Study characteristics

Methods

Randomised controlled trial, parallel design.

Trial duration 2 years.

Single centre, university hospital, USA.

Participants

Inclusion criteria: CF; 1 to 12 months post‐lung transplantation; ambulatory.
Exclusion criteria: primary graft failure or other post‐operative morbidities that precluded long‐term survival; renal insufficiency (serum creatinine > 3.0 mg/dl); or pregnancy.

Total participants: n = 34 (17 female).
Treatment group: n = 16 (7 female); mean (SD) age 27.5 years (6.6 years).

Control group: n = 18 (10 female); mean (SD) age 29.1 years (6.4 years).

Groups similar in age, gender, baseline T‐scores, renal function, hospitalisation rates, immunosuppressant levels, change in lung function and BMI over study period.

13 in treatment group and 12 controls had baseline T‐scores < ‐2.5 at a minimum of 1 site; all others ‐1 < T < ‐2.5 at a minimum of 1 site.

Interventions

Treatment group: intravenous pamidronate (30 mg every 3 months) plus oral vitamin D (800 IU/day) and oral calcium (1 g/day).

Control group: oral vitamin D (800 IU/day) and oral calcium (1 g/day).

Outcomes

Primary outcome

1. BMD (spine; 0, 6, 12, 18, 24 months; DXA Hologic QDR 1000/W Waltham MA).

Secondary outcomes

1. BMD femur (at 0, 6, 12, 18, 24 months; DXA Hologic QDR 1000/W Waltham MA).

2. New fractures: number of fractures during study; long bone using clinical data, rib using postero‐anterior chest radiographs, vertebral using lateral chest radiographs.

3. Kyphosis angles (degrees): thoracic spine curvature using lateral chest radiographs using a modification of method of Cobb (at 0, 24 months).

4. Adverse events: number during study; thrombophlebitis, cellulitis, bone pain, fever, hypocalcaemia defined as serum calcium < 7.8 mg/dl, hypervitaminosis defined as serum 25‐hydroxyvitamin D > 55 ng/ml.

5. Bone biomarkers: serum osteocalcin, urine cross‐linked N‐telopeptides of type 1 collagen, urine free deoxypyridinoline (at 0, 3, 12, 24 months; also 2, 14 days after first pamidronate infusion in intervention group).

6. Serum calcium, vitamin D (25‐hydroxyvitamin D, 1,25‐dihydroxyvitamin D) and PTH levels (at 0, 3, 12, 24 months).

7. Withdrawals.

8. Survival.

Notes

44 people with CF were eligible during the course of this study, 7 died immediately post‐operatively and were therefore not eligible for this trial. As outlined above, 3 people died during the course of the study before the first primary endpoint measurement. 34 people were included in the final analyses.

Funding was provided by grants from the Cystic Fibrosis Foundation and the Verne S Caviness General Center for Clinical Research.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Blocks of four" design stated (stratified on basis of gender and severity of osteoporosis using spine Z score of ‐3.0), but actual method of randomisation is not discussed.

Allocation concealment (selection bias)

Unclear risk

Not discussed.

Blinding (performance bias and detection bias)
All outcomes

High risk

Person(s) responsible for participants care and participants were not blinded. Of outcome assessors, only the radiologist who interpreted the DXA scans was blinded.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

It was described that 3 participants died during the course of the study before the first primary endpoint measurement (causes of death were 1 each from sepsis, acute respiratory distress syndrome and obliterative bronchiolitis). These participants were excluded from the final analysis of baseline characteristics and outcome data. However, it was not reported which treatment group they were in.

Selective reporting (reporting bias)

High risk

Serum and urine biochemical measurements that were measured at 2 days (only after first pamidronate infusion in intervention group) were not reported.

Other bias

Unclear risk

None identified.

Study characteristics

Methods

Randomised controlled trial; parallel design; double‐blind placebo‐controlled.

Trial duration 1 year for primary outcome measure (trial was intended to be 2 years duration).

Single centre, adult CF centre, USA.

Participants

Inclusion criteria: CF; ambulatory; DXA showed a spine or femur T‐score of ‐1 or less.
Exclusion criteria: primary graft failure or other post‐operative morbidities that precluded long‐term survival; renal insufficiency (serum creatinine > 3.0 mg/dl); active upper gastrointestinal disease; chronic oral glucocorticoid usage (> 10 mg every day); organ transplantation; a history of bisphosphonate intolerance or use; and pregnancy.

101 participants consented to be screened, 86 qualified and 53 started protocol and were randomised.

Total participants: n = 48 (23 female).
Treatment group: n = 24 (9 female); mean (SD) age 28 years (7 years).

Control group: n = 24 (14 female); mean (SD) age 27 years (9 years).

At baseline, osteoporosis was found in 3 participants and osteopenia was present in 20 participants in both the treatment and control groups.

Interventions

Treatment group: oral alendronate (10 mg daily) plus oral vitamin D (800 IU/day) and oral calcium carbonate (1000 mg/day).

Control group: oral vitamin D (800 IU/day) and oral calcium carbonate (1000 mg/day).

Outcomes

Primary outcome

1. BMD spine (at 0, 6, 12, 18, 24 months; DXA Hologic QDR 1000/W Waltham MA, with 12 months data as primary outcome).

Secondary outcomes

1. BMD femur (at 0, 6, 12, 18, 24 months; DXA Hologic QDR 1000/W Waltham MA).

2. New fractures: number of fractures during study; long bone using clinical data, rib using postero‐anterior chest radiographs, vertebral using lateral chest radiographs.

3. Adverse events: number during study; fever; bone pain.

4. Biochemical measurements: serum (parathyroid hormone, 25‐hydroxyvitamin D, 1,25‐dihydroxyvitamin D, osteocalcin, bone‐specific ALP) and urine (cross‐linked N‐telopeptides and deoxypyridinoline).

5. Withdrawals.

6. Survival.

Notes

Funded by the US Food and Drug Administration, Merck and Co. Inc., the Clinical Nutrition Research Unit, the Verne S Caviness General Center for Clinical Research at University of North Carolina, the Cystic Fibrosis Foundation and the National Institute of Diabetes and Digestive and Kidney Diseases.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

"Blocks of four" design stated, but actual method of randomisation is 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.

Clinicians or persons delivering treatment: unclear if clinicians involved in the study and clinicians managing the medical problems of the participants were all blinded.

Outcome assessors: stated that the musculoskeletal radiologist who analysed baseline and end‐of‐study chest radiographs for fracture was blinded, not specifically stated that other outcome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes

High risk

Withdrawals up to 6 months:

5 withdrawals in total, but not stated whether they were in treatment or control group, so 48 participants were evaluable. Reasons for dropping out: pregnancy (n = 1); diarrhoea and weight loss (n = 3); dysphagia (n = 1). The 3 participants with diarrhoea reported abdominal cramping, loss of appetite, and diarrhoea before the medications began that worsened during the study but persisted after the study medications were discontinued, 1 participant was on alendronate and 2 on placebo.

Withdrawals between 6 and 12 months:

4 withdrawals from each group were described.

Treatment group: 4 dropouts; reasons were: transplanted (n = 1); moved (n = 2); non‐compliance (n = 1).
Placebo group: 4 dropouts; reasons were: transplanted (n = 2); died (n = 1); moved (n = 1).

Withdrawals between 1 and 2 years:
Treatment group: 9 dropouts; reasons were: moved (n = 2); committed to only 1 year (n = 7).
Placebo group: 7 dropouts; reasons were: moved (n = 1); committed to only 1 year (n = 6).

The primary endpoint measure was analysed in 40/53 (75%) participants, hence there is a risk of attrition bias.

Stated that an intention‐to‐treat principle was used in the analyses of the treatment endpoints.

Selective reporting (reporting bias)

Low risk

Outcome measures that were described in the methods section were reported in the results section.

Other bias

High risk

Described that protocol was originally designed to be 2 years in length, but few participants were willing to consent to such a lengthy study, so protocol was revised to measure the primary endpoint at 12 months.

Study characteristics

Methods

2 phases:

1. observational phase ‐ 12‐month open‐label trial; followed by

2. intervention phase ‐ 12‐month, parallel, double‐blind randomised, placebo‐controlled trial (included some participants from the observational phase dependent upon criteria as below).

Multicentre: 10 CF regional centres in Italy.

Participants

Observational phase

• Inclusion criteria: aged 2 to 30 years, clinically stable CF, regular menses in female participants who have been through menarche, low bone mineral apparent density age (defined as bone mineral apparent density Z score < ‐2.0 of aged < 18 years, or < ‐2.3 if aged > 18 years).

• Exclusion criteria: 2 or more episodes of hypercalcaemia (serum calcium > 0.26 mmol/L) or hypercalciuria (urinary calcium:creatinine ratio > 0.3), contra‐indications to calcifediol or alendronate, transplantation within the past 3 months, other diseases or drugs (except glucocorticoids) associated with bone loss.

Total participants: n = 171 (84 female).
Age 5 to 18 years: n = 151.
Age 18 to 30 years: n= 20.

Intervention phase

• Inclusion criteria: participants who after 12 months in the observational phase did not have an increase in bone mineral apparent density by 5% or more.

• Exclusion criteria: participants who after 12 months in the observational phase had increased their bone mineral apparent density by 5% or more.

Total participants: n = 128 (63 female).
Age 5 to 18 years: n = 113.
Age 18 to 30 years: n = 15.

Interventions

Observational phase (12 months)

All participants:

• received counselling to adjust their dietary calcium intake to the recommended daily allowance;

• were prescribed oral calcifediol (15 ug/day if bodyweight < 20 kg; 25 ug/day if bodyweight 20 kg to 30 kg; 35 ug/day if bodyweight > 30 kg);

• stopped previous vitamin D supplementation (cholecalciferol 400 IU/day).

Interventional phase (12 months)

• Treatment group:

  • recommended daily allowance of dietary calcium;

  • oral calcifediol (15 ug/day if bodyweight < 20 kg; 25 ug/day if bodyweight 20 kg to 30 kg; 35 ug/day if bodyweight > 30 kg);

  • oral alendronate (5 mg/day if bodyweight < 25 kg or 10 mg/day if bodyweight > 25 kg).

• Control group:

  • recommended daily allowance of dietary calcium;

  • oral calcifediol (15 ug/day if bodyweight < 20 kg; 25 ug/day if bodyweight 20 kg to 30 kg; 35 ug/day if bodyweight > 30 kg);

  • oral placebo.

Outcomes

Primary outcome

• Lumbar spine bone mineral apparent density and Z score with reference (measured 6‐monthly with calculation of mean % change of bone mineral apparent density between baseline and 12 months and between 12 months and 24 months); each participant was always assessed with the same instrument (5 Holigic QDR 4500, 4 Holigic QDR 2000, and 1 Norland XR‐36); each centre had standardised protocols for positioning, scanning, data analysis and calibration.

Secondary outcomes

• Vertebral radiographs after 12 months and 24 months ‐ to detect fractures (according to GEnant's method for vertebral morphometry).

• Incident fractures, height, weight, Tanner pubertal stage were recorded 3‐monthly.

• Biochemistry measures:

  • serum concentrations of calcium, phosphate, N‐parathyroid hormone, 25‐OH vitamin D, markers of bone turnover (osteocalcin, bone‐specific alkaline phosphatase, C‐terminal telopeptide of pro‐collagen 1), blood cell count, hepatic and renal function tests, protein electrophoresis ‐ measured 3‐monthly.

  • urinary measure of bone turnover (N‐terminal telopeptide of procollagen 1) ‐ measured 3‐monthly.

  • serum 1,25(OH) vitamin D ‐ measured at 6 months.

Notes

Funded by Telethon Foundation (Italy).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

The random allocation was undertaken centrally by a statistician using a computer‐generated list of random numbers.

Allocation concealment (selection bias)

Low risk

For each participant enrolled in the randomised phase, the centre of enrolment and participant code, age, and sex were sent to the co‐ordinating centre, which allocated the participant to the alendronate group (odd numbers) or placebo group (even numbers) and sent an unlabelled drug package for that participant. There were 10 centres involved, hence allocation would have been concealed.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Participants, caregivers and the co‐ordinator were masked to treatment allocation until completion of the trial.

The authors confirmed that outcome assessors (nuclear medicine physicians and radiologists) were also blinded.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Every participant who was enrolled in the randomised phase of the study completed the study and their data were analysed and reported. There were no withdrawals and no participants lost to follow‐up. 

Selective reporting (reporting bias)

Low risk

Details of bone density and vertebral radiographs and biochemistry (bone turnover markers, serum calcium, PTH, 25OH vitamin D, 1,25 vitamin D and urinary calcium, phosphate) were reported.

Details of other biochemistry were not reported in details but stated that "no relevant biochemical or haematological anomalies").

Other bias

Unclear risk

There was a 12‐month observation phase in which all participants received counselling to adjust their dietary calcium intake to the recommended daily allowance, they were prescribed oral calcifediol (15 ug/day if bodyweight was under 20 kg; 25 ug/day if bodyweight was between 20 kg and 30 kg; and 35 ug/day if bodyweight was over 30 kg) and previous vitamin D supplementation (cholecalciferol 400 IU/day) was withdrawn (Bianchi 2013). The trial only included those participants in the intervention phase who did not have an increase in bone mineral apparent density by 5% or more after 12 months in the observational phase. If these participants were also included, it is possible the results of the antiresorptive intervention would have shown an even greater positive effect.

Study characteristics

Methods

Randomised, double‐blinded, placebo‐controlled trial; parallel design.

Trial duration 6 months (originally intended for 12 months).

Unclear if single or multicentre trial.

Participants

Inclusion criteria: CF; osteopenia of the lumbar spine (T‐scores ‐1.0 to ‐2.5); serum 25‐hydroxyvitamin D levels ≥ 20 ng/ml prior to infusion.
Exclusion criteria: existing osteoporosis, prior treatment with bisphosphonates or previous lung transplant.

N = 40 planned for enrolment but only 5 enroled (3 in treatment group, gender split not provided) 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

1. BMD lumbar spine (at 0, 6 months (originally planned additionally for 12 months)).

2. 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 characterised by severe chest and back pain. Along with musculoskeletal pain, 1 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

High 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. Did not report on fractures as an outcome however, which is curious for a study on bisphosphonate therapy to improve BMD, even to report that none occurred. 

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 characterised by severe chest and back pain. Along with musculoskeletal pain, 1 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.

Study characteristics

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 1 of 3 sites (hip (femoral neck), lumbar spine 2 to 4 (L2 to L4) and distal forearm) in the month before trial commencement.

Exclusion criteria: pre‐existing, symptomatic, fragility fractures; untreated hyperthyroidism, primary hyperparathyroidism or hypogonadism; bisphosphonate treatment in the 3 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 trial.

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 trial. 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, 1 participant was lost to follow‐up, 1 participant's BMD decreased to withdrawal threshold, 2 participants were poorly compliant to study protocols and in 1 participant, both of the latter 2 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.

Study characteristics

Methods

Randomised controlled trial; parallel design.

Trial duration planned for 1 year, but was shortened to 6 months because of adverse events.

Single centre, UK.

Participants

Inclusion criteria: CF; no organ transplantation; 70% of all eligible participants in a longitudinal BMD study recruited after 1 year of follow‐up; no prior treatment with bone‐sparing agents; BMD Z score of ≦ ‐2 at lumbar spine, proximal femur or distal forearm.

Total participants: n = 31 (9 female); mean (SD) age 26.1 (5.8) years; mean (SD) BMI 21.1 (2.7) kg/m²; mean (SD) FEV₁ 50.9 (20.3) % of predicted treatment. Groups similar with respect to age, initial BMD, bone biochemistry and respiratory disease severity.

Treatment group: n = 15 (more females in this group but exact number not reported).

Control group: n = 16.

3 participants did not complete the study (1 participant in the treatment group received a double lung transplant and 1 participant in each group died of respiratory failure).

Interventions

Treatment group: intravenous pamidronate 30 mg every 3 months for 6 months (2 doses) plus oral calcium (1 g daily).

Control group: oral calcium (1 g daily).

All participants with pancreatic insufficiency (relevant to all except 1 in control group) continued long‐term oral vitamin D (900 IU/day).

Outcomes

• BMD lumbar spine, proximal femur (total hip) (at 0, 6 months; DXA Hologic QDR 4500 Waltham MA).

• BMD distal radius, ultra distal radius (at 0, 6 months; SXA).

• Adverse events (bone pain).

• Withdrawals (total, due to adverse events).

• Survival.

Notes

Received funding from the Cystic Fibrosis Trust in the UK.

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

High risk

Not possible to blind as they did not give placebo infusions, so participants and clinicians would know who was in the treatment group and who in the control group.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Withdrawals were reported; 1 participant in each group died of respiratory failure and 1 participant in the treatment group underwent a double lung transplant.

Selective reporting (reporting bias)

Unclear risk

Outcome measures that were described in the methods section were reported in the results section. Did not report on fractures as an outcome however, which is curious for a study on bisphosphonate therapy to improve BMD, even to report that none occurred. 

Other bias

High risk

Trial duration planned for 1 year, but was shortened to 6 months because of adverse events.

Study characteristics

Methods

Randomised, double‐blinded, placebo‐controlled trial; parallel design.

Trial duration 24 months.

Multicentre: 4 sites in UK, 1 site in Ireland.

Participants

Inclusion criteria: CF (diagnosis on the basis of a positive sweat test or gene analysis and a consistent CF phenotype); >18 years, low BMD defined as lumbar spine, total hip or femoral neck BMD Z score < 1.

Exclusion criteria: prescription of daily oral glucocorticoids for 6 weeks or more in the 12 months preceding the study; breastfeeding, pregnancy, desire to become pregnant within 3 years; listed for, or recipient of solid organ transplant; history of gastroscopy proven oesophageal abnormalities; renal impairment (elevated serum creatinine and an estimated creatinine clearance of  30 ml/min or less); hypocalcaemia; previous prescription of bone active drugs (bisphosphonates, hormone replacement therapy, raloxifene, calcitriol, calcitonin, teriparatide); biochemical evidence of vitamin D deficiency in the 12 months prior to the screening visit (25‐hydroxyvitamin D level < 10 ng/ml and PTH > 45 pg/ml); previous poor clinic attendance; previous poor adherence; pre‐terminal illness or other serious concomitant illness.

Female participants of reproductive age were advised not to become pregnant for at least 12 months after study completion.

Total participants: n = 36 (9 females).

Treatment group: n = 17 (4 females); mean (SD) age 30.2 (12) years.

Control group: n = 19 (5 females); mean (SD) age 27.8 (8.0) years.

Interventions

Treatment group: once weekly oral risedronate 35 mg.

Control group: once weekly identical placebo.

Both groups were both prescribed Calcichew D3 Forte 2 tablets daily which provides 1000 mg calcium + 800 IU vitamin D3/day. Participants were advised to continue their standard multivitamin supplements.

Outcomes

• BMD assessed by DXA at lumbar spine, total hip and femoral neck (at baseline, 12 and 24 months).

• Lateral thoracic and lumbar spine X‐rays to assess for new vertebral fractures (at baseline and 24 months).

• Recorded X‐ray confirmed fractures (3, 6, 12, 18 and 24 months).

• Adverse events (at 3, 6, 12, 18 and 24 months).

• Biochemical measurements: serum concentration of C‐terminal cross‐linked telopeptide of collagen type 1 (CTX) (at baseline and 6‐month visits in 24 patients (12 risedronate, 12 placebo).

• Withdrawals.

• Survival.

Notes

Concomitant medications were recorded at study visits (3, 6, 12, 18 and 24 months).

Pregnancy tests were performed in females at study visits (3, 6, 12, 18 and 24 months).

Funded by unrestricted educational grants from Proctor & Gamble (Norwich, USA) and the Cystic Fibrosis Trust, with support to investigators from the UK National Institute of Health and Care Research.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Participants were allocated to risedronate or placebo using a computer program to minimise differences between groups in treatment centre, sex and baseline lumbar spine BMD.

Allocation concealment (selection bias)

Low risk

Only the study pharmacist had access to the treatment allocation.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Identical placebo used.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Withdrawals are described in full and fairly equally spread across groups.

Intervention group

In first 12 months: 3 out of 17 in the oral risedronate group withdrew from the trial completely (due to bone pain) and 3 participants discontinued the medication (1 citing bone pain and the other 2 participants citing muscle aches or generalised pain) but remained in the trial for follow‐up.

Between 12 and 24 months: 1 further participant withdrew, citing bone pain.

At 24 months: 12 participants in the intervention group remained in trial with 9 still taking the drug.

Placebo group

Immediately after randomisation: 1 participant in the placebo group withdrew consent before taking the medication. Therefore, only 18 participants were commenced on placebo.

In first 12 months: 2 participants in the placebo group withdrew consent and 1 participant had died.

By 24 months: 3 participants in the placebo group had withdrawn consent and 4 participants had died, hence at 24 months, 12 participants remained in the control group.

Primary outcome data included 12/17 of risedronate group (although only 9 still on drug); 12/19 placebo group. In the published abstract, it was not clear if the analysis included the 3 participants.

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.

Study characteristics

Methods

Randomised controlled trial; parallel design; open‐comparison. 

12‐month duration.

Participants

Inclusion criteria: CF, BMD Z score < ‐2 SD.

Exclusion criteria: not detailed.

Total participants: n = 20 (12 males, 8 females; age range 24 +/‐5 years).

Treatment group: n = 10 (7 males, 3 females; age range 23.4 +/‐ 2.46 years).

Control group: n = 10 (6 males, 4 females; age range 25.9 +/‐ 6.0 years).

Groups similar BMI, FEV1, bone density, Z score at study onset.

Interventions

Treatment group: alendronate/colecalciferol (70 mg/2800 ME) once a week + colecalciferol/calcium (200 ME/500 mg) twice a day.

Control group: colecalciferol/calcium (400 ME/500 mg) twice a day.

Outcomes

• BMD assessed by DXA at lumbar spine and proximal femur (at baseline and 12 months).

• Biochemical measurement: osteocalcin and beta‐cross laps (at baseline, 3 and 12 months). 

• Vertebral and non‐vertebral fractures.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No mention of how sequence was generated.

Allocation concealment (selection bias)

Unclear risk

No mention of concealment.

Blinding (performance bias and detection bias)
All outcomes

High risk

Open comparison.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Does not explicitly mention whether or not there were withdrawals from the trial.

Selective reporting (reporting bias)

Unclear risk

Insufficient detail in results.

Other bias

Unclear risk

No mention of funding or conflict of interest.

Study characteristics

Methods

Randomised, placebo‐controlled trial, parallel design.

Trial duration: 12 months.

Multicentre: 6 Canadian CF specialty clinics.

Participants

Inclusion criteria: participants had CF confirmed by positive sweat test result or DNA acid analysis and a BMD T score of 1.0, as determined by DXA.

Exclusion criteria: organ transplantation; endoscopy‐proven oesophagitis, gastritis, and ulceration; metabolic bone disorders; severe renal disease; use of systemic corticosteroids (dose 7.5 mg/day) or other drugs known to influence bone metabolism in the previous 6 months; osteomalacia and other documented contraindications.

Total adults randomised: n = 56 (22 female). 9 withdrew, 47 completed trial.

Treatment group: n = 27 (10 female); mean (SD) age 28.1 (7.7) years. 4 withdrew, 23 completed trial.

Control group: n = 29 (12 female); mean (SD) age 30.9 (9.7) years. 5 withdrew, 24 completed trial.

Interventions

Treatment group: oral alendronate (70 mg) once weekly for 12 months.

Control group: placebo.

Medication was taken while sitting upright and with water only on an empty stomach at least 30 minutes before first food or beverage of the day. In addition, all participants received 800 IU of vitamin D and 1000 mg of calcium (500 mg supplementation, 500 mg from diet) daily.

Outcomes

In‐clinic assessments at baseline, 6 and 12 months; telephone follow‐up conducted by study staff at months 3 and 9.

1. Compliance (measured through pill counts at each visit and patient self‐report during telephone contact).

2. Physical examination ‐ vital signs (at baseline, 6 and 12 months).

3. Biochemical measurements: serum and urine tests (at baseline, 6 and 12 months).

4. Pulmonary function tests: including FEV₁ and FVC (at baseline, 6 and 12 months).

5. Medical Outcomes Study 36‐item short form version 2 (SF‐36v2) (at baseline, 6 and 12 months).

6. Radiographs of the thoracic and lumbar spine, and DXA (at baseline, 6 and 12 months).

7. Adverse events and drug reactions (reported spontaneously and at each contact).

Safety analyses included all vertebral fractures, osteoporosis‐related fractures, adverse reactions, and abnormal findings that had been detected through laboratory tests and physical examinations.

Documentation for all adverse events were blinded and adjudicated by the external Data Safety Monitoring Committee. All adverse events were reported regardless of attribution to study medication.

Notes

Participants who received at least 80% of the drug were classified as being adherent to the protocol. 5 participants completed the trial protocol but received sub‐optimal dosing (< 80% adherence; treatment group, 3 participants; control group, 2 participants). 1 of the participants in the treatment group missed > 50% of doses.

Stopping and study withdrawal rules were monitored by an external Data Safety Monitoring Committee.

During the trial, 3 participants in the treatment group used oral corticosteroids compared to none in the control group.

Study funding provided by Merck Frosst Canada.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomisation code, stratified according to institution was prepared by an independent randomisation centre and block allocation was employed to ensure equitable distribution to each treatment group.

Allocation concealment (selection bias)

Low risk

The randomisation code was prepared by an independent randomisation centre and the medication treatment arm was concealed from all participants, central and local site coordinators, physicians, staff, and caregivers.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Person(s) responsible for participants care, participants and outcome assessors were blinded to treatment group allocation.

A medical physicist, who was blinded to the study treatment arm and study status, reviewed all DXA scans. Radiographs were sent to the central methods centre, and read independently by 2 radiologists who were blinded to the study treatment arm. Differences between radiologists were resolved by consensus.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All analyses were performed as intention‐to‐treat and included all available data. Withdrawals were described.

Treatment group: 27 randomised, 4 withdrew (2 non‐compliance, 1 due to adverse event, 1 withdrew consent). 23 completed study.

Control group: 29 randomised, 5 withdrew (2 non‐compliance, 2 due to adverse event, 1 lost to follow‐up). 24 completed study.

Selective reporting (reporting bias)

Low risk

Outcome measures that were described in the methods section were reported in the results section. It was reported that there were no differences in baseline CRP, 25‐hydroxyvitamin D, PTH or CTX levels between the risedronate group who experienced bone pain and those that did not (but data not shown).

Other bias

Low risk

None identified.