Abstract
Background
Neuromuscular exercise (NEXA) and celecoxib each are effective for treating knee osteoarthritis (OA), but the potential benefits of combination therapy remain unclear. The aim of this study was to investigate the effects of NEXA in addition to celecoxib compared to celecoxib alone on pain and physical function in patients with symptomatic and radiographic knee OA.
Methods
A prospective, assessor-blinded, two-arm, superiority randomised controlled trial. Sixty participants with Kellgren and Lawrence (KL) grade 2–3 symptomatic knee OA were included and randomly assigned 1:1 to undergo 12 weeks NEXA and celecoxib or to receive celecoxib 200 mg once daily alone. The primary outcomes were visual analog scale (VAS) and total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score at 6 months. The secondary outcomes included the Knee injury and Osteoarthritis Outcome Score (KOOS), six-minute walk test, and Timed Up and Go (TUG) test at 3 months and 6 months.
Results
At 6 months, the between-group differences in the VAS score (mean difference, -10.30; 95% CI, -19.38 to -1.23; P = 0.026) and total WOMAC score (mean difference, -10.40; 95% CI, -15.54 to -5.27; P < 0.001) were statistically in favour of the NEXA and celecoxib group. There was evidence that NEXA in addition to celecoxib were superior to celecoxib alone for KOOS symptoms score (P = 0.040), KOOS activities of daily living score (P < 0.001), KOOS sport and recreation score (P = 0.014), KOOS quality of life score (P = 0.036), six-min walk test (P = 0.006), and TUG test (P = 0.001) at 6 months. The NEXA and celecoxib group achieved significantly higher proportions of patients above the minimal clinically important difference in total WOMAC score (78.6% vs. 51.9% for absolute improvement; 75% vs. 37% for relative improvement) at 6 months.
Conclusions
Compared with celecoxib alone, there was a beneficial effect of NEXA in addition to celecoxib on pain and physical function in patients with symptomatic and radiographic knee OA at 6 months.
Trial registration
ChiCTR-IOR-14,005,414, 31/10/2014.
Supplementary Information
The online version contains supplementary material available at 10.1186/s13102-025-01263-7.
Keywords : Osteoarthritis, Neuromuscular exercise, Celecoxib, Physical function, Knee
Background
Knee osteoarthritis (OA) is a highly and increasingly prevalent musculoskeletal condition and one of the leading causes of disability [1]. OA has been shown to be associated with joint pain, stiffness, loss of function, reduced quality of life, and mortality [2]. Treatment of OA traditionally comprises nonpharmacological and pharmacological management, and in some cases, surgery may be considered [3, 4]. Current treatments for OA have limited efficacy or come with adverse side effects, and few can stop or reverse the progression of OA [5]. In recent years, clinical interventions, as the symptom management strategies, aim to improve pain and physical function in patients with OA [3]. Effective management of OA requires long-term treatment strategies.
Celecoxib, a selective cyclooxygenase-2 inhibitor, has been commonly used and recommended for pain relief in knee OA [6, 7]. A previous systematic review by Puljak et al. suggested that celecoxib is slightly better than placebo and some traditional non-steroidal anti-inflammatory drugs (NSAIDs) in reducing pain and improving physical function [8]. Celecoxib could provide short-term alleviation of symptoms by inhibiting inflammation and modulating the pain response, but there is some question about its long-term safety and effects [7, 9]. Strategies to enhance both efficacy and safety without extending treatment duration, such as combination with other therapies, may offer potential benefits. However, there is still insufficient evidence to fully support these combined therapies [7].
Neuromuscular exercise (NEXA), an exercise program that emphasizes quality of movement and alignment of the trunk and lower limb, can improve pain and physical function in patients with OA [10, 11]. A previous randomized controlled trial (RCT) by Bennell et al. suggested that NEXA and quadriceps strengthening exercise may have similar improvement in pain and function in patients with moderate varus malalignment and mostly moderate-to-severe medial knee OA [10]. NEXA has been shown to reduce knee-joint loads and improve cartilage matrix quality in those with mild knee OA [12]. It has been implemented in several countries as part of the Good Life with osteoArthritis in Denmark (GLA: D®) program [13]. NEXA had no better effect than instruction in analgesic use for knee joint load or patient-reported outcome measures after the 2-month intervention [12]. However, one-year positive effects of NEXA on knee symptoms have been shown when compared to instruction in analgesic use [14]. Hence, NEXA may be a potential treatment approach for improving function in patients with OA, especially in the long-term follow-up periods. It is unclear whether NEXA in addition to one pharmacological intervention has additional benefits. While both NEXA and celecoxib are established therapies for knee OA, their combination remains unexplored despite potential synergy. No clinical trials have directly compared NEXA in addition to celecoxib against celecoxib alone. Mechanistically, NEXA improves proprioception and muscle coordination, which may complement anti-inflammatory effects of celecoxib. The combination of NEXA and celecoxib may offer a comprehensive approach to joint health by addressing both mechanical and inflammatory aspects of joint disease. This aligns with current guidelines advocating multimodal OA management [15].
Therefore, the aim of this study was to investigate the effects of NEXA in addition to celecoxib compared to celecoxib alone on pain and physical function in patients with symptomatic and radiographic knee OA. We hypothesised that NEXA in addition to celecoxib would demonstrate greater improvement in physical function than celecoxib alone at 12-week follow-up; the combination would show superior pain reduction and sustained functional benefits in those with knee OA at 24-week follow-up.
Methods
Design
This was a single-centre, two-arm, assessor-blinded, superiority RCT. The study was prospectively registered with the Chinese Clinical Trial Registry (ChiCTR-IOR-14005414). The contents of this study adhere to the CONSORT reporting guidelines [16].
Participants
Participants were recruited between November 2014 and June 2016 from the outpatient rehabilitation centre at West China hospital, Sichuan university. The inclusion criteria were age between 40 years and 70 years; body mass index (BMI) of ≤ 35 kg/m2; Kellgren and Lawrence (KL) grade 2–3; moderate-to-severe knee pain ≥ 40 on a 100-mm visual analog scale (VAS) for more than 3 months. Exclusion criteria included taking moderate analgesics, opioids, glucocorticoids within 3 months prior to study participation; allergic to sulfa drugs; absolute contraindication for exercise or celecoxib therapy; pregnancy; severe liver or renal insufficiency; history of bone or cartilage metabolic disease (e.g., rheumatoid arthritis, gout); history of knee trauma, meniscus and ligament damage; history of cardiovascular disease and diabetes; any history of asthma, urticaria or other allergic reaction after using NSAIDs; any history of gastrointestinal ulcer; any serious medical condition that would affect general health status; severe cognitive impairments, sensory aphasia, severe mental illnesses and other conditions that prevent participants from understanding basic instructions. All participants provided written informed consent after receiving standardized education materials (video presentation and illustrated booklet) explaining trial procedures, risks, benefits, and follow-up requirements.
Randomization and blinding
Before randomisation, all baseline measures and demographic data were collected. Participants were randomly assigned 1:1 to NEXA and celecoxib or celecoxib group according to a computer-generated random number list based on randomly varying block sizes of 2, 4, and 6. The allocation was concealed in opaque, sealed, consecutively numbered envelopes. Envelopes were stored with the trial coordinator and opened strictly sequentially only after confirming participant eligibility and obtaining written consent. Allocation sequence was developed by an independent biostatistician using R software. The participants and physiotherapists delivering the rehabilitation could not be blinded due to the nature of the intervention. Outcome assessors were blinded to treatment allocation. Outcome assessors underwent standardized training on evaluation techniques prior to study initiation. All participants were informed to maintain confidentiality regarding treatment specifics, with explicit prohibitions against discussing therapeutic interventions during follow-up assessments conducted by outcome assessors.
Interventions
Neuromuscular exercise
We applied the principles of NEXA described by Bennell et al. [10] In brief, participants assigned to NEXA and celecoxib group performed 6 exercises including forward and backward sliding or stepping, sideways exercises, functional hip muscle strengthening, functional knee muscle strengthening, step-ups and down, balance. Participants performed exercises 3 times per week (two sessions supervised individually by physiotherapists and one session at home, each session 60 min) for 12 weeks. Home exercise adherence was ensured through live video supervision by physiotherapists during all remote sessions, allowing real-time correction of movement technique. Participants maintained exercise logs documenting completed sets and repetitions, perceived exertion, and knee pain levels, which were electronically submitted within 24 h post-session. Progression was achieved by varying the direction, repetitions, and velocity of the movements, as determined by the physiotherapist. Exercise progression is determined by the physiotherapists through the assessment of the quality of the exercise performance as well as by the modified rating perceived exertion (RPE) score [17] the patient gives for each exercise (self-rated as 5–8 of 10). Elastic band, foam cushion, towel, and bottle filled with water were used during the exercise sessions. Satisfactory treatment adherence was defined as attendance to at least 29 exercise sessions in total (80%), comprising both supervised physiotherapy and home exercise components.
Exercise-related pain monitoring followed established safety thresholds [18]. VAS scores up to 2 were classified as ‘safe’, 2–5 as ‘acceptable’, and > 5 as ‘high risk’. Transient exercise-related pain (VAS scores 2–5) was allowed during and immediately after training, provided that the increase in resting pain returned to normal resting pain level within 24 h after the exercise session [12, 18]. Participants were informed to expect potential delayed-onset muscle soreness (DOMS) and mild joint irritation, and they were allowed to take acetaminophen as rescue medication.
Celecoxib
All participants received celecoxib 200 mg orally once per day for 12 weeks [19, 20]. If pain relief from 200 mg celecoxib was not sufficient, participants were allowed to take acetaminophen 500 mg (≤ 2000 mg/d) as rescue medication according to their pain intensities [21]. The threshold for insufficient pain relief was defined as a 100-mm VAS ≥ 40 mm. Medication adherence was tracked through patient diaries documenting daily intake frequency, cumulative dosage, and treatment duration. Other analgesics and intra-articular injections were not allowed.
Outcome measurements
All outcomes were assessed at baseline, 12-week post-intervention and 24-week follow-up at West China hospital, Sichuan university by an experienced physician who was blinded to treatment allocation throughout the study. Adverse events severity was graded using the Common Terminology Criteria for Adverse Events (CTCAE) [22].
Primary outcomes
The primary outcomes were 100-mm VAS [23] for pain and total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score [24] for function at 24 weeks. Total WOMAC scores range from 0 to 96 (best to worst). WOMAC contains 24 items and consists of three subscales: pain, stiffness, and physical function. Further analysis was performed to evaluate the number of patients who achieved the minimal clinically important difference (MCID) for the primary outcomes. The MCID was defined as 15 points and 20% relative improvement for the VAS and 12 points and 33% relative improvement for the total WOMAC [25–27].
Secondary outcomes
The secondary outcomes were the Knee injury and Osteoarthritis Outcome Score (KOOS) [28], six-minute walk test [29], and Timed Up and Go (TUG) test [30] at the end of treatment (12 weeks) and at 24-week follow-up. KOOS is composed of five subscales: symptoms, pain, activities of daily living, sport and recreation, and quality of life. Each subscale scores range from 0 to 100 (worst to best).
Sample size calculation
The sample size was calculated to detect a 12-point difference in total WOMAC score [26, 31] for test of equivalence of the groups with 80% power, an alpha level of 0.05 using two-sided t-tests and standard deviation (SD) of 14.5. From this, a total sample size of 24 participants per group was required (48 participants in total). The sample size calculation was performed using G*Power 3.1.9.2. To account for an estimated dropout rate of 20%, the study was designed to include 30 participants per group (60 participants in total).
Statistical analysis
The primary analysis was performed using the intention-to-treat (ITT) population. Descriptive statistics at baseline were expressed as mean and SD for continuous variables or frequency and percentage for categorical variables. Outcome analyses were reported as mean and SD, including the estimated mean differences between groups with 95% confidence intervals (CI). The baseline demographic characteristics were compared between groups using an independent samples Student’s t-test for normally distributed data. The normality of continuous baseline data was confirmed by Shapiro-Wilk test. For categorical outcomes including rescue medication usage, MCID achievement (predefined thresholds), and baseline characteristics (smoker status, sex, KL grade), Pearson chi-square tests were used. For continuous outcomes, a linear mixed model (LMM) was used to detect the difference between groups from baseline to follow-up visits. The model included participants as random effects and treatment, time, and treatment × time interaction as fixed effects, while adjusting for baseline values of the respective outcome. Post-hoc analyses with Bonferroni correction were conducted to assess between-group differences at each time point if a significant treatment × time interaction was detected. Missing data were handled implicitly by the LMM. Estimated effect sizes were evaluated by calculating Cohen’s d. Cohen’s d effect sizes were obtained by dividing the estimated mean differences by the pooled SD, calculated separately at each follow-up time point. Effect sizes were categorized as small (d = 0.2), medium (d = 0.5), and large (d = 0.8) [32]. Sensitivity analyses were performed by repeating the analyses on the per-protocol (PP) population including only those participants who received 80% or more of their allocated intervention. All analyses were conducted in Stata 18.0.
Patient and public involvement
Patients and the public were not involved in the design, conduct and dissemination of this research.
Results
Participants
Between 30 November 2014 and 30 June 2016, a total of 97 individuals were screened for eligibility, of which 37 were excluded. Thus, sixty participants were enrolled and randomly allocated to the NEXA and celecoxib (n = 30) or celecoxib (n = 30) group (Fig. 1). At the 24-week assessment, 5 participants (NEXA and celecoxib, n = 2; celecoxib, n = 3) withdrew from follow-up. The mean age of participants was 60.7 years; 70% were female; and mean BMI was 27.7 kg/m2. Baseline characteristics were similar between groups (Table 1). In the NEXA and celecoxib group, 22 participants (73.3%) completed all 36 sessions (24 supervised and 12 home exercise), and 93% attended more than 29 sessions. Notably, 76.7% (23/30) completed more than 10 home exercise sessions and 90% (27/30) completed more than 19 supervised exercise sessions. Twenty-two participants completed all 12 home exercise sessions, and 25 participants fully adhered to the 24 supervised exercise sessions. During the 12-week intervention, rescue acetaminophen use was observed in 26.7% (8/30) of the NEXA and celecoxib group and 20.7% (6/29) of the celecoxib group, with no statistically significant between-group difference (P = 0.59). Both groups exhibited similar rescue medication patterns, with median durations of 9 days in the NEXA and celecoxib group versus 12 days in the celecoxib group.
Fig. 1.
CONSORT flow diagram. CONSORT, Consolidated Standards of Reporting Trials; NEXA, neuromuscular exercise
Table 1.
Baseline characteristics of the participants
| Characteristic | NEXA and Celecoxib (n = 30) | Celecoxib (n = 30) |
|---|---|---|
| Age (years) | 61.7 ± 5.5 | 59.8 ± 5.9 |
| Female sex, n (%) | 22 (73.3) | 20 (66.7) |
| BMI (kg/m2) | 27.7 ± 2.8 | 27.6 ± 2.9 |
| Smoker, n (%) | 3 (10) | 4 (13.3) |
| Joint space width (mm) | 3.6 ± 1.0 | 3.5 ± 1.0 |
| Kellgren-Lawrence grade, n (%) | ||
| 2 | 18 (60) | 15 (50) |
| 3 | 12 (40) | 15 (50) |
| 100-mm VAS for pain | 58.8 ± 12.6 | 59.9 ± 13.5 |
| WOMAC | ||
| Pain | 10.5 ± 3.1 | 10.6 ± 2.8 |
| Stiffness | 4.4 ± 1.4 | 4.3 ± 1.5 |
| Function | 31.3 ± 10.3 | 32.9 ± 9.7 |
| Total | 46.2 ± 13.1 | 47.7 ± 13.4 |
| KOOS | ||
| Symptoms | 53.9 ± 15.4 | 52.0 ± 15.0 |
| Pain | 49.1 ± 13.8 | 50.4 ± 13.8 |
| Activities of Daily Living | 54.1 ± 15.1 | 51.6 ± 14.3 |
| Sport and Recreation | 30.7 ± 15.1 | 31.3 ± 14.3 |
| Quality of Life | 38.5 ± 17.0 | 35.7 ± 15.1 |
| six-min walk test (m) | 436.3 ± 44.7 | 428.5 ± 47.2 |
| TUG test (s) | 10.2 ± 2.1 | 11.0 ± 2.3 |
a Data are presented as mean ± SD unless otherwise stated. There was no significant difference between the groups for any outcome measure. NEXA, neuromuscular exercise; BMI, body mass index; VAS: Visual analogue scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index; KOOS, Knee injury and Osteoarthritis Outcome Score; TUG, Timed Up and Go
Primary outcomes
In the ITT population, the mean (± SD) total WOMAC scores at 24 weeks were 24.29 ± 9.59 in the NEXA and celecoxib group and 35.56 ± 10.87 in the celecoxib group (95% CI, -15.54 to -5.27; P < 0.001). At 24 weeks, VAS score was significantly lower in the NEXA and celecoxib group (31.64 ± 16.49 mm) than the celecoxib group (42.96 ± 20.72 mm; 95% CI, -19.38 to -1.23; P = 0.026) (Table 2). The sensitivity analyses performed on the PP population further confirmed the results of the primary analysis (online supplemental Table 1).
Table 2.
Primary and secondary outcomes at the end of treatment (12 weeks) and at 24 weeks from intention-to-treat analysis
| Outcomes | NEXA and Celecoxib (n = 30) | Celecoxib (n = 29) |
Estimated treatment difference (95% CI) | Cohen’s d | P value |
|---|---|---|---|---|---|
| 100-mm VAS on pain | |||||
| 12 weeks | 36.20 ± 18.51 | 39.45 ± 17.11 | -2.72 (-11.52 to 6.09) | -0.15 | 0.545 |
| 24 weeks | 31.64 ± 16.49 | 42.96 ± 20.72 | -10.30 (-19.38 to -1.23) | -0.55 | 0.026 |
| WOMAC | |||||
| Pain | |||||
| 12 weeks | 6.57 ± 3.30 | 7.28 ± 2.71 | -0.66 (-2.08 to 0.76) | -0.22 | 0.359 |
| 24 weeks | 5.86 ± 3.19 | 7.59 ± 3.70 | -1.62 (-3.08 to -0.16) | -0.47 | 0.030 |
| Stiffness | |||||
| 12 weeks | 2.90 ± 1.32 | 2.97 ± 1.15 | -0.13 (-0.69 to 0.42) | -0.10 | 0.652 |
| 24 weeks | 2.93 ± 1.36 | 3.07 ± 1.33 | -0.18 (-0.74 to 0.38) | -0.13 | 0.530 |
| Function | |||||
| 12 weeks | 16.87 ± 7.70 | 23.17 ± 9.86 | -5.68 (-9.47 to -1.88) | -0.64 | 0.003 |
| 24 weeks | 15.50 ± 6.90 | 24.89 ± 8.27 | -8.69 (-12.56 to -4.82) | -1.14 | < 0.001 |
| Total | |||||
| 12 weeks | 26.33 ± 11.35 | 33.41 ± 12.61 | -6.39 (-11.43 to -1.35) | -0.53 | 0.013 |
| 24 weeks | 24.29 ± 9.59 | 35.56 ± 10.87 | -10.40 (-15.54 to -5.27) | -1.02 | < 0.001 |
| KOOS | |||||
| Symptoms | |||||
| 12 weeks | 67.77 ± 14.27 | 62.90 ± 14.01 | 3.32 (-2.03 to 8.66) | 0.23 | 0.224 |
| 24 weeks | 69.96 ± 20.72 | 62.26 ± 15.96 | 5.77 (0.25 to 11.28) | 0.31 | 0.040 |
| Pain | |||||
| 12 weeks | 63.90 ± 13.81 | 63.45 ± 11.01 | 1.27 (-4.35 to 6.89) | 0.10 | 0.658 |
| 24 weeks | 66.64 ± 12.94 | 61.44 ± 17.16 | 5.03 (-0.74 to 10.80) | 0.33 | 0.088 |
| Activities of Daily Living | |||||
| 12 weeks | 72.93 ± 11.23 | 65.97 ± 14.49 | 5.94 (0.44 to 11.43) | 0.46 | 0.034 |
| 24 weeks | 77.21 ± 10.08 | 63.41 ± 12.17 | 12.68 (7.08 to 18.29) | 1.14 | < 0.001 |
| Sport and Recreation | |||||
| 12 weeks | 42.33 ± 16.54 | 38.97 ± 16.76 | 3.55 (-1.35 to 8.45) | 0.21 | 0.155 |
| 24 weeks | 44.82 ± 17.77 | 37.96 ± 17.50 | 6.29 (1.28 to 11.30) | 0.36 | 0.014 |
| Quality of Life | |||||
| 12 weeks | 51.77 ± 19.50 | 46.31 ± 20.09 | 2.31 (-3.26 to 7.87) | 0.12 | 0.417 |
| 24 weeks | 54.43 ± 23.79 | 44.37 ± 21.42 | 6.13 (0.40 to 11.85) | 0.27 | 0.036 |
| six-min walk test (m) | |||||
| 12 weeks | 519.44 ± 56.79 | 483.35 ± 55.24 | 30.02 (6.23 to 53.80) | 0.54 | 0.013 |
| 24 weeks | 523.72 ± 54.87 | 479.67 ± 64.43 | 34.30 (9.91 to 58.69) | 0.57 | 0.006 |
| TUG test (s) | |||||
| 12 weeks | 8.10 ± 1.51 | 9.33 ± 1.51 | -0.82 (-1.47 to -0.18) | -0.55 | 0.012 |
| 24 weeks | 8.11 ± 1.57 | 9.60 ± 1.84 | -1.11 (-1.77 to -0.44) | -0.65 | 0.001 |
a Data are presented as mean ± SD unless otherwise stated. Statistically significance (P < 0.05). NEXA, neuromuscular exercise; CI, confidence interval; VAS: Visual analogue scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index; KOOS, Knee injury and Osteoarthritis Outcome Score; TUG, Timed Up and Go
b Estimated treatment difference and P values are adjusted for baseline values of the respective outcome
Regarding MCID achievement for total WOMAC score at 24 weeks, the NEXA and celecoxib group had a greater proportion of patients above the MCID for 12 points of absolute improvement (NEXA and celecoxib, 78.6%; celecoxib, 51.9%; P = 0.037) and 33% relative improvement (NEXA and celecoxib, 75%; celecoxib, 37%; P = 0.005) compared with the celecoxib group. Regarding MCID achievement for VAS score at 24 weeks, there was no statistically significant difference in the proportion of patients above the MCID between the two treatment groups (Fig. 2).
Fig. 2.
Proportions of participants achieving the MCID for (A-B) total WOMAC score and (C-D) VAS score. MCID, minimal clinically important difference; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index; VAS, visual analog scale
Secondary outcomes
In the secondary outcomes, the estimated treatment differences between groups at 12 weeks were 5.9 points (95% CI, 0.44 to 11.43; P = 0.034) for KOOS activities of daily living score; 30 m (95% CI, 6.23 to 53.80; P = 0.013) for six-min walk test; and 0.8 s (95% CI, -1.47 to -0.18; P = 0.012) for TUG test. At 24 weeks, the between-group differences in the KOOS symptoms score, KOOS activities of daily living score, KOOS sport and recreation score, KOOS quality of life score, six-min walk test, and TUG test were statistically in favour of the NEXA and celecoxib group. (Table 2). The sensitivity analyses identified the difference, of borderline statistical significance (P = 0.039), for the KOOS pain score at 24 weeks in the PP population (estimated treatment differences, 6.23, 95% CI, 0.33 to 12.13); no different results in the other secondary outcomes were observed in the sensitivity analysis. (online supplemental Table 1).
Safety
Three participants discontinued intervention because of adverse events. None of the participants experienced grade 3, 4, or 5 adverse events, according to the scale of the CTCAE [22]. Adverse events occurred in 1 (3.3%) patient in the NEXA and celecoxib group (diarrhoea) and 2 (6.9%) patients in the celecoxib group (diarrhoea, pruritus), which were considered as related to the study drug by the investigators.
Discussion
This study found that NEXA in addition to celecoxib, compared with celecoxib alone, had a beneficial effect on pain and physical function in patients with symptomatic and radiographic knee OA at 6 months; the improvement in physical function was observed at 3 months. The NEXA and celecoxib group achieved a significantly higher proportion of patients above the MCID at 6 months for total WOMAC score when compared with the celecoxib group. However, at the end of treatment (3 months), there were no clinically important differences in physical function between the two groups. None of the serious treatment-related adverse events occurred during the study period.
Notably, 93% of the NEXA in addition to celecoxib group met predefined adherence criteria, which is a marked improvement over historical NEXA adherence rates [10, 14]. The observed improvement in adherence may reflect the concurrent use of NEXA with analgesic pharmacotherapy effectively addressing pain-mediated barriers to exercise engagement. However, self-reported home exercise adherence may still introduce bias. Future studies should adopt sensitivity analyses stratifying by adherence levels to control for this limitation. Standardized adherence monitoring tools, such as wearable sensors, could further reduce measurement heterogeneity.
In our study, a statistically significant improvement was observed for pain and physical function in patients with knee OA when using NEXA in addition to celecoxib therapy at 6 months, and for physical function at 3 months. Our results are in keeping with the findings of previous studies [10, 33, 34], which found that NEXA therapy significantly improved symptoms. Here, they only assessed outcomes in short-term follow-up, whereas our study focused on the combination of NEXA and celecoxib therapy and had a longer follow-up in those with knee OA, which may have increased our ability to observe the long-term effects and safety. In addition, our results showed the statistically significant improvement in physical function following intervention was sustained for up to 6 months, which may be due to past participation in exercise as participants may continue exercise on their own. Sustained NEXA training may promote joint stabilization through neuromuscular adaptation. Additionally, unmeasured behavioural factors, such as progressive self-driven increases in daily physical activity facilitated by early functional gains, which could further amplify long-term outcomes. An RCT by Holsgaard-Larsen et al. demonstrated that 8-week NEXA had superior effects on knee symptoms compared with instructions in optimized pharmacological treatment at the 12-month follow-up, though no between-group differences in pain were observed at either 2 or 12 months [14]. This would suggest long-term NEXA program may provide more effective long-term relief of symptoms. Here, they included patients who had a clinical diagnosis of knee OA, with or without radiographic changes, whereas in our study we included participants with symptomatic and radiographic (KL grade 2–3) knee OA. Besides the duration of treatment, standardizing OA definitions in future research would enhance cross-study comparability.
To assess the clinically significant differences between groups, the absolute and relative values of the MCID for primary outcomes were utilized that had been applied in previous OA studies. The observed effects of NEXA in addition to celecoxib on physical function at 6 months in our study were both statistically significant and clinically important. However, the effects of NEXA in addition to celecoxib on pain were not considered to be clinically significant at 3 months and 6 months. Hence, there remain some concerns about widespread use. Further, there is evidence to suggest that multimodal exercise (strength training in addition to NEXA and education) may provide additional benefits in those with knee OA [35, 36]. Future studies are required to consider more comprehensive exercise programs. Kim et al. suggested that structural improvement requires a longer follow-up to reflect the regenerative and chondroprotective effects [37]. Future studies should confirm the long-term effects of NEXA and celecoxib on structural changes.
There were several strengths to our study. First, to our knowledge we are the first to explore the long-term effects of NEXA in addition to celecoxib on pain and physical function in patients with symptomatic and radiographic knee OA. Second, this study demonstrated high adherence and low dropout rate in the long-term follow-up periods. Further, our study utilized the MICD for primary outcomes to determine whether differences between groups were clinically significant.
There are several potential limitations in our study. First, patients assigned to NEXA and celecoxib group had more visits with the physiotherapist than patients in the celecoxib group, which resulted in more contact time and providers have more opportunities to address patient needs. This discrepancy in provider contact time was an inherent limitation of the pragmatic trial design, potentially introducing attention bias. Future trials could include a sham exercise control group receiving equal therapist time for non-therapeutic activities (e.g., passive range-of-motion). Second, participants performing NEXA and physiotherapists delivering exercise could not be blinded to treatment allocation due to the nature of interventions. This could have introduced bias. Third, the sample size calculation relied on parameters from previous studies rather than pilot data, which may limit generalizability to populations with distinct baseline characteristics. Fourth, the exercise protocol’s monitoring framework depended on subjective measures including patient-reported DOMS evaluations and home exercise videos, lacking biochemical validation (e.g., serum creatine kinase) or wearable motion sensors to objectively quantify muscle stress and movement quality. In addition, this trial lacked a control group that patients performed NEXA alone. Consequently, we cannot determine whether the long-term functional improvements resulted from the sustained effects of NEXA alone, synergistic effects with celecoxib, or patient self-management after supervised training. Future studies comparing NEXA alone against combination therapy are needed to clarify these relationships.
Conclusions
This study suggests that NEXA in addition to celecoxib, compared with celecoxib alone, provides symptomatic and functional improvements in patients with symptomatic and radiographic knee OA at 6 months. The addition of NEXA did not result in greater improvements in pain compared to celecoxib alone at 12-week follow-up.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Acknowledgements
The authors express their gratitude to all the patients who participated in the research.
Abbreviations
- BMI
Body mass index
- CI
Confidence intervals
- ITT
Intention-to-treat
- KL
Kellgren and Lawrence
- KOOS
Knee injury and Osteoarthritis Outcome Score
- LMM
Linear mixed model
- MCID
Minimal clinically important difference
- NEXA
Neuromuscular exercise
- OA
Osteoarthritis
- PP
Per-protocol
- RCT
Randomized controlled trial
- SD
Standard deviation
- TUG
Timed up and go
- VAS
Visual analog scale
- WOMAC
Western ontario and mcmaster universities osteoarthritis index
Author contributions
XY and CH contributed to the conception and design. HS, XL and XY did the analysis and interpretation of data. HS, XL and CH did the data collection. XY, HS, TW and JL wrote the article and did the critical revision of the article. XY is responsible for the overall content as the guarantor.
Funding
This study was supported by the National Natural Science Foundation of China (No. 82102646).
Data availability
Data that support findings of this study are available from the corresponding author upon reasonable request.
Declarations
Ethics approval and consent to participate
This study involves human participants and was approved by the Medical Ethics Committee of West China hospital, Sichuan university (2014/177). Participants gave informed consent to participate in the study before taking part.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
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References
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Data Availability Statement
Data that support findings of this study are available from the corresponding author upon reasonable request.