Zoledronic acid may improve survival by strengthening immune system

Patients treated with the osteoporosis drug zoledronic acid after hip fracture are less likely to die of cardiovascular events and pneumonia, a study suggests.

For years, zoledronic acid has been known to have an associated mortality benefit, with a pivotal study showing a 28 percent reduction in the risk of death. [N Engl J Med 2007;357:1799-1809]

The new study, conducted by Dr. Cathleen S. Colón-Emeric and colleagues, reveals that only 8 percent of the said mortality benefit is due to secondary fracture reduction. The lower risk of death associated with zoledronic acid may also be mediated by its effect on acute events. [J Bone Miner Res 2009; July 6 DOI:10.1359/jbmr.090704]

The authors retrospectively analyzed data of the randomized, controlled trial that originally reported the beneficial effect of zoledronic acid on mortality – in which some 2,111 patients with a recent hip fracture were treated with either zoledronic acid or placebo as a yearly infusion.

“Because zoledronic acid is the first osteoporosis medication shown to improve mortality, it is important to understand how it happens ... it is not simply the decrease in fractures which reduces the patient’s chance of dying, there must be other effects of the drug as well,” said Colón-Emeric, lead author of the study. “Our analyses suggest a possible impact on infections and heart disease that should be studied further.”

After adjustment for baseline risk factors, Colón-Emeric et al. found that zoledronic acid-treated patients were less likely to die of arrhythmias (interaction P=0.02) or pneumonia (interaction P=0.04) than placebo-treated patients.

“If further studies find that zoledronic acid has beneficial effects on other organ systems besides bone, that could potentially lead to new understanding about the mechanism of disease and new treatments,” said Colón-Emeric, who is an associate professor of medicine at Duke University Medical Center, US.

Overall, the incidence of acute events was similar in both treatment groups, the difference being that zoledronic acid-treated patients were less likely to die from these events.

The Duke researchers believe the drug may exert its added mortality benefit by strengthening the body’s immune system, although the exact mechanism is, as yet, unknown.

“We know it affects the immune system and inflammation, and both of those are important in fighting infection and cardiovascular disease,” said Colón-Emeric. “It may be that the drug is changing the body’s ability to fight off and recover from those illnesses.”

The effect of zoledronic acid was similar across most subgroups and disease states that were included in the trial, with the mortality benefit extending even to those aged 85 and older.

However, individuals with greater frailty, such as those living in a nursing home prior to breaking their hip or those with a high degree of cognitive impairment, failed to derive a significant death benefit from the drug.

“While making treatment decisions based on post-hoc subgroup analyses is inadvisable, clinicians should give consideration to zoledronic acid’s death benefit, which manifests in the second year of treatment, and to their patients’ remaining life expectancy and competing risks of mortality,” state the authors.