Knee osteoarthritis (OA) is a leading cause of pain and disability (11) and has significant socioeconomical costs globally as it accounts for 83% of the total OA burden (36). Early OA causes changes in the biochemical composition of cartilage, such as loss of integrity of the collagen matrix and decrease in glycosaminoglycan (GAG) content (6). There is no known cure for OA, and thus, the main goal of OA management is pain relief and improving physical function (20). Therapeutic exercise, either land- or water-based, has been shown to evoke acute positive posttreatment effects on these goals (5,39). However, although the effects of therapeutic exercise on pain are lost 6 months after the cessation of the exercise, small but significant improvements in self-reported physical function are sustained up to 24 months (5).
Active lifestyle with exercise has been shown to be beneficial for the maintenance of the biomechanical properties of cartilage both in healthy humans (31,33,34) and animals (13,14). Thus, physical activity could be effective for the maintenance of cartilage health. Studies of the immediate posttreatment effects of exercise interventions on human cartilage are sparse, but show that the loading created by the exercise interventions can improve the estimated biochemical composition of tibiofemoral (24,27) and patellofemoral (16) cartilage. In addition to positive cartilage responses observed in these studies (16,24,27), impact (16,22), aquatic (24), and neuromuscular (27) exercises are shown not to be harmful for the estimated biochemical composition of the knee articular cartilage in population with mild knee OA (16,22,24) or at high risk of developing knee OA (27). Also, exercise is well tolerated in these populations (16,22,24,27). Furthermore, Teichtal et al. (31) observed in a longitudinal follow-up study with healthy population that over 2 yr of vigorous physical activity is associated with a reduced rate of patella cartilage loss and has a trend toward a reduced risk for worsening patella cartilage defects.
In osteoarthritic population, there are no known long-term follow-up studies investigating the relationship between knee articular cartilage and leisure-time physical activity (LTPA). Therefore, the aim of the present study was to investigate the relationship between 12 months of LTPA and the biochemical composition of tibiofemoral cartilage in postmenopausal women with mild knee OA.
This study was a 12-month follow-up to our previously reported 4-month registered randomised controlled trial (ISRCTN65346593) with two experimental arms: 1) aquatic resistance training and 2) control (24). Therefore, the term “original intervention” is used to mean the period of 4-month RCT and “follow-up” denotes to the 12-month period after the end of the intervention and is the focus of the current study. This analysis, which exploited the data from the previous intervention study, followed the published protocol without changes (38). The participants were women age 60–68 yr with mild knee OA and were divided into tertiles based on their average monthly LTPA (MET task hours [METh]) during the follow-up period. The study protocol (Dnro 19U/2011) was approved by the Ethics Committee of the Central Finland Health Care District and conforms to the Declaration of Helsinki. Written informed consent was obtained from all participants before enrolment.
Originally, postmenopausal women experiencing knee pain on most days from the Jyväskylä region in Central Finland were voluntarily recruited through advertisements in local newspapers. Preliminary eligibility to the original intervention was assessed using a structured telephone interview (n = 323), followed by evaluation of OA severity in the tibiofemoral joint with radiographs (confirmed mild tibiofemoral joint OA grades I or II according to the Kellgren Lawrence classification) (n = 180) and finally through medical screening (n = 111). In total, 87 participants were included in the original intervention study. Inclusion criteria to the original intervention were: 1) a postmenopausal woman age 60–68 yr, 2) experiencing knee pain on most days, 3) participating in no more intensive exercise than brisk walking ≤ twice a week, 4) radiographic changes in tibiofemoral joint K/L I or II, 5) no cancer or chemotherapy before the study, 6) no medical contraindications or other limitations to full participation in an intensive aquatic training program, and 7) complete T2 data. Exclusion criteria included: 1) a T-score < −2.5 (indicating osteoporosis) (12) measured from the femoral neck using dual-energy X-ray absorptiometry, 2) resting knee pain visual analogue scale >50/100, 3) a body mass index (BMI) of >34 kg·m−2 (due to confounding factors related to obesity in relation to original intervention), 4) surgery of the knee due to trauma or knee instability, 5) meniscectomy within the last 12 months, 6) inflammatory joint disease, 7) intra-articular steroid injections in the knee during the previous 12 months, 8) contraindications to magnetic resonance imaging (MRI), and 9) allergies to contrast agents or renal insufficiency. Additionally, in this study, all LTPA diaries needed to be returned from the follow-up period. In total, 84 participants attended the 12-month postintervention follow-up study.
Each participant’s LTPA (26) from the 12-month study period was recorded using an LTPA diary implemented in our previous studies (16,22,24). Participants marked their LTPA each day for 12 months and were instructed only to mark activities that lasted at least 20 min at a time (i.e., duration, type, and intensity). Duration was reported in minutes and was converted into hours. MET-hours per month was calculated by multiplying each marked activity by self-evaluated intensity (1, light; 2, moderate; 3, vigorous) according to Ainsworth et al. (1). Participants were divided into tertiles based on their average monthly METh for the 12-month period: lowest, middle, and highest tertile (Table 1). Compliance for returning all diaries from the follow-up period was 97.4%. An example LTPA diary is provided in the supplemental digital content (see Appendix A, Supplemental Digital Content 1, example LTPA diary from one follow-up month, http://links.lww.com/MSS/A877).
Primary Outcome Measures
Primary outcome measures for this study, T2 relaxation time (T2) mapping (ms) and the delayed gadolinium-enhanced MRI of cartilage (dGEMRIC index, ms), were measured using a Siemens Magnetom Symphony Quantum 1.5-T scanner (Siemens AG, Medical Solutions, Erlangen, Germany). These methods provide information on the response of tibiofemoral cartilage to physiological loading (21,27). T2 is a surrogate for the properties of the collagen network with lower values corresponding to better integrity and orientation of the collagen fibers and the hydration of the articular cartilage (18,30). dGEMRIC index measures estimated GAG content of the knee articular cartilage with higher values corresponding to higher estimated GAG concentration (2). The MRI were performed by external radiographers and segmentation was performed blinded to original group allocation. Single sagittal slice images from the center of the medial and lateral femoral condyles were taken from the affected knee with the highest K/L grade for both T2 and dGEMRIC index measurements. In cases of identical grading bilaterally, the right knee was imaged. Images were manually segmented using an in-house MATLAB application with built-in motion correction for dGEMRIC (Mathworks, Inc. Natick, MA). In this study, we divided the femoral cartilage into three regions of interest (ROI): anterior, central, and posterior. As illustrated in Figure 1, anterior and posterior borders of the anterior and posterior meniscus were used as landmarks to define the margins of the femoral and tibial cartilage ROI. dGEMRIC indices were corrected for BMI (32). Precision, scan–rescan, (CVRMS) of dGEMRIC in asymptomatic subjects is 7% for full-thickness ROI and 5% for bulk cartilage (23). In our laboratory, the interobserver error (CVRMS) for T2 full-thickness ROI was 1.3% to 3.3% and 2.8% to 4.0% for dGEMRIC. The full MRI protocol and example images are provided in the supplemental digital content (see Appendix B, Supplemental Digital Content 2, MRI protocol and example of image segmentations, http://links.lww.com/MSS/A878).
Cardiorespiratory fitness (V˙O2 peak, mL·kg−1·min−1) was estimated using the UKK 2 km walking test (UKK Institute, Tampere, Finland) (19) and isometric knee extension and flexion force (N·kg−1) of the affected knee was measured at a 60° angle using an adjustable dynamometer chair (Good strength; Metitur Ltd, Jyväskylä Finland) (29). Physical performance measurements have been described in detail in our study protocol (38).
Self-assessed impact of OA symptoms
Self-assessed impact of OA on pain, other symptoms, activities of daily living, sports and recreations, and knee-related quality of life were assessed using the validated Finnish (15) Likert version of the knee injury and OA outcome score (KOOS) questionnaire (28). Scores for each domain range from 0 to 100, with the score of 0 indicating extreme and 100 no knee problems.
The results are presented as means and SD. Statistical significance for the hypothesis of linearity between physical activity tertiles (lowest, middle, and highest) with cartilage and physical performance traits were evaluated by using ANOVA and ANCOVA. T2 was adjusted for baseline value, height and weight. dGEMRIC index (already adjusted for BMI), and secondary outcomes were adjusted for baseline value only. The normality of the variables was tested by using the Shapiro–Wilk W test. Because two participants (2.6%) had missing LTPA diary data, last observation carried forward method was used. Statistical analyses were performed using statistical software (Stata, release 14.1; StataCorp, College Station, TX).
During the 12-month follow-up, eight (10%) participants dropped out of the study. One participant died due to diagnosed cancer and one due to unknown reasons. In addition, one participant withdrew due to activated Ménière disease, two due to personal reasons, one due to hip arthroplasty, one due to radiotherapy for breast cancer, and one did not return the physical activity diaries from the entire follow-up period. Therefore, 76 (90%) participants completed the 12-month follow-up period. The division into METh tertiles was: 1 = lowest (n = 25), 2 = middle (n = 25) and 3 = highest (n = 26). Importantly, there was no difference between the LTPA METh tertiles according to the original intervention study groups (i.e., members of the training and control group) in the beginning or during the follow-up (Table 1).
Demographic and clinical characteristics of the study participants according to the LTPA (METh) in the beginning of the follow-up period (i.e., baseline) are shown in Table 2. At the baseline, there was a linear inverse relationship between body mass (P < 0.001), BMI (P < 0.001), cardiorespiratory fitness (V˙O2 peak, P < 0.001), muscle force (knee extension, P < 0.001; knee flexion, P = 0.011), and LTPA level. Most common LTPA during the 12-month follow-up period were walking (including Nordic walking) (mean: 1 h 5 min·wk−1, 1 h 38 min·wk−1, and 3 h·wk−1 in the tertiles, respectively) and LTPA described as “other” (e.g., gardening and cleaning) (mean: 55 min·wk−1, 1 h 13 min·wk−1, and 1 h 28 min·wk−1 in the tertiles, respectively). Average monthly MET-hours in LTPA tertiles for each follow-up month are provided in the supplemental digital content (see Appendix C, Supplemental Digital Content 3, Average monthly MET-hours in LTPA tertiles, http://links.lww.com/MSS/A879).
To ensure accuracy, each MRI image was inspected for quality, and exclusion required full agreement within the research group. All T2 data sets were included in the analysis. One complete dGEMRIC index data set was not measured due to participant’s rejection of contrast agent injection. Additionally, from the dGEMRIC index, 21 participants had movement artifact in the medial condyle, while in the lateral condyle, 17 participants had either artery-flow pulsating artifact or movement artifact and one inaccurate location of the slice compared with baseline image. These data sets were therefore missing from the final analysis. In total, 54 and 57 complete data sets for medial and lateral condyles, respectively, were available for quantitative dGEMRIC analysis.
T2 and dGEMRIC index change during the 12-month follow-up and P value for linearity in relation to LTPA level are given in Table 3. In knee cartilage regions, there was a statistically significant linear relationship showing that dGEMRIC index in posterior ROI of the lateral (P = 0.003) and medial (P = 0.006) femoral cartilage increased with higher LTPA level during 12-month period. Furthermore, these changes were seen in the posterior lateral femoral cartilage superficial (P = 0.004) and deep (P = 0.007) ROI and in the posterior medial superficial ROI (P < 0.001) (Fig. 2). No linear relationship was observed between LTPA level and changes in T2 relaxation time (Table 3), physical performance characteristics, or self-assessed impact of OA symptoms (KOOS) during 12 months (Table 4).
To our knowledge, we are the first to demonstrate that long-term (12 months) LTPA level is related to regional increases in estimated GAG content of tibiofemoral cartilage in postmenopausal women with mild knee OA as measured with dGEMRIC index. This linear relationship was observed in the posterior region of medial and lateral femoral cartilage, which is less loaded during activities of daily living than the central region (37). Cardiorespiratory fitness, muscle force, and all KOOS dimensions remained at the follow-up initiation level, and no linearity with LTPA tertiles was observed during 12 months.
Our results indicate that people with higher levels of LTPA during the 12-month follow-up period also had larger increases in the dGEMRIC index (i.e., estimated GAG content) within the cartilage of the posterior ROI of the medial and lateral femoral condyle. It has been suggested that in the dGEMRIC index, higher values correspond to higher knee articular cartilage GAG concentration (2). This can be interpreted to mean that when exposed to sufficient loading stimulus and environment, all chondrocytes, including cells extracted from OA cartilage, have a latent loading adaptation ability to regenerate and proliferate matrix (e.g., GAG and collagen) (10,31). Furthermore, our results are suggesting that persons with mild knee OA may have a lower threshold for chondrocyte adaptation in the posterior region of the femoral cartilage, which is less loaded during the activities of daily living compared with the central region. Our previous findings support this suggestion (24). Aforementioned results are also supported by several animal (3,13,14) and human studies in healthy population (31,33,34) and in people at a high risk of developing knee OA after surgery for meniscal injury (27), showing the beneficial relationship between a physically active lifestyle and the maintenance of the biochemical properties of cartilage.
It has been suggested that GAG loss is an early feature in OA, and it occurs primarily in the superficial region of cartilage (4,25), but the nature of responses and the exact region in osteoarthritic cartilage to exercise is not yet fully understood. In our present study, the dGEMRIC index (i.e., estimated GAG content) responded to LTPA similarly in the superficial and deep cartilage (i.e., full thickness) in the posterior ROI of medial and lateral femoral cartilage. Our results are in line with the study by Hawezi et al. (9), who also showed that a change in the dGEMRIC index due to a change in the physical activity level occurred both in the superficial and deep cartilage regions (i.e., full-thickness) in people with a risk of developing OA. However, this full-thickness effect may be at least partly explained by the relatively large decrease in the dGEMRIC index seen in the deep ROI of the posterior condyle. Additionally, the diffusion of the contrast agent is influenced by the cartilage thickness, where thinner cartilage results in a lower dGEMRIC index (8). In our study, cartilage thickness was not measured, leaving this issue open to speculation and for further investigation.
In our study, no linear relationship was observed between a 12-month period of LTPA and changes in T2 relaxation time. T2 measures different cartilage attributes than dGEMRIC index, indicating that a low T2 value corresponds to better integrity and orientation of the collagen fibers and a decrease in the hydration of the articular cartilage (18,30). In our previous exercise intervention study, we found that a 4-month progressive aquatic resistance training program (i.e., full range of motion with high repetition low shear and compressive cyclic forces) improved the estimated biochemical composition of the medial posterior tibiofemoral cartilage as measured with T2 (24). The benefit of this type of loading pattern for integrity and orientation of the collagen fibers is also supported by our previous land-based RCT (16,22). Koli et al. (16) showed that a 12-month progressively implemented high-impact and intensive jumping exercise (i.e., impact exercises were shear with moderate compression in the patellofemoral joint) in postmenopausal women with mild knee OA improved the estimated biochemical composition of the patellar cartilage as measured with T2. Using the same intensive intervention, Multanen et al. (22) showed that no positive or negative effect was observed in the biochemical composition of tibiofemoral cartilage (i.e., T2 or dGEMRIC index). The LTPA may not have exposed the knee joint to optimal and sufficient intensity and loading to cause adaptation in the integrity of the collagen-interstitial water environment (T2) in the tibiofemoral cartilage. However, GAG concentration (i.e., dGEMRIC index) may be more responsive to intermittent impact and compression type of loading in people with mild tibiofemoral knee OA and may therefore partly explain the findings of this study. This explanation is also supported by Roos and Dahlberg (27). More controlled (type of exercise, loading, frequency, duration and intensity) exercise interventions are needed to determine the most optimal loading and intensity for improving overall cartilage quality in osteoarthritic population.
In this study, walking (including Nordic walking) accounted for 40% of the total LTPA.
Gait on level surface requires knee range of motion from nearly full extension to 60° to 65° flexion (37), and knee flexion of over 90° is required to produce contact between posterior ROI of femur and central tibia (7). Therefore, the biomechanics of gait do not solely explain why an increase in dGEMRIC index was observed in the posterior ROI of cartilage. The average peak knee joint loading during normal gait is in the range of 2 to 4.5 times body weight (17,40). Thus, it can be speculated that the effects of intermittent impact and compressive loading during gait to knee central cartilage might have had favorable adjacent effects on less customary loaded posterior cartilage (e.g., trough pressure changes and muscle contraction) with a higher LTPA level. This higher repetitive mechanical stimulus might have been sufficient to cause beneficial changes, such as improved fluid flow and nutrient diffusion in the posterior ROI of the femoral cartilage. On the other hand, repetitive knee bending exposure (i.e., deep knee bending or kneeling for 30 min or more) has been associated with an increased risk of prevalent cartilage lesion especially in patellofemoral compartment in men and women between the ages 45 and 55 yr with a risk for OA (35). In our study, the activity described as “other” (e.g., gardening and cleaning) accounted for 23% of the total LTPA. These activities might have included nonrepetitive uncustomary loading to the knee (i.e., higher knee flexion with larger range of motion), which can be hypothesized to have caused beneficial changes in less loaded posterior ROI of femoral cartilage. In our previous study (24), we discussed that the chondrocytes in the posterior region of the femoral cartilage in persons with mild knee OA may have a lower threshold for adaption compared with the central region, and in contrast, the chondrocytes in the central region of the femur and tibia cartilage may require a higher or atypical loading compared to customary loading to stimulate an adaptive response. Thus, posterior less customary loaded medial and lateral femoral condyle cartilage might be more responsive to light exercise than the central cartilage. Therefore, even light LTPA performed regularly in the long term may be sufficient enough to positively stimulate the less customary loaded posterior region of medial and lateral femoral cartilage, which was observed in our study as increased estimated GAG concentration. Also, LTPA even at the highest level was well tolerated and did not increase clinical symptoms in women with mild knee OA.
The strengths of this study include the long-term follow-up period (12 months) and high adherence to the end measurements with no harms observed as LTPA level increased. In addition, each participant’s daily physical activity was monitored each day throughout the whole 12-month follow-up period. Strict imaging procedure and segmentation rules ensured good stability and repeatability of the T2 relaxation time and dGEMRIC indices. This limits the possible effects of the magic angle (particularly T2) and partial volume effects. The long imaging time in dGEMRIC mapping might result in motion artefact, which was controlled for in our study by using a motion correction technique built into the in-house software as well as a strict inclusion–exclusion criterion for image quality (i.e., excessive movement and pulsating artefact). This study also had some minor limitations, which were related to the MRI imaging and analyzation technique. We used a 1.5-T scanner, whereas a 3.0-T scanner would have produced better spatial resolution and a higher signal-to-noise ratio. In some cases, occasionally thinned and deteriorated cartilage and movement (despite the motion correction technique) or pulsating artery artefact prevented reliable segmentation of cartilage resulting in lost data. Also, the single-slice segmentation method used in this study assesses only a restricted region of the cartilage, whereas the multislice method might have produced a more comprehensive representation of the tibiofemoral cartilage. The segmentation software automatically divided cartilage of each full-thickness ROI into deep and superficial compartments (50%/50%). However, due to the 1.5-T scanner used, segmented cartilage thickness ranged from two to five voxels, thus reducing the spatial accuracy. Due to the strict inclusion criteria in the original intervention study (24), our results cannot be directly applied to people with later stage OA or older or extremely obese women and men. Finally, the authors acknowledge that so far there is no “golden standard” method to measure how exercise directly affects the biochemical composition of cartilage in vivo. Therefore, the different quantitative magnetic resonance imaging parameters and their interactions are not yet fully understood (2), and further investigations about the interaction between exercise, cartilage, and these parameters are needed.
In conclusion, these results suggest that higher LTPA level is related to regional increases in estimated GAG content of tibiofemoral cartilage as measured with dGEMRIC index during a 12-month period. These results have an important role when assessing physical activity levels for cartilage quality related exercise intervention studies and also in clinical rehabilitation in postmenopausal women with mild tibiofemoral knee OA.
This study was funded by the Academy of Finland and The Social Insurance Institution of Finland (KELA). M. M. and B. W. have been compensated for their work by the grants from the Finnish Cultural Foundation and in addition, B. W. is from the Yrjö Jahnsson Foundation. The results of the present study do not constitute endorsement by ACSM and are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. The authors have no conflicts of interest to disclose.
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