Rheum 2000;43:1905Y15 3. Zhang W, Nuki G, Moskowitz RW, et al: OARSI recommendations for the management of hip and knee osteoarthritis: Part III: Changes in evidence following systematic cumulative update of research published through January 2009. Osteoarthritis Cartilage 2010;18:476Y99 4. Crielaard JM, Henrotin Y: Scientific basis of physical therapy and rehabilitation in the management of patients with osteoarthritis, in Reginster JY, Pelletier JP, Martel-Pelletier J, et al, (eds): Osteoarthritis Clinical and Experimental Aspects. Berlin, Germany, Springer-Verlag, 1999, pp 453Y79 5. Rand SE, Goerlich C, Marchand K, et al: The physical therapy prescription. Am Fam Physician 2007;76: 1661Y6 6. Baker KG, Robertson VJ, Duck FA: A review of therapeutic ultrasound: Biophysical effects. Phys Ther 2001;81:1351Y8 7. Lucas B: Treatment options for patients with osteoarthritis of the knee. Br J Nurs 2005;14:976Y81 8. Iversen MD: Rehabilitation interventions for pain and disability in osteoarthritis. Am J Nurs 2012;112 (suppl):S32Y7 9. Nakamura T, Fujihara S, Yamamoto-Nagata K, et al: Low-intensity pulsed ultrasound reduces the inflammatory activity of synovitis. Ann Biomed Eng 2011;39:2964Y71 10. Sanchez AL, Richardson J, Maclntyre NJ: Efficacy of ultrasound therapy for the management of knee osteoarthritis: A systematic review with meta-analysis. Osteoarthritis Cartilage 2010;18;1117Y26 11. Kellgren JH, Lawrence JS: Radiologic assessment of osteoarthritis. Ann Rheum Dis 1957;16;494Y502 12. Frane JW: A method of biased coin randomization, its implementation, and its validation. Drug Info J 1998;32:423Y32 13. Rutjes AW, Nu¨esch E, Sterchi R, et al: Therapeutic ultrasound for osteoarthritis of the knee or hip. Cochrane Database Syst Rev 2010;1:1Y43 14. Tu¨zu¨n EH, Eker L, Aytar A, et al: Acceptability, reliability, validity and responsiveness of the Turkish version of WOMAC osteoarthritis index. Osteoarthritis Cartilage 2005;13:28Y33 15. Gundog M, Atamaz F, Kanyilmaz S, et al: Interferential current therapy in patients with knee osteoarthritis: Comparison of the effectiveness of different amplitude-modulated frequencies. Am J Phys Med Rehabil 2012;91:107Y13 16. Cohen J: Statistical Power Analysis for the Behavioral Sciences. Hillsdale, NJ, Erlbaum, 1988, p 567 17. Rutjes AWS, Nu¨esch E, Sterchi R, et al: Transcutaneous electrostimulation for osteoarthritis of the knee. Cochrane Database Syst Rev 2009;7; CD002823
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18. Ozgonenel L, Aytekin E, Durmusoglu G: A double-blind trial of clinical effects of therapeutic ultrasound in knee osteoarthritis. Ultrasound Med Biol 2009;35:44e9 19. Tascioglu F, Kuzgun S, Armagan O, et al: Short-term effectiveness of ultrasound therapy in knee osteoarthritis. J Int Med Res 2010;38:1233Y42 20. Falconer J, Hayes KW, Chang RW: Effect of ultrasound on mobility in osteoarthritis of the knee. A randomized clinical trial. Arthritis Care Res 1992;5:29Y35 21. Ulus Y, Tander B, Akyol Y, et al: Therapeutic ultrasound versus sham ultrasound for the management of patients with knee osteoarthritis: A randomized double-blind controlled clinical study. Int J Rheum Dis 2012;15:197Y206 22. Nolte PA, Klein-Nulend J, Albers GH, et al: Low intensity ultrasound stimulates endochondral ossification in vitro. J Orthop Res 2001;19:301Y7 23. Korstjens CM, Nolte PA, Burger EH, et al: Stimulation of bone cell differentiation by low intensity ultrasoundVA histomorphometric in vitro study. J Orthop Res 2004;22:495Y500 24. Korstjens CM, van der Rijt RH, Albers GH, et al: Lowintensity pulsed ultrasound affects human articular
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chondrocytes in vitro. Med Biol Eng Comput 2008; 46:1263Y70 25. Srbely JZ, Dickey JP, Lowerison M, et al: Stimulation of myofascial trigger points with ultrasound induces segmental antinociceptive effects: A randomized controlled study. Pain 2008;139:260Y6 26. Huang MH, Lin YS, Lee CL, et al: Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis. Arch Phys Med Rehabil 2005;86: 1545Y51 27. Baker KG, Robertson VJ, Duck FA: A review of therapeutic ultrasound: Biophysical effects. Phys Ther 2001;81:1351Y8 28. Johnson M, Din A: Ethnocultural differences in the analgesic effects of placebo transcutaneous electrical nerve stimulation on cold-induced pain in healthy subjects: A preliminary study. Complement Ther Med 1997;5:74Y9 29. Atamaz FC, Durmaz B, Baydar M, et al: Comparison of the efficacy of transcutaneous electrical nerve stimulation, interferential currents, and shortwave diathermy in knee osteoarthritis: A double-blind, randomized, controlled multicenter study. Arch Phys Med Rehabil 2012;93:748Y56
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Osteoarthritis
ORIGINAL RESEARCH ARTICLE
Affiliations: From the Department of Physical Medicine and Rehabilitation, Medical Faculty of Ege University, Izmir, Turkey.
Correspondence: All correspondence and requests for reprints should be addressed to: Funda Calis Atamaz, MD, Ege Universitesi Tip Fakultesi, Fiziksel Tıp ve Rehabilitasyon Anabilim Dali, Bornova, Izmir 35040, Turkey.
Efficacy of Therapeutic Ultrasound for the Management of Knee Osteoarthritis A Randomized, Controlled, and Double-Blind Study ABSTRACT
Disclosures: Equipment and financial support were provided by Ege University for this project. Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article.
0894-9115/14/9305-0405 American Journal of Physical Medicine & Rehabilitation Copyright * 2013 by Lippincott Williams & Wilkins DOI: 10.1097/PHM.0000000000000033
Cakir S, Hepguler S, Ozturk C, Korkmaz M, Isleten B, Atamaz FC: Efficacy of therapeutic ultrasound for the management of knee osteoarthritis: a randomized, controlled, and double-blind study. Am J Phys Med Rehabil 2014;93:405Y412.
Objective: The aim of this study was to compare whether the effectiveness of continuous ultrasound (US) was superior against pulsed US and against sham US in knee osteoarthritis.
Design: A randomized controlled study was carried out on 60 patients diagnosed with knee osteoarthritis according to American College of Rheumatology. The patients were randomized into the following three treatments: (1) continuous US (at a frequency of 1 MHz with intensity of 1 W/cm2), (2) pulse US (same frequency and intensity on 1:4 pulse ratio), and (3) sham US. All treatments were applied with 5-cm2 head US device five times a week for 2 weeks in addition to home exercise program including quadriceps isometric exercise, muscle strength exercises, and stretching exercises of the lower extremity muscles for at least three times per week. Assessments were performed at baseline, at the end of the treatment, and at the end of the treatments and at the sixth month using the following measurements: Western Ontario and McMaster University Osteoarthritis IndexYpain, stiffness, function, visual analog scaleYpain at rest, visual analog scaleYpain on movement, visual analog scaleYdisease severity, and 20-m walking time. Among these parameters, the Western Ontario and McMaster University Osteoarthritis IndexYpain was the primary outcome.
Results: All groups showed a significant improvement in all parameters in both following visits (P G 0.05). However, there was no significant difference between the groups. Although the mean reduction percent in Western Ontario and McMaster University Osteoarthritis IndexYpain was significantly higher in group I (continuous US) when compared to sham group (46.5% vs 28.9%, P G 0.05) at the end of the treatment, this result was not found in other pain parameters.
Conclusions: The present study demonstrated that all assessment parameters significantly improved in all groups without a significant difference. This result suggested that therapeutic US provided no additional benefit in improving pain and functions in addition to exercise training. Key Words: www.ajpmr.com
Osteoarthritis, Therapeutic Ultrasound, Thermal Therapy
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O
steoarthritis (OA) is a chronic degenerative disease of joints characterized by marginal osteophyte formation, subchondral bone changes and focal loss of articular cartilage.1 Although it may affect many joints, weight-bearing joints like knee joint are especially at risk for OA. Because it has been reported as being a major cause of significant morbidity and an extensive use of health-care resources in elderly population, its therapy is essential in the world-wide. According to recent guidelines, primary objective is to reduce of pain and to improve functional disability in the treatment of OA.2Y4 Thermal therapies are widely used in knee OA for these purposes since it is well known that heat increases tissue metabolism, collagen elasticity, capillary blood flow and decreases muscle spasms.5 Therapeutic ultrasound (US) is one of the thermal therapy modalities used in knee OA.5Y7 According to the results of the studies comparing the effects of therapeutic US with those of sham US, it could be effective for decreasing pain and improving physical functions in patients with knee OA. Therapeutic US can also be used for its non-thermal (chemical, biologic, mechanic) effects in a pulse mode.5,9,10 It is widely used by physical therapists for acute pain and inflammation of OA. Moreover, some authors reported that US delivered with a pulsed mode and with low intensity had more effects on pain improvement when it was compared with continuous US.10 However, there is limited scientific evidence to support the use of both modalities of US in patients with knee OA due to the inadequacies in the quality of and appropriateness of randomized controlled trials. Similarly, it cannot be concluded exactly which modality of US is the most effective in relieving the pain of knee OA without inflammation. In this study, it was aimed to compare the effectiveness of continuous US and pulsed US in the knee OA. At the same time, the effects of these modalities of US were compared with those of sham US in addition to exercise training.
MATERIALS AND METHODS Patients and Study Design The randomized, controlled, double-blind and factorial design study, the outpatients with knee pain for at least at 6 months least, diagnosed knee OA according to American College of Rheumatology, confirmed with radiologically in KellgrenYLawrence grades of 2 or 3,11 aged 40Y80 years were eligible. The patients who had an experience of any physical therapy agent, intra-articular corticosteroid therapy
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or chondroprotective agents during the 30 days prior to the study or viscosupplementation treatment within 6 months prior to the study were excluded. The patients were also excluded if they had a diagnosis of joint infection, neoplasm, diabetes mellitus, paresis, osteonecrosis, recent trauma, ascertained/suspected pregnancy or lactating and poor general health status. The other exclusion criteria were any history of contraindication of heat therapy or previous major surgery. The study was approved by the institutional review board at each center, and all participants provided written informed consent. During the therapy period and within 1 week before the treatment patients were not allowed to take non-steroidal antiinflammatory drugs (NSAIDs). Paracetamol use up to 2000 mg/day was allowed. Other drugs for systemic diseases were not stopped. Randomization was carried out by using covariate adaptive randomization with Frane method.12 The patients were randomized into following three treatments: I. continuous US, II. pulse US and III. sham US. All patients, investigators and analysts were blinded with the exception of the safety monitoring board member (SH), but this member did not assess the patients. All treatments were applied with 5 cm2 head US device for 5 times a week for 2 weeks by same device and same physiotherapist (Enraf Nonius Sonoplus 190). Continuous US was administered at a frequency of 1 MHz with intensity of 1 W/cm2. Pulse US was used for same frequency and intensity on 1:4 pulse ratios. These treatment parameters were chosen according to previous studies.13 The patients in the sham group received exactly the same treatment procedure as the treatment groups, except that the power switch was off. Each treatment was continued approximately 12 minutes over the painful area in the knee region with full contact in a supine position. All patients instructed to perform home exercise program including quadriceps isometric exercise, muscle strength exercises (chair lift and mini-squats exercises) and stretching exercises of the lower extremity muscles at least for 3 times per week. To ensure that exercises were learned properly, a complete set of premade exercise cards which have shown all exercises were also hand out. At the following visits, the patients were instructed to regularly perform their exercises.
Assessments Firstly, patients_ age, weight, body mass index (BMI), disease duration, current drug therapies
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were recorded. All assessments were carried out at baseline, at the end of the treatment and 6th months by the same physician who was unaware for the patient_s group of treatment. Primary outcome was Western Ontario and McMaster University Osteoarthritis Index (WOMAC)Ypain.14 In addition, 100 mm VAS was used in assessing knee pain at rest and knee pain on movement. The patients were also asked to assess their disease severity by using VAS. In addition, the following clinical parameters were used to assess the response to the treatment: WOMAC-stiffness, WOMAC-function, 20 meter walking time (sc).
Sample Size The treatment response was defined as a 40% improvement in WOMAC-pain scores, which corresponds to an average decrease of 8 points.15 The number of patients recruited was determined according to a power of 0.80, a P value of 0.05 and
30% dropout rate with paired t test. The needed patient number was 12 for each group.
Statistics Statistical analyses were performed with the 15.0 Statistical Package for the Social Sciences (SPSS). All the results were expressed as mean T SD (standard deviation). A P value below 0.05 was considered a statistical significance. The repeated measurements analysis of variance was used to evaluate over the time of observation for the clinical assessment parameters. Post Hoc test was Bonferroni test. Comparison analysis was carried out between treatment groups by One-way analysis of variance (ANOVA) test. In addition, standardized effect sizes (Cohen d) with 95% confidence intervals (95% CI) were calculated as a difference between mean scores divided by the pooled SD.16
FIGURE 1 Participant flowchart and assessment. www.ajpmr.com
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RESULTS Figure 1 summarizes the patient recruitment, participation and attrition during the study. No patient reported any complain leading to noncompliance. No patient received other therapy except the intake of paracetamol during follow-up. Fifty eight patients completed the study. One patient in group 1 could not attend follow-up visit at 6th month due to health problems not related knee pain. One patient in group 3 stated not enough time to attend as a reason at 6th month. As shown in Table 1, there were no significant differences among the groups at baseline. In the Table 2, the clinical characteristics related with pain are presented. All groups showed a significant improvement in all pain parameters in both following visits (P G 0.05). However, there was no significant difference among the groups. Although the mean reduction percent in WOMACpain was significantly higher in group I (continuous US) when compared to sham group (P G 0.05) after the treatment, this result was not found in other pain parameters. The Cohen d value was also 0.9 for sham group after the treatment while other treatment groups showed the Cohen d values higher than 1.0. Table 3 presents functional clinical parameters. A significant improvement of WOMAC- function was seen in all groups during the follow-up (P G 0.05) without any difference among the groups. The Cohen d values were also higher than 1.0 for all groups. When the patient_s judgment for her/his disease severity was measured on a VAS, this parameter was significantly decreased in all patients. There was no statistical significant difference among the groups. Moreover, the mean reduction percents from baseline for these parameters were similar in all patients.
In all groups, 20 meter walking times were significantly improved after the treatments (P G 0.05), although the mean reduction percents from baseline were not sufficient in clinically. The Cohen d values showed small effect sizes in this parameter. On the other hand, this improvement did not continue at 6th month.
DISCUSSION The present study demonstrated that all assessment parameters significantly improved in all groups without a significant difference. This result suggested that therapeutic US provided no additional benefit in improving pain and functions in addition to exercise training. Although therapeutic US is a frequently used modality in clinical practice of knee OA, the quality of the evidence based on randomized controlled studies is low due to considerable results_ heterogeneity, lack of blindness and insufficient follow-up.10,13 Moreover, there is no standardized application approach regarding its intensity, mode and therapeutic dose. Despite the sensory differences between treatment and sham groups, blinding represents an important, distinct aspect of randomized controlled trials and prevents bias. Indeed, in the review of studies in therapeutic US, it has been reported that the studies had high risk of bias.10,13 The inclusion of patients who had no experience of any physical therapy agent may allow blinding of the patients in such studies if a sham intervention is identical in appearance from the control intervention as reported previously.17 Based on this belief, we excluded the patients who had an experience of any physical therapy agent to achieve blinding. Another issue is short follow-up period of these studies because clinical evaluations were carried out
TABLE 1 Characteristics of the Patients at Baseline
Age (year, mean TSD) Sex * Women (%) Men (%) BMI (kg/m2, mean T SD) Duration (year, mean T SD) Side* Right (%) Left (%)
Group 1
Group 2
Group 3
(n = 20)
(n = 20)
(n = 20)
P Value
56.9 T 8.8
58.2 T 9.9
57.1 T 7.8
0.894
14 (70) 6 (30) 27.9 T 4.4 4.0 T 2.9
16 (80) 4 (20) 30.9 T 4.0 5.1 T 4.1
17 (85) 3 (15) 29.5 T 5.9 4.5 T 3.8
0.714
12 (60) 8 (40)
11 (55) 9 (45)
12 (60) 8 (40)
0.515
0.146 0.508
One way-ANOVA test, * Chi-square test. BMI: Body mass index.
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TABLE 2 The characteristics related with pain during the study Group 1- Continuous US
Group 2- Pulsed US
Group 3- Sham US
(n = 20)
(n = 20)
(n = 20)
Mean T SD WOMAC-pain At baseline l At end of treatment Mean difference 95% Cl Effect size (d) 6th month Mean difference 95% Cl Effect size (d) VAS-pain at rest At baseline l At end of treatment Mean difference 95% Cl Effect size (d) 6th month Mean difference 95% Cl Effect size (d) VAS-pain on movement At baseline l At end of treatment Mean difference 95% Cl Effect size (d) 6th month Mean difference 95% Cl Effect size (d)
15.9 T 4.3 8.5 T 4.5* 7.4 4.8 to 10.0 1.7 9.5 T 2.6*
%
46.5
40.3
2.1 to 10.7 1.8 57.9 T 20.2 28.3 T 18.2* 49.6 39.4 to 54.8 1.5 21.4 T 17.8* 36.5 22.7 to 50.3 1.9 75.5 T 18.3 37.0 T 23.0* 38.5 26.8 to 42.2 1.9 38.7 T 16.2* 36.8 26.8 to 42.0 2.1
51.1
63.0
51.0
48.7
Mean T SD 14.5 T 3.1 9.5 T 3.9* 5.0 2.4 to 7.6 1.4 11.3 T 2.2* 3.2 0.8 to 5.6 1.2 55.7 T 17.8 26.9 T 19.5* 28.8 17.8 to 39.8 1.5 20.2 T 14.1* 35.5 21.5 to 49.5 2.2 73.0 T 19.9 48.7 T 18.6* 24.3 18.4 to 28.2 1.3 37.5 T 24.1* 35.5 29.8 to 39.2 1.6
%
34.5
22.1
51.7
63.7
33.3
48.6
Mean T SD 14.9 T 4.3 10.6 T 4.8* 4.3 1.4 to 7.7 0.9 11.1 T 2.6* 3.8 1.1 to 6.5 1.1 53.6 T 19.1 27.8 T 21.9* 25.8 18.6 to 33.0 1.3 22.3 T 14.2* 31.3 14.9 to 47.7 1.9 72.2 T 21.8 39.4 T 27.2* 32.8 24.5 to 41.5 1.3 38.1 T 27.0* 34.1 28.6 to 39.4 1.4
%
Pl
28.9
0.029
25.5
0.069
48.1
0.781
58.4
0.485
45.4
0.082
47.2
0.578
* P G 0.05. repeated measurements analysis of variance. l One way ANOVA test for the reductions. %: Reduction in the baseline value. US: US. WOMAC: The Western Ontario and McMaster University Osteoarthritis Index. VAS: Visual analog scale.
only at baseline and at the end of the treatment. When it is compared with those of the studies about efficacy of US on knee OA,18Y21 it seems that we had sufficient follow-up period. Most importantly, the main problem which was reported the cause of low quality of the evidence in review of therapeutic US was results_ heterogeneity. The reason was that US treatment had been used different intensity, mode and therapeutic dose in various studies. For example, some authors reported that US delivered with a pulsed mode and with low intensity had more effects on pain improvement with non-thermal effects.10,13 In vitro studies support the useful effects of pulsed US with its anabolic effects on cartilage. It has been showed that it stimulated chondrocyte proliferation and matrix production in human articular cartilage.22,23 www.ajpmr.com
There are also the studies shown that it stimulated osteogenesis and fracture healing.24 On the other hand, therapeutic US is primarily used for its thermal effects. Deep heating with US can produce increased capillary permeability and tissue metabolism, enhancement of fibrous tissue extensibility and elevation of the pain threshold leading pain relief effect.6,25 So indeed, the studies used continuous US reported significant improvements in pain parameters.18,26 According to these results, it cannot be concluded exactly what is optimal dosage and mode for the most effect in relieving pain on the knee OA. Moreover, it is well known that the resultant tissue temperature following application of US will primarily depend on the extent of conduction into surrounding tissues and dissipation by blood Therapeutic Ultrasound for Knee Osteoarthritis
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TABLE 3 The results of the functional parameters Group 1- Continuous US
Group 2- Pulsed US
Group 3- Sham US
(n = 20)
(n = 20)
(n = 20)
Mean T SD WOMAC-function At baseline l At end of treatment Mean difference 95% Cl Effect size (d) 6th month Mean difference 95% Cl Effect size (d) 20 meter walking time (sc) At baseline l At end of treatment Mean difference 95% Cl Effect size (d) 6th month Mean difference 95% Cl Effect size (d) VAS-disease severity At baseline l At end of treatment Mean difference 95% Cl Effect size (d) 6th month Mean difference 95% Cl Effect size (d)
55.7 T 13.4 35.6 T 12.6* 20.1 17.8 to 22.4 1.5 32.6 T 11.3* 23.1 17.9 to 28.3 1.9 15.4 T 4.1 13.7 T 2.4* 1.7 1.1 to 2.3 0.5 15.1 T 1.9 0.3 j0.1 to 0.9 0.1 73.9 T 19.2 34.2 T 21.6* 39.7 34.1 to 45.3 1.9 30.0 T 11.6* 43.9 38.2 to 49.6 2.8
Mean T SD
%
52.4 T 11.9 37.2 T 12.6* 15.2 12.7 to 17.7 1.2 37.1 T 6.2* 15.3 12.1 to 18.5 1.6
36.1
41.5
15.5 T 2.5 14.3 T 2.3* 1.2 1.0 to 1.4 0.5 16.8 T 3.3 j1.3 j1.9 to 0.5 0.4
11.0
1.9
67.9 T 18.7 30.8 T 20.8* 37.1 32.5 to 41.7 1.9 32.5 T 10.7* 35.4 31.8 to 39.0 2.3
53.7
59.4
%
29.0
29.2
7.7
j8.3
54.6
52.1
Mean T SD 52.5 T 15.4 38.9 T 16.9* 13.6 11.0 to 16.2 0.8 35.5 T 8.1* 17.0 14.2 to 20.0 1.4 14.7 T 2.8 13.3 T 2.7* 1.4 0.9 to 1.9 0.5 15.1 T 2.4 j0.4 j0.9 to 0.1 0.2 68.4 T 20.5 33.5 T 27.7* 34.9 29.4 to 40.4 1.4 29.5 T 11.0* 38.9 31.2 to 46.6 2.4
%
Pl
25.9
0.057
32.4
0.067
9.5
0.124
j2.7
0.055
51.0
0.851
56.9
0.245
* P G 0.05. repeated measurements analysis of variance. l One way ANOVA test for reductions. %: Reduction in the baseline value. US: US. WOMAC: The Western Ontario and McMaster University Osteoarthritis Index. VAS: Visual analog scale.
perfusion.27 Since dissipation by blood perfusion is highly variable and poor in fatty tissue, higher doses of US may be used in obese patients to receive the same intensity at the target tissue. Considering this uncertainty of treatment parameters, we selected treatment parameters based on previous data.13 Then, we attempted to compare efficacy of pulse and continuous US in addition to exercise therapy. Our findings showed that pain was significantly decreased in both US groups without a difference. The parameters related with functions were also improved in both treatments. At the same time, we detected similar findings in sham group as a surprising finding. Because the patients in the sham group were given exercise training, we cannot conclude the effect of sham intervention on pain relief. Nevertheless, this finding suggested that neither pulsed US
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nor continuous US provided additional benefit in improving pain. In a similar study conducted by Tascioglu et al,19 pain relief with respect to VAS and WOMAC was significantly more in the group of US with pulsed mode. However, in that study, continuous mode of US was administered with intensity of 2 W/cm2 while we used 1 W/cm2. Considering the conclusion reported by Sanchez AL10 that US applied using low intensity and pulsed mode could be more effective, it can be explained why we did not find a significant difference between pulsed US and continuous US groups with 1 W/cm2 intensity in contrast to that study. Another statement can be addressed that exercise training was not prescribed in that study although it is well known that exercise reduces pain and improves function in patients with knee OA. In
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the study of Ulus et al,21 the authors concluded that the effect of US could be masked by the exercises because they could not find a difference between groups similar to our study. Pain already decreased up to 60% even at 6th month (Table 2) in our study. Then, we cannot state whether exercise had alone impact on this result and US provided no additional benefit in analgesia. However, in this stance, it should be discussed the effect of sham intervention on pain relief. Since many study found that the patients in the sham group showed significant improvement when compared with baseline values, the authors reported that the sham effect could be attributable to various factors such as age, diagnosis, study design, therapist and patient relationship or cultural differences.28 These factors may be contributed to pain relief in our sham group. Our study has several limitations. Firstly, we did not record the intake of paracetamol even through paracetamol use up to 2000 mg/day was allowed. The analgesic use was significantly higher in sham group although there was no difference with respect to improve pain parameters in previous data.29 Considering this data, it can be concluded that the intake of paracetamol may be higher in our sham group. Another limitation of the study could be the lack of a group consisting of US alone, because we cannot conclude whether US without exercise has similar effects on improvement for knee pain. Further trials may be needed to expose amount of paracetamol use in the patients, and to present solely the efficacy of US without exercise. Treatment parameters can be addressed as another limitation of the study. For example, pulse US is usually used in higher intensities then continuous one in contrast to our study. Ten almost daily sessions within 2 weeks may be discussed that it is much more than usually accepted. However, there is no standardized intervention for US as stated in the review of Rutjes et al.13 This result suggests that physician should consider the type of the patient population to be targeted in selecting treatment parameters. In conclusion, this randomized and controlled study which compared the effectiveness of continuous US, pulsed US and sham in addition to exercise training in the knee OA showed that all assessment parameters significantly improved in all groups without a significant difference. This result has to be confirmed by further well designed controlled studies. REFERENCES 1. Lawrence JS, Bremner JM, Bier F: Osteo-arthrosis. Prevalence in the population and relationship between symptoms and x-ray changes. Ann Rheum Dis 1966;25:1Y24 www.ajpmr.com
2. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines: Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. Arthritis Rheum 2000;43:1905Y15 3. Zhang W, Nuki G, Moskowitz RW, et al: OARSI recommendations for the management of hip and knee osteoarthritis: Part III: Changes in evidence following systematic cumulative update of research published through January 2009. Osteoarthritis Cartilage 2010;18:476Y99 4. Crielaard JM, Henrotin Y: Scientific basis of physical therapy and rehabilitation in the management of patients with osteoarthritis, in Reginster JY, Pelletier JP, Martel-Pelletier J, et al, (eds): Osteoarthritis Clinical and Experimental Aspects. Berlin, Germany, Springer-Verlag, 1999, pp 453Y79 5. Rand SE, Goerlich C, Marchand K, et al: The physical therapy prescription. Am Fam Physician 2007;76: 1661Y6 6. Baker KG, Robertson VJ, Duck FA: A review of therapeutic ultrasound: Biophysical effects. Phys Ther 2001;81:1351Y8 7. Lucas B: Treatment options for patients with osteoarthritis of the knee. Br J Nurs 2005;14:976Y81 8. Iversen MD: Rehabilitation interventions for pain and disability in osteoarthritis. Am J Nurs 2012;112 (suppl):S32Y7 9. Nakamura T, Fujihara S, Yamamoto-Nagata K, et al: Low-intensity pulsed ultrasound reduces the inflammatory activity of synovitis. Ann Biomed Eng 2011;39:2964Y71 10. Sanchez AL, Richardson J, Maclntyre NJ: Efficacy of ultrasound therapy for the management of knee osteoarthritis: A systematic review with meta-analysis. Osteoarthritis Cartilage 2010;18;1117Y26 11. Kellgren JH, Lawrence JS: Radiologic assessment of osteoarthritis. Ann Rheum Dis 1957;16;494Y502 12. Frane JW: A method of biased coin randomization, its implementation, and its validation. Drug Info J 1998;32:423Y32 13. Rutjes AW, Nu¨esch E, Sterchi R, et al: Therapeutic ultrasound for osteoarthritis of the knee or hip. Cochrane Database Syst Rev 2010;1:1Y43 14. Tu¨zu¨n EH, Eker L, Aytar A, et al: Acceptability, reliability, validity and responsiveness of the Turkish version of WOMAC osteoarthritis index. Osteoarthritis Cartilage 2005;13:28Y33 15. Gundog M, Atamaz F, Kanyilmaz S, et al: Interferential current therapy in patients with knee osteoarthritis: Comparison of the effectiveness of different amplitude-modulated frequencies. Am J Phys Med Rehabil 2012;91:107Y13 16. Cohen J: Statistical Power Analysis for the Behavioral Sciences. Hillsdale, NJ, Erlbaum, 1988, p 567 17. Rutjes AWS, Nu¨esch E, Sterchi R, et al: Transcutaneous electrostimulation for osteoarthritis of the knee. Cochrane Database Syst Rev 2009;7; CD002823
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18. Ozgonenel L, Aytekin E, Durmusoglu G: A double-blind trial of clinical effects of therapeutic ultrasound in knee osteoarthritis. Ultrasound Med Biol 2009;35:44e9 19. Tascioglu F, Kuzgun S, Armagan O, et al: Short-term effectiveness of ultrasound therapy in knee osteoarthritis. J Int Med Res 2010;38:1233Y42 20. Falconer J, Hayes KW, Chang RW: Effect of ultrasound on mobility in osteoarthritis of the knee. A randomized clinical trial. Arthritis Care Res 1992;5:29Y35 21. Ulus Y, Tander B, Akyol Y, et al: Therapeutic ultrasound versus sham ultrasound for the management of patients with knee osteoarthritis: A randomized double-blind controlled clinical study. Int J Rheum Dis 2012;15:197Y206 22. Nolte PA, Klein-Nulend J, Albers GH, et al: Low intensity ultrasound stimulates endochondral ossification in vitro. J Orthop Res 2001;19:301Y7 23. Korstjens CM, Nolte PA, Burger EH, et al: Stimulation of bone cell differentiation by low intensity ultrasoundVA histomorphometric in vitro study. J Orthop Res 2004;22:495Y500 24. Korstjens CM, van der Rijt RH, Albers GH, et al: Lowintensity pulsed ultrasound affects human articular
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chondrocytes in vitro. Med Biol Eng Comput 2008; 46:1263Y70 25. Srbely JZ, Dickey JP, Lowerison M, et al: Stimulation of myofascial trigger points with ultrasound induces segmental antinociceptive effects: A randomized controlled study. Pain 2008;139:260Y6 26. Huang MH, Lin YS, Lee CL, et al: Use of ultrasound to increase effectiveness of isokinetic exercise for knee osteoarthritis. Arch Phys Med Rehabil 2005;86: 1545Y51 27. Baker KG, Robertson VJ, Duck FA: A review of therapeutic ultrasound: Biophysical effects. Phys Ther 2001;81:1351Y8 28. Johnson M, Din A: Ethnocultural differences in the analgesic effects of placebo transcutaneous electrical nerve stimulation on cold-induced pain in healthy subjects: A preliminary study. Complement Ther Med 1997;5:74Y9 29. Atamaz FC, Durmaz B, Baydar M, et al: Comparison of the efficacy of transcutaneous electrical nerve stimulation, interferential currents, and shortwave diathermy in knee osteoarthritis: A double-blind, randomized, controlled multicenter study. Arch Phys Med Rehabil 2012;93:748Y56
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