Treatment of low bone density in young people with cystic fibrosis: A multicentre, prospective, open-label observational study of calcium and calcifediol followed by a randomised placebo-controlled trial of alendronate

Summary Background Long-term complications of cystic fibrosis include osteoporosis and fragility fractures, but few data are available about effective treatment strategies, especially in young patients. We investigated treatment of low bone mineral density in children, adolescents, and young adults with cystic fi brosis. Methods We did a multicentre trial in two phases. We enrolled patients aged 5-30 years with cystic fi brosis and low bone mineral density, from ten cystic fi brosis regional centres in Italy. The fi rst phase was an open-label, 12-month observational study of the eff ect of adequate calcium intake plus calcifediol. The second phase was a 12-month, double-blind, randomised, placebo-controlled, parallel group study of the effi cacy and safety of oral alendronate in patients whose bone mineral apparent density had not increased by 5% or more by the end of the observational phase. Patients were randomly assigned to either alendronate or placebo. Both patients and investigators were masked to treatment assignment. We used dual x-ray absorptiometry at baseline and every 6 months thereafter, corrected for body size, to assess lumbar spine bone mineral apparent density. We assessed bone turnover markers and other laboratory parameters every 3-6 months. The primary endpoint was mean increase of lumbar spine bone mineral apparent density, assessed in the intention-totreat population. This study is registered with ClinicalTrials.gov, number NCT01812551. Findings We screened 540 patients and enrolled 171 (mean age 13.8 years, SD 5.9, range 5-30). In the observational phase, treatment with calcium and calcifediol increased bone mineral apparent density by 5% or more in 43 patients (25%). 128 patients entered the randomised phase. Bone mineral apparent density increased by 16.3% in the alendronate group (n=65) versus 3·1% in the placebo group (n=63; p=0.0010). 19 of 57 young people (33.3%) receiving alendronate attained a normal-for-age bone mineral apparent density Z score. In the observational phase, fi ve patients had moderate episodes of hypercalciuria, which resolved after short interruption of calcifediol treatment. During the randomised phase, one patient taking alendronate had mild fever versus none in the placebo group; treatment groups did not diff er signifi cantly for other adverse events. Interpretation Correct calcium intake plus calcifediol can improve bone mineral density in some young patients with cystic fi brosis. In those who do not respond to calcium and calcifediol alone, alendronate can safely and eff ectively increase bone mineral density. Funding Telethon Foundation (Italy).