Bone Abstracts

Brittle bones have been reported in children, adolescents and adults with cystic fibrosis (CF), independently of sex; this has been termed CF-related bone disease. In CF patients with the F508del mutation in the (Cftr) gene, vertebral fractures and the subsequent dorsal kyphosis decrease pulmonary function, thus accelerating the course of the disease. Mice with the homozygous F508del mutation in CFTR develop a severe osteopenic phenotype early on, in both sexes (Le Henaff et al. 2012). Miglustat (N-butyldeoxynojyrimicin, Zavesca), a drug approved for type I Gaucher disease and Niemann–Pick type C disease, was reported to normalize sodium and CFTR-dependent chloride transport in human F508del CFTR lung cells and in nasal mucosa in F508del CF mice.

We evaluated the efficacy of oral miglustat treatment in restoring bone mass in F508del CF mice. The bone microarchitecture of 6 weeks old F508del male mice, relative to wild-type (WT) littermates was evaluated after an administration of 120 mg/kg per day miglustat by oral gavage for 28 days using in vivo micro-CT, bone histomorphometry, and analysis of dynamic parameters of bone formation. Levels of two serum growth factors, IGF1, and 17β-estradiol (E₂) were also determined.

A once-a-day oral treatment with miglustat normalized bone volume and improved bone micro-architecture of the lumbar spine in F508del mice after 4 weeks. This increase of vertebral bone volume was related to both an increased bone formation rate and increased serum E₂ level with no changes in IGF1 levels in miglustat-treated F508del mice.

This study provides first evidence that oral administration of miglustat normalizes bone mass by increasing bone formation rate in F508del mice; these findings support the therapeutic potential of miglustat in patients with CF-related bone disease.

Supported by the France Association Vaincre la Mucoviscidose and the Champagne-Ardenne Region, France; miglustat kindly provided by Actelion Pharmaceuticals, Switzerland.