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Question In postmenopausal women with osteopenia, does zoledronate reduce fragility fractures? Methods Design Randomized placebo-controlled trial. ACTRN12609000593235. Allocation {Concealed}*. Blinding Blinded (patients and trial staff). Follow-up period 6 years. Setting Auckland region of New Zealand. Patients 2000 postmenopausal women 65 years of age (mean age 71 y) who were ambulatory and had a total hip or femoral neck T-score of 1.0 to 2.5 at either hip. Exclusion criteria included spinal osteoporosis with a T-score 3.0, estimated glomerular filtration rate <30 mL/min/1.73 m2, major systemic disease, metabolic bone disease, cancer in the past 2 years, or regular use of bone-active drugs in the past year. Intervention Zoledronate, 5-mg infusion (n =1000), or saline placebo (n =1000), given every 18 months to a maximum of 4 infusions. Outcomes Primary outcome was fragility fracture (nonvertebral fracture or vertebral fracture confirmed by radiography). Other outcomes included symptomatic fracture, vertebral fracture, height change, all-cause mortality, and adverse events. Patient follow-up 96% completed 6-year follow-up or died (intention-to-treat analysis). Main results The main results are in the Table. Zoledronate and placebo did not differ for serious adverse events (SAEs) overall (40% vs 44%, odds ratio 0.84, 95% CI 0.70 to 1.00). No patients in either group had osteonecrosis of the jaw. Conclusion In older postmenopausal women with osteopenia, zoledronate reduced nonvertebral or vertebral fragility fractures at 6 years. Zoledronate vs placebo in older women with osteopenia Outcomes Events/1000 woman-y At 6 y Zoledronate Placebo RRR (95% CI) NNT (CI) Fragility fracture 22 39 35% (19 to 47) 15 (10 to 28) Symptomatic fracture 31 47 25% (9 to 37) 20 (12 to 60) Vertebral fracture 4.2 11 54% (26 to 72) 36 (22 to 96) All-cause mortality 4.5 7.0 34% (5 to 59) Not significant Event rates Height loss 1 cm 32% 41% 22% (11 to 32) 11 (8 to 22) Abbreviations defined in Glossary. RRR and CI calculated from placebo event rates and hazard ratios or odds ratios in article. NNT and CI provided by author for fracture outcomes and calculated from placebo event rate and odds ratio for height loss. Symptomatic vertebral fracture or any nonvertebral fracture. Commentary Whether to initiate drug treatment to prevent fractures in women with osteopenia is controversial. In 1998, the Fracture Intervention Trial found that alendronate for 4 years did not reduce clinical fractures in this patient population (1). These findings are in contrast to the results of the 6-year trial by Reid and colleagues, which evaluated zoledronate, a more potent antiresorptive agent. Fracture risk was higher in the zoledronate trial because women were slightly older (mean age 71 vs 68 y), and in contrast to the alendronate trial, some women had clinically defined osteoporosis (13% had existing radiographic vertebral fractures, and 8% had 1 bone mineral density [BMD] T-score < 2.5). Zoledronate for 3 years in postmenopausal women with osteoporosis reduced risk for hip fracture in a previous trial (2) but not in the current trial, which predominantly comprised women with osteopenia. Reid and colleagues found that zoledronate was well-tolerated and did not increase risk for SAEs. However, the sample size was too small to reliably examine incidence of osteonecrosis of the jaw or atypical femoral fractures (AFF), rare but serious harms of bisphosphonates. Evidence suggesting that AFFs increase with longer treatment duration (3) and higher baseline BMD (4) has reduced enthusiasm for bisphosphonates in osteopenia. The results of Reid and colleagues' trial should not be generalized to younger women or men, and cost-effectiveness studies are warranted before routinely prescribing zoledronate for osteopenia. Instead, clinicians should focus on initiating bisphosphonates in patients with clinically recognized osteoporosis (BMD T-score 2.5 or presence of vertebral or hip fracture). Only 1 in 3 patients with hip fractures in the USA receive drug treatment to prevent future fractures (5). The American College of Physicians' guidelines recommend shared clinical decision making in older women with osteopenia who are at high risk for fractures (6).