title: Hypophosphatasia and the risk of atypical femur fractures: a case-control study.
abstract: Case reports have linked adult hypophosphatasia as a possible cause of atypical femur fractures (AFF) associated with bisphosphonate use. Adult hypophosphatasia is an asymptomatic genetic condition which results in low alkaline phosphatase and elevated pyridoxal phosphate. We conducted a case-control study to assess the role of hypophosphatasia and atypical femur fracture.
  
  
  
  We recruited 13 control patients who took long term bisphosphonates without complication and 10 patients who sustained atypical femur fractures (mean bisphosphonate use, 9 years both cohorts). Patients underwent clinical exam and measurement of alkaline phosphatase and pyridoxal phosphate (PLP) levels. In addition, DNA was extracted and the ALPL gene was sequenced in both cohorts.
  
  
  
  Low alkaline phosphatase levels (<55 U/L) were seen in 5/10 AFF patients and 5/13 control patients. Two control patients demonstrated low alkaline phosphatase levels and elevated PLP. The alkaline phosphatase (ALPL) gene exons and intron splice sites were sequenced in the atypical femur fracture and control cohorts and no coding mutations were identified in any subjects. Atypical femur fracture patients demonstrated more varus hip alignment (p < 0.048) with no significant difference in mechanical axis.
  
  
  
  We found no evidence of hypophosphatasia as a risk factor for atypical femur fractures. Laboratory findings of mildly low alkaline phosphatase activity were equally common in atypical and control cohorts and may be due to long term bisphosphonate use.
  
  
  
  Clinicaltrials.gov number NCT01360099 . Prospectively registered May 20, 2011. First patient enrolled June 14, 2011.
authors: Investigation performed at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 10 Center Dr., Mail Code 1468, Bethesda, MD, 20892-1150, USA. timothy.bhattacharyya@nih.gov.
authors: Timothy
authors: T
authors: Bhattacharyya
authors: National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA.
authors: Smita
authors: S
authors: Jha
authors: Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892-1849, USA.
authors: Hongying
authors: H
authors: Wang
authors: Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892-1849, USA.
authors: Daniel L
authors: DL
authors: Kastner
authors: Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892-1849, USA.
authors: Elaine F
authors: EF
authors: Remmers
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D004164:Diphosphonates / Q000009:adverse effects*; D005260:Female; D005264:Femoral Fractures / Q000209:etiology*; D006801:Humans; D007014:Hypophosphatasia / Q000150:complications*; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies
chemical_list: D004164:Diphosphonates