Three-year results of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial show that a single, annual intravenous infusion of zoledronic acid can decrease risk of vertebral fracture by 70% and the risk of hip fracture by 41% among women with osteoporosis.
A single, annual intravenous (IV) infusion of zoledronic acid can decrease the risk of vertebral fracture by 70% and the risk of hip fracture by 41% among women with osteoporosis, according to the 3-year results of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial. The results were published in the New England Journal of Medicine (NEJM).
The HORIZON trial included 7,765 postmenopausal women aged 65 to 89 years with bone mineral density (BMD) T scores of –2.5 or lower at the femoral neck, with or without evidence of existing vertebral fracture, or a T score of –1.5 or lower, with evidence of ≥2 mild or ≥1 moderate vertebral fractures. Patients who previously received a bisphosphonate were eligible for the study after completing a washout period, the length of which was dependent on the length of bisphosphonate use. Concomitant use of hormone therapy, raloxifine, calcitonin, tibolone, tamoxifen, dehydroepiandrosterone, ipriflavone, and medroxyprogesterone was permitted throughout the study.
The use of zoledronic acid was associated with a 70% reduction in the risk of morphometric vertebral fracture (incidence, 3.3%) compared with placebo (incidence, 10.9%) during the 3-year period (RR=0.30; 95% CI, 0.24–0.38). The rate of hip fracture was 41% lower among patients receiving zoledronic acid (incidence, 1.4%) compared with patients receiving placebo (incidence, 2.5%; HR=0.59; 95% CI, 0.42–0.83). The incidence of nonvertebral fractures, all clinical fractures, and clinical vertebral fractures was reduced by 25%, 33%, and 77%, respectively, among patients receiving zoledronic acid compared with patients receiving placebo (P<.001 for all comparisons).
The incidence of adverse events, including changes in liver function, were similar between the 2 groups; however, the incidence of arrhythmia was greater among patients who received zoledronic acid (6.9%) compared with patients who received placebo (5.3%; P=.003). A greater number of patients in the zoledronic acid group experienced serious atrial fibrillation (AF) (n=50) compared with those in the placebo group (n=20; P<.001). The authors stated that among the 50 patients receiving zoledronic acid who experienced AF, 47 patients experienced the event >30 days after infusion "by which time zoledronic acid is undetectable in the circulation." The authors stated that there is no recognized mechanism linking bisphosphonates to arrhythmia or AF and suggested further study of the increased incidence of arrhythmia.
Two cases of osteonecrosis of the jaw were identified (1 in the placebo group and 1 in the zoledronic acid group); both were resolved with therapy.
The authors concluded that annual infusions of zoledronic acid significantly decrease fracture risk beyond the reported 40% to 50% demonstrated with oral bisphosphonate treatment and should be considered as a promising approach, especially in light of the relatively poor adherence to oral bisphos-
phonate regimens; approximately 50% of patients do not adhere to oral treatment regimens after 1 year.
In an accompanying editorial, Juliet Compston, MD, FRCP, stated that the HORIZON trial efficacy data are "impressive" and that the magnitude of effect of once-yearly, IV zoledronic acid is at least as effective as that demonstrated with other available treatments. Dr Compston stated that the increased incidence of arrhythmia "is a potential concern, and a causal relationship must be given serious consideration."
Black DM, Delmas PD, Eastell R, et al; for the HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809–1822.
Compston J. Treatments for osteoporosis-Looking beyond the HORIZON [editorial]. N Engl J Med. 2007;356:1878–1880.