Once-a-Year IV Drug Scores for Postmenopausal Osteoporosis

SAN FRANCISCO, May 2 -- A successful once-a-year drug to treat postmenopausal osteoporosis, even though administered by an IV infusion, may be welcomed by women who dislike a weekly or monthly pill, researchers here reported.

The once-yearly infusion of zoledronic acid (Reclast) reduced the risk of vetebral, hip, and other fractures in postmenopausal women with osteoporosis, Dennis M. Black, Ph.D., of the University of California here, and colleagues, reported in the May 3 issue of the New England Journal of Medicine.

In a randomized, double-blind, placebo-controlled trial of 7,765 women (mean age 73), at three years, vertebral fractures in patients treated with a yearly zoledronic-acid infusion were reduced by 70%, hip fractures were down 41%, and nonvertebral fractures decreased 25%, the investigators said.

Over a three year period, a single yearly infusion of zoledronic acid equaled, even outdid, reported results for weekly or monthly oral drugs, Dr. Black said.

Two oral bisphosphonates, alendronate (Fosamax) and risedronate (Actonel). have been effective, he said. However, Dr. Black added, the pills must be taken with a full glass of water when the patient is fasting, and the patient must remain upright for at least 30 minutes. After a year, many patients who take oral medications stop treatment, and most appear to be taking less than 80% of their prescribed pills by 12 months.

The findings for zoledronic acid, given FDA approval in April, came from a multicenter international trial, known as the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) pivotal fracture trial.

The trial included 3,889 patients with evidence of osteoporosis who were randomly assigned to a single 15-minute infusion of zoledronic acid (5 mg), while 3,876 patients were randomized to placebo treatment. All patients received daily oral calcium (1,000 to 1,500 mg) and vitamin D (400 to 1,200 IU).

The patients were monitored for 36 months with quarterly telephone interviews and clinic visits at six, 12, 24, and 36 months, the researchers said.

Zoledronic acid treatment reduced the risk of morphometric vertebral fractures by 70% over three years. compared with placebo (3.3% in the zoledronic-acid group versus 10.9% in the placebo group; relative risk 0.30, 95% confidence interval, 0.24 to 0.38).

The risk of hip fracture was reduced by 41% (1.4% in the zoledronic group versus 2.5% in the placebo group; hazard ratio, 0.59; CI, 0.42 to 0.83).

Nonverterbral fractures, clinical fractures, and clinical vertebral fractures were reduced by 25%, 33%, and 77%, respectively (P

An increased risk of serious arrhythmia had not been previously associated with zoledronic acid or other bisphosphonates, the researchers wrote. The observed association might have been due to chance but should be further explored in other trials of zoledronic acid and reanalyses of data from other bisphosphonate trials, the researchers said.

There were no differences in the occurrence of other serious events, such as stroke, or death due to stroke, the researchers reported.

Also, there was a small increase in inflammatory ocular events within the first 15 days after infusion, as reported with other bisphosphonates. All such events were treated and resolved with outpatient treatment.

During the three-year period., the 70% reduction in the vertebral fracture rate was greater than the three-year reductions previously observed for oral bisphosphonates of 40% to 50%, and the reduction in fracture rates with other antiresorptive agents, the researchers said. In addition all other fracture categories, including nonvertebral and clinical vertebral fractures, were significantly reduced.

"Given the relatively poor adherence to oral bisphonate therapy in clinical practice, annual infusion of zoledronic acid may provide a promising approach to reducing fracture risk," the researchers concluded.

In an accompanying editorial, Juliet Compston, M.D., F.R.C.P., of Cambridge University in England wrote that in clinical practice, the choice of oral or intravenous treatment will depend on a number of factors, including patient preference.

The efficacy data from the HORIZON study are impressive, she wrote. Although direct comparisons with other treatments cannot be made in the absence of head-to-head studies, the magnitude of the effect appears to be at least similar to and possibly better than (in the case of vertebral fractures) that reported for other interventions.

Although the once-yearly regimen for zoledronic acid is likely to be attractive to some women, the need for intravenous infusion may deter others. In the growing population of very elderly women with osteoporosis, oral bisphosphonates are unsuitable for a substantial minority and zoledronic acid may provide a potential alternative for these women, she said.

Despite the availability of effective treatments for osteoporosis, poor adherence to drug regimens presents a major challenge to health professionals. Even a single infusion of zoledronic acid appears to protect for at least a year, Dr. Compston said. However, the practicality and acceptability of annual IV therapy in large numbers of women remains to be tested.

Nevertheless, she said, "increased treatment choices for patients are to be welcomed and may provide one means of improving adherence and treatment outcomes in osteoporosis."

Dr. Compston, the editorialist, reported serving on advisory boards for Procter & Gamble, Servier, Nycomed, Shire, and Crescent Diagnostics; receiving speaking fees from Procter & Gamble, Nycomed, Servier, Shire, and Eli Lilly; serving on data and safety monitoring boards for Novartis and Amgen, receiving research grants from Procter & Gamble and Servier; and having served as an expert witness in medicolegal and patent disputes related to alendronate.