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  4. Progressive Nature of HPP

Hypophosphatasia (HPP) is a progressive, life-threatening disease.1-4

Symptoms may occur at any time and can lead to progressive functional impairment.1,5-9

 

Impaired skeletal development and mineral homeostasis can cause devastating and unpredictable systemic manifestations throughout life.1,2,10,11

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About the systemic and functional consequences.

Low alkaline phosphatase (ALP) activity is the underlying cause of morbidities and premature mortality in hypophosphatasia.1,10,12
 
 

Systemic manifestations can increase mortality risk in neonates, infants, and young children with hypophosphatasia.1-3

 
Respiratory failure is the most common cause of death in neonates and infants with hypophosphatasia1,2
Vitamin B6–responsive seizures are a fatal prognostic indicator in neonates and infants with hypophosphatasia1,2,4
 

Mortality in patients with untreated HPP, birth to 5 years of age4

Adapted from Whyte et al, 2014. Kaplan-Meier plot of survival (time from birth to death). Overall survival was 27%. The probability of survival (95% CI) was 42% (0.277, 0.550), 31% (0.189, 0.444), 29% (0.170, 0.421), and 27% (0.152, 0.398) at 1, 2, 3, and 4 years, respectively, after which it remained constant (therefore, figure has been truncated).4

Data from a noninterventional, retrospective chart review study designed to understand the natural history of 48 patients ≤5 years of age with severe perinatal- and infantile-onset HPP. Patients included in the study were those diagnosed with HPP based on at least one of the following: serum biomarker levels (below-normal ALP and above-normal pyridoxal 5‘-phosphate [PLP] or phosphoethanolamine [PEA]), below-normal ALP and radiographic abnormalities, or genetic analysis of the ALPL gene. Additionally, onset of HPP must have occurred prior to 6 months of age based on signs that included at least one of the following: respiratory compromise, rachitic chest deformity, and/or vitamin B6–responsive seizures.4

 

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About the progressive symptoms of hypophosphatasia in neonates and infants.

Low alkaline phosphatase activity results in impaired bone mineralization, which can lead to premature death, progressive physical disability, and poor quality of life.1,2,10,11
 
 

Lifelong skeletal health depends on optimizing bone mass in childhood and adolescence.13,14

 
Bone mass is largely developed in childhood and adolescence, and children with low mineralization are at risk for osteopenia, osteoporosis, and increased fracture later in life.13,14
 
 

A failure to build quality bone in childhood and adolescence may increase the risk of fractures, osteoporosis, and disability into adulthood.14,15

 
 
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About the systemic impacts of hypophosphatasia in children and adolescents.

 
 

Skeletal complications progress into adulthood in patients with hypophosphatasia.1,4,9,11

 

Lifetime fracture prevalence is lower in the general population than in patients with hypophosphatasia4,11,16,17,e

  • <15% of healthy children ≤14 years of age have ever experienced a fracture17
  • <45% of healthy women and <55% of healthy men have ever experienced a fracture17
 

In adulthood, a majority of patients with hypophosphatasia will experience devastating skeletal manifestations.1,4,9,11

 
 
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About how the devastating consequences of hypophosphatasia can progress and worsen in adulthood.1,4,9,11

 
 

bData from a noninterventional, retrospective chart review study designed to understand the natural history of 48 patients ≤5 years of age with severe perinatal- and infantile-onset HPP. Patients included in the study were those diagnosed with HPP based on at least one of the following: serum biomarker levels (below-normal alkaline phosphatase and above-normal PLP or PEA), below-normal alkaline phosphatase and radiographic abnormalities, or genetic analysis of the ALPL gene. Additionally, onset of HPP must have occurred prior to 6 months of age based on signs that included at least one of the following: respiratory compromise, rachitic chest deformity, and/or vitamin B6–responsive seizures.4

cData from a retrospective, multinational, noninterventional natural history study of childhood HPP in patients 5 to 15 years of age (N=32).18

dCombined data from the HPP Impact Patient Survey/HPP Outcomes Survey Telephone (HIPS/HOST), an Internet questionnaire and telephone survey that queried demographics, HPP-related illness history, disease progression, and health-related quality of life. One hundred twenty-five adults participated.7

eData from a self-reported survey of a nationally representative general population sample of 45,293 individuals in England, plus a special boost sample of 10,111 drawn from the ethnic minority population.17

fData from HIPS, an Internet questionnaire that queried demographics, HPP-related illness history, disease progression, and health-related quality of life. Eighty-nine adults participated.7

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References:
  1. Rockman-Greenberg C. Hypophosphatasia. Pediatr Endocrinol Rev. 2013;10(suppl 2):380-388.
  2. Baumgartner-Sigl S, Haberlandt E, Mumm S, et al. Pyridoxine-responsive seizures as the first symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T>C, p.M226T; c.1112C>T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene. Bone. 2007;40(6):1655-1661.
  3. Eade AWT, Swannell AJ, Williamson N. Pyrophosphate arthropathy in hypophosphatasia. Ann Rheum Dis. 1981;40(2):164-170.
  4. Whyte MP, Leung E, Wilcox W, et al; for Study 011-10 Investigators. Hypophosphatasia: a retrospective natural history study of the severe perinatal and infantile forms. Poster presented at: 2014 Pediatric Academic Societies and Asian Society for Pediatric Research Joint Meeting; May 3-6, 2014; Vancouver, BC.
  5. Beck C, Morbach H, Wirth C, Beer M, Girschick HJ. Whole-body MRI in the childhood form of hypophosphatasia. Rheumatol Int. 2011;31(10):1315-1320.
  6. Mohn A, De Leonibus C, de Giorgis T, Mornet E, Chiarelli F. Hypophosphatasia in a child with widened anterior fontanelle: lessons learned from late diagnosis and incorrect treatment. Acta Paediatr. 2011;100(7):e43-e46.
  7. Data on file, Alexion Pharmaceuticals.
  8. Taketani T, Onigata K, Kobayashi H, Mushimoto Y, Fukuda S, Yamaguchi S. Clinical and genetic aspects of hypophosphatasia in Japanese patients. Arch Dis Child. 2014;99(3):211-215.
  9. Weber TJ, Sawyer EK, Moseley S, Odrljin T, Kishnani PS. Fracture and surgical burden in pediatric and adult patients with hypophosphatasia: results from patient-reported outcome surveys [IOF abstract P146]. Osteoporos Int. 2015;26(suppl 1):C89.
  10. Whyte MP. Hypophosphatasia: nature’s window on alkaline phosphatase function in humans. In: Bilezikian JP, Raisz LG, Martin TJ, eds. Principles of Bone Biology. Vol 2. 3rd ed. San Diego, CA: Academic Press; 2008:1573-1598.
  11. Weber TJ, Sawyer EK, Moseley S, Odrljin T, Kishnani PS. Burden of disease in adult patients with hypophosphatasia: results from patient-reported outcome surveys. Poster presented at: Endocrine Society Annual Meeting; March 5-8, 2015; San Diego, CA.
  12. Whyte MP. Hypophosphatasia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 4. 8th ed. New York, NY: McGraw-Hill; 2001:5313-5329.
  13. Bachrach LK. Acquisition of optimal bone mass in childhood and adolescence. Trends Endocrinol Metab. 2001;12(1):22-28.
  14. Davies JH, Evans BAJ, Gregory JW. Bone mass acquisition in healthy children. Arch Dis Child. 2005;90(4):373-378.
  15. US Department of Health and Human Services. Bone Health and Osteoporosis: a Report of the Surgeon General. Rockville, MD: US Department of Health and Human Services; 2004.
  16. Whyte MP, Madson KL, Munns CF, et al. A retrospective, multi-national, non-interventional, natural history study of the childhood form of hypophosphatasia [abstract LB-OR01]. Endocrine Society’s 97th Annual Meeting and Expo website. https://endo.confex.com/endo/2015endo/webprogram/Paper22822.html. Accessed October 26, 2017.
  17. Donaldson LJ, Reckless IP, Scholes S, Mindell JS, Shelton NJ. The epidemiology of fractures in England. J Epidemiol Community Health. 2008;62(2):174-180.
  18. Phillips D, Griffin D, Przybylski T, et al. Gait assessment in children with childhood hypophosphatasia: impairments in muscle strength and physical function. Poster presented at: Endocrine Society Annual Meeting; March 5-8, 2015; San Diego, CA.