The Food and Drug Administration has approved dosing the osteoporosis drug zoledronic acid (Reclast) once every 2 years for the prevention of bone loss in postmenopausal women, making it the first bisphosphonate in its class to get the nod for a 2-year indication.
The approval is based on results of the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly (HORIZON) prevention trial in which a single infusion of the zoledronic acid agent significantly increased bone mass relative to placebo at 2 years in postmenopausal women with osteopenia, according to a statement by the drug manufacturer, Novartis Pharmaceuticals Corp.
The 2-year double-blind, placebo-controlled study was presented in April at an international symposium sponsored by the National Osteoporosis Foundation in Washington by Dr. Chris Recknor.
HORIZON comprised 581 women aged 45 years and older with low bone mineral density (T scores of −1 to −2.5) who were randomized to receive one of three regimens: 5 mg zoledronic acid at study onset and at 1 year; 5 mg zoledronic acid at study onset and placebo at 1 year; or placebo at study onset and at 1 year. The subjects' mean age was 60 years. Most (93%) were white.
The study's main outcomes were 24-month changes in bone mineral density (BMD) at the lumbar spine, trochanter, femoral neck, distal radius, and total hip. The secondary end points were changes in markers of bone turnover.
Both of the Reclast treatment groups showed significantly increased BMD, compared with placebo. At 24 months (1 year after the second infusion), both active groups showed similar BMD increases at all sites that were significantly different from BMD changes with placebo (see chart), reported Dr. Recknor, who is an internist specializing in osteoporosis in Gainesville, Ga.
Specifically, treatment with a single zoledronic acid infusion increased spine BMD by 6.3% among women in the early menopause group (within 5 years of menopause) and by 5.4% among those in the late menopause group, according Novartis's June 1 announcement of the new indication.
Both zoledronic acid regimens showed significant reductions in bone turnover markers compared with placebo. Markers in the double-infusion group were significantly lower than those in the single-infusion group.
Adverse events were most commonly observed in the first 3 days after the first infusion, when they were significantly more common in both active groups (60% vs. 25%). The most frequently reported were pain, fever, chills, myalgia, nausea, and headache. Adverse events were significantly lower after the second infusion, occurring in 18% of the double-infusion group, 11% of the single-infusion group, and 12% of the placebo group, Dr. Recknor reported.
Already approved as a once-yearly infusion for the treatment of women with postmenopausal osteoporosis and men with osteoporosis, as well as for the treatment of Paget disease of bone and the prevention and treatment of glucocorticoid-induced osteoporosis, Reclast is now the first and only approved single-dose, biyearly infusion for the prevention postmenopausal osteoporosis, according to the Novartis statement.
At the osteoporosis symposium in April, Dr. Recknor said in an interview using the drug prophylactically “allows clinicians a little more lead time in treating these patients, many of whom are at increased risk of a low-stress fracture.” Furthermore, the HORIZON results raise a tantalizing possibility. “You may be able to give this drug a couple of times to perimenopausal women and prevent the entire problem of bone loss.”
The less-frequent dosing is being touted as an advance by Dr. Mone Zaidi, director of the Mount Sinai Bone Program at Mount Sinai School of Medicine, New York, because of the convenience of biyearly treatment compared with daily, weekly, and monthly regimens.
“There were not many differences that were either statistically significant or clinically meaningful between the two treated groups in the [HORIZON] study. Once every 2 years is an excellent way to go forward, which would improve compliance in the early postmenopausal woman who rapidly loses bone,” he said in an interview after the Novartis's announcement of the new indication.
Another study presented at the osteoporosis symposium shed light on zoledronic acid's role in preventing bone loss in women who've already had a hip fracture.
A subanalysis of a second HORIZON study showed that zoledronic acid indeed benefits patients with a recent fracture—and particularly the very elderly and those with the poorest bone quality.
The HORIZON Recurrent Fracture Trial included 2,127 patients with a recent hip fracture who were randomized to an annual infusion of 5 mg zoledronic acid or placebo and followed for up to 5 years. HORIZON-RFT concluded that the drug reduced the rate of recurrent fracture by 35% (N. Engl. J. Med. 2007;357:1799–809).