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Accepted Manuscript The effect of quadriceps-strengthening exercise on quadriceps and knee biomechanics during walking in knee osteoarthritis: A two- centre randomized controlled trial Paul DeVita, Jens Aaboe, Cecilie Bartholdy, Joshua M. Leonardis, Henning Bliddal, Marius Henriksen PII: S0268-0033(18)30090-1 DOI: doi:10.1016/j.clinbiomech.2018.09.016 Reference: JCLB 4605 To appear in: Clinical Biomechanics Received date: 12 February 2018 Accepted date: 12 September 2018 Please cite this article as: Paul DeVita, Jens Aaboe, Cecilie Bartholdy, Joshua M. Leonardis, Henning Bliddal, Marius Henriksen , The effect of quadriceps-strengthening exercise on quadriceps and knee biomechanics during walking in knee osteoarthritis: A two-centre randomized controlled trial. Jclb (2018), doi:10.1016/ j.clinbiomech.2018.09.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AC CE PT ED M AN US CR IP T 1 THE EFFECT OF QUADRICEPS-STRENGTHENING EXERCISE ON QUADRICEPS AND KNEE BIOMECHANICS DURING WALKING IN KNEE OSTEOARTHRITIS: A TWO-CENTRE RANDOMIZED CONTROLLED TRIAL Paul DeVita 1 , Jens Aaboe 2 , Cecilie Bartholdy 2 , Joshua M Leonardis 1 , Henning Bliddal 2 , Marius Henriksen 2 1 Biomechanics Laboratory, Department of Kinesiology, East Carolina University, Greenville, NC, USA. 2 The Parker Institute, Department of Rheumatology, Copenhagen University Hospital Bispebjerg- Frederiksberg, Copenhagen, Denmark. Correspondence: Paul DeVita, Ph.D. 332 Ward Sports Medicine Building Department of Kinesiology East Carolina University Greenville, NC 27858 Tel: (252) 737 - 4563 Fax: (252) 737 - 4689 Email: devitap@ecu.edu ACCEPTED MANUSCRIPT AC CE PT ED M AN US CR IP T 2 ABSTRACT Objective To assess the effect of quadriceps strengthening on quadriceps muscle force, power, and work and tibio-femoral compressive loads during walking in adults with knee osteoarthritis. Methods Study design: Two-center, randomized, controlled trial. Intervention: Patients with knee osteoarthritis were randomly allocated to quadriceps strengthening program (3 times weekly) or no attention control group. Main outcome measures: Primary outcome was change from baseline in peak quadriceps force during walking at 12 weeks. Secondary outcomes included quadriceps power and work, knee compression forces during walking estimated with musculoskeletal modeling, muscle strength and pain and function. Outcomes were measured at baseline and 12 weeks. Results 30 patients were randomized to receive either training (n=15) or no attention (n=15). At follow-up, there were no statistical differences between groups for maximum quadriceps force, quadriceps positive power, negative work, and positive work, and knee compressive force. Maximum negative quadriceps power in early stance was statistically significantly increased 36% in the training group compared to the control group which was most likely partially a response to faster walking velocity at follow-up. Muscle strength and patient reported pain and function were improved in the training group compared to the control group. Conclusions Quadriceps strength training leads to increased muscle strength and improved symptomatic and functional outcomes but does not change quadriceps or knee joint biomechanics during walking. The biomechanical mechanism of improved health with strength training in knee osteoarthritis patients remains unknown. ClinicalTrials.gov Identifier: NCT01538407 ACCEPTED MANUSCRIPT AC CE PT ED M AN US CR IP T 3 Keywords: muscle force, muscle power, muscle work, knee compressive force, strength training, musculoskeletal model, WOMAC, pain, function ACCEPTED MANUSCRIPT AC CE PT ED M AN US CR IP T 4 INTRODUCTION Quadriceps muscle strength is typically lower in people with knee osteoarthritis (OA) compared to healthy adults and quadriceps weakness is a risk factor for initiation and progression of knee OA (Hurley, 1999; Oiestad et al., 2015; Serrao et al., 2015; Slemenda et al., 1997; Slemenda et al., 1998). Accordingly, strengthening exercise regimens increase quadriceps muscle strength and sensorimotor function and reduce neural inhibition (all tested isokinetically) and also improve clinical outcomes, such as pain, physical function and quality of life (Baker et al., 2001; Hurley and Newham, 1993; Hurley and Scott, 1998; McAlindon et al., 2014). Thus, quadriceps strengthening programs are firmly entrenched in the rehabilitation literature (McAlindon et al., 2014; Zhang et al., 2007) and in public health policy in the United States by the National Institutes of Health (NIH-OA) and the Center for Disease Control and Prevention (CDC-OA). Absolute quadriceps strength and quadriceps strengthening in particular are thought to stabilize the knee against undesirable displacement forces (Markolf et al., 1978) and to protect the knee from pathologic loadings thus preventing structural damage during daily activities (Brandt et al., 2009; Hurley, 1999; Segal et al., 2010; Topp et al., 2002). It is theorized that quadriceps strength training will increase quadriceps force during locomotion and thereby enable the muscle along with the patellar tendon to more effectively unload the knee joint (Anwer and Alghadir, 2014; Hurley, 1999; Vincent and Vincent, 2012). Further, the theory suggests that increased quadriceps force would also increase its energy absorbing capacity (i.e. negative work) potentially reducing the stress reaching the knee joint surfaces (Hurley, 1999; Mikesky et al., 2000). Intuitively, this would theoretically explain the suggested shock absorbing function of periarticular knee muscle strength (Brandt et al., 2009; Mikesky et al., 2000). While one or more biomechanical responses elicited through quadriceps strength training may be linked to reduced pain and improved physical function in people with knee OA, no empirical evidence has causally identified any underlying biomechanical mechanisms associated with increased quadriceps strength. This point was highlighted by Bennell et al in their comprehensive meta-analyses of nearly 500 related publications (Bennell et al., 2011). For example, Knoop et al ACCEPTED MANUSCRIPT AC CE PT ED M AN US CR IP T 5 (Knoop et al., 2015) concluded after a thigh muscle strengthening program, that muscle strengthening is one of the mechanisms responsible for the beneficial effects of exercise. However, they reported only correlational data showing associations between improved thigh muscle strength and symptomatic improvements but they did not identify any change in quadriceps muscle function or knee joint loads after strengthening. The maximum knee adduction moment (KAM) during walking, has often been used as a proxy for the medial to lateral load distribution in people with knee OA (Aaboe et al., 2011; Baliunas et al., 2002; Chang et al., 2015) and potentially could identify the biomechanical outcomes of quadriceps strengthening. However, the KAM is typically neither related to maximum quadriceps strength nor is it influenced by strength training (Foroughi et al., 2011; Hunt et al., 2013; Lim et al., 2008; Lim et al., 2009; Sled et al., 2010; Thorp et al., 2010) although Karamanidis et al did show reduced KAM during inclined walking after 14 weeks of strength training (Karamanidis et al., 2014). More directly related to quadriceps muscle function, increased strength through training did not change the sagittal plane knee moments during step-up (McQuade and de Oliveira, 2011), level walking (Chang et al., 2016) or inclined walking (Karamanidis et al., 2014) tasks. We suggest there is a disparity between the theoretical notion that quadriceps strengthening improves quadriceps function and knee biomechanics during locomotion and the data to support it. In fact, to our knowledge no study has yet investigated the effects of quadriceps strengthening exercises on quadriceps muscle power and work muscle during locomotion. The aim of the study was to assess the effect of quadriceps muscle strengthening on quadriceps muscle force, power, and work production and tibio-femoral compressive joint loads during walking in adults with knee OA. By demonstrating whether or not increasing the capacity of the quadriceps muscle through strengthening changes quadriceps biomechanics during walking, we will provide original data that directly investigates possible biomechanical pathways to symptomatic improvement in knee OA patients with exercise. ACCEPTED MANUSCRIPT AC CE PT ED M AN US CR IP T 6 METHODS Study design This was a two-center study based on the collaboration between The College of Health and Human Performance, East Carolina University, USA and The Parker Institute, Bispebjerg-Frederiksberg Hospital, Denmark. The study was conducted at two separate motion analysis laboratories, using identical test protocols, methodology and study design in order to cluster all data and to publish the results in a pooled analysis. Accordingly, this study is a randomized controlled two-center trial including adults with tibio-femoral OA (ClinicalTrials.gov/ NCT01538407). All study procedures were approved by the Institutional Review Boards at both sites and all research participants at each site provided written informed consent to participate. Each subject was entered into the study after the presence of tibio-femoral knee OA was verified by a rheumatologist or orthopedist according the criteria of the American College of Rheumatology (Altman et al., 1986) . At each center participants were randomly and equally (1:1) allocated to a 12 weeks of quadriceps strengthening group or a control group (no attention) by two of the co-authors (J.A. and J.L.). The randomization sequence was made before commencement of study activities by a computer random number generator. Participants allocated to the training group had to complete a minimum of 80% of the training bouts (30 out of 36 possible bouts) to be considered adherent to the protocol. All methods were applied consistently for all participants throughout the study; no procedures were altered during the study. Participants Participants were included if clinical symptoms and radiographic findings of tibio-femoral OA were verified in one or both knees. Otherwise participants were in general good health aged between 45 and 70 years and with body mass index (BMI) of 19<BMI<34 kg/m 2 . Exclusion criteria included (but were not limited to) knee joint effusion, subjects dependent on walking device or signs and symptoms of clinically significant cardiovascular diseases, autoimmune disorders, diabetes or neurologic disorders. ACCEPTED MANUSCRIPT AC CE PT ED M AN US CR IP T 7 Strength training Quadriceps strengthening consisted of supervised and facility based sessions (3 times/week) including leg extension, leg press and forward lunge exercises each performed in 3 sets of 10 repetitions with loads. The initial two weeks were performed at 60% 3RM, the following two weeks at 70% 3RM and the remaining 8 weeks at 85% 3RM. Training load was progressed by means of bi-weekly estimates of muscle strength (3RM test) to ensure a consistent training load between 60%–85% 3RM. Muscle strengthening exercises on both lower extremities were performed according to the standard progressive resistance and overload principle (36). Before each session participants performed 5-10 minutes of warming up on a treadmill or stationary bicycle. Each training session lasted about 60 minutes. Gait analysis Gait analysis data were acquired using infrared 3D motion analysis systems (Qualisys MacReflex 240, Gothenburg, Sweden and Vicon MX13, Oxford, UK, both operating at 100 Hz) in combination with adhesive reflective markers placed directly on the skin of the subjects in a modified Helen Hayes configuration. Force platforms (AMTI, LG6-4-2000, Newton, MA, USA operating at 1,000 Hz) embedded in the laboratory floor captured ground reaction forces which were temporarily and spatially synchronized with the kinematic data. The digitized Cartesian coordinates of the reflective markers were digitally filtered bi-directionally through a second order low-pass Butterworth digital filter with a 6-Hz cut-off frequency. In cases of bilateral OA, the knee with more pain at baseline based on patient report was measured and analyzed. During all trials subjects walked in their own comfortable shoes. Subjects were familiarized to the task by walking at a self-selected speed across the walkways for 10 m and until a self-selected target walking speed was determined. Since exercise increases walking speed in people with knee OA (e.g. (Messier et al., 2004), self-selected and not a standard speed was used to provide greater ecological validity and to maximize the potential for observing altered quadriceps and knee joint forces. Walking speed was monitored with a set of two photocells connected to a clock at each site. Subsequently, 10 acceptable trials per person (clean force plate hits) were collected and used for statistical evaluation. We examined the quality of the ten-trial procedure by calculating all within-participant coefficients of variation (CV) for the locomotion variables in this study. The trials within each ten- ACCEPTED MANUSCRIPT AC CE PT ED M AN US CR IP T 8 trial sample were highly consistent with extremely low inter-trial CVs which averaged 14% compared to the between participant CVs which averaged 44%. Three dimensional joint angular kinematics were determined from the filtered linear position data and joint reaction forces and moments were calculated using standard inverse dynamics approach and Visual 3D software (C- Motion, Rockville, MD). The analyses focused on the stance phase of the gait cycle which was defined as heel strike to toe-off as determined by the vertical ground reaction force with a 10 N threshold. All trials were analyzed individually and subsequently each variable was averaged across trials for each participant. Outcome measures All participants had body mass and height, 3D gait analyses, isokinetic muscle strength, functional performance tests and data from the Western Ontario and McMaster Osteoarthritis Index (WOMAC) collected before and after a 12-week intervention period. The primary outcome variables were maximum quadriceps muscle force and power and quadriceps work and the maximum total knee (tibio-femoral) compressive force during 1 st half of stance, the period of maximum quadriceps activation and knee extensor torque. Estimates of muscle forces and joint compressive forces were calculated using the kinematic and kinetic data from the gait analyses in combination with a biomechanical model used previously and described in detail (DeVita and Hortobagyi, 2001; Messier et al., 2011) and used extensively for knee OA individuals (Messier et al., 2005; Messier et al., 2011; Messier et al., 2013b). The muscle and joint force predictions compare favorably to those from other biomechanical models (see (Messier et al., 2011) for summary) and the knee joint force predictions were highly similar to the measured forces from an individual with an above knee prosthesis (Messier et al., 2013a). We extended the calculations from previous work to include quadriceps muscle power. Quadriceps length was determined in each kinematic frame based on knee joint angular position from equations by Chow et al (Chow et al., 1999) and quadriceps shortening or lengthening velocity was then derived as the time derivative of muscle length. Quadriceps power was calculated as the product of quadriceps muscle force and velocity. To further investigate the effects of strengthening exercises on knee mechanics, maximum ACCEPTED MANUSCRIPT AC CE PT ED M AN US CR IP T 9 knee flexion and maximum internal knee extensor torque both occurring at approximately 20% of the stance phase were also included in the analyses. The maximal isokinetic muscle strength (MVC) was measured at 60 °/sec using a dynamometer (HUMAC NORM, CSMi, Stoughton, MA and KinCom, Chattex, Chattanooga, TN). The subjects were seated and firmly strapped into the dynamometer chair, and the axis of rotation was aligned with the axis of joint rotation (knee flexion/extension). The distal part of the subject’s leg was held against the dynamometer with a cuff. The subjects were asked to perform the given movement in a full range of motion with maximal effort and force, and loud verbal encouragement was given during the tests, as well as visual feedback from the dynamometer computer monitor. After familiarization with the test protocol, each test series consisted of 3 maximum torque values and the maximum value was extracted for statistical analysis. Radiographic evaluation Standard semi-flexed anterior posterior standing radiograph was taken (Philips Optimus). A trained musculoskeletal radiologist performed the Kellgren-Lawrence (K/L) score in all standing radiographs as originally described by Kellgren and Lawrence (Kellgren and Lawrence, 1957). Using this method the medial knee tibio-femoral joints were categorized into 5 grades from 0 to 4, assessing the stage of knee OA. Statistical analysis The sample in this study was set to 40 in total. However during the trial it became apparent that we would not reach this enrolment level, thus it was decided only to enroll a total of 30 with 15 participants in each group. The statistical analyses are based on per protocol population defined as participants with gait analysis data at baseline and at follow-up after the 12 weeks intervention period and adherence to the strength training program (minimum 80%). Gait variables were averaged across the 10 trials per participant at each test session and these mean values were statistically analyzed. We performed one-way ANCOVAs on the change scores within each group ACCEPTED MANUSCRIPT AC CE PT ED M AN US CR IP T 10 with the baseline values used as the co-variate. Level of statistical significance was accepted if p<0.05. To further explore possible relationships among clinical and biomechanical variables we correlated the change in maximum quadriceps isokinetic strength with the change in WOMAC pain and function scores and these three variables with changes in knee joint and quadriceps force, power, and work variables. Figure 1 RESULTS Thirty-five adults with knee OA volunteered for the study, four were excluded at screening due to knee joint effusion (n=1), excessive BMI (n=1), or they declined to participate upon further information (n=2; Figure 1). In total we included 31 participants, 18 females and 13 males; one male left the study however after changing employment because he could not meet the training schedule. The 30 remaining participants had a mean age of 57.1 (SD 7.7) years and BMI 27.1 (4.0) kg/m 2 (Table 1). Following randomization the groups were as expected comparable at baseline, and differed by less than 4%, on average, in age, height, BMI and K/L score (Pre-test K/L for all subjects was 2.65). All participants in the strength training group adhered to the protocol and completed at least 30 sessions (80%) of the possible 36 training sessions. All included participants completed the follow-up tests; however, 1 subject did not perform the WOMAC questionnaire. Four subjects (two in each group) had incomplete muscle strength test data, which were accounted for by multiple imputations. One participant in the training group left the study after ~50% of the training sessions because of a change in employment and this person could no longer meet the training schedule. All participants were recruited, trained and analyzed between September, 2011 and April, 2013. Table 1 ACCEPTED MANUSCRIPT AC CE PT ED M AN US CR IP T 11 Quadriceps strength training produced significant group differences in quadriceps strength and pain, function and total WOMAC scores (Table 2), Quadriceps muscle strength increased 25% in the training group compared to only 2% in the control group. The effect size for this difference was 0.90. Changes in pain, function, and total WOMAC scores were 43%, 62% and 55% larger in training compared to control group with effect sizes over 1.00 for each variable and with non- overlapping 95% confidence intervals for the pre-test – post-test difference scores for each group (data not shown). The analysis showed statistically non-significant differences in the group difference scores for maximum quadriceps force and maximum compressive knee force during walking (figure 2). A statistically significant effect in the difference score was evident for maximum negative quadriceps power in early stance, with a 36% increase (i.e. more negative) in the training group compared to 1% decrease in the control group and an effect size of 0.91. The group differences in negative quadriceps work and maximum positive quadriceps power and work in early stance however were not statistically significant. Maximum knee flexion and knee internal extension torque during loading phase were also not statistically significantly different between groups after the treatment period. Self-selected walking velocity during the gait tests was statistically significantly increased by 3% in the training group compared to a 3% decrease the control group with a large effect size for the difference of 0.98. Eighteen of the twenty correlation coefficients between changes in clinical and biomechanical gait scores were statistically non-significant (p>0.05, Table 3). Changes in maximum knee compression and maximum quadriceps force were inversely related to changes in pain and function (p<0.05), meaning that higher knee compression and quadriceps forces were associated with less pain and improved function. None of the participants reported any pain or discomfort associated with the training during or after the study period. Table 2 Figure 2 Table 3 ACCEPTED MANUSCRIPT AC CE PT ED M AN US CR IP T 12 DISCUSSION In this randomized controlled trial we investigated the effects of quadriceps strength training on quadriceps muscle force, power and work, and knee compression force during walking in people with knee OA. To our knowledge this study is the first attempt to directly investigate the proposition that quadriceps strength training alters quadriceps locomotor function in people with knee OA. Specifically, we explored the idea that these symptomatic improvements were mediated through enhanced quadriceps muscle function and reduced knee joint loads during walking. Indeed, quadriceps strength training did improve the mechanical capacity of the muscle by increasing its maximum strength. Strength training also reduced the participants’ pain and disability and increased self-selected walking velocity and these results well agree with previous work (Chang et al., 2016; Fransen et al., 2003; Juhl et al., 2014; McAlindon et al., 2014). Additionally, quadriceps strengthening greatly improves underlying neural control and reduces neural inhibition of the quadriceps strongly suggesting that quadriceps capacity during locomotion would be enhanced (Hurley and Newham, 1993; Hurley and Scott, 1998). With one or possibly two exceptions however and within the limitations of our protocol (e.g. a moderate 12 weeks of training, testing at only one walking speed), the increased quadriceps strength was not reflected in the walking biomechanics: quadriceps force, maximum positive power, negative work and positive work were all statistically unchanged after the training period. The exception was that maximum negative quadriceps power in early stance was increased in the training group compared to the control group. The possible exception was that quadriceps negative work in the early portion of stance may have increased and we may have had a type II statistical error since the associated negative power was increased and the p-value for the work comparison was 0.061. We suggest however that the increased negative power and possibly work functions were direct responses to the increased walking velocity likely due to reduced pain as observed only in the training group and not primary responses of increased quadriceps strength. In fact, changes in maximum negative quadriceps power and negative work were uncorrelated to the change in quadriceps strength as were changes in maximum quadriceps force, positive power and work and knee joint compressive force across all participants (all p>0.05). ACCEPTED MANUSCRIPT AC CE PT ED M AN US CR IP T 13 Further, we observed only two significant relationships out of 18 examined among changes in the clinical WOMAC variables and the biomechanical variables of knee joint and quadriceps force, power and work suggesting that improvements in pain and function were associated with increases in knee compression forces and quadriceps forces, respectively (table 3). However, these associations need confirmation as they may have occurred by chance due to multiple testing. We conclude that improved clinical and symptomatic outcomes after quadriceps strength training were not due to altered or improved quadriceps muscle function or knee joint loads in level walking. Our results refute the theory that strength training induces a biomechanical unloading mechanism at the knee joint (Segal et al., 2010; Topp et al., 2002). This conclusion supports the observation of Bennell et al (Bennell et al., 2011) who showed the literature cannot support the idea that exercise can alter the mechanical load in the knee. Our results also support Sharma et al (Sharma et al., 2003) who conjectured that muscle strength may be a poor measure of muscle contribution to joint function in people with knee OA. Also, a recent study showed that exercise therapy had no effects on a range of ankle, knee and hip gait biomechanics variables (Henriksen et al., 2014). The mechanism through which quadriceps strength training elicits favorable responses in people with knee OA remains elusive and unknown. Further, our results are analogous to those of Beijersbergen et al (Beijersbergen et al., 2013) who showed from an extensive literature review the biomechanical mechanism of how strength and power training improves walking speed in old adults also remains unknown. It appears that the biomechanics-rehabilitation literature has yet to connect improved neuromuscular and physiological properties elicited through physical activity or exercise and the manifestation of reduced symptoms and disability in the OA or aged populations during activities of daily living. Messier et al reported quadriceps muscle and knee joint compressive forces in response to diet, exercise, and diet and exercise treatments. They showed that a general exercise regimen including aerobic training and quadriceps strength training did not reduce maximal quadriceps force and knee joint compressive force during walking in the absence of weight loss in knee OA participants (Messier et al., 2011). Further, general exercise alone had minimal change in knee compression (i.e. ACCEPTED MANUSCRIPT AC CE PT ED M AN US CR IP T 14 3%) compared with diet (10%) and diet and exercise (10%) programs in a large sample of knee OA participants (Messier et al., 2013b). Combined with our results, improved pain and function seem to be more strongly mediated through reduced body weight than improved muscle function. We respectfully submit that biomechanical mechanisms in OA should distinguish between force and energy issues. Muscles generate or produce force and mechanical energy but they dissipate only energy. Thus, improved muscle function should not be considered to absorb forces to reduce joint loads (Baker et al., 2001; Igawa and Katsuhira, 2014). As identified in both the OA and healthy gait literature, increased muscle force would clearly increase load on the joint surfaces because muscles compress joints (Baker et al., 2001; Kim et al., 2009; Sasaki et al., 2008; Schipplein and Andriacchi, 1991; Shelburne et al., 2006). Through eccentric lengthening contractions, such as performed by the quadriceps in the loading phase of gait, muscles reduce mechanical energy associated with total body mass (DeVita et al., 2007) but not with joint surfaces, a proposed, protective outcome of muscle contraction (Brandt et al., 2009). Indeed, knee joint loading during gait directly loads the joint surfaces, performing work on the cartilage inducing cartilage strain and thinning in knee OA patients and in individuals with injured anterior cruciate ligaments (Andriacchi et al., 2009; Chehab et al., 2014). Our data showed that strength training increased walking dynamics by increasing walking velocity while at the same time reduced pain and improved function. With a lack of associated knee joint and quadriceps muscle adaptations to increased maximal muscle strength, we conjecture the beneficial effects of strength training may be mediated through a broader, systemic response to the physical activity and not a specific, joint and muscle centered response. For example, higher levels of physical activity were associated with lower levels of inflammatory markers in knee OA patients (Penninx et al., 2004). This work was conducted as a two-center study, and even though we used identical test- protocols and laboratory set-up, there may be subtle differences in the methods that we could not control for. This is a possible limitation, but gathering data from more than one laboratory is also a strength; we showed similar outcomes in WOMAC (ECU 6.8; Parker 5.6), isokinetic strength (ECU 0.93; Parker 1.21 Nm/kg), gait biomechanics (maximum knee force: ECU 35.3; Parker 38.9 N/kg; ACCEPTED MANUSCRIPT AC CE PT ED M AN US CR IP T 15 maximum quadriceps force: ECU 19.0, Parker 20.7 N/kg) and quadriceps muscle responses to strength training at both sites (data not shown). We also draw note to the fact that the present participants were limited on average to middle-aged adults who were overweight but not obese. Older and obese adults may respond differently to the training program. Our prediction of quadriceps muscle length and subsequently muscle power were based solely on the sagittal plane angular position of the knee joint. As such, we cannot distinguish individual contributions from muscle fiber and tendon components or include potentially influential effects of muscle activation and tendon mechanical properties nor how these properties may have changed over the training period. Otherwise, we expect our results are generalizable to the adult population with knee OA but with few other health ailments. Certainly muscle strength and muscle function are pivotal for knee OA patients in terms of improvements in pain and physical function (Fransen et al., 2003; Juhl et al., 2014; McAlindon et al., 2014). However, while quadriceps weakness may increase the risk of structural deterioration in knee OA (Oiestad et al., 2015) and while high muscle strength may protect against knee OA progression, our results do not support the underlying mechanism of exercise induced knee unloading through improved muscle function leading to reduced pain and disability. This outcome is novel and demonstrates for the first time responses in quadriceps muscle power and work during locomotion to quadriceps strength training exercise in knee OA patients. The findings of this study suggest that pain relief and improvements in function are not explained by altered quadriceps forces or knee joint loads after strengthening the quadriceps through strength training. ACCEPTED MANUSCRIPT AC CE PT ED M AN US CR IP T 16 ACKNOWLEDGEMENTS The authors thank Mr. Patrick Rider for his technical assistance in data collection and analysis at East Carolina University. Mr. Lars Bo Jørgensen (Physical Therapist) is acknowledged for his assistance in exercise delivery at The Parker Institute. We thank senior biostatistician and professor of clinical epidemiology Robin Christensen for his assistance when designing the study, for providing guidance on the statistical analyses, and for providing editorial recommendations. AUTHOR CONTRIBUTIONS All authors made substantial contributions to 1) the conception and design of the study, or acquisition of data, or analysis and interpretation of data; 2) drafting the article; and 3) final approval of the version to be submitted ROLE OF THE FUNDING SOURCE: This work was funded by the Biomechanics Laboratory in the Department of Kinesiology at East Carolina University, The Danish Rheumatism Association and The Oak Foundation CONFLICT OF INTEREST The authors report no conflicts of interest. ACCEPTED MANUSCRIPT AC CE PT ED M AN US CR IP T 17 REFERENCES: Aaboe, J., Bliddal, H., Messier, S.P., Alkjaer, T., Henriksen, M., 2011. Effects of an intensive weight loss program on knee joint loading in obese adults with knee osteoarthritis. Osteoarthritis Cartilage 19, 822-828. Altman, R., Asch, E., Bloch, D., Bole, G., Borenstein, D., Brandt, K., Christy, W., Cooke, T.D., Greenwald, R., Hochberg, M., et al., 1986. 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Zhang, W., Moskowitz, R.W., Nuki, G., Abramson, S., Altman, R.D., Arden, N., Bierma-Zeinstra, S., Brandt, K.D., Croft, P., Doherty, M., Dougados, M., Hochberg, M., Hunter, D.J., Kwoh, K., Lohmander, L.S., Tugwell, P., 2007. OARSI recommendations for the management of hip and knee osteoarthritis, part I: critical appraisal of existing treatment guidelines and systematic review of current research evidence. Osteoarthritis Cartilage 15, 981-1000. ACCEPTED MANUSCRIPT AC CE PT ED M AN US CR IP T 23 FIGURE LEGENDS: Figure 1. Participant flow schematic diagram. Figure 2. Pre- and post-test group mean curves for A) quadriceps muscle force, B) quadriceps muscle power, and C) knee compressive force during the support phase of walking. Solid, dashed lines are pre- and post-tests. Dotted lines are ± 1 standard deviation of baseline values. ACCEPTED MANUSCRIPT AC CE PT ED M AN US CR IP T 24 Table 1. Baseline characteristics of knee OA participants Control Group Training Group (n = 15) (n = 15) Gender Females no. (%) 8 (53.3) 10 (66.7) Males no. (%) 7 (46.7) 5 (33.3) Age (years 56.2 ± 8.9 58.1 ± 6.5 Height (m) 1.73 ± 0.11 1.73 ± 0.07 Body mass (kg) 83.8 ± 18.7 79.4 ± 14.8 BMI (kgm -2 ) 27.9 ± 3.9 26.4 ± 4.0 Kellgren Lawrence score* Score 1 3 2 Score 2 1 4 Score 3 8 7 Score 4 3 2 Except where indicated results are mean ± standard deviation ACCEPTED MANUSCRIPT AC CE PT ED M AN US CR IP T 25 Table 2. Pre- and post-test means (standard deviations) of primary and secondary variables and ANCOVA probability Control Group Traning Group P* Pre-test Post-test Pre-test Post-test Isokinetic quadriceps muscle strength (Nm/kg) 1.12 1.17 0.96 1.21 0.037 (0.35) (0.40) (0.39) (0.42) WOMAC Pain 6.67 7.33 6.43 3.64 0.001 (3.31) (4.72) (3.18) (2.55) WOMAC Function 22.9 21.1 17.7 6.8 0.003 (10.7) (12.9) (9.7) (9.5) WOMAC Total 33.1 31.6 27.3 12.4 0.001 (14.5) (18.2) (13.1) (12.3) Gait Variables: Maximum quadriceps force (N/kg) 21.7 20.9 17.4 20.2 0.125 (5.9) (5.4) (5.4) (6.0) Maximum knee compressive force (N/kg) 40.7 38.4 34.6 37.5 0.161 (5.4) (6.2) (6.7) (6.2) Maximum negative quadriceps power (W/kg) -1.40 -1.38 -1.00 -1.36 0.003 (0.68) (0.86) (0.80) (1.05) Quadriceps negative work (J/kg) -0.114 -0.113 -0.091 -0.118 0.061 (0.063) (0.070) (0.061) (0.078) Maximum positive quadriceps power (W/kg) 0.804 0.806 0.632 0.770 0.153 (0.390) (0.401) (0.445) (0.513) Quadriceps positive work (J/kg) 0.087 0.102 0.071 0.086 0.354 (0.056) (0.065) (0.055) (0.063) Maximum knee flexion (deg) -19.0 -19.6 -16.4 -16.4 0.236 (6.5) (6.7) (7.5) (5.6) Maximum internal knee extensor torque (Nm/kg) 0.673 0.692 0.522 0.639 0.187 (0.278) (0.257) (0.267) (0.279) Walking velocity (m/s) 1.49 1.45 1.43 1.47 0.014 (0.16) (0.17) (0.21) (0.23) mean values across participants and sd in () P*: probability value from ANCOVA with adjustment for baseline scores, BOLD : P<0.05 ACCEPTED MANUSCRIPT AC CE PT ED M AN US CR IP T 26 Table 3. Correlation coefficients among changes from baseline in clinical (isokinetic strength) and biomechanical gait variables (all participants, n = 30) Correlation with: Variable Pain Function Strength Maximum isokinetic strength -0.111 -0.046 Maximum knee compression -0.515 -0.478 0.161 Maximum quadriceps force -0.474 -0.522 0.032 Maximum negative quadriceps power 0.306 0.098 -0.211 Negative quadriceps work 0.283 0.124 -0.119 Maximum positive quadriceps power -0.416 -0.361 0.065 Positive quadriceps work -0.231 -0.222 -0.106 Absolute values > 0.497 statistically significantly different than 0, p<0.05 ACCEPTED MANUSCRIPT AC CE PT ED M AN US CR IP T 27 Highlights: Quadriceps strength training or no training were given to groups of knee osteoarthritis patients. Training increased strength and reduced pain but did not change quadriceps or knee forces in walking Biomechanical mechanism of improved health with strengthening in knee OA patients remains unknown. ACCEPTED MANUSCRIPT Figure 1 Figure 2
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