Hypophosphatasia and How Alkaline Phosphatase Promotes Mineralization

Whyte, Michael P.

doi:10.1016/b978-0-12-804182-6.00028-9

Cited by 23 publications

(21 citation statements)

References 136 publications

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“…1,[3][4][5] PPi potently inhibits mineralization by blocking hydroxyapatite crystal formation. 6,7 Thus, the superabundance of PPi in HPP often leads to rickets during growth. 6,7 TNSALP dephosphorylates PLP (the principal circulating form of vitamin B6) to pyridoxal, which allows it to cross cell plasma membranes and be rephosphorylated intracellularly to PLP.…”

Section: Implications Of All the Available Evidencementioning

confidence: 99%

Asfotase alfa for infants and young children with hypophosphatasia: 7 year outcomes of a single-arm, open-label, phase 2 extension trial

Whyte

Simmons

Moseley

et al. 2019

The Lancet Diabetes & Endocrinology

109

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Background: Our Phase 2, open-label study of 11 infants and young children with lifethreatening perinatal or infantile hypophosphatasia (HPP) demonstrated 1-year safety and efficacy of asfotase alfa, an enzyme replacement therapy. We report outcomes over ~7 years. Methods: Patients received asfotase alfa (1 mg/kg thrice weekly subcutaneously; adjusted to 3 mg/kg thrice weekly if required). HPP skeletal manifestations were evaluated on the Radiographic Global Impression of Change (RGI-C) scale (−3=severe worsening; +3=complete/near complete healing). Respiratory support, growth, and cognitive and motor function were also evaluated. Findings: Ten patients completed a 6-month treatment period and entered an extension; nine received asfotase alfa for ≥6 years and completed the study, with four treated >7 years. Skeletal healing was sustained over 7 years of treatment; all evaluable patients had RGI-C scores ≥+2 at Years 6 and 7. No patient who completed the study required respiratory support after Year 4. Weight Z-scores improved to within normal range from Year 3 to study end; length/height Z-scores improved but remained below normal. Age-equivalent scores on Gross Motor, Fine Motor, and Cognitive subscales of the Bayley Scales of Infant and Toddler Development also improved. Treatment was generally well tolerated; adverse events were similar to those previously published. Interpretation: Patients with perinatal or infantile HPP treated with asfotase alfa for up to 7 years showed early, sustained improvements in skeletal mineralization. Respiratory function, growth, and cognitive and motor function also improved. Asfotase alfa is safe and effective in perinatal/infantile HPP.

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Section: Implications Of All the Available Evidencementioning

confidence: 99%

Asfotase alfa for infants and young children with hypophosphatasia: 7 year outcomes of a single-arm, open-label, phase 2 extension trial

Whyte

Simmons

Moseley

et al. 2019

The Lancet Diabetes & Endocrinology

109

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“…Hypophosphatasia (HPP) is a rare, inherited, systemic metabolic disease characterized by low tissue‐nonspecific alkaline phosphatase (TNSALP) activity . Signs, symptoms, and complications of HPP in children and adults can include impaired skeletal mineralization, HPP rickets, bone deformities, fractures, short stature, pain, muscle weakness, and reduced physical function such as compromises in ambulation . As a result, patients with HPP may have impaired overall functional status, reduced ability to perform activities of daily living, and a lower quality of life .…”

Section: Introductionmentioning

confidence: 99%

“…(1,2) Signs, symptoms, and complications of HPP in children and adults can include impaired skeletal mineralization, HPP rickets, bone deformities, fractures, short stature, pain, muscle weakness, and reduced physical function such as compromises in ambulation. (3)(4)(5)(6)(7) As a result, patients with HPP may have impaired overall functional status, reduced ability to perform activities of daily living, and a lower quality of life. (3,6) Improvement in physical function is an important goal in the management of HPP.…”

Section: Introductionmentioning

confidence: 99%

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Reliability and Validity of the 6‐Minute Walk Test in Hypophosphatasia

et al. 2019

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This investigation evaluated the reliability and validity of the 6‐Minute Walk Test (6MWT) in patients with pediatric hypophosphatasia (HPP). Children (aged 6 to 12 years; n = 11), adolescents (13 to 17 years; n = 4), and adults (18 to 65 years; n = 9) completed the 6MWT at screening and baseline in two clinical studies of asfotase alfa. Test‐retest reliability of the 6MWT, evaluated with Pearson's correlation coefficients ( r ) for screening versus baseline, was high for children ( r = 0.95; p < 0.0001), adolescents ( r = 0.81; p = 0.125), and adults ( r = 0.94; p = 0.0001). The most conservative minimal clinically important differences, estimated using distribution‐based methods, were 31 m (children and adults) and 43 m (adolescents). In children, the 6MWT correlated significantly with scores on measures of skeletal disease, which included the Radiographic Global Impression of Change scale ( r = 0.50; p < 0.0001) and the Rickets Severity Scale ( r = −0.78; p < 0.0001), such that distance walked increased as the severity of skeletal disease decreased. Significant ( p < 0.0001) correlations with the 6MWT distance walked were also observed for children with scores on parent‐reported measures of disability ( r = −0.67), ability to function in activities of daily living ( r = 0.71 to 0.77), and parent‐reported measures of pain ( r = −0.39). In adolescents and adults, 6MWT distance walked correlated significantly ( p < 0.05) with measures of lower extremity function ( r = 0.83 and 0.60, respectively), total pain severity ( r = −0.41 and −0.36, respectively), and total pain interference ( r = −0.41 and −0.49, respectively). Collectively, these data indicate that the 6MWT is a reliable, valid measure of physical functioning in patients with pediatric HPP. © 2018 The Authors. JBMR Plus Published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

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“…Signs and symptoms of HPP can manifest in utero through adulthood and can vary widely [1, 3]. In children, common manifestations include radiographic evidence of abnormal mineralization in provisional zones of the long bones, knocked/bowed knees, muscle weakness, musculoskeletal pain, fractures, poor growth, and premature tooth loss with roots intact [1, 4, 5]. Musculoskeletal aspects of HPP can impair mobility and ambulation, which may have implications for activities of daily living, community participation, and quality of life.…”

Section: Introductionmentioning

confidence: 99%