Once-Yearly Bisphosphonate Infusion Slashes Fracture Rates


PHILADELPHIA — Once-yearly therapy with zoledronic acid has resulted in impressive reductions in fracture incidence at the three most common fracture sites in postmenopausal women with osteoporosis, according to phase III findings presented at the annual meeting of the American Society for Bone and Mineral Research.

An annual infusion of 5 mg of zoledronic acid (Reclast) reduced clinical vertebral fractures by 75%, hip fractures by 40%, and nonvertebral fractures by 25% at the end of 3 years, said Dennis Black, Ph.D., a professor of epidemiology at the University of California, San Francisco.

Zoledronic acid is currently FDA approved (under the name Zometa) for the treatment of patients with hypercalcemia of malignancy, multiple myeloma, and documented bone metastases from solid tumors. The company is working with the FDA to gain approval for the treatment of osteoporosis.

The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly (Horizon) Pivotal Fracture Trial was a randomized, double-blind, placebo-controlled trial involving 7,736 postmenopausal women with osteoporosis from 27 countries. The trial was funded by Novartis; Dr. Black disclosed a significant financial relationship with Novartis.

In the trial, women randomized to the treatment group received an annual infusion of zoledronic acid (5 mg). All women received calcium (1,000–1,500 mg/day) and vitamin D (400–1,200 IU/day).

Women were included in the trial if they were aged 65–89 years (mean age, 73 years) with either a femoral neck T score of −2.5 or less or prevalent vertebral fracture and a femoral neck T score of −1.5 or less.

Women were recruited into two groups based on their osteoporosis treatment history. A total of 6,084 women were not currently taking an osteoporosis drug and had minimal prior therapy; 1,652 women were currently taking a selective estrogen-receptor modulator, calcitonin, or hormone therapy for osteoporosis at baseline.

Primary end points included new morphologic vertebral fractures in women not currently taking an osteoporosis drug and hip fractures in both those undergoing and those not undergoing treatment at baseline. Secondary end points included nonvertebral fractures, change in bone mineral density (BMD) measured by dual-energy x-ray absorptiometry, changes in biochemical markers of bone metabolism, and changes in bone density and size determined by quantitative CT. Safety end points included evaluation of adverse events, assessment of bone histology by histomorphometry, and postdose monitoring for acute changes in renal laboratory values.

A total of 3,875 women were randomized to zoledronic acid (3,045 in stratum I and 830 in stratum II), while 3,861 were randomized to placebo (3,039 in stratum I and 822 in stratum II). Dr. Black presented data from the trial start-up to March 31, 2006 (the study was scheduled to end in June 2006). Mean follow-up was 2 years and 8 months. Retention was 84%.

Overall, 3.8% of women receiving treatment had morphometric vertebral fractures at 3 years, compared with 12.8% of women on placebo, representing a 70% reduction. During the first 2 years, there was a 71% reduction, and during the first year, there was a 60% reduction.

“There was a 40% reduction in the risk of hip fractures [at 3 years] that was also highly statistically significant,” Dr. Black said. Clinical vertebral fractures were reduced by 75% and nonvertebral fractures were reduced by 25% in treated women, compared with those on placebo. Lumbar spine BMD was increased by 7% and total hip BMD was increased by 6% in treated women, compared with those on placebo.

In addition, bone markers were measured in a subsample of 605 women (300 on zoledronic acid and 305 on placebo). There was a decline in beta C-telopeptide of type 1 collagen (β-CTX), a bone resorption marker, following the first infusion. “The values remain relatively constant over the 36 months of the study,” Dr. Black said.

The mean β-CTX values for women on zoledronic acid remained within the premenopausal reference range. There was no progressive decline in β-CTX levels over 3 years.

Additional sampling was performed just after the third infusion at 24 months to determine in more detail how β-CTX levels responded to zoledronic acid infusion. “There is an immediate decline in β-CTX values within 10 days after the infusion. But then the levels begin to increase fairly linearly over the course of that third year,” Dr. Black said.

Likewise, there was a decline in bone-specific alkaline phosphatase values following the first infusion of zoledronic acid, but the values remained fairly constant with no progressive decline following subsequent infusions. These values were also within the reference range for premenopausal women.

There were no differences between the treatment and placebo groups in terms of any adverse event, serious adverse events, or discontinuations due to adverse events.


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