Bisphosphonates for osteoporosis in people with cystic fibrosis

Cystic fibrosis is a serious genetic disorder that affects many organs (e.g. lung and pancreas). It commonly leads to reduced bone mineral density, known as osteoporosis, which increases the likelihood of fractures. The short-term and long-term effects of fractures (e.g. rib and vertebral) may make lung disease worse. Bisphosphonates are drugs that increase bone mineral density by slowing down bone resorption. They are used to treat osteoporosis caused by menopause or the use of corticosteroid drugs.

The evidence available was limited to six trials with participants who had not undergone lung transplants (total of 203 adults) and one trial with 34 adults who had undergone lung transplantation. Bisphosphonates consistently increased bone mineral density at the lumbar spine and hip regions. The rates of fractures (vertebral and non-vertebral) or deaths were not reduced by bisphosphonate therapy. 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 are also required to further assess gastrointestinal adverse effects associated with oral bisphosphonates. Trials in larger populations are needed to determine effects on fracture rate and survival.

Authors' conclusions: 

Oral and intravenous bisphosphonates increase bone mineral density in people with cystic fibrosis. Severe bone pain and flu-like symptoms may occur with intravenous agents. Additional trials are needed to determine if bone pain is more common or severe (or both) with the more potent zoledronate and if corticosteroids ameliorate or prevent these adverse events. Additional trials are also required to further assess gastrointestinal adverse effects associated with oral bisphosphonates. Trials in larger populations are needed to determine effects on fracture rate and survival.

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Background: 

Osteoporosis is a bone mineralisation disorder 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.

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 strategy: 

We searched the Cystic Fibrosis and Genetic Disorders Group Trials Register of references (identified from electronic database searches and handsearches of journals and abstract books) on 13 January 2014.

Additional searches of PubMed were performed on 13 January 2014.

Selection criteria: 

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

Data collection and analysis: 

Two authors independently selected trials and extracted data. Trial investigators were contacted to obtain missing data.

Main results: 

Nine trials were identified and seven (with a total of 237 adult participants) were included.

Data were combined (when available) from six included studies in participants without a lung transplant. Data showed that there was no significant reduction in fractures between treatment and control groups at 12 months, odds ratio 0.72 (95% confidence interval 0.13 to 3.80). No fractures were reported in studies with follow-up at 24 months. However, in patients taking bisphosphonates after six months the percentage change in bone mineral density increased at the lumbar spine, mean difference 4.61 (95% confidence interval 3.90 to 5.32) and at the hip or femur, mean difference 3.35 (95% confidence interval 1.63 to 5.07); but did not significantly change at the distal forearm, mean difference -0.49 (95% confidence interval -2.42 to 1.45). In patients taking bisphosphonates, at 12 months the percentage change in bone mineral density increased at the lumbar spine, mean difference 6.10 (95% confidence interval 5.10 to 7.10) and at the hip or femur, mean difference 4.35 (95% confidence interval 2.99 to 5.70). At 24 months, in patients treated with bisphosphonates the percentage change in bone mineral density also increased at the lumbar spine, mean difference 5.49 (95% confidence interval 4.38 to 6.60) and at the hip or femur, mean difference 6.05 (95% confidence interval 3.74 to 8.36). There was clinical heterogeneity between studies and not all studies reported all outcomes. Bone pain was the most common adverse event with intravenous agents. Flu-like symptoms were also increased in those taking bisphosphonates.

In participants with a lung transplant (one study), intravenous pamidronate did not change the number of new fractures. At axial sites, bone mineral density increased with treatment compared to controls: percentage change in bone mineral density at lumbar spine, mean difference 6.20 (95% confidence interval 4.28 to 8.12); and femur mean difference 7.90 (95% confidence interval 5.78 to 10.02).

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