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. 2023 Jan 10;1(1):CD002010.
doi: 10.1002/14651858.CD002010.pub5.

Bisphosphonates for osteoporosis in people with cystic fibrosis

Tomas C Jeffery  1 , Anne B Chang  2 , Louise S Conwell  3   4
Affiliations

Bisphosphonates for osteoporosis in people with cystic fibrosis

Tomas C Jeffery et al. Cochrane Database Syst Rev. .

Abstract

Background: Osteoporosis is a disorder of bone mineralisation occurring in about one third of adults with cystic fibrosis. Bisphosphonates can increase bone mineral density and decrease the risk of new fractures in post-menopausal women and people receiving long-term oral corticosteroids. This is an updated version of a previous review.

Objectives: To assess the effects of bisphosphonates on the frequency of fractures, bone mineral density, quality of life, adverse events, trial withdrawals, and survival in people with cystic fibrosis.

Search methods: We searched the Cystic Fibrosis and Genetic Disorders Group's Trials Register of references (identified from electronic database searches and hand searches of journals and abstract books) on 5 May 2022. We performed additional searches of PubMed, clinicaltrials.gov and the WHO ICTRP (International Clinical Trials Registry Platform) on 5 May 2022.

Selection criteria: Randomised controlled trials of at least six months duration studying bisphosphonates in people with cystic fibrosis.

Data collection and analysis: Authors independently selected trials, extracted data and assessed risk of bias in included studies. Trial investigators were contacted to obtain missing data. We judged the certainty of the evidence using GRADE.

Main results: We included nine trials with a total of 385 participants (272 adults and 113 children (aged five to 18 years)). Trial durations ranged from six months to two years. Only two of the studies were considered to have a low risk of bias for all the domains. Bisphosphonates compared to control in people with cystic fibrosis who have not had a lung transplant Seven trials included only adult participants without lung transplants, one trial included both adults and children without lung transplantation (total of 238 adults and 113 children). We analysed adults (n = 238) and children (n = 113) separately. Adults Three trials assessed intravenous bisphosphonates (one assessed pamidronate and two assessed zoledronate) and five trials assessed oral bisphosphonates (one assessed risedronate and four assessed alendronate). Bisphosphonates were compared to either placebo or calcium (with or without additional vitamin D). Data showed no difference between treatment or control groups in new vertebral fractures at 12 months (odds ratio (OR) 0.22, 95% confidence interval (CI) 0.02 to 2.09; 5 trials, 142 participants; very low-certainty evidence) and two trials (44 participants) reported no vertebral fractures at 24 months. There was no difference in non-vertebral fractures at 12 months (OR 2.11, 95% CI 0.18 to 25.35; 4 trials, 95 participants; very low-certainty evidence) and again two trials (44 participants) reported no non-vertebral fractures at 24 months. There was no difference in total fractures between groups at 12 months (OR 0.57, 95% CI 0.13 to 2.50; 5 trials, 142 participants) and no fractures were reported in two trials (44 participants) at 24 months. At 12 months, bisphosphonates may increase bone mineral density at the lumbar spine (mean difference (MD) 6.31, 95% CI 5.39 to 7.22; 6 trials, 171 participants; low-certainty evidence) and at the hip or femur (MD 4.41, 95% 3.44 to 5.37; 5 trials, 155 participants; low-certainty evidence). There was no clear difference in quality of life scores at 12 months (1 trial, 47 participants; low-certainty evidence), but bisphosphonates probably led to more adverse events (bone pain) at 12 months (OR 8.49, 95% CI 3.20 to 22.56; 7 trials, 206 participants; moderate-certainty evidence). Children The single trial in 113 children compared oral alendronate to placebo. We graded all evidence as low certainty. At 12 months we found no difference between treatment and placebo in new vertebral fractures (OR 0.32, 95% CI 0.03 to 3.13; 1 trial, 113 participants) and non-vertebral fractures (OR 0.19, 95% CI 0.01 to 4.04; 1 trial, 113 participants). There was also no difference in total fractures (OR 0.18, 95% CI 0.02 to 1.61; 1 trial, 113 participants). Bisphosphonates may increase bone mineral density at the lumbar spine at 12 months (MD 14.50, 95% CI 12.91 to 16.09). There was no difference in bone or muscle pain (MD 3.00, 95% CI 0.12 to 75.22), fever (MD 3.00, 95% CI 0.12 to 75.22) or gastrointestinal adverse events (OR 0.67, 95% CI 0.20 to 2.26). The trial did not measure bone mineral density at the hip/femur or report on quality of life. Bisphosphonates compared to control in people with cystic fibrosis who have had a lung transplant One trial of 34 adults who had undergone lung transplantation compared intravenous pamidronate to no bisphosphonate treatment. It did not report at 12 months and we report the 24-month data (not assessed by GRADE). There was no difference in the number of fractures, either vertebral or non-vertebral. However, bone mineral density increased with treatment at the lumbar spine (MD 6.20, 95% CI 4.28 to 8.12) and femur (MD 7.90, 95% CI 5.78 to 10.02). No participants in either group reported either bone pain or fever. The trial did not measure quality of life.

Authors' conclusions: Oral and intravenous bisphosphonates may increase bone mineral density in people with cystic fibrosis, but there are insufficient data to determine whether treatment reduces fractures. Severe bone pain and flu-like symptoms may occur with intravenous bisphosphonates. Before any firm conclusions can be drawn, trials in larger populations, including children, and of longer duration are needed to determine effects on fracture rate and survival. Additional trials are needed to determine if bone pain is more common or severe (or both) with the more potent zoledronate and if corticosteroids can ameliorate or prevent these adverse events. Future trials should also assess gastrointestinal adverse effects associated with oral bisphosphonates.

Trial registration: ClinicalTrials.gov NCT01702415 NCT01882400.

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Conflict of interest statement

Tomas Jeffery declares no known potential conflict of interest.

Louise S Conwell declares she has worked as a consultant to Zealand Pharma A/S on studies in the field of congenital hyperinsulinism. All remuneration going to an account within Children's Health Queensland Hospital and Health Service to be used towards clinical service enhancement for the field of congenital hyperinsulinism.

Anne B Chang declares no known potential conflict of interest.

Figures

1
1
Selection process for this update.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Forest plot of comparison between bisphosphonates versus control (without lung transplantation), Outcome 1a Number of participants with any fracture.
5
5
Forest plot of comparison between bisphosphonates versus control (without lung transplantation), Outcome 1b i. Number of participants with non‐vertebral fractures.
6
6
Forest plot of comparison between bisphosphonates versus control (without lung transplantation), Outcome 1b ii. Number of participants with vertebral fractures.
1.1
1.1. Analysis
Comparison 1: Bisphosphonates versus control (without lung transplantation) ‐ adults (18 years and over), Outcome 1: Total fractures
1.2
1.2. Analysis
Comparison 1: Bisphosphonates versus control (without lung transplantation) ‐ adults (18 years and over), Outcome 2: Non‐vertebral fractures
1.3
1.3. Analysis
Comparison 1: Bisphosphonates versus control (without lung transplantation) ‐ adults (18 years and over), Outcome 3: Vertebral fractures
1.4
1.4. Analysis
Comparison 1: Bisphosphonates versus control (without lung transplantation) ‐ adults (18 years and over), Outcome 4: % change in BMD, lumbar spine [DXA]
1.5
1.5. Analysis
Comparison 1: Bisphosphonates versus control (without lung transplantation) ‐ adults (18 years and over), Outcome 5: % change in BMD, lumbar spine [DXA] (end of trial data only)
1.6
1.6. Analysis
Comparison 1: Bisphosphonates versus control (without lung transplantation) ‐ adults (18 years and over), Outcome 6: % change in BMD, total hip/femur [DXA]
1.7
1.7. Analysis
Comparison 1: Bisphosphonates versus control (without lung transplantation) ‐ adults (18 years and over), Outcome 7: % change in BMD, total hip/femur [DXA] (end of trial data only)
1.8
1.8. Analysis
Comparison 1: Bisphosphonates versus control (without lung transplantation) ‐ adults (18 years and over), Outcome 8: % change in BMD, distal radius [SXA]
1.9
1.9. Analysis
Comparison 1: Bisphosphonates versus control (without lung transplantation) ‐ adults (18 years and over), Outcome 9: % change in BMD, distal radius [SXA] (end of trial data only)
1.10
1.10. Analysis
Comparison 1: Bisphosphonates versus control (without lung transplantation) ‐ adults (18 years and over), Outcome 10: % change in BMD, ultra distal radius [SXA]
1.11
1.11. Analysis
Comparison 1: Bisphosphonates versus control (without lung transplantation) ‐ adults (18 years and over), Outcome 11: QoL
1.12
1.12. Analysis
Comparison 1: Bisphosphonates versus control (without lung transplantation) ‐ adults (18 years and over), Outcome 12: Bone pain
1.13
1.13. Analysis
Comparison 1: Bisphosphonates versus control (without lung transplantation) ‐ adults (18 years and over), Outcome 13: Fever
1.14
1.14. Analysis
Comparison 1: Bisphosphonates versus control (without lung transplantation) ‐ adults (18 years and over), Outcome 14: Withdrawals due to adverse events
1.15
1.15. Analysis
Comparison 1: Bisphosphonates versus control (without lung transplantation) ‐ adults (18 years and over), Outcome 15: Withdrawals (total)
1.16
1.16. Analysis
Comparison 1: Bisphosphonates versus control (without lung transplantation) ‐ adults (18 years and over), Outcome 16: Survival
2.1
2.1. Analysis
Comparison 2: Bisphosphonates versus control (without lung transplantation) ‐ children up to 18 years of age, Outcome 1: Total fractures
2.2
2.2. Analysis
Comparison 2: Bisphosphonates versus control (without lung transplantation) ‐ children up to 18 years of age, Outcome 2: Non‐vertebral fractures
2.3
2.3. Analysis
Comparison 2: Bisphosphonates versus control (without lung transplantation) ‐ children up to 18 years of age, Outcome 3: Vertebral fractures
2.4
2.4. Analysis
Comparison 2: Bisphosphonates versus control (without lung transplantation) ‐ children up to 18 years of age, Outcome 4: % change in BMD, lumbar spine, DXA
2.5
2.5. Analysis
Comparison 2: Bisphosphonates versus control (without lung transplantation) ‐ children up to 18 years of age, Outcome 5: Bone or muscle pain
2.6
2.6. Analysis
Comparison 2: Bisphosphonates versus control (without lung transplantation) ‐ children up to 18 years of age, Outcome 6: Fever
2.7
2.7. Analysis
Comparison 2: Bisphosphonates versus control (without lung transplantation) ‐ children up to 18 years of age, Outcome 7: Gastrointestinal adverse events
2.8
2.8. Analysis
Comparison 2: Bisphosphonates versus control (without lung transplantation) ‐ children up to 18 years of age, Outcome 8: Headache
2.9
2.9. Analysis
Comparison 2: Bisphosphonates versus control (without lung transplantation) ‐ children up to 18 years of age, Outcome 9: Any adverse event
2.10
2.10. Analysis
Comparison 2: Bisphosphonates versus control (without lung transplantation) ‐ children up to 18 years of age, Outcome 10: Withdrawals, due to adverse events
2.11
2.11. Analysis
Comparison 2: Bisphosphonates versus control (without lung transplantation) ‐ children up to 18 years of age, Outcome 11: Withdrawals, total
2.12
2.12. Analysis
Comparison 2: Bisphosphonates versus control (without lung transplantation) ‐ children up to 18 years of age, Outcome 12: Survival
3.1
3.1. Analysis
Comparison 3: Bisphosphonates versus control (with lung transplantation) ‐ adults (18 years and over), Outcome 1: Total Fractures
3.2
3.2. Analysis
Comparison 3: Bisphosphonates versus control (with lung transplantation) ‐ adults (18 years and over), Outcome 2: Non‐vertebral fractures
3.3
3.3. Analysis
Comparison 3: Bisphosphonates versus control (with lung transplantation) ‐ adults (18 years and over), Outcome 3: Vertebral fractures
3.4
3.4. Analysis
Comparison 3: Bisphosphonates versus control (with lung transplantation) ‐ adults (18 years and over), Outcome 4: % change in BMD, lumbar spine, DXA
3.5
3.5. Analysis
Comparison 3: Bisphosphonates versus control (with lung transplantation) ‐ adults (18 years and over), Outcome 5: % change in BMD, femur, DXA
3.6
3.6. Analysis
Comparison 3: Bisphosphonates versus control (with lung transplantation) ‐ adults (18 years and over), Outcome 6: Bone pain
3.7
3.7. Analysis
Comparison 3: Bisphosphonates versus control (with lung transplantation) ‐ adults (18 years and over), Outcome 7: Withdrawals, due to adverse events
3.8
3.8. Analysis
Comparison 3: Bisphosphonates versus control (with lung transplantation) ‐ adults (18 years and over), Outcome 8: Withdrawals, total
3.9
3.9. Analysis
Comparison 3: Bisphosphonates versus control (with lung transplantation) ‐ adults (18 years and over), Outcome 9: Survival
See this image and copyright information in PMC

Update of

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