RARE DISEASE
Hypophosphatasia
Hypophosphatasia
Hypophosphatasia
Synonyms: HPP, Phosphoethanolaminuria, Rathbun disease
Synonyms: HPP, Phosphoethanolaminuria, Rathbun disease
Synonyms: HPP, Phosphoethanolaminuria, Rathbun disease
Drug discovery
7
drugs
With orphan designations
Overview
Hypophosphatasia (HPP) is a rare inherited metabolic disorder caused by loss-of-function mutations in the ALPL gene, leading to deficient tissue-nonspecific alkaline phosphatase (TNSALP) activity. This results in impaired bone and tooth mineralization, with clinical manifestations ranging from perinatal lethality (severe skeletal hypomineralization, respiratory failure) to adult-onset osteomalacia, recurrent fractures, and premature tooth loss. Key biochemical markers include persistently low serum alkaline phosphatase (ALP) activity and elevated substrates like pyridoxal 5’-phosphate (PLP) and inorganic pyrophosphate (PPi) [1][2][10].
Burden
Pediatrics: Growth impairment, failure to thrive, skeletal deformities, developmental delays, and high mortality in untreated perinatal/infantile forms [4][10][12].
Adults: Chronic pain, recurrent fractures (e.g., metatarsal, femoral pseudofractures), premature tooth loss, and reduced quality of life [5][7][14].
Systemic complications: Nephrocalcinosis, hypercalcemia, and arthropathy from PPi accumulation [5][7][17]. Delayed diagnosis exacerbates morbidity [1][5].
Therapies
Enzyme replacement therapy: Asfotase alfa (subcutaneous) improves bone mineralization, survival in pediatric-onset HPP, and functional outcomes in adults [6][13][17].
Supportive care: Physical/occupational therapy, dental interventions (implants, orthodontics), NSAIDs for pain, and vitamin B6 for seizures [3][8][18].
Avoid bisphosphonates; consider teriparatide/romosozumab for fractures with caution [8][17].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases
Research Papers
480 drug discovery papers about Hypophosphatasia, with 4 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
480 drug discovery papers about Hypophosphatasia, with 4 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-13 | Evolving Therapeutic Paradigms in Pediatric Hypophosphatasia: From Survival-Driven Care to Integrated Precision Management.
Hypophosphatasia (HPP) encompasses a group of inherited metabolic bone disorders characterized by defective skeletal mineralization and variable clinical severity in childhood. Substantial allelic heterogeneity contributes to a broad pediatric clinical spectrum, ranging from life-threatening perinatal disease to milder phenotypes characterized by chronic functional impairment. Historically, management relied primarily on supportive interventions aimed at sustaining survival, without modifying the underlying enzymatic defect. The introduction of enzyme replacement therapy (ERT) with asfotase alfa has fundamentally altered the natural history of pediatric HPP by supplementing deficient alkaline phosphatase activity at sites of active mineralization, thereby improving skeletal integrity, enhancing survival in severe forms, and supporting long-term functional gains. This therapeutic shift has redirected clinical priorities from survival alone toward sustained functional development and health-related quality of life. Nevertheless, variability in disease expression and therapeutic response persists, reflecting both diagnostic timing and the molecular heterogeneity of ALPL variants, whose phenotypic consequences cannot be predicted with complete certainty. Growing recognition of the importance of early diagnosis has prompted exploratory efforts toward systematic identification strategies, including neonatal screening initiatives reported in selected populations, which suggest the potential for earlier therapeutic intervention during active skeletal development. Together, these considerations highlight pediatric HPP as a model of precision-oriented management in rare metabolic bone disease, where timely diagnosis and targeted enzyme replacement must be aligned with long-term, multidisciplinary care to optimize outcomes.
2026-08-09 | Low ALP Screening Reveals High Prevalence of Mild Hypophosphatasia in Chinese Children
This dataset accompanies the research article titled “Low ALP Screening Reveals High Prevalence of Mild Hypophosphatasia in Chinese Children” (Manuscript No. jc.2026-01596). The aims of this study was to (1) establish a systematic, laboratory-based screening algorithm in a large-scale pediatric cohort to facilitate early identification of HPP and characterize ALPL variants through next-generation sequencing and in vitro functional validation; (2) delineate the clinical heterogeneity of HPP, with emphasis on milder phenotypes and previously underrecognized neurobehavioral presentations. The dataset consists of five files: “Zhang_jc.2026-01596_Supplemental fig1, Revised Supplemental table 1, Revised Supplemental table 2, Revised Supplemental table 3, Revised Supplemental table 4”. 1. Zhang_jc.2026-01596_Supplemental fig1: Distribution of primary reasons for initial hospital visit among children and adolescents with persistent low serum ALP, stratified by ALPL variant status. Reasons for visit were categorized into routine physical examination, pediatric surgical conditions, otorhinolaryngological disorders, neuropsychiatric conditions, growth-related concerns, and other miscellaneous conditions. The total cohort (n=339) (A) was divided into two subgroups: subjects without (n=225) (B) and subjects with ALPL gene variants (P/LP/VUS, n=114) (C). 2. Revised Supplemental table 1: Age- and sex-specific reference intervals for serum alkaline phosphatase in Chinese children. 3. Revised Supplemental table 2: Detailed ALPL variants and ACMG classifications identified in suspected HPP patients. 4. Revised Supplemental table 3: Detailed ALPL variants and ACMG classifications identified in heterozygous carriers. 5. Revised Supplemental table 4: Clinical, biochemical, and genetic characteristics of pediatric patients with suspected hypophosphatasia. This study was approved by the Ethics Committee of the Children’s Hospital of Soochow University (No. 2023036) and was conducted in strict accordance with the Declaration of Helsinki. Written informed consent was obtained from the parents or legal guardians of all participants.
2026-07-30 | Enzyme replacement therapy with asfotase alfa in children with hypophosphatasia – safety and effectiveness: narrative review
Hypophosphatasia is a metabolic illness caused by mutations in the ALPL gene, which lead to impaired bone mineralization and multiple whole-body complications, including premature tooth loss.The implementation of enzyme replacement treatment (ERT) with asfotase alfa has provided a substantial role in the management and prognosis of children with hypophosphatasia.This review shows current data on the efficiency, safety, and limitations of ERT with asfotase alfa in pediatric patients.The literature search was conducted on PubMed.Articles were published between 2015 and 2025.Special attention was given to clinical studies, case reports, and review articles that included pediatric patients with hypophosphatasia who were enrolled in enzyme replacement therapy with asfotase alfa.The available evidence shows that asfotase alfa improves survival, bone mineralization, and quality of life.The ERT, moreover, ameliorates respiratory symptoms and mobility problems, especially in perinatal and infantile forms of hypophosphatasia.Early treatment yields better clinical outcomes.The therapy is generally well tolerated, and adverse effects are mostly mild.At the same time, there are some important unresolved issues, including limited long-term safety data and differences in therapy response.The treatment carries potential for immunogenicity.Unfortunately, scientists cannot specify the exact dosage of medicine and how long patients should be treated with it.Asfotase alfa is an effective and moderately safe treatment option for children with HPP.More research is needed to assess the long-term safety profile of outcomes.This is very important to find proper doses.
2026-07-29 | Seventeen-year follow-up of hypophosphatasia diagnosed in middle-aged siblings harboring a novel intronic and a rare missense ALPL gene mutation.
Hypophosphatasia (HPP) is the rare inborn-error-of-metabolism that features impaired mineralization of the skeleton and teeth due to a deactivating mutation or mutations of the gene ALPL which encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). We report 17-year follow-up of twin sisters and a brother referred in middle-age for painful proximal femoral "stress fractures" and then diagnosed with HPP. They reported generalized muscle and bone pain, metatarsal fractures, arthropathy and, since childhood, tooth loss. Their concordant findings were explained by compound heterozygosity in ALPL for a rare maternal missense mutation (c.1403C > T, p.Ala468Val) in exon 12, together with a novel presumably paternal change (c.863-14G > A) predicting a cryptic mRNA splice site in intron 8. Fractures continued during follow-up until one sister received a three-and-one-half-year course of hydroxyapatite-targeted TNSALP supplementation therapy (asfotase alfa) during which substantial improvement occurred in her clinical, biochemical, and functional parameters as well as quality of life. Following subsequent unplanned treatment cessation she suffered significant clinical deterioration, including new fractures and loss of mobility. Her bone histopathology documented osteomalacia. Treatment resumption restored its benefits. Among ten asymptomatic family members evaluated in this four-generation kindred, eight were carriers heterozygous for either ALPL mutation. Those harboring the maternal missense defect manifested mild hypophosphatasemia, suggesting a dominant-negative mutation effect. This experience underscores the importance of in-depth phenotyping and then clinical follow-up to characterize ALPL variant combinations, and for maintaining effective asfotase alfa treatment.
2026-06-16 | Experiences with the use of asfotase alfa in three patients with childhood-onset hypophosphatasia.
Hypophosphatasia (HPP) is a rare inherited metabolic disorder characterized by deficient activity of serum alkaline phosphatase due to loss-of-function mutations in the ALPL gene. Diagnosis confirmation, management, and follow-up of HPP are challenging, and clinical guidance is scant due to the difficulty in gathering high-level evidence. Asfotase alfa is the first long-term enzyme replacement therapy indicated in patients with pediatric-onset HPP to treat the bone manifestations of the disease. In the absence of large clinical studies, sharing clinical observations is an important source of information and support for clinicians. This article presents three case studies. A woman affected by HPP with manifestations of the disease at pediatric age began asfotase alfa therapy at the age of 43 years, resulting in improvements in bone density and epilepsy management. A man diagnosed with HPP in childhood had a severely compromised quality of life. He experienced improvements in bone fragility, respiratory function, sleep quality, and physical function with asfotase alfa therapy. Finally, a woman with infantile-onset HPP, presenting with severe bone deformity, musculoskeletal pain, pseudofractures, and cardiovascular and neurological involvement, showed radiological and clinical improvements in bone health, reduced pain, and increased walking autonomy during asfotase alfa treatment. Delayed diagnosis of HPP is common and can cause morbidity. Asfotase alfa significantly improves clinical outcomes in childhood-onset HPP, even when initiated in adulthood. Asfotase alfa therapy provides benefits beyond bone health. Monitoring treatment response requires a comprehensive clinical evaluation beyond DXA measurements. Real-world clinical experience is crucial for optimizing treatment strategies for HPP.
2026-08-13 | Evolving Therapeutic Paradigms in Pediatric Hypophosphatasia: From Survival-Driven Care to Integrated Precision Management.
Hypophosphatasia (HPP) encompasses a group of inherited metabolic bone disorders characterized by defective skeletal mineralization and variable clinical severity in childhood. Substantial allelic heterogeneity contributes to a broad pediatric clinical spectrum, ranging from life-threatening perinatal disease to milder phenotypes characterized by chronic functional impairment. Historically, management relied primarily on supportive interventions aimed at sustaining survival, without modifying the underlying enzymatic defect. The introduction of enzyme replacement therapy (ERT) with asfotase alfa has fundamentally altered the natural history of pediatric HPP by supplementing deficient alkaline phosphatase activity at sites of active mineralization, thereby improving skeletal integrity, enhancing survival in severe forms, and supporting long-term functional gains. This therapeutic shift has redirected clinical priorities from survival alone toward sustained functional development and health-related quality of life. Nevertheless, variability in disease expression and therapeutic response persists, reflecting both diagnostic timing and the molecular heterogeneity of ALPL variants, whose phenotypic consequences cannot be predicted with complete certainty. Growing recognition of the importance of early diagnosis has prompted exploratory efforts toward systematic identification strategies, including neonatal screening initiatives reported in selected populations, which suggest the potential for earlier therapeutic intervention during active skeletal development. Together, these considerations highlight pediatric HPP as a model of precision-oriented management in rare metabolic bone disease, where timely diagnosis and targeted enzyme replacement must be aligned with long-term, multidisciplinary care to optimize outcomes.
2026-08-09 | Low ALP Screening Reveals High Prevalence of Mild Hypophosphatasia in Chinese Children
This dataset accompanies the research article titled “Low ALP Screening Reveals High Prevalence of Mild Hypophosphatasia in Chinese Children” (Manuscript No. jc.2026-01596). The aims of this study was to (1) establish a systematic, laboratory-based screening algorithm in a large-scale pediatric cohort to facilitate early identification of HPP and characterize ALPL variants through next-generation sequencing and in vitro functional validation; (2) delineate the clinical heterogeneity of HPP, with emphasis on milder phenotypes and previously underrecognized neurobehavioral presentations. The dataset consists of five files: “Zhang_jc.2026-01596_Supplemental fig1, Revised Supplemental table 1, Revised Supplemental table 2, Revised Supplemental table 3, Revised Supplemental table 4”. 1. Zhang_jc.2026-01596_Supplemental fig1: Distribution of primary reasons for initial hospital visit among children and adolescents with persistent low serum ALP, stratified by ALPL variant status. Reasons for visit were categorized into routine physical examination, pediatric surgical conditions, otorhinolaryngological disorders, neuropsychiatric conditions, growth-related concerns, and other miscellaneous conditions. The total cohort (n=339) (A) was divided into two subgroups: subjects without (n=225) (B) and subjects with ALPL gene variants (P/LP/VUS, n=114) (C). 2. Revised Supplemental table 1: Age- and sex-specific reference intervals for serum alkaline phosphatase in Chinese children. 3. Revised Supplemental table 2: Detailed ALPL variants and ACMG classifications identified in suspected HPP patients. 4. Revised Supplemental table 3: Detailed ALPL variants and ACMG classifications identified in heterozygous carriers. 5. Revised Supplemental table 4: Clinical, biochemical, and genetic characteristics of pediatric patients with suspected hypophosphatasia. This study was approved by the Ethics Committee of the Children’s Hospital of Soochow University (No. 2023036) and was conducted in strict accordance with the Declaration of Helsinki. Written informed consent was obtained from the parents or legal guardians of all participants.
2026-07-30 | Enzyme replacement therapy with asfotase alfa in children with hypophosphatasia – safety and effectiveness: narrative review
Hypophosphatasia is a metabolic illness caused by mutations in the ALPL gene, which lead to impaired bone mineralization and multiple whole-body complications, including premature tooth loss.The implementation of enzyme replacement treatment (ERT) with asfotase alfa has provided a substantial role in the management and prognosis of children with hypophosphatasia.This review shows current data on the efficiency, safety, and limitations of ERT with asfotase alfa in pediatric patients.The literature search was conducted on PubMed.Articles were published between 2015 and 2025.Special attention was given to clinical studies, case reports, and review articles that included pediatric patients with hypophosphatasia who were enrolled in enzyme replacement therapy with asfotase alfa.The available evidence shows that asfotase alfa improves survival, bone mineralization, and quality of life.The ERT, moreover, ameliorates respiratory symptoms and mobility problems, especially in perinatal and infantile forms of hypophosphatasia.Early treatment yields better clinical outcomes.The therapy is generally well tolerated, and adverse effects are mostly mild.At the same time, there are some important unresolved issues, including limited long-term safety data and differences in therapy response.The treatment carries potential for immunogenicity.Unfortunately, scientists cannot specify the exact dosage of medicine and how long patients should be treated with it.Asfotase alfa is an effective and moderately safe treatment option for children with HPP.More research is needed to assess the long-term safety profile of outcomes.This is very important to find proper doses.
2026-07-29 | Seventeen-year follow-up of hypophosphatasia diagnosed in middle-aged siblings harboring a novel intronic and a rare missense ALPL gene mutation.
Hypophosphatasia (HPP) is the rare inborn-error-of-metabolism that features impaired mineralization of the skeleton and teeth due to a deactivating mutation or mutations of the gene ALPL which encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). We report 17-year follow-up of twin sisters and a brother referred in middle-age for painful proximal femoral "stress fractures" and then diagnosed with HPP. They reported generalized muscle and bone pain, metatarsal fractures, arthropathy and, since childhood, tooth loss. Their concordant findings were explained by compound heterozygosity in ALPL for a rare maternal missense mutation (c.1403C > T, p.Ala468Val) in exon 12, together with a novel presumably paternal change (c.863-14G > A) predicting a cryptic mRNA splice site in intron 8. Fractures continued during follow-up until one sister received a three-and-one-half-year course of hydroxyapatite-targeted TNSALP supplementation therapy (asfotase alfa) during which substantial improvement occurred in her clinical, biochemical, and functional parameters as well as quality of life. Following subsequent unplanned treatment cessation she suffered significant clinical deterioration, including new fractures and loss of mobility. Her bone histopathology documented osteomalacia. Treatment resumption restored its benefits. Among ten asymptomatic family members evaluated in this four-generation kindred, eight were carriers heterozygous for either ALPL mutation. Those harboring the maternal missense defect manifested mild hypophosphatasemia, suggesting a dominant-negative mutation effect. This experience underscores the importance of in-depth phenotyping and then clinical follow-up to characterize ALPL variant combinations, and for maintaining effective asfotase alfa treatment.
2026-06-16 | Experiences with the use of asfotase alfa in three patients with childhood-onset hypophosphatasia.
Hypophosphatasia (HPP) is a rare inherited metabolic disorder characterized by deficient activity of serum alkaline phosphatase due to loss-of-function mutations in the ALPL gene. Diagnosis confirmation, management, and follow-up of HPP are challenging, and clinical guidance is scant due to the difficulty in gathering high-level evidence. Asfotase alfa is the first long-term enzyme replacement therapy indicated in patients with pediatric-onset HPP to treat the bone manifestations of the disease. In the absence of large clinical studies, sharing clinical observations is an important source of information and support for clinicians. This article presents three case studies. A woman affected by HPP with manifestations of the disease at pediatric age began asfotase alfa therapy at the age of 43 years, resulting in improvements in bone density and epilepsy management. A man diagnosed with HPP in childhood had a severely compromised quality of life. He experienced improvements in bone fragility, respiratory function, sleep quality, and physical function with asfotase alfa therapy. Finally, a woman with infantile-onset HPP, presenting with severe bone deformity, musculoskeletal pain, pseudofractures, and cardiovascular and neurological involvement, showed radiological and clinical improvements in bone health, reduced pain, and increased walking autonomy during asfotase alfa treatment. Delayed diagnosis of HPP is common and can cause morbidity. Asfotase alfa significantly improves clinical outcomes in childhood-onset HPP, even when initiated in adulthood. Asfotase alfa therapy provides benefits beyond bone health. Monitoring treatment response requires a comprehensive clinical evaluation beyond DXA measurements. Real-world clinical experience is crucial for optimizing treatment strategies for HPP.
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Drug Discovery Landscape
7 orphan drug designations for Hypophosphatasia, including 2 approved therapies.
7 orphan drug designations for Hypophosphatasia, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
a reversible, competitive inhibitor of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) that binds to the ATP pocket within ENPP1 | small molecules | FDA | 2026-06-25 | — | Alesta Therapeutics B.V. |
rapidly expanding (REC-01) mesenchymal stem cell | cell therapies | FDA | 2025-02-21 | — | PuREC Co., Ltd. |
tenapanor hydrochloride | — | FDA | 2023-11-14 | — | Ardelyx, Inc. |
recombinant human alkaline phosphatase | proteins | FDA | 2015-05-13 | — | -Pharma BV |
Recombinant human alkaline phosphatase | proteins | EMA | 2015-01-15 | — | AM-Pharma B.V. |
Recombinant human tissue non-specific alkaline phosphatase - Fc - deca-aspartate fusion protein [Strensiq] | proteins | EMA | 2008-12-03 | 2015-09-01 | Alexion Europe SAS |
Asfotase alfa [Strensiq] | proteins | FDA | 2008-09-12 | 2015-10-23 | Alexion Pharmaceuticals, Inc. |
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