Hypophosphatasia (HPP): Diagnosis, Features and Treatment

Hypophosphatasia is an inherited metabolic bone disease. Loss of activity of tissue-nonspecific alkaline phosphatase (TNSALP) impairs skeletal and dental mineralization [1, 2]. Expression ranges from fatal perinatal disease to adults whose only problems are recurrent fractures or tooth loss. Diagnosis is frequently delayed, particularly in adults, and the low alkaline phosphatase (ALP) result that should prompt the diagnosis is often overlooked [2]. This article covers the genetics, clinical spectrum, diagnostic approach, and current treatment, with attention to the orthopedic presentation.

Definition and Terminology

HPP results from pathogenic variants in ALPL, the gene encoding TNSALP [1, 2]. TNSALP is the “tissue-nonspecific” isoenzyme, found in bone, liver, and kidney [3]. It is therefore more accurate to speak of TNSALP deficiency than of a deficiency of a “bone isoenzyme.”

Epidemiology

Estimated birth prevalence of severe forms is about 1/300,000 in Europe and 1/100,000 in North America [4, 5]. Milder forms are considerably more common. One genetic model estimated the prevalence of moderate, dominantly inherited disease in Europe at about 1/6,370 [5]. Prevalence is higher in some founder populations, with a figure of up to 1/2,500 suggested for Canadian Mennonites [6].

Genetics and Inheritance

Nearly 500 ALPL variants have been implicated in HPP, most of them missense [7]. Inheritance can be autosomal recessive or autosomal dominant, and both patterns have been reported within one family [7]. Some missense variants act in a dominant-negative manner, which explains dominantly inherited mild disease [6].

Genetic testing is regarded as standard practice where available [7]. Sequencing detects about 95% of causative variants [6]. Two caveats matter:

• Some patients have persistently low ALP without an identifiable ALPL variant [7].
• Variants of uncertain significance are common enough that dedicated resources exist for interpreting them [7].

Pathophysiology

TNSALP dephosphorylates several extracellular substrates, chiefly inorganic pyrophosphate (PPi), pyridoxal-5′-phosphate (PLP), and phosphoethanolamine (PEA) [2]. PPi inhibits mineralization, so its accumulation explains rickets or osteomalacia, tooth loss, and calcific arthropathies [1]. Impaired mineralization may also raise serum calcium and phosphate [12].

Clinical Forms

Classification rests mainly on age at diagnosis and on whether bone symptoms are present. The recognized forms are perinatal, prenatal benign, infantile, childhood, adult, and odontohypophosphatasia (dental disease only) [4]. Genotype–phenotype correlation is imperfect, and presentation can differ widely even within one family [2, 4].

Clinical Presentation

Perinatal and infantile disease

Perinatal HPP is almost always fatal soon after birth [8]. Mortality in perinatal and infantile forms has been reported at 50–100%, typically from respiratory complications [9]. Radiographs in severe pediatric disease can show characteristic changes at the growth plate, including radiolucent “tongues” extending into the metaphysis [1].

Childhood disease

Childhood HPP typically presents with rickets-like features, impaired mobility, and premature loss of primary teeth. Severity varies widely.

Adult disease

In adults, symptoms are often mild and non-specific, including fatigue, headache, depression, and anxiety [2]. The orthopedic clues are:

• Recurrent, poorly healing metatarsal stress fractures [10].
• Pseudofractures, including lateral subtrochanteric femoral pseudofractures that present as thigh or hip pain [10, 11].
• Premature loss of primary dentition and a family history suggestive of HPP [10].
• Calcific arthropathy, including chondrocalcinosis, reflecting PPi excess [1].
• Poor bone healing after fracture, which has been observed [12].

Laboratory Evaluation

Test	Typical finding in HPP	Interpretive note
Serum ALP	Persistently low	Confirm the reduction is not explained by another condition or drug [2]
Serum PLP	Elevated	Described as a sensitive and specific biochemical marker [1]
PEA (serum or urine)	Usually elevated	Less reliable for diagnosis than PLP [1]
PPi	Elevated (TNSALP substrate)	Substrate levels fell on enzyme replacement in trials [19]
Calcium, phosphate	May be raised	Reflects impaired skeletal mineralization [12]

Diagnostic Approach

Diagnosis integrates clinical features, laboratory profile, radiographic findings, and ALPL analysis [2]. For adults, an International Working Group systematic review pooled 119 papers and proposed four major and five minor criteria. A diagnosis is supported by two major criteria, or one major plus two minor [13]. These criteria derive from largely retrospective data on small numbers of patients and are consensus-based [2]. The Japanese clinical practice guideline recommends ALPL testing for definitive diagnosis and genetic counseling [14].

Differential Diagnosis and Pitfalls

Low ALP on bisphosphonates. Most people with ALP suppressed on bisphosphonate therapy do not have HPP, so the diagnosis rests on confirming persistent hypophosphatasemia with supporting biochemistry or genetics [2].

Other causes of pseudofractures. Subtrochanteric pseudofractures also occur in X-linked hypophosphatemia, so the biochemical profile separates the two [11]. ENPP1-related disease may enter the differential in some settings [15].

Misdiagnosis as osteoporosis. Adults with HPP are often treated as osteoporotic. Antiresorptive therapy is considered inappropriate when HPP is the underlying disorder [15]. A single case report described atypical subtrochanteric femoral fractures after four years of alendronate and then zoledronate. Metatarsal stress fractures had begun within months of starting therapy, and HPP was diagnosed only afterwards [10]. The causal role of HPP in atypical femoral fractures remains unproven. A small case–control study (10 atypical-fracture cases, 13 long-term bisphosphonate controls) found no evidence that HPP was a risk factor [16]. The evidence supports a high index of suspicion, not a firm causal claim.

Management

Enzyme replacement therapy

Asfotase alfa is a recombinant, bone-targeted human TNSALP given subcutaneously [8]. A 2012 open-label study of 11 infants and young children with life-threatening disease reported 1-year radiographic healing of rickets, better respiratory status, and better physical function [17, 8]. A seven-year extension reported sustained improvement in skeletal mineralization, with respiratory, growth, and motor and cognitive function also improving. Three of the 11 patients (27%) had serious drug-related adverse events, which were chronic hepatitis, a post-injection reaction, and craniosynostosis with conductive deafness [18].

Survival data come from comparison with historical controls. In treated perinatal and infantile patients, survival was 95% versus 42% at 1 year and 84% versus 27% at 5 years (P < .0001) [9]. The design is not randomized, so these figures are suggestive rather than definitive. In 13 children aged 6–12 years who were substantially impaired, the therapy showed sustained efficacy with low anti-drug antibody titers [8].

Adults and milder disease

Evidence in adults is limited. The main source is a small, open-label phase 2 study (n = 19, ages 13–66). Reported only as a conference abstract, it found the six-minute walk distance rose from 355 m to 450 m in those treated for 5 years, and 15 of 19 completed that period [19]. Reviews describe pediatric trials plus data in pediatric-onset adults as the basis for asfotase alfa use, and note that alternatives remain limited [20]. Evidence of benefit in adult-onset or oligosymptomatic disease is therefore weak. The interest in treating milder disease mentioned in your source text is a hypothesis that remains largely unproven.

Monitoring and team care

Consensus guidance recommends a coordinated multidisciplinary approach, with defined laboratory, efficacy, and safety monitoring in patients on asfotase alfa [21]. That guidance is expert opinion, not trial-derived.

Orthopedic considerations

No verified evidence-based protocol for fracture fixation or perioperative management in HPP was identified. Because of the reported poor fracture healing [12], suspected cases are best co-managed with a metabolic bone specialist.

Emerging therapy

Efzimfotase alfa is a next-generation enzyme replacement therapy given every two weeks in phase 3 trials. In September 2026 the FDA accepted its application for priority review in patients aged 2 years and older, with an action date expected in the first half of 2027 [22]. In the phase 3 HICKORY trial in treatment-naive adolescents and adults, it missed statistical significance on the primary six-minute walk endpoint [23]. These findings come from company announcements and trade press, and I could not verify full peer-reviewed results [22, 23].

Key Learning Points

• Think of HPP in adults with recurrent metatarsal stress fractures, pseudofractures, or early tooth loss, and check ALP.
• Persistently low ALP needs confirmation and supporting tests (PLP, ALPL sequencing) before the diagnosis is made [2, 1].
• Do not label low ALP as HPP without excluding other causes, especially drug effect [2].
• Review any antiresorptive therapy in patients with suspected or confirmed HPP [15, 10].
• Enzyme replacement has its strongest evidence in severe pediatric disease, and adult data are limited [9, 19].

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References

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22. AstraZeneca. Efzimfotase alfa granted Priority Review in the US as treatment for patients with hypophosphatasia aged 2 years and older. Press release, 18 September 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/efzimfotase-alfa-granted-priority-review-us-as-treatment-for-patients-with-hypophosphatasia-aged-2-years-and-older.html
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