medwireNews: Women with osteopenia treated with zoledronate for 6 years continue to have a reduced risk for nonvertebral fracture, compared with placebo, for up to 3.5 years after their last infusion, suggests a 4-year observational extension of a randomized controlled trial.
Ian Reid (University of Auckland, New Zealand) and co-authors write in The Lancet Diabetes & Endocrinology that the rate of nonvertebral fractures per 1000 woman–years increased from 15 fractures in years 4–6 of the main study among women who were assigned to receive zoledronate to 24 in years 6–8 of the extension phase and then significantly to 42 fractures in years 8–10. The latter rate was comparable to that found in placebo-treated participants in years 4–6, say the researchers.
Recognizing that the fracture rate reduction was only “substantially maintained” for the first 1.5–3.5 years after the last zoledronate infusion, the team suggests that after completion of initial treatment, “although continuing zoledronate administration every 18 months might be optimal, ongoing treatment at 2–3-year intervals might also maintain substantial prevention of fracture.”
The extension study included 796 women aged an average of 77 years who were followed-up for 3230 woman–years of observation and a mean of 4.24 years. During this time, 47% of patients used bisphosphonates, 19% glucocorticoids, 11% anti-estrogen therapy for breast cancer, 2% hormone replacement therapy, and 1% teriparatide. Of the 41 women who took only bisphosphonates during this time, 78% did so after incident fracture, as did 41% of the 17 women who took a combination of bone-active agents.
In multivariable analysis, the risk for incidence fracture during the extension period was significantly associated with total hip bone mineral density (BMD; relative risk = 0.73 per 0.1 g/cm2) and a history of nonvertebral fracture (relative risk = 1.74) at year 6.
Total hip BMD was significantly higher at both year 6 and 10 versus baseline, by increases of 4.2% and 0.8%, respectively, but there was a significant decrease between years 6 and 10. Total body BMD increased from baseline by 2.2% and 0.8% at years 6 and 10, and again the 10-year value was significantly better than baseline but significantly lower than at year 6.
In addition, reductions in total hip BMD at 6 and 10 years of follow-up were significantly associated with loss of fat mass, lean mass, and weight.
“The loss of antifracture efficacy by years 8–10 is reflected in the loss of most of the previous gains in total hip and total body BMD by year 10,” say Reid and colleagues.
The authors conclude that “administration of zoledronate reduces fracture risk, and its discontinuation for 4 years reverses that, but an individual’s key clinical risk factors are important in the context of these changes in overall fracture risk.”
In a related comment, Matthew Drake, from the Mayo Clinic in Rochester, Minnesota, USA, observes that “rather than a prolonged break of 3–5 years for patients who meet the criteria as recommended by the [American Society for Bone and Mineral Research] Task Force guidelines, reinitiation of zoledronate 3 years from the most recently provided zoledronate dose might be appropriate to limit the risk for future fractures."
He notes that the current study population was limited to women older than 65 years of age and of European ancestry and recommends that future studies should determine “whether these findings can be applied to a broad population in clinical practice to safely reduce fracture risk.”
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