Do drugs proposed to protect or harm joints change serious osteoarthritis events? A meta-analysis of adverse event tables from 881 randomized trials
- 1Hubei University of Medicine
Abstract
ObjectivesObservational 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.
MethodsWe 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.
ResultsThe 881 placebo- or usual-care-controlled trials included 1.75 million participants and 9,408 osteoarthritis-related SAEs. The tables reproduced CANTOSs 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).
ConclusionsOver 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 messagesWhat is already known on this topic O_LIObservational 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. C_LI
What this study adds O_LIGLP-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. C_LI
How this study might affect research, practice or policy O_LITrial registries can test osteoarthritis repurposing signals for large, short-term effects before dedicated trials are funded; slow structural effects still need such trials. C_LI
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BibTeX
@misc{xu2026drugs,
title = {{Do drugs proposed to protect or harm joints change serious osteoarthritis events? A meta-analysis of adverse event tables from 881 randomized trials}},
author = {Z. Xu and M. Pan and J. Cheng and X. Chen and J. Luo and X. Guo and X. Zhu},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.13.26365377},
url = {https://www.medrxiv.org/content/10.64898/2026.10.13.26365377v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Do drugs proposed to protect or harm joints change serious osteoarthritis events? A meta-analysis of adverse event tables from 881 randomized trials
AU - Z. Xu
AU - M. Pan
AU - J. Cheng
AU - X. Chen
AU - J. Luo
AU - X. Guo
AU - X. Zhu
PY - 2026
DA - 2026/10/13
PB - medRxiv
DO - 10.64898/2026.10.13.26365377
UR - https://www.medrxiv.org/content/10.64898/2026.10.13.26365377v1
AB - ObjectivesObservational 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. MethodsWe 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. ResultsThe 881 placebo- or usual-care-controlled trials included 1.75 million participants and 9,408 osteoarthritis-related SAEs. The tables reproduced CANTOSs 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). ConclusionsOver 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 messagesWhat is already known on this topic O_LIObservational 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. C_LI What this study adds O_LIGLP-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. C_LI How this study might affect research, practice or policy O_LITrial registries can test osteoarthritis repurposing signals for large, short-term effects before dedicated trials are funded; slow structural effects still need such trials. C_LI
ER -