Background: Clodronate reduced clinical fractures in unselected, older women. It is known that mortality and cardiovascular events increase following fracture. Bisphosphonates are thought to influence both mortality and cardiovascular outcomes. It is uncertain if bisphosphonates can ‘reverse’ the deleterious consequences of fracture. Here, we report rates of fatal and non-fatal events in participants with and without a fracture during follow-up.
Methods: Unselected women (>75 years) were randomised to oral clodronate or placebo over three years. Fractures (any clinical or hip) were adjudicated centrally at the Northern General Hospital (Sheffield, UK). Cardiovascular adverse events (myocardial infarction (MI), stroke, heart failure, atrial fibrillation (AF)) were adjudicated from hospital discharge summaries and deaths obtained from the NHS central registry.
Results: 5212 women were included. Mean age was 78 years (76 to 82), 2,357 (46%) had a prior fracture. There were 762 (14.6%) deaths, and 1,117 (21.4%) major adverse cardiovascular events. Rates of MI were lower in those on clodronate compared with those on placebo (7/281, 2.49% versus 16/339, 4.72%; odds ratio=0.52, 95%CI=0.21 to 1.28) in those that sustained a clinical fracture during follow-up. This association was reversed in those that did not sustain a fracture (118/2325, 5.08% versus 87/2267, 3.84%; OR=1.34 [1.01 to 1.78]). However, rates of AF were greater in those on clodronate (17/281, 6.05%) compared with placebo (9/339 2.65%) [OR=2.36 (1.04 to 5.38)] in those that experienced a fracture. Rates were balanced in those that did not experience a fracture [62/2325, 2.67% versus 62/2267, 2.73%; 0.97 (0.68 to 1.39)]. Findings were less robust when analysing by hip fracture owing to very low event rates.
Interpretation: Clodronate may have additional benefit in reducing MI following a fracture but may be associated with increased AF. Event rates were low and nearly half the included participants had a history of fracture possibly influencing outcomes.