title: Effect of miglustat on bone disease in adults with type 1 Gaucher disease: a pooled analysis of three multinational, open-label studies.
abstract: BACKGROUND
  Bone manifestations are a source of disability among patients with Gaucher disease (GD) and a focus of disease management. The effect of enzyme replacement therapy (ERT) on GD bone disease can be limited and may take up to 8 years to become manifest. Miglustat, a glucosylceramide synthase inhibitor, may have a positive influence on GD bone disease.
  
  
  OBJECTIVE
  The aim of this analysis was to evaluate the effects of miglustat on bone manifestations and bone mineral density (BMD) in patients with type 1 GD.
  
  
  METHODS
  This was a pooled analysis of data collected prospectively over an observation period of 2 years from patients who participated in 3 multinational, open-label clinical trials evaluating the efficacy and tolerability of miglustat 100 mg TID (the currently approved therapeutic dose). Bone manifestations were assessed qualitatively and in relation to treatment and spleen status. The effects of miglustat on BMD were assessed by dual-energy x-ray absorptiometry at the lumbar spine and/or femoral neck. Bone response was defined as a positive change in BMD, based on the change in BMD Z-score from baseline to months 6, 12, and 24. Changes in BMD were also analyzed according to spleen status and baseline severity of osteopenia.
  
  
  RESULTS
  The analysis involved 72 patients, including 41 (57%) who had received previous ERT and 20 (28%) who had undergone splenectomy. Patients' mean (SD) age was 41.2 (13.1) years. The most frequent bone-related manifestations at study entry were osteoporosis (43/63 [68%] patients) and bone pain (41/65 [63%] patients). At 2 years, 54/65 (83%) patients reported no bone pain. The reductions in bone pain were comparable among all subgroups, including high-risk patients (ie, splenectomized). No new cases of bone crisis, avascular necrosis, or pathologic fractures were reported. BMD Z-scores were improved from baseline at both the lumbar spine and femoral neck at each time point (months 6, 12, and 24) (P < 0.001). As early as 6 months after the initiation of miglustat monotherapy, significant increases from baseline in the BMD Z-score were observed at both the lumbar spine (mean, 0.15; P = 0.022) and femoral neck (0.23; P < 0.001); the increases remained significant at 12 months (0.19 [P = 0.012] and 0.21 [P = 0.017], respectively) and 24 months (0.21 [P = 0.015] and 0.18 [P = 0.039]). Significant increases in BMD Z-scores were observed at the femoral neck in splenectomized patients (P < 0.001) and at both sites in osteoporotic patients (lumbar spine: P < 0.001; femoral neck: P = 0.006).
  
  
  CONCLUSIONS
  This pooled analysis of 3 open-label studies of miglustat 100 mg TID suggests that miglustat monotherapy may reduce the incidence of bone pain and improve BMD in patients with type 1 GD, including those with a history of splenectomy and/or osteoporosis.
authors.affiliation: Department of Neurology and Pediatrics, New York University School of Medicine, New York, New York, USA. pastores@med.nyu.edu
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Pastores
authors.forename: Deborah
authors.initials: D
authors.lastname: Elstein
authors.forename: Martin
authors.initials: M
authors.lastname: Hrebícek
authors.forename: Ari
authors.initials: A
authors.lastname: Zimran
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D015519:Bone Density / Q000187:drug effects; D001851:Bone Diseases, Metabolic / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005776:Gaucher Disease / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D010146:Pain / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D010147:Pain Measurement; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D004791:Enzyme Inhibitors; D017485:1-Deoxynojirimycin; C059896:miglustat; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase