Methods

Randomised controlled trial, parallel design, trial duration 2 years.
Randomised in a "blocks of four" design, stratified on basis of gender and severity of osteoporosis using spine z‐score of ‐3.0;
Participant and provider not blinded, not all outcome assessors were blinded, only the radiologist who interpreted the DXA scans;
Generation of allocation sequence was stated ("blocks of four" design). Allocation concealment was unclear;
3 participants died during the course of the study, before the first primary end point measurement, and were excluded from the analyses, including the final analysis of baseline characteristics. The causes of death were one each from sepsis, acute respiratory distress syndrome and obliterative bronchiolitis. It was not reported whether they received intervention;

Participants

Single centre, university hospital, USA;

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;

N = 34 (16 in treatment group); 17 female (7 in treatment group).
Treatment group: mean (SD) age 27.5 years (6.6 years); control group 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 body mass index over study period.

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

Interventions

Intravenous pamidronate (30 mg every 3 months) for study duration of 2 years;

All participants received oral vitamin D (800IU/day) and oral calcium (1g/day).

Outcomes

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

Secondary outcomes:
BMD (femur; 0, 6, 12, 18, 24 months; DXA Hologic QDR 1000/W Waltham MA);
New fractures (number of fractures during study; long bone using clinical data, rib using posteroanterior chest radiographs, vertebral using lateral chest radiographs);
Kyphosis angles (degrees; 0, 24 months; thoracic spine curvature using lateral chest radiographs using a modification of method of Cobb);
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);
Bone biomarkers (serum osteocalcin, urine cross‐linked N‐telopeptides of type 1 collagen, urine free deoxypyridinoline; 0, 3, 12, 24 months; also 2, 14 days after first pamidronate infusion in intervention group);
Serum calcium, vitamin D (25‐hydroxyvitamin D, 1,25‐dihydroxyvitamin D) and PTH levels (0, 3, 12, 24 months);
Withdrawals;
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 end point measurement. 34 people were included in the final analyses.

Risk of bias

Bias

Authors' judgement

Support for judgement

Adequate sequence generation?

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?

Unclear risk

Not discussed.

Blinding?
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 addressed?
All outcomes

Unclear risk

It was described that 3 participants died during the course of the study before the first primary end point measurement. 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.

Free of selective reporting?

High risk

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

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).

Generation of allocation sequence was stated ("blocks of four" design). Allocation concealment was unclear.

Withdrawals ‐ before 6‐month DXA
5 participants in total, but not stated from which group, so 48 participants were evaluable. Reasons for dropping out:pregnancy (n=1); diarrhoea and weight loss (n=3); dysphagia (n=1). The three 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, one participant was on alendronate and two on placebo.

Withdrawals ‐ between 6 and 12 months
Intervention group: 4 drop‐outs; reasons were: transplanted = 1; moved = 2; non‐compliance = 1.
Placebo group: 4 drop‐outs; reasons were: transplanted = 2; died = 1; moved = 1.

Withdrawals between 1 and 2 years
Intervention group: 9 drop‐outs; reasons were: moved = 2; committed to only 1 year = 7.
Placebo group: 7 drop‐outs; reasons were: moved = 1; committed to only one year = 6.

Participants

Single centre, adult CF centre, USA.

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, renal insufficiency (serum creatinine > 3.0mg/dl), a history of bisphosphonate intolerance or use, and pregnancy.

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

N = 48 (24 in treatment group); 23 female (9 in treatment group).
Treatment group: mean (SD) age 28 years (7 years); control group: 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 group.

Interventions

Oral alendronate (10mg daily);

All participants received oral vitamin D (800IU/day) and oral calcium carbonate (1000mg/day).

Outcomes

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

Secondary outcomes:
BMD (femur; 0, 6, 12, 18, 24 months; DXA Hologic QDR 1000/W Waltham MA);
New fractures (number of fractures during study; long bone using clinical data, rib using posteroanterior chest radiographs, vertebral using lateral chest radiographs);
Adverse events (number during study; fever, bone pain);
Serum (parathyroid hormone, 25‐hydroxyvitamin D, 1,25‐dihydroxyvitamin D, osteocalcin, bone‐specific ALP) and urine (cross‐linked N‐telopeptides and deoxypyridinoline) biochemical measurements;
Withdrawals;
Survival.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Adequate sequence generation?

Unclear risk

"Blocks of four" design stated, but actual method of randomisation is not discussed.

Allocation concealment?

Unclear risk

Not discussed.

Blinding?
All outcomes

Unclear risk

Described as "double‐blind".

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

Participants: blinded.

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

Incomplete outcome data addressed?
All outcomes

Unclear 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.

5 withdrawals between commencement of protocol and 6‐month outcome measures were described, but not delineated whether they were in treatment or control group.

4 withdrawals from each group (between 6 months and 12 months outcome measures) were described.

The primary end‐point 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.

Free of selective reporting?

Low risk

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

Methods

Randomised, double‐blinded, placebo‐controlled trial; parallel design. Trial duration 6 months (originally intended for 12 months).
Generation of allocation sequence and allocation concealment were unclear.

Participants

N = 40 planned for enrolment but only 5 enrolled (3 in treatment group) before study stopped by Data and Safety Monitoring Board (see notes).

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.

Interventions

Intravenous zoledronate, 5 mg infusion administered on a single occasion over 20 minutes.

All participants received supplemental oral vitamin D (800 IU) and oral calcium (1000mg) daily.

Outcomes

BMD (lumbar spine) ‐ 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^oF 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

Adequate sequence generation?

Unclear risk

Not reported.

Allocation concealment?

Unclear risk

Not discussed.

Blinding?
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 addressed?
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.

Free of selective reporting?

High risk

Abstract only but outcome measures were described in the results.

Free of other bias?

Unclear risk

Insufficient data in abstract to be clear.

Methods

Randomised, double‐blinded, placebo‐controlled trial; parallel design. Trial duration 24 months.
Generation of allocation sequence and allocation concealment were unclear.

Participants

Multientre, 2 sites, CF clinics, Australia.

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 three 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.

N=22 (10 in treatment group); 17 male (7 in treatment group), 5 females (3 in treatment group).

Treatment group: mean (SD) age 30.1 (2.2) years; control group: mean (SD) age 28.6 (2.4) years. Age range over all: males 21 to 47 years, females 19 to 28 years.

Interventions

Treatment group: intravenous zoledronic acid (zoledronate) in 100mls of normal saline infused over 15 minutes every 3 months for 21 months (eight infusions in total). For 5 out of 63 doses, 4mg zoledronate was administered, then dose reduced to 2mg for subsequent doses (due to febrile reactions to the higher dose in several participants).

Placebo group: 100 mls 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 prednisolone 25 mg orally per 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:‐ baseline, 6, 12 and 24 months.

Plain x‐rays of thoracic and lumbar spine: baseline and 24 months (additional films taken as indicated to confirm any suspected fractures).

Biochemical measurements (baseline and two weeks before the 6, 12, 18 and 24 months time‐points: urea; creatinine; ALP; ALT; bilirubin; calcium (corrected); calcium (ionised); phosphate; 25‐hydroxyvitamin D; PTH; complete blood count and differential.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Adequate sequence generation?

Unclear risk

Not discussed.

Allocation concealment?

Unclear risk

Not discussed.

Blinding?
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 addressed?
All outcomes

Unclear risk

Withdrawals described.

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).

Free of selective reporting?

Low risk

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

Methods

Randomised controlled trial; parallel design. Trial duration planned for 1 year, but was shortened to 6 months because of adverse events.

Generation of allocation sequence and allocation concealment were unclear.

Not stated if participants, providers or outcome assessors (or all) were blinded.

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).

Participants

Single centre, UK.

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

N = 31 (15 in treatment group); 9 female (more in treatment group but exact number not reported).

Mean (SD) age 26.1 (5.8) years; BMI 21.1 (2.7) kg/m²; FEV1 50.9 (20.3) % of predicted treatment. Groups similar with respect to age, initial BMD, bone biochemistry and respiratory disease severity.

3 participants (2 from treatment group) withdrew.

Interventions

Intravenous pamidronate 30 mg every 3 months for 6 months (2 doses).

All participants with pancreatic insufficiency (relevant to all except one in control group) continued long term oral vitamin D (900 IU/day); all participants in both groups received oral calcium (1g daily).

Outcomes

BMD (lumbar spine; proximal femur (total hip); 0, 6 months; DXA Hologic QDR 4500 Waltham MA);
BMD (distal radius, ultradistal radius; 0, 6 months; SXA);
Adverse events (bone pain);
Withdrawals (total, due to adverse events);
Survival.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Adequate sequence generation?

Unclear risk

Not reported.

Allocation concealment?

Unclear risk

Not discussed.

Blinding?
All outcomes

Unclear risk

Not reported.

Incomplete outcome data addressed?
All outcomes

Low risk

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

Free of selective reporting?

Low risk

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

Free of other bias?

Unclear risk

Given insufficient data, we are unclear of other bias.