Unilateral-dominant reduction in muscle volume in female knee osteoarthritis patients: computed tomography-based analysis of bilateral sides

Background Muscle weakness is associated with osteoarthritis pathology. A recent study demonstrated that measuring muscle volume using computed tomography (CT)-based analysis and comparing bilateral muscles in the same patient allowed for accurate evaluation of muscle volume in unilateral hip osteoarthritis (OA) patients. Here, we evaluated muscle volume using CT-based analysis and compared bilateral muscles in knee OA (KOA) patients. Methods CT images were obtained from 35 female radiographic KOA patients the day prior to total knee replacement surgery. Muscle volume (MV) was semi-automatically analyzed. Knee extension muscle strength (MS) was determined using a hand-held dynamometer. The severity of KOA patients’ clinical symptoms was examined using four domains of the Japanese Orthopedic Association (JOA) score. We compared the difference in MS (ΔMS) and MV (ΔMV) between the operated side (OS), which exhibited severe radiographic OA or severe pain, and the contralateral side (CS). Results JOA score was significantly lower in the OS than CS. MV and MS were also significantly lower in the OS than CS. There was no correlation between MV and MS or between MV and MS as a percentage of body weight on either side. However, ΔMV was positively correlated with ΔMS and pain on walking in the JOA. Conclusions We evaluated MV and MS using bilateral CT images of the legs of KOA patients. A reduction in MV was observed on the OS, and was correlated with a reduction in MS and pain on walking. Bilateral CT image analysis may be useful for evaluating the relationship between OA pathology and muscle atrophy.

understand the relationship between the muscle and OA pathology.
Previous studies have proposed that translational studies that fill the gap between basic and clinical research using three-dimensional imaging data provide a basis for creating anatomical models of the human anatomy and may allow orthopedic surgeons to determine ideal practices before orthopedic surgery [8][9][10]. Computed tomography (CT) is used for various applications, including the evaluation of orthopedic tumors [11] and fractures [12], and preoperative planning of orthopedic surgery [13]. CT is also regularly used to quantify muscle volume (MV) at regions around the knee and hip [14][15][16]. In particular, the cross-sectional area (CSA) of the affected region determined from CT images is measured to evaluate MV [14][15][16]. However, these measurements vary widely and are dependent on the location at which the section is taken. In addition, muscle mass varies greatly from person to person due to differences in height or body mass index (BMI), making it difficult to conduct comparisons and accurately elucidate the effect of KOA on muscle mass. A recent study showed that muscle volume in unilateral hip OA patients could be accurately evaluated by measuring muscle volume using CT-based analysis and comparing bilateral muscles in the same patient [17].
Here, we evaluated muscle volume using CT-based analysis and conducted comparisons between bilateral muscles in KOA patients.

Methods
The study protocol received ethics approval from the Institutional Review Board (IRB) for Clinical Research and Treatment of Kitasato University (IRB approval number: B20-133).
According to power analysis conducted with α = 0.05 and power = 0.80 using G*POWER3, 34, and 17 samples were needed to obtain a statistically significant difference in muscle strength (MS) and MV, respectively, between the operated and contralateral sides. Therefore, we obtained CT images from 35 female patients with radiographic KOA the day prior to total knee replacement surgery. Four domains of the Japanese Orthopedic Association (JOA) score, namely, pain on walking (domain I), pain on ascending or descending stairs (domain II), range of motion (domain III), and joint effusion (domain IV) [18], were used to evaluate symptom severity (Table 1).

Muscle strength
Knee extension MS was determined using a hand-held dynamometer (μTas F-1; Anima, Tokyo) as participants were seated on a chair with their hips and knees flexed at 90°. Knee extension MS was expressed as the raw value in Newtons (N) and as a percentage of body weight (% BW). The difference in MS (ΔMS) between the operated side (OS), which exhibited severe radiographic OA or severe pain, and the contralateral side (CS) was calculated using the following equation: CT-based analysis of femoral muscle volume Axial CT images were used to measure patients' femoral MV. CT images comprising a 10-mm region of interest were taken 200 mm above the knee joint at 1-mm thickness and semi-automatically analyzed using the MIMI Table 1 The Japanese Orthopedic Association (JOA) score for patients with knee osteoarthritis I. Pain on walking (total 30 points) Walking 1 km or more usually with no pain, without regard for mild pain, or rarely feeling pain with certain activities 30 Walking 1 km or more regardless of pain 25 Walking 500 m or more, but less than 1 km without regard for pain 20 Walking 100 m or more, but less than 500 m without regard for pain 15 Walking indoors or nearby, but less than 100 m without regard for pain 10 Inability to walk 5 Inability to stand 0 II. Pain on ascending or descending stairs (total 25 points)

No pain 25
Pain with handrails, but no pain with step-by-step ambulation 20 Pain relieved by using handrails 15 Pain with step-by-step ambulation, pain relieved by using handrails 10 Pain even with step-by-step ambulation and handrail use 5 Inability to ascend or descend because of pain 0

III. Range of motion (total 35 points)
Squatting 35 Sideways or cross-legged sitting 30 Flexion or arc of motion of 110°or more 25  CS® software (Materialise Japan Co., Ltd., Yokohama, Japan) (Fig. 1). Femoral MV was compared between OS and CS. Differences in MV between OS and CS were calculated using the following equation:

Statistical analysis
Differences between OS and CS were examined using paired t test. The relationship between MV and MS was evaluated using Spearman's correlation coefficient. A P value of < 0.05 was considered statistically significant. Statistical analysis was performed using the SPPSS software (Version 25.0; SPSS, IBM, Armonk, NY, USA).

Study participant's demographic information
The participants' demographic and clinical information are provided in Table 2. Participants' mean age was 72.4 ± 7.4 years and body mass index was 26.1 ± 4.1 kg/m 2 . There was no difference in the ratio of Kellgren/ Lawrence (K/L) grades between the OS and CS. Total JOA score and the score for all four domains (pain on walking, pain on ascending or descending stairs, range of motion, and joint effusion) were significantly lower in the OS than CS.

Muscle strength and volume
MS and MS as a percentage of body weight were significantly reduced in the OS compared to CS (P = 0.001; Table 3). MV was also significantly reduced in the OS compared to CS (P = 0.001; Table 3). No correlation was found between MV and MS (Fig. 2a) or MV and MS as a percentage of body weight on the OS (Fig. 2b). However, ΔMV was positively correlated with ΔMS on the OS (r = 0.651, P < 0.001; Fig. 2c).

Relationship between clinical score, muscle strength, and muscle volume
There was no correlation between the total JOA score and the score for three domains (pain on ascending or descending stairs, range of motion, and joint effusion) and ΔMS (Fig. 3a, c-e) or ΔMV (Fig. 4a, c-e).

Discussion
Previous studies have shown that KOA patients exhibit a reduction in muscle mass in the lower limbs compared to age-matched healthy controls [6,19,20]. However, a cohort study reported a weak association between bone mass, measured based on bioimpedance analysis (BIA) using a body composition analyzer, on muscle strength in KOA patients [19]. Consistent with previous reports,  we found no correlation between MS and MV. However, bilateral MV analysis using CT images taken from KOA subjects showed a unilateral decrease in MV on the side with severe OA and that this reduction was strongly correlated with a reduction in MS. CT-based analysis of bilateral sides may therefore be a useful tool for evaluating muscle weakness in KOA patients due to the exclusion of parameters such as age and BMI, which affect muscle mass and strength (Table 4).
There is a logical biomechanical explanation for the association between leg muscle mass and knee symptoms. Periarticular muscles, which keep injured and degenerated knees structurally stable and supported, with greater mass relative to total body mass provide better stability, resulting in less pain. Several studies examining changes to the muscles in the lower limbs have shown that low impact exercises like swimming and cycling are beneficial for reducing pain in patients with KOA [21,22]. Therefore, low impact therapeutic approaches may be important for relieving pain in KOA patients.
Several reports have suggested that unilateral mechanical unloading is a cause of muscle reduction [23][24][25]. Studies in humans have reported that, as a result of unilateral lower limb unloading, there is a 7% decrease in muscle CSA after 21 days [24] and a 16% decrease after 35 days [23,25]. In the present study, MV was reduced by approximately 6% on the side with severe OA, and this reduction was associated with pain on walking. Underuse of the muscle due to pain may therefore explain the unilateral reduction in MV in KOA patients.
This study has several limitations (Table 4). First, the analyzed muscle comprises several different muscles, including the rectus femoris, biceps femoris, and adductor longus. Assessment of individual muscles is necessary to obtain a practical understanding of functional disability in patients with KOA. Second, our study was a crosssectional study. Longitudinal studies are needed to clarify the relationship between OA development and muscle reduction. Finally, patients with bilateral KOA were included among the participants in this study.

Conclusion
We evaluated MV using bilateral CT images of the legs of patients with severe knee pain. MV was reduced on the side with severe OA and this reduction was correlated with a decrease in MS and pain. Bilateral CT image analysis may be useful for evaluating the link between OA and muscle pathology due to the ability to exclude parameters such as age and BMI, which affect muscle mass and strength. Further investigation using a longitudinal study may clarify the relationship between OA development and muscle reduction.  Table 4 Advantages and limitations of this study

Advantages Limitations
• CT-based analysis of bilateral muscle volume accurately reflects muscle strength in patients with KOA. • CT-based analysis of bilateral muscle volume enables exclusion of parameters such as age and BMI, which affect muscle mass and strength.
• The analyzed muscle comprises several different muscles, including the rectus femoris, biceps femoris, and adductor longus. • This study was a cross-sectional study.
• Patients with bilateral knee osteoarthritis were included among the participants.
CT computed tomography, KOA knee osteoarthritis, BMI body mass index