Six-Year Study of Zoledronate for Osteopenia Shows Reduction in Fragility Fractures

Giving zoledronate every 18 months for 6 years reduced the risk of fragility fractures—both vertebral and nonvertebral—in older women with hip bone mineral density indicating osteopenia, a recent study published in The New England Journal of Medicine reported.

Learn more about bone health.

Zoledronate belongs to a class of drugs called bisphosphonates; they can prevent fractures in patients with osteoporosis, but their efficacy in women with osteopenia is unknown. There is an unmet clinical need in that most fractures in postmenopausal women occur in those with osteopenia, or moderate bone loss.

The double-blind, randomized control trial involved 2000 women, average age 71, with osteopenia.¹ One quarter had previously had a fracture.

They had t-scores between —1.0 to –2.5 at either the total hip or the femoral neck on either side. A score of -2.5 is needed for a diagnosis of osteoporosis.

After 6 years, 122 women in the drug group had broken a bone versus 190 of those on placebo, a 37% lowered risk (hazard ratio [HR] with zoledronate, 0.63; 95% confidence interval, 0.50 to 0.79; P <.001).

For every 15 women like this treated for 6 years, 1 fracture was prevented. As compared with the placebo group, women who received zoledronate had a lower risk of nonvertebral fragility fractures (HR, 0.66; P = .001), symptomatic fractures (HR, 0.73; P = .003), vertebral fractures (odds ratio, 0.45; P = .002), and height loss (P <.001).

Two rare problems tied to bisphosphonates—deterioration of the jawbone and unusual leg fractures&mdash;did not occur, but the study wasn't big enough to rule out the risk.

Because zoledronate is administered intravenously and infrequently, it may avoid some of the patient adherence issues as other drugs, the researchers said.

In an accompanying editorial,² Clifford J. Rosen, MD, wrote that there were 3 factors in this study that made the results unique:

1. It showed that zoledronate given less frequently than once a year was associated with not only a greater increase in bone mass than in the placebo group but also a significantly lower risk of vertebral and nonvertebral fractures. It was also of long duration and has strong statistical significance.
2. Treatment with intravenous zoledronate was effective in preventing fractures among women with an average T score of −1.27 at the total hip and −1.64 at the femoral neck. This is in contrast to a previous trial of oral alendronate in women who did not have prevalent fractures but had osteopenia, although Rosen wrote the reasons for this difference are not clear. He noted that zoledronate is a more potent antiresorptive agent than alendronate, and at least one third of the participants in the current trial had clinical risk factors that placed them at higher risk for fracture (ie, a baseline 10-year risk of hip fracture of more than 3% or a baseline 10-year risk of any osteoporotic fracture of more than 20%), even though the bone mineral density was considered to indicate osteopenia.
3. Six years of intermittent treatment with zoledronate resulted in relatively few adverse events, although the current trial was not powered to assess more rare side effects, such as osteonecrosis of the jaw and atypical femoral fractures.

Rosen said the results should impact clinical practice, given the effectiveness of infrequent administration of zoledronate in reducing the risk of fragility fracture. The study is also a good reminder that “treatment decisions go well beyond bone mineral density and should focus particularly on age and a history of previous fractures,” Rosen wrote. These results should not be extrapolated to younger postmenopausal women (50 to 64 years of age) with osteopenia, he added.

References

1. Reid IR, Horne AM, Mihov B, et al. Fracture prevention with zoledronate in older women with osteopenia [published online October 1, 2018]. NEJM. doi: 10.1056/NEJMoa1808082.

2. Rosen CJ. A not-so-new treatment for old bones [published online October 1, 2018]. NEJM. doi: 10.1056/NEJMe1812434.