WHAT IS HPP?
clinical
signs/symptoms
persistently
low ALP1,6
Hypophosphatasia is an inherited, multisystemic, rare metabolic disorder characterized by clinical signs/symptoms + persistently low alkaline phosphatase activity that may progress over time.1,6
Patients with hypophosphatasia have a loss-of-function mutation on the ALPL gene causing low levels of alkaline phosphatase enzyme activity.1
clinical
signs/symptoms
persistently
low ALP1,6
Persistently low alkaline phosphatase activity can be defined as 2 or more age- and sex-adjusted ALP levels below normal range in intervals of more than 30 days.6,7
*Limitations: An alkaline phosphatase level of below 40 U/L is not conclusive for a diagnosis of hypophosphatasia. Patient should be evaluated for other symptoms of hypophosphatasia and differential diagnoses should be ruled out.
Clinicians should ensure that reported laboratory results for ALP reflect age- and sex-adjusted reference ranges for the specific patient
Check with your lab for their appropriate age- and sex-adjusted reference range
Graph adapted from the Canadian Laboratory initiative on Pediatric Reference Intervals (CALIPER) project. CALIPER samples from 1072 male and 1116 female participants (newborn to 18 years) were used to calculate age- and sex-specific reference intervals. No variation in ALP based on ethnic differences was observed. Check with your lab for their appropriate age- and sex-adjusted reference range.13
As we continue to learn about hypophosphatasia, we are truly understanding that it is a multisystemic disease and not just a skeletal disease.
Persistently low alkaline phosphatase activity can be defined as 2 or more age- and sex-adjusted ALP levels below normal range in intervals of more than 30 days and can lead to progressive and varying symptoms in several systems of the body beyond the skeletal system.1-7
These signs/symptoms may emerge at any time and can progress to potentially become debilitating.1,15,16
Use this discussion guide with your patients to identify the multisystemic impact of HPP on their daily life
Download Discussion Guide
This list may not be exhaustive.
This list may not be exhaustive.
Hypophosphatasia manifests across a wide spectrum of severity. Patients can face progressive, potentially debilitating symptoms that may impair their quality of life.1,16
Neonates and infants with hypophosphatasia have a high risk of mortality and failure to thrive, making early and accurate diagnosis critical.1,2,24,25
In patients with hypophosphatasia, symptom presentation may not accurately represent the degree of disease progression2,4,26-28
73% of cases of untreated neonatal and infantile hypophosphatasia were fatal before the age of 5
58% of cases were fatal by 1 year of age
64% required respiratory support, most commonly invasive ventilation†
95% of cases requiring invasive ventilation were fatal
The manifestations and complications of hypophosphatasia can place significant functional burden on neonatal and infant patients, such as1,17:
Respiratory failure or insufficiency requiring support
Severe skeletal hypomineralization
*Data from a multinational, noninterventional, retrospective chart review study designed to understand the natural history of 48 patients ≤5 years of age with perinatal- and infantile-onset HPP.29
†Data on respiratory support was available for 45 of the 48 patients.29
Adapted from Whyte M, et al. Poster presented at: Pediatric Academic Societies and Asian Society for Pediatric Research Joint Meeting; May 3-6, 2014; Vancouver, BC, Canada.
Because symptoms of hypophosphatasia can mimic more common diseases, it is often overlooked and can lead to ineffective treatment that can exacerbate hypophosphatasia.30-32
Treatments used for other more common diseases can be harmful to patients with hypophosphatasia4,32,34:
Hypophosphatasia can progress and become more debilitating1-4,15,33
References: 1. Rockman-Greenberg C. Hypophosphatasia. Pediatr Endocrinol Rev. 2013;10(suppl 2):380-388. 2. Hӧgler W, Langman C, Gomes da Silva H, et al. Diagnostic delay is common among patients with hypophosphatasia: initial findings from a longitudinal, prospective, global registry. BMC Musculoskelet Disord. 2019;20(1):80. 3. Seefried L, Dahir K, Petryk A, et al. Burden of illness in adults with hypophosphatasia: data from the Global Hypophosphatasia Patient Registry. J Bone Miner Res. 2020;35(11):2171-2178. 4. Weber TJ, Sawyer EK, Moseley S, Odrljin T, Kishnani PS. Burden of disease in adult patients with hypophosphatasia: results from two patient-reported surveys. Metabolism. 2016;65(10):1522-1530. 5. Bianchi ML, Bishop NJ, Guañabens N, et al; Rare Bone Disease Action Group of the European Calcified Tissue Society Hypophosphatasia in adolescents and adults: overview of diagnosis and treatment. Osteoporos Int. 2020;31(8):1445–1460. 6. McKiernan FE, Berg RL, Fuehrer J. Clinical and radiographic findings in adults with persistent hypophosphatasemia. J Bone Miner Res. 2014;29(7):1651–1660. 7. Vieira LHR, Peixoto KC, Flósi CL, de Farias MLF, Madeira M. Active search of adult patients with persistently low serum alkaline phosphatase levels for the diagnosis of hypophosphatasia. Arch Endocrinol Metab. 2021;65(3):289-294. 8. Adeli K, Higgins V, Nieuwesteeg M, et al. Biochemical marker reference values across pediatric, adult, and geriatric ages: establishment of robust pediatric and adult reference intervals on the basis of the Canadian Health Measures Survey. Clin Chem. 2015;61(8):1049-1062. 9. Schumann G, Klauke R, Canalias F, et al. IFCC primary reference procedures for the measurement of catalytic activity concentrations of enzymes at 37°C. Part 9: reference procedure for the measurement of catalytic concentration of alkaline phosphatase. Clin Chem Lab Med. 2011;49(9):1439-1446. 10. Quest Diagnostics. Alkaline phosphatase. Accessed April 3, 2023. https://testdirectory.questdiagnostics.com/test/test-detail/234/alkaline-phosphatase?p=r&q=Alkaline%20Phosphatase&cc=MASTER 11. Labcorp. Alkaline phosphatase. Accessed April 3, 2023. https://www.labcorp.com/tests/001107/alkaline-phosphatase 12. ARUP Laboratories. Alkaline phosphatase isoenzymes, serum or plasma. Accessed April 3, 2023. https://ltd.aruplab.com/Tests/Pub/0021020 13. Colantonio DA, Kyriakopoulou L, Chan MK, et al. Closing the gaps in pediatric laboratory reference intervals: a CALIPER database of 40 biochemical markers in a healthy and multiethnic population of children. Clin Chem. 2012;58(5):854–868. 14. Bishop N, Munns CF, Ozono K. Transformative therapy in hypophosphatasia. Arch Dis Child. 2016;101(6):514–515. 15. Rush ET, Moseley S, Petryk A. Burden of disease in pediatric patients with hypophosphatasia: results from the HPP Impact Patient Survey and the HPP Outcomes Study Telephone interview. Orphanet J Rare Dis. 2019;14(1):201. 16. Pierpont EI, Simmons JH, Spurlock KJ, et al. Impact of pediatric hypophosphatasia on behavioral health and quality of life. Orphanet J Rare Dis. 2021;16(1):80. 17. Kishnani PS, Rush ET, Arundel P, et al. Monitoring guidance for patients with hypophosphatasia treated with asfotase alfa. Mol Genet Metab. 2017;122(1-2):4-17. 18. Colazo JM, Hu JR, Dahir KM, et al. Neurological symptoms in hypophosphatasia. Osteoporos Int. 2019;30(2):469-480. 19. Fallon MD, Teitelbaum SL, Weinstein R, et al. Hypophosphatasia: clinicopathologic comparison of the infantile, childhood, and adult forms. Medicine (Baltimore). 1984;63(1):12–24. 20. Whyte MP, Leung E, Wilcox WR, et al. Natural history of perinatal and infantile hypophosphatasia: a retrospective study. J Pediatr. 2019;209:116–124.e4. 21. NORD. Hypophosphatasia. Accessed March 30, 2023. https://rarediseases.org/rare-diseases/hypophosphatasia/ 22. Mornet E, Nunes ME. Hypophosphatasia. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews®. University of Washington; 2007. Accessed March 30, 2023. https://www.ncbi.nlm.nih.gov/books/NBK1150/ 23. Whyte MP. Hypophosphatasia: nature’s window on alkaline phosphatase function in humans. In: Bilezikian JP, Raisz LG, Martin TJ, eds. Principles of Bone Biology. 3rd ed. Academic Press; 2008:1573-1598. 24. Baumgartner-Sigl S, Haberlandt E, Mumm S, et al. Pyridoxine-responsive seizures as the first symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T>C, p.M226T; c.1112C>T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene. Bone. 2007;40(6):1655-1661. 25. Eade AW, Swannell AJ, Williamson N. Pyrophosphate arthropathy in hypophosphatasia. Ann Rheum Dis. 1981;40(2):164–170. 26. Braunstein NA. Multiple fractures, pain, and severe disability in a patient with adult-onset hypophosphatasia. Bone Rep. 2015;4:1-4. 27. Salles JP. Hypophosphatasia: biological and clinical aspects, avenues for therapy. Clin Biochem Rev. 2020;41(1):13–27. 28. Conti F, Ciullini L, Pugliese G. Hypophosphatasia: clinical manifestation and burden of disease in adult patients. Clin Cases Miner Bone Metab. 2017;14(2):230–234. 29. Whyte M, Leung E, Wilcox W, et al. Hypophosphatasia: a retrospective natural history study of the severe perinatal and infantile forms. Poster presented at: Pediatric Academic Societies and Asian Society for Pediatric Research Joint Meeting; May 3-6, 2014; Vancouver, BC, Canada. 30. Nunes ME. Hypophosphatasia. 2007 Nov 20 [Updated 2023 Mar 30]. In Adam P, Mirzaa GM, Pagon RA, et al, eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Accessed March 30, 2023. http://www.ncbi.nlm.nih.gov/books/NBK1150/? 31. Mohn A, De Leonibus C, de Giorgis T, Mornet E, Chiarelli F. Hypophosphatasia in a child with widened anterior fontanelle: lessons learned from late diagnosis and incorrect treatment. Acta Paediatr. 2011;100(7):e43-e46. 32. Sutton RAL, Mumm S, Coburn SP, Ericson KL, Whyte MP. “Atypical femoral fractures” during bisphosphonate exposure in adult hypophosphatasia. J Bone Miner Res. 2012;27(5):987–994. 33. Szabo SM, Tomazos IC, Petryk A, et al. Frequency and age at occurrence of clinical manifestations of disease in patients with hypophosphatasia: a systematic literature review. Orphanet J Rare Dis. 2019;14(1):85. 34. Shapiro JR, Lewiecki EM. Hypophosphatasia in adults: clinical assessment and treatment considerations. J Bone Miner Res. 2017;32(10):1977–1980.
Patients treated with enzyme replacement therapies have experienced life-threatening hypersensitivity reactions, including anaphylaxis. Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy.
Initiate STRENSIQ under the supervision of a healthcare provider with appropriate medical monitoring and support measures. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue STRENSIQ and immediately initiate appropriate medical treatment, including use of epinephrine. Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur [see Warnings and Precautions (5.1)].
Patients treated with enzyme replacement therapies have experienced life-threatening hypersensitivity reactions, including anaphylaxis. Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy.
Initiate STRENSIQ under the supervision of a healthcare provider with appropriate medical monitoring and support measures. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue STRENSIQ and immediately initiate appropriate medical treatment, including use of epinephrine. Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur [see Warnings and Precautions (5.1)].
Life-threatening Hypersensitivity Reactions, Including Anaphylaxis, have been reported in STRENSIQ-treated patients. Signs and symptoms consistent with anaphylaxis included difficulty breathing, choking sensation, nausea, periorbital edema, and dizziness. These reactions have occurred within minutes after subcutaneous administration of STRENSIQ and have been observed more than 1 year after treatment initiation. Other hypersensitivity reactions have also been reported in STRENSIQ-treated patients, including vomiting, fever, headache, flushing, irritability, chills, erythema, rash, pruritus, and oral hypoesthesia. Consider the risks and benefits of re-administering STRENSIQ following a severe reaction. If the decision is made to re-administer, monitor patients for a reoccurrence of signs and symptoms of a severe hypersensitivity reaction.
Lipodystrophy: Localized lipodystrophy, including lipoatrophy and lipohypertrophy has been reported at injection sites after several months in patients treated with STRENSIQ in clinical trials. Advise patients to follow proper injection technique and to rotate injection sites.
Ectopic Calcifications: Patients with HPP are at increased risk for developing ectopic calcifications. Events of ectopic calcification, including ophthalmic (conjunctival and corneal) and renal (nephrocalcinosis, nephrolithiasis), have been reported in the clinical trial experience with STRENSIQ. There was insufficient information to determine whether or not the reported events were consistent with the disease or due to STRENSIQ. No visual changes or changes in renal function were reported resulting from the occurrence of ectopic calcifications.
Ophthalmology examinations and renal ultrasounds are recommended at baseline and periodically during treatment with STRENSIQ to monitor for signs and symptoms of ophthalmic and renal ectopic calcifications and for changes in vision or renal function.
Possible Immune-Mediated Clinical Effects: In clinical trials, most STRENSIQ-treated patients developed anti-asfotase alfa antibodies and neutralizing antibodies which resulted in reduced systemic exposure of asfotase alfa. In postmarketing reports, some STRENSIQ-treated patients with initial therapeutic response subsequently developed recurrence and worsening in disease-associated laboratory and radiographic biomarkers (some in association with neutralizing antibodies) suggesting possible immune-mediated effects on STRENSIQ’s pharmacologic action resulting in disease progression. The effect of anti-asfotase alfa antibody formation on the long-term efficacy of STRENSIQ is unknown. There are no marketed anti-asfotase alfa antibody tests. If patients experience progression of HPP symptoms or worsening of disease-associated laboratory and imaging biomarkers after a period of initial therapeutic response to STRENSIQ, consider obtaining anti-asfotase alfa antibody testing by contacting STRENSIQ Medical Information at Alexion at 1-888-765-4747 or by email at medinfo@alexion.com. Close clinical follow up is recommended.
In clinical trials, the most common adverse reactions (≥ 10%) reported were injection site reactions (63%), lipodystrophy (28%), ectopic calcifications (14%), and hypersensitivity reactions (12%). Possible immune-mediated clinical effects have been identified during post-approval use of STRENSIQ.
Laboratory tests utilizing alkaline phosphatase (ALP) as a detection reagent could result in erroneous test results for patients receiving treatment due to the presence of asfotase alfa in clinical laboratory samples. Inform laboratory personnel that the patient is being treated with STRENSIQ and discuss use of an alternative testing platform which does not utilize an ALP-conjugated test system.
Elevated serum ALP measurements detected through clinical laboratory testing are expected in patients receiving STRENSIQ due to circulating concentrations of asfotase alfa. Do not rely on serum ALP measurements for clinical decision making in patients treated with STRENSIQ.
Pregnancy & Lactation: There are no available data on STRENSIQ use in pregnant women, the presence of STRENSIQ in human milk, or the effects on the breastfed infant or on milk production, to inform a drug associated risk.
To report SUSPECTED ADVERSE REACTIONS, contact Alexion Pharmaceuticals, Inc. at 1-844-259-6783 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
STRENSIQ® (asfotase alfa) is indicated for the treatment of patients with perinatal/infantile- and juvenile-onset hypophosphatasia (HPP).
Please see full Prescribing Information for STRENSIQ (asfotase alfa), including Boxed WARNING regarding hypersensitivity reactions including anaphylaxis.
