Confidential: For Review Only - BMJ · Confidential: For Review Only 1 1 Exercise therapy is a credible alternative to 2 arthroscopic partial meniscectomy for pre- 3 osteoarthritic

Confidential: For Review O

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Exercise therapy is a credible alternative to arthroscopic

partial meniscectomy for pre-osteoarthritic knees: A

randomised controlled trial with 2-year follow-up.

The Odense-Oslo Meniscectomy versus Exercise (OMEX)

study.

Journal: BMJ

Manuscript ID BMJ.2015.030744

Article Type: Research

BMJ Journal: BMJ

Date Submitted by the Author: 04-Dec-2015

Complete List of Authors: Kise, Nina; Martina Hansens Hospital, orthopaedic dep Risberg, May Arna; Department of Sports Medicine, Norwegian School of Sport Sciences, PO box 4014 Ullevål Stadion, N-0806 Oslo, Norway Stensrud, Silje; Oslo and Akershus University College of Applied Sciences, PO box 4 St. Olavs plass, NO-0130 Oslo, Norway Ranstam, Jonas; Clinical Sciences Lund, Orthopaedics Engebretsen, Lars; Oslo University Hospital, Orthopaedic Center Roos, Ewa; Institute of Sports Science and Clinical Biomechanics,

Keywords:

https://mc.manuscriptcentral.com/bmj

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Figure 1. Flow chart The ITT analyses of primary and secondary outcomes are based upon the patient groups in this Consort flow chart. The compound of the groups used in the PP and ATanalyses is presented

in a flow chart in Figure S2 in the supplementary appendix.

215x279mm (300 x 300 DPI)

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Figure 2. Changes in KOOS4 from baseline to 2-year follow-up ITT analysis. Mixed linear models regression analysis of covariance stratified by gender and study site with

adjustment for baseline scores. The within-subject covariance structure has compound symmetry.

There were no statistically significant differences between the groups at any observation points: 95% CI and

P-values for 3, 12 and 24 months are -5.0 to 5.3 (0.952), -0.5 to 9.8 (0.079), and -6.1 to 4.3 (0.723).

1058x769mm (72 x 72 DPI)

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Figure 3. Muscle strength assessed as total work knee extension from baseline to 12-month follow-up

ITT analysis. Mixed linear models regression analysis of covariance stratified by gender and study site with

adjustment for baseline scores. The within-subject covariance structure has compound symmetry.

There are statistically significant differences between the groups at 3 and 12 months: 95% CI (and P-values) for 3 and 12 months are -153.4 to -67.4 (<0.001), and -98.7 to -12.2 (0.012).

1058x769mm (72 x 72 DPI)

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Exercise therapy is a credible alternative to 1

arthroscopic partial meniscectomy for pre-2

osteoarthritic knees: A randomised controlled trial with 2-3

year follow-up. 4

The Odense-Oslo Meniscectomy versus Exercise (OMEX) study. 5

6

Nina Jullum Kise, MD1 7

May Arna Risberg, PT, PhD, Professor2 8

Silje Stensrud, PT, PhD3 9

Jonas Ranstam, PhD CStat, Professor (former)4 10

Lars Engebretsen, MD, PhD, Professor5 11

Ewa M. Roos, PT, PhD, Professor6 12

13

Key words: 14

Knee pain, Middle-aged, Knee arthroscopy, Meniscus, Exercise therapy 15

16

Word count: 4039 words 17

18

19

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1Nina Jullum Kise, NJK. Orthopaedic surgeon. Department of Orthopaedic Surgery, Martina Hansens 20

Hospital, PO box 823, N-1306 Sandvika, Norway 21

2May Arna Risberg, MAR. Physiotherapist / Professor. Norwegian Research Center for Active 22

Rehabilitation (NAR) / Department of Orthopaedic Surgery, Oslo University Hospital, Norway / 23

Department of Sports Medicine, Norwegian School of Sport Sciences, PO box 4014 Ullevål Stadion, N-0806 24

Oslo, Norway 25

3Silje Stensrud, SS. Physiotherapist / Researcher. Oslo and Akershus University College of Applied 26

Sciences, PO box 4 St. Olavs plass, NO-0130 Oslo, Norway 27

4Jonas Ranstam, JR. Independent statistician / Professor (former). Mdas AB, Rotfruktsgatan 12B, SE-28

21754 Ystad, Sweden 29

5Lars Engebretsen, LE. Orthopaedic surgeon / Professor. Department of Orthopaedic Surgery, Oslo 30

University Hospital, Norway / Oslo Sports Trauma Research Center (OSTRC), Norwegian School of Sport 31

Sciences, PO box 4014 Ullevål Stadion, N-0806 Oslo, Norway 32

6Ewa M. Roos, EMR. Physiotherapist / Professor. Research Unit for Musculoskeletal Function and 33

Physiotherapy, Institute of Sports Science and Clinical Biomechanics, University of Southern Denmark, 34

Campusvej 55, DK-5230 Odense, Denmark 35

36

Corresponding author: 37

Nina Jullum Kise, MD, Department of Orthopaedic Surgery, Martina Hansens Hospital, PO box 823, N-1306 38

Sandvika, Norway, [email protected], [email protected] 39

40

41

42

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ABSTRACT 43

Objective To determine the effect of exercise therapy and arthroscopic partial 44

meniscectomy on knee function in middle-aged patients with degenerative meniscal 45

tears in predominantly pre-osteoarthritic knees. 46

Design Randomised controlled trial. 47

Setting Orthopaedic departments at two public hospitals and two physiotherapy clinics 48

in Norway. 49

Participants 140 middle-aged patients (mean age 49.5 years, range 35.7-59.9) with 50

MRI-verified degenerative medial meniscal tear, 96% had no definite radiographic 51

osteoarthritis. 52

Interventions 12-week supervised exercise therapy alone or arthroscopic partial 53

meniscectomy alone. 54

Main outcome measure Intention-to-treat analysis of the between-group difference in 55

change in KOOS4 (defined a priori as the mean score from KOOSPain, KOOSSymptoms, 56

KOOSSports/Rec and KOOSQOL) from baseline to 2-year follow-up. Secondary outcomes are 57

the five KOOS subscales, SF-36, HUNT activity index and global rating of change in knee 58

function. Muscle strength and performance tests were evaluated at baseline, 3 and 12 59

months. 60

Results Both treatment groups revealed a significant improvement in knee function 61

measured with KOOS4 with no statistically significant between-group difference at 2 62

years. The exercise therapy group had greater improvement in KOOSsymptoms at 2 years 63

(5.4 points, 95% CI from 0.5 to 10.2; P=0.031) and greater improvement in all muscle 64

strength tests at 3 and 12 months. There were no serious adverse events in either group 65

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during the 2-year follow-up. Nineteen percent of the participants allocated to exercise 66

therapy crossed over to surgery during the 2-year follow-up with no additional benefit. 67

Conclusion In this first comprehensive randomised controlled trial comparing exercise 68

therapy alone to arthroscopic partial meniscectomy alone, there was no between-group 69

difference at 2 years. Our results should encourage clinicians and middle-age patients 70

with degenerative meniscal tear and no definite radiographic osteoarthritis to consider 71

supervised structured exercise therapy as the primary treatment option. 72

73

Trial registration www.clinicaltrials.gov (NCT01002794) 74

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INTRODUCTION 75

Background and objectives 76

In the Western world, as many as 300 in every 100,000 people undergo arthroscopic 77

partial meniscectomy annually.(1-3) In Denmark, the surgery rate doubled from 2000 to 78

2011,(4) with three out of four patients being above 35 years of age.(4) In patients, such 79

as these, most meniscal tears are degenerative, and may be regarded as the first sign of 80

osteoarthritis (OA).(5, 6) 81

82

In a recent meta-analysis, Thorlund et al. concluded that a small, but inconsequential, 83

benefit is seen from treatment interventions that involve arthroscopy. This small effect 84

is of short duration and absent at one year after surgery.(7) Only one(8) out of eight 85

randomised controlled studies (RCTs)(8-15) found greater pain relief one year after 86

treatment with partial meniscectomy combined with exercise therapy compared to 87

treatment with exercise therapy alone.(8) Short- and long-term follow-up studies have 88

shown that exercise therapy improves function and activity level in patients with 89

degenerative meniscal tears, whether they undergo surgical treatment or not.(9-11, 15) 90

91

No studies have compared the effect of surgery alone with exercise alone. Of the eight 92

published RCTs (8-15), five (8-12) were designed to study the effect of surgery in 93

addition to exercise therapy. In one study(15), the patients in the exercise group 94

received additional pharmacological treatment (NSAIDs, analgesics) and the two 95

remaining studies(13, 14) compared meniscectomy to sham surgery. Considering the 96

large amount of surgery performed worldwide, with or without postoperative exercise 97

therapy, and the inconsequential short-term additional pain relief seen from surgery in 98

addition to exercise, RCTs are needed to explore the comparative treatment effect of 99

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partial meniscectomy alone and supervised exercise therapy alone. Furthermore, only 100

two of the eight published RCTs included patients with no definite radiographic OA(14, 101

15). The aim of this study was to compare the 2-year treatment effect on patient-102

reported outcomes from exercise therapy versus arthroscopic partial meniscectomy in 103

middle-aged patients with an MRI-verified degenerative meniscal tear. 104

105

METHODS 106

Trial design 107

An RCT with two parallel intervention groups (1:1 ratio) compared exercise therapy 108

alone to arthroscopic partial meniscectomy alone. Follow-ups were performed at 3, 12 109

and 24 months, with the 2-year follow-up as the primary end point. While 3- and 12-110

month data were collected during a clinical visit, the follow-up at 2 years was conducted 111

by mail and only patient-reported outcomes were collected. 112

113

Participants 114

Between October 2009 and September 2012, participants were recruited from the 115

orthopaedic departments at Oslo University Hospital (OUH) (October 2009-April 2011) 116

and Martina Hansens Hospital (May 2011-September 2012), in Norway. All patients 117

provided informed written consent prior to participation. The RCT was performed 118

according to the Declaration of Helsinki and it was approved by the Regional Ethics 119

Committee of the Health Region of South-East Norway, and registered at 120

www.clinicaltrials.gov (NCT01002794). 121

122

Inclusion criteria were: age 35-60 years; unilateral knee pain for more than two months 123

without a significant trauma (defined as sudden onset of knee pain resulting from a 124

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single physical impact event); MRI-verified medial degenerative meniscal tear; and, at 125

most, radiographic changes equivalent to grade 2 according to the Kellgren-Lawrence 126

classification (KL).(16) A degenerative meniscal tear was defined as an intrameniscal 127

linear MRI signal penetrating one or both surfaces of the meniscus.(17) Furthermore, 128

the patients had to be eligible for arthroscopy, able to perform physical activities and 129

exercise, and to understand the Norwegian language. The standing posterior-anterior 130

radiographs were taken in a fixed-flexion position, using a Synaflexer® frame.(18) 131

Eligibility for surgery was confirmed by one of two orthopaedic surgeons based upon 132

patient history, physical examination and MRI findings. Exclusion criteria were: acute 133

trauma, locked knee, ligament injury, and knee surgery in the index knee during the 134

previous two years. 135

136

Interventions 137

The exercise therapy was carried out at one of two clinics, (Norwegian Sports Medicine 138

Clinic (NIMI) and Gnist Trening og Helse AS), using the same protocol and started as 139

soon as possible after randomisation, or later if preferred by the patient. The exercise 140

therapy program, previously been described in detail(19), consisted of progressive 141

neuromuscular and strength exercises over 12 weeks, performed during a minimum of 142

two and a maximum of three sessions per week (24-36 sessions). 143

The participants filled in exercise diaries and compliance with exercise was assessed as 144

the total number of exercise sessions completed out of 24 sessions. ‘Excellent 145

compliance’ was pre-defined as participation in 24 or more sessions (100%), 146

‘satisfactory compliance’ as 19-23 sessions (80-100%), and ‘poor compliance’ as 18 or 147

fewer sessions (less than 80%). In the per protocol analysis, completing 18 or fewer 148

sessions was defined as not following the protocol. Likewise, if participants in the APM-149

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group received physiotherapist-instructed exercise therapy postoperatively of adequate 150

quality for at least 18 sessions, they were defined as not following the protocol. 151

152

The arthroscopic surgery was performed as soon as possible after randomisation with 153

timing dependent upon waiting lists and patient preference. The arthroscopic 154

intervention was similar in both hospitals, performed as standard operations for 155

arthroscopic partial meniscectomy, and the participants followed normal preoperative, 156

perioperative, and postoperative routines. Six orthopaedic surgeons with at least ten 157

years of clinical experience performed the operations. 39 (61%) operations were 158

performed by one surgeon, the other surgeons performed 1-15 operations. The 159

participants were discharged from hospital on the day of surgery and were advised to 160

use two crutches postoperatively until gait normalised and no swelling or discomfort 161

occurred during weight-bearing. Written and oral instructions for simple home 162

exercises, aimed at regaining knee range of motion and reducing swelling, were 163

provided to the participants before hospital discharge. They were encouraged to 164

perform the exercises two to four times daily (See supplementary appendix Figure S1a-d 165

for written instructions). Five persons in the APM-group received passive postoperative 166

physiotherapy (median 2 sessions, range 1-3), but none had supervised exercise 167

therapy. 168

169

Surgery was performed with the patient under general anaesthesia, with or without 170

thigh tourniquet, antibiotic prophylaxis, or antithrombotic prophylaxis. Arthroscopes 171

with 30-degree optics and standard arthroscopic instruments were used. Ringer acetate 172

was used for lavage. Normal procedure involved two portals: anteromedial and 173

anterolateral, and if surgically required, additional portals were made and a lavage 174

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cannula was inserted laterally in the cranial recess. A diagnostic procedure including 175

evaluation of additional injuries (ligaments, cartilage) preceded systematic probing of 176

both menisci, and finally, all unstable meniscal tissue was resected. 177

178

Outcomes 179

The primary outcome was change from baseline to 2 years in KOOS4, defined as the 180

average score for four of the five KOOS subscale scores covering Pain, other Symptoms, 181

Function in Sport and Recreation (Sport/Rec), and knee-related Quality of Life (QOL). 182

The KOOS is reliable and has content validity for patients with meniscal tears and 183

osteoarthritis.(20, 21) It consists of 42 items scored from 0-4 on a Likert scale. Subscale 184

scores are calculated separately and transformed to a 0 (worst) to 100 (best) scale. The 185

questionnaires were completed during clinical visits at baseline, 3- and 12-month 186

follow-ups and distributed and collected by mail at the 2-year follow-up. 187

188

Secondary outcomes were changes from baseline to 2-year follow-up in the five KOOS 189

subscales, in a 5-point global rating of change scale(22) and in a Medical Outcomes 190

Study 36-Item Short-Form Health Survey (SF-36). For the global rating of change scale, 191

the participants were asked to evaluate their knee function at follow-ups compared with 192

knee function before inclusion as much better, better, unchanged, worse or much 193

worse.(22) The SF-36 is a self-administered questionnaire containing 36 items which 194

measure health perception on eight multi-item dimensions covering functional status, 195

well-being, and overall evaluation of health,(23) analysed as one physical component 196

summary (PCS) and one mental component summary (MCS). 197

For evaluation of physical activity level, an activity index based upon the physical 198

activity questions used in the HUNT1 study(24) was included as a secondary outcome. 199

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This activity index has been found to be reproducible and provides a useful measure of 200

leisure time physical activity for men.(24) The participants were asked to score 201

frequency, duration and intensity of their physical activity level on Likert scales and the 202

activity score was calculated according to the formula used in the HUNT 1 study,(24) 203

giving an index ranging from 0 (lowest) to 15 (highest) physical activity. 204

205

Tests of muscle strength and lower extremity performance were conducted at baseline, 206

3- and 12-month follow-ups. Data were collected using detailed test protocols by 207

experienced physiotherapists, who were familiar with the test procedures from 208

previous studies. The test protocol included a 10-minute warm-up on a stationary 209

bicycle, followed by muscle strength tests and lower extremity performance tests. The 210

first leg to be tested was determined by randomisation and the same order was applied 211

at the follow-ups. 212

213

A Biodex 6000 dynamometer was used to test quadriceps and hamstrings concentric 214

isokinetic muscle strength. The outcomes were peak torque and total work for both 215

quadriceps and hamstrings at 60 degrees per second. The reliability for isokinetic 216

muscle tests has previously been reported to be satisfactory.(25) 217

218

Three reliable and valid performance tests(26-28) were used for evaluation of lower 219

extremity function: the one-leg hop test for distance (measuring length in centimeters), 220

the 6-meter timed hop test (measuring time in seconds) and the knee-bends test 221

(measuring maximum number in 30 seconds). These test procedures have been 222

described previously.(29) 223

224

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Adverse events (AEs) and serious adverse events (SAEs) were recorded and categorised 225

into index knee or other sites. At all follow-ups, all participants were asked about 226

potential AEs and at the 2-year follow-up, medical charts from the participating 227

hospitals were checked. Any situations where participants sought health care were 228

defined as AEs. Death, cardiovascular or gastrointestinal events, deep vein thrombosis, 229

pulmonary embolism, systemic or local infection were categorised as SAEs. Knee 230

symptoms like pain, swelling, instability, and decreased range of motion were 231

categorised as AEs if the participants sought treatment for the AE. The participants were 232

encouraged to contact the participating hospitals for extraordinary clinical visits with 233

the orthopaedic surgeon if needed. 234

235

Sample size 236

The sample size calculation was based upon the primary outcome change in KOOS4 from 237

baseline to 2-year follow-up. To detect a 10-point difference with a standard deviation of 238

15, with a level of power of 90% and a level of significance of 0.05, and an estimated 239

15% dropout rate at 2 years, 56 participants were needed in each group. 240

241

Randomisation 242

Participants contributed to baseline data collection and testing before they were 243

randomly allocated to one of two parallel intervention groups, treated with either 244

arthroscopic partial meniscectomy (APM-group) or exercise therapy (ET-group). A 245

statistician at OUH determined the computer-generated randomisation sequence, 246

stratified by gender in blocks of eight, and concealed from the surgeons who enrolled 247

and assessed the participants. The allocations were kept in sequentially numbered 248

opaque envelopes that were opened by the participants after enrollment. 249

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250

Blinding 251

The test assessors were blinded to group allocation and long pants or neoprene sleeves 252

were worn by participants over both knees to hide possible surgical scars and preserve 253

blinding of group allocation. The statistician was blinded to group allocation during the 254

analysis. 255

256

Patient involvement 257

Patients were not involved neither in the design of this RCT, nor the recruitment to or 258

conduct of the trial. The research question was developed independently of patients’ 259

priorities, experience, and preferences. To ensure content validity, patients provided 260

content during development of KOOS, the primary outcome measure of this study. At 261

follow-ups the patients were asked about harms. Patients' experience of burden of the 262

respective interventions were not collected. When the results of this RCT are published, 263

information will be conveyed to the participants in lay language in a pamphlet 264

distributed by e-mail. 265

266

Statistical methods 267

The statistical analyses were performed according to the a priori published statistical 268

analysis plan (http://static.sdu.dk/mediafiles//5/E/5/%7B5E568A02-9475-4127-269

9B6C-0ADA7235DF77%7DSAP%20OMEX%2020.03.15.pdf). IBM SPSS® Statistics 270

Version 22 (IBM Corp, Armonk, NY, USA) was used for descriptive analysis of baseline 271

data and Stata® v14 (StataCorp. 2015. College Station, TX, USA) was used for analysis of 272

outcomes at 3, 12 and 24 months. 273

274

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All participants assigned to treatment were included in the primary efficacy analysis 275

(intention-to-treat (ITT) analysis). Between-group comparison of the primary end point, 276

change in KOOS4 from baseline to 2-year follow-up, was made with the use of Repeated 277

Measures Mixed Model stratified by gender and study site and with adjustment for 278

baseline imbalance of KOOS4 scores. The Repeated Measures Mixed Model was based on 279

the assumption that observations within a participant are equally correlated, i.e. that the 280

within-participant covariance structure had compound symmetry. 281

282

Between-group comparisons of the change from baseline to the 12- and 24-month 283

follow-ups on secondary outcomes measures (the five KOOS subscales, muscle strength 284

and performance tests, HUNT activity index and SF-36 PCS and MCS) were analysed 285

with ITT analyses similar to the primary outcome measure. Analysis of global rating of 286

change was performed using a Chi Square Test for trend, stratified for inclusion site. 287

Differences between the intervention groups at baseline were explored with unpaired T-288

Tests for continuous variables and independent samples Mann-Whitney-U Tests for 289

categorical variables. In addition to the ITT analysis, per protocol (PP) and as-treated 290

(AT) analyses were performed for the primary outcome KOOS4. 291

292

The KOOS, SF-36, muscle strength and performance scores are presented as means with 293

95% confidence intervals (95% CI). Regarding KOOS, a 95% CI that excluded differences 294

greater than 10 units between groups was interpreted as indicating the absence of a 295

clinically meaningful difference.(20) 296

297

RESULTS 298

Participant flow 299

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Out of 341 patients assessed for eligibility, 140 (41%) were randomised to the two 300

treatment groups, each with 70 participants. All 140 participants completed the baseline 301

questionnaires and baseline tests. 129 participants (92%) completed the 302

questionnaires at 3 and 12 months and 126 participants (90%) completed the 303

questionnaires at 2 years (Figure 1). 304

305

In the ET-group, 43 out of 70 (61%) participants completed the exercise therapy 306

program with satisfactory (17 participants) or excellent (26 participants) compliance. 307

These participants completed on average 25 exercise sessions (median 25, range 19-36). 308

Ten participants (14%) declined exercise therapy, and 2 (3%) did not return their 309

exercise diaries. 310

In the APM-group, 6 participants out of 70 (9%) did not undergo surgery, either due to 311

their own preference (1 participant) or because of lack of indication for operation at the 312

day of surgery (5 participants)(Figure 1). 313

The participants were included as randomised in the ITT analyses, but those not 314

completing the assigned treatments were excluded from the PP analysis (See 315

supplementary appendix, Figure S2). 316

317

Thirteen out of 70 participants (19%) in the ET-group crossed over to receive surgical 318

treatment between 3 and 16 months (mean 6 months) after inclusion. Of these, 319

approximately half had completed at least 19 exercise sessions. Participants who 320

crossed over to surgery were analysed in the APM-group in the AT analysis (See 321

supplementary appendix, Figure S2). 322

No participants in the APM-group crossed over to exercise therapy, defined as having at 323

least 18 sessions of supervised exercise. 324

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325

Due to persistent knee pain and catching of the knee, two participants (3%) in the APM-326

group were reoperated on at 12 and 15 months, respectively, and one cross-over 327

participant underwent a reoperation 6 months after the primary operation. One 328

participant in the APM-group (KL grade 1) and one participant crossing over from the 329

ET-group to arthroscopic partial meniscectomy (KL grade 1) underwent osteotomy at 6 330

and 16 months respectively after the index surgery, due to increasing pain and further 331

impaired knee function that was diagnosed as being caused by OA by the surgeon who 332

followed them clinically. A third participant, in the APM-group (KL grade 1), was 333

diagnosed with OA and treated with physical therapy and NSAIDs. 334

335

Baseline data 336

Participant baseline characteristics, including OA severity according to KL, are 337

presented in Table 1. At baseline, there were no differences between the treatment 338

groups regarding demographic data, body mass index (BMI), educational level, smoking 339

habits, use of analgesics due to knee pain, duration of knee symptoms, radiographic OA-340

grade, physical and mental health status assessed by SF-36, knee function assessed by a 341

visual analogue scale (VAS), muscle strength, functional performance, KOOS4, or the 342

KOOS subscales: Pain, ADL and Sport/Rec. The APM-group had higher activity level 343

measured with the HUNT activity index (mean points ± SD; 4.0 ± 2.9 vs. 2.5 ± 2.2, 344

P=0.002), fewer knee symptoms measured with KOOSSymptoms (mean points ± SD; 78 ± 345

15 vs. 70 ± 17, p=0.005) and better knee-related QOL measured with KOOSQOL (mean 346

points ± SD; 46 ± 16 vs. 40 ± 17, P=0.046)(Table 1). 347

348

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On an extra inspection of radiographs, it was found that one participant allocated to the 349

ET-group had KL grade 3, which was an exclusion criterion. The participant was thus 350

unintentionally included, but had fulfilled all the follow-ups and was included in all 351

appropriate analyses, as a sensitivity analysis that excluded this participant showed no 352

difference in results. 353

354

Table 1. Baseline characteristics 355

Baseline characteristics analysed with independent sample t-tests (continuous 356 variables) and non-parametric independent sample tests (categorical variables). 357

358

Baseline characteristics

ET-group (n = 70)

APM-group (n=70)

P-value

Demographics

Men - n (%) 43 (61 %) 43 (61 %) P=1.000

Right knee - n (%) 41 (59 %) 41 (59 %) P=0.920

Age - years, mean ±SD 49.9 ±6.2 49.1 ±6.1 P=0.209

Body mass index - kg/m2, mean ±SD 26.3 ±4.5 26.0 ±4.5 P=0.456

Smoker - n (%) 3 (4.2 %) 11 (16 %) P=0.042

Analgesics daily - n (%) 3 (4.2 %) 3 (4.2 %) P=1.000

Primary school only - n (%) 3 (4.2 %) 2 (2.9 %) P=0.652

University level - n (%) 37 (53 %) 36 (51 %) P=0.821

Radiographic knee OA severity (Kellgren-Lawrence classification)

Grade 0 – n (%) 49 (70%) 51 (73%)

P=0.665 Grade 1– n (%) 18 (26%) 16 (23%)

Grade 2– n (%) 2 (3%) 3 (4%)

Grade 3– n (%) 1 (1%) 0

Pain and function

Duration of pain - months, mean ±SD 17.9 ±20.5 12.4 ±17.0 P=0.076

VAS ( for knee function) - score

(0-100, worse to best), mean ±SD

59.9 ±20.8

64.6 ±19.2

P=0.103

Activity level

HUNT activity index score (0-15, worst to best),

mean ±SD

2.5 ±2.2 4.0 ±2.9 P= 0.002

KOOS (0-100, worst to best)

KOOS4, mean ±SD 54 ±18 60 ±14 P=0.055

KOOSPain, mean ±SD 63 ±21 68 ±15 P=0.171

KOOSSymptoms, mean ±SD 70 ±17 78 ±15 P=0.005

KOOSADL, mean ±SD 75 ±21 80 ±16 P=0.150

KOOSSport/Rec, mean ±SD 44 ±26 48 ±23 P=0.374

KOOSQOL, mean ±SD 40 ±17 46 ±16 P=0.046

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359 ET= exercise therapy; APM= arthroscopic partial meniscectomy, OA= osteoarthritis; VAS= visual analogue 360 scale; HUNT= Helseundersøkelsen i Nord-Trøndelag; KOOS=Knee injury and Osteoarthritis Outcome 361 Score; SF-36=36-Item Short Form Health Survey; PCS=physical component summary; MCS= mental 362 component summary; Nm=Newtonmetre; J=Joule. 363 364

Outcomes 365

In the ITT analysis, there was no significant between-group difference in mean change 366

from baseline to 2-year follow-up in KOOS4 score (0.9 points, 95% CI -4.3 to 6.1; 367

P=0.723) after adjustment for baseline imbalance and randomisation stratification 368

factors. The mean improvements were 25.3 points (95% CI 21.6 to 29.0) in the ET-group 369

and 24.4 points (95% CI 20.7 to 28.0) in the APM-group (Figure 2). Likewise, in the ITT 370

analyses there were no statistically significant between-group differences in change in 371

KOOS4 from baseline to follow-ups at 3 and 12 months (Figure 2). 372

373

Table 2. Secondary outcomes: Changes in patient-reported outcomes from 374

baseline to 2 years. 375

376

ITT analysis. Mixed linear models regression analysis of covariance stratified by gender 377

and study site with adjustment for baseline scores. The within-subject covariance 378

structure has compound symmetry. 379

Outcome

ET-group

APM-group

Between-group

difference*

P-value

SF-36 (0-100, worst to best)

SF-36 PCS, mean ±SD 46.4 ±7.7 47.3 ±6.1 P=0.104

SF-36 MCS, mean ±SD 54.7 ±9.1 55.6 ±6.7 P=0.454

Muscle strength (higher is better)

Peak torque extension – Nm, mean ±SD 180.2 ±46.6 183.5 ±49.7 P=0.523

Total work extension – J, mean ±SD 863.3 ±224.1 881.2 ±241.3 P=0.671

Peak torque flexion – Nm, mean ±SD 86.6 ±25.5 89.3 ±24.7 P=0.142

Total work flexion – J, mean ±SD 478.8 ±175.3 499.3 ±145.5 P=0.131

Performance tests

One leg hop test – cm, mean ±SD (higher is better)

76.6 ±32.7

83.2 ±35.5

P=0.256

6-meter timed hop test – sec, mean ±SD (lower is better)

3.1 ±1.7

2.7 ±1.2

P=0.130

Knee-bends 30-sec test – n, mean ±SD (higher is better)

28 ±11

30 ±10

P=0.525

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Mean (95% CI)

n=62 n=61

KOOSPain, points

23.2 (19.4 to 27.0)

21.7 (18.0 to 25.5)

-1.4 (-6.8 to 3.9)

0.596

KOOSSymptoms, points

17.4 (14.0 to 20.9)

12.0 (8.7 to 15.4)

-5.4 (-10.2 to -0.5)

0.031

KOOSADL, points

15.4 (12.2 to 18.6)

13.8 (10.7 to 16.9)

-1.6 (-6.1 to 2.9)

0.480

KOOSSport/Rec, points

29.3 (24.0 to 34.7)

30.8 (25.4 to 36.1)

1.4 (-6.2 to 9.1)

0.714

KOOSQOL, points

31.2 (26.8 to 35.7)

33.1 (28.7 to 37.5)

1.8 (-4.5 to 8.1)

0.575

HUNT activity index,

points

1.4 (0.7 to 2.0)

0.9 (0.3 to 1.5)

-0.5 (-1.4 to 0.5)

0.338

SF-36 PCS, points

5.6 (3.9 to 7.3)

7.0 (5.4 to 8.7)

1.4 (-1.1 to 3.8)

0.262

SF-36 MCS, points

0.9 (-1.0 to 2.7)

-0.3 (-2.1 to 1.5)

-1.2 (-3.8 to 1.3)

0.339

380

*Between-group differences; Negative values: ET-group higher scores than APM-group, 381

positive values: APM-group higher scores than ET-group. 382

383

PP and AT analyses of between-group differences in mean change from baseline to 2-384

year follow-up in KOOS4 score gave similar results to the ITT analysis; in the PP analysis 385

the difference was 2.1 points (95% CI -3.8 to 8.1; P=0.474) and in the AT analysis, 2.0 386

points (95% CI -4.2 to 8.1; P=0.522), both in favour of the ET-group. 387

388

The number of participants included in the ITT analysis was 62 and 64 in the ET-group 389

and APM-group, respectively (Figure 1). Both the PP and AT analyses included 34 390

participants in the ET-group, and 58 and 70 participants in the APM-group, respectively 391

(See supplementary appendix, Figure S2). 392

393

Ancillary analyses 394

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Patient-reported secondary outcomes are presented in Table 2 (and in supplementary 395

appendix, Tables S2 and S3). From baseline to 2-year follow-up, there were no 396

significant between-group differences with the exception of the ET-group having 5.4 397

points greater improvement in KOOSSymptoms than the APM-group (95% CI 0.5 to 10.2; 398

P=0.0308). There were no significant differences between the groups regarding changes 399

in HUNT activity index, SF-36 or Global rating of change. 400

401

The ET-group had significantly greater improvement in all muscle strength tests both at 402

3- and 12-month follow-ups (P-values ranging from <0.001 to 0.034). As an example, 403

change in total work for knee extension is illustrated in Figure 2. Changes in all muscle 404

strength tests and knee performance tests are presented in Table S3 in the 405

supplementary appendix. The ET-group had greater improvement in the 6-meter timed 406

hop test than the APM-group at 3 months (P=0.018) and 12 months (P=0.036), but not 407

in the knee-bend test or the one leg hop test. 408

409

Harms 410

From baseline to 2-year follow-up, no SAEs were registered in either group. During the 411

same period, 23% of the participants in each group experienced pain, swelling, 412

instability, stiffness or decreased range of motion in the index knee serious enough to 413

seek consultation. 21% and 14% of the participants in the ET-group and the APM-group, 414

respectively, experienced similar symptoms in the contralateral knee. 415

416

DISCUSSION 417

In this first comprehensive RCT comparing exercise alone with arthroscopic partial 418

meniscectomy alone, we found no difference in our primary patient-reported outcome 419

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at 2 years, confirming findings from previous studies evaluating the effect of surgery 420

additional to exercise compared with exercise alone(8-12). While most previous studies 421

involved populations with a large proportion of concomitant OA(8, 11-13), in our study, 422

only 4% had definite radiographic OA. Thus, our study extends previous findings to 423

those with early or no OA. 424

425

Self-reported secondary outcomes confirmed the primary outcome, with the exception 426

of KOOSSymptoms where the exercise group reported fewer symptoms such as swelling, 427

mechanical problems and restricted range of motion at 2 years. 428

429

This is the first treatment study for meniscal tears to include muscle strength measures. 430

We found that muscle strength was immediately increased and maintained at 12 months 431

in the exercise group. In the surgical group, muscle strength was reduced at 3 months 432

and only slightly better than baseline at 12 months. Muscle strength is important for 433

physical function, but interestingly in this study, the significantly greater improvement 434

in muscle strength in the exercise group did not translate into greater improvement in 435

self-reported function or consistently better functional performance. Knee extensor 436

weakness is a risk factor for developing OA,(30) and longer-term follow-up studies will 437

show if exercise therapy and thigh muscle strength have the potential to mediate the 438

high risk for radiographic OA seen in patients with degenerative meniscal tears treated 439

with arthroscopic partial meniscectomy. 440

441

The strengths of this study are the RCT design, the multiple assessments, the high 2-year 442

follow-up frequency, the use of valid and reliable patient-reported outcomes, as well as 443

inclusion of muscle strength and performance tests(20, 21) and the blinding of the 444

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assessors. 445

446

The study has limitations. We did not include a sham surgery group as a control group. 447

This might have given information about the natural development of degenerative 448

meniscal tears without treatment interventions. However, sham operations are known 449

to bias patients’ self-reporting, creating a placebo effect caused by the patients’ 450

expectations of good results after surgical treatment. 451

452

A limitation of comparing surgical with nonsurgical treatment is the possibility of cross-453

over from the non-surgical group to the surgical group. Cross-over in our study was 454

based on a clinical evaluation by the orthopaedic surgeon initiated either by the 455

participant or the physiotherapist. We failed to apply a more strict approach to 456

determining cross-over, such as requiring the evaluation of the patient’s symptoms and 457

QOL with a questionnaire that had a pre-set cut-off score. 458

459

All analyses were adjusted for baseline values. This is important since the participants in 460

the APM-group had a higher activity level, fewer knee symptoms and higher of life at 461

baseline. In addition, they were slightly younger, had lower BMI, and reported knee pain 462

for a shorter time than the participants randomised to exercise, but these differences 463

were not statistically significant. Their better baseline status may have provided 464

participants in the APM-group with an advantage and, if anything, better results at 465

follow-ups would be expected. This, however, was not the case. 466

467

Initially, the RCT was planned to be carried out at one hospital only, but due to slow 468

patient flow, the recruitment was taken over from patient number 54 by a hospital with 469

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a higher patient volume. To ensure consistency of recruiting procedures in both 470

hospitals, the two recruiters participated in the first six recruiting sessions at the second 471

hospital, and protocols and procedures were thoroughly discussed. Likewise, the 472

surgical procedures at both hospitals were discussed among participating surgeons to 473

ensure similar protocols and procedures. It is important to note that since there was no 474

recruitment in parallel at the two hospitals, patients randomised to either treatment at a 475

given time were drawn from the same pool of patients. There were no differences in 476

participant characteristics between those included at both sites. For geographical 477

reasons, patients recruited at the second hospital and allocated to exercise therapy were 478

treated at the second physiotherapy clinic. Multiple familiarisation sessions were held to 479

ensure similar protocols at both treating clinics, and potential differences were 480

minimised by the first physiotherapist going through the procedures and giving 481

comprehensive instructions about the exercise program to the second physiotherapist. 482

483

Our study extends previous findings of no additional benefit from arthroscopic surgery 484

into a younger, slimmer and more physically active population. Compared with previous 485

studies, (8-15, 31) our participants were younger (mean age 49.5 years), slimmer (BMI 486

26.2) and had fewer radiographic changes (72% had no radiographic changes; 24% had 487

osteophytes (KL1); and only 4% had definite OA). (11-15) They also had a higher 488

activity level (mean HUNT activity index of 3.0) than a younger (20-39 years old) 489

Norwegian county population, (24) and only 10% reported daily smoking, compared 490

with 20% of persons aged 45-65 years reported by Statistics Norway 491

(http://www.ssb.no). 492

Our study shows similar results after treatment for degenerative meniscal tears with 493

either exercise therapy or arthroscopic meniscal resection in a younger, slimmer, more 494

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active, non-smoking population with less OA. 495

496

Arthroscopic surgery of the knee is considered to be low-risk surgery, the most common 497

SAE being deep venous thrombosis with 4.13 (95% CI 1.78 to 9.60) events per 1000 498

procedures, followed by infection, pulmonary embolism, and death. (7) No SAEs 499

occurred in either treatment group in our study, indicating that in this comparatively 500

younger, slimmer and more active population, both treatment options were equally safe. 501

502

In this first comprehensive RCT comparing exercise therapy alone with arthroscopic 503

partial meniscectomy alone, we found equal improvement in knee function at 2 years. 504

19% of participants allocated to exercise therapy crossed over to surgery during the 2-505

year follow-up, with no additional benefit. There were no SAEs in either group during 506

the 2- year follow-up. 507

508

Our results should encourage clinicians and middle-aged patients with degenerative 509

meniscal tear in pre-osteoarthritic knees to consider supervised structured exercise 510

therapy as the primary treatment option. 511

512

513

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Acknowledgements 514

The authors acknowledge the patients in this study for participation. Further, they 515

acknowledge research coordinators Kristin Bølstad and Emilie Jul-Larsen for the 516

organisation of the participants, and physiotherapists Marte Lund, Karin Rydevik and 517

Christian Vilming for assistance in data collection. They also acknowledge the 518

Norwegian Sports Medicine Clinic (NIMI), Oslo, Norway, for supporting the Norwegian 519

Research Center for Active Rehabilitation (NAR) with rehabilitation facilities and 520

research staff. NAR is a collaboration between the Norwegian School of Sports Sciences, 521

Department of Orthopaedic Surgery, Oslo University Hospital, and NIMI. Finally, they 522

acknowledge the Department of Orthopaedic Surgery, Oslo University Hospital and the 523

Department of Orthopaedic Surgery, Martina Hansens Hospital, Bærum, for accessibility 524

to the outpatient and surgical clinics. 525

526

Competing interests 527

All authors have completed the Unified Competing Interest form at 528

www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) 529

and declare that they have no support from any company for the submitted work; no 530

relationships with any company that might have an interest in the submitted work in the 531

previous 3 years; their spouses, partners, or children have no financial relationships that 532

may be relevant to the submitted work; and they have no non-financial interests that 533

may be relevant to the submitted work. 534

535

Funding 536

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This RCT was funded by the Health Region of South-East Norway. The funding covered 537

expenses to exercise therapy and research salary the corresponding author. The 538

researchers were independent from the funder. 539

540

Authors’ contributions 541

Ewa M. Roos, May Arna Risberg and Silje Stensrud developed the concept and design for 542

this trial. Silje Stensrud, Lars Engebretsen and Nina Jullum Kise conducted the data 543

collection. Nina Jullum Kise drafted the article. Jonas Ranstam performed the statistical 544

analyses. All authors participated in the analysis and interpretation of the data, revision 545

of the article and final approval of the version to be published. 546

547

All authors had full access to all of the data including statistical reports and tables in the 548

study and can take responsibility for the integrity of the data and the accuracy of the 549

data analysis. 550

551

Exclusive license 552

The corresponding author has the right to grant on behalf of all authors and does grant 553

on behalf of all authors, a worldwide license to the Publishers and its licensees in 554

perpetuity, in all forms, formats and media to 1) publish, reproduce, distribute, display 555

and store the contribution, 2) translate the contribution to other languages, create 556

adaptions, reprints, include within collections and create summaries, extracts and/or 557

abstracts of the contribution and convert or allow conversion into any format including 558

limitation audio, 3) create any other derivate work(s) based in whole or part of the 559

contribution, 4) to exploit all subsidiary rights to exploit all subsidiary rights that 560

currently exists or as may exist in the future in the contribution, 5) the inclusion of 561

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electronic links from the contribution to third party material where-ever it may be 562

located, and 6) license any third party to do any or all of the above. 563

564

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Transparency declaration 565

The lead author (NJK) affirms that the manuscript is an honest, accurate, and 566

transparent account of the study being reported; that no important aspects of the study 567

have been omitted; and that any discrepancies from the study as planned have been 568

explained. Data sharing: No additional data are available. 569

570

Ethics approval 571

The study was approved by the Regional Ethics Committee of the Health Region of 572

South-East Norway (ref. no. 2009/230). 573

The study is registered in www.clinicaltrials.gov (NCT01002794). 574

575

576

577

578

579

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Figure legends 580

581

Figure 1. Flow chart The ITT analyses of primary and secondary outcomes are based upon 582 the patient groups in this Consort flow chart. The compound of the groups used in the PP and 583 ATanalyses is presented in a flow chart in Figure S2 in the supplementary appendix. 584

585

Figure 2. Changes in KOOS4 from baseline to 2-year follow-up 586




590

There were no statistically significant differences between the groups at any 591

observation points: 95% CI and P-values for 3, 12 and 24 months are -5.0 to 5.3 (0.952), 592

-0.5 to 9.8 (0.079), and -6.1 to 4.3 (0.723). 593

594

595

596

Figure 3. Muscle strength assessed as total work knee extension from baseline to 597

12-month follow-up 598

599




603

There are statistically significant differences between the groups at 3 and 12 months: 604

95% CI (and P-values) for 3 and 12 months are -153.4 to -67.4 (<0.001), and -98.7 to -605

12.2 (0.012). 606

607

608

609

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Documents

Confidential: For Review Only - BMJ · Confidential: For Review Only 1 1 Exercise therapy is a credible alternative to 2 arthroscopic partial meniscectomy for pre- 3 osteoarthritic