Fracture Prevention with Zoledronate in Older Women with Osteopenia

The New England Journal of Medicine

Oct 2018

DOI: 10.1056/NEJMoa1808082

Citations:295

Influential Citations:15

Interventional (Human) Studies

COI

Enhanced Details

Methods

Randomized, double-blind, placebo-controlled trial; 2000 ambulatory postmenopausal women aged ≥65 with osteopenia (T score −1.0 to −2.5 at the total hip or femoral neck on either side); recruited from electoral registers in Auckland, New Zealand; followed for 6 years.

Intervention

Zoledronate 5 mg intravenous infusion, four infusions at 18-month intervals over 6 years; dietary calcium intake advised at 1 g/day (calcium supplements not provided); cholecalciferol (Vitamin D3) supplementation for participants not already taking vitamin D: 2.5 mg before the first infusion and 1.25 mg per month during the trial.

Results

Zoledronate reduced fragility fracture risk over 6 years (first fracture): 122/1000 vs 190/1000 in placebo (hazard ratio 0.63; 95% CI 0.50–0.79; P<0.001); number needed to treat to prevent one fracture = 15. Nonvertebral fragility fractures HR 0.66 (P=0.001); symptomatic fractures HR 0.73 (P=0.003); vertebral fractures OR 0.45 (P=0.002); height loss reduced (P<0.001). Death and cancer risks did not increase; hip fracture risk not significantly different. Conclusion: In older women with osteopenia, zoledronate every 18 months for 6 years lowers the risk of fragility fractures and supports use for fracture prevention in this population.

Limitations

Limitations include generalizability limited to ambulatory postmenopausal women aged ≥65 with osteopenia; not powered to assess rare adverse events such as osteonecrosis of the jaw or atypical femoral fractures; prespecified secondary endpoints not adjusted for multiplicity; some placebo participants started bisphosphonates during the trial, potentially biasing results.

Abstract

BACKGROUND Bisphosphonates prevent fractures in patients with osteoporosis, but their efficacy in women with osteopenia is unknown. Most fractures in postmenopausal women occur in those with osteopenia, so therapies that are effective in women with osteopenia are needed. METHODS We conducted a 6‐year, double‐blind trial involving 2000 women with osteopenia (defined by a T score of ‐1.0 to ‐2.5 at either the total hip or the femoral neck on either side) who were 65 years of age or older. Participants were randomly assigned to receive four infusions of either zoledronate at a dose of 5 mg (zoledronate group) or normal saline (placebo group) at 18‐month intervals. A dietary calcium intake of 1 g per day was advised, but calcium supplements were not provided. Participants who were not already taking vitamin D supplements received cholecalciferol before the trial began (a single dose of 2.5 mg) and during the trial (1.25 mg per month). The primary end point was the time to first occurrence of a nonvertebral or vertebral fragility fracture. RESULTS At baseline, the mean (±SD) age was 71±5 years, the T score at the femoral neck was ‐1.6±0.5, and the median 10‐year risk of hip fracture was 2.3%. A fragility fracture occurred in 190 women in the placebo group and in 122 women in the zoledronate group (hazard ratio with zoledronate, 0.63; 95% confidence interval, 0.50 to 0.79; P<0.001). The number of women that would need to be treated to prevent the occurrence of a fracture in 1 woman was 15. As compared with the placebo group, women who received zoledronate had a lower risk of nonvertebral fragility fractures (hazard ratio, 0.66; P=0.001), symptomatic fractures (hazard ratio, 0.73; P=0.003), vertebral fractures (odds ratio, 0.45; P=0.002), and height loss (P<0.001). CONCLUSIONS The risk of nonvertebral or vertebral fragility fractures was significantly lower in women with osteopenia who received zoledronate than in women who received placebo. (Funded by the Health Research Council of New Zealand; Australian New Zealand Clinical Trials Registry number, ACTRN12609000593235.) show less