title: 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.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Telethon Foundation (Italy).
authors.affiliation: Centro Malattie Metaboliche Ossee, Istituto Auxologico Italiano IRCCS, Milan, Italy. Electronic address: ml.bianchi@auxologico.it.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Bianchi
authors.affiliation: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Colombo
authors.affiliation: CRR Fibrosi Cistica, Azienda Ospedalierouniversitaria di Verona, Verona, Italy.
authors.forename: Baroukh M
authors.initials: BM
authors.lastname: Assael
authors.affiliation: Laboratorio Analisi Cliniche, Istituto Auxologico Italiano IRCCS, Milan, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Dubini
authors.affiliation: CRR Fibrosi Cistica, Clinica Pediatrica, Policlinico Universitario, Messina, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Lombardo
authors.affiliation: CRR Fibrosi Cistica, Dipartimento di Pediatria, Policlinico Umberto I, Rome, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Quattrucci
authors.affiliation: CRR Fibrosi Cistica, Divisione Gastroenterologia, Ospedale Bambin Gesù, Vatican City.
authors.forename: Sergio
authors.initials: S
authors.lastname: Bella
authors.affiliation: CRR Fibrosi Cistica, Ospedale dei Bambini, ARNAS Civico, Palermo, Italy.
authors.forename: Mirella
authors.initials: M
authors.lastname: Collura
authors.affiliation: CRR Fibrosi Cistica Adulti, Azienda Ospedaliera Universitaria San Luigi Gonzaga, Orbassano, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Messore
authors.affiliation: CRR Fibrosi Cistica, Dipartimento Pediatria, Università Federico II, Naples, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Raia
authors.affiliation: CRR Fibrosi Cistica, Divisione di Pediatria, Istituto Burlo Garofolo, Trieste, Italy.
authors.forename: Furio
authors.initials: F
authors.lastname: Poli
authors.affiliation: CRR Fibrosi Cistica, Unità Operativa di Pediatria, Ospedale Misericordia, Grosseto, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Bini
authors.affiliation: Dipartimento di Scienze Radiologiche Oncologiche Anatomo-patologiche, Università La Sapienza, Rome, Italy.
authors.forename: Carlina V
authors.initials: CV
authors.lastname: Albanese
authors.affiliation: Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Turin, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: De Rose
authors.affiliation: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.
authors.forename: Diana
authors.initials: D
authors.lastname: Costantini
authors.affiliation: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Romano
authors.affiliation: CRR Fibrosi Cistica, Clinica Pediatrica, Policlinico Universitario, Messina, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Pustorino
authors.affiliation: CRR Fibrosi Cistica, Clinica Pediatrica, Policlinico Universitario, Messina, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Magazzù
authors.affiliation: CRR Fibrosi Cistica, Dipartimento di Pediatria, Policlinico Umberto I, Rome, Italy.
authors.forename: Serenella
authors.initials: S
authors.lastname: Bertasi
authors.affiliation: CRR Fibrosi Cistica, Divisione Gastroenterologia, Ospedale Bambin Gesù, Vatican City.
authors.forename: Vincenzina
authors.initials: V
authors.lastname: Lucidi
authors.affiliation: CRR Fibrosi Cistica, Ospedale dei Bambini, ARNAS Civico, Palermo, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Traverso
authors.affiliation: CRR Fibrosi Cistica, Dipartimento Pediatria, Università Federico II, Naples, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Coruzzo
authors.affiliation: UOC Neonatologia Pediatria Adolescentologia, Azienda Ospedaliera Desio-Vimercate, Vimercate, Italy.
authors.forename: Amelia D
authors.initials: AD
authors.lastname: Grzejdziak
mesh_terms: D015502:Absorptiometry, Photon; D000293:Adolescent; D019386:Alendronate / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D016723:Bone Remodeling / Q000187:drug effects; D002112:Calcifediol / Q000008:administration & dosage*; D002118:Calcium / Q000008:administration & dosage*; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000150:complications*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging; D008297:Male; D011446:Prospective Studies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; D050071:Bone Density Conservation Agents; D002112:Calcifediol; D002118:Calcium; D019386:Alendronate