Infrequent Zoledronate at 50-60 Years Prevents Fractures

Women in early menopause treated with zoledronate in just two infusions, 5 years apart, show a significantly reduced risk of sustaining a vertebral fracture and better maintenance of bone mineral density (BMD) over a 10-year period than those receiving just one or no infusions over the period, suggesting the infrequent, early dosing to be a beneficial preventive fracture risk strategy.

“The results show that prevention of vertebral fractures in early postmenopausal women is possible with very infrequent infusions of zoledronate,” the authors wrote in the study, published online on January 15 in the New England Journal of Medicine.

The infrequent zoledronate regimen “is worth discussing with 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,” first author Mark J. Bolland, MB, PhD, of the Department of Medicine, University of Auckland, Auckland, New Zealand, told Medscape Medical News.

Most fracture prevention measures focus on those at a higher risk for fracture, such as the elderly, those with previous fractures, or those with low BMD. However, while decreases in BMD, linked to an increased fracture risk, are well-known to occur in most postmenopausal women, some bone loss can occur even prior to menopause.

Zoledronate, a bisphosphonate typically administered to higher-risk individuals in annual or every 18-month infusions, has benefits in stabilizing BMD and slowing bone turnover. However, studies have shown the drug to have a prolonged duration of action, with a single 5-mg infusion having effects on stabilizing BMD beyond 5 years.

Options for Preventing Fractures in Early Menopause ‘Should Be Addressed’ in Future Guidelines

To investigate whether infusions given as infrequently as once every 10 or 5 years in early menopausal women could help maintain their BMD near peak levels, Bolland and colleagues conducted a 10-year, prospective, double-blind trial of 1054 early menopausal women who had a mean age of 56 years at baseline.

The women, who all had normal BMD at baseline, were randomized to receive either an infusion of zoledronate 5 mg at baseline and at 5 years, zoledronate 5 mg at baseline and placebo at 5 years, or placebo at both timepoints.

Among the 1003 patients (95.2%) who completed 10 years of follow-up, the primary endpoint of a new morphometric vertebral fracture occurred in 22 women (6.3%) in the group that received zoledronate at both timepoints and 23 women (6.6%) in the zoledronate-placebo group compared with 39 women (11.1%) in the all-placebo group.

In terms of relative risk (RR), those receiving zoledronate at both timepoints had a 44% reduced risk of developing a morphometric vertebral fracture compared with the all-placebo group (RR, 0.56; P = .04), while the zoledronate-placebo group had a 41% reduced risk vs the all-placebo group (RR, 0.59; P= .08).

For the secondary endpoints of risk for fragility fracture, any fracture, and major osteoporotic fracture, the RR with zoledronate at both timepoints vs all-placebo were 0.72, 0.70, and 0.60, respectively. And when the zoledronate-placebo group was compared with all-placebo, the respective RRs were 0.79, 0.77, and 0.71.

At 5 years, the differences in changes in BMD at the total hip and spine between the two zoledronate groups and the all-placebo group ranged from 4.9 to 6.6 percentage points, while at 10 years, the differences between the all-zoledronate and all-placebo groups were from 7.4 to 8.8 percentage points. The differences between zoledronate-placebo and all-placebo were 5.0-6.3 percentage points.

Importantly, key markers of bone turnover increased in the all-placebo group at 5 years, whereas the measures decreased by approximately 30%-40% in each of the zoledronate groups.

In the second 5 years, the bone turnover markers gradually increased in the zoledronate-placebo group but remained below baseline levels at 10 years, while the levels in the all-zoledronate group remained unchanged at 5 years and 10 years.

Bolland noted that “the reductions in fractures observed in the study are of similar size to those seen in trials of older women and men where annual or 18-month doses are used.”

In addition to having an excellent safety profile for up to 9 years as an annual treatment, the cost of zoledronate, particularly with such infrequent use, is low, as the drug is generic.

“This [strategy] gives women in their 50s and 60s who are concerned about their fracture risk a good option for preventing fractures that they could discuss with their doctor,” Bolland said. “This group of people are not considered in many current guidelines, but these options should be addressed in future ones.”

Study ‘Warrants Reconsideration’ of a Medication Approach in Fracture Prevention

Commenting on the study, Jad Sfeir, MD, an endocrinologist and geriatrician with the Mayo Clinic’s Osteoporosis-Calcium Disorders Specialty Group in Rochester, Minnesota, notes that the strategy of using medication to prevent fractures in women with moderate fracture risk, such as those in this trial, has largely been abandoned in recent years, “primarily due to concerns about long-term side effects associated with prolonged use of antifracture medications.”

“However, the benefits observed in this trial suggest that a preventive approach using zoledronate warrants reconsideration for early postmenopausal women who have additional risk factors for fractures and cannot or prefer not to use postmenopausal hormone replacement therapy,” he told Medscape Medical News.

“The risks are minimal, given the infrequent exposure to zoledronate.”

The results indicate that the number needed to treat to prevent one vertebral fracture is 21, which Sfeir says is “a reasonable figure given the therapy’s low cost and minimal side effects.”

While commending the study’s valuable insights, Sfeir cautions that “the findings should not be generalized to older women or those with a higher risk of fractures.”

Also, “importantly, all participants in the trial were of European descent, so the results cannot be applied to women of other ethnicities, who may have significantly different baseline fracture risks relative to their bone densities.”

Ultimately, the availability of the potential low-cost, safe prevention strategy “underscores the importance of early screening,” Sfeir added.

“Postmenopausal women with additional fracture risk factors should undergo bone mineral density screening. Based on their risk profile, a comprehensive fracture prevention plan may include infrequent zoledronate treatment.”

The study was funded by grants from the Health Research Council of New Zealand. One author disclosed being a shareholder of Auckland Bone Density, which provides bone density scans, and another author disclosed financial relationships with several pharmaceutical companies unrelated to this study. Sfeir had no relevant disclosures to report.