Potential mediators of the mortality reduction with zoledronic acid after hip fracture

Abstract

Zoledronic acid reduces the risk of death by 28% after hip fracture, but the mechanisms are not known. This exploratory analysis sought to identify potential pathways for the reduction in mortality with zoledronic acid after hip fracture. This was a retrospective analysis of a randomized, controlled trial. Patients with recent hip fracture (n = 2111) were treated with zoledronic acid or placebo infusion yearly, as well as calcium and vitamin D supplementation. Causes of death were adjudicated by a blinded central review committee. Baseline comorbidities, events occurring during the study period, including subsequent fracture, change in bone density, infections, cardiovascular events, arrhythmias, and falls, were included in multivariable analyses. In a model adjusted for baseline risk factors, zoledronic acid reduced the risk of death by 25% [95% confidence interval (CI) 0.58–0.97). The effect was consistent across most subgroups. Subsequent fractures were significantly associated with death (hazard ratio 1.72, 95% CI 1.17–2.51) but explained only 8% of the zoledronic acid effect. Adjusting for acute events occurring during follow-up eliminated the death benefit, and zoledronic acid–treated subjects were less likely to die from pneumonia (interaction p = .04) and arrhythmias (interaction p = .02) than placebo-treated subjects. Only 8% of zoledronic acid’s death benefit is due to a reduction in secondary fractures. Zoledronic acid may have an effect on cardiovascular events and pneumonia. Further studies of zoledronic acid in other acute illnesses may be warranted.

Post–hip fracture use of prescribed calcium plus vitamin D or vitamin D supplements and antiosteoporotic drugs is associated with lower mortality: A nationwide study in Finland

“…According to Kanis and colleagues, (17) 17% to 32% of deaths (depending on age) after hip fracture were causally related to the fracture. In the zoledronic acid study by Colon-Emeric and colleagues, (18) subsequent fractures were significantly associated with death (HR ¼ 1.72, 95% CI 1.17-2.51) but explained only 8% of the zoledronic acid effect. Zoledronic acid also may have an effect on cardiovascular events and pneumonia, (18) and fracture prevention seems to explain only a minor proportion of the mortality reduction.…”

Deprescribing in the Last Year of Life

“…31 An analysis of subgroups revealed that nursing home residents and those with significant cognitive impairment did not gain a mortality benefit from zoledronic acid. 32 The number of hospitalisations for adverse drug reactions may be increasing in Australia, particularly in older patients. A Western Australian study reported that the number of adverse drug reactions from 1981 to 2002 increased tenfold for men and sevenfold for women over the age of 80 years.…”

New drugs for osteoporosis

“…6 The mechanisms responsible for mortality reduction in patients treated with zoledronic acid remain unclear, but may be related to an effect on reducing cardiovascular events and pneumonia. 7 If treatment was deferred for two weeks after the fracture, the improvements in bone mineral density and reductions in mortality and re-fracture rate were greater. 8 …”