Skip to main content

Advertisement

SpringerLink
Log in

Hypophosphatasia: Review of Bone Mineral Metabolism, Pathophysiology, Clinical Presentation, Diagnosis, and Treatment

  • Review Paper
  • Published:
Clinical Reviews in Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

Hypophosphatasia (HPP) is a rare, inherited form of rickets or osteomalacia due to reduced activity of tissue non-specific alkaline phosphatase (TNSALP) caused by a loss of function mutation in the TNSALP gene marked by a low serum alkaline phosphatase. The ratio of PPi to Pi is crucial in the mineralization process. This process is regulated by the interaction of three phosphatases present in matrix vesicles: the mineralization promotors TNSALP and phosphatase orphan 1 (PHOSPHO1) and the mineralization inhibitor nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1). HPP is seen worldwide affecting all races. The broad-ranging clinical severity of HPP is correlated to the pattern of inheritance and degree of TNSALP activity, with lower levels of activity seen in the more severe autosomal recessive forms. HPP is marked by compromise of phase 2 hydroxyapatite crystal formation beyond the matrix vesicle resulting in skeletal hypomineralization, spontaneous fractures, tooth loss, and chondrocalcinosis. The major forms in declining order of severity include the following: perinatal, infantile, childhood, and adult HPP in addition to OdontoHPP and benign prenatal HPP. Biochemistry typically reveals a low serum alkaline phosphatase and elevated alkaline substrates such as pyridoxal-5′-phosphate (PLP) and phosphoethanolamine (PEA). Asfotase alfa, a recent novel enzyme replacement therapy for the treatment of HPP, has transformed this once lethal disease to one that is less severe.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Whyte M. Hypophosphatasia. In: Glorieux FH, Pettifor JM, Juppner H, editors. Pediatric bone: biology and diseases. San Diego, CA: Academic Press; 2012. p. 771–94.

    Chapter  Google Scholar 

  2. Bianchi ML. Hypophosphatasia: an overview of the disease and its treatment. Osteoporos Int. 2015;26(12):2743–57.

    Article  CAS  PubMed  Google Scholar 

  3. Millan, J.L. and M.P. Whyte, Alkaline Phosphatase and Hypophosphatasia. Calcif Tissue Int, 2015.

  4. Whyte MP. Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2016;12(4):233–46.

    Article  CAS  PubMed  Google Scholar 

  5. Rathbun JC. Hypophosphatasia; a new developmental anomaly. Am J Dis Child. 1948;75(6):822–31.

    Article  CAS  PubMed  Google Scholar 

  6. Sobel EH et al. Rickets, deficiency of alkaline phosphatase activity and premature loss of teeth in childhood. Pediatrics. 1953;11(4):309–22.

    CAS  PubMed  Google Scholar 

  7. Mc CR, Morrison AB, Dent CE. The excretion of phosphoethanolamine and hypophosphatasia. Lancet. 1955;268(6855):131.

    Google Scholar 

  8. Russell RG. Excretion of inorganic pyrophosphate in HYPOPHOSPHATASIA. Lancet. 1965;2(7410):461–4.

    Article  CAS  PubMed  Google Scholar 

  9. Whyte MP et al. Markedly increased circulating pyridoxal-5′-phosphate levels in hypophosphatasia. Alkaline phosphatase acts in vitamin B6 metabolism. J Clin Invest. 1985;76(2):752–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Greenberg CR et al. A homoallelic Gly317-- > Asp mutation in ALPL causes the perinatal (lethal) form of hypophosphatasia in Canadian mennonites. Genomics. 1993;17(1):215–7.

    Article  CAS  PubMed  Google Scholar 

  11. Mornet E et al. A molecular-based estimation of the prevalence of hypophosphatasia in the European population. Ann Hum Genet. 2011;75(3):439–45.

    Article  PubMed  Google Scholar 

  12. Taketani T et al. Clinical and genetic aspects of hypophosphatasia in Japanese patients. Arch Dis Child. 2014;99(3):211–5.

    Article  PubMed  Google Scholar 

  13. Whyte MP et al. Homozygosity for TNSALP mutation 1348c > T (Arg433Cys) causes infantile hypophosphatasia manifesting transient disease correction and variably lethal outcome in a kindred of black ancestry. J Pediatr. 2006;148(6):753–8.

    Article  CAS  PubMed  Google Scholar 

  14. Terkeltaub RA. Inorganic pyrophosphate generation and disposition in pathophysiology. Am J Physiol Cell Physiol. 2001;281(1):C1–c11.

    CAS  PubMed  Google Scholar 

  15. Weiss MJ et al. Structure of the human liver/bone/kidney alkaline phosphatase gene. J Biol Chem. 1988;263(24):12002–10.

    CAS  PubMed  Google Scholar 

  16. Smith M et al. Regional assignment of the gene for human liver/bone/kidney alkaline phosphatase to chromosome 1p36.1-p34. Genomics. 1988;2(2):139–43.

    Article  CAS  PubMed  Google Scholar 

  17. Silvent J et al. Molecular evolution of the tissue-nonspecific alkaline phosphatase allows prediction and validation of missense mutations responsible for hypophosphatasia. J Biol Chem. 2014;289(35):24168–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mornet E. Molecular genetics of hypophosphatasia and phenotype-genotype correlations. Subcell Biochem. 2015;76:25–43.

    Article  CAS  PubMed  Google Scholar 

  19. Mornet E et al. Clinical utility gene card for: hypophosphatasia - update 2013. Eur J Hum Genet. 2014:22(4).

  20. Griffin CA et al. Human placental and intestinal alkaline phosphatase genes map to 2q34-q37. Am J Hum Genet. 1987;41(6):1025–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Whyte MP et al. Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients. Bone. 2015;75:229–39.

    Article  CAS  PubMed  Google Scholar 

  22. Fauvert D et al. Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles. BMC Med Genet. 2009;10:51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Hu JC et al. Characterization of a family with dominant hypophosphatasia. Eur J Oral Sci. 2000;108(3):189–94.

    Article  CAS  PubMed  Google Scholar 

  24. Lia-Baldini AS et al. A new mechanism of dominance in hypophosphatasia: the mutated protein can disturb the cell localization of the wild-type protein. Hum Genet. 2008;123(4):429–32.

    Article  CAS  PubMed  Google Scholar 

  25. Lia-Baldini AS et al. A molecular approach to dominance in hypophosphatasia. Hum Genet. 2001;109(1):99–108.

    Article  CAS  PubMed  Google Scholar 

  26. Hofmann C et al. Unexpected high intrafamilial phenotypic variability observed in hypophosphatasia. Eur J Hum Genet. 2014;22(10):1160–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Clarke B. Normal bone anatomy and physiology. Clin J Am Soc Nephrol. 2008;3(Suppl 3):S131–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Anderson HC. Molecular biology of matrix vesicles. Clin Orthop Relat Res. 1995;314:266–80.

    Google Scholar 

  29. Wuthier RE, Lipscomb GF. Matrix vesicles: structure, composition, formation and function in calcification. Front Biosci (Landmark Ed). 2011;16:2812–902.

    Article  CAS  Google Scholar 

  30. Anderson HC. Vesicles associated with calcification in the matrix of epiphyseal cartilage. J Cell Biol. 1969;41(1):59–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Millan JL. The role of phosphatases in the initiation of skeletal mineralization. Calcif Tissue Int. 2013;93(4):299–306.

    Article  CAS  PubMed  Google Scholar 

  32. Millan JL, Plotkin H. Hypophosphatasia - pathophysiology and treatment. Actual osteol. 2012;8(3):164–82.

    PubMed  PubMed Central  Google Scholar 

  33. Anderson HC, Garimella R, Tague SE. The role of matrix vesicles in growth plate development and biomineralization. Front Biosci. 2005;10:822–37.

    Article  CAS  PubMed  Google Scholar 

  34. Robison R, Soames KM. The possible significance of Hexosephosphoric esters in ossification: part II. The phosphoric esterase of ossifying cartilage. Biochem J. 1924;18(3–4):740–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Whyte MP. Physiological role of alkaline phosphatase explored in hypophosphatasia. Ann N Y Acad Sci. 2010;1192:190–200.

    Article  CAS  PubMed  Google Scholar 

  36. Hofmann C, Girschick HJ, Mentrup B, Graser S, Seefried L, Liese J, Jakob F. Clinical aspects of hypophosphatasia: an update. Clin Rev Bone Mineral Metab. 2013;11(2):60–70.

    Article  CAS  Google Scholar 

  37. Neuman MW, Neuman WF. Emerging concepts of the structure and metabolic functions of bone. Am J Med. 1957;22(1):123–31.

    Article  CAS  PubMed  Google Scholar 

  38. Miao D, Scutt A. Histochemical localization of alkaline phosphatase activity in decalcified bone and cartilage. J Histochem Cytochem. 2002;50(3):333–40.

    Article  CAS  PubMed  Google Scholar 

  39. Fonta C et al. Postnatal development of alkaline phosphatase activity correlates with the maturation of neurotransmission in the cerebral cortex. J Comp Neurol. 2005;486(2):179–96.

    Article  PubMed  Google Scholar 

  40. Fleisch H, Russell RG, Straumann F. Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis. Nature. 1966;212(5065):901–3.

    Article  CAS  PubMed  Google Scholar 

  41. Fleisch H et al. Inhibition of aortic calcification by means of pyrophosphate and polyphosphates. Nature. 1965;207(5003):1300–1.

    Article  CAS  PubMed  Google Scholar 

  42. Fleisch H et al. Effect of condensed phosphates on calcification of chick embryo femurs in tissue culture. Am J Phys. 1966;211(3):821–5.

    CAS  Google Scholar 

  43. Terkeltaub R. Physiologic and pathologic functions of the NPP nucleotide pyrophosphatase/phosphodiesterase family focusing on NPP1 in calcification. Purinergic Signal. 2006;2(2):371–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ho AM, Johnson MD, Kingsley DM. Role of the mouse ank gene in control of tissue calcification and arthritis. Science. 2000;289(5477):265–70.

    Article  CAS  PubMed  Google Scholar 

  45. Ryan LM. The ank gene story. Arthritis Res. 2001;3(2):77–9.

    Article  CAS  PubMed  Google Scholar 

  46. Fraser D, Yendt ER, Christie FH. Metabolic abnormalities in hypophosphatasia. Lancet. 1955;268(6858):286.

    Article  CAS  PubMed  Google Scholar 

  47. Anderson HC et al. Matrix vesicles in osteomalacic hypophosphatasia bone contain apatite-like mineral crystals. Am J Pathol. 1997;151(6):1555–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Hessle L et al. Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization. Proc Natl Acad Sci U S A. 2002;99(14):9445–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Harmey D et al. Concerted regulation of inorganic pyrophosphate and osteopontin by akp2, enpp1, and ank: an integrated model of the pathogenesis of mineralization disorders. Am J Pathol. 2004;164(4):1199–209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Anderson HC et al. Impaired calcification around matrix vesicles of growth plate and bone in alkaline phosphatase-deficient mice. Am J Pathol. 2004;164(3):841–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Orimo H. The mechanism of mineralization and the role of alkaline phosphatase in health and disease. J Nippon Med Sch. 2010;77(1):4–12.

    Article  CAS  PubMed  Google Scholar 

  52. Wennberg C et al. Functional characterization of osteoblasts and osteoclasts from alkaline phosphatase knockout mice. J Bone Miner Res. 2000;15(10):1879–88.

    Article  CAS  PubMed  Google Scholar 

  53. Chuck AJ et al. Crystal deposition in hypophosphatasia: a reappraisal. Ann Rheum Dis. 1989;48(7):571–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Guanabens N et al. Calcific periarthritis as the only clinical manifestation of hypophosphatasia in middle-aged sisters. J Bone Miner Res. 2014;29(4):929–34.

    Article  CAS  PubMed  Google Scholar 

  55. Whyte MP, Murphy WA, Fallon MD. Adult hypophosphatasia with chondrocalcinosis and arthropathy. Variable penetrance of hypophosphatasemia in a large Oklahoma kindred. Am J Med. 1982;72(4):631–41.

    Article  CAS  PubMed  Google Scholar 

  56. Baumgartner-Sigl S et al. Pyridoxine-responsive seizures as the first symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677 T > C, p.M226 T; c.1112C > T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene. Bone. 2007;40(6):1655–61.

    Article  CAS  PubMed  Google Scholar 

  57. Nunes ML et al. Pyridoxine-dependent seizures associated with hypophosphatasia in a newborn. J Child Neurol. 2002;17(3):222–4.

    Article  PubMed  Google Scholar 

  58. Yamamoto H et al. A successful treatment with pyridoxal phosphate for west syndrome in hypophosphatasia. Pediatr Neurol. 2004;30(3):216–8.

    Article  PubMed  Google Scholar 

  59. Kermer V et al. Knockdown of tissue nonspecific alkaline phosphatase impairs neural stem cell proliferation and differentiation. Neurosci Lett. 2010;485(3):208–11.

    Article  CAS  PubMed  Google Scholar 

  60. Scriver CR, Cameron D. Pseudohypophosphatasia. N Engl J Med. 1969;281(11):604–6.

    Article  CAS  PubMed  Google Scholar 

  61. Cole DE et al. Increased serum pyridoxal-5′-phosphate in pseudohypophosphatasia. N Engl J Med. 1986;314(15):992–3.

    Article  CAS  PubMed  Google Scholar 

  62. Heaton BW, McClendon JL. Childhood pseudohypophosphatasia. Clinical and laboratory study of two cases. Tex Dent J. 1986;103(9):4–8.

    CAS  PubMed  Google Scholar 

  63. Silver MM, Vilos GA, Milne KJ. Pulmonary hypoplasia in neonatal hypophosphatasia. Pediatr Pathol. 1988;8(5):483–93.

    Article  CAS  PubMed  Google Scholar 

  64. Whyte MP et al. Hypophosphatasia: levels of bone alkaline phosphatase immunoreactivity in serum reflect disease severity. J Clin Endocrinol Metab. 1996;81(6):2142–8.

    CAS  PubMed  Google Scholar 

  65. Barcia JP, Strife CF, Langman CB. Infantile hypophosphatasia: treatment options to control hypercalcemia, hypercalciuria, and chronic bone demineralization. J Pediatr. 1997;130(5):825–8.

    Article  CAS  PubMed  Google Scholar 

  66. Kozlowski K et al. Hypophosphatasia. Review of 24 cases. Pediatr Radiol. 1976;5(2):103–17.

    Article  CAS  PubMed  Google Scholar 

  67. Watanabe A et al. Prenatal genetic diagnosis of severe perinatal (lethal) hypophosphatasia. J Nippon Med Sch. 2007;74(1):65–9.

    Article  PubMed  Google Scholar 

  68. Suzumori N et al. Prenatal diagnosis of familial lethal hypophosphatasia using imaging, blood enzyme levels, chorionic villus sampling and archived fetal tissue. J Obstet Gynaecol Res. 2011;37(10):1470–3.

    Article  PubMed  Google Scholar 

  69. Henthorn PS, Whyte MP. Infantile hypophosphatasia: successful prenatal assessment by testing for tissue-non-specific alkaline phosphatase isoenzyme gene mutations. Prenat Diagn. 1995;15(11):1001–6.

    Article  CAS  PubMed  Google Scholar 

  70. Moore CA et al. Mild autosomal dominant hypophosphatasia: in utero presentation in two families. Am J Med Genet. 1999;86(5):410–5.

    Article  CAS  PubMed  Google Scholar 

  71. Blau K et al. Prenatal diagnosis of hypophosphatasia. Lancet. 1977;2(8048):1139.

    Article  CAS  PubMed  Google Scholar 

  72. Fraser D. Hypophosphatasia. Am J Med. 1957;22(5):730–46.

    Article  CAS  PubMed  Google Scholar 

  73. Shohat M et al. Perinatal lethal hypophosphatasia; clinical, radiologic and morphologic findings. Pediatr Radiol. 1991;21(6):421–7.

    Article  CAS  PubMed  Google Scholar 

  74. Arun R et al. Scoliosis in association with infantile hypophosphatasia: a case study in two siblings. Spine (Phila Pa 1976). 2005;30(16):E471–6.

    Article  CAS  Google Scholar 

  75. Silva I et al. Childhood hypophosphatasia with myopathy: clinical report with recent update. Acta Reumatol Port. 2012;37(1):92–6.

    CAS  PubMed  Google Scholar 

  76. Reibel A et al. Orodental phenotype and genotype findings in all subtypes of hypophosphatasia. Orphanet J Rare Dis. 2009;4:6.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Bloch-Zupan, A., Hypophosphatasia: diagnosis and clinical signs - a dental surgeon perspective. Int J Paediatr Dent, 2016.

  78. Cohn, C., Hypophosphatasia - report of 3 cases. Oral Health Journal: p. 24–28.

  79. Kjellman M et al. Five cases of hypophosphatasia with dental findings. Int J Oral Surg. 1973;2(4):152–8.

    Article  CAS  PubMed  Google Scholar 

  80. Chapple IL. Hypophosphatasia: dental aspects and mode of inheritance. J Clin Periodontol. 1993;20(9):615–22.

    Article  CAS  PubMed  Google Scholar 

  81. Moulin P et al. Hypophosphatasia may lead to bone fragility: don’t miss it. Eur J Pediatr. 2009;168(7):783–8.

    Article  PubMed  Google Scholar 

  82. Berkseth KE et al. Clinical spectrum of hypophosphatasia diagnosed in adults. Bone. 2013;54(1):21–7.

    Article  CAS  PubMed  Google Scholar 

  83. Whyte MP et al. Adult hypophosphatasia. Clinical, laboratory, and genetic investigation of a large kindred with review of the literature. Medicine (Baltimore). 1979;58(5):329–47.

    Article  CAS  Google Scholar 

  84. Khandwala HM, Mumm S, Whyte MP. Low serum alkaline phosphatase activity and pathologic fracture: case report and brief review of hypophosphatasia diagnosed in adulthood. Endocr Pract. 2006;12(6):676–81.

    Article  PubMed  Google Scholar 

  85. Sutton RA et al. "atypical femoral fractures" during bisphosphonate exposure in adult hypophosphatasia. J Bone Miner Res. 2012;27(5):987–94.

    Article  CAS  PubMed  Google Scholar 

  86. Whyte MP. Atypical femoral fractures, bisphosphonates, and adult hypophosphatasia. J Bone Miner Res. 2009;24(6):1132–4.

    Article  PubMed  Google Scholar 

  87. Barvencik F et al. Skeletal mineralization defects in adult hypophosphatasia--a clinical and histological analysis. Osteoporos Int. 2011;22(10):2667–75.

    Article  CAS  PubMed  Google Scholar 

  88. McKiernan FE, Berg RL, Fuehrer J. Clinical and radiographic findings in adults with persistent hypophosphatasemia. J Bone Miner Res. 2014;29(7):1651–60.

    Article  CAS  PubMed  Google Scholar 

  89. Brittain JM, Oldenburg TR, Burkes Jr EJ. Odontohypophosphatasia: report of two cases. ASDC J Dent Child. 1976;43(2):106–11.

    CAS  PubMed  Google Scholar 

  90. Macfarlane JD, Swart JG. Dental aspects of hypophosphatasia: a case report, family study, and literature review. Oral Surg Oral Med Oral Pathol. 1989;67(5):521–6.

    Article  CAS  PubMed  Google Scholar 

  91. Wang ZY et al. Current concepts in odontohypophosphatasia form of hypophosphatasia and report of two cases. BMC Oral Health. 2016;16(1):70.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Stevenson DA et al. Autosomal recessive hypophosphatasia manifesting in utero with long bone deformity but showing spontaneous postnatal improvement. J Clin Endocrinol Metab. 2008;93(9):3443–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Wenkert D et al. Hypophosphatasia: nonlethal disease despite skeletal presentation in utero (17 new cases and literature review). J Bone Miner Res. 2011;26(10):2389–98.

    Article  CAS  PubMed  Google Scholar 

  94. Matsushita M et al. Benign prenatal hypophosphatasia: a treatable disease not to be missed. Pediatr Radiol. 2014;44(3):340–3.

    Article  PubMed  Google Scholar 

  95. McKiernan FE et al. Acute hypophosphatasemia. Osteoporos Int. 2014;25(2):519–23.

    Article  CAS  PubMed  Google Scholar 

  96. Whyte MP et al. Dysosteosclerosis presents as an "osteoclast-poor" form of osteopetrosis: comprehensive investigation of a 3-year-old girl and literature review. J Bone Miner Res. 2010;25(11):2527–39.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Masi L et al. Taxonomy of rare genetic metabolic bone disorders. Osteoporos Int. 2015;26(10):2529–58.

    Article  CAS  PubMed  Google Scholar 

  98. Gibbon VE et al. Mseleni joint disease: a potential model of epigenetic chondrodysplasia. Joint Bone Spine. 2010;77(5):399–404.

    Article  PubMed  Google Scholar 

  99. Ponce A et al. Benign familial hypophosphatasemia. Rev Clin Esp. 1996;196(5):342.

    CAS  PubMed  Google Scholar 

  100. Thompson MD et al. Hyperphosphatasia with seizures, neurologic deficit, and characteristic facial features: five new patients with Mabry syndrome. Am J Med Genet A. 2010;152a(7):1661–9.

    Article  PubMed  Google Scholar 

  101. Whyte MP et al. Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012;366(10):904–13.

    Article  CAS  PubMed  Google Scholar 

  102. Chodirker BN et al. Increased plasma pyridoxal-5′-phosphate levels before and after pyridoxine loading in carriers of perinatal/infantile hypophosphatasia. J Inherit Metab Dis. 1990;13(6):891–6.

    Article  CAS  PubMed  Google Scholar 

  103. Riancho-Zarrabeitia L et al. Clinical, biochemical and genetic spectrum of low alkaline phosphatase levels in adults. Eur J Intern Med. 2016;29:40–5.

    Article  CAS  PubMed  Google Scholar 

  104. Russell RG et al. Inorganic pyrophosphate in plasma in normal persons and in patients with hypophosphatasia, osteogenesis imperfecta, and other disorders of bone. J Clin Invest. 1971;50(5):961–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Taillandier A et al. Molecular diagnosis of hypophosphatasia and differential diagnosis by targeted next generation sequencing. Mol Genet Metab. 2015;116(3):215–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Fallon MD et al. Hypophosphatasia: clinicopathologic comparison of the infantile, childhood, and adult forms. Medicine (Baltimore). 1984;63(1):12–24.

    Article  CAS  Google Scholar 

  107. Fraser D, Laidlaw JC. Treatment of hypophosphatasia with cortisone. Lancet. 1956;270(6922):553.

    Article  CAS  PubMed  Google Scholar 

  108. Bishop N. Clinical management of hypophosphatasia. Clin Cases Miner Bone Metab. 2015;12(2):170–3.

    PubMed  PubMed Central  Google Scholar 

  109. Whyte MP et al. Enzyme replacement therapy for infantile hypophosphatasia attempted by intravenous infusions of alkaline phosphatase-rich Paget plasma: results in three additional patients. J Pediatr. 1984;105(6):926–33.

    Article  CAS  PubMed  Google Scholar 

  110. Taketani T et al. Ex vivo expanded allogeneic mesenchymal stem cells with bone marrow transplantation improved osteogenesis in infants with severe hypophosphatasia. Cell Transplant. 2015;24(10):1931–43.

    Article  PubMed  Google Scholar 

  111. Tadokoro M et al. New bone formation by allogeneic mesenchymal stem cell transplantation in a patient with perinatal hypophosphatasia. J Pediatr. 2009;154(6):924–30.

    Article  CAS  PubMed  Google Scholar 

  112. Whyte MP et al. Marrow cell transplantation for infantile hypophosphatasia. J Bone Miner Res. 2003;18(4):624–36.

    Article  PubMed  Google Scholar 

  113. Cahill RA et al. Infantile hypophosphatasia: transplantation therapy trial using bone fragments and cultured osteoblasts. J Clin Endocrinol Metab. 2007;92(8):2923–30.

    Article  CAS  PubMed  Google Scholar 

  114. Vahle JL et al. Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance to human safety. Toxicol Pathol. 2002;30(3):312–21.

    Article  CAS  PubMed  Google Scholar 

  115. Whyte MP, Mumm S, Deal C. Adult hypophosphatasia treated with teriparatide. J Clin Endocrinol Metab. 2007;92(4):1203–8.

    Article  CAS  PubMed  Google Scholar 

  116. Camacho PM, Painter S, Kadanoff R. Treatment of adult hypophosphatasia with teriparatide. Endocr Pract. 2008;14(2):204–8.

    Article  PubMed  Google Scholar 

  117. Camacho, P.M., et al., Adult hypophosphatasia treated with teriparatide: report of two patients and review of the literature. Endocr Pract, 2016.

  118. Schalin-Jantti C et al. Parathyroid hormone treatment improves pain and fracture healing in adult hypophosphatasia. J Clin Endocrinol Metab. 2010;95(12):5174–9.

    Article  CAS  PubMed  Google Scholar 

  119. Gagnon C et al. Lack of sustained response to teriparatide in a patient with adult hypophosphatasia. J Clin Endocrinol Metab. 2010;95(3):1007–12.

    Article  CAS  PubMed  Google Scholar 

  120. Laroche M. Failure of teriparatide in treatment of bone complications of adult hypophosphatasia. Calcif Tissue Int. 2012;90(3):250.

    Article  CAS  PubMed  Google Scholar 

  121. Sheen CR et al. Pathophysiological role of vascular smooth muscle alkaline phosphatase in medial artery calcification. J Bone Miner Res. 2015;30(5):824–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Bobryshev YV et al. Role of bone-type tissue-nonspecific alkaline phosphatase and PHOSPO1 in vascular calcification. Curr Pharm Des. 2014;20(37):5821–8.

    Article  CAS  PubMed  Google Scholar 

  123. Whyte, M.P., et al., Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia. J Clin Endocrinol Metab, 2015: p. jc20153462.

  124. Whyte MP, Madson KL, Phillips D, Reeves AL, McAlister WH, Yakimoski A, Mack KE, Hamilton K, Kagan K, Fujita KP, Thompson DD, Moseley S, Odrljin T, Rockman-Greenberg C. Asfotase alfa: sustained efficacy and tolerability in children with hypophosphatasia treated for 5 Years. JCI Insight. 2016;1(9):11.

    Article  Google Scholar 

  125. Science, U.N.L.o, Safety and Efficacy Study of Asfotase Alfa in Adolescents and Adults With Hypophosphatasia. 2015: ClinicalTrials.gov.

  126. Sciences, U.N.L.o, Open-Label Study of Asfotase Alfa in Infants and Children ≤ 5 Years of Age With Hypophosphatasia. 2016: ClinicalTrials.gov.

  127. Sciences, U.N.L.o, Extension Study of Protocol ENB-002-08 - Study of Asfotase Alfa in Infants and Young Children With Hypophosphatasia. 2015: ClinicalTrials.gov.

  128. Science, U.N.L.o, Extension Study of Protocol ENB-006-09 - Study of Asfotase Alfa in Children With Hypophosphatasia. 2015: ClinicalTrials.gov.

  129. Coe JD, Murphy WA, Whyte MP. Management of femoral fractures and pseudofractures in adult hypophosphatasia. J Bone Joint Surg Am. 1986;68(7):981–90.

    Article  CAS  PubMed  Google Scholar 

Download references

Author’s Contributions

All authors contributed equally to the construction of this manuscript.

Author information

Authors and Affiliations

  1. Edward Hines Junior VA Medical Center, Hines, IL, USA

    Farah Meah & Nicholas Emanuele

  2. Loyola University Medical Center, Maywood, IL, USA

    Arshi Basit & Mary Ann Emanuele

Authors
  1. Farah Meah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arshi Basit
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicholas Emanuele
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mary Ann Emanuele
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Farah Meah.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animals Rights and Informed Consent

The article does not contain any studies with human or animal subjects performed by the any of the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Meah, F., Basit, A., Emanuele, N. et al. Hypophosphatasia: Review of Bone Mineral Metabolism, Pathophysiology, Clinical Presentation, Diagnosis, and Treatment. Clinic Rev Bone Miner Metab 15, 24–36 (2017). https://doi.org/10.1007/s12018-016-9225-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12018-016-9225-1

Keywords

Search

Navigation