Level 1 [likely reliable] evidence

Osteopenia places postmenopausal women at increased risk for fragility fracture, which can increase morbidity and mortality. To date, no randomized trial has demonstrated therapeutic benefit of bisphosphonate therapy for fracture prevention in women with osteopenia.

New Zealand investigators conducted a randomized trial comparing zoledronate 5 mg infusion every 18 months with placebo infusion to assess the effectiveness for preventing fragility fracture among women with osteopenia.1 Postmenopausal women aged ≥65 years with a total hip or femoral neck T-score between -1 and -2.5 were included in the trial. Women with a hip T-score <-2.5 on one side but between -1 and -2.5 on the contralateral side were also included in the trial. Patients were followed for 6 years for the primary endpoint, which was time to first occurrence of a fragility fracture. Symptomatic fractures was one of several secondary endpoints.

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In an intention-to-treat analysis, there was a statistically significant reduction in the cumulative incidence of first fragility fracture in the zoledronate group compared with placebo (NNT 15). There was also a statistically significant reduction in symptomatic fractures (hazard ratio 0.73, NNT 22 over 6 years). When women with an osteoporotic hip on one side were excluded from the analysis, there was still a statistically significant reduction in fragility fractures.

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Nearly twice as many women in the zoledronate group declined any additional infusion due to an acute reaction during the first infusion. The rate of adverse events was similar in the 2 groups, with no documented osteonecrosis of the jaw or atypical femur fractures. The zoledronate group experienced a significantly lower rate of cancers, although the clinical significance of this secondary outcome is uncertain. Short-term adverse events were not reported.


  1. Reid IR, Horne AM, Mihov B, et al. Fracture prevention with zoledronate in older women with osteopenia. N Engl J Med. 2018;379(25):2407-2416.