Once-yearly zoledronate-an effective preventative therapy for new fractures after hip fracture

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Abstract

BACKGROUND

Secondary osteoporotic fracture and increased mortality are common after hip fracture.

OBJECTIVE

To evaluate the efficacy and safety of once-yearly zoledronate for the prevention of new fractures after hip fracture.

DESIGN AND INTERVENTION

The Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Recurrent Fracture trial was an international, multicenter, randomized, double-blind, placebo-controlled trial of men and women aged ≥50 years who had sustained a low-trauma hip fracture and who were unwilling or unable to take an oral bisphosphonate. Eligible participants were enrolled within 90 days after surgical repair of the hip fracture and randomly allocated to receive either zoledronate or placebo. A loading dose of vitamin D was given 14 days before the first infusion of study medication. A once-yearly 5 mg intravenous dose of zoledronate or placebo was infused over a 15 min period. Concomitant therapy with nasal calcitonin, hormone replacement, selective estrogen-receptor modulators, tibolone, or external hip protectors was permitted. In addition, all patients received daily calcium and vitamin D supplementation. Study visits were every 12 months and included measurement of BMD by dual-energy X-ray absorptiometry and fracture assessment by radiography.

OUTCOME MEASURES

The primary outcome measure was the incidence of new fractures. Secondary outcome measures included change in BMD and the incidence and severity of adverse events.

RESULTS

The study enrolled a total of 2,127 patients (mean age 74.5 years), 1,065 of whom received zoledronate. The median follow-up was 1.9 years and 71.3% of the participants completed the trial. A total of 424 new fractures occurred in 231 patients. The fracture rate was 8.6% in the zoledronate group and 13.9% in the placebo group (relative risk reduction 35%, P = 0.001). The mean time to fracture was 39.8 and 36.4 months in the zoledronate and placebo groups, respectively. The rate of new vertebral fracture was 1.7% with zoledronate and 3.8% with placebo (P = 0.02). Similarly, the rate of new nonvertebral fracture was 7.6% with zoledronate and 10.7% with placebo (P = 0.03). By contrast, however, new hip fracture rates were not significantly different. BMD at the total hip and femoral neck increased in the zoledronate group, but declined at both sites in the placebo group (P >0.001 for both comparisons). A total of 101 patients in the zoledronate group and 141 in the placebo group died during follow- up (9.6% versus 13.3%, hazard ratio 0.72; P = 0.01). Total and serious adverse events were similar in the two groups; however, patients in the zoledronate group were more likely to experience pyrexia, myalgia, bone pain, and musculoskeletal pain.

CONCLUSION

A once-yearly infusion of zoledronate after hip fracture was associated with a reduced rate of new fractures and improved patient survival.

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