What is hypophosphatasia (HPP)?

Making the HPP connection1-3

HPP is a rare, inherited, multisystemic, progressive metabolic disorder characterized by low alkaline phosphatase (ALP) enzyme activity. HPP is a heterogeneous disease and disease manifestations may occur at any age. Patients with HPP may present with symptoms that affect one or more areas of the body, such as dental, neurological, muscular, renal, and/or skeletal areas. Due to this clinical variability, patients may present with new, recurring, and/or progressing symptoms that can lead to a high disease burden and a diminished quality of life.

HPP is potentially life-threatening in infants and patients may experience multisystemic, unpredictable, and devastating or life-limiting consequences that impact their quality of life.

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The biochemical hallmark of HPP is persistently low age- and sex-adjusted ALP1,2,4

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Under normal circumstances1

  • ALP dephosphorylates inorganic pyrophosphate (PPi) releasing inorganic phosphate (Pi)
  • Pi binds to calcium (Ca2+) to form hydroxyapatite crystals that mineralize bone

In HPP, ALP is deficient1,5

  • Mutations in the ALPL gene cause low ALP activity
  • PPi accumulates and prevents hydroxyapatite crystal formation and bone mineralization

ALP is a key enzyme needed for bone mineralization. Under normal conditions, ALP dephosphorylates inorganic pyrophosphate (PPi) and releases inorganic phosphate (Pi), which then binds with calcium to form hydroxyapatite crystals—the building blocks of bone mineralization.1

In HPP, ALP is deficient. Loss-of-function mutations in the ALPL gene cause low ALP activity, so PPi accumulates and prevents hydroxyapatite crystal formation and bone mineralization.1,6

ALP deficiency results in the skeletal defects and multisystemic complications of HPP.

Check your patient’s current and historical ALP levels from their comprehensive metabolic panel against normal age- and sex-adjusted references ranges.

base extracellular-callout blue-protein blue-protein-2 yellow-enzyme ppi-callout alp-callout blue-protein-upright blue-protein-downright blue-arrow blue-orb blue-orb arrow-down-right arrow-up-right blue-protein-binding pi-callout arrow-right ca-callout hydrox healthy-bone small-blue-protein

Image created for Alexion Pharmaceuticals, Inc. for illustrative purposes.

Image created for Alexion Pharmaceuticals, Inc. for illustrative purposes.

Under normal circumstances1

  • ALP dephosphorylates inorganic pyrophosphate (PPi) releasing inorganic phosphate (Pi)
  • Pi binds to calcium (Ca2+) to form hydroxyapatite crystals that mineralize bone

In HPP, ALP is deficient1,5

  • Mutations in the ALPL gene cause low ALP activity
  • PPi accumulates and prevents hydroxyapatite crystal formation and bone mineralization
Normal ALP Bone Pathway

Image created for Alexion Pharmaceuticals, Inc. for illustrative purposes.

ALP Deficient Bone Pathway

Image created for Alexion Pharmaceuticals, Inc. for illustrative purposes.

ALP is a key enzyme needed for bone mineralization. Under normal conditions, ALP dephosphorylates inorganic pyrophosphate (PPi) and releases inorganic phosphate (Pi), which then binds with calcium to form hydroxyapatite crystals—the building blocks of bone mineralization.1

In HPP, ALP is deficient. Loss-of-function mutations in the ALPL gene cause low ALP activity, so PPi accumulates and prevents hydroxyapatite crystal formation and bone mineralization.1,6

ALP deficiency results in the skeletal defects and multisystemic complications of HPP.

Check your patient’s current and historical ALP levels from their comprehensive metabolic panel against normal age- and sex-adjusted references ranges.

Low ALP can differentiate HPP from other metabolic disorders4,7

Low ALP chart comparing ALP levels with various disorders 
Low ALP chart comparing ALP levels with various disorders

Persistently low ALP may differentiate HPP from other conditions1,4

While some conditions may lead to transient decreases in ALP, patients with HPP have persistently low* ALP levels. Persistently low ALP levels should raise suspicion of HPP, especially when coupled with common symptoms of HPP such as musculoskeletal pain and/or weakness, premature tooth loss, or previous nontraumatic fractures.

*Persistently low may be defined as at least 2 values below normal within 6 months.1,8

Chart comparing low ALP levels and conditions associated with low ALP 
Chart comparing low ALP levels and conditions associated with low ALP 

Not an exhaustive list of conditions associated with low levels of ALP.

Low ALP Activity May Lead to Neurological Symptoms in HPP1,3,10,11

Pyridoxal 5`-phosphate (PLP) (ie, active form of vitamin B6) deficiency in the CNS results in deficient GABA activity

Neurological symptoms with HPP - Older Children and Adults
Neurological symptoms with HPP - Older Children and Adults

Learn more about neurological symptoms in adults

Image created for Alexion Pharmaceuticals, Inc. for illustrative purposes.

Lynn Kohlmeier, MD - Adult Endocrinologist

Learn more about low ALP in HPP

Lynn Kohlmeier, MD  (01:41)

Adult Endocrinologist

Age- and sex-adjusted ALP reference intervals must be used to accurately diagnose HPP, especially in children1,9

While high ALP levels typically raise red flags, low ALP levels may be overlooked.1

Age- and sex-adjusted ALP reference ranges (U/L)9,12-16
Chart displaying age- and sex-adjusted ALP reference intervals  ALP chart key 
Chart displaying age- and sex-adjusted ALP reference intervals  ALP chart key 

*Check with your lab for their appropriate age- and sex-adjusted reference range.9

NOTE: Graph adapted from the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) project. CALIPER samples from 1072 male and 1116 female participants (newborn to 18 years) were used to calculate age- and sex-specific reference intervals. No variation in ALP based on ethnic differences was observed.9


References: 1. Rockman-Greenberg C. Pediatr Endocrinol Rev. 2013;10(suppl 2):380-388. 2. Bianchi ML, et al. Osteoporos Int. 2020;31(8):1445-1460. doi: 10.1007/s00198-020-05345-9 3. Colazo JM, et al. Osteoporos Int. 2019;30(2):469-480. doi: 10.1007/s00198-018-4691-6 4. McKiernan FE, et al. J Bone Miner Res. 2014;29(7):1651-1660. doi: 10.1002/jbmr.2178 5. Whyte MP. Hypophosphatasia. In: Thakker RV, Whyte MP, Eisman JA, Igarashi T, eds. Genetics of Bone Biology and Skeletal Disease. Elsevier Inc; 2013:337-360. 6. Mornet E, et al. Hypophosphatasia. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews®. University of Washington; 2007. Accessed November 4, 2021. https://www.ncbi.nlm.nih.gov/books/NBK1150/ 7. Bloch-Zupan. Int J Paediatr Dent. 2016;26(6):426-438. doi: 10.1111/ipd.12232 8. Kim WR, et al. Hepatology. 2008;47(4):1363-70. doi: 10.1002/hep.22109 9. Colantonio DA, et al. Clin Chem. 2012;58(5):854-868. doi: 10.1373/clinchem.2011.177741 10. Taketani T. Subcell Biochem. 2015;76:309-322. 11. Surtees R, et al. Future Neurol. 2006;1(5):615-620. 12. Adeli K, et al. Clin Chem. 2015;61(8):1049-1062. doi:10.1373/clinchem.2015.240515 13. Schumann G, et al. Clin Chem Lab Med. 2011;49(9):1439-1446. doi:10.1515/CCLM.2011.621 14. Quest Diagnostics. Alkaline phosphatase. Accessed August 31, 2021. https://testdirectory.questdiagnostics.com/test/test-detail/234/alkaline-phosphatase?cc=MASTER 15. Labcorp. Alkaline phosphatase. Accessed August 31, 2021. https://www.labcorp.com/tests/001107/alkaline-phosphatase 16. ARUP Laboratories. Alkaline phosphatase isoenzymes, serum or plasma. Accessed August 31, 2021. https://ltd.aruplab.com/Tests/Pub/0021020.