Maria Luisa Bianchi1, Carla Colombo2, Baroukh M Assael3, Antonella Dubini4, Mariangela Lombardo5, Serena Quattrucci6, Sergio Bella7, Mirella Collura8, Barbara Messore9, Valeria Raia10, Furio Poli11, Rita Bini12, Carlina V Albanese13, Virginia De Rose14, Diana Costantini2, Giovanna Romano2, Elena Pustorino5, Giuseppe Magazzù5, Serenella Bertasi6, Vincenzina Lucidi7, Gabriella Traverso8, Anna Coruzzo10, Amelia D Grzejdziak15. 1. Centro Malattie Metaboliche Ossee, Istituto Auxologico Italiano IRCCS, Milan, Italy. Electronic address: ml.bianchi@auxologico.it. 2. Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy. 3. CRR Fibrosi Cistica, Azienda Ospedalierouniversitaria di Verona, Verona, Italy. 4. Laboratorio Analisi Cliniche, Istituto Auxologico Italiano IRCCS, Milan, Italy. 5. CRR Fibrosi Cistica, Clinica Pediatrica, Policlinico Universitario, Messina, Italy. 6. CRR Fibrosi Cistica, Dipartimento di Pediatria, Policlinico Umberto I, Rome, Italy. 7. CRR Fibrosi Cistica, Divisione Gastroenterologia, Ospedale Bambin Gesù, Vatican City. 8. CRR Fibrosi Cistica, Ospedale dei Bambini, ARNAS Civico, Palermo, Italy. 9. CRR Fibrosi Cistica Adulti, Azienda Ospedaliera Universitaria San Luigi Gonzaga, Orbassano, Italy. 10. CRR Fibrosi Cistica, Dipartimento Pediatria, Università Federico II, Naples, Italy. 11. CRR Fibrosi Cistica, Divisione di Pediatria, Istituto Burlo Garofolo, Trieste, Italy. 12. CRR Fibrosi Cistica, Unità Operativa di Pediatria, Ospedale Misericordia, Grosseto, Italy. 13. Dipartimento di Scienze Radiologiche Oncologiche Anatomo-patologiche, Università La Sapienza, Rome, Italy. 14. Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Turin, Italy. 15. UOC Neonatologia Pediatria Adolescentologia, Azienda Ospedaliera Desio-Vimercate, Vimercate, Italy.
Abstract
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 fibrosis. METHODS: We did a multicentre trial in two phases. We enrolled patients aged 5-30 years with cystic fibrosis and low bone mineral density, from ten cystic fibrosis regional centres in Italy. The first phase was an open-label, 12-month observational study of the effect of adequate calcium intake plus calcifediol. The second phase was a 12-month, double-blind, randomised, placebo-controlled, parallel group study of the efficacy 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-to-treat 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, five 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 differ significantly for other adverse events. INTERPRETATION: Correct calcium intake plus calcifediol can improve bone mineral density in some young patients with cystic fibrosis. In those who do not respond to calcium and calcifediol alone, alendronate can safely and effectively increase bone mineral density. FUNDING: Telethon Foundation (Italy).
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 fibrosis. METHODS: We did a multicentre trial in two phases. We enrolled patients aged 5-30 years with cystic fibrosis and low bone mineral density, from ten cystic fibrosis regional centres in Italy. The first phase was an open-label, 12-month observational study of the effect of adequate calcium intake plus calcifediol. The second phase was a 12-month, double-blind, randomised, placebo-controlled, parallel group study of the efficacy 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-to-treat 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, five 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 differ significantly for other adverse events. INTERPRETATION: Correct calcium intake plus calcifediol can improve bone mineral density in some young patients with cystic fibrosis. In those who do not respond to calcium and calcifediol alone, alendronate can safely and effectively increase bone mineral density. FUNDING: Telethon Foundation (Italy).
Authors: Denise L Jacobson; Jane C Lindsey; Catherine Gordon; Rohan Hazra; Hans Spiegel; Flavia Ferreira; Fabiana R Amaral; Jesica Pagano-Therrien; Aditya Gaur; Kathy George; Jane Benson; George K Siberry Journal: Clin Infect Dis Date: 2020-08-22 Impact factor: 9.079
Authors: Daniela A Rubin; Kathleen S Wilson; Camila E Orsso; Erik R Gertz; Andrea M Haqq; Diobel M Castner; Marilyn Dumont-Driscoll Journal: Genes (Basel) Date: 2020-08-24 Impact factor: 4.096