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01-09-2019 | Hypophosphatasia | Consensus Statement

Hypophosphatasia: Canadian update on diagnosis and management

Authors: A.A. Khan, R. Josse, P. Kannu, J. Villeneuve, T. Paul, S. Van Uum, C.R. Greenberg

Published in: Osteoporosis International | Issue 9/2019

Abstract

Summary

Hypophosphatasia (HPP) is a rare inherited disorder of bone and mineral metabolism caused by loss of function mutations in the ALPL gene. The presentation in children and adults can be extremely variable and natural history is poorly understood particularly in adults. Careful patient evaluation is required with consideration of pharmacologic intervention in individuals meeting criteria for therapy.

Introduction

The purposes of this review are to present current evidence regarding the diagnosis and management of hypophosphatasia in children and adults and provide evidence-based recommendations for management.

Method

A MEDLINE, EMBASE, and Cochrane database search and literature review was completed. The following consensus recommendations were developed based on the highest level of evidence as well as expert opinion.

Results

Hypophosphatasia is a rare inherited disorder of bone and mineral metabolism due to loss of function mutations in the tissue non-specific alkaline phosphatase (ALPL) gene causing reductions in the activity of the tissue non-specific isoenzyme of alkaline phosphatase (TNSALP). Deficient levels of alkaline phosphatase result in elevation of inhibitors of mineralization of the skeleton and teeth, principally inorganic pyrophosphate. The impaired skeletal mineralization may result in elevations in serum calcium and phosphate. Clinical features include premature loss of teeth, metatarsal and subtrochanteric fractures as well as fragility fractures. Poor bone healing post fracture has been observed. Myalgias and muscle weakness may also be present. In infancy and childhood, respiratory and neurologic complications can occur.

Conclusions

HPP is associated with significant morbidity and mortality. Pharmacologic intervention can result in significant clinical improvement. This Canadian position paper provides an overview of the musculoskeletal, renal, dental, respiratory, and neurologic manifestations of hypophosphatasia. The current state of the art in the diagnosis and management of hypophosphatasia is presented.

Whyte MP (2017) Hypophosphatasia: an overview for 2017. Bone 102:15–25CrossRefPubMed

Millán JL, Whyte MP (2016) Alkaline Phosphatase and Hypophosphatasia. Calcif Tissue Int 98:398–416CrossRefPubMed

Le Du MH, Millan JL (2002) Structural evidence of functional divergence in human alkaline phosphatases. J Biol Chem 277(51):49808–49814CrossRefPubMed

Caswell AM, Whyte MP, Russell RG (1991) Hypophosphatasia and the extracellular metabolism of inorganic pyrophosphate: clinical and laboratory aspects. Crit Rev Clin Lab Sci 28(3):195–232CrossRef

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

Mornet E (2017) Genetics of hypophosphatasia. Arch Pediatr 24(5S2):5S51–5S56CrossRefPubMed

Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, Norris S, Flack-Ytter Y, Glasziou P, Debeer H et al (2011) GRADE guidelines: 1. Introduction - GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 64(4):383–394CrossRefPubMed

Robison R (1923) The possible significance of hexosephosphoric esters in ossification. Biochem J 17:286–293CrossRefPubMedPubMedCentral

Bianchi ML (2015) Hypophosphatasia: an overview of the disease and its treatment. Osteoporos Int 26:2743–2757CrossRefPubMed

10.

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

11.

Sharom FJ, Lehto MT (2002) Glycosylphosphatidylinositol-anchored proteins: structure, function, and cleavage by phosphatidylinositol-specific phospholipase C. Biochem Cell Biol 80(5):535–549CrossRefPubMed

12.

Wong YW, Low MG (1994) Biosynthesis of glycosylphosphatidylinositol-anchored human placental alkaline phosphatase: evidence for a phospholipase C-sensitive precursor and its post-attachment conversion into a phospholipase C-resistant form. Biochem J 301:205–209CrossRefPubMedPubMedCentral

13.

Nosjean O, Koyama I, Goseki M, Roux B, Komoda T (1997) Human tissue non-specific alkaline phosphatases: sugar-moiety-induced enzymic and antigenic modulations and genetic aspects. Biochem J 321:297–303CrossRefPubMedPubMedCentral

14.

Fedde KN, Blair L, Silverstein J, Coburn SP, Ryan LM, Weinstein RS, Waymire K, Narisawa S, Millán J, MacGregor G, Whyte MP (1999) Alkaline phosphatase knock-out mice recapitulate the metabolic and skeletal defects of infantile hypophosphatasia. J Bone Miner Res 14(12):2015–2026CrossRefPubMed

15.

Fedde KN, Whyte MP (1990) Alkaline phosphatase (tissue-nonspecific isoenzyme) is a phosphoethanolamine and pyridoxal-5′-phosphate ectophosphatase: normal and hypophosphatasia fibroblast study. Am J Hum Genet 47(5):767–775PubMedPubMedCentral

16.

Lei W, Nguyen H, Brown N, Ni H, Kiffer-Moreira T, Reese J, Millán J, Paria BC (2013) Alkaline phosphatases contribute to uterine receptivity, implantation, decidualization, and defense against bacterial endotoxin in hamsters. Reproduction 146(5):419–432CrossRefPubMedPubMedCentral

17.

Narisawa S, Yadav MC, Millán JL (2013) In vivo overexpression of tissue-nonspecific alkaline phosphatase increases skeletal mineralization and affects the phosphorylation status of osteopontin. J Bone Miner Res 28(7):1587–1598CrossRefPubMed

18.

Hoshi K, Amizuka N, Oda K, Ikehara Y, Ozawa H (1997) Immunolocalization of tissue non-specific alkaline phosphatase in mice. Histochem Cell Biol 107(3):183–191CrossRefPubMed

19.

Miao D, Scutt A (2002) Histochemical localization of alkaline phosphatase activity in decalcified bone and cartilage. J Histochem Cytochem 50(3):333–340CrossRefPubMed

20.

Ali SY, Sajdera SW, Anderson HC (1970) Isolation and characterization of calcifying matrix vesicles from epiphyseal cartilage. Proc Natl Acad Sci U S A 67(3):1513–1520CrossRefPubMedPubMedCentral

21.

Morris DC, Masuhara K, Takaoka K, Ono K, Anderson HC (1992) Immunolocalization of alkaline phosphatase in osteoblasts and matrix vesicles of human fetal bone. Bone and Mineral 19(3):287–298CrossRefPubMed

22.

Golub EE (2009) Role of matrix vesicles in biomineralization. Biochim Biophys Acta 1790(12):1592–1598CrossRefPubMedPubMedCentral

23.

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

24.

Fleisch H, Russell RGG, Straumann F (1966) Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis. Nature. 212(5065):901–903CrossRefPubMed

25.

Van Den Bos T, Handoko G, Niehof A, Ryan LM, Coburn SP, Whyte MP, Beertsen W (2005) Cementum and dentin in hypophosphatasia. J Dent Res 84(11):1021–1025CrossRefPubMed

26.

Olsson A, Matsson L, Blomquist HK, Larsson Å, Sjödin B (1996) Hypophosphatasia affecting the permanent dentition. J Oral Pathol Med 25(6):343–347CrossRefPubMed

27.

Colazo J, Hu JR, Dahir KM, Simmons JH (2018) Neurological symptoms in Hypophosphatasia. Osteoporos Int:1–12

28.

Colantonio DA, Kyriakopoulou L, Chan MK, Daly CH, Brinc D, Venner AA, Pasic MD, Armbruster D, Adeli K (2012) Closing the gaps in pediatric laboratory reference intervals: a caliper database of 40 biochemical markers in a healthy and multiethnic population of children. Clin Chem 58(5):854–868CrossRefPubMed

29.

Mornet E (2018) Hypophosphatasia. Metabolism 82:142–155CrossRefPubMed

30.

Fraser D (1957) Hypophosphatasia. Am J Med 22(5):730–746CrossRefPubMed

31.

Orton NC, Innes AM, Chudley AE, Bech-Hansen NT (2008) Unique disease heritage of the Dutch-German mennonite population. Am J Med Genet A 146A:1072–1087CrossRefPubMed

32.

Greenberg CR, Evans JA, McKendry-Smith S, Redekopp S, Haworth JC, Mulivor R, Chodirker BN (1990) Infantile hypophosphatasia: localization within chromosome region 1p36.1-34 and prenatal diagnosis using linked DNA markers. Am J Hum Genet 46(2):286–292PubMedPubMedCentral

33.

Balasubramaniam S, Bowling F, Carpenter K, Earl J, Chaitow J, Pitt J, Mornet E, Sillence D, Ellaway C (2010) Perinatal hypophosphatasia presenting as neonatal epileptic encephalopathy with abnormal neurotransmitter metabolism secondary to reduced co-factor pyridoxal-5′-phosphate availability. J Inherit Metab Dis 33(Suppl 3):S25–S33CrossRefPubMed

34.

Hofmann C, Liese J, Schwarz T, Kunzmann S, Wirbelauer J, Nowak J, Hamann J, Girschick H, Graser S, Dietz K, Zeck S, Jakob F, Mentrup B (2013) Compound heterozygosity of two functional null mutations in the ALPL gene associated with deleterious neurological outcome in an infant with hypophosphatasia. Bone 55:150–157CrossRefPubMed

35.

Whyte MP, Mahuren JD, Vrabel LA, Coburn SP (1985) Markedly increased circulating pyridoxal-5′-phosphate levels in hypophosphatasia. Alkaline phosphatase acts in vitamin B₆ metabolism. J Clin Investig 76(2):752–756CrossRefPubMedPubMedCentral

36.

Yamamoto H, Sasamoto Y, Miyamoto Y, Murakami H, Kamiyama N (2004) A successful treatment with pyridoxal phosphate for West syndrome in hypophosphatasia. Pediatr Neurol 30(3):216–218CrossRefPubMed

37.

Nunes M, Mugnol F, Bica I, Fiori MR (2002) Pyridoxine-dependent seizures associated with hypophosphatasia in a newborn. J Child Neurol 17(3):222–224CrossRefPubMed

38.

Rockman-Greenberg C (2013) Hypophosphatasia. Pediatric Endocrinology Reviews Supplementary 2:380–388

39.

Whyte MP, Rockman-Greenberg C, Ozono K, Riese R, Moseley S, Melian A, Thompson D, Bishop N, Hofmann C (2016) Asfotase alfa treatment improves survival for perinatal and infantile hypophosphatasia. J Clin Endocrinol Metab 101(1):334–342CrossRefPubMed

40.

Leung ECW, Mhanni AA, Reed M, Whyte MP, Landy H, Greenberg CR (2013) Outcome of perinatal hypophosphatasia in manitoba mennonites: a retrospective cohort analysis. Journal of Inherited Metabolic Disease Reports 11:73–78

41.

Wenkert D, McAlister WH, Coburn SP, Zerega JA, Ryan LM, Ericson KL, Hersh JH, Mumm S, Whyte MP (2011) Hypophosphatasia: Nonlethal disease despite skeletal presentation in utero (17 new cases and literature review). J Bone Miner Res 26(10):2389–2398CrossRefPubMed

42.

Collmann H, Mornet E, Gattenlohner S, Beck C, Girschick H (2009) Neurosurgical aspects of childhood hypophosphatasia. Childs Nerv Syst 25:217–223CrossRefPubMed

43.

Waymire KG, Mahuren JD, Jaie JM, Guilarte TR, Coburn SP, MacGregor GR (1995) Mice lacking tissue non-specific alkaline phosphatase die from seizures due to defective metabolism of vitamin B-6. Nat Genet 11(1):45–51CrossRefPubMed

44.

Kermer V, Ritter M, Albuquerque B, Leib C, Stanke M, Zimmermann H (2010) Knockdown of tissue nonspecific alkaline phosphatase impairs neural stem cell proliferation and differentiation. Neurosci Lett 485(3):208–211CrossRefPubMed

45.

Vos T, Allen C, Arora M, Barber RM, Bhutta ZA, Brown A, Carter A, Casey DC, Charlson FJ, Chen AZ et al Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 388:1545–1602

46.

Whyte MP (2013) Hypophosphatasia. In: Thakker RV, Whyte MP, Eisman JA, Igarashi T (eds) Genetics of Bone Biology and Skeletal Disease. Academic Press, New York, pp 337–360CrossRef

47.

Rodrigues TL, Foster BL, Silverio KG, Martins L, Casati MZ, Sallum EA, Somerman MJ, Nociti FH (2012) Hypophosphatasia-associated deficiencies in mineralization and gene expression in cultured dental pulp cells obtained from human teeth. J Endod 38(7):907–912CrossRefPubMedPubMedCentral

48.

Brittain JM, Oldenburg TR, Burkes EJ Jr (1976) Odontohypophosphatasia: report of two cases. ASDC J Dent Child 43:106–111PubMed

49.

Atar M, Körperich EJ (2010) Systemic disorders and their influence on the development of dental hard tissues: a literature review. J Dent 38(4):296–306CrossRefPubMed

50.

Beumer J, Trowbridge HO, Silverman S, Eisenberg E (1973) Childhood hypophosphatasia and the premature loss of teeth. A clinical and laboratory study of seven cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 35(5):631–640CrossRef

51.

Silva I, Castelão W, Mateus M, Branco JC (2012) Childhood hypophosphatasia with myopathy: clinical report with recent update. Acta Reumatol Port 37(1):92–96PubMed

52.

Berkseth KE, Tebben PJ, Drake MT, Hefferan TE, Jewison DE, Wermers RA (2013) Clinical spectrum of hypophosphatasia diagnosed in adults. Bone 54(1):21–27CrossRefPubMed

53.

Weber TJ, Sawyer EK, Moseley S, Odrljin T, Kishnani PS (2016) Burden of disease in adult patients with hypophosphatasia: results from two patient-reported surveys. Metab Clin Exp 65(10):1522–1530CrossRefPubMed

54.

Holger C, Da Silva HG, Fang S, Linglart A, Ozono K, Petrryk A, Rockman-Greenberg C, Seefried L, Kishnani P (2018) Diagnostic delays are common for patients with hypophosphatasia: initial observations from a global HPP registry. Pediatric Endocrine Society-Pediatric Academic Society - PES-PAS; Toronto, Canada

55.

Lefever E, Witters P, Gielen E, Vanclooster A, Meersseman W, Morava E, Cassiman D, Laurent M (2018) Hypophosphatasia in adults: clinical spectrum and its association with genetics and metabolic substrates. JCD S1094–6950(18):30244–30240

56.

Coe JD, Murphy WA, Whyte MP (1986) Management of femoral fractures and pseudofractures in adult hypophosphatasia. J Bone Joint Surg 68(7):981–990CrossRefPubMed

57.

Khandwala HM, Mumm S, Whyte MP (2006) Low serum alkaline phosphatase activity and pathologic fracture: case report and brief review of hypophosphatasia diagnosed in adulthood. Endocr Pract 12:676–681CrossRefPubMed

58.

Sutton RA, Mumm S, Coburn SP, Ericson KL, Whyte MP (2013) “Atypical femoral fractures” during bisphosphonate exposure in adult hypophosphatasia. J Bone Miner Res 27:987–994CrossRef

59.

Whyte MP (2009) Atypical femoral fractures, bisphosphonates, and adult hypophosphatasia. J Bone Miner Res 24(6):1132–1134CrossRefPubMed

60.

Beck C, Morbach H, Richl P, Stenzel M, Girschick HJ (2009) How can calcium pyrophosphate crystals induce inflammation in hypophosphatasia or chronic inflammatory joint diseases? Rheumatol Int 29:229–238CrossRefPubMed

61.

Guañabens N, Mumm S, Möller I, González-Roca E, Peris P, Demertzis JL, Whyte MP (2014) Calcific periarthritis as the only clinical manifestation of hypophosphatasia in middle-aged sisters. J Bone Miner Res 29(4):929–934CrossRefPubMed

62.

Shapiro JR, Lewiecki EM (2017) Hypophosphatasia in adults: clinical assessment and treatment considerations. J Bone Miner Res 32(10):1977–1980CrossRefPubMed

63.

Bowen RAR, Hortin GL, Csako G, Otañez OH, Remaley AT (2010) Impact of blood collection devices on clinical chemistry assays. Clin Biochem 43(1–2):4–25CrossRefPubMed

64.

Turan S, Topcu B, Gökçe I, Güran T, Atay Z, Omar A, Akcay T, Bereket A (2011) Serum alkaline phosphatase levels in healthy children and evaluation of alkaline phosphatasez-scores in different types of rickets. J Clin Res Pediatr Endocrinol 3(1):7–11CrossRefPubMedPubMedCentral

65.

Lum G (1995) Significance of low serum alkaline phosphatase activity in a predominantly adult male population. Clin Chem 41(4):515–518PubMed

66.

Macfarlane JD, Souverijn JH, Breedveld FC (1992) Clinical significance of a low serum alkaline phosphatase. Neth J Med 40(1–2):9–14PubMed

67.

Lum G, Marquardt C, Khuri SF (1989) Hypomagnesemia and low alkaline phosphatase activity in patients’ serum after cardiac surgery. Clin Chem 35:664–667PubMed

68.

Shaver WA, Bhatt H, Combes B (1986) Low serum alkaline phosphatase activity in Wilson’s disease. Hepatology. 6:859–863CrossRefPubMed

69.

Saraff V, Narayanan VK, Lawson AJ, Shaw NJ, Preece MA, Högler W (2016) A diagnostic algorithm for children with low alkaline phosphatase activities: lessons learned from laboratory screening for hypophosphatasia. J Pediatr 172:181–186e1CrossRefPubMed

70.

Whyte MP, Mumm S, Deal C (2007) Adult hypophosphatasia treated with teriparatide. J Clin Endocrinol Metab 92:1203–1208CrossRefPubMed

71.

Camacho PM, Mazhari AM, Wilczynski C, Kadanoff R, Mumm S, Whyte MP (2016) Adult hypophosphatasia treated with teriparatide: report of 2 patients and review of the literature. Endocr Pract 22(8):941–950CrossRefPubMed

72.

Camacho PM, Painter S, Kadanoff R (2008) Treatment of adult hypophosphatasia with teriparatide. Endocr Pract 14(2):204–208CrossRefPubMed

73.

Doshi KB, Hamrahian AH, Licata AA (2009) Teriparatide treatment in adult hypophosphatasia in a patient exposed to bisphosphonate: a case report. Clinical Cases Mineral Bone Metabolism 6(3):266–269

74.

Gagnon C, Sims NA, Mumm S, McAuley S, Jung C, Poulton I, Ng KW, Ebeling P (2010) Lack of sustained response to teriparatide in a patient with adult hypophosphatasia. J Clin Endocrinol Metab 95(3):1007–1012CrossRefPubMed

75.

Deeb AA, Bruce SN, Morris AAM, Cheetham TD (2000) Infantile hypophosphatasia: disappointing results of treatment. Acta Paediatr 89:730–743CrossRefPubMed

76.

Millán JL, Narisawa S, Lemire I, Loisel TP, Boileau G, Leonard P, Gramatikova S, Terkeltaub R, Camacho NP, McKee MD, Crine P, Whyte MP (2007) Enzyme replacement therapy for murine hypophosphatasia. J Bone Miner Res 23(6):777–787CrossRefPubMedCentral

77.

Whyte MP, Fujita KP, Moseley S, Thompson DD, McAlister WH (2018) Validation of a novel scoring system for changes in skeletal manifestations of hypophosphatasia in newborns, infants, and children: the radiographic global impression of change scale. J Bone Miner Res 33:868–874CrossRefPubMed

78.

Whyte MP, Greenberg CR, Salman NJ, Bober MB, McAlister WH, Wenkert D, Van Sickle B, Simmons J, Edgar T, Bauer M, Hamdan M, Bishop N, Lutz R, McGinn M, Craig S, Moore J, Taylor J, Cleveland R, Cranley W, Lim R, Thacher T, Mayhew J, Downs M, Millán J, Skrinar A, Crine P, Landy H (2012) Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med 366(10):904–913CrossRefPubMed

79.

Okazaki Y, Kitajima H, Mochizuki N, Kitaoka T, Michigami Y, Ozono K (2016) Lethal hypophosphatasia successfully treated with enzyme replacement from day 1 after birth. Eur J Pediatr 175:433–437CrossRefPubMed

80.

Costain G, Moore A, Munroe L, Williams A, Shaul R, Rockman-Greenberg C, Offringa M, Kannu P (2017) Enzyme replacement therapy in perinatal hypophosphatasia: care report of a negative outcome and lessons for clinical practice. Mol Genet Metab 14:22–26

81.

Kishnani PS, Rush ET, Arundel N, Dahir K, Fraser W, Harmatz P, Linglart A, Munns CF, Nunes ME, Saal HM, Seefreed L, Ozono K (2017) Monitoring guidelines for patients with hypophoshatasia treated with asfotase alfa. Mol Genet Metab 122:4–17CrossRefPubMed

82.

Mori M, DeArmey SL, Weber TJ, Kishnani PS (2016) Case series: odontohypophosphatasia or missed diagnosis of childhood/adult-onset hypophosphatasia? – Call for a long-term follow-up of premature loss of primary teeth. Bone Reports 5:228–232CrossRefPubMedPubMedCentral

83.

Kishnani PS, Rockman-Greenberg C, Rauch F, Bhatti MT, Moseley S, Denker AE, Watsky E, Whyte MP (2019) Five-year efficacy and safety of asfotase alfa therapy for adults and adolescents with hypophosphatasia. Bone 121:149–162CrossRefPubMed

Title: Hypophosphatasia: Canadian update on diagnosis and management
Authors: A.A. Khan
R. Josse
P. Kannu
J. Villeneuve
T. Paul
S. Van Uum
C.R. Greenberg
Publication date: 01-09-2019
Publisher: Springer London
Keyword: Hypophosphatasia
Published in: Osteoporosis International / Issue 9/2019
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-019-04921-y

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Hypophosphatasia: Canadian update on diagnosis and management

Abstract

Summary

Introduction

Method

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Summary

Introduction

Method

Results

Conclusions

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