The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Human ALPL / tissue-nonspecific alkaline phosphatase (TNAP): functional-annotation report

Executive summary

The requested identity is unambiguous: human ALPL (approved name alkaline phosphatase, biomineralization associated; UniProt P05186) encodes tissue-nonspecific alkaline phosphatase—TNAP/TNSALP/AP-TNAP—not an unrelated similarly named protein. The protein’s GPI anchoring, alkaline-phosphatase catalytic core, metal-dependent active site, and homodimeric organization agree with the supplied InterPro/Pfam annotations. Independent human genetic evidence links ALPL to perinatal, infantile, childhood, adult, and odonto-hypophosphatasia (HPP). (OpenTargets Search: -ALPL, villasuarez2021hypophosphatasiaaunique pages 2-4, imam2024structuralandfunctional pages 1-2)

Its best-established physiological function is extracellular hydrolysis of inorganic pyrophosphate (PPi), lowering a potent inhibitor of hydroxyapatite propagation while generating inorganic phosphate (Pi). TNAP thereby controls the local PPi/Pi balance required for bone and tooth mineralization. A second firmly established function is dephosphorylation of extracellular pyridoxal-5′-phosphate (PLP), allowing uptake of the dephosphorylated vitamin-B6 vitamer and supporting intracellular neurotransmitter synthesis. TNAP is catalytically broad rather than substrate-specific: phosphoethanolamine (PEA), ATP/ADP/AMP, phosphorylated osteopontin and other phosphate monoesters can be hydrolyzed, but their organism-level importance is less uniformly established than that of PPi and PLP. (villasuarez2021hypophosphatasiaaunique pages 2-4, imam2024structuralandfunctional pages 1-2, imam2024structuralandfunctional pages 15-17, choida2019updateonthe pages 1-2)

Table: This table ranks the main functional and translational findings for human ALPL/TNAP by how established they are, separating canonical human physiology from newer, mainly preclinical roles. It is useful as a quick guide to what is firmly supported for annotation versus what should be labeled emerging.

1. Identity verification and nomenclature

Mandatory checks

1. Gene/protein match: The literature consistently states that ALPL encodes tissue-nonspecific alkaline phosphatase. The terms TNAP, TNSALP, TNS-ALP and TNALP refer to this protein; “liver/bone/kidney alkaline phosphatase” reflects tissue-dependent glycoforms of the same ALPL product rather than separate genes. (villasuarez2021hypophosphatasiaaunique pages 2-4, graser2021tnapasa pages 1-2, imam2024structuralandfunctional pages 1-2)
2. Organism: The target is Homo sapiens. The retrieved human literature and Open Targets record identify human ALPL as ENSG00000162551 and associate it specifically with human HPP phenotypes. (OpenTargets Search: -ALPL)
3. Family/domain consistency: TNAP belongs to the alkaline-phosphatase superfamily and has the expected conserved catalytic core—a mixed β-sheet flanked by α-helices—with AP-specific metal coordination. Reported structural regions include the catalytic domain, N-terminal arm/helix, homodimer interface, crown domain and a calcium-binding region. These findings align with the supplied Alkaline_phosphatase/PF00245 and catalytic-site/domain annotations. (villasuarez2021hypophosphatasiaaunique pages 2-4, imam2024structuralandfunctional pages 1-2)
4. Ambiguity assessment: No evidence indicated that “ALPL” in the cited human studies referred to another gene or organism. Animal Alpl/Akp2 studies are used only where explicitly labeled as models.

2. Molecular architecture, maturation and localization

TNAP is synthesized as a precursor in the secretory pathway, undergoes N-linked glycosylation, and is attached through a C-terminal glycosylphosphatidylinositol (GPI) anchor to the exoplasmic leaflet of the plasma membrane. Its catalytic domain therefore faces the extracellular milieu. GPI cleavage can release catalytically active soluble enzyme into extracellular fluids and circulation. High expression occurs in mineralizing osteoblast/chondrocyte and dental compartments, with substantial liver and kidney expression; TNAP is also present in cerebral microvascular endothelium and other tissues. (villasuarez2021hypophosphatasiaaunique pages 2-4, graser2021tnapasa pages 1-2)

The active enzyme is predominantly a homodimer, and dimerization is important for stability and catalytic competence. Each monomer has a metal-dependent catalytic center described as containing two Zn²⁺ and one Mg²⁺; structural treatments also discuss a calcium-binding region. N-linked glycosylation and intact metal loading are important for activity and cell-surface expression. The crown domain contributes to substrate/environment interactions, including collagen or mineralizing extracellular-matrix association, whereas the N-terminal arm contributes to dimer organization. (villasuarez2021hypophosphatasiaaunique pages 2-4, graser2021tnapasa pages 1-2, imam2024structuralandfunctional pages 1-2)

Thus, the principal functional location is outside the cell at the cell–matrix interface, particularly on matrix-vesicle and mineralizing-cell membranes. This topology is essential: TNAP modifies extracellular phosphate metabolites immediately adjacent to nascent mineral rather than serving principally as an intracellular signaling phosphatase. (villasuarez2021hypophosphatasiaaunique pages 2-4, choida2019updateonthe pages 1-2)

3. Catalytic reaction and substrate specificity

General reaction

TNAP is an alkaline, metal-dependent phosphomonoesterase. Its generic reaction is:

phosphate monoester + H₂O → dephosphorylated product + Pi.

For PPi, the physiologically central reaction is:

PPi + H₂O → 2 Pi.

The conserved AP fold and metal center stabilize substrate and reaction intermediates. The enzyme accepts chemically diverse phosphate-containing substrates, so “tissue-nonspecific” also accurately describes broad distribution and broad catalytic scope; physiological relevance depends strongly on tissue, compartment and substrate availability. (imam2024structuralandfunctional pages 1-2, imam2024structuralandfunctional pages 15-17)

Evidence-ranked substrates

Inorganic pyrophosphate—highest confidence. Extracellular PPi blocks hydroxyapatite nucleation/propagation. TNAP hydrolysis both removes this inhibitor and increases available Pi, lowering the PPi/Pi ratio at mineralization sites. Human ALPL loss-of-function causes PPi accumulation and defective skeletal and dental mineralization, providing unusually strong genetic validation of this reaction in vivo. (villasuarez2021hypophosphatasiaaunique pages 2-4, imam2024structuralandfunctional pages 1-2, choida2019updateonthe pages 1-2)

Pyridoxal-5′-phosphate—high confidence. Phosphorylated PLP does not efficiently cross plasma membranes. TNAP converts extracellular PLP to pyridoxal, which enters cells and can be rephosphorylated. Severe TNAP deficiency consequently compromises brain vitamin-B6 availability and B6-dependent neurotransmitter production, explaining PLP-responsive seizures in severe HPP. Elevated circulating PLP is also a useful biochemical indicator of deficient TNAP activity. (imam2024structuralandfunctional pages 1-2, choida2019updateonthe pages 1-2, rush2024proposeddiagnosticcriteria pages 5-7)

Phosphoethanolamine—established substrate/biomarker, less certain systems role. PEA accumulates in HPP and urinary PEA supports diagnosis. Its status as a TNAP substrate is well established, but the causal contribution of PEA accumulation to major HPP manifestations is much less clear than the PPi and PLP mechanisms. (graser2021tnapasa pages 1-2, choida2019updateonthe pages 1-2)

Extracellular nucleotides—moderate confidence for broad physiological importance. TNAP can hydrolyze ATP, ADP and AMP and thereby intersect purinergic signaling. In principle, this removes extracellular ATP/ADP signals and can contribute to adenosine production, complementing ENPP/CD39/CD73 ectonucleotidase systems. ATP hydrolysis also contributes Pi and can feed the extracellular PPi/Pi mineralization network. Nevertheless, the quantitative importance of TNAP relative to dedicated ectonucleotidases is cell- and context-dependent. (imam2024structuralandfunctional pages 1-2, imam2024structuralandfunctional pages 15-17)

Additional proposed substrates. Phosphorylated osteopontin and lipopolysaccharide have been reported as substrates, suggesting effects on mineralization inhibition and inflammatory signaling. A 2024 structural/evolutionary review also highlights phosphocholine metabolism and phosphocreatine hydrolysis in a mitochondrial creatine futile cycle associated with adaptive thermogenesis. These expanding roles are credible mechanistic developments but should be annotated as emerging—particularly the phosphocreatine/thermogenesis function—rather than as equally established human functions. (villasuarez2021hypophosphatasiaaunique pages 2-4, imam2024structuralandfunctional pages 1-2, imam2024structuralandfunctional pages 15-17)

4. Core biochemical pathways

4.1 ENPP1–PPi–TNAP mineralization axis

Extracellular ATP is converted by ENPP-family enzymes, particularly ENPP1, into PPi. PPi prevents inappropriate hydroxyapatite growth, whereas TNAP removes PPi at skeletal and dental sites. Mineralization therefore depends on a regulated balance between PPi production and destruction, not simply on total calcium or phosphate. TNAP’s position explains both sides of its biology: insufficient activity causes rickets/osteomalacia, whereas excess activity in inappropriate vascular or soft-tissue contexts can favor pathological calcification. (imam2024structuralandfunctional pages 1-2, imam2024structuralandfunctional pages 15-17)

TNAP is enriched on mineralizing membranes and matrix vesicles, where its local action supports crystal initiation and extension into extracellular matrix. Its interaction with collagen-rich environments and dephosphorylation of inhibitors such as PPi—and potentially phosphorylated osteopontin—couple enzymatic phosphate metabolism to extracellular-matrix mineralization. (villasuarez2021hypophosphatasiaaunique pages 2-4)

4.2 Vitamin-B6/neurotransmitter pathway

TNAP sits upstream of cellular vitamin-B6 utilization by making extracellular PLP membrane-permeable. The resulting intracellular B6 cofactor pool supports enzymes involved in neurotransmitter metabolism, including GABA synthesis. This provides a precise biochemical explanation for neonatal or infantile B6-responsive seizures in severe ALPL deficiency; it is not merely a secondary consequence of skeletal disease. (imam2024structuralandfunctional pages 1-2, choida2019updateonthe pages 1-2)

4.3 Purinergic and inflammatory signaling

By dephosphorylating extracellular nucleotides, TNAP can alter P2-receptor agonist concentrations and downstream inflammatory, endothelial and thrombotic signaling. Dephosphorylation of microbial LPS has also been proposed as an anti-inflammatory mechanism. Expert reviews regard these as biologically plausible and experimentally supported extensions of TNAP function, while emphasizing that they are less completely defined in humans than biomineralization. (villasuarez2021hypophosphatasiaaunique pages 2-4, graser2021tnapasa pages 1-2, imam2024structuralandfunctional pages 1-2)

4.4 Metabolic and thermogenic roles

The 2024 review places TNAP within a broader network involving phosphocholine/choline metabolism, membrane-lipid synthesis and phosphocreatine turnover. The reported mitochondrial phosphocreatine-phosphatase activity supplies a mechanistic link to a creatine-driven futile cycle and non-shivering thermogenesis. This represents an important recent conceptual expansion, but current annotation should note that organism-level evidence is derived mainly from experimental models rather than direct human ALPL-deficiency physiology. (imam2024structuralandfunctional pages 1-2, imam2024structuralandfunctional pages 15-17)

5. Human genetic evidence: hypophosphatasia

Loss-of-function variants in ALPL cause hypophosphatasia, definitively linking reduced TNAP activity to defective mineralization. Clinical severity ranges from lethal perinatal disease through infantile/childhood rickets to adult osteomalacia and isolated dental disease. Severe disease is usually recessive; milder disease can be recessive or dominant, including dominant-negative effects at the homodimer. Disease-associated substitutions occur in the catalytic/metal-binding regions, dimer interface, crown domain, N-terminal arm and GPI-anchor-related regions, supporting the functional importance inferred from structure. (villasuarez2021hypophosphatasiaaunique pages 2-4, graser2021tnapasa pages 1-2, choida2019updateonthe pages 1-2)

The molecular chain is:

ALPL loss of function → low extracellular TNAP activity → PPi, PLP and PEA accumulation → impaired hydroxyapatite propagation plus impaired vitamin-B6 handling → skeletal/dental disease and, in severe cases, seizures. (villasuarez2021hypophosphatasiaaunique pages 2-4, choida2019updateonthe pages 1-2)

More than 400 ALPL variants had been catalogued in the 2021 literature, approximately 74% missense; a 2025 expert review cited at least 450 pathogenic variants. This extensive allelic heterogeneity, residual enzyme activity, dominant-negative effects and modifier factors explain why genotype alone does not perfectly predict phenotype. (villasuarez2021hypophosphatasiaaunique pages 2-4, dahir2025medicalmanagementof pages 1-2)

Published prevalence estimates vary sharply with ancestry, ascertainment and phenotype. Reviews report severe HPP at roughly 1:100,000–1:300,000 in North America/Europe, approximately 1:300,000 in Europe in one model, and around 1:2,500 among Canadian Mennonites. Model-based estimates for moderate and mild disease are much higher—approximately 1:6,370 and as high as 1:3,100 in a Spanish estimate—but these should not be interpreted as directly measured population prevalence. (villasuarez2021hypophosphatasiaaunique pages 2-4, graser2021tnapasa pages 1-2)

6. Diagnosis and current expert guidance

The November 2024 International HPP Working Group report is the most relevant recent expert framework. It was developed from a systematic review/meta-analysis of 93 publications, coupled with consensus among multidisciplinary experts with substantial HPP experience. Persistently low serum ALP must be interpreted against age- and sex-specific reference intervals and alternative causes of hypophosphatasemia must be excluded. (rush2024proposeddiagnosticcriteria pages 1-3, rush2024proposeddiagnosticcriteria pages 5-7)

For children and adolescents, low ALP is an obligate entry criterion. Major criteria include pathogenic/likely pathogenic ALPL variant(s), elevated natural substrates, premature non-traumatic loss of primary teeth and radiographic rickets. Minor criteria include short stature, delayed motor milestones, chronic musculoskeletal pain, impaired mobility, genu varum/valgum, craniosynostosis, nephrocalcinosis/nephrolithiasis, hypotonia and B6-responsive seizures. The proposed diagnostic threshold is two major criteria, or one major plus two minor criteria. (rush2024proposeddiagnosticcriteria pages 5-7, rush2024proposeddiagnosticcriteria pages 3-4)

Useful biochemical tests include plasma PLP and urinary PEA; PPi can be informative but is less routinely available. Importantly, an ALPL variant is powerful evidence but biochemical and phenotypic correlation remain necessary because penetrance and variant effects vary. (rush2024proposeddiagnosticcriteria pages 1-3, rush2024proposeddiagnosticcriteria pages 5-7)

7. Current applications and real-world implementation

Enzyme replacement

Asfotase alfa is recombinant, mineral-targeted TNAP enzyme replacement. It was approved in 2015 by the FDA, EMA and Health Canada for pediatric-onset HPP, converting knowledge of TNAP’s extracellular mineralization mechanism into a direct replacement strategy. A seminal early study reported radiographic rickets healing by six months in 9 of 11 infants/young children. Longer-term studies and registries support improved survival in life-threatening perinatal/infantile HPP and improvements in mobility, physical function, pain and quality of life in children and pediatric-onset adults. (choida2019updateonthe pages 1-2, dahir2025medicalmanagementof pages 3-4, dahir2025medicalmanagementof pages 1-2, santos2025dentalmanifestationsof pages 18-18)

Global HPP Registry analyses summarized in 2025 compared 99 untreated with 114 treated pediatric-onset adults. A broader analysis of 270 adults found that 38% had at least five manifestations and 57% had involvement of at least three organ systems, illustrating that ALPL deficiency is clinically multisystemic even though its primary biochemical lesion is precise. These observational data support real-world benefit but are vulnerable to confounding by indication because more severely affected patients are more likely to receive therapy. (dahir2025medicalmanagementof pages 3-4)

Treatment burden remains important. Asfotase alfa ordinarily requires three to six subcutaneous injections per week. Injection-site reactions occurred in approximately 78% of patients in two short-term treatment-emergent adverse-event studies, and discontinuation in clinical practice has been reported near 40%, chiefly because of adverse effects or perceived insufficient efficacy. These observations motivate longer-acting products and gene-based approaches. (dahir2025medicalmanagementof pages 11-12)

Biomarker and laboratory use

Serum alkaline-phosphatase activity is a routine clinical measurement, but functional annotation requires caution: circulating total ALP includes different tissue and gene products, while liver and bone ALP activities largely represent differently glycosylated ALPL-derived TNAP. Persistently low age/sex-adjusted ALP, combined with elevated PLP/PEA and compatible clinical findings, is more informative for HPP than a single measurement. (villasuarez2021hypophosphatasiaaunique pages 2-4, rush2024proposeddiagnosticcriteria pages 5-7)

Emerging therapies

A second-generation enzyme, efzimfotase alfa, was reported in 2025 as undergoing clinical testing; preclinical/pharmacokinetic comparisons indicated approximately 21-fold higher intravenous and 17-fold higher subcutaneous plasma exposure than asfotase alfa. Clinical superiority has not yet been established by the cited evidence. (dahir2025medicalmanagementof pages 11-12)

AAV8 vectors encoding bone-targeted TNAP-D10 and earlier lentiviral approaches have improved survival, circulating ALP, PPi and skeletal phenotypes in Alpl-deficient mice. In adult HPP/pseudo-HPP mouse models, a single AAV8-TNAP-D10 administration produced sustained ALP activity and skeletal improvement without detected soft-organ ectopic calcification over the reported observation interval. These are promising proof-of-concept results, but ALPL gene therapy remains preclinical, not a current human implementation. (santos2025dentalmanifestationsof pages 18-19)

8. Recent research developments, 2023–2024

The most consequential 2024 basic-science synthesis is Imam et al., published November 2024, which integrates TNAP with the wider alkaline-phosphatase superfamily. It emphasizes the conserved AP fold and metal chemistry while identifying TNAP-specific structural features likely to govern its unusually broad extracellular substrate range. It also reframes TNAP and ENPP enzymes as complementary members of shared metabolic networks rather than isolated phosphatases. URL: https://doi.org/10.3390/metabo14120659. (imam2024structuralandfunctional pages 1-2, imam2024structuralandfunctional pages 15-17)

That review also highlights a major conceptual development: TNAP may participate in phosphocreatine-driven adaptive thermogenesis and phosphocholine/choline metabolism in addition to mineralization, vitamin-B6 processing and nucleotide turnover. These results broaden functional hypotheses for ALPL but do not overturn the evidence hierarchy—PPi and PLP remain the most securely established physiological substrates in humans. (imam2024structuralandfunctional pages 1-2, imam2024structuralandfunctional pages 15-17)

The principal 2024 clinical development was the International Working Group’s pediatric diagnostic framework, published November 2024, which converted heterogeneous literature into an obligate low-ALP criterion and weighted major/minor criteria. URL: https://doi.org/10.1007/s00198-023-06843-2. Its value is standardization; its limitation is that much of the underlying literature consists of rare-disease case series rather than large prospective validation cohorts. (rush2024proposeddiagnosticcriteria pages 1-3, rush2024proposeddiagnosticcriteria pages 5-7, rush2024proposeddiagnosticcriteria pages 8-9)

A 2024 adult case report examining circulating miRNAs during asfotase alfa treatment screened more than 800 miRNAs and selected 84 based on prior case-control differences; after 16 months, several patient-reported and functional measures improved, including a 33.89% increase in six-minute walk distance. Because this is a single patient, it is hypothesis-generating biomarker work rather than validation of miRNAs as treatment-monitoring tools.

9. Expert interpretation and recommended functional annotation

A defensible primary annotation is:

ALPL encodes a GPI-anchored, homodimeric, Zn²⁺/Mg²⁺-dependent extracellular alkaline phosphatase that hydrolyzes inorganic pyrophosphate and other phosphate monoesters. At skeletal and dental mineralization fronts it lowers extracellular PPi and supplies Pi, enabling hydroxyapatite growth. It also dephosphorylates PLP to support cellular vitamin-B6 uptake.

Substrate specificity should be described as broad, not as exclusive for PPi. PPi is the dominant mineralization substrate; PLP is the dominant substrate explaining neurological disease; PEA is an established substrate and diagnostic marker with uncertain causal significance; nucleotide, LPS, osteopontin, phosphocholine and phosphocreatine functions are context-dependent or emerging. (villasuarez2021hypophosphatasiaaunique pages 2-4, imam2024structuralandfunctional pages 1-2, imam2024structuralandfunctional pages 15-17)

The strongest causal evidence is the convergence of human Mendelian genetics, biochemical substrate accumulation, structural mapping of pathogenic variants, animal loss-of-function models and rescue by recombinant TNAP. Conversely, claims that TNAP is a master regulator of inflammation, lipid metabolism or thermogenesis should remain qualified until tissue-specific perturbation and human studies establish effect sizes relative to other phosphatases and ectonucleotidases. (OpenTargets Search: -ALPL, graser2021tnapasa pages 1-2, imam2024structuralandfunctional pages 1-2)

Key references

• Imam I, et al. Structural and Functional Integration of Tissue-Nonspecific Alkaline Phosphatase Within the Alkaline Phosphatase Superfamily. Metabolites. Published November 2024. https://doi.org/10.3390/metabo14120659. (imam2024structuralandfunctional pages 1-2)
• Rush E, et al. Proposed diagnostic criteria for hypophosphatasia in children and adolescents. Osteoporosis International. Published November 2024. https://doi.org/10.1007/s00198-023-06843-2. (rush2024proposeddiagnosticcriteria pages 1-3)
• Villa-Suárez JM, et al. Hypophosphatasia: A Unique Disorder of Bone Mineralization. International Journal of Molecular Sciences. Published April 2021. https://doi.org/10.3390/ijms22094303. (villasuarez2021hypophosphatasiaaunique pages 2-4)
• Graser S, et al. TNAP as a New Player in Chronic Inflammatory Conditions and Metabolism. International Journal of Molecular Sciences. Published January 2021. https://doi.org/10.3390/ijms22020919. (graser2021tnapasa pages 1-2)
• Choida V, Bubbear JS. Update on the management of hypophosphatasia. Therapeutic Advances in Musculoskeletal Disease. Published July 2019. https://doi.org/10.1177/1759720X19863997. (choida2019updateonthe pages 1-2)
• Dahir KM, Dunbar NS. Medical Management of Hypophosphatasia: Review of Data on Asfotase Alfa. Current Osteoporosis Reports. Published March 2025; used here principally to summarize 2023–2024 registry and treatment evidence. https://doi.org/10.1007/s11914-025-00906-5. (dahir2025medicalmanagementof pages 3-4, dahir2025medicalmanagementof pages 11-12)

References

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3. (imam2024structuralandfunctional pages 1-2): Iliass Imam, Gilles Rautureau, Sébastien Violot, Eva Drevet Mulard, David Magne, and Lionel Ballut. Structural and functional integration of tissue-nonspecific alkaline phosphatase within the alkaline phosphatase superfamily: evolutionary insights and functional implications. Metabolites, 14(12):659, Nov 2024. URL: https://doi.org/10.3390/metabo14120659, doi:10.3390/metabo14120659. This article has 12 citations.

4. (imam2024structuralandfunctional pages 15-17): Iliass Imam, Gilles Rautureau, Sébastien Violot, Eva Drevet Mulard, David Magne, and Lionel Ballut. Structural and functional integration of tissue-nonspecific alkaline phosphatase within the alkaline phosphatase superfamily: evolutionary insights and functional implications. Metabolites, 14(12):659, Nov 2024. URL: https://doi.org/10.3390/metabo14120659, doi:10.3390/metabo14120659. This article has 12 citations.

5. (choida2019updateonthe pages 1-2): V. Choida and J. S. Bubbear. Update on the management of hypophosphatasia. Therapeutic Advances in Musculoskeletal Disease, Jul 2019. URL: https://doi.org/10.1177/1759720x19863997, doi:10.1177/1759720x19863997. This article has 43 citations and is from a peer-reviewed journal.

6. (graser2021tnapasa pages 1-2): Stephanie Graser, Daniel Liedtke, and Franz Jakob. Tnap as a new player in chronic inflammatory conditions and metabolism. Jan 2021. URL: https://doi.org/10.3390/ijms22020919, doi:10.3390/ijms22020919. This article has 37 citations.

7. (rush2024proposeddiagnosticcriteria pages 1-3): Eric Rush, Maria Luisa Brandi, Aliya Khan, Dalal S. Ali, Hatim Al-Alwani, Khulod Almonaei, Farah Alsarraf, Severine Bacrot, Kathryn M. Dahir, Karel Dandurand, Chad Deal, Serge Livio Ferrari, Francesca Giusti, Gordon Guyatt, Erin Hatcher, Steven W. Ing, Muhammad Kassim Javaid, Sarah Khan, Roland Kocijan, E. Michael Lewiecki, Agnes Linglart, Iman M’Hiri, Francesca Marini, Mark E. Nunes, Cheryl Rockman-Greenberg, Christian Roux, Lothar Seefried, Susan R. Starling, Leanne Ward, Liang Yao, Romina Brignardello-Petersen, and Jill H. Simmons. Proposed diagnostic criteria for the diagnosis of hypophosphatasia in children and adolescents: results from the hpp international working group. Osteoporosis International, 35:1-10, Nov 2024. URL: https://doi.org/10.1007/s00198-023-06843-2, doi:10.1007/s00198-023-06843-2. This article has 44 citations and is from a domain leading peer-reviewed journal.

8. (rush2024proposeddiagnosticcriteria pages 5-7): Eric Rush, Maria Luisa Brandi, Aliya Khan, Dalal S. Ali, Hatim Al-Alwani, Khulod Almonaei, Farah Alsarraf, Severine Bacrot, Kathryn M. Dahir, Karel Dandurand, Chad Deal, Serge Livio Ferrari, Francesca Giusti, Gordon Guyatt, Erin Hatcher, Steven W. Ing, Muhammad Kassim Javaid, Sarah Khan, Roland Kocijan, E. Michael Lewiecki, Agnes Linglart, Iman M’Hiri, Francesca Marini, Mark E. Nunes, Cheryl Rockman-Greenberg, Christian Roux, Lothar Seefried, Susan R. Starling, Leanne Ward, Liang Yao, Romina Brignardello-Petersen, and Jill H. Simmons. Proposed diagnostic criteria for the diagnosis of hypophosphatasia in children and adolescents: results from the hpp international working group. Osteoporosis International, 35:1-10, Nov 2024. URL: https://doi.org/10.1007/s00198-023-06843-2, doi:10.1007/s00198-023-06843-2. This article has 44 citations and is from a domain leading peer-reviewed journal.

9. (rush2024proposeddiagnosticcriteria pages 3-4): Eric Rush, Maria Luisa Brandi, Aliya Khan, Dalal S. Ali, Hatim Al-Alwani, Khulod Almonaei, Farah Alsarraf, Severine Bacrot, Kathryn M. Dahir, Karel Dandurand, Chad Deal, Serge Livio Ferrari, Francesca Giusti, Gordon Guyatt, Erin Hatcher, Steven W. Ing, Muhammad Kassim Javaid, Sarah Khan, Roland Kocijan, E. Michael Lewiecki, Agnes Linglart, Iman M’Hiri, Francesca Marini, Mark E. Nunes, Cheryl Rockman-Greenberg, Christian Roux, Lothar Seefried, Susan R. Starling, Leanne Ward, Liang Yao, Romina Brignardello-Petersen, and Jill H. Simmons. Proposed diagnostic criteria for the diagnosis of hypophosphatasia in children and adolescents: results from the hpp international working group. Osteoporosis International, 35:1-10, Nov 2024. URL: https://doi.org/10.1007/s00198-023-06843-2, doi:10.1007/s00198-023-06843-2. This article has 44 citations and is from a domain leading peer-reviewed journal.

10. (dahir2025medicalmanagementof pages 3-4): Kathryn McCrystal Dahir and Nancy S. Dunbar. Medical management of hypophosphatasia: review of data on asfotase alfa. Current Osteoporosis Reports, Mar 2025. URL: https://doi.org/10.1007/s11914-025-00906-5, doi:10.1007/s11914-025-00906-5. This article has 14 citations and is from a peer-reviewed journal.

11. (dahir2025medicalmanagementof pages 1-2): Kathryn McCrystal Dahir and Nancy S. Dunbar. Medical management of hypophosphatasia: review of data on asfotase alfa. Current Osteoporosis Reports, Mar 2025. URL: https://doi.org/10.1007/s11914-025-00906-5, doi:10.1007/s11914-025-00906-5. This article has 14 citations and is from a peer-reviewed journal.

12. (dahir2025medicalmanagementof pages 11-12): Kathryn McCrystal Dahir and Nancy S. Dunbar. Medical management of hypophosphatasia: review of data on asfotase alfa. Current Osteoporosis Reports, Mar 2025. URL: https://doi.org/10.1007/s11914-025-00906-5, doi:10.1007/s11914-025-00906-5. This article has 14 citations and is from a peer-reviewed journal.

13. (santos2025dentalmanifestationsof pages 18-19): Elis J Lira dos Santos, Fatma F Mohamed, Kaitrin Kramer, and Brian L Foster. Dental manifestations of hypophosphatasia: translational and clinical advances. JBMR Plus, Jan 2025. URL: https://doi.org/10.1093/jbmrpl/ziae180, doi:10.1093/jbmrpl/ziae180. This article has 20 citations and is from a peer-reviewed journal.

14. (santos2025dentalmanifestationsof pages 18-18): Elis J Lira dos Santos, Fatma F Mohamed, Kaitrin Kramer, and Brian L Foster. Dental manifestations of hypophosphatasia: translational and clinical advances. JBMR Plus, Jan 2025. URL: https://doi.org/10.1093/jbmrpl/ziae180, doi:10.1093/jbmrpl/ziae180. This article has 20 citations and is from a peer-reviewed journal.

15. (rush2024proposeddiagnosticcriteria pages 8-9): Eric Rush, Maria Luisa Brandi, Aliya Khan, Dalal S. Ali, Hatim Al-Alwani, Khulod Almonaei, Farah Alsarraf, Severine Bacrot, Kathryn M. Dahir, Karel Dandurand, Chad Deal, Serge Livio Ferrari, Francesca Giusti, Gordon Guyatt, Erin Hatcher, Steven W. Ing, Muhammad Kassim Javaid, Sarah Khan, Roland Kocijan, E. Michael Lewiecki, Agnes Linglart, Iman M’Hiri, Francesca Marini, Mark E. Nunes, Cheryl Rockman-Greenberg, Christian Roux, Lothar Seefried, Susan R. Starling, Leanne Ward, Liang Yao, Romina Brignardello-Petersen, and Jill H. Simmons. Proposed diagnostic criteria for the diagnosis of hypophosphatasia in children and adolescents: results from the hpp international working group. Osteoporosis International, 35:1-10, Nov 2024. URL: https://doi.org/10.1007/s00198-023-06843-2, doi:10.1007/s00198-023-06843-2. This article has 44 citations and is from a domain leading peer-reviewed journal.

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Citations

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2. villasuarez2021hypophosphatasiaaunique pages 2-4
3. dahir2025medicalmanagementof pages 3-4
4. dahir2025medicalmanagementof pages 11-12
5. imam2024structuralandfunctional pages 1-2
6. rush2024proposeddiagnosticcriteria pages 1-3
7. graser2021tnapasa pages 1-2
8. choida2019updateonthe pages 1-2
9. imam2024structuralandfunctional pages 15-17
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11. rush2024proposeddiagnosticcriteria pages 3-4
12. dahir2025medicalmanagementof pages 1-2
13. santos2025dentalmanifestationsof pages 18-18
14. rush2024proposeddiagnosticcriteria pages 8-9
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