Participants

This preliminary study employed a cross-sectional design. Elderly participants who reported current knee pain were identified via a mailed survey and were invited to visit a research center in Kyoto in September 2019. This study was conducted in accordance with the Declaration of Helsinki and was approved by the ethics committee of Kyoto University (approval no. R2151-1). Written informed consent was obtained from all participants before their enrolment. All participants had a history of pain in one or both knees. The eligibility criteria were (1) age ≥ 45 years, (2) knees with early and severe osteoarthritis (OA) (i.e., K&L grade 1–2 and 3–4, respectively, according to the original version [15]) in one or both knees in the medial tibiofemoral compartment as evaluated using weight-bearing anteroposterior radiographs, and (3) ability to walk independently on a flat surface without the use of any ambulatory assistive device. Participants with bilateral KOA were not considered separately from those with unilateral KOA because it was necessary to increase the sample size. The exclusion criteria were (1) a history of knee surgery, (2) rheumatoid arthritis, (3) periarticular fracture, (4) concurrent neurological problems, or (5) knees with pre-radiographic OA (i.e., K&L grade 0).

Measurements

For all participants, demographic data and knee pain were evaluated as individual characteristics and covariates. Outcome measures were radiographic evaluation and measurement of maximum quadriceps strength and the RFD.

Demographic data and knee pain

Data on age, sex, and height were self-reported by participants. Weight was measured on a scale, with the participants clothed but barefoot. Body mass index was calculated by dividing weight in kilograms by the square of height in meters. Knee pain over previous several days was evaluated using a VAS.

Radiographic evaluation

Anteroposterior radiographs of both knees in the fully extended weight-bearing and foot map positions were obtained at enrolment. The radiographic severity of the medial compartment in the tibiofemoral joint was assessed by a trained examiner. The K&L grade was scored as follows: 0, normal; 1, doubtful joint space narrowing (JSN) and possible osteophyte; 2, definite osteophyte and possible JSN; 3, multiple osteophytes, definite JSN, some sclerosis, and possible deformity of bone ends; and 4, large osteophyte, marked JSN, severe sclerosis, and definite deformity of bone ends. The intra- and inter-rater agreements for the K&L grade determination were excellent (intra-rater: κ = 0.88, 95% CI = 0.83–0.92; inter-rater: κ = 0.84, 95% CI = 0.79–0.90) [16]. To permit analysis the association of outcome measures with radiographic severity, the present sample was classified, as reported previously [17], into mild KOA (K&L grade 1–2) and severe KOA (K&L grade 3–4).

Maximum quadriceps strength and RFD

The maximum voluntary isometric contraction (MVC) in both legs was measured using a handheld dynamometer (HHD) (Mobie, Sakai Medical Co., Ltd, Japan; accuracy: ± 2% rated output), in accordance with a previously validated method for community-dwelling elderly patients prone to falling [18, 19]. The HHD is a simple tool for objectively quantifying muscle strength and is widely used in clinical practice. Participants were instructed to remain seated in an upright position, and the knee was placed at 90° flexion. The HHD was attached 10 cm proximal to the lateral malleolus and held in place with an inelastic strap looped around the therapy bed and fastened. The length of the strap allows for isometric contraction with the knee at 90° flexion during testing. Participants were instructed to extend their legs for 5 seconds as fast and as hard as possible. A few practice attempts were made before the actual measurement. Strong verbal encouragement was provided to ensure maximal effort. There were no complaints of knee pain from the participants during the RFD and maximal muscle strength measurements. The results of quadriceps strength test were recorded in Newtons (N), and two repetitions were performed. Force measures were acquired and passed through an analog-to-digital converter (Power Lab, AD Instruments, Australia), sampled at 1,000 Hz, and plotted using LabChart 8 software (AD Instruments, Australia). The distances from the center of the force pad to the knee were recorded for each participant and used to convert measured forces into joint torques. Torque values were calculated by multiplying the obtained force values by the distances from the center of the force pad to the knee. MVC in the quadriceps was defined as the maximal torque value obtained from two attempts. The MVC was normalized to body mass. We assessed the RFD over the first 200 ms of maximal isometric contraction, whereby the onset of contraction was deemed as the point at which torque had increased 4 Newton-meter (Nm) above the baseline value [20]. The RFD was analyzed at 200 ms from the onset of torque [21]. The RFD was normalized to body mass and MVC torque (%MVC) [20, 22]. The average of two repetitions was used for statistical analysis.

Statistical analysis

To minimize any bias introduced by similarities between the right and left knees of the same participants, only one knee per participant (index knee) was analyzed. The index knee was defined as the more painful knee currently or in the past. For participants who reported equally painful knees, the index knee was selected randomly using a computer-generated permuted block randomization scheme [23].

The characteristics of the participants are presented as mean ± standard deviation (SD) for continuous variables and as numbers and percentages for nominal and ordinal variables. The Mann–Whitney U-test was used to determine group differences between participants with mild and severe KOA because the dependent variable was not normally distributed as determined by the Shapiro-Wilk test.

To test the hypothesis that individuals with severe KOA would display a significantly decreased quadriceps RFD, the Mann–Whitney U-test was used to assess the differences between participants with mild and severe KOA.

Moreover, to test that the results of the Mann–Whitney U-test did not change after adjusting for covariates and to test the hypothesis that the decreased quadriceps RFD would be greater than the decrease in maximum quadriceps strength in individuals with severe KOA, the following posthoc analysis was performed. To compare between-group differences for mild and severe KOA, an independent measures analysis of covariance was performed, with age (years), sex, and knee pain VAS (mm) as covariates. The effect size (ES), Hedges’ g, was calculated as the standardized mean difference (SMD) with mean ± SD and 95% CI using Review Manager Software (RevMan 5.3; Cochrane Collaboration, Oxford, UK) for the quadriceps RFD and maximum quadriceps strength. The Cohen scale was used to interpret ES, where 0.2 represents a small effect, 0.5 a moderate effect, and 0.8 a large effect. Data analyses were performed using JMP Pro 15.0 (SAS Institute, Cary, NC, USA). A p-value of < 0.05 was considered significant.

Decreased quadriceps RFD in severe KOA

Participants with severe KOA had a significantly lower quadriceps RFD (p = 0.009) but not maximum strength (p = 0.50) when compared to group with mild KOA (Table 2).

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Table 2. Differences between participants with mild and severe KOA in the quadriceps RFD and maximum quadriceps strength.

https://doi.org/10.1371/journal.pone.0262508.t002

When adjusted for age, sex, and knee pain VAS, participants with severe KOA exhibited a significantly decreased quadriceps RFD (between-group difference: 0.88; 95% CI: 0.23 to 1.54). The quadriceps RFD exhibited a large effect (ES: -1.07; 95% CI: -1.83 to -0.30) (S1 Table). When adjusted for age, sex, and knee pain VAS, participants with severe KOA did not exhibit significantly decreased maximum quadriceps strength (between-group difference: 0.06; 95% CI: -0.09 to 0.21). Maximum quadriceps strength exerted a small effect (ES: -0.22; 95% CI: -0.96 to 0.52) (S2 Table).

Study limitations

This preliminary study has several limitations. First, the participants were motivated individuals given that they actively enrolled by responding to e-mails and were recruited via public relations magazine advertisements; thus, there may have been a selection bias. Second, since a power calculation was not performed, the relationship between severe KOA and weakness of maximum quadriceps strength cannot be determined. Third, since this study was preliminary, it included only a small number of individuals with severe KOA, which may bias the incidence of severe KOA events. Therefore, in this study, the Mann–Whitney U-test was performed, followed by analysis of covariance as a post hoc analysis. Moreover, women constitute a majority of the sample in this studied. Therefore, we conducted a sensitivity analysis to see if the results remained the same after excluding the males (S4 Table). However, it is necessary to increase the sample size and confirm the results with different analysis methods in the future. Finally, given the cross-sectional nature of this study, causal associations of severe KOA with the quadriceps RFD could not be determined. Further investigations, including prospective studies that clarify causal associations, are required to confirm our results.