UBC Faculty Research and Publications

Comparison of neuromuscular and quadriceps strengthening exercise in the treatment of varus malaligned… Bennell, Kim L; Egerton, Thorlene; Wrigley, Tim V; Hodges, Paul W; Hunt, Michael; Roos, Ewa M; Kyriakides, Mary; Metcalf, Ben; Forbes, Andrew; Ageberg, Eva; Hinman, Rana S Dec 5, 2011

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STUDY PROTOCOL Open AccessComparison of neuromuscular and quadricepsstrengthening exercise in the treatment of varusmalaligned knees with medial knee osteoarthritis:a randomised controlled trial protocolKim L Bennell1*, Thorlene Egerton1, Tim V Wrigley1, Paul W Hodges2, Michael Hunt3, Ewa M Roos4,Mary Kyriakides1, Ben Metcalf1, Andrew Forbes5, Eva Ageberg6,7 and Rana S Hinman1AbstractBackground: Osteoarthritis of the knee involving predominantly the medial tibiofemoral compartment is commonin older people, giving rise to pain and loss of function. Many people experience progressive worsening of thedisease over time, particularly those with varus malalignment and increased medial knee joint load. Therefore,interventions that can reduce excessive medial knee loading may be beneficial in reducing the risk of structuralprogression. Traditional quadriceps strengthening can improve pain and function in people with knee osteoarthritisbut does not appear to reduce medial knee load. A neuromuscular exercise program, emphasising optimalalignment of the trunk and lower limb joints relative to one another, as well as quality of movement performance,while dynamically and functionally strengthening the lower limb muscles, may be able to reduce medial knee load.Such a program may also be superior to traditional quadriceps strengthening with respect to improved pain andphysical function because of the functional and dynamic nature. This randomised controlled trial will investigatethe effect of a neuromuscular exercise program on medial knee joint loading, pain and function in individuals withmedial knee joint osteoarthritis. We hypothesise that the neuromuscular program will reduce medial knee load aswell as pain and functional limitations to a greater extent than a traditional quadriceps strengthening program.Methods/Design: 100 people with medial knee pain, radiographic medial compartment osteoarthritis and varusmalalignment will be recruited and randomly allocated to one of two 12-week exercise programs: quadricepsstrengthening or neuromuscular exercise. Each program will involve 14 supervised exercise sessions with aphysiotherapist plus four unsupervised sessions per week at home. The primary outcomes are medial knee loadduring walking (the peak external knee adduction moment from 3D gait analysis), pain, and self-reported physicalfunction measured at baseline and immediately following the program. Secondary outcomes include the externalknee adduction moment angular impulse, electromyographic muscle activation patterns, knee and hip musclestrength, balance, functional ability, and quality-of-life.Discussion: The findings will help determine whether neuromuscular exercise is superior to traditional quadricepsstrengthening regarding effects on knee load, pain and physical function in people with medial knee osteoarthritisand varus malalignment.Trial Registration: Australian New Zealand Clinical Trials Registry reference: ACTRN12610000660088* Correspondence: k.bennell@unimelb.edu.au1The University of Melbourne, Centre for Health, Exercise and SportsMedicine, Department of Physiotherapy, School of Health Sciences,Melbourne, Vic, AustraliaFull list of author information is available at the end of the articleBennell et al. BMC Musculoskeletal Disorders 2011, 12:276http://www.biomedcentral.com/1471-2474/12/276© 2011 Bennell et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.BackgroundKnee osteoarthritis (OA) is a common chronic joint dis-ease and costly public health problem. It leads to pain,loss of function and reduced quality-of-life [1]. The eco-nomic impact of knee OA is substantial and will furtherincrease as the population ages and obesity rates esca-late [2-4]. There is no cure for the condition and typi-cally about one third of people with knee OA willexperience structural deterioration [5] with many ofthese ultimately requiring knee joint replacement sur-gery [6].Knee OA usually affects the medial tibiofemoral jointcompartment [7], probably because of the increased loadborne on this compartment during normal walking [8].Around three quarters of people with knee OA havevarus malalignment measured statically on x-ray [9].Increasing varus malalignment usually occurs because ofprogressive loss of cartilage and joint space in this com-partment. People with medial knee OA and varus mala-lignment exhibit unique characteristics and responses totreatment compared to people with more neutral align-ment. These individuals show greater functional declineover time [10] and are at a 3- to 4-fold greater risk ofstructural disease progression than those with more neu-trally aligned knees [11]. Importantly, quadricepsstrengthening exercise, a cornerstone of traditional treat-ment for OA, has been shown to be ineffective at redu-cing pain in people with varus malalignment [12]. Thus,there is a need to develop and evaluate interventions forthis particular sub-group of people with knee OA.The poorer prognosis for people with medial knee OAand varus malalignment is likely due to the greater com-pressive load borne on the diseased medial compart-ment in these people compared to those with moreneutrally aligned knees. Varus malalignment causes theground reaction force vector to pass more medially tothe knee joint centre during gait resulting in increasedloads across the medial compartment [8]. Higher com-pressive knee loads are implicated in knee OA develop-ment and progression. This is highlighted by in vivoanimal experiments [13], and by the positive relationshipof knee OA to obesity [14,15] and occupations involvingheavy lifting or prolonged kneeling or squatting [16].Three dimensional gait analysis is typically used toinfer compressive joint loads. The most widely studiedparameter in knee OA is the external knee adductionmoment (KAM) [17]. The KAM tends to force the kneeinto varus and thus compresses the medial joint com-partment and stretches lateral structures [18]. The KAMis generally higher in people with medial knee OA andvarus malalignment compared to those without [19,20].Importantly, longitudinal studies have shown that ahigher KAM is associated with the development of kneepain in older people [21] and with a 6.5-fold increase inrisk of OA structural progression for a one unit increasein KAM [22]. Of major relevance is that the KAMappears to be amenable to change with non-surgicaltreatments such as shoes, gait modification strategiesand braces by amounts that would correspond to a sub-stantive reduction in risk of disease progression in kneeOA [23-26]. Thus, the KAM is an important target out-come for treatments aimed at slowing disease progres-sion as well as reducing symptoms. The mostcommonly reported indices of the KAM are the overallpeak value, the two typical individual KAM peaks (earlyand late stance), and the area under the KAM-timecurve, known as the KAM angular impulse.As an important determinant of the KAM is frontalplane knee alignment [8], interventions which aim toreduce dynamic varus knee alignment during walkingand other functional weight bearing tasks can potentiallyreduce the KAM. Similarly, strategies that aim to bringthe frontal ground-reaction force vector closer to theknee joint centre-for example by bringing the body cen-tre of mass closer to the knee-may also be beneficial inreducing the KAM. Although valgus knee braces areeffective at improving knee alignment and reducingknee load [27,28], and thus seem a logical treatmentchoice, knee braces are often associated with adverseeffects [29] and reduced compliance in patients withknee OA, limiting their clinical applicability [30]. Incontrast, exercise is recommended by all clinical guide-lines for knee OA [31,32], is associated with relativelyfew adverse effects [33,34] and has the potential toreduce the KAM [26].Quadriceps strengthening has traditionally been animportant component of exercise programs for kneeOA. This is because quadriceps weakness is a frequentfinding among people with knee OA [35-41], has beenimplicated in disease pathogenesis [42-44] and is asso-ciated with pain severity, physical dysfunction and func-tional decline [20,45]. Numerous high quality clinicaltrials have shown that quadriceps strength training iseffective at improving pain and physical function inknee OA [46,47]. However, isolated quadriceps strength-ening is ineffective at reducing pain in the subgroup ofpeople with varus malalignment [12], nor does it reducethe KAM in those with neutral or varus malalignedknees [12,48,49]. This may be because traditional quad-riceps strength training aims primarily to increase thequantity of muscle output, rather than targeting the bio-mechanical contributors to medial compartment kneeload [50]. Thus, it is apparent that alternative exerciseprograms are needed to reduce knee load and alleviatesymptoms for people with medial compartment OA andvarus malalignment.Bennell et al. BMC Musculoskeletal Disorders 2011, 12:276http://www.biomedcentral.com/1471-2474/12/276Page 2 of 12Neuromuscular exercise is a relatively broad class ofexercise programs incorporating programs known byterms such as functional exercise, proprioceptive, agility,or perturbation training. Neuromuscular exercises aretypically performed in functional weight-bearing posi-tions emphasising quality and efficiency of movement,as well as alignment of the trunk and lower limb joints.Some also focus on elements such as responses to per-turbations. Neuromuscular exercise offers promise forthis patient sub-group. By focussing on improving theposition of the knee in relation to the hip and ankle,specific neuromuscular exercises may enhance activationof the muscle groups most capable of generating aninternal moment to counteract the external KAM dur-ing functional weight-bearing tasks. Such muscle groupsinclude the hip adductors [51], the tensor fascia lata, lat-eral hamstrings, quadriceps and lateral gastrocnemius[52-55]. Furthermore, given that varus malalignmentcombined with ineffective dynamic muscle stability canmanifest as lateral thrusting of the knee during earlystance phase of walking (which is associated withincreased risk of disease progression [56]), neuromuscu-lar exercises emphasising control of lateral knee move-ment during weight-bearing activities may also bebeneficial.Research from other populations has demonstratedthat neuromuscular exercise can affect knee functionalperformance, knee biomechanics and activation patternsof the surrounding knee musculature. Neuromuscularexercises are now commonly used for prevention andrehabilitation of knee injuries in young athletic indivi-duals [57,58]. However, neuromuscular programs foryounger people focus on sports specific tasks such asjumping, landing and cutting activities which are notappropriate for older individuals with knee OA. Neuro-muscular training programs are thus best consideredand designed as ‘task-directed’, that is, aimed at enhan-cing neuromuscular control for the specific activities ofdaily living important to the OA population, and theircommon impairments. Our neuromuscular training pro-gram is thus directed towards improving activities ofdaily living including walking.There has been limited research into the benefits ofneuromuscular exercise for people with knee OA withonly four published studies available [26,59-61]. Theseare limited by mostly small sample sizes and an absenceof control intervention groups. Furthermore, a relativelybroad, heterogenous range of exercises have beenemployed, some much more vigorous than others. Asingle case study [59] reported improvements in pain,physical function and knee instability in a 73-year oldwoman with severe medial knee OA with a 6-week neu-romuscular exercise program. This exercise programinvolved agility and perturbation techniques adaptedfrom those prescribed for younger individuals with ante-rior cruciate ligament insufficiency. Using a differentneuromuscular program with exercises focused onstrengthening and functional activities, a pilot case seriesconducted in 13 people [26] showed a reduction in theKAM during a single leg sit-to-stand task following the8 week program. Another uncontrolled feasibility study[60] showed no worsening of symptoms and few joint-specific adverse events among 38 patients with severeknee OA following a median of 13 group-delivered neu-romuscular training sessions. These preliminary findingshighlighted the feasibility and potential efficacy of neu-romuscular exercise for reducing knee load and alleviat-ing symptoms in people with medial knee OA and varusmalalignment. However, a recent large randomised con-trolled trial (RCT) in 183 people with knee OA com-pared the addition of a neuromuscular program-particularly involving destabilizing activities designed toimprove the individual’s response to perturbations-to astandard strengthening exercise program. The studyfound that the additional program did not improvetreatment effects for pain and function over and abovethose of the standard exercise program alone [61]. Theauthors surmised that there might be sub-groups ofindividuals who achieve an added benefit with this exer-cise approach. Importantly this study did not measureoutcomes relevant to disease progression such as kneeload. Further research is thus needed to determine theefficacy of neuromuscular exercise programs on theseoutcomes and for knee OA patient sub-groups.The primary objective of this RCT is to compare theeffects of a specific neuromuscular exercise programwith those of traditional quadriceps strengthening exer-cise on the KAM, pain and physical function in animportant knee OA subgroup, people with medial tibio-femoral OA and knee varus malalignment.Primary hypothesesH1: The external peak KAM during walking will bereduced by a neuromuscular exercise program but notby a quadriceps strengthening program.H2: A neuromuscular exercise program will improveself-reported physical function and reduce pain to agreater extent than a quadriceps strengthening program.Secondary hypothesesH3: The KAM angular impulse during walking will bereduced by a neuromuscular exercise program but notby a quadriceps strengthening program.H4: A neuromuscular exercise program will lead togreater improvements in muscle activation patterns, hipstrength, balance, functional ability, quality-of-life andperceived change than a quadriceps strengthening pro-gram, whilst greater improvements in quadricepsBennell et al. BMC Musculoskeletal Disorders 2011, 12:276http://www.biomedcentral.com/1471-2474/12/276Page 3 of 12strength will be found with the quadriceps strengtheningprogram.Methods/DesignTrial designSingle assessor-blinded, parallel design RCT, which con-forms to CONSORT guidelines for non-pharmacologicalstudies [62] (Figure 1).ParticipantsA sample of 100 men and women aged ≥ 50 years withpainful medial knee OA will be recruited from the com-munity in metropolitan Melbourne, Australia. A numberof recruitment strategies will be used including (i)advertising through local clubs, community centers,newspapers, Arthritis Australia and University websites,University staff newsletters, radio, and Facebook; (ii) pla-cing brochures and study posters in medical and phy-siotherapy clinics; (iii) conducting presentations aboutknee OA in the local community, and (iv) using ourdatabase of people with medial knee OA and varusmalalignment who were recruited from the communityfor prior studies and have given consent for futurecontact.People will be eligible if they report average knee painover the past week ≥ 25 on a 100 mm visual analoguescale, have predominant pain/tenderness over the medialknee region, and have radiographic evidence of medialtibiofemoral joint OA with varus knee alignment. Shortlimb, weight-bearing, postero-anterior radiographs willAnalysisAllocationEnrolmentInterventionAssessed for eligibility by telephone Ineligible:Fail inclusion criteriaMeet exclusion criteriaRefuse to participateAssessed for eligibility by x-ray Ineligible:Fail inclusion criteriaMeet exclusion criteriaAllocated to quadriceps strengthening program Allocated to neuromuscular exercise program Physiotherapists (n=10) Private physiotherapy clinics14 x individual treatment sessions plus home program over 12 weeks14 x individual treatment sessions plus home program over 12 weeksRandomisationBaseline assessmentIntention-to-treat analysis Week 13 assessment – immediately post treatment sessionsFigure 1 Flow diagram of study protocol.Bennell et al. BMC Musculoskeletal Disorders 2011, 12:276http://www.biomedcentral.com/1471-2474/12/276Page 4 of 12be taken with a caudal angle of 10° to achieve superim-posed tibial plateau. Specific radiographic inclusion cri-teria are: (i) Kellgren-Lawrence grade ≥ 2 [63]; (ii)mechanical axis angle of < 181° for females or < 183°for males indicating varus alignment; (iii) medial tibiofe-moral joint narrowing grade > lateral tibiofemoral jointnarrowing grade [64]; and (iv) medial compartmentosteophyte grade ≥ lateral compartment osteophytegrade [64]. Mechanical knee alignment will be convertedfrom the anatomic axis measured from the knee x-ray[65] using our regression equation [66]. This methodhas good to excellent correlation (r = 0.65-0.88) betweenanatomical and mechanical axes thus avoiding the addi-tional cost and radiation of a long limb x-ray.Exclusion criteria will include: (i) knee surgery orintra-articular corticosteroid injection within past sixmonths; (ii) current or past (within four weeks) oral cor-ticosteroid use; (iii) systemic arthritic conditions; (iv)history of hip or knee joint replacement or tibial osteot-omy surgery; (v) any other condition affecting lowerlimb function; (vi) participation in a strengthening orneuromuscular exercise program within the past sixmonths or planning to commence exercise or othertreatment for knee OA; (vii) other non-pharmacologicaltreatment for their knee pain in the past six monthsincluding physiotherapy, acupuncture, massage therapy;or (viii) unable to ambulate without a gait aid. Peoplewho have been on glucosamine, chondroitin and/ornon-steroidal anti-inflammatory drugs will not beexcluded. Participants who are already wearing orthoticsor insoles will be permitted to continue using them dur-ing the trial. Participants will be requested to refrainfrom seeking other forms of treatment during the trial.ProcedureEligibility of prospective participants will be confirmedinitially by telephone screening questions then on radio-graphic examination. Baseline and follow-up assessmentswill be carried out at the Department of Physiotherapy,the University of Melbourne by the same assessor whowill remain blinded to exercise group allocation. Partici-pants will visit a physiotherapist 14 times over the 12-week intervention period: twice in the first and secondweeks, and weekly thereafter. Ethical approval has beenobtained from the University of Melbourne HumanResearch Ethics Committee (HREC No. 0932813). Allparticipants will provide written informed consent.Randomisation and allocation concealmentAll eligible participants will be consecutively randomisedinto either the quadriceps strengthening program or theneuromuscular exercise program. Consecutively num-bered, sealed, opaque envelopes containing exercisegroup allocation will be prepared by a researcher withno other involvement in the study. Exercise group allo-cation will be randomised within random permutedblocks of six or eight generated a priori using the ran-dom number function in Excel and stratified accordingto treating therapist so that all physiotherapists will deli-ver approximately equal numbers in each exercise groupto control for therapist variation.InterventionsTen physiotherapists in private practices at various loca-tions throughout metropolitan Melbourne, Australia willprovide the interventions. Each physiotherapist will deli-ver both exercise programs. The physiotherapists havean average of 13 (range 2-42) years experience sincequalification and 12 (range 2-30) years of post-graduateclinical musculoskeletal experience. Three (30%) havepostgraduate Masters qualifications in sports or manipu-lative/musculoskeletal therapy. The physiotherapists willattend a three hour training session covering delivery ofboth exercise programs and receive a detailed treatmentmanual describing each exercise intervention. Afterinitiation of the trial, telephone meetings will be held todiscuss issues experienced in the clinic and solutionswill be suggested. This procedure will reinforce similartreatment administration among therapists. Physiothera-pists will be supplied with weights and elastic bands toprovide to the study participants.One knee will be the focus of the treatment and eval-uated. Focussing on one knee only is to minimise theburden of exercise and laboratory testing time. If partici-pants have bilateral symptoms, the most symptomaticeligible knee or the right knee, in the case of equallysymptomatic knees, will be nominated. Some of theneuromuscular exercises are performed weight-bearingon both legs, while other exercises are performedweight-bearing on one leg. In the latter, the weight-bearing leg is the affected leg. In contrast, the quadri-ceps strengthening exercises are performed in non-weight-bearing positions with the affected leg only.Each supervised exercise session in both programs willlast 30-40 minutes. Participants in both groups will beasked to perform their prescribed exercises at homefour times per week in addition to performing them atthe scheduled supervised physiotherapy visits. A briefre-assessment will be performed by the physiotherapistat each physiotherapy session in order to ascertain anyadverse effects occurring during the preceding week andto check quality and form of exercise performance. Thefindings from this assessment will help guide phy-siotherapists’ decisions regarding progression of theexercises.Neuromuscular exercisesAs alluded to in the introduction, the neuromuscularexercises aim to improve the position of the trunk andBennell et al. BMC Musculoskeletal Disorders 2011, 12:276http://www.biomedcentral.com/1471-2474/12/276Page 5 of 12lower limb joints relative to one another, as well asquality of movement performance, while dynamicallyand functionally strengthening the lower limb muscles.As it would be difficult to focus participants’ attentionon preferentially activating muscle groups that cancounteract varus malalignment (eg. the hip adductors[51], the tensor fascia lata, lateral hamstrings, quadricepsand lateral gastrocnemius [52-55]) in isolation, a morepragmatic approach to training will be adopted wherebyparticipants will be instructed to improve control ofknee and hip muscles by practicing more neutral kneepositioning during a series of specified exercises/tasks.The participants will be instructed to aim at positioningtheir knee over the foot, and to avoid a medial or lateralposition of the knee in relation to the foot. It isacknowledged however, that a knee over foot positionmay not be achievable for people with varus malalign-ment. Lateral thrusting of the knee is to be avoided andcontrolled at all times as much as possible. Specificexercises have been selected on the basis that theyinvolve movement of the knee in synergy with all jointsin the lower extremity, are weight-bearing (closed-chain)and are functionally relevant. Participants will beinstructed to also focus on maintaining neutral pelvicalignment during performance of the exercises. It wasfelt important to include at least one exercise thatwould challenge postural stability and thereby encourageactivity of anti-gravity postural muscles. The selectedexercises were developed from a range of sources[26,60,67].Progression will be provided by varying the repeti-tions, direction, and velocity of the movements; increas-ing the load; and/or changing the support surface. Eachof the six exercises in the program and their levels andfrequencies are described in detail in Additional File 1.Participants in the neuromuscular exercise group will bemade aware of the following points:• Quality of performance is critical and the partici-pant must attempt to position their knee over thefoot throughout the movements.• Knee flexion should not exceed 30° during theexercises (except when performing the chair standexercise). This was to minimise the risk of increasingknee pain and is relevant to the range of knee flex-ion during walking, our primary outcome.• Although some discomfort is expected, the exer-cises should be performed within tolerable levels ofpain. Pain should subside to usual levels by the nextday with no increase in swelling following the exer-cise session. Participants are assisted in determiningwhether pain levels during and for a short time afterthe exercises are acceptable by using a pain monitor-ing scale where zero is “no pain” and ten is “pain asbad as it could be”. Pain up to two on the scale isconsidered ‘safe’, pain up to a level of five is consid-ered ‘acceptable’ as long as temporary, and painabove five is considered ‘high risk’ [60].• Safety should be ensured by using hand support orhaving hand support within easy reach. This is usedfor balance support and for maintaining quality ofperformance throughout the movements.• Participants should be challenged by the exercises.During all exercises, the level of effort experiencedshould be self-rated as at least 5 out of 10 on amodified Borg Rating of Perceived Exertion (RPE)CR-10 scale [68].If the physiotherapist considers that a specific exerciseis aggravating the participant’s pain, then the therapistwill reduce the resistance, dosage and/or level of theexercise until the pain flare settles. Progression of exer-cises is an essential component of the program and willbe determined by the physiotherapists based on theirassessment of the quality of the exercise performance,on the RPE score for each exercise and on the partici-pant-reported pain response. All participants should beprogressed during the treatment phase of the study,although it is expected that not all will reach the finalprogression stage on all exercises.Quadriceps strengtheningThe aim of the program is to improve the strength ofthe quadriceps and is based on the program in our pre-vious RCT [12]. The participants in the quadricepsstrengthening group will complete five specific non-weight-bearing exercises with the affected (most symp-tomatic or right) leg:1. Quads over a roll (inner range knee extension)-using resistance of ankle weights.2. Knee extension in sitting-start sitting with knee at90° flexion, fully extend using resistance of ankleweights.3. Knee extension with hold at 30° knee flexion-startsitting with knee at 90° flexion, extend to 30° usingresistance of ankle weights.4. Straight leg raise-start supine, raise leg to 30° hipflexion using resistance of ankle weights.5. Elastic band exercise-start sitting with knee at 90°flexion, extend to 60° against resistance of elastic band.Ten repetitions will be performed in each set of quad-riceps exercises. Two sets will be performed at the startof the program, progressing to three sets as quickly aspossible. The starting weight should be the participant’s10-repetition maximum weight if possible. However, thestarting weight can also be determined by asking theparticipant their level of effort which should be 5-8 outof ten (hard to very hard) on the modified Borg RPECR-10 scale for strength training [68]. Each repetitionBennell et al. BMC Musculoskeletal Disorders 2011, 12:276http://www.biomedcentral.com/1471-2474/12/276Page 6 of 12will be performed slowly and in a controlled manner.The end position is held for five seconds initially andprogressed to ten seconds. Breath holding during theisometric component of the exercises can increase bloodpressure; therefore participants will be instructed tocontinue breathing throughout each phase (concentric,isometric and eccentric) of the exercises. Exercisesshould be carried out within tolerable levels of pain.The same pain monitoring scale as described above willbe used and pain should subside to usual levels by thenext day with no increase in swelling following the exer-cise session. If joint swelling or ‘unacceptable’ painoccurs, the resistance, frequency and/or number of repe-titions will be reduced. Progression is again an impor-tant part of the program and participants will aim toincrease their ankle weight or elastic band resistance atregular intervals during the program as guided by theirphysiotherapist. During all exercises, the level of effortexperienced should be self-rated as at least five out often (hard) on a RPE CR-10 scale for strength training[68].Treatment integrityStudy physiotherapists will keep standardised treatmentnotes. Selected treatment sessions will be attended by aresearcher to document adherence to the protocol. Par-ticipants will be questioned at the end of their treatmentabout their physiotherapy treatment experience.Outcome measures (Table 1)External knee adduction momentParticipants will undergo a 3D gait analysis to assessdynamic loading of the knee during walking at a self-selected speed. Movement will be recorded using a 12-camera motion analysis system (Vicon MX, Oxford, UK)and force plates (AMTI, MA, USA) as participants walkbarefeet along a 10 m level walkway with speed moni-tored by two photoelectric beams. Five successful trials(complete foot strike from one foot on a force plate)will be obtained for each leg. The motion of reflectivemarkers (sample rate 120 Hz) and the ground reactionforce (sample rate 1200 Hz) will be used to calculate theexternal KAM using inverse dynamics via the Universityof Western Australia (UWA) model, programmed inVicon Body Builder [69]. Test-retest reliability (coeffi-cient of multiple determination, r2) of knee adduction/abduction moment curves averaged over six trials usingUWA model was reported as at least 0.75 [69]. The pri-mary variable of interest is the overall peak KAM nor-malised for body weight times height (Nm/BW*HT%)Table 1 Summary of measures to be collected.Primary outcome measures Data collection instrumentExternal peak knee adduction moment (KAM) 3-dimensional gait analysis system and University of Western Australia (UWA) functional modelAverage overall pain in past week 100 mm visual analogue scalePhysical function in past 48 hours WOMAC Osteoarthritis Index 3.1 Likert version physical function subscaleSecondary outcome measuresKAM angular impulse 3-dimensional gait analysis system and (UWA) functional modelPain and stiffness WOMAC Osteoarthritis Index 3.1 Likert versionParticipant global rating of change overall andfor pain and function7-point ordinal scaleMuscle activation and co-contraction patterns Surface electromyography during walkingHip and knee muscle strength Isometric knee flexors and extensors (isokinetic dynamometer), hip abductors and rotators(instrumented manual muscle tester), and hip extensors (force transducer).Physical performance Single limb standing time (seconds)Step testFour square testTimed stair climb (ascent and descent)30 second sit-to-stand testHealth-related quality of life Assessment of Quality of Life Instrument version 2 (AQoL II)Other measuresMechanical knee alignment X-ray (baseline)Disease severity X-ray (baseline)Physical activity levels Physical Activity Scale for the Elderly (PASE)Adverse events Participant log-book (follow-up)Adherence/Treatment session attendance Participant log-book (follow-up)Therapist treatment records (follow-up)All measures recorded at baseline and follow-up (week 13) unless otherwise stated.Bennell et al. BMC Musculoskeletal Disorders 2011, 12:276http://www.biomedcentral.com/1471-2474/12/276Page 7 of 12[70] and averaged over the five trials. KAM angularimpulse (the positive area under the KAM-time curve)will be calculated as a secondary outcome variable.Self-reported pain and physical functionThe primary pain outcome is average overall knee painduring the past week. This, together with pain on walk-ing during the past week, will be assessed using 100 mmvisual analogue scales with terminal descriptors of “nopain” and “worst pain possible”. Such measurement hasdemonstrated reliability in OA [71]. Pain will also beassessed, along with stiffness and physical function,using the disease-specific Western Ontario McMasterUniversities (WOMAC) Osteoarthritis Index [72]. Thephysical function subscale, which comprises 17 ques-tions, will be used as a primary outcome measure ofself-reported physical function.At the follow-up assessment, participants will ratetheir perceived a) overall change, as well as change in b)pain and in c) physical function with the exercise pro-gram (compared to baseline) on a seven-point ordinalscale (1-much worse to 7-much better). Scales of thiskind are frequently used as an external criterion forcomparison with changes in scores of other outcomes[73]. Measuring participant-perceived change using arating of change scale has been shown to be a clinicallyrelevant and stable concept for interpreting truly mean-ingful improvements from the individual perspective[74].Muscle co-contraction and activation patternsMuscle activity recordings will be made during thewalking trials using surface electromyography (EMG)from lateral muscles (biceps femoris, lateral gastrocne-mius, tensor fascia lata), medial muscles (medial ham-strings, medial gastrocnemius) and quadriceps (vastusmedialis, vastus lateralis, rectus femoris). EMG signalswill be band-pass filtered between 20 Hz-500 Hz andsampled at 1200 Hz synchronously with the Vicon cam-era data via a telemetered 8-channel Noraxon Telemyo9000 system (Noraxon, AZ, USA). EMG recordings dur-ing maximal isometric knee flexion, knee extension, hipabduction and plantar flexion will be used for normali-sation of EMG data. Total activation, relative activationof individual muscles and abducting/adducting musclegroups, and co-contraction, will be assessed.Muscle strengthMaximum, normalised, isometric strength (Nm/kg) willbe recorded for key hip and knee muscle groups. Quad-riceps and hamstring strength will be measured at 60°knee flexion in sitting using an isokinetic dynamometer(KinCom 125-AH, Chattanooga Corp, TN, USA). Parti-cipants will perform 3 maximal contractions for a periodof five seconds each with the best of the 3 trials beingused for the analysis. Isometric hip abductor and hipinternal and external rotation muscle strength will bemeasured using a hand held dynamometer (LafayetteManual Muscle Test System 01163, Lafayette, IN). Forhip abduction, the participant will lie supine with thehip in a neutral position. For internal and external rota-tion, the participant will sit with the hip and knee at 90°flexion. Isometric hip extensor strength will be mea-sured using a ceiling mounted Shimpo FGC-50 forcetransducer (Nidec-Shimpo, Kyoto, Japan) and digitalinclinometer (SmartTool, MD Building Products, OK,USA), with the participant in supine and their hip in 20°flexion. For the hip strength measurements, the mean oftwo maximal trials will be used in the analysis [75]. Dur-ing all strength measurements strong verbal encourage-ment will be given and this is standardised betweenparticipants.Physical performance measuresBalance tests-1) Single limb standing balance will betimed (seconds) up to 30 seconds [76]. The best attemptfrom two trials will be recorded. 2) The number of stepsby the non-study leg onto a 15 cm high step and backto the floor in 15 sec will be recorded with the partici-pant carrying out the task as quickly as possible (Steptest) [77,78]. 3) The Four-square step test will also beperformed, where two sticks are used to make a crossshape on the floor and the time taken to step fromquadrant 1 to 2, then to 3, 4, 1, 4, 3, 2 and 1 again asquickly as possible is recorded [79].Timed stair climb-The time (seconds) to walk up anddown six 17.5 cm high steps as quickly as possible,using a hand rail if they prefer, will be recorded [80].Thirty second sit-to-stand test-The number of sit-stand-sits in 30 seconds achieved with the participantcarrying out the task as quickly as possible will berecorded [81]. The task will be performed on a standardheight chair without use of upper limbs.Health-related quality of lifeHealth-related quality of life will be measured using theAssessment of Quality of Life instrument version two(AQoL II). The AQoL II has 20 questions that cover sixdimensions of health-related quality of life includingindependent living, social relationships, physical senses,coping, pain and psychological wellbeing. The AQoLhas strong psychometric properties and is more respon-sive than other widely-used scales [82,83]. It produces asingle utility index that ranges from -0.04 (worst possi-ble health-related quality of life) to 1.00 (full health-related quality of life). A clinically important differencein health-related quality of life can be defined as achange of 0.04 AQoL units [84].Other measuresDisease severity will be gauged from the baseline kneex-ray and classified using the Kellgren-Lawrence gradingsystem [63]. Baseline demographic information includingsocial factors, medication use, co-morbidities and otherBennell et al. BMC Musculoskeletal Disorders 2011, 12:276http://www.biomedcentral.com/1471-2474/12/276Page 8 of 12treatments will be recorded as well as measures taken ofheight and weight. Co-interventions, adherence andadverse effects will be determined from the participants’log books and the physiotherapists’ treatment notes.Habitual physical activity will be measured using thePhysical Activity Scale for the Elderly (PASE), a self-report questionnaire that has been shown to be reliable,valid and sensitive to change in people with knee OA[85,86]. It records both the level and type of recreationaland occupational physical activity undertaken by partici-pants over the previous week. The PASE was developedand validated in samples of older adults (age 55+ years)[87].Sample sizeOur three primary endpoints are the overall peak KAMduring the stance phase of walking, VAS overall kneepain, and WOMAC physical function scores. The mini-mum clinically important difference to be detected for achange in KAM is unknown. However, a reduction inKAM of 7.5% may be associated with a significantdecrease in the risk of disease progression, based on theresults of Miyazaki et al [22], who found an increasedprogression risk of over 6 times associated with anapproximately 20% greater KAM. This magnitude ofreduction appears to be achievable with exercise as apilot study showed a 14% reduction with similar neuro-muscular exercise in knee OA [26]. The minimum clini-cally important difference to be detected in OA trials isa change in pain of 18 mm on VAS [88] and a changeof six physical function WOMAC units (out of 58) [89].Based on our previous data, we assume a commonbetween-participant standard deviation of change inKAM of 0.4 Nm/BW*HT%, 30 mm for pain, and 12units for WOMAC physical function. These statisticsindicate a smaller standardized effect size of interest(Cohen’s d) of 0.5 for physical function than the d = 0.6for pain and d = 0.75 for KAM. Given this, the requiredsample for a two-tailed comparison of the two exercisegroups using analysis of covariance with baseline valuesas covariates, when d = 0.5, power is 0.8 and type Ierror is .05 is 41 participants per group. To allow for a15% dropout rate a total of 100 participants will berecruited.Data and statistical analysisMain comparative analyses between groups will be per-formed in a blinded fashion using an intention-to-treatapproach with p-values of less than 0.05 consideredsignificant. To account for missing data, multipleimputation of missing follow-up measures, assumingmissing data are missing at random and follow a mul-tivariate normal distribution [90], will be performed asa sensitivity analysis. For continuous outcome mea-sures, differences in mean change (baseline minus fol-low-up) will be compared between groups usinganalysis of covariance adjusted for baseline values ofthe outcome. Walking speed will also be included as acovariate for the KAM parameters if follow-up walkingspeed differs. Model diagnostic checks will utilise resi-dual plots. Results will be presented as estimated dif-ferences with 95% confidence intervals [91]. We willalso perform a per protocol analysis as appropriate.Effect sizes will be calculated for all measures with aneffect size of 0.2 considered small, 0.5 medium and 0.8large [92]. Participant perceived overall change andchange in pain and in physical function will be com-pared between groups using log binomial regression.Results will be presented as relative risks with 95%confidence intervals.TimelineEthics approval was obtained in April 2010 from theHuman Research Ethics Committee of the University ofMelbourne. Recruitment and training of the phy-siotherapists was undertaken in May 2010 and recruit-ment of participants has commenced. All participantsare expected to have completed the study by end 2012.DiscussionThe need to develop efficacious treatment approaches forknee OA that are capable of not only ameliorating symp-toms but also slowing disease progression is an importantresearch and clinical objective [93]. Our study is based onthe premise that while the static structural malalignmentitself cannot be altered in individuals with medial kneeOA, except via surgical procedures, other factors contri-buting to higher knee load are potentially modifiablewith exercise interventions. If the loading forces can bereduced within the medial tibiofemoral compartmentduring weight bearing, structural degeneration may beslowed in addition to achieving symptom relief.Our study is the first RCT to investigate the effect ofneuromuscular exercise on knee load, pain and functionin people with medial knee OA and varus malalignment.Strengths of the study design are the pragmatic natureof treatment delivery which occurs in community phy-siotherapy clinics by several practicing physiotherapists,and the reproducibility of both exercise programs.These features will improve the generalisabilty of thefindings. Importantly however, both programs are indivi-dualised with regard to the level of exercise intensityand both incorporate progression. In addition, the studyis adequately powered for all three primary outcomemeasures and our recruitment strategy will result in awell characterised, homogenous sample.Bennell et al. BMC Musculoskeletal Disorders 2011, 12:276http://www.biomedcentral.com/1471-2474/12/276Page 9 of 12This trial evaluates an innovative neuromuscular exer-cise program that aims to reduce medial knee load andpain and improve function in people with medial com-partment OA and varus malalignment. The findingsmay lead to a more effective exercise treatment optionthan currently exists for this important subgroup of peo-ple with knee OA.Additional materialAdditional file 1: Neuromuscular exercises.AcknowledgementsThis trial is being funded by the National Health and Medical ResearchCouncil (Project #628644). None of the funders have any role in the studyother than to provide funding. KLB is funded in part by an AustralianResearch Council Future Fellowship.The Study Physiotherapists providing the physiotherapy treatments areKatherine Edmonds, Frances Gray, Jonathan Harris, Susan Hong Labberton,Arthur Lee, Tim McCoy, Jack Mest, Gabrielle Molan, Michael Ranger, and TimSimpson.Author details1The University of Melbourne, Centre for Health, Exercise and SportsMedicine, Department of Physiotherapy, School of Health Sciences,Melbourne, Vic, Australia. 2The University of Queensland, School of Healthand Rehabilitation Sciences, St Lucia, Brisbane, QLD, Australia. 3University ofBritish Columbia, Department of Physical Therapy, Vancouver, BC, Canada.4University of Southern Denmark, Institute of Sports Science and ClinicalBiomechanics, Odense, Denmark. 5Monash University, Department ofEpidemiology and Preventive Medicine, Melbourne, Vic, Australia. 6LundUniversity, Department of Orthopedics, Clinical Sciences Lund, Lund,Sweden. 7Lund University, Department of Health Sciences, Lund, Sweden.Authors’ contributionsKLB, MH and RH conceived the project and KLB is leading the co-ordinationof the trial. KLB, RH, TW, PH, MH, ER, AF and EA assisted with protocoldesign and procured the project funding. TW and BM designed thebiomechanical and physical impairment measures. KLB, RH, PH, MH, EA andER designed the neuromuscular exercise program and KLB and RH trainedthe therapists. AF performed the sample size calculations and designed thestatistical analyses. KLB and TE wrote the first draft of the manuscript. TEwrote the protocol manual and the final drafts of this manuscript. BM is theblinded assessor on the project while MK recruits and screens theparticipants and manages the project. All authors participated in the trialdesign, provided feedback on drafts of this paper and read and approvedthe final manuscript.Competing interestsThe authors declare that they have no competing interests.Received: 15 November 2011 Accepted: 5 December 2011Published: 5 December 2011References1. 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Upper Saddle River, N.J.: Pearson/Prentice Hall;, 3 2009.93. Buckwalter JA, Stanish WD, Rosier RN, Schenck RC Jr, Dennis DA, Coutts RD:The increasing need for nonoperative treatment of patients withosteoarthritis. Clin Orthop Relat Res 2001, , 385: 36-45.Pre-publication historyThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/12/276/prepubdoi:10.1186/1471-2474-12-276Cite this article as: Bennell et al.: Comparison of neuromuscular andquadriceps strengthening exercise in the treatment of varus malalignedknees with medial knee osteoarthritis: a randomised controlled trialprotocol. BMC Musculoskeletal Disorders 2011 12:276.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitBennell et al. BMC Musculoskeletal Disorders 2011, 12:276http://www.biomedcentral.com/1471-2474/12/276Page 12 of 12


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