Chapman 2009.

Methods	Randomised, double‐blinded, placebo‐controlled trial; parallel design. Trial duration 24 months. Multicentre, 2 sites, CF clinics, Australia.
Participants	Inclusion criteria: CF (diagnosis previously made by sweat chloride test and an appropriate CF phenotype); ≥ 18 years; bone density T‐score <‐1.5 in at least one of three sites (hip (femoral neck), lumbar spine 2 to 4 (L2 to L4) and distal forearm) in the month before study commencement. Exclusion criteria: pre‐existing, symptomatic, fragility fractures; untreated hyperthyroidism, primary hyperparathyroidism or hypogonadism; bisphosphonate treatment in the three months before starting the study; serum calcium concentration below the lower limit of the laboratory normal range; serum creatinine concentration more than 1.5 times the upper limit of the laboratory normal range; serum ALT, ALP or bilirubin more than 3 times the upper limit of the laboratory normal range; on the waiting list for lung transplantation; pregnant or lactating; considered unlikely to complete the study. Total participants: n = 22 (5 females). Age range over all: males 21 to 47 years, females 19 to 28 years. Treatment group: n = 10 (3 female); mean (SD) age 30.1 (2.2) years. Control group: n = 12 (2 females) mean (SD) age 28.6 (2.4) years.
Interventions	Treatment group: intravenous zoledronic acid (zoledronate) in 100 ml of normal saline infused over 15 minutes every 3 months for 21 months (8 infusions in total). For 5 out of 63 doses, 4 mg zoledronate was administered, then dose reduced to 2 mg for subsequent doses (due to febrile reactions to the higher dose in several participants). Placebo group: 100 ml normal saline as above. All participants were prescribed calcium carbonate 600 mg and vitamin D2 1000 IU each twice daily at least 3 days before the first treatment infusion and continued throughout the study. All participants were prescribed oral prednisolone 25 mg/day for 3 days starting on the morning of the first infusion; repeated with subsequent infusions if a reaction to the first infusion was thought likely. If there were side effects of the study infusion that were considered to be possibly due to the infusion during the first or any subsequent infusion, at the discretion of the investigator and participant, oral analgesia (paracetamol) was also administered for subsequent infusions.
Outcomes	Bone density at hip (femoral neck), lumbar spine (L2 ‐ L4) and distal forearm (at baseline, 6, 12 and 24 months) Plain x‐rays of thoracic and lumbar spine (at baseline and 24 months (additional films taken as indicated to confirm any suspected fractures)) Biochemical measurements: urea; creatinine; ALP; ALT; bilirubin; calcium (corrected); calcium (ionised); phosphate; 25‐hydroxyvitamin D; PTH; complete blood count and differential (at baseline and 2 weeks before the 6, 12, 18 and 24 months)
Notes	Novartis Pharmaceuticals Pty Ltd, Australia partly funded this trial.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Described as randomised, but process not discussed.
Allocation concealment (selection bias)	Unclear risk	Not discussed.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Described as 'double‐blind'. Participants: blinded. Outcome assessors: DXA scans were performed and analysed by personnel blinded to treatment assignment. Not specifically discussed if clinicians or persons delivering treatment and other outcome assessors were all blinded.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Withdrawals described and equal across groups ‐ there were 3/10 in treatment group and 5/12 in control group. In the treatment group, 2 participants withdrew due to side‐effects, 1 due to psychiatric illness. In the placebo group, one participant was lost to follow‐up, one participant's BMD decreased to withdrawal threshold, 2 participants were poorly compliant to study protocols and in one participant, both of the latter two reasons were applicable. However, it was unclear which specific participants had BMD measurements available at each time‐point, particularly for forearm measures (fewer measurements compared with lumbar spine and femoral neck).
Selective reporting (reporting bias)	Low risk	Outcome measures that were described in the methods section were reported in the results section.
Other bias	Low risk	None identified.