Correlation of Knee Instability With Alignment And Repetitive Physical Activity In Patients With Knee Osteoarthritis: A Cross-Sectional Study

Objectives. Malalignment, dynamic knee instability, and repetitive physical activity are considered biomechanical risk factors for knee osteoarthritis (KOA), though the correlations among these factors are poorly understood. The purpose of this study was to elucidate the relationship between knee instability and alignment, and to determine the effects of repetitive physical activity on knee instability in patients with KOA. Methods. The study subjects were 68 patients with radiographic tibiofemoral KOA and 68 control subjects. Each participant underwent clinical evaluation, muscle strength test, radiography, and knee instability test. Instability was evaluated before and after repetitive stepping exercise using triaxial accelerometer. Results. Mediolateral acceleration correlated (p<0.01) with two coronal alignments (mechanical axis; HKA and joint line convergent angle; JLCA). Pearson correlation coecient was small (r=0.23-0.24) before but increased after stepping (r=0.28-0.33). Increased mediolateral acceleration after stepping correlated with JLCA (r=0.37, p<0.001) . There were signicant differences in coronal alignments, gait speed, mediolateral acceleration, and accelerations in all directions between the control and KOA groups. Anteroposterior acceleration did not correlate with sagittal knee alignment. Multiple logistic regression analysis identied HKA/JLCA, and increased mediolateral acceleration after stepping as signicant diagnostic predictors of KOA. Conclusion. We found a direct relationship between knee instability and knee alignment or repetitive physical activity. Repetitive stepping activity signicantly increased mediolateral acceleration in KOA patients, compared to the control. Stepping increased the correlation between mediolateral acceleration and coronal alignment. In knees with large JLCA, repetitive stepping provided much larger mediolateral instability. Our results suggest that, in addition to JLCA, the increase in mediolateral acceleration after repetitive physical activity, possibly contributes to the development of KOA.


Introduction
Malalignment of the knee is a major risk factor for the development and progression of knee osteoarthritis (KOA) (1)(2)(3). Evidence suggests that changes in the geometry of the articular surface affect the biomechanical properties of the joint, which can ultimately result in damage of the articular cartilage (4)(5)(6)(7). Another pathological factor in KOA is mechanical stress resulting from high physical activity of daily living or occupation (8)(9)(10)(11)(12). For example, prolonged or repeated squatting (8, 10,11) and stressful stair climbing activity are considered risk factors for KOA (8, 9,12), although a few groups have argued that high physical activity is not associated with the incidence or worsening of KOA (13,14).
Knee joint laxity and instability are also major factors that contribute to the physical function of the knee joint and risk factors for KOA (15)(16)(17)(18)(19)(20). In this regard, varus thrust during walking is considered a risk factor for radiographically-con rmed progression of medial (RKOA) (21,22), and for the development and worsening of MRI-con rmed medial tibiofemoral lesion (23). Knee thrust is usually diagnosed by physical examination, though Change et al (24) used a motion analysis system to demonstrate a close association in OA patients between knee thrust and peak varus angle and angular velocity. However, only a few studies have examined the direct relationship between knee instability and alignment or physical activity. Kuroyanagi et al (25) used the varus-valgus angle, representing the amount of thrust, and demonstrated its correlation with radiographic alignment. Our group reported an increase in the anteroposterior and mediolateral laxity of the knee after stair climbing in patients with mild KOA (26). However, the knee joint laxity was only measured in that study under static conditions. To our knowledge, there is no information on dynamic knee joint instability during physical activity in RKOA. Figure 1 illustrates the pathological relationship between the above-mentioned mechanical factors and RKOA. To our knowledge, little is known regarding the correlation of knee instability or alignment with repetitive physical activity. Since early 1990s, several studies applied accelerometry to evaluate the knee joint under dynamic instability conditions (27)(28)(29)(30)(31). For example, a signi cant decrease in the lateral thrust, as measured by accelerometry, was reported in patients with varus OA knees using lateral wedge insole (28). Advanced technological development in accelerometry was applied by Turcot et al (31) to determine tri-axial instability of the tibiofemoral joint.
We hypothesized that signi cant relationships exist between knee instability or alignment with repetitive physical activity. To test our hypothesis, we determined the relationship between dynamic knee joint instability and coronal/sagittal knee alignment, and the effect of repetitive physical activity on knee instability in patients with RKOA. We used tri-axial accelerometry to evaluate tibiofemoral instability. Repetitive squatting has been reported previously to study the effects of high physical activity on the knee joint (8, 10, 11), however, this form of activity could potentially cause considerable pain in patients with KOA. For this reason, we used stepping exercise in this study as representative high physical activity in daily living. The main purpose of this study was to elucidate the relationship between knee instability and alignment, and to determine the effects of repetitive physical activity on knee instability in patients with RKOA

Subjects
City dwellers aged ≥ 50 years were invited through advertisements to volunteer in this study. Power analysis using G Power 3.1.9 (Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany) estimated participation of at least 64 subjects in order to detect group differences, with two-tailedαof 0.05, power of 80%, and effect size of 0.5. We excluded subjects with patellofemoral malalignment, diagnosed previously with rheumatoid arthritis or severe spinal stenosis, and also subjects who had undergone knee surgery previously, as well as paraplegic subjects and those who could not stand on one leg or climb up/down stairs. All subjects underwent radiological assessment of the knee for KOA using the Kellgren-Lawrence (K/L) scoring system (in this system, grade 0 signi es no OA and grade 4 represents severe OA). Based on the results of radiographic examination, the selected study subjects were 68 participants (34 men and 34 women) with radiographic K/L grade 0-1 (here called the control group), and 68 (34 men and 34 women) with K/L grade 2-4. Only the index knee was selected for analysis in each participant.
There were no signi cant differences in age and side of the knees between the control and OA groups. However, the body mass index (BMI) of the OA group was signi cantly larger than that of the control (Table 1).

Clinical evaluation
Subjects were asked to ll in the knee injury and osteoarthritis outcome score (KOOS) (32). KOOS assesses ve outcomes; pain, symptoms, activity of daily living (ADL), sport and recreational function, and knee-related quality of life. The KOOS meets the basic criteria of outcome measures and is used to evaluate the course of knee injury and treatment outcome (32). Since the study subjects were patients with primary KOA, we evaluated the activities of daily living (KOOS-A), pain (KOOS-P), and OA-related symptoms (KOOS-S).

Assessment of muscle strength
The isokinetic strength of the quadriceps and hamstring muscles was evaluated by the Biodex System Dynamometer (Biodex Medical Systems, NY) at angular speed 60°/sec. Each subject was tested three times and the highest value was chosen for analysis.

Radiography
Standing radiographs of the knee in anteroposterior (AP), lateral, and skyline views were obtained in all participants. Furthermore, all subjects underwent uoroscopic-assisted, standing AP and full length AP radiographs in a semi-exed position. The AP radiograph of the knee was obtained with the radiographic beam pointing parallel to the medial tibial plateau. The full length one-leg standing AP radiograph of the leg was used to express the varus valgus alignment of the leg using the mechanical axis; the hip-knee ankle angle (HKA), which represents the angle between the line connecting the center of the femoral head and the center of the tibia plateau and the line connecting the center of the tibia plateau and center of the ankle, (Fig. 2a). The joint line convergent angle (JLCA) (33) was obtained using the one-leg standing AP radiograph. The JLCA represents the angle between the line connecting the most distal point of the medial and lateral femoral condyles and the line connecting the proximal medial and lateral edges of the tibia plateau (Fig. 2b). Using the AP radiographs, the medial slope angle of the tibia plateau (MS) was de ned as the angle between the line connecting the proximal medial and lateral edges of the tibia plateau and the line connecting the two points of center of the tibial shaft (7 cm and 12 cm distal to the tibial plateau) (Fig. 2b). Finally, the posterior slope angle of the medial tibial condyle (PS) was measured. It represents the angle between the line connecting the anterior and posterior edges of the medial tibial condyle and the line of the anterior margin of the tibia, distal to the tibial tubercle (Fig. 2c).

Accelerometry
Three small triaxial accelerometric wireless sensors (WAA-006™, Tekscan, MA) were attached to the bular head, lateral femoral condyle, and lateral side of the leg, with skin tape and 7 cm-wide Velcro band.
A pressure sensor (FlexiForce™, Nitta, Japan) was also attached to the heel with skin tape. The subject was instructed to walk on a 10 m at oor at own comfortable natural speed, then step up and down 20 times on a 20 cm-high stepper, and nally walk on the at oor. The sampling rate was 1 kHz for accelerometry and 50 Hz for the heel pressure sensor. The data of the femur, tibia and heel pressure sensors were synchronized, and the difference in accelerometry between the femur and the tibia was analyzed (WAA Data Analyzer, ATR-Promotions, Kyoto, Japan). The data were ltered using a Butterworth low-pass lter with a cutoff frequency of 10Hz, and the triaxial acceleration of the femur relative to the tibia was obtained (Fig. 2). The range between the positive peak and the following negative peak was de ned as the magnitude of the acceleration. The rst 10 acceleration waves starting from the heel were selected and the average values were used for the following analysis.

Statistical analysis
Reproducibility of measurements of accelerometry of the knee joint was tested in 10 KOA patients on two separate days. The average intraclass correlation (ICC) for antero-posterior direction was 0.99 before stepping and 0.93 after stepping. The ICC for mediolateral direction was 0.97 before stepping and 0.86 after stepping and for proximal and distal direction, it was 0.90 before stepping and 0.95 after stepping.
The association between accelerometry and the alignments was analyzed using Pearson's correlation analysis.
Two-tailed unpaired t-test and multiple logistic regression analysis were used for analysis of the clinical outcome, knee muscle strength, radiographic, gait speed and accelerometric data comparison between the OA and control groups. Effect size as Cohen's d (34) was calculated to scale and rank the difference in all measures between the two groups.
All statistical analyses were conducted using the EZR software ver. 1.27 (35), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modi ed version of R commander designed to add statistical functions frequently used in biostatistics.
The level of statistical signi cance was set at p < 0.05.

Results
All subjects completed the study protocol without additional knee pain.
In the sagittal plane, PS did not correlate with acceleration in the antero-posterior direction; bY, aY, and a-bY (p = 0.92, 0.57, and 0.18 respectively) ( Table 2).  Within the coronal alignments, HKA and JLCA were larger (p < 0001), and MS smaller (p < 0.01) signi cantly in the RKOA group, but not the sagittal knee alignment (PS) (p = 0.14), compared with the control group (Table 3).  The walking speed of the OA group was signi cantly slower (p < 0.001) than that of the control. Before stepping, acceleration of the OA group was signi cantly larger than the control group in only mediolateral direction (bZ). However, accelerations after stepping and the change in acceleration after stepping were signi cantly larger in both proximal-distal (aX and a-bX) and anteroposterior directions (aY and a-bY), as well as mediolateral direction (aZ and a-bZ) (p < 0.01). (Table 3).

Discussion
In this study, we measured dynamic knee instability using tri-axial accelerometer before and after repetitive stepping activity and demonstrated signi cant relationship between mediolateral knee instability and coronal alignment of the knee.
In the coronal plane, the load distribution across the femorotibial joint is estimated predominantly in knees with normal alignment. Knees with varus deformity receive the total load almost entirely on the medial compartment (36). The mechanical stress concentrated on the medial compartment produces high adduction moment of the knee and opening of the lateral side of the joint, which is described as varus thrust (37). The degree of lateral opening is indicated directly by JLCA and indirectly by HKA. Accordingly, mediolateral acceleration, which quantitatively represents varus thrust, likely correlates signi cantly with HKA and JLCA.
Maeyama and coworkers (38) measured three directions of acceleration. They reported that the overall magnitude of acceleration of the dysplastic hip was signi cantly larger than that of the contralateral normal hip. They found a signi cantly high correlation between radiographic center-edge angle and the overall magnitude of acceleration (r=-0.73, p < 0.0001). The hip joint has ball and socket anatomy, which is supported by many muscles multi-directionally. Thus, instability related to the bony structure is often strongly responsible for dynamic joint instability. On the other hand, the anatomical morphology of the knee joint is more complex. In addition, the joint is supported by not only the surrounding muscles, but also by a series of ligaments, supporting structures and soft tissues. Therefore, any instability associated with the bony structures, described as knee alignment, may be less responsible for dynamic knee instability.
The JLCA has been used recently to describe the magnitude of medial and lateral coronal soft tissue laxity in tibial osteotomy for KOA (39). Although the JLCA re ects the effect of soft tissue laxity, and it varies greatly in subjects with KOA (40), its signi cance in the understanding of the pathogenesis of KOA is unclear. In the present study, JLCA correlated signi cantly with the a-b Z, indicating JLCA may be a valuable marker to estimate mediolateral acceleration after stepping activity. In addition, multiple logistic regression analysis identi ed it as a marker for the radiographic diagnosis of KOA. Therefore, JLCA could be a potentially useful radiographic index for evaluation of KOA pathology.
The MS/PS is the anatomical angle of the tibia plateau that re ects joint con guration. Driban et al (6) showed that a greater coronal tibial slope signi cantly affected the load distribution, and it was associated with increased risk of incident accelerated KOA, particularly among knees with malalignment.
On the other hand, using a musculoskeletal model for healthy adults, Van Rossom et al (7) demonstrated that small changes in coronal tibial slope had a less pronounced effect on the load distribution, though coronal plane malalignment signi cantly affected it. In the present study, although the MS was signi cantly smaller (proximal tibial surface inclines more medially) in patients with RKOA compared to that of the control, it was not helpful in the diagnosis of KOA even after adjustment for other variables.
Furthermore, we did not nd the signi cant difference of PS between the control and RKOA groups, and the PS did not correlate with acceleration in the antero-posterior direction. In this regard, Van Rossom et al (7) reported that transverse plane malalignment only minimally affected the load distribution. Further research is needed to determine how individual joint geometry in uences knee joint instability and the risk of KOA.
Our results also showed signi cantly larger mediolateral acceleration in patients with RKOA, compared with the control. However, the difference became insigni cant after adjustment for all other variables.
Turcot et al (31) demonstrated signi cant high acceleration in anteroposterior and mediolateral directions in patients with KOA compared to the control, and concluded that the accelerometric method used in their study could discriminate between asymptomatic subjects and patients with medial KOA. They also indicated that the difference between their results and those reported by Lafortune et al (27) were probably related to differences in gait velocity, location of the accelerometer, and sensor xation method. Walking speed is a major factor affecting gait (41). However, we instructed our subjects to walk at their own natural pace so as to conduct the test under similar daily activity. In fact, our RKOA patients walked signi cantly slower than the control (p < 0.0001, Cohen'd = 0.84). With respect to the placement of the accelerometer, the femoral sensor was attached on the lateral epicondyle of the femur, while the tibial sensor was xed to the bular head. These sites were easy to locate on the skin. In addition, accelerometer should be placed on the lateral aspect of the leg for more accurate measurement (42). In our study, we measured body synchronous movements through the use of several sensors with good reproducibility of the obtained relative femorotibial acceleration. Care should also be taken to reduce artifacts produced by the sensor-skin mounting technique. In this regard, the use of exoskeleton may be advantageous relative to skin tape, although we used skin tape and rmly rapped wide Velcro band when placing the sensors on the skin.
After adjustment for all variables, the only signi cant difference in acceleration between RKOA patients and the control group was the average increase in mediolateral acceleration after repetitive stepping.
Mediolateral instability occurred much more in patients with RKOA after 20 stepping activities on the 20cm-high stepper.
Luepongsak et al (43) reported that among several daily living activities, descending stairs was associated with the highest forces across the knees and hips. Sahlström et al (44) applied gait analysis and demonstrated that climbing stairs is associated with a signi cant increase in knee moment in healthy subjects. Another study showed that malalignment and overweight can increase mechanical stress on the knee joint (45). In addition to our previous study in patients with KOA (26), a few studies also reported that certain physical exercises can induce knee joint laxity in athletes (46-48).
With regard to the soft tissues around the knee joint, previous studies demonstrated a strong relationship between decreased stiffness and reduced strength of the medial collateral ligament under cyclic loading (46). Others reported greater co-contraction of the medial muscle in response to medial knee joint laxity in patients with medial KOA (49). In our study, isokinetic knee muscle strength was signi cantly lower in the OA group compared to the control subjects. In this regard, muscle weakness is a known risk factor for KOA (50)(51). In the elderly, repetitive physical exercise, such as stepping exercise, even for a relatively short period of time, may cause muscle fatigue (52) and reduce stiffness of the collateral ligament (46), as the knee becomes more unstable.
In this study, JLCA signi cantly correlated with medio-lateral acceleration after repetitive stepping (aZ and a-b Z). This suggests that knees with large JLCA are potentially susceptible to the development or progression of KOA. Our study also demonstrated a signi cant increase in mediolateral acceleration in KOA patients after repetitive stepping, compared with non-OA subjects. In addition, a-b Z was a signi cant independent marker of KOA, suggesting that such activities during daily living are probably associated with the pathogenesis of KOA.
Our study has certain limitations. With regard to the stepping protocol, we set the height of the step and frequency of stepping up and down so that all subjects were able to complete the test without suffering further knee pain. The results would have been different if the exercise level had been harder or tailored to the daily activity of the individual patient. Nevertheless, the results showed signi cantly larger postexercise increase in mediolateral acceleration in patients with RKOA relative to the non-OA control, suggesting repetitive physical exercise may play a role in mechanical pathology for KOA. Another limitation of the study was the cross-sectional design. Further longitudinal studies are needed to determine whether coronal alignment abnormality and increased acceleration after repetitive stepping are risk factors for the development or progression of KOA.

Conclusions
In summary, we found a direct relationship between knee instability and knee alignment or repetitive physical activity. Repetitive stepping activity resulted in a signi cant increase in mediolateral acceleration in RKOA patients, compared to the control. The correlation between mediolateral acceleration and coronal alignment increased after stepping compared with before stepping. In knees with large JLCA, repetitive stepping activity provided much larger mediolateral instability. Our results suggest that increases in mediolateral acceleration after repetitive physical activity as well as JLCA seem to contribute to the pathogenesis of KOA. Association between three risk factors for knee osteoarthritis. The relationship between dynamic knee instability and alignment or repetitive physical activity is unknown.