title: Decreased fracture rate, pharmacogenetics and BMD response in 79 Swedish children with osteogenesis imperfecta types I, III and IV treated with Pamidronate.
abstract: Osteogenesis imperfecta (OI) is an inherited heterogeneous bone fragility disorder, usually caused by collagen I mutations. It is well established that bisphosphonate treatment increases lumbar spine (LS) bone mineral density (BMD), as well as improves vertebral geometry in severe OI; however, fracture reduction has been difficult to prove, pharmacogenetic studies are scarce, and it is not known at which age, or severity of disease, treatment should be initiated.
  
  
  
  COL1A1 and COL1A2 were analyzed in 79 children with OI (type I n=33, type III n=25 and type IV n=21) treated with Pamidronate. Data on LS BMD, height, and radiologically confirmed non-vertebral and vertebral fractures were collected prior to, and at several time points during treatment.
  
  
  
  An increase in LS BMD Z-score was observed for all types of OI, and a negative correlation to Δ LS BMD was observed for both age and LS BMD Z-score at treatment initiation. Supine height Z-scores were not affected by Pamidronate treatment, The fracture rate was reduced for all OI types at all time points during treatment (overall p<0.0003, <0.0001 and 0.0003 for all OI types I, III and IV respectively). The reduced fracture rate was maintained for types I and IV, while an additional decrease was observed over time for type III. The fracture rate was reduced also in individuals with continued low BMD after >4yrs Pamidronate. Twice as many boys as girls with OI type I were treated with Pamidronate, and the fracture rate the year prior treatment was 2.2 times higher for boys (p=0.0236). Greater Δ LS BMD, but smaller Δ fracture numbers were observed on Pamidronate for helical glycine mutations in COL1A1 vs. COL1A2. Vertebral compression fractures did not progress in any individual during treatment; however, they did not improve in 9%, and these individuals were all >11years of age at treatment initiation (p<0.0001).
  
  
  
  Pamidronate treatment in children with all types of OI increased LS BMD, decreased fracture rate, and improved vertebral compression fractures. Fracture reduction was prompt and maintained during treatment, irrespective of age at treatment initiation and collagen I mutation type.
authors.affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden. Electronic address: katarina.lindahl@medsci.uu.se.
authors.forename: K
authors.initials: K
authors.lastname: Lindahl
authors.affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden; Science for Life Laboratory, Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Kindmark
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden.
authors.forename: C-J
authors.initials: CJ
authors.lastname: Rubin
authors.affiliation: Department of Dental Medicine, Division of Pediatric Dentistry, Karolinska Institutet, Stockholm, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Malmgren
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Genetics, Karolinska University Hospital Stockholm, Stockholm, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Grigelioniene
authors.affiliation: Neuropediatric unit, Karolinska University Hospital and Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Söderhäll
authors.affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Ö
authors.initials: Ö
authors.lastname: Ljunggren
authors.affiliation: Neuropediatric unit, Karolinska University Hospital and Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Åström
mesh_terms: D001827:Body Height / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D024042:Collagen Type I / Q000235:genetics; D004252:DNA Mutational Analysis; D004164:Diphosphonates / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D050723:Fractures, Bone / Q000150:complications / Q000188:drug therapy* / Q000453:epidemiology* / Q000503:physiopathology; D050815:Fractures, Compression / Q000188:drug therapy / Q000235:genetics; D005998:Glycine / Q000235:genetics; D006801:Humans; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D009154:Mutation / Q000235:genetics; D010013:Osteogenesis Imperfecta / Q000150:complications / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D000077268:Pamidronate; D010597:Pharmacogenetics; D013548:Sweden / Q000453:epidemiology
chemical_list: D024042:Collagen Type I; D004164:Diphosphonates; D000077268:Pamidronate; D005998:Glycine
keywords: Bisphosphonate; Collagen type I; Fracture; Mutation; Osteogenesis imperfecta; Pharmacogenetics