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Patients who had undergone surgical repair of hip fracture after a minor fall and who were then given an annual intravenous infusion of zoledronic acid were less likely to have a new vertebral fracture, to have a new non-vertebral fracture, or to die, a new study has found.
The international, double blind, placebo controlled study was released early by the New England Journal of Medicine (doi: 10.1056/NEJMoa074941). The trial was sponsored by Novartis, the manufacturer of the drug, which is marketed as Reclast in the United States and Aclasta in the United Kingdom.
Just over a third of patients aged over 50 who have had a hip fracture are likely to die within two years, write the authors of an accompanying editorial (doi: 10.1056/NEJMe078192), and many who survive “do not regain their prefracture level of mobility and thereby endure loss of independence and deterioration in health-related quality of life.” Such patients are also at higher risk of having a new hip fracture or other fracture.
All patients in the study, which was headquartered at Duke University Medical Center in Durham, North Carolina, were able to walk before their hip fracture, and only 42% had osteoporosis diagnosed by dual energy, x ray absorptiometry.
The study compared 1065 patients who received 5 mg of zoledronic acid and 1062 patients who received placebo within 90 days of surgical repair of their hip fracture. Patients received another infusion once a year afterwards. Both groups of patients received supplemental vitamin D and calcium. Some patients—9.3% in the zoledronic acid group and 11.8% in the placebo group—received concomitant treatment such as nasal calcitonin, selective oestrogen receptor modulators, hormone replacement, tibolone, and external hip protectors.
The average age of the patients was 74.5 years, their average body mass index was about 25, and about three quarters of the patients in each group were women. The median follow-up period was 1.9 years, and 71.3% of the patients completed the trial.
The percentage of patients who had a new clinical fracture was 8.6% in the zoledronic acid and 13.9% in the placebo group (hazard ratio 0.65 (95% confidence interval 0.5 to 0.84); P=0.001). Among the patients who had a new clinical fracture, the time to fracture was 39.8 months in the zoledronic acid group and 36.4 months in the placebo group.
New hip fractures occurred in 2% of the patients receiving zoledronic acid and 3.5% of those on placebo, a non-significant reduction in risk. But new vertebral fractures occurred in 1.7% of the patients taking zoledronic acid and 3.8% of the patients taking placebo (hazard ratio 0.54 (0.32 to 0.92); P=0.02), and new non-vertebral fractures occurred in 7.6% and 10.7%, respectively, of the patients (hazard ratio 0.73 (0.55 to 0.98); P=0.03).
“We observed a relative reduction of 28% in the risk of death in the zoledronic acid group,” the authors wrote, adding that this may be partly due to the lesser risk of new fractures in this group. Of the 2111 patients included in the study (16 patients did not receive the drug or placebo), 242 died (12%). In the zoledronic acid group, 101 of 1054 patients died (9.6%), whereas in the placebo group 141 of 1057 patients died (13.3%) (hazard ratio 0.72 (0.56 to 0.93); P=0.01).
No cases were reported of osteonecrosis of the jaw, which has been seen after treatment with some other bisphosphonates.
The authors of the editorial, Karim Anton Calis and Frank Pucino, from the National Institutes of Health and the United States Pharmacopeia, noted concern over sponsorship by Novartis of the study and over its placebo controlled design. Nevertheless, they say, “No other controlled clinical trial has previously shown efficacy of any osteoporosis medication for reducing the recurrence of fracture in patients who already had broken a hip.”