Effect of Pulsed Low-Intensity Ultrasonography on Symptom Relief and Tibiofemoral Articular Cartilage Thickness Among Veterans Affairs Enrollees With Knee Osteoarthritis: A Randomized Clinical Trial.

Importance: Osteoarthritis (OA) is a major cause of disability in the US, with no approved treatments to slow progression, but animal models suggest that pulsed low-intensity ultrasonography (PLIUS) may promote cartilage growth. Objective: To evaluate the efficacy of PLIUS in providing symptom reduction and decreased loss of tibiofemoral cartilage thickness in patients with knee OA. Design, Setting, and Participants: A phase 2A, sham-controlled, parallel, double-blind randomized clinical trial was conducted at 2 Veterans Affairs hospitals in Salt Lake City, Utah, and San Diego, California, from May 22, 2015, to January 31, 2019. Data were analyzed from June 27, 2020, to October 20, 2020. Participants recruited through the US Department of Veterans Affairs (N = 132) with clinical and radiographic evidence of early knee OA were randomly assigned to receive PLIUS or a sham device, self-administered for 20 minutes daily over the medial compartment of the knee. All enrollees participated in a 4-week prerandomization sham run-in period, followed by a 48-week treatment period. Randomization was stratified by study site and Kellgren-Lawrence grades 1 (n = 15), 2 (n = 51), and 3 (n = 66). Intervention: Participants either received 48 weeks of PLIUS or sham ultrasonography. Main Outcomes and Measures: The trial incorporated 2 coprimary outcomes: symptomatic improvement assessed by Outcome Measures in Rheumatology Clinical Trials-Osteoarthritis Research Society International Responder Criteria (ie, met if either >50% improvement in pain and function with at least a 20% absolute improvement of at least 2 of the following 3 factors: improvement by at least 20% [pain, function, and patient global assessment] with at least a 10-mm absolute improvement), and cartilage preservation assessed as change in central medial femoral condyle cartilage thickness by magnetic resonance imaging. Intention-to-treat analysis was used. Results: The mean (SD) participant age was 63.6 (10.7) years and 119 were men (90.2%). The mean (SD) duration of OA symptoms was 13.4 (12.3) years. In the PLIUS group, 70.4% (95% CI, 58.2%-82.6%) of the participants experienced symptomatic improvement, compared with 67.3% (95% CI, 54.9%-79.7%) of participants in the sham group (P = .84); there was no statistically significant difference in response rates between the treatment groups, and the between-group rate difference of 3.1% (95% CI, -14.3% to 20.5%) did not meet the predefined 10% threshold for clinically significant symptomatic improvement from application of PLIUS. At 48 weeks of treatment, central medial femoral condyle cartilage thickness decreased by a mean (SD) of 73.8 (168.1) µm in the PLIUS group and by 42.2 (297.0) µm in the sham group. This 48-week mean change between the 2 groups did not reach statistical significance (P = .44), and the between-group 48-week difference of -31.7 µm (95% CI, -129.0 µm to 65.7 µm) did not meet the predefined threshold. There were 99 nonserious adverse events in the PLIUS group and 89 in the sham group during the trial. No serious adverse events were deemed related to the study device. Conclusions and Relevance: PLIUS, as implemented in this study, demonstrated neither symptomatic benefit nor a decrease in loss of tibiofemoral cartilage thickness in knee OA. Trial Registration: ClinicalTrials.gov Identifier: NCT02034409.

Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT.

BACKGROUND: Knee osteoarthritis (OA) is a major cause of pain and functional limitation in older adults, yet longer-term studies of medical treatment of OA are limited. OBJECTIVE: To evaluate the efficacy and safety of glucosamine and chondroitin sulphate (CS), alone or in combination, as well as celecoxib and placebo on painful knee OA over 2 years. METHODS: A 24-month, double-blind, placebo-controlled study, conducted at nine sites in the US ancillary to the Glucosamine/chondroitin Arthritis Intervention Trial, enrolled 662 patients with knee OA who satisfied radiographic criteria (Kellgren/Lawrence grade 2 or 3 changes and baseline joint space width of at least 2 mm). This subset continued to receive their randomised treatment: glucosamine 500 mg three times daily, CS 400 mg three times daily, the combination of glucosamine and CS, celecoxib 200 mg daily, or placebo over 24 months. The primary outcome was a 20% reduction in Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain over 24 months. Secondary outcomes included an Outcome Measures in Rheumatology/Osteoarthritis Research Society International response and change from baseline in WOMAC pain and function. RESULTS: Compared with placebo, the odds of achieving a 20% reduction in WOMAC pain were celecoxib: 1.21, glucosamine: 1.16, combination glucosamine/CS: 0.83 and CS alone: 0.69, and were not statistically significant. CONCLUSIONS: Over 2 years, no treatment achieved a clinically important difference in WOMAC pain or function as compared with placebo. However, glucosamine and celecoxib showed beneficial but not significant trends. Adverse reactions were similar among treatment groups and serious adverse events were rare for all treatments.

The effect of glucosamine and/or chondroitin sulfate on the progression of knee osteoarthritis: a report from the glucosamine/chondroitin arthritis intervention trial.

OBJECTIVE: Osteoarthritis (OA) of the knee causes significant morbidity and current medical treatment is limited to symptom relief, while therapies able to slow structural damage remain elusive. This study was undertaken to evaluate the effect of glucosamine and chondroitin sulfate (CS), alone or in combination, as well as celecoxib and placebo on progressive loss of joint space width (JSW) in patients with knee OA. METHODS: A 24-month, double-blind, placebo-controlled study, conducted at 9 sites in the United States as part of the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), enrolled 572 patients with knee OA who satisfied radiographic criteria (Kellgren/Lawrence [K/L] grade 2 or grade 3 changes and JSW of at least 2 mm at baseline). Patients with primarily lateral compartment narrowing at any time point were excluded. Patients who had been randomized to 1 of the 5 groups in the GAIT continued to receive glucosamine 500 mg 3 times daily, CS 400 mg 3 times daily, the combination of glucosamine and CS, celecoxib 200 mg daily, or placebo over 24 months. The minimum medial tibiofemoral JSW was measured at baseline, 12 months, and 24 months. The primary outcome measure was the mean change in JSW from baseline. RESULTS: The mean JSW loss at 2 years in knees with OA in the placebo group, adjusted for design and clinical factors, was 0.166 mm. No statistically significant difference in mean JSW loss was observed in any treatment group compared with the placebo group. Treatment effects on K/L grade 2 knees, but not on K/L grade 3 knees, showed a trend toward improvement relative to the placebo group. The power of the study was diminished by the limited sample size, variance of JSW measurement, and a smaller than expected loss in JSW. CONCLUSION: At 2 years, no treatment achieved a predefined threshold of clinically important difference in JSW loss as compared with placebo. However, knees with K/L grade 2 radiographic OA appeared to have the greatest potential for modification by these treatments.