Infrequent Zoledronate Infusions Reduced Vertebral Fractures Soon After Menopause

Intravenous zoledronate (Reclast) administered once every 5 years reduced the incidence of morphometric vertebral fractures in early postmenopausal women, a randomized trial showed.

Over 10 years of follow-up, a new morphometric vertebral fracture occurred in 6.3% of women who received zoledronate at baseline and at 5 years, in 6.6% of those who received zoledronate at baseline and placebo at 5 years, and in 11.1% of those who received placebo at both time points:

• Two infusions of zoledronate vs two infusions of placebo: relative risk (RR) 0.56, 95% CI 0.34-0.92, P=0.04
• Zoledronate and placebo vs two infusions of placebo: RR 0.59, 95% CI 0.36-0.97, P=0.08

The relative risk of fragility fracture, any fracture, and major osteoporotic fracture was 0.72 (95% CI 0.55-0.93), 0.70 (95% CI 0.56-0.88), and 0.60 (95% CI 0.42-0.86), respectively, when two infusions of zoledronate were compared with two infusions of placebo, and 0.79 (95% CI 0.61-1.02), 0.77 (95% CI 0.62-0.97), and 0.71 (95% CI 0.51-0.99), respectively, when zoledronate and placebo was compared with two infusions of placebo, reported Mark Bolland, MB, ChB, PhD, of the University of Auckland in New Zealand, and colleagues in the New England Journal of Medicine.

At baseline, the average T score at the lumbar spine or hip among women in all three groups indicated normal bone mineral density.

“We think that many people will be surprised that a single infusion of zoledronate prevents fractures over 10 years by a very similar amount to two infusions given [5 years apart],” Bolland told MedPage Today.

In a 2007 randomized trial, an annual infusion of zoledronate reduced the risk of morphometric vertebral fracture by 70% during a 3-year period. According to the drug’s label, a 5-mg zoledronate infusion should be administrated once a year for the treatment of postmenopausal osteoporosis and every 2 years for the prevention of osteoporosis.

“Decreases in bone mineral density, which are almost universal among postmenopausal women, start before menopause, with an average loss of bone density of 0.5 to 1% per year thereafter,” Bolland’s group pointed out, adding that most fracture-prevention strategies focus on those at highest risk for fractures. “However, this focus is severely limited because only 20% of fractures occur in women with a bone mineral density that indicates osteoporosis.”

Instead, they recommended a shift towards fracture prevention via prevention of bone loss in certain low-risk, early postmenopausal women — an approach endorsed by accompanying editorial author Roland Chapurlat, MD, PhD, of the Université Claude Bernard-Lyon in France.

“These results are important not only because vertebral fracture is a major fracture but also because the results provide clinical perspectives for the prevention of primary fractures,” Chapurlat wrote. “It has been widely accepted that osteoporosis medications are mainly efficacious in women with the lowest bone mineral density T scores.”

Infrequent doses of a generic treatment like zoledronate “will result in a low cumulative dose and minimize both the costs and the side effects of treatment,” he added.

The study authors agreed, noting that the cost of the treatment — to both the individual patients and to health systems — would likely be low because the drug is generic and administration is infrequent.

Bolland said this preventive approach is ideal for patients without a high risk for fracture. “It is worth [clinicians discussing] with their patients, as some may be interested in this approach to primary fracture prevention when they are at low or intermediate risk of fracture, rather than waiting until they are at high risk of fracture before offering treatment,” he said.

For this prospective, double-blind trial, the researchers included 1,054 postmenopausal women ages 50 to 60 (mean age 56) living in Auckland, with a bone mineral density T score at the lumbar spine, femoral neck, or total hip that was lower than 0 (scores of -1 or higher typically indicate normal bone density). A T score of -2.5 or less at any of these sites — the threshold for osteoporosis — was one of the grounds for exclusion. Of these women, 95.2% completed 10 years of follow-up.

Most participants were of European ancestry, and 11% to 17.6% of women in each treatment group had a nonvertebral fracture after the age of 45.

Change in bone mineral density at the lumbar spine and total hip increased after the first zoledronate infusion, while it decreased in the placebo group. However, bone mineral density remained relatively steady after a second zoledronate infusion, which the researchers said was seen in a previous trial.

Bolland’s group said the findings were exclusive to early postmenopausal women without osteoporosis, and may not apply to older women, men, or those with osteoporosis.

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