Zoledronic Acid Significantly Reduces Recurrent Hip Fractures, Deaths in Osteoporosis

September 19, 2007 (Honolulu) — A 15-minute annual intravenous infusion of the bisphosphonate zoledronic acid (Reclast; Novartis Pharmaceuticals Corp, East Hanover, New Jersey), if given within 90 days of a hip fracture in older patients, reduces the risk for a second fracture by 35% and reduces the risk for death by 28%.
Those are the findings of the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Recurrent Fracture Trial (HORIZON-RFT), presented here during the 29th Annual Meeting of the American Society for Bone and Mineral Research (ASBMR).
Principal investigator Kenneth W. Lyles, MD, of the Department of Endocrinology and Professor of Medicine at Duke University in Durham, North Carolina, presented the 2-year results of HORIZON-RFT, an ongoing trial involving 2111 patients with hip fractures who were at least 50 years old at baseline.
Median age was 76 years (range, 50 - 98 years), and 76% were women. All patients received a loading dose of vitamin D2 or D3 at 800 to 1200 IU and elemental calcium at 1000 to 1500 mg. Two weeks later, they were randomized to zoledronic acid 5 mg intravenously once a year or placebo.
"The hip fractures in these patients were, by definition, osteoporotic, because they occurred as a result of falls from a standing height or less... that meets the definition of an osteoporotic fracture," Dr. Lyles commented in an interview with Medscape during the meeting. "We also found that about 45% of our population had a history of previous clinical fractures."
At 2 years, 92 (8.59%) of the 1054 patients randomized to zoledronic acid and 139 (13.88%) of the 1057 patients randomized to placebo had had clinical fractures.
The relative risk reduction for recurrent fractures was 35% (hazard ratio [HR], 0.65; confidence interval [CI], 0.50 - 0.84; P = .002) with active treatment.
The risk for vertebral fractures was reduced by 46% (HR, 0.54; CI, 0.32 - 0.92; P = .0210) and risk for nonvertebral fractures by 27% (HR, 0.73; CI, 0.55 - 0.98; P = .0338) with zoledronic acid.
The risk for hip fractures was reduced by 30% (HR, 0.70; CI, 0.55 - 0.98; P = .1815) with active treatment vs placebo.
There were no serious or significant adverse events in either treatment group, and there were no differences between the groups in the incidence of adverse cardiovascular events or adverse long-term effects on renal function.
There were 101 (9.58%) deaths in the zoledronic acid group vs 141 (13.34%) deaths in the placebo group, for a 28% reduction in the risk for mortality (HR, 0.72; CI, 0.56 - 0.93; P = .0117).
"These data show that we can go beyond cutting the risks of future fractures to reducing the death rate after these disabling fractures.... These data absolutely indicate that treatment is needed after an osteoporotic fracture," Dr. Lyles asserted.
However, even if patients are prescribed a bisphosphonate, only approximately 40% to 60% are still taking them after 1 year, Dr. Lyles pointed out.
Compliance can be a significant problem, Steven R. Goldring, MD, professor of medicine at Harvard Medical School in Boston, Massachusetts, and president of ASBMR, told Medscape.
"This therapy, that relies on intravenous administration, has the potential advantage of insuring compliance in patients who otherwise might not take oral equivalents regularly. It also requires only a single yearly treatment," Dr. Goldring said.
"This is the same problem as with blood pressure medication or any other treatment. People just don't want to take pills," Dr. Lyles commented. An annual 15-minute infusion "gets around the compliance issue," he said.
There is a caveat with zoledronic acid treatment, the principal investigator of HORIZON-RFT cautioned. "We want to make sure people have plenty of vitamin D around. You don't want to give [zoledronic acid] if the patient is vitamin D deficient or has a low calcium level."
The results of the study were released online in the September 17 Online First issue of the New England Journal of Medicine to coincide with Dr. Lyles' presentation at ASBMR.
Dr. Lyles has received funding from Novartis, Procter and Gamble, Sanofi-Aventis, and Amgen and is a coinventor with Novartis Pharmaceuticals on the use of a US patent for zoledronic acid. The complete list of disclosures is available in the original article.
29th Annual Meeting of the ASBMR: Concurrent Oral Session 10, 1055. Presented September 17, 2007.
N Engl J Med. Published online September 17, 2007.