Abstract
BACKGROUND: Drug development for osteoarthritis (OA) has faced significant challenges, mainly due to the lack of alignment between joint structure observations and patient-reported outcomes (PROs), such as pain. Weight loss has been linked to positive effects on symptomatic outcomes. Blood-based biomarkers indicating collagen and extracellular matrix turnover can be used to measure injury severity in specific tissues, offering a more precise assessment of disease progression. This study aimed to explore the relationship between obesity and PROs and its impact on serum and urinary biomarkers of bone (CTX-I and osteocalcin), synovial (type III collagen degradation and C3M), and cartilage (type II collagen degradation, CTX-II, and C2M) turnover. METHODS: This post hoc exploratory analysis examined data from 806 patients with persistent knee OA pain who participated in two clinical trial of oral salmon calcitonin (NCT00704847 [2008-06] and NCT00486434 [2007-06]. Participants were categorized by baseline BMI (lean, overweight, and obese) and two-year weight change (gain/loss ≥5%). Biomarkers were measured at baseline and at the 2-year follow-up. RESULTS: The cohort primarily consisted of white women, with a median age of 64 years and a median BMI of 29 kg/m(2). WOMAC total scores, function, and stiffness were significantly higher in obese patients than in overweight and lean patients; however, pain scores did not differ significantly. WOMAC total, function, and pain scores significantly improved in patients who lost or maintained their weight compared with those who gained weight. The bone resorption biomarker CTX-I increased by 1.58-fold [95% CI 1.39, 1.81], 1.37-fold [1.28, 1.47], and 1.11-fold [0.95, 1.28] in the weight loss, stable weight, and weight gain groups, respectively. The cartilage degradation marker C2M increased by 1.15-fold [0.95, 1.39], whereas the interstitial matrix degradation marker C3M decreased by 0.84-fold [0.73, 0.97] in the weight loss group. CONCLUSION: Obesity exacerbates OA symptoms. While weight loss improves symptoms and reduces synovial inflammation, measured by biomarkers, it may also heighten the risk of excessive bone and cartilage loss, when using specific collagen degradation biomarkers. This study is a post-hoc analysis of data from the CSMC trials with clinicaltrial.gov numbers NCT00704847 (2008-06-24) and NCT00486434 (2007-06-14).