Fracture Prevention with Zoledronate in Older Women with Osteopenia

N Engl J Med. 2018 Dec 20;379(25):2407-2416. doi: 10.1056/NEJMoa1808082. Epub 2018 Oct 1.


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 .).

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute-Phase Reaction / chemically induced
  • Aged
  • Bone Density / drug effects
  • Bone Density Conservation Agents / adverse effects
  • Bone Density Conservation Agents / therapeutic use*
  • Bone Diseases, Metabolic / drug therapy*
  • Bone Remodeling / drug effects
  • Calcium / therapeutic use
  • Dietary Supplements
  • Double-Blind Method
  • Female
  • Fractures, Bone / prevention & control*
  • Humans
  • Infusions, Intravenous
  • Intention to Treat Analysis
  • Iritis / chemically induced
  • Proportional Hazards Models
  • Zoledronic Acid / adverse effects
  • Zoledronic Acid / therapeutic use*


  • Bone Density Conservation Agents
  • Zoledronic Acid
  • Calcium

Associated data

  • ANZCTR/ACTRN12609000593235