SAN FRANCISCO, California— A single intravenous 5-mg dose of zoledronic acid (Reclast®, Novartis Pharmaceuticals Corp), given once yearly, can significantly reduce the risk of vertebral, hip, and other fractures in postmenopausal women with osteoporosis, according to results from the 3-year HORIZON-Pivotal Fracture Trial (HORIZON-PFT) that appear in the May 3, 2007, issue of the New England Journal of Medicine.¹ Zoledronic acid also improved bone mineral density (BMD) and bone metabolism markers, but the new agent's greatest advantage may be convenience.

"The unique delivery system and unique regimen will have important public health implications," study coauthor Felicia Cosman, MD, clinical director of the National Osteoporosis Foundation, in Washington, DC, and medical director of the Clinical Research Center at Helen Hayes Hospital, in West Haverstraw, New York, told CIAOMed. Zoledronic acid is an intravenous aminobisphosphonate that impairs the key metabolic pathways of mature osteoclasts and possibly stabilizes bone against resorption.

While  biophosphonates are effective in reducing the risk of fractures, they are associated with relatively poor adherence. "I think we will be able to bypass some of the issues with compliance and persistence with other osteoporosis medications with zoledronic acid," Dr. Cosman said. "Just by showing up [at] a doctor's office, you can get a treatment once a year that can be extremely effective at reducing risk of fracture and preventing osteoporosis fractures. It's so easy and so infrequent that I think we will get more people to stay on the program, and that will allow the dramatic effects we see in studies to translate into real world effectiveness," she said.

Just how dramatic is the effect?

Over the 3-year study period, the risk of new vertebral fractures was reduced from 10.9 with placebo to 3.3 in the zoledronic acid group, a reduction of about 70% (P <.001). Hip fractures were reduced by 41% (P <.001), clinical vertebral fractures by 77% (P <.001), nonvertebral fractures by 25%, and clinical fractures by 33%.

Total hip BMD was increased by 6.02% with zoledronic acid as compared to placebo. The mean value of serum β-CTX, a marker of bone turnover, dropped within the first 6 months of treatment and remained in the premenopausal range. BSAP, a marker of bone formation, also decreased within 6 months and remained low throughout the 3-year study.

The 70% reduction in vertebral fractures is greater than what has been observed with oral bisphosphonates. "The fact that we haven't been able to see the same benefits with other medication is because patients haven't been able to stay on them because of side effects, and they are not so easy to take," Dr. Cosman said.

Safety profile is also favorable

There were no significant differences in serious adverse events between the treatment versus placebo groups. Zoledronic acid had no cumulative effect on renal function. Some patients had increases in serum creatinine levels, but these were transient, and the patients resumed treatment. The medication does not appear to increase the risk of jaw osteonecrosis, the researchers note.

Zoledronic acid was, however, associated with an increased incidence of serious atrial fibrillation (50 cases vs 20 cases in the placebo group).

"We are still looking at this," Dr. Cosman said. "We haven't seen it in other clinical trials with zoledronic acid, and we haven't seen it with postmarketing experience. Investigators plan to continue  to see if there is a real signal, she added. "We have to be able to define risks if there are any, but it's just such a highly effective drug and in general it's very safe and very well tolerated."

New drug also may benefit hospitalized hip fracture patients

Juliet Compston, MD, FRCP, of the University of Cambridge School of Clinical Medicine and Addenbrooke's National Health Service Trust, in Cambridge, United Kingdom, points out in an accompanying editorial² that "although a direct comparison with other treatments cannot be made in the absence of head-to-head studies of fracture outcome, the magnitude of effect appears to be at least similar to and possibly better than (in the case of vertebral fractures) that reported for other interventions."

There is a definite niche for this drug, she writes. "Intravenous zoledronic acid may be particularly appropriate in women who get admitted to the hospital with a fracture (especially a hip fracture) for whom the first infusion could be given during their hospital stay, " she writes. "Intravenous administration ensures the treatment is correctly delivered and avoids the stringent administration instructions required for oral bisphosphonates."

References

1. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809-1822.
2. Compston J. Treatments for osteoporosis—looking beyond the HORIZON. N Engl J Med.2007;356:1878-1879.