title: Effective NSAID treatment indicates that hyperprostaglandinism is affecting the clinical severity of childhood hypophosphatasia.
abstract: BACKGROUND
  Hypophosphatasia (HP) is an inborn error of bone metabolism characterized by a genetic defect in the gene encoding the tissue-nonspecific alkaline phosphatase (TNSALP). There is a lack of knowledge as to how the variability and clinical severity of the HP phenotype (especially pain and walking impairment) are related to metabolic disturbances or impairments, subsequent to the molecular defect.
  
  
  METHODS
  We analyzed the changes in clinical symptoms and the prostaglandin (PG) metabolism in response to treatment with non-steroidal anti-inflammatory drugs (NSAIDs) in six children affected by childhood HP. In addition, by exposing HP fibroblasts to pyridoxal phosphate and/or calcium pyrophosphate in vitro, we analyzed whether the alterations in PG levels are sequelae related to the metabolic defect.
  
  
  RESULTS
  Childhood HP patients, who often complain about pain in the lower limbs without evident fractures, have systemic hyperprostaglandinism. Symptomatic anti-inflammatory treatment with NSAIDs significantly improved pain-associated physical impairment. Calcium pyrophosphate, but not pyridoxal phosphate, induced cyclooxygenase-2 (COX-2) gene expression and PG production in HP and normal fibroblasts in vitro.
  
  
  CONCLUSIONS
  Clinical features of childhood HP related to pain in the lower legs may be, at least in part, sequelae related to elevated PG levels, secondary to the primary metabolic defect. Consequently, NSAID treatment does improve the clinical features of childhood HP.
authors.affiliation: Children's Hospital, University of Würzburg, Germany. Hermann.Girschick@mail.uni-wuerzburg.de
authors.forename: H J
authors.initials: HJ
authors.lastname: Girschick
authors.forename: P
authors.initials: P
authors.lastname: Schneider
authors.forename: I
authors.initials: I
authors.lastname: Haubitz
authors.forename: O
authors.initials: O
authors.lastname: Hiort
authors.forename: H
authors.initials: H
authors.lastname: Collmann
authors.forename: M
authors.initials: M
authors.lastname: Beer
authors.forename: Y S
authors.initials: YS
authors.lastname: Shin
authors.forename: H W
authors.initials: HW
authors.lastname: Seyberth
mesh_terms: D000293:Adolescent; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001842:Bone and Bones / Q000378:metabolism; D002131:Calcium Pyrophosphate; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007014:Hypophosphatasia / Q000188:drug therapy* / Q000378:metabolism* / Q000652:urine; D066298:In Vitro Techniques; D008297:Male; D000077239:Meloxicam; D009288:Naproxen / Q000627:therapeutic use; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism; D011453:Prostaglandins / Q000652:urine*; D011732:Pyridoxal Phosphate; D013843:Thiazines / Q000627:therapeutic use; D013844:Thiazoles / Q000627:therapeutic use
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011453:Prostaglandins; D013843:Thiazines; D013844:Thiazoles; D009288:Naproxen; D011732:Pyridoxal Phosphate; D011451:Prostaglandin-Endoperoxide Synthases; D000077239:Meloxicam; D002131:Calcium Pyrophosphate