OBJECTIVE: Reduced bone mineral density (BMD) and increased rates of atraumatic fracture are observed in cystic fibrosis (CF) patients, causing increasing morbidity as this population ages. The study aimed to assess the safety, tolerability and effect on BMD of intravenous zoledronate in adults with CF and osteopaenia. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. SETTING: Adult CF outpatient clinics at two hospitals. PATIENTS: Twenty-two non-transplanted CF patients aged > or = 18 years with a bone densitometry T-score of < -1.5 at one of three sites (lumbar spine, femoral neck, distal forearm) were studied. Participants were randomized to receive either 2 mg zoledronate i.v. (n = 10) or normal saline (placebo, n = 12) every 3 months for 2 years (8 infusions). All participants received calcium and vitamin D supplements twice daily. MEASUREMENTS: Percentage change in areal BMD from baseline. RESULTS: Lumbar spine BMD increased from baseline more with zoledronate than placebo at 6 months (5.35 +/- 0.76 vs. 1.19 +/- 1.20%, P = 0.012), 12 months (6.6 +/- 1.5 vs. 0.35 +/- 1.55%, P = 0.011) and 24 months (6.14 +/- 1.86 vs. 0.44 +/- 0.10, P = 0.021). Femoral neck BMD increased more after zoledronate than placebo at 6 months (3.2 +/- 1.6 vs.-1.43 +/- 0.43%, P = 0.019), 12 months (4.12 +/- 1.8 vs.-1.59 +/- 1.4%, P = 0.024) and 24 months (4.23 +/- 1.3 vs.-2.5 +/- 1.41%, P = 0.0028). Forearm BMD did not change. Zoledronate was associated with flu-like and musculoskeletal side effects, particularly after the first infusion. There were no fractures in either group. CONCLUSION: Intravenous zoledronate was significantly more effective than placebo for increasing BMD in adults with CF and osteopaenia, but side effects limited its tolerability.