An annual infusion of zoledronic acid reduced the rate of new clinical fractures and improved survival in patients who had recently undergone surgical repair of a hip fracture, according to Dr. Kenneth W. Lyles and associates in the HORIZON Recurrent Fracture Trial.
The Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) study, supported by Novartis, is an international clinical trial that directly compared the potent bisphosphonate with placebo in 2,127 patients who were followed for a mean of 2 years, the investigators reported in a Sept. 17 posting on the New England Journal of Medicine Web site.
“It is noteworthy that no other controlled clinical trial has previously shown efficacy of any osteoporosis medication for reducing the recurrence of fracture in patients who already had a broken hip,” Dr. Karim Calis and Dr. Frank Pucino said in an editorial comment accompanying the HORIZON investigators' report.
All of the study subjects had sustained a hip fracture after minimal trauma and had undergone surgical repair, then received their first intravenous infusion within 90 days. They also received daily oral calcium and vitamin D supplements, and were allowed to have concomitant therapy with nasal calcitonin, selective estrogen receptor modulators (SERMs), hormone therapy, tibolone, or external hip protectors.
A total of 1,065 patients were randomly assigned to receive IV zoledronic acid and 1,062 to receive IV placebo once yearly. All the subjects were either intolerant of oral bisphosphonates or refused to take them. Mean patient age was 74 years.
A total of 424 new clinical fractures occurred during follow-up. The rate was 8.6% with zoledronic acid and 13.9% with placebo. Zoledronic acid thus significantly reduced the relative risk of a new clinical fracture by 35%, said Dr. Lyles of Duke University Medical Center, Durham, N.C., and his associates.
A total of 242 subjects died during follow-up. Mortality was 9.6% with zoledronic acid and 13.3% with placebo, for a significant 28% reduction in relative risk.
Bone mineral density at the hip increased 2.6% at 1 year, 4.7% at 2 years, and 5.5% at 3 years in the group receiving zoledronic acid. In contrast, it declined in the placebo group 1.0%, 0.7%, and 0.9%, respectively.
Similarly, bone mineral density at the femoral neck increased 0.8%, 2.2%, and 3.6% in the zoledronic acid group, while it declined in the placebo group 1.0%, 0.7%, and 0.9%. All of these differences were significant, the investigators said (N. Engl. J. Med. 2007 Sept. 17 [Epub doi:10.1056/NEJMoa074941]).
The rates of overall adverse events and serious adverse events were similar in the two groups. There were no differences in the frequencies of cardiovascular adverse effects nor in rates of renal toxic effects, even though the incidence of mild to moderate kidney disease was high at baseline.
There were no cases of osteonecrosis of the jaw, which previous research has suggested might be associated with zoledronic acid. Similarly, despite some concern that the drug might impair fracture healing, there was no evidence of delayed union of fractured bone in those who took it.
In their editorial comment, Dr. Calis and Dr. Pucino, both of the National Institutes of Health, Bethesda, Md., termed the study results “powerful and compelling.”
“The reduction in fracture incidence and death was striking and clearly establishes the need for pharmacologic intervention in patients who fracture a hip,” they noted (N. Engl. J. Med. 2007 Sept. 17 [Epub10.10565/NEJMe078192]).
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