Abstract


Joseph Biskupiak*1, Casey Tak1, Minkyoung Yoo1, Diana Brixner1, Ioannis C. Tomazos2, Gilbert L’Italien2, Bonnie Donato2 and Andrew E. Denker2

1University of Utah, Salt Lake City, UT, 2Alexion Pharmaceuticals, Inc., New Haven, CT

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Joseph Biskupiak*1, Casey Tak1, Minkyoung Yoo1, Diana Brixner1, Ioannis C. Tomazos2, Gilbert L’Italien2, Bonnie Donato2 and Andrew E. Denker2

1University of Utah, Salt Lake City, UT, 2Alexion Pharmaceuticals, Inc., New Haven, CT

Hypophosphatasia (HPP) is a rare, systemic metabolic disease caused by loss-of-function mutation(s) in the ALPLgene, leading to low tissue-nonspecific alkaline phosphatase activity. Signs and symptoms are heterogeneous, ranging from severely impaired bone mineralization, seizures, and hypercalcemia in infants to multiple fractures, severe pain, impaired mobility, and disability in adults. HPP is often misdiagnosed due to low awareness and lack of age-/sex-adjusted alkaline phosphatase (ALP) reference ranges. Burden of disease in HPP patients is poorly understood. We sought to determine fracture burden in pediatric and adult patients with probable HPP from an electronic health record (EHR) database.
The study population was derived from the University of Utah Health Care EHR database housing data from 1.6 million individuals (Jan 1990–Dec 2014). We queried the database for disorders of phosphorous metabolism (ICD9 275.3) or low age-/sex-adjusted ALP (CPT 84705). Patients with persistently low age-/sex-adjusted ALP activity (≥2 measurements, low/never normal, no bisphosphonates) were screened for clinical, biochemical, and radiographic evidence of HPP: seizures/respiratory failure in children <5 y old; elevated serum pyridoxal-5'-phosphate; elevated urine phosphoethanolamine; family history; radiographic evidence of hypomineralization/osteopenia/rickets; osteomalacia; history of nontraumatic and/or multiple fractures/premature tooth loss/craniosynostosis. Patients with ≥1 of these manifestations were considered probable HPP patients. Fracture burden was assessed by Kaplan-Meier (KM) analysis as time to incident fracture and time to subsequent fractures with comorbidities identified by ICD9/CPT codes. Fractures were coded for each visit. Since EHR data did not differentiate between incident and subsequent fractures; incident fractures were defined as first fracture and subsequent so defined after 8 weeks of follow-up. University of Utah IRB approved the protocol.
Eighty-three patients (29 children [≤17 y]; 54 adults [≥18 y]) had probable HPP with persistently low age-/sex-adjusted ALP and relevant symptomatology. Mean follow-up was 5.7 y, and median number of serum ALP tests was 7 (range 2–85). 78 (94%) patients had ≥1 fracture (cumulative total 447 fractures), with a mean (SD) of 5.4 (7.29), median of 3 (25th percentile 2; 75th percentile 6), and range of 0–55 fractures. KM analysis showed median time to 1st fracture was 2.88 y and 3rd fracture was 7.32 y. Frequent comorbidities were skeletal complications other than fracture (80; 96.4%), pain (51; 61.4%), and depression and anxiety in children (18; 62.1%) and adults (49; 90.7%).
Patients with probable HPP had a significant burden of disease associated with skeletal manifestations such as high proportion of fractures and pain with comorbidities of depression and anxiety.

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