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Zoledronic acid once yearly slows osteopenia loss: benefit seen in elderly after hip fracture.

WASHINGTON -- A single yearly infusion of zoledronic acid appears to prevent further bone loss in postmenopausal women with osteopenia and in women who have already had a hip fracture, two randomized controlled trials have concluded.

This is the first time the drug has been shown to be an effective preventive agent in treating osteopenic patients, said Dr. Chris Recknor, who presented the data in a poster session at an international symposium sponsored by the National Osteoporosis Foundation.

The 2-year Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly (HORIZON) prevention study cohort comprised 531 postmenopausal women with low bone mineral density (T scores of -1 to -2.5). They were randomized to one of three treatment regimens: two placebo infusions, given 12 months apart; two infusions of zoledronic acid 5 mg, given 12 months apart; or one infusion of 5 mg zoledronic acid, followed 12 months later by a placebo infusion.

The subjects' mean age was 60 years. Most (93%) were white. The study's main out comes 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, said Dr. Recknor, an internist specializing in the treatment of osteoporosis in Gainesville, Ga.

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.)

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.

The study raises a tantalizing possibility, Dr. Recknor said in an interview. "You may be able to give this drug a couple of times to perirnenopausal women and prevent the entire problem of bone loss."

A subanalysis of a second HORIZON study has shown that zoledronic acid also benefits patients who have had a hip fracture--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).

The subanalysis examined response rates within specific patient groups, said Denise Orwig, Ph.D., who presented the trial data during a poster session at the meeting. The analysis showed that patients at the highest risk for a recurrent fracture--those who were at least 85 years old or who had a T score of less than -2.5 at the total hip--benefited the most from the treatment.

Although it's unclear why the oldest, least-dense bones benefited the most, the finding does carry a strongly positive clinical implication, "this study showed us that these individuals can benefit and that we can have a big short-term impact on their bone density and possibly even reduce the risk of more fractures due to continued bone loss," said Dr. Orwig of the department of epidemiology and preventive medicine at the University of Maryland Medical Center, Baltimore.

In a third study presented at the meeting, a single infusion of zoledronic acid suppressed serum markers of bone turnover better than 6 months of daily oral raloxifene in postmenopausal women with low bone mineral density.

Although women who received the 5mg infusion of zoledronic acid had significantly more immediate adverse events than those receiving a placebo infusion, the long-term adverse event rate was similar in both groups, said Dr. Andrey Kriegman, senior medical director for osteoporosis in the United States for Novartis Pharmaceuticals Corp.

The trial randomized 110 postmenopausal women (mean age, 60 years) to either the active infusion followed by 6 months of daily oral placebo, or a placebo infusion followed by 6 months of daily raloxifene (60 mg). Most (86%) were white; they were a mean of 13 years postmenopausal. About a third (37%) had a mean T score of -2.5 or lower at the lumbar spine, total hip, or femoral neck; the rest had a T score of -2.5 to -1.5.

The study's primary end points were the 6-month measurement of the urine N-telopeptide of type I collagen (NTx) corrected for creatinine, and bone-specific alkaline phosphatase (BSAP). Measurements of these markers at 2 and 4 months were the secondary end points.

The mean NTx/creatinine ratio was significantly lower in the zoledronic acid group than in the raloxifene group at all time points. At 6 months, the level had decreased by 14% more in the zoledronic acid group than in the raloxifene group.

The rate of immediate adverse events was significantly higher in the zoledronic acid group, an expected finding, Dr. Kriegrnan said in an interview.

Novartis sponsored all of the studies. Dr. Orwig has received research funding from the company. Dr. Recknor is on the Novartis speakers bureau.
HORIZON Prevention Study:
24-Month Changes in Bone Mineral Density

                  2 ZOL      ZOL +     2 Placebo
                Infusions   Placebo    Infusions

Lumbar spine         5%        4.4%      -1.3%
Total hip            3%        2.3%      -1.5%
Femoral neck         2%        1.6%      -1.4%
Trochanter         4.8%          4%        -1%
Distal radius    -0.07%      -0.18%      -2.4%

Source: Novartis Pharmaceuticals Corp.
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Author:Sullivan, Michele G.
Publication:Family Practice News
Date:May 1, 2009
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