Work

Do drugs proposed to protect or harm joints change serious osteoarthritis events? A meta-analysis of adverse event tables from 881 randomized trials

Year: 2026

Type: preprint

Study designs: Systematic Review, Meta-Analysis

Abstract: Objectives Observational studies report large, conflicting associations between common drugs and hip or knee replacement. We tested them in the serious adverse event (SAE) tables of randomized trials on ClinicalTrials.gov . Methods We included randomized drug trials with ≥500 participants. A language model classified arms from summaries without outcome counts (masked by instruction only). We pooled osteoarthritis-related SAEs by drug class as Mantel–Haenszel risk ratios (RRs). Because the plan followed a preliminary analysis of 72 trials, we report estimates rather than tests, checked by positive and negative controls and calibration. Results The 881 placebo- or usual-care-controlled trials included 1.75 million participants and 9,408 osteoarthritis-related SAEs. The tables reproduced CANTOS’s own canakinumab effect (RR 0.57, 95% CI 0.39 to 0.82), the anti-nerve growth factor excess (2.31, 1.82 to 2.92) and two of three modest effects specified before extraction: gallbladder disease with glucagon-like peptide-1 receptor agonists (GLP-1RAs; 1.36, 1.22 to 1.51) and ketoacidosis with sodium– glucose cotransporter-2 (SGLT2) inhibitors (1.96, 1.48 to 2.60). In the same trials, osteoarthritis-related SAEs did not differ detectably with GLP-1RAs (0.97, 0.86 to 1.10; calibrated 0.87, 0.54 to 1.41) or SGLT2 inhibitors (0.96, 0.82 to 1.12; calibrated 0.86, 0.53 to 1.40). Other proposed drugs gave imprecise estimates. Post hoc, 8 of 21 published observational estimates differed from randomized ones, in both directions (3 to 6 after calibration). Conclusions Over about two years, GLP-1RAs and SGLT2 inhibitors had no detectable effect on osteoarthritis-related SAEs in trials that detected their known effects. Slow or modest structural effects remain possible. Key messages What is already known on this topic Observational studies associate glucose-lowering drugs, bisphosphonates and warfarin with large and conflicting changes in the risk of hip or knee replacement; randomized evidence is limited to a few exploratory analyses of single trials. What this study adds GLP-1 receptor agonists and SGLT2 inhibitors had no detectable effect on serious osteoarthritis events over about two years, in randomized trials whose adverse-event tables detected these drugs’ known effects. How this study might affect research, practice or policy Trial registries can test osteoarthritis repurposing signals for large, short-term effects before dedicated trials are funded; slow structural effects still need such trials.

Source: medRxiv

DOI: 10.64898/2026.10.13.26365377