Boyle 2005.

Methods	Randomised, double‐blinded, placebo‐controlled trial; parallel design. Trial duration 6 months (originally intended for 12 months).
Participants	Inclusion criteria: CF; osteopenia of the lumbar spine (T‐scores ‐1.0 to ‐2.5); serum 25‐hydroxyvitamin D levels ≥ 20ng/ml prior to infusion. Exclusion criteria: existing osteoporosis, prior treatment with bisphosphonates or previous lung transplant. N = 40 planned for enrolment but only 5 enrolled (3 in treatment group) before study stopped by Data and Safety Monitoring Board (see notes).
Interventions	Treatment group: intravenous zoledronate, 5 mg infusion administered on a single occasion over 20 minutes plus supplemental oral vitamin D (800 IU) and oral calcium (1000 mg) daily Control group: supplemental oral vitamin D (800 IU) and oral calcium (1000 mg) daily
Outcomes	BMD lumbar spine (at 0, 6 months (originally planned additionally for 12 month)) Change from baseline in serum C‐telopeptides (at 3, 6 months (originally planned additionally for 9 and 12 months))
Notes	The study was stopped by its Data and Safety Monitoring Board after 3 participants experienced dramatic musculoskeletal pain, 2 requiring emergency room assessment. Symptoms began 6 to 8 hours after infusion, peaked at 12 to 18 hours, and were characterized by severe chest and back pain. Along with musculoskeletal pain, one participant also experienced a fever of 104°F lasting for several hours and a rise in tumour necrosis factor‐α. Although the most severe symptoms resolved within 48 to 72 hours, participants reported continued arthralgias for up to a week.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Described as randomised, but process not reported.
Allocation concealment (selection bias)	Unclear risk	Not discussed.
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Described as 'double‐blind'. Participants: blinded. Not discussed if clinicians or persons delivering treatment and outcome assessors were both blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Based on interpretation of data, we have presumed that the 3 participants who had severe bone pain were the 3 in the treatment group. Clarification from the author was requested but not received.
Selective reporting (reporting bias)	Unclear risk	Abstract only but outcome measures were described in the results.
Other bias	High risk	The study was stopped by its Data and Safety Monitoring Board after 3 participants experienced dramatic musculoskeletal pain, 2 requiring emergency room assessment. Symptoms began 6 to 8 hours after infusion, peaked at 12 to 18 hours, and were characterized by severe chest and back pain. Along with musculoskeletal pain, one participant also experienced a fever of 104oF lasting for several hours and a rise in Tumour Necrosis Factor‐α. Although the most severe symptoms resolved within 48 to 72 hours, participants reported continued arthralgias for up to a week.