Robert Desborough1, Philip Nicklin2, Fatma Gossiel3, Meena Balasubramanian4, Jennifer S Walsh3, Anna Petryk5, Megan Teynor5, Richard Eastell6. 1. Hull Royal Infirmary, Hull, UK. 2. Academic Unit of Bone Metabolism, University of Sheffield, Sheffield, UK. 3. Academic Unit of Bone Metabolism, University of Sheffield, Sheffield, UK; Mellanby Centre for Musculoskeletal Research, University of Sheffield, Sheffield, UK. 4. Sheffield Clinical Genetics Service, Sheffield Children's National Health Service, Foundation Trust, Western Bank, Sheffield, UK; Mellanby Centre for Musculoskeletal Research, University of Sheffield, Sheffield, UK. 5. Alexion Pharmaceuticals, Inc., Boston, MA, USA. 6. Academic Unit of Bone Metabolism, University of Sheffield, Sheffield, UK; Mellanby Centre for Musculoskeletal Research, University of Sheffield, Sheffield, UK. Electronic address: r.eastell@sheffield.ac.uk.
Abstract
OBJECTIVES: This study sought to identify the clinical and biochemical characteristics that would help distinguish hypophosphatasia (HPP) from other metabolic bone diseases in adult patients attending a metabolic bone clinic by comparing patients who have genetically confirmed HPP with a group of patients with low bone mineral density (BMD) in the osteoporotic or osteopenic range. METHODS: Data were collected from February 2016 to October 2018 for 41 patients (n = 20 in the HPP group, n = 21 in the low-BMD group) attending the metabolic bone clinic at Sheffield, United Kingdom (UK) or who were recruited via the Rare UK Diseases Study (RUDY) platform during the same period. A study questionnaire was administered to all patients, and assessments were conducted for laboratory values, physical functions, BMD, and spine imaging. RESULTS: Patients with HPP were characterized as being younger, more likely to have metatarsal or femoral shaft fractures, and less likely to have vertebral fractures compared with patients in the low-BMD group. The HPP group had lower total and bone-specific alkaline phosphatase, higher pyridoxal 5'-phosphate (PLP), and lower, albeit sufficient, 25-hydroxyvitamin D. Low-BMD group had lower C-terminal telopeptide and tartrate-resistant acid phosphatase 5b (61.9% were on bisphosphonates at enrollment). Dual X-ray absorptiometry (DXA) analysis found that the HPP group had higher total hip and lumbar BMD T- and Z-scores compared with the low-BMD group. There were no differences found between the two groups with physical functional assessments. Results of receiver operating characteristic analysis indicated strong diagnostic accuracy of these biomarkers for HPP. Thresholds of total alkaline phosphatase (ALP) activity of 43 IU/L or less and PLP level of 120 nmol/L or more were determined to be potentially clinically useful for distinguishing HPP from other metabolic bone diseases. CONCLUSION: This study supported the use of ALP and PLP measurements as predictive of HPP diagnosis along with certain demographic and clinical characteristics (younger age, metatarsal or femoral fractures without low mean BMD T- and Z-scores on a DXA scan) that can aid in recognizing adults who should be further evaluated for HPP. The critical values identified need to be applied to an independent sample to be tested for diagnostic accuracy.
OBJECTIVES: This study sought to identify the clinical and biochemical characteristics that would help distinguish hypophosphatasia (HPP) from other metabolic bone diseases in adult patients attending a metabolic bone clinic by comparing patients who have genetically confirmed HPP with a group of patients with low bone mineral density (BMD) in the osteoporotic or osteopenic range. METHODS: Data were collected from February 2016 to October 2018 for 41 patients (n = 20 in the HPP group, n = 21 in the low-BMD group) attending the metabolic bone clinic at Sheffield, United Kingdom (UK) or who were recruited via the Rare UK Diseases Study (RUDY) platform during the same period. A study questionnaire was administered to all patients, and assessments were conducted for laboratory values, physical functions, BMD, and spine imaging. RESULTS: Patients with HPP were characterized as being younger, more likely to have metatarsal or femoral shaft fractures, and less likely to have vertebral fractures compared with patients in the low-BMD group. The HPP group had lower total and bone-specific alkaline phosphatase, higher pyridoxal 5'-phosphate (PLP), and lower, albeit sufficient, 25-hydroxyvitamin D. Low-BMD group had lower C-terminal telopeptide and tartrate-resistant acid phosphatase 5b (61.9% were on bisphosphonates at enrollment). Dual X-ray absorptiometry (DXA) analysis found that the HPP group had higher total hip and lumbar BMD T- and Z-scores compared with the low-BMD group. There were no differences found between the two groups with physical functional assessments. Results of receiver operating characteristic analysis indicated strong diagnostic accuracy of these biomarkers for HPP. Thresholds of total alkaline phosphatase (ALP) activity of 43 IU/L or less and PLP level of 120 nmol/L or more were determined to be potentially clinically useful for distinguishing HPP from other metabolic bone diseases. CONCLUSION: This study supported the use of ALP and PLP measurements as predictive of HPP diagnosis along with certain demographic and clinical characteristics (younger age, metatarsal or femoral fractures without low mean BMD T- and Z-scores on a DXA scan) that can aid in recognizing adults who should be further evaluated for HPP. The critical values identified need to be applied to an independent sample to be tested for diagnostic accuracy.