TORONTO – Patients who continued annual treatment with zoledronic acid for 6 years had significantly better bone mineral density and fewer morphometric vertebral fractures than did patients who received 3 years of treatment and then stopped, in a controlled study with more than 1,200 patients.
Dennis M. Black, Ph.D
Six continuous years of annual zoledronic acid treatment also proved safe, making continued treatment with this bisphosphonate formulation an option for patients who might benefit, Dennis M. Black, Ph.D., said at the annual meeting of the American Society for Bone and Mineral Research.
“After 3 years, it might be beneficial for some women, particularly those at high vertebral fracture risk, to continue zoledronic acid for an additional 3 years,” said Dr. Black, professor of epidemiology and biostatistics at the University of California, San Francisco. “These new findings show that continued treatment with zoledronic acid for 6 years continues to maintain bone mass and reduced vertebral fracture risk with no change to its favorable safety profile compared with discontinuation of treatment after 3 years,” he said in a written statement.
On the other hand, the decision to continue bisphosphonate treatment long term must be individualized, he said. It may be possible to identify women who would benefit from a drug holiday.
With the new finding, zoledronic acid joins other bisphosphonates, such as alendronate, shown to prevent loss of bone density when the drug is continued after several years of treatment. In a prior report, continuing treatment with alendronate for 5 years following an initial 5 years of treatment led to less bone density loss than in patients who switched from alendronate to placebo (JAMA 2006;296:2927-38). The same alendronate study failed to show that continued bisphosphonate treatment led to a reduced rate of morphometric vertebral fractures, compared with stopping alendronate.
The new zoledronic acid findings came from an extension of the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial, which compared a single, annual infusion of zoledronic acid with placebo in postmenopausal women with osteoporosis during 3 years of treatment (N. Engl. J. Med. 2007;356:1809-22).
Dr. Black and his associates randomized 1,233 women who completed the zoledronic acid arm of the study to either continue with another 3 years of annual infusions of 5 mg zoledronic acid or switch to placebo. Their average age was 76, and about 55% had a femoral neck T score of less than –2.5.
At the end of the study, the percent change in femoral neck bone mineral density, compared with the level at entry into the study, averaged 1% higher in patients treated with zoledronic acid, a statistically significant difference in the study’s primary end point. Femoral neck bone mineral density in the zoledronic acid–treated patients increased by an average of 1.4% over their baseline 6 years earlier (when they started on the drug), compared with those who switched off the bisphosphonate after 3 years, also a statistically significant difference.
The rate of morphometric vertebral fractures during the 3 years of the new study totaled 6% in the patients on placebo and 3% in those on zoledronic acid, a statistically significant difference. The two treatment arms showed no significant difference in their rates of nonvertebral fractures. Continued zoledronic acid treatment also led to reduced blood levels of a marker of bone turnover compared with the patients who received placebo injections.
Six years of annual zoledronic acid treatment appeared safe, with no excess of adverse events or serious adverse events compared with the patients on 3 years of placebo. The researchers looked especially closely at cardiovascular events; the only significant, between-treatment difference was in new hypertensive adverse events, which occurred significantly more often in the patients who received placebo for 3 years.
The HORIZON Pivotal Fracture Trial was funded by Novartis, which markets zoledronic acid (Aclasta). Dr. Black said that he has served as a consultant and done teaching for Amgen Inc. and Nycomed, and that he has received research contracts from Amgen, Merck & Co., Novartis, and Roche/Genentech.