Infrequent zoledronate infusions prevent vertebral fractures in early postmenopausal women

In early postmenopausal women, intravenous infusions of zoledronate once every 5 years could help reduce the risk of vertebral fractures, according to a recent study.

“Prevention of vertebral fractures in early postmenopausal women is possible with infrequent infusions of zoledronate,” said the researchers. “Early postmenopausal women who wish to reduce their risk of fracture could consider a strategy involving the administration of zoledronate every 5 or 10 years.”

The researchers conducted a 10-year, prospective, double-blind study involving 1,054 early postmenopausal women (mean age 56 years) with bone mineral density (BMD) T-scores lower than zero (T-score of -1.0 or higher is considered normal bone density) in the lumbar spine, femoral neck, or hip. Participants were randomly assigned to receive an infusion of zoledronate 5 mg at baseline and at 5 years (zoledronate-zoledronate group, n=352), zoledronate at baseline and placebo at 5 years (zoledronate-placebo group, n=351), or placebo at both timepoints (placebo-placebo group, n=351). To determine the occurrence of morphometric vertebral fractures, spinal radiographs were obtained at baseline and at 5 and 10 years. [N Engl J Med 2025;392:239-248]

At 10-year follow-up, only 6.3 percent of patients in the zoledronate-zoledronate arm and 6.6 percent in the zoledronate-placebo arm had morphometric vertebral fractures, while 11.1 percent occurred in the placebo-placebo arm.

The risk of morphometric vertebral fracture was lower among patients who received zoledronate-zoledronate than those who received placebo alone (relative risk [RR], 0.56; p=0.04), as well as those given zoledronate-placebo (RR, 0.59, p=0.08).

“Results showed that 10 years after trial initiation, zoledronate administered at baseline and at 5 years was effective in preventing morphometric vertebral fracture in early postmenopausal women,” said the researchers.

Secondary endpoints

Compared with placebo only-treated patients, the risk of fragility fracture, any fracture, and major osteoporotic fracture was lower in those treated with zoledronate only (RRs, 0.72, 0.70, and 0.60, respectively) and zoledronate-placebo (RRs, 0.79, 0.77, and 0.71).

“Of note, for all fracture categories, the RRs tended to be slightly lower in the zoledronate-zoledronate group than the zoledronate-placebo group,” the researchers said.

BMD, bone turnover markers

At 10 years, the differences in BMD changes at the total hip and spine between the all-zoledronate and all-placebo groups were from 7.4–8.8 percentage points; the differences between the zoledronate-placebo and all-placebo groups were from 5.0–6.3 percentage points.

At 5 years, markers of bone turnover had increased in the placebo only group, while a decrease of approximately 30–40 percent was observed in each of the zoledronate groups. “Markers of bone turnover remained low in the zoledronate-zoledronate group at 10 years; these markers increased after 5 years in the zoledronate-placebo group but were still below baseline levels after 10 years,” the researchers said.

Several studies have shown that the benefit of zoledronate on BMD and bone turnover markers, surrogate markers of bone health, persists for 5–10 years after one or two annual infusions. [J Bone Miner Res 2022;37:3-11; CMAJ 2017;189:E1130-E1136] “Persistent effects of zoledronate of similar duration with respect to BMD and bone turnover markers were also seen in the current trial,” the researchers noted.

Overall, these data suggest that fracture prevention strategies can be effective for early postmenopausal women, and although the benefits may be small for those at low risk of fracture, such strategies, including infrequent infusions of zoledronate, could have a significant impact on the reduction of fractures in the population, said the researchers.

“Infrequent infusions of zoledronate to prevent vertebral fractures and bone loss in early postmenopausal women offer a clinically realistic therapeutic option for women who are concerned about bone loss or their future risk of fracture,” they noted.