What is Hypophosphatasia

Hypophosphatasia is an inherited disorder of bone and mineral metabolism that occurs as a result of an inactivating mutation of a gene that encodes the tissue-nonspecific alkaline phosphatase enzyme.

Clinical features of this condition are highly variable and can present with fetal death, severe osteomalacia in the pediatric population, and a seemingly silent disease such as osteoporosis in adults. Patients have low serum alkaline phosphatase, elevated vitamin B6 (with pyridoxal 5-phosphate), and high urine phosphoethanolamine levels. Asfotase alfa is now FDA-approved for pediatric patients with this condition.

Pathophysiology of Hypophosphatasia

Hypophosphatasia occurs due to a loss of function mutation of the ALPL gene, which encodes the ubiquitous tissue-non-specific isoenzyme of ALP (TNSALP). Alkaline phosphatases represent a large group of enzymes found in various tissues. These enzymes catalyze the hydrolysis of various phosphate-containing substrates, which ultimately results in the release of inorganic phosphate.

There are at least four isoenzymes of alkaline phosphatase; these include placental alkaline phosphatase (PLAP), germ cell alkaline phosphatase (GCAP), intestinal alkaline phosphatase (IAP), and tissue nonspecific alkaline phosphatase.

Tissue nonspecific alkaline phosphatase shares at least 50% homology with the other three isoenzymes and is abundant in hepatic, skeletal, and renal tissue1.

Tissue nonspecific alkaline phosphatase is responsible for the liberation of inorganic phosphate from various extracellular substrates, including inorganic pyrophosphate, pyridoxal 5-phosphate, and phosphoethanolamine. Osteoblasts then utilize the generated phosphate during bone mineralization (hydroxyapatite crystals).

Pyridoxal 5-phosphate, a phosphorylated version of pyridoxine (vitamin B6), is the coenzyme for glutamic acid carboxylase – an enzyme required to form gamma-aminobutyric acid (GABA, an inhibitory central nervous system modulator). In patients with Hypophosphatasia, defective processing of vitamin B6 results in its accumulation in serum.

Also, the hydrolysis of pyridoxal 5 phosphate results in the formation of an un-phosphorylated version of vitamin B6, which subsequently crosses the blood-brain barrier. Pyridoxal 5-phosphate is then regenerated from vitamin B6 in neuronal cells, where it plays a role as a coenzyme of GABA synthesis.

The defective activity of tissue nonspecific alkaline phosphatase results in decreased synthesis of gamma-aminobutyric acid, a critical inhibitory modulator in the central neural system. Consequently, this predisposes patients to neuronal hyperexcitability and increases their risk for seizures.

History (Original characterization of Hypophosphatasia)

The index case of Hypophosphatasia was first reported in 1988 by Weiss et al. This was reported as a missense mutation of A162T (c.535G>A) in the ALPL gene. Since this initial report, various mutations have been reported in the literature, including nonsense mutations, installations, splicing mutations, and deletions2.

Clinical features of Hypophosphatasia

clinical features of Hypophosphatasia are highly variable. It may present lethal outcomes during intrauterine life, severe pediatric skeletal disease, or a mild late adult-onset variant characterized by osteoporosis. Patients may also present with significant musculoskeletal pain, joint pain (arthropathy), multiple fragility fractures, dental caries, and premature loss of teeth.

  • Rickets and osteomalacia
  • Fractures
  • Early loss of both primary and secondary dentition (poor bone mineralization and dental caries).
  • Seizures (vitamin B6 supplementation may improve symptoms)
  • Nephrocalcinosis and chronic pain
  • Short and deformed limbs



  • Low serum alkaline phosphatase
  • increase in urinary phosphoethanolamine (PEA)
  • Increased serum vitamin B6 level
  • Increased serum pyridoxal 5-phosphate
  • High serum inorganic phosphate
  • Hypercalcemia may occur in infants

Reliance on low serum alkaline phosphatase is a reason for workgroup for Hypophosphatasia is problematic since various conditions can result in a low serum alkaline phosphatase. These conditions include nutritional deficiencies, early pregnancy, hypothyroidism, Cushing’s syndrome, zinc deficiency, and anemia.

Radiographic findings

  • Fractures and pseudofractures (Looser’s zone)
  • Metaphyseal radiolucency
  • Renal calcifications
  • Rickets changes.
  • Bone deformities such as bowing

Genetic screening

This condition can be inherited in either an autosomal dominant (AD) or autosomal recessive (AR) pattern. For a couple with the AR genetic mutation in the ALPL gene, 1 in 4 children has a risk of inheriting the condition. The lack of complete penetrance means that even amongst carriers with an autosomal dominant mutation, not all patients will develop the condition3.


A recombinant alkaline phosphatase enzyme replacement therapy known as asfotase alfa (Strensiq) is FDA approved for the treatment of juvenile Hypophosphatasia. Although late adult onset hypophosphatasia is characterized by less severe bone disease, severe pain and reduced quality of life may be indications for treatment with asfotase alfa4.

Of note, anti-asfotase alfa antibodies may develop in patients on this therapy; there is no evidence of resistance to treatment with this medication.

Estimating the dose of Asfotase alfa

Asfotase alfa (Strensiq) is available in single dose vials for subcutaneous administration : 18 mg/0.45 mL, 28 mg/0.7 mL, 40 mg/mL, or 80 mg/0.8 mL. For perinatal or infantile-onset, 2mg per kg body weight should be administered subcutaneously, three times a week. The dose can then be increased to 3mg per kg body weight, three times a week.

The known side effects of asfotase alfa

  • Hypersensitivity reactions
  • Lipodystrophy involving preferred injection sites
  • Ectopic calcifications (ophthalmic and renal)

PTH analogs have been utilized in adults with multiple fractures. However, bisphosphonate therapy should be avoided in these patients since bisphosphonates (Indeed, bisphosphonates have a similar conformation to inorganic pyrophosphate ) can act as a substrate for alkaline phosphatase). Endogenous pyrophosphate is a potent inhibitor of bone mineralization. Bisphosphonates, being close structural analogs to inorganic pyrophosphate, may promote poor bone mineralization. Also, there have been reports of atypical femoral fractures in this patient population after exposure to bisphosphonate therapy. Close dental follow-up is recommended since patients are predisposed to various dental anomalies, including enamel hypoplasia, delayed teeth eruption, and premature loss of teeth5.


  1. Mornet, E. Hypophosphatasia. Best Pract. Res. Clin. Rheumatol. 22, 113–127 (2008).
  2. Fenn, J. S., Lorde, N., Ward, J. M. & Borovickova, I. Hypophosphatasia. J. Clin. Pathol. 74, 635–640 (2021).
  3. Choida, V. & Bubbear, J. S. Update on the management of hypophosphatasia. Ther. Adv. Musculoskelet. Dis. 11, 1759720X19863997 (2019).
  4. Michigami, T. et al. Clinical Practice Guidelines for Hypophosphatasia*. Clin. Pediatr. Endocrinol. 29, 9–24 (2020).
  5. Millán, J. L. & Whyte, M. P. Alkaline Phosphatase and Hypophosphatasia. Calcif. Tissue Int. 98, 398–416 (2016).

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