OSTEOPOROSIS

Annual infusion of zoledronic acid reduces risk of fracture

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.

Lyles KW, Colon-Emeris C, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357. DOI: 10.1056/NEJMoa074941.

Zoledronic acid (Zometa) is indicated for the treatment of high levels of serum calcium associated with Paget’s disease and various malignancies (multiple myeloma, breast, prostate, and lung). These two studies explore use of this agent to prevent fracture in postmenopausal women with osteoporosis—a use for which it proved effective. Other benefits may include improved compliance and ease of administration in some women.

Black and colleagues conducted their randomized, double-blind, placebo-controlled trial to assess the effect of annual infusion of zoledronic acid on the risk of fracture over a 3-year period. A total of 3,889 postmenopausal women with osteoporosis (mean age, 73 years; range, 65–89 years) were assigned to receive a single 15-minute, 5-mg infusion of the drug at baseline, 12 months, and 24 months, and a total of 3,876 women received placebo. Approximately half the women were from Europe, and the other half were from North and South America and Asia. All women received oral daily calcium (1,000–1,500 mg) and vitamin D (400–1,200 U), and all were monitored for 36 months.

The risk of vertebral fracture was reduced in the treatment group by 70% over 3 years, compared with the placebo group (3.3% or 92 women in the treatment group versus 10.9% or 310 women receiving placebo). The risk of hip fracture was reduced by 41% in the treatment group (1.4% or 52 women receiving zoledronic acid versus 2.5% or 88 women in the placebo group). (For all comparisons, P<.001.)

The most common postdose symptoms, seen within 3 days of infusion, included fever, flu-like symptoms, myalgia, headache, and arthralgias. There were more serious adverse events related to atrial fibrillation in the women receiving zoledronic acid (50 women receiving zoledronic acid versus 20 in the placebo group; P<.001).

Treatment is a valuable option for carefully selected populations

The trial by Black and colleagues holds great promise for some patients, especially those who have (or appear to have) upper gastrointestinal intolerance of oral bisphosphonates or who may have difficulty adhering to the positional requirements (i.e., remaining upright) of oral therapy. This may be especially true of patients in nursing homes. Once-yearly intravenous (IV) infusion may also make compliance easier for these patients.

One important detail of this trial: Of almost 8,000 women studied, the youngest was age 65. The implication: Don’t automatically assume this regimen is an appropriate alternative for younger osteopenic women who perceive themselves to have acid reflux.

Women at extremely high risk of fracture also benefit

Fracture is most likely to occur in women who have already experienced it (FIGURE 1). Lyles and colleagues chose this population for their study of once-yearly infusion of zoledronic acid. The study involved 2,127 patients within 90 days after repair of low-trauma hip fracture. Subjects were randomized to receive 5-mg IV zoledronic acid annually or placebo in a blinded fashion. All patients also received vitamin D and calcium supplements. Mean age was 74.5 years, as might be expected in a hip-fracture cohort, and median follow-up was 1.9 years.

New clinical fractures occurred in 8.6% of women in the zoledronic acid group and 13.9% of the placebo group—a 35% risk reduction with IV zoledronic acid (P=.001). Deaths occurred in 101 of 1,054 patients (9.6%) in the zoledronic acid group and 141 of 1,057 patients (13.3%) in the placebo group. This was a reduction of 28% in death from any cause in the zoledronic acid group (P=.01).

The most frequent adverse events in patients receiving zoledronic acid were pyrexia, myalgia, and bone and musculoskeletal pain. No cases of osteonecrosis of the jaw were reported. Rates of atrial fibrillation and stroke were similar in both the zoledronic acid and placebo groups.

This study provides further evidence that, for extremely high-risk women (those who have already suffered hip fracture), yearly zoledronic acid may be an extremely useful tool, especially for elderly women, in whom compliance with any medication—weekly or monthly—may be difficult.

FIGURE 1 Once a fracture occurs, another is likely

Although the risk of new fractures is heightened in women who have already experienced one, Lyles and colleagues found a 35% risk reduction with zoledronic acid.

Parathyroid hormone reduces vertebral fractures in osteoporotic women