Antifracture effects of zoledronate persist for up to 3.5 years, study suggests
Fracture rates rose from 15 per 1,000 woman-years in the last two years of a six-year trial to 24 fractures in the first two years of follow-up. In the next two years of follow-up, the rate substantially increased to 42 fractures per 1,000 woman-years.
Reduced nonvertebral fracture rates persisted up to 3.5 years after older women with osteopenia received the last of four zoledronate infusions but rose substantially in the subsequent two years, new research shows.
An initial six-year trial carried out in New Zealand found that zoledronate administered at 18-month intervals lowered fragility fractures by one-third in women ages 65 years and older with osteopenia. Researchers then carried out a four-year observational study extension. Individuals were asked to notify study staff of any new fractures within the follow-up period. They were also contacted by phone at 7.5 and 9 years to update their health status and invited to an on-site visit 10 years after the trial began. A total of 762 participants randomized to receive zoledronate in the initial trial were included in the extension. Average follow-up duration was 4.24 years, and 727 participants completed the 10-year evaluation. Findings were published by The Lancet Diabetes & Endocrinology on March 4.
Throughout the extension, 25 women died, six withdrew from the study, and four were lost to follow-up. A total of 92 women experienced 114 nonvertebral fractures during the four years. Nonvertebral fracture rates rose from 15 fractures (95% CI, 10 to 21 fractures) per 1,000 woman-years in the last two years of the trial to 24 fractures (95% CI, 17 to 33 fractures) in the first two-years of follow-up. In years 8 to 10, the rate increased further to 42 fractures (95% CI, 32 to 53 fractures) per 1,000 woman-years , similar to that of the placebo group in the last two years of the trial (incidence rate ratio, 1.10; 95% CI, 0.78 to 1.54). History of nonvertebral fracture and total hip bone mineral density (BMD) at year 6 predicted incident fractures in the follow-up period, while change in total hip BMD did not. During the extension, total hip BMD fell from 4.2% above study baseline to 0.8% above baseline (P<0.0001). No participants experienced osteonecrosis of the jaw or atypical femoral fractures during follow-up.
Findings suggest that "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 authors wrote. However, they cautioned that the current study did not test this possibility.
The lack of follow-up for the control group is a limitation to the study. Results also may not be generalizable to men and women of other ages.
In an accompanying editorial, authors highlighted the new research, noting it adds "substantially more granularity to that previously available to the ASBMR [American Society of Bone and Mineral Research] Task Force authors."
In particular, the new data suggest that "rather than a prolonged break of 3–5 years for patients who meet the criteria as recommended by the ASBMR 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."