Low Alkaline Phosphatase and Impaired Mineralisation
- Hypophosphatasia (HPP) is an inherited metabolic bone disease caused by LOSS-OF-FUNCTION mutations in the ALPL gene, which encodes TISSUE-NONSPECIFIC ALKALINE PHOSPHATASE (TNSALP); the enzyme deficiency impairs skeletal and dental mineralisation.
- The DIAGNOSTIC CLUE is a paradoxically LOW serum ALKALINE PHOSPHATASE - the opposite of most bone diseases (rickets, osteomalacia, Paget's, fracture healing) which RAISE ALP - so a persistently LOW ALP in a patient with fractures or bone disease should prompt the diagnosis.
- Deficient TNSALP causes accumulation of its substrates: INORGANIC PYROPHOSPHATE (PPi - a potent inhibitor of mineralisation, so it builds up and blocks bone formation and causes chondrocalcinosis/pseudogout), PYRIDOXAL-5'-PHOSPHATE (PLP/vitamin B6 - hence B6-dependent seizures in severe infantile disease), and PHOSPHOETHANOLAMINE (PEA, raised in urine).
- The clinical SPECTRUM is broad and severity is inversely related to age of onset: perinatal (often lethal) and infantile (failure to thrive, rickets, HYPERCALCAEMIA, craniosynostosis, seizures), childhood (rickets, bowing, short stature, and the characteristic PREMATURE LOSS OF PRIMARY TEETH with intact roots), adult (osteomalacia, recurrent poorly-healing stress/pseudofractures of the metatarsals and subtrochanteric femur, chondrocalcinosis/pseudogout), and odonto-HPP (dental only).
- The cardinal ORTHOPAEDIC PITFALL: BISPHOSPHONATES are CONTRAINDICATED in HPP - they are pyrophosphate analogues that further inhibit mineralisation and can precipitate ATYPICAL FEMORAL FRACTURES; a low ALP must be recognised BEFORE prescribing them for a 'fragility' fracture.
- DIAGNOSIS combines a low ALP with raised substrates (serum PLP/B6, urinary PEA), characteristic radiographs (rickets with 'tongue-like' metaphyseal lucencies in children; osteomalacia/pseudofractures in adults) and ALPL genetic testing; the key TREATMENT advance is ASFOTASE ALFA, a bone-targeted recombinant TNSALP enzyme-replacement therapy that transforms outcomes in perinatal/infantile/childhood HPP, with supportive care, B6 for seizures, and avoidance of bisphosphonates and excess vitamin D.
- “HPP = ALPL/TNSALP deficiency; the clue is a LOW serum alkaline phosphatase (opposite of other bone diseases).
- “Substrate build-up: PPi (inhibits mineralisation, chondrocalcinosis), PLP/B6 (seizures), urinary PEA. Childhood hallmark = premature loss of PRIMARY teeth.
- “Do NOT give bisphosphonates (PPi analogues - worsen it / atypical femoral fractures). Treat with asfotase alfa (enzyme replacement).
Biochemistry & Pathophysiology
The enzyme and its job. Hypophosphatasia (HPP) is an inherited metabolic bone disease caused by loss-of-function mutations in ALPL, the gene for tissue-nonspecific alkaline phosphatase (TNSALP). At the mineralising surface TNSALP hydrolyses inorganic pyrophosphate (PPi), a potent inhibitor of hydroxyapatite formation, and removing it allows mineralisation to proceed.
What goes wrong. With TNSALP deficient, PPi accumulates and blocks mineralisation of bone and teeth, giving rickets and osteomalacia. The excess also deposits as calcium pyrophosphate, which is the chondrocalcinosis and pseudogout of the disease.
The other substrates. Two more of the enzyme's substrates build up, and both are used in diagnosis. Pyridoxal-5'-phosphate (PLP, vitamin B6) fails to enter the brain, which causes the B6-dependent seizures of severe infantile disease. Phosphoethanolamine (PEA) is raised in the urine.
The signature. Because the enzyme itself is deficient, the serum alkaline phosphatase is LOW. Most bone diseases (rickets, osteomalacia, Paget's disease, fracture healing) raise it, so a persistently low ALP in a patient with fractures or bone disease, premature tooth loss or chondrocalcinosis should prompt the diagnosis.
Inheritance: Why Some Are Recessive and Some Dominant
The gene. ALPL, on chromosome 1, encodes TNSALP, which works as a functional dimer. There are many disease-causing variants, giving the broad genotype-phenotype spectrum.
Severe disease is recessive. The perinatal and infantile forms are autosomal recessive: they require two loss-of-function alleles, homozygous or compound heterozygous.
Milder disease can be dominant or recessive. The childhood, adult and odonto forms may arise from a single allele, particularly a dominant-negative variant, in which the mutant subunit poisons the wild-type partner in the dimer. This is why a parent or sibling with only a low ALP (a carrier, or mild or odonto HPP) may be found when a severely affected child is diagnosed, and the compound heterozygous versus heterozygous split in the cited series turns on this pattern.
Counselling. Recurrence risk depends on the pattern: biallelic for severe disease, with each parent a carrier, versus dominant transmission in some milder pedigrees. Test the family, not just the index patient; the general principles are in the Genetics & Inheritance in Orthopaedics topic.
Clinical Spectrum & Diagnosis
The spectrum. Severity is inversely related to age of onset, from lethal perinatal disease to tooth loss alone.
- Perinatal: profound hypomineralisation, frequently lethal from respiratory failure
- Infantile: failure to thrive, rickets, hypercalcaemia and hypercalciuria, craniosynostosis, seizures and respiratory problems
- Childhood: rickets, bowing, short stature, delayed walking or a waddling gait, and the characteristic premature loss of primary teeth with the root intact
- Adult: osteomalacia, recurrent poorly-healing stress fractures and pseudofractures, classically of the metatarsals and the subtrochanteric femur, with chondrocalcinosis or pseudogout, early tooth loss and chronic musculoskeletal pain
- Odonto-HPP: dental disease only
Making the diagnosis. The diagnosis combines the low ALP with the biochemistry, radiographs and genetics:
- A low serum ALP, adjusted for age and sex
- Raised substrates: serum PLP (B6) and urinary PEA
- Radiographs: 'tongue-like' metaphyseal radiolucencies in children; osteomalacia with Looser-zone pseudofractures in adults
- ALPL genetic testing
A Low ALP Is Not Always HPP: The Differential
A low ALP points to HPP only after two steps: distinguishing it from the rickets and osteomalacia mimics, and excluding the other causes of a low ALP.
Separate HPP from the rachitic mimics. Nutritional (vitamin-D-deficiency) rickets, renal osteodystrophy and hypophosphataemic rickets and osteomalacia (XLH, oncogenic) all raise the ALP as osteoblasts work overtime, whereas HPP lowers it. A child with a rachitic radiograph but a low ALP therefore has HPP until proven otherwise. Calcium and phosphate help too: HPP infants are often hypercalcaemic, unlike the low or normal calcium of nutritional rickets. The mimics themselves are covered in the Rickets, Vitamin D Deficiency and XLH/Oncogenic Osteomalacia topics.
Exclude the other causes of a genuinely low ALP. ALP is a zinc and magnesium metalloenzyme and a marker of bone and liver turnover, so it also falls in hypothyroidism, hypomagnesaemia or zinc deficiency, malnutrition, severe anaemia, Wilson's disease, glucocorticoid excess or Cushing's, recent bisphosphonate or denosumab therapy, vitamin D toxicity, multiple myeloma, massive transfusion and major illness.
Then confirm. Repeat an age- and sex-adjusted ALP and exclude these causes; only then pursue HPP with the raised substrates and ALPL genetics.
Management
Enzyme replacement. Asfotase alfa is a bone-targeted recombinant TNSALP enzyme-replacement therapy. It markedly improves survival, skeletal mineralisation and growth in perinatal, infantile and childhood HPP, and early diagnosis is essential to start it in time.
Supportive care. Care is multidisciplinary: vitamin B6 for the B6-dependent seizures of severe infantile disease, respiratory support, orthopaedic care of fractures and deformity, dental care, physiotherapy, and management of hypercalcaemia in infants.
Fracture care. Fractures heal poorly. Optimise fixation, anticipate delayed union or nonunion, and treat the underlying disease, with asfotase alfa where indicated.
Vitamin D and teriparatide. Avoid excessive vitamin D or calcium loading, which risks hypercalcaemia. Teriparatide has been used off-label in some adults.
Bisphosphonates are contraindicated in hypophosphatasia. They are pyrophosphate analogues, so they further inhibit mineralisation and can precipitate atypical femoral fractures; giving them is a recognised error. A patient with fragility or stress fractures and a persistently low alkaline phosphatase may have HPP, so check the ALP before treating a 'fragility fracture' as routine osteoporosis, and refer suspected HPP to metabolic-bone specialists for confirmation and enzyme-replacement consideration.
Mnemonics & Memory Aids
LOW ALP
Hook:Everything turns on a LOW ALP.
DON'T GIVE
Hook:In HPP, DON'T GIVE bisphosphonates - GIVE asfotase alfa.
Clinical Decision Scenarios
Practise clinical reasoning and management decisions out loud
“An adult presents with recurrent metatarsal stress fractures and a persistently low alkaline phosphatase. What diagnosis must you consider, and why does it change management?”
“How does hypophosphatasia present across the age spectrum, and what is the diagnostic biochemistry?”
Cause & biochemistry
- ALPL loss-of-function → deficient TNSALP
- LOW serum alkaline phosphatase (the clue; others RAISE ALP)
- Substrate build-up: PPi (inhibits mineralization), PLP/B6 (seizures), urinary PEA
Spectrum
- Perinatal (lethal) / infantile (FTT, hypercalcaemia, seizures)
- Childhood: rickets + premature loss of PRIMARY teeth (intact roots)
- Adult: osteomalacia, metatarsal/subtrochanteric pseudofractures, chondrocalcinosis; odonto = dental only
Diagnosis
- Low ALP + raised serum PLP (B6) + urinary PEA
- Radiographs: tongue-like metaphyseal lucencies (child) / Looser zones (adult)
- ALPL genetic testing
Management
- Asfotase alfa (recombinant TNSALP ERT) - early diagnosis essential
- B6 for seizures; treat fractures (poor healing); MDT/dental care
- AVOID bisphosphonates (atypical femoral fractures) and excess vitamin D
Evidence & Key Studies
Hypophosphatasia in childhood: diagnosis to management
- HPP results from loss-of-function ALPL mutations causing deficient TNSALP activity and is diagnosed from combined clinical, laboratory (low ALP), radiographic and genetic findings.
- Clinical heterogeneity makes diagnosis challenging, so early recognition is essential.
- Asfotase alfa, a bone-targeted recombinant TNSALP enzyme-replacement therapy, has improved prognosis.
Phenotypic and genotypic spectrum of Indian patients with hypophosphatasia
- Five genetically proven HPP patients ranged from an infant (failure to thrive, hypercalcaemia, low ALP) and an adolescent (genu valgum, delayed dentition, 'tongue-like' metaphyseal translucencies) to adults with vertebral fractures and musculoskeletal pain.
- Compound heterozygous ALPL variants caused severe early disease; heterozygous variants caused milder adult disease; an infant inappropriately received bisphosphonate before HPP was recognised.
- Asfotase alfa produced remarkable growth improvement, underscoring the need to recognise a low ALP and avoid harmful treatment.
The ALPL/TNSALP basis, the diagnostic combination including a low ALP, and the role of asfotase alfa come from the cited Im & Cho review, and the clinical spectrum (infantile hypercalcaemia, 'tongue-like' metaphyseal translucencies, adult fractures), the harm of inappropriate bisphosphonate use and the response to asfotase alfa from the cited Dhananjaya case series. The substrate biochemistry (PPi, PLP/B6, PEA) and the bisphosphonate contraindication are standard, well-established teaching. (See also our Rickets/ Osteomalacia and Calcium/Metabolic Bone topics.)