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

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.