Once-Yearly Zoledronic Acid for Treatment of Postmenopausal Osteoporosis

Abstract

Although bisphosphonates do inhibit bone resorption in postmenopausal women and lessen the risk of vertebral and hip fractures, as many as half of patients no longer adhere to prescribed oral treatment after 12 months. A single intravenous infusion of zoledronic acid reportedly decreases bone turnover and improves bone mineral density (BMD) for at least a year. In the HORIZON (Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly) Pivotal Fracture Trial, an international, randomized, double-blind, placebo-controlled study, postmenopausal women ranging in age from 65 to 89 years were assigned to receive either a 15-minute IV infusion of 5 mg of zoledronic acid or placebo at yearly intervals up to 24 months. All women received a daily supplement of 1000-1500 mg of calcium and 400-1200 IU of vitamin D. Participants had a bone mineral density (BMD) T score of -2.5 or less at the femoral neck or a score of -1.5 or less with 1 or more vertebral fractures. The efficacy analysis included 7736 patients, and the safety analysis, 7714 patients. The 3-year incidence of vertebral fracture was 10.9% in the placebo group and 3.3% in women given zoledronic acid, a 70% reduction (relative risk, 0.30; 95% confidence interval [CI], 0.24-0.38). Similar effects were noted after 1 and 2 years. Hip fractures were reduced 41% in actively treated women (hazard ratio, 0.59; 95% CI, 0.42-0.83). Nonvertebral fractures, all clinical fractures, and clinical vertebral fractures all were significantly less frequent in women given zoledronic acid-by 25%, 33%, and 77%, respectively. Actively treated women lost significantly less height than placebo recipients (-4.2 mm vs. -7.0 mm). BMD rose significantly at all measurement sites in the active treatment group compared to placebo recipients. Biochemical markers of bone turnover-including serum C-telopeptide of type I collagen, bone-specific alkaline phosphatase, and N-terminal propeptide of type I collagen-all decreased significantly with active treatment. Postdose symptoms were more frequent in actively treated women, but there were no significant group differences in numbers of deaths. Renal function was not compromised by zoledronic acid therapy. Serious atrial fibrillation was more frequent in actively treated women than in placebo patients (1.3% vs. 0.5%), as was the prevalence of inflammatory ocular disorders, mainly conjunctivitis. One patient in each group had potential osteonecrosis of the jaw. In this large-scale trial, once-a-year infusion of zoledronic acid was associated with a sustained decrease in vertebral, hip, and other fractures in postmenopausal women with osteoporosis over a 3-year period. Treatment was generally well tolerated and had a favorable safety profile.