Review question
What are the effects of bisphosphonates (drugs that prevent the loss of bone mass), either oral (taken by mouth) or intravenous (given directly into a vein), on osteoporosis in people with cystic fibrosis (CF)?
Background
Cystic fibrosis is a serious genetic disorder that affects many organs in the body (e.g. lungs and pancreas). Around 23.5% of people with CF experience reduced bone mineral density (BMD), commonly known as osteoporosis, which increases the likelihood of bone fractures. The short-term and long-term effects of fractures (e.g. ribs and in the spine) may make lung disease worse, and hospitalisation more frequent. Bisphosphonates are drugs that increase BMD by slowing down how fast bone is resorbed. They are used to treat osteoporosis caused by the menopause or the use of corticosteroid drugs. We wanted to know if bisphosphonates affect the frequency of bone fractures, BMD and quality of life, and if they have any side effects in people with CF. This is an update of a previous review.
Search date
The evidence is current to 5 May 2022.
Study characteristics
We included nine trials with 272 adults and 113 children (aged five to 18 years) lasting from six months to two years. Eight trials included 238 adults without lung transplants; three of these gave intravenous bisphosphonates (one gave pamidronate and two gave zoledronate) and five trials gave oral bisphosphonates (one gave risedronate and four gave alendronate). Trials compared bisphosphonates to either placebo (drug with no active treatment) or calcium (with or without additional vitamin D). One of these eight trials, comparing oral alendronate to placebo, also included 113 children and we analysed their results separately. The last trial of 34 adults who had undergone lung transplantation compared intravenous pamidronate to no bisphosphonate treatment.
Key results
Bisphosphonates consistently increased BMD in adults at the lumbar spine and hip regions. It also increased BMD in children at the lumbar spine. Treatment with bisphosphonates did not appear to reduce the rates of fractures (either in the spine or elsewhere) or deaths in adults or children. However, this may be related to the small numbers of participants involved and the short duration of the trials. Severe bone pain and flu-like symptoms were commonly linked to intravenous bisphosphonates, especially in people not using corticosteroids. More research is needed to assess the effect of pre-treatment with corticosteroids. Additional trials are needed to determine if bone pain is more common or severe (or both) with the stronger drug zoledronate and if corticosteroids lessen or prevent these adverse events. Additional trials should also assess gastrointestinal adverse effects in the stomach and digestive tract which are linked to oral bisphosphonates. Trials with larger numbers of participants with longer follow-up are needed to show how bisphosphonates affect fracture rate and survival. More trials including children with cystic fibrosis should be undertaken to better understand the effects, benefits and harms these drugs may have on them.
Bisphosphonates compared to control in people with CF who have not had a lung transplant
Adults
Five trials (142 participants) reported no difference between treatment or control groups in new vertebral or non-vertebral fractures at 12 months and two trials (44 participants) reported no fractures at 24 months. At 12 months, results from six trials (171 participants) showed bisphosphonates may increase BMD at the lumbar spine and five trials (155 participants) reported the same effect on BMD at the hip or femur. There was no clear difference in quality of life (QoL) scores at 12 months, but bisphosphonates probably led to more bone pain at 12 months as reported by seven trials (206 participants).
Children
At 12 months we found no difference between treatment and placebo in new vertebral or non-vertebral fractures. Bisphosphonates may increase BMD at the lumbar spine at 12 months. There was no difference in bone or muscle pain, in fever or in gastrointestinal side effects. The trial did not measure BMD at the hip/femur or report on QoL.
Bisphosphonates compared to control in people with CF who have had a lung transplant
This trial only reported results at 24 months. There was no difference in the number of fractures, either vertebral or non-vertebral, but BMD increased with treatment at the lumbar spine and femur. No one in either group reported either bone pain or fever. The trial did not measure QoL.
Certainty of the evidence
The certainty of the evidence was mixed and we had some concerns regarding different aspects of bias in all trials. At least three of the trials were partially funded by pharmaceutical companies. In one trial the people looking at the bone scans and reporting them may have known which participants had been treated with bisphosphonates; this knowledge may have affected their objectivity. Two trials did not report on fractures, but we do not think these are likely to have significantly changed the review's results.
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.
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.
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.
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.
Randomised controlled trials of at least six months duration studying bisphosphonates in people with cystic fibrosis.
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.
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.