Treatment of Low Bone Density in Cystic Fibrosis.

Study Overview
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Brief Summary
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Cystic fibrosis (CF) -- an autosomal recessive genetic disease affecting about 60,000 individuals worldwide, including about 3,800 in Italy -- is often associated with low bone mineral mass. The current aggressive therapies have ensured a much longer survival of CF patients but this has led to a higher frequency of osteoporosis and bone fractures, a serious problem which not only affects quality of life, but also hinders further therapeutic measures. The aim of this study, conducted on a large group of children, adolescents and young adults with CF, has been the evaluation of bone mass changes after 1 year of a simple treatment with RDA-adjusted dietary calcium plus 25-OH vitamin D supplementation, and the feasibility and efficacy of alendronate treatment (for another year) in patients not responding to calcium + 25-OH vitamin D alone.

Detailed Description
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The study included 2 phases. Phase 1 (1-year open-label observational study): following baseline evaluation, bone mass changes have been studied with a simple therapy of adequate calcium intake and 25-OH vitamin D supplements in all eligible subjects (N=171). Phase 2 (1-year double-blind, randomized, placebo-controlled, parallel group study): the 128 subjects showing an insufficient response to calcium + 25-OH vitamin D alone (bone mass increase <5%) at the end of Phase 1, were randomized into 2 groups and assigned to alendronate treatment (N=65) or placebo (N=63) (in addition to calcium and 25-OH vitamin D as during Phase 1). The study has been carried out by the Coordinator's Institution (Istituto Auxologico Italiano)in collaboration with most Regional Reference Centers for CF in Italy.

Official Title
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Osteoporosis in Cystic Fibrosis: Study of Bone Mass and Bone Metabolism, and Prospective Randomized Therapeutic Trial.

Conditions
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Osteoporosis, Cystic Fibrosis

Intervention / Treatment
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* Drug: Alendronate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age 2-30 years clinically stable condition regular menses in females low Bone Mineral Apparent Density for age (defined as BMAD Z-score ≤-2.0 if age ≤18 years or ≤-2.5 if age >18 years). Exclusion Criteria: two or more episodes of hypercalcemia and/or hypercalciuria contraindications to 25-OH vitamin D or alendronate treatment recent transplantation other diseases or medications (glucocorticoids excepted) associated with bone loss.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Alendronate<br>128 subjects participated in the study's Phase 2 (1-year double-blind, randomized, placebo-controlled, parallel group study). 65 subjects were randomized to this arm. Oral alendronate dose: 5 mg/day, if body weight ≤25 kg; 10 mg/day, if body weight >25 kg. | Drug: Alendronate<br>* As active drug, we used Alendros (Abiogen Pharma, Pisa, Italy), distributed to the patients in plain bottles and boxes (bearing only the center and patient codes).<br>* Other names: Alendros;|
| Placebo Comparator: Placebo<br>128 subjects participated in the study's Phase 2 (1-year double-blind, randomized, placebo-controlled, parallel group study). 63 subjects were randomized to this arm. Oral placebo (inactive pills). | Drug: Placebo<br>* Placebo was distributed to the patients in plain bottles and boxes (bearing only the center and patient codes).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bone mineral density increase at lumbar spine. | Bone mineral density evaluated by DXA. Bone mineral apparent density calculated to correct for bone size (growing subjects). Z-score calculated. Measurements: Phase 1 (171 subjects): Baseline, 6 months, 12 months. Phase 2 (128 subjects, randomized to 2 arms: placebo or alendronate): 18 months, 24 months. | up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in bone turnover markers. | Bone turnover markers: (serum) osteocalcin (OC), bone specific alkaline phosphatase (BSAP), C-terminal telopeptide of procollagen 1 (CTx); (urine) terminal telopeptide of procollagen 1 (NTx). | baseline and up to 24 months | 
| Fracture rate. | Appendicular fractures were evaluated at baseline (previous fractures) and throughout the 2 years of study (incident fractures) with X-rays. Vertebral fractures were evaluated at the end of Phase 1 (12th month) and at the end of Phase 2 (24th month) with lateral thoracic and lumbar spine X-rays. | at 12th and 24th month | 
| Adverse effects of alendronate. | Evaluated on the basis of lab tests (calcemia, calciuria, blood cell count, liver and kidney function), FEV1 changes, and other signs/symptoms (e.g. pain, fever, etc.) | continuously throughout Phase 2 (2nd year of study) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cystic fibrosis, children, adolescents, low bone mass, osteoporosis, alendronate, fractures