Evaluation of Cartilage Degeneration Using MRI T1ρ Mapping after Locomotion Training in Patients with Early Knee Osteoarthritis

ABSTRACT

Objectives : This study aimed to assess the qualitative effects of locomotion training (LT) on articular cartilage using magnetic resonance imaging T1ρ mapping.

Methods : Fifteen patients with early knee osteoarthritis participated in the study. They performed a series of exercises, including one-leg stands, squats, heel raises, and front lunges, on a daily basis for 12 weeks. Knee joint function and physical performance were evaluated before and 3 months after completing the LT program. Additionally, a questionnaire was administered to assess patient-reported outcomes. The quality of articular cartilage was evaluated through magnetic resonance imaging using T1ρ mapping. T1ρ values were quantified on sagittal planes with ten regions of interest.

Results : Regarding physical function, the time required for one-leg stands was significantly increased following LT, and the right functional reach test and the 30-s chair stand test showed improvement. T1ρ values were significantly reduced at 0° relative to the anatomical axis of the femur, whereas other regions of interest showed no significant change after LT.

Conclusions : LT significantly improved muscle strength and balance in patients with early knee osteoarthritis. LT also improved the T1ρ values of articular cartilage at 0° relative to the anatomical axis of the femur. This change may reflect that LT mitigates cartilage degeneration following the application of moderate mechanical stress to the loading region. We propose that LT represents a safe and effective exercise therapy for early knee osteoarthritis, with the potential to improve both motor function and articular cartilage quality.

INTRODUCTION

Japan has the highest aging rate globally, with 29.1% of the population aged 65 years or older. Among individuals requiring long-term care, musculoskeletal disorders—including osteoarthritis and osteoporosis—are the leading cause.^1,2) To address this, the Japanese Orthopaedic Association proposed the concept of locomotive syndrome (LS) in 2007, aiming to prevent and manage mobility decline associated with these conditions.

Knee osteoarthritis is one of the most common musculoskeletal disorders in Japan, affecting approximately 25 million individuals, of whom 8 million report symptoms.³⁾ Exercise is recognized as an effective intervention for managing LS and knee osteoarthritis. Locomotion training (LT)—including one-leg stands, squats, heel raises, and front lunges—has been recommended as a practical regimen tailored to various physical fitness levels.^4,5,6)

Although the clinical benefits of exercise therapy for knee osteoarthritis are well documented, its effects on the quality of articular cartilage remain unclear. Articular cartilage comprises mainly water, type II collagen, and proteoglycans. In the early stages of osteoarthritis, proteoglycan loss occurs before collagen degradation.^7,8) Detecting such early changes is critical for timely intervention.

Conventional imaging methods, including radiography and standard magnetic resonance imaging (MRI), primarily assess cartilage morphology and are insufficient for evaluating biochemical changes. In contrast, T1ρ mapping using 3T MRI can accurately detect reductions in proteoglycans, which have a high metabolic turnover, making it possible to assess early degeneration of articular cartilage.⁹⁾ T1ρ mapping is a quantitative MRI technique that measures the T1ρ relaxation time, which reflects interactions between motion-restricted water molecules and macromolecules such as proteoglycans. A longer (higher) T1ρ relaxation time generally indicates a reduction in proteoglycan content, which is an early sign of cartilage degeneration. Conversely, shorter (lower) T1ρ times suggest healthy cartilage with preserved proteoglycan levels.^10,11) T1ρ mapping refers to the generation of voxel-wise parametric images where the intensity of each pixel represents the calculated T1ρ value at that location, thereby enabling regional assessment of cartilage composition.

In this study, we hypothesized that LT for early stage knee osteoarthritis improves cartilage quality. We aimed to assess qualitative changes in knee articular cartilage using MRI T1ρ mapping.

MATERIALS AND METHODS

Study Design

This study was approved by the Ethics Committee of Kanai Hospital (ERB-61). Written informed consent was obtained from all participants included in the study. This retrospective study was conducted in accordance with the relevant guidelines and regulations and was aligned with the reporting guideline STROBE.

Participants

The study included 15 patients undergoing exercise therapy for LS and who met the following criteria between February 2023 and April 2023. All participants provided informed consent to participate in the study. The inclusion criteria were as follows: female participants aged 40–80 years, with a body mass index less than 30 kg/m², and early stage osteoarthritis of the knee (Kellgren–Lawrence grade 1 or 2 on plain radiographs), regardless of the presence or absence of knee pain. The exclusion criteria were as follows: patients who were unable to ambulate without assistance, patients with cognitive decline (Hasegawa dementia scale score of ≤23), patients residing in a special nursing home, geriatric healthcare facility, or long-term medical care facility (convalescent bed), and patients with a history of hospitalization within 1 month of providing consent. In addition, patients with a history of trauma or surgery to the lower limb or spine within 3 months of the consent date, those with a pacemaker, those who were pregnant, those unable to undergo MRI (because of the presence of metal in the body, claustrophobia), and those unable to maintain a body position for 20 min were excluded from the study. The use of acetaminophen, nonsteroidal anti-inflammatory drugs, tramadol, and duloxetine, as well as the intra-articular administration of hyaluronic acid or steroids, and the topical application of anti-inflammatory drugs that could interfere with the efficacy and safety assessment of the study, were prohibited during the study period. All subjects in this study were female, with a mean age of 68.5 ± 4.8 years and a mean body mass index of 23.4 ± 4.6 kg/m². Patient background information is presented in Table 1.

Table 1. Patient information

Parameter	Female (n=15)
Age (years)	68.5±4.8
Height (cm)	155.6±5.8
Weight (kg)	56.7±11.72
Body mass index (kg/m2)	23.4±4.6
K-L grade 1	4
K-L grade 2	11

Data shown as mean ± standard deviation or number.

K-L, Kellgren–Lawrence.

Exercise Training

Within 2 weeks of enrollment, subjects were instructed to perform the following exercises: three sets of one-leg stands for 1 min on each side, three sets of squats (five to six repetitions), two to three sets of heel raises (10 to 20 repetitions), and two to three sets of front lunges (five to ten repetitions). At the outset of the LT program, a physiotherapist provided initial instructions. Thereafter, subjects were responsible for continuing the program at home for 30 min per day, every day, for a total of 12 weeks. The subjects were required to record the number of daily exercises in a notebook, noting the target values. Additionally, the physiotherapist contacted the subjects once per week to ensure they were performing the LT correctly.

Outcome Measures

Knee joint function was assessed using the following measurements: femoral circumference (OSU), lower leg circumference (USU), and knee range of motion. These measurements were recorded before the start of LT and 3 months after. To assess patient-reported outcomes, the following questionnaires were administered: the EuroQol five-dimension 5-level questionnaire (EQ-5D-5l), the Knee injury and Osteoarthritis Outcome Score (KOOS), which includes a pain subscale, and the 25-item Geriatric Locomotive Function Scale (GLFS-25). Physical function was evaluated using several tests, including the one-leg stand time, Timed Up-and-Go Test (TUG), Functional Reach Test (FRT), 6-min Walk Test (6MWT), 30-s Chair Stand Test (CS-30), Two-Step Test, two-step value, and Stand-up Test.¹²⁾ Cartilage was evaluated qualitatively using MRI T1ρ mapping of the knee joint.

MRI T1-ρ mapping

All knees were imaged using a 3.0T MR scanner (Philips Achieva dStream) with an eight-channel knee coil both before and 3 months after completing the exercise therapy. Luke et al.¹³⁾ reported that a 3-month exercise intervention led to changes in cartilage quality, as assessed using T1ρ and T2 mapping. Similarly, Thudium et al.¹⁴⁾ observed changes in aggrecan concentration using biomarkers. Based on these findings, we considered it appropriate to evaluate articular cartilage 3 months after implementing LT in this study. The imaging protocol was based on the method of Yamasaki et al.¹⁵⁾ and included a T1ρ-prepared three-dimensional fat-suppressed gradient echo sequence with a parallel imaging technique. The imaging parameters were as follows: repetition time (TR), 7.2 ms; echo time (TE), 3.9 ms; flip angle, 10°; field of view, 120 × 120 mm; matrix, 224 × 224; slice thickness, 3.3 mm; slice gap, 0 mm; bandwidth, 706 Hz/pixel; number of excitations, 1; and number of slices, 30. A spin-lock pulse with a frequency of 500 Hz was applied. T1ρ-weighted images were acquired with five different time-of-spin-lock (TSL) values: 1, 10, 20, 30, and 40 ms. The acquisition time for each TSL was 151 s.

To evaluate the relationship between LT and the articular cartilage of the medial femoral condyle, two slices of the central part of the femoral medial condyle were analyzed (Fig. 1). Ten points were set at 10° intervals along the articular surface between the point of intersection of the anatomical axis of the femur and the articular surface of the medial condyle and the posterior area at approximately 90° relative to the anatomical axis. Regions of interest (ROIs) were set with their centers at these points, extending 5° in an anterior–posterior direction. The depth of the ROIs in the articular cartilage was set to encompass the superficial and intermediate zones. Subsequently, preoperative and postoperative T1ρ values were quantified using AZE Virtual Place AVP-001A software (Canon Medical Systems, Otawara, Japan) (Fig. 2). Only the boundary region was excluded to avoid partial volume effects. All measurements were conducted blindly and independently by two orthopedic surgeons with varying levels of experience: one with 8 years and the other with 14 years of experience. The final results represent an average of the measurements taken by each investigator.

Fig. 1.

Ten evaluation points were established at 10° intervals along the articular surface of the medial condyle. Regions of interest (ROIs) were centered at these points, with ROI depth encompassing the superficial and intermediate layers of the articular cartilage.

Fig. 2.

T1ρ color maps for a 63-year-old woman with Kellgren–Lawrence grade 2 knee osteoarthritis. At the 0° peripheral region, comparison of before and after LT shows a color shift from red to green, indicating a potential improvement in cartilage quality.

Statistical Analyses

Data are expressed as mean ± standard deviation and were analyzed using EZR (Saitama Medical Center, Jichi Medical University), a graphical user interface for R (version 2.13.0; The R Foundation for Statistical Computing). The results were compared using paired t-tests. Statistical significance was recognized for P < 0.05.

RESULTS

Knee function was evaluated before and 3 months after LT. No significant changes were observed in lower limb circumference, range of motion, EQ-5D-5l index values, KOOS scores, or GLFS-25 scores following the intervention. However, significant improvements were noted in specific functional parameters. Both right and left one-leg standing times increased, and the CS-30 test showed a statistically significant improvement. Additionally, the FRT on the right side demonstrated a significant increase. These findings suggest that LT led to improvements in dynamic balance and lower limb muscular endurance (Tables 2 and 3).

Table 2. Outcome measures before LT and 3 months after LT

Parameter	Before LT	After LT	P value
Rt OSU (cm)	42.5±4.1	42.7±4.1	0.67
Lt OSU (cm)	42.7±4.5	42.9±4.5	0.57
Rt USU (cm)	35.7±2.8	35.4±3.0	0.33
Lt USU (cm)	35.5±2.9	35.3±2.8	0.33
Rt flexion ROM (°)	150.3±7.2	149.3±5.9	0.53
Lt flexion ROM (°)	148.3±9.6	148.7±6.1	0.81
Rt extention ROM (°)	−3.3±3.6	−2.3±3.7	0.08
Lt extention ROM (°)	−3.3±3.6	−2.7±3.2	0.33
EQ-5D-5l	0.872	0.878	0.792
GLFS-25	8.7±6.7	8.3±6.7	0.73
Rt one-leg standing time (s)	48.6±47.6	64.6±45.3	0.04*
Lt one-leg standing time (s)	39.8±36.2	58.6±47.0	0.03*
TUG (s)	6.8±1.0	6.2±1.3	0.08
Rt FRT (cm)	26.2±8.2	31.0±6.2	0.03*
Lt FRT (cm)	28.5±7.5	31.4±3.9	0.12
6MWT (s)	6.9±8.6	4.8±1.3	0.36
6MWT fast (s)	3.8±0.7	3.8±1.0	1
CS-30	16.1±5.2	18.9±5.3	0.02*
Two-Step Test (cm)	216.1±31.2	202.9±61.6	0.51
Two-step value	1.4±0.2	1.3±0.4	0.51
Stand-up test	5.3±1.0	5.0±0.9	0.21

Data shown as mean ± standard deviation.

Rt, right; Lt, left; ROM, range of motion.

^* P<0.05.

Table 3. KOOS before LT and 3 months after LT

Scale	Before LT	After LT	P value
Total	88.06±10.58	89.60±8.73	0.83
Symptoms	87.38±12.65	88.57±14.43	0.33
Pain	86.85±13.90	90.37±9.08	0.3
Daily living	92.47±7.54	93.33±7.22	0.73
Sport/recreation	81.33±16.95	84.00±16.92	0.58
Quality of life	82.10±19.31	80.83±17.59	0.6

MRI-based T1ρ mapping revealed a significant decrease in T1ρ values at the 0° ROI, indicating an improvement in cartilage quality at that location. No significant changes were observed at other angular positions (Table 4). A representative case demonstrated prominent cartilage changes in the 0° peripheral region on T1ρ color maps obtained before and after LT (Fig. 2).

Table 4. T1ρ values before LT and 3 months after LT

ROI	T1ρ value (ms)		P value
	Before LT	After LT
0°	70.6±11.2	63.4±11.1	0.04*
10°	67.6±15.4	64.8±11.8	0.51
20°	64.0±12.7	64.7±12.1	0.84
30°	61.2±11.0	60.6±6.3	0.86
40°	60.3±13.8	57.5±4.9	0.49
50°	57.5±11.0	54.6±7.3	0.32
60°	57.6±11.4	56.1±7.7	0.63
70°	60.5±10.5	61.8±5.5	0.68
80°	60.3±12.3	61.9±6.7	0.65
90°	58.7±9.1	60.0±6.6	0.67

^* P<0.05.

DISCUSSION

The most important result of this study is that LT for early osteoarthritis of the knee not only markedly increased muscle strength and balance but also elevated T1ρ values at 0° relative to the anatomical axis of the femur. This change may reflect that LT mitigates cartilage degeneration following the application of moderate mechanical stress to the loading region. We propose that LT represents a safe and effective exercise therapy for early osteoarthritis of the knee, with the potential to improve both motor function and articular cartilage quality.

The first-line treatment for knee osteoarthritis is conservative therapy, which includes lifestyle counseling, exercise therapy, pharmacological interventions, and orthotic devices. Exercise therapy encompasses a variety of modalities, such as muscle strengthening (e.g., quadriceps training and lower limb extension and raising training), aerobic exercise, and tai chi. These exercises have been demonstrated to improve pain relief, functional capacity, and activities of daily living.^16,17,18,19) However, high-load exercise therapy has been found to have adverse effects on osteoarthritis. Thudium et al.¹⁴⁾ conducted a comparative study between a high-load training group (exercising at 70%–80% of one repetition maximum, 1RM) and a low-load training group (exercising at 40–50% 1RM). Their findings indicated no significant difference in type II collagen production between the two groups, but cartilage degeneration progressed in the high-load training group. Similarly, Yamaguchi et al.²⁰⁾ analyzed the progression of knee osteoarthritis in a rat model, where the anterior cruciate ligament was injured and subjected to various exercise loads. The results indicated that high-intensity exercise exacerbated existing knee osteoarthritis. Therefore, in the context of exercise therapy for knee osteoarthritis, moderate-intensity exercise is recommended over high-intensity exercise, especially considering the elderly patient population.

Consistent with existing guidelines and classifications, LT is generally considered to be low- to moderate-intensity exercise, depending on the specific movements and the participant’s physical condition.^21,22) In our study, the LT program included bodyweight-based exercises such as standing on one leg, squats (shallow knee bends), and heel raises, performed at a frequency of three sessions per week, with two or three sets per exercise. No external loading (e.g., weights or resistance bands) was applied. Based on the American College of Sports Medicine criteria, this corresponds to low to moderate intensity, particularly in older adults (50%–60% 1RM, two or three times/week).²³⁾ Such training has been shown to increase joint fluid viscosity and hyaluronic acid concentration, improve quadriceps strength, and not accelerate cartilage degeneration—indicating that LT may improve or maintain cartilage quality while avoiding the adverse effects reported with high-load exercise.^14,24,25)

Osteoarthritis is a pathological condition characterized by mechanical stress, inflammatory cytokines, chemical stress (such as nitric oxide and oxygen), and heat stress. Our previous research demonstrated that heat shock protein 70, which is expressed in response to cellular stress, promotes aggrecan synthesis and inhibits apoptosis, thereby protecting cartilage from stress.^26,27,28,29) Tiderius et al.³⁰⁾ conducted a comparative analysis among three groups of healthy volunteers: those with a sedentary lifestyle who did not engage in regular exercise, those who engaged in moderate exercise, such as jogging or gym workouts, on average twice a week, and those who ran an average of 90 km per week. The study demonstrated that the concentration of glycosaminoglycans in the cartilage of the healthy volunteers who engaged in regular exercise was significantly higher than that in the non-exercise group. In a comparative analysis conducted by Roos and Dahlberg,³¹⁾ an exercise group and a non-exercise group of patients who had undergone meniscectomy were compared. The exercise group participated in three sessions per week for 4 months. The findings revealed an elevation in glycosaminoglycan concentration within the cartilage of the exercise cohort. Conversely, T1ρ mapping using MRI has been widely employed in many case-control studies to evaluate the quality of knee articular cartilage. These studies have demonstrated that T1ρ values increase with age in healthy individuals and that patients with knee osteoarthritis exhibit significantly higher T1ρ values than healthy controls. This trend has also been confirmed by a systematic review and meta-analysis.^{11,32,33,34,35,36,37,38)} Moreover, it has been reported that T1ρ values increase in parallel with the severity of knee osteoarthritis.^39,40,41) T1ρ values have been shown to inversely correlate with the glycosaminoglycan content of cartilage in both in vivo and in vitro studies, in conjunction with collagen anisotropy and water content.^{42,43,44,45,46)} Overall, these findings support the idea that T1ρ values reflect cartilage quality in knee osteoarthritis and that T1ρ mapping is a useful method for assessing qualitative changes in articular cartilage. We focused on the medial femoral condyle because the cartilage in this region is generally thicker and more reliably visualized on MRI, allowing for more accurate T1ρ measurements. In contrast, the medial tibial cartilage is relatively thin, which makes it more susceptible to measurement errors. As a result, in this study, improvement in cartilage quality following LT was statistically significant in only one of the ten evaluated regions—specifically, the region at 0°, which intersects the anatomical axis of the femur. We acknowledge that this may appear to be a limited finding; however, we believe that it holds both biomechanical and clinical significance. Although previous biomechanical studies have reported that the peak loading area of the medial femoral condyle lies approximately between 20° and 30° in the sagittal plane, the 0° region defined in our study corresponds to the anterior portion of the major weight-bearing area during the early stance phase of gait. Therefore, this region is considered to receive consistent mechanical stimulation even during walking.^47,48,49) Furthermore, Yoon et al.⁵⁰⁾ segmented the articular cartilage surface of the medial femoral condyle into proximal (anterior), central, and distal (posterior) regions in the sagittal plane, and reported that the central region—which includes the 0° region in our study—is particularly susceptible to mechanical loading. These findings indicate that the observed response in this region may have been induced by the LT intervention. The changes observed at 0° may reflect an early adaptive response at the anterior margin of the loading area, potentially representing a preliminary stage before cartilage remodeling extends to more posterior regions. Additionally, although the P value reached only marginal significance, this may indicate that early stage cartilage changes are occurring in a localized manner. With continued LT, such changes may eventually extend to broader areas of the cartilage. Conversely, this result also implies that the moderate mechanical stress exerted on the articular cartilage at this site by LT may induce the expression of aggrecan in chondrocytes through the action of heat shock protein 70 and other molecular biological mechanisms, thereby contributing to the attenuation of cartilage degeneration. Based on these findings, it is hypothesized that LT represents a safe and effective exercise therapy for early stage knee osteoarthritis, with the potential to improve both motor function and articular cartilage quality. Although physical function improved following LT, this may reflect enhanced muscle strength or neuromuscular performance rather than a direct consequence of improvement in cartilage quality. No direct correlation was evaluated between cartilage quality and physical function; therefore, causality cannot be established.

This study had some limitations. First, it was conducted as a single-arm intervention without a control group, which limits the ability to attribute observed changes solely to the LT. The improvements in cartilage quality and physical function may have been influenced by other factors, including natural variation, placebo effects, or participants’ increased health awareness through their involvement in the study. Second, the sample size was relatively small, which may limit the generalizability of the findings. Third, the follow-up period was limited to 3 months, and the long-term effects of the intervention remain unknown. Finally, T1ρ mapping was used to evaluate cartilage quality; however, histological confirmation was impossible. Further randomized controlled trials with larger sample sizes and longer follow-up periods are necessary to validate these findings.

CONCLUSION

The results of the one-leg stands, 30-s chair stand test, and FRT showed significant improvement after daily LT over a period of 3 months in patients with early knee osteoarthritis. These findings suggest that LT is an effective method for improving muscle strength and balance in patients with early knee osteoarthritis. Moreover, MRI analysis revealed a significant increase in T1ρ values at 0° relative to the anatomical axis of the femur, indicating that LT mitigates cartilage degeneration after the application of moderate mechanical stress to the loading region.

ACKNOWLEDGMENTS

We thank Harmonize Inc. for assistance in this study.

CONFLICTS OF INTEREST

The authors declare no conflict of interest.

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