Therapie der Hypophosphatasie

 

 Permissions and Reprints

Zusammenfassung

Die Hypophosphatasie (HPP) als Folge einer genetisch bedingt defizienten Aktivität der gewebeunspezifischen alkalischen Phosphatase (TNAP) ist geprägt durch ein ausgesprochen weites Spektrum möglicher Manifestationen, sowohl hinsichtlich der Art der Symptomatik als auch bzgl. des Schweregrades der assoziierten Einschränkungen. Eine adäquate Behandlung erfordert insofern immer auch eine multimodale Herangehensweise unter spezieller Berücksichtigung der individuellen Ausprägung der Erkrankung.

Für Patienten, bei denen die Erkrankung im Kindesalter aufgetreten ist, steht in Europa zur Behandlung der Knochenmanifestation mit Asfotase alfa (Strensiq) eine Enzymersatztherapie zur Verfügung. Sowohl in den Zulassungsstudien als auch in der klinischen Anwendung zeigen sich bei schwer betroffenen Kindern prinzipiell sehr erfreuliche radiologische und funktionelle Verbesserungen und ein verbessertes Gesamtüberleben. Auch bei Erwachsenen mit zulassungsentsprechender Krankheitsausprägung zeigen erste Ergebnisse eine deutliche Verbesserung der krankheitsassoziierten Einschränkungen und funktionelle Verbesserungen. Inzwischen gibt es auch ermutigende Daten zur Sicherheit und Wirksamkeit von Asfotase alfa über mehrere Behandlungsjahre.

Während die oftmals als stark belastend empfundenen entzündlichen Schmerzen häufig gut auf eine intermittierende, bedarfsangepasste Behandlung mit NSAR ansprechen, sind im Hinblick auf die muskuloskelettale Gesamtgesundheit nachhaltige, langfristig ausgerichtete supportive Maßnahmen mit spezifischen Trainingskonzepten und einer alters- und bedarfsgerechten orthopädietechnischen Versorgung zu empfehlen. Das Potenzial diätetischer Maßnahmen zur Beeinflussung des Phosphat- und Vitamin-B6-Stoffwechsels bedarf sicher noch weiterer Untersuchungen. Bezüglich spezifisch knochenwirksamer Strategien sind primär antiresorptive Substanzen nach aktueller Datenlage kritisch zu betrachten, wohingegen osteoanabole Konzepte grundsätzlich möglich erscheinen.

Sinnvollerweise sollte die Gesamtheit aller therapeutischen Maßnahmen an einem Zentrum mit entsprechender Erfahrung koordiniert und überblickt werden, wobei ein Großteil der konkreten Maßnahmen im aktiven Austausch auch heimatnah umgesetzt werden kann.

Abstract

Hypophosphatasia due to genetically determined deficient activity of the tissue non-specific alkaline phosphatase (TNAP) is characterized by a wide spectrum of potential clinical manifestations, both, regarding the type of symptoms, as well as the severity of associated deficits. Appropriate treatment strategies should be built on a multimodal approach specifically considering individual disease manifestation.

For patients with disease onset before adulthood, enzyme replacement therapy with Asfotase alfa (Strensiq) is approved in Europe to treat the bone manifestation of the disease. Both, available data from clinical trials as well as clinical routine experience confirm basically encouraging results of that treatment in severely affected children with substantial improvement regarding radiographic and functional outcome parameters as well as overall survival. Even in adult patients with severe disease manifestation pursuant to the approval, first results confirm substantial amelioration of disease-specific deficits and functional improvements. Meanwhile, there is also data supporting safety and efficacy of long-term treatment Asfotase alfa over several years.

While inflammatory pain, which is typically perceived as being burdensome, can commonly be addressed successfully with NSAIDs on-demand, overall musculoskeletal health requires sustained, multimodal, supportive treatment strategies including exercise interventions as well as age and health state adjusted technical orthopedic support. The use and potential clinical impact of Phosphate and Vitamin B6 on the course of the disease requires further investigation. Current data regarding the use of bone-targeted compounds is critical in terms of antiresorptives while osteoanabolic treatment strategies appear feasible.

Ideally, the entirety of therapeutic measures should be coordinated and overlooked at an experienced center while individual tasks can preferably be accomplished at local facilities near the patient’s home.

Publication History

Article published online:
23 November 2020

© 2020. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

• 1 Mornet E, Hofmann C, Bloch-Zupan A. et al. Clinical utility gene card for: Hypophosphatasia - update 2013. Eur J Hum Genet 2014; 22: 4. DOI: 10.1038/ejhg.2013.177.
  CrossrefPubMedGoogle Scholar
• 2 Millán JL, Whyte MP. Alkaline Phosphatase and Hypophosphatasia. Calcif Tissue Int. 2016; 98: 398-416 . DOI: 10.1007/s00223-015-0079-1.
  CrossrefPubMedGoogle Scholar
• 3 Whyte MP. Hypophosphatasia – aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol 2016; 12 (04) : 233-246
  CrossrefPubMedGoogle Scholar
• 4 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 DOI: 10.1002/jbmr.4130
  Google Scholar
• 5 Fraser D. Hypophosphatasia. Am J Med 1957; 22 (05) : 730-746
  CrossrefPubMedGoogle Scholar
• 6 Högler 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 (01) : 80. DOI: 10.1186/s12891-019-2420-8.
  CrossrefPubMedGoogle Scholar
• 7 Whyte MP. Hypophosphatasia: An overview For 2017. Bone 2017; 102: 15-25
  CrossrefPubMedGoogle Scholar
• 8 Hofmann C. Klinik und Diagnostik der Hypophosphatasie im Kindesalter. Osteologie 2017; 26 (01) : 32-35
  Article in Thieme ConnectGoogle Scholar
• 9 Seefried L, Genest F. Klinik und Diagnostik der Hypophosphatasie im Erwachsenenalter. Osteologie 2017; 26 (01) : 36-41
  Article in Thieme ConnectGoogle Scholar
• 10 Hofmann C, Seefried L, Jakob F. Asfotase alfa: Enzyme replacement for the treatment of bone disease in hypophosphatasia. Drugs Today (Barc) 2016; 52 (05) : 271-285
  CrossrefGoogle Scholar
• 11 Whyte MP, Kishnani PS, Greenberg CR. et al. Hypophosphatasia: Enzyme replacement therapy (asfotase alfa) decreases TNSALP substrate accumulation and improves functional outcomes in affected adolescents and adults. Bull Group Int Rech Sci Stomatol Odontol 2012; 51 (01) : e35
  Google Scholar
• 12 Whyte MP, Rockman-Greenberg C, Ozono K. et al. Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia. J Clin Endocrinol Metab 2016; 101 (01) : 334-342
  CrossrefPubMedGoogle Scholar
• 13 Whyte MP, Simmons JH, Moseley S. et al. Asfotase alfa for infants and young children with hypophosphatasia: 7 year outcomes of a single-arm, open-label, phase 2 extension trial. Lancet Diabetes Endocrinol 2019; 7 (02) : 93-105
  CrossrefPubMedGoogle Scholar
• 14 Hofmann CE, Harmatz P, Vockley J. et al. Efficacy and Safety of Asfotase Alfa in Infants and Young Children With Hypophosphatasia: A Phase 2 Open-Label Study. J Clin Endocrinol Metab 2019; 104 (07) : 2735-2747
  CrossrefPubMedGoogle Scholar
• 15 Whyte MP, Madson KL, Phillips D. et al. Asfotase alfa therapy for children with hypophosphatasia. JCI Insight 2016; 1 (09) : e85971
  Google Scholar
• 16 Kishnani PS, Rockman-Greenberg C, Rauch F. et al. Five-year efficacy and safety of asfotase alfa therapy for adults and adolescents with hypophosphatasia. Bone 2019; 121: 149-162
  CrossrefPubMedGoogle Scholar
• 17 Rolvien T, Schmidt T, Schmidt FN. et al. Recovery of bone mineralization and quality during asfotase alfa treatment in an adult patient with infantile-onset hypophosphatasia. Bone 2019; 127: 67-74
  CrossrefPubMedGoogle Scholar
• 18 Freitas TQ, Franco AS, Pereira RMR. Improvement of bone microarchitecture parameters after 12 months of treatment with asfotase alfa in adult patient with hypophosphatasia: Case report. Med (Baltimore) 2018; 97 (48) : e13210
  CrossrefGoogle Scholar
• 19 Remde H, Cooper MS, Quinkler M. Successful Asfotase Alfa Treatment in an Adult Dialysis Patient With Childhood-Onset Hypophosphatasia. J Endocr Soc 2017; 1 (09) : 1188-1193
  CrossrefPubMedGoogle Scholar
• 20 Genest F, Rak D, Petryk A. et al. Physical Function and Health-Related Quality of Life in Adults Treated With Asfotase Alfa for Pediatric-Onset Hypophosphatasia. JBMR Plus 2020: e10395 DOI: 10.1002/jbm4.10395.
  CrossrefGoogle Scholar
• 21 Gospe 3rd SM. Santiago-Turla C, DeArmey SM et al. Ectopic Ocular Surface Calcification in Patients With Hypophosphatasia Treated With Asfotase Alfa. Cornea 2019; 38 (07) : 896-900
  CrossrefPubMedGoogle Scholar
• 22 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
  CrossrefPubMedGoogle Scholar
• 23 Fachinformation Strensiq®, S.D.
• 24 Schmidt T, Mussawy H, Rolvien T. et al. Clinical, radiographic and biochemical characteristics of adult hypophosphatasia. Osteoporos Int 2017; 28 (09) : 2653-2662
  CrossrefPubMedGoogle Scholar
• 25 Sebastián-Serrano Á, de Diego-García L, Henshall DC. et al. Haploinsufficient TNAP Mice Display Decreased Extracellular ATP Levels and Expression of Pannexin-1 Channels. Front Pharmacol 2018; 9: 170
  CrossrefPubMedGoogle Scholar
• 26 Sebastián-Serrano Á, Engel T, de Diego-García L. et al. Neurodevelopmental alterations and seizures developed by mouse model of infantile hypophosphatasia are associated with purinergic signalling deregulation. Hum Mol Genet 2016; 25 (19) : 4143-4156
  CrossrefPubMedGoogle Scholar
• 27 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 (01) : 201
  CrossrefPubMedGoogle Scholar
• 28 Weber TJ, Sawyer EK, Moseley S. et al. Burden of disease in adult patients with hypophosphatasia: Results from two patient-reported surveys. Metabolism 2016; 65 (10) : 1522-1530
  CrossrefPubMedGoogle Scholar
• 29 Michel BA. [Sports in patients with systemic inflammatory musculoskeletal diseases]. Orthopade 1997; 26 (11) : 972-975
  CrossrefPubMedGoogle Scholar
• 30 Booth J, Moseley GL, Schiltenwolf M. et al. Exercise for chronic musculoskeletal pain: A biopsychosocial approach. Musculoskeletal Care 2017; 15 (04) : 413-421
  CrossrefPubMedGoogle Scholar
• 31 Ambrose KR, Golightly YM. Physical exercise as non-pharmacological treatment of chronic pain: Why and when. Best Pract Res Clin Rheumatol 2015; 29 (01) : 120-130
  CrossrefPubMedGoogle Scholar
• 32 Kuehn K, Hahn A, Seefried L. Mineral intake and clinical symptoms in adult patients with Hypophosphatasia. J Clin Endocrinol Metab. 2020 105. dgaa324. DOI: 10.1210/clinem/dgaa324
  Google Scholar
• 33 Genest F, Seefried L. Klinischer Stellenwert des Serum-Magnesiumwertes und der Supplementation bei Hypophosphatasie. Osteologie. 2018 ; 27: A48–A49
  Google Scholar
• 34 Girschick HJ. , Mornet E, Beer M et al. Chronic multifocal non-bacterial osteomyelitis in hypophosphatasia mimicking malignancy. BMC Pediatr 2007; 7: 3
  CrossrefPubMedGoogle Scholar
• 35 Girschick HJ, Schneider P, Haubitz I. et al. Effective NSAID treatment indicates that hyperprostaglandinism is affecting the clinical severity of childhood hypophosphatasia. Orphanet J Rare Dis 2006; 1: 24
  CrossrefPubMedGoogle Scholar
• 36 Sutton RA, Mumm S, Coburn SP. et al. “Atypical femoral fractures” during bisphosphonate exposure in adult hypophosphatasia. J Bone Miner Res 2012; 27 (05) : 987-994
  CrossrefPubMedGoogle Scholar
• 37 Whyte MP. Atypical femoral fractures, bisphosphonates, and adult hypophosphatasia. J Bone Miner Res 2009; 24 (06) : 1132-1134
  CrossrefPubMedGoogle Scholar
• 38 Genest F, Seefried L. Subtrochanteric and diaphyseal femoral fractures in hypophosphatasia-not atypical at all. Osteoporos Int 2018; 29 (08) : 1815-1825
  CrossrefPubMedGoogle Scholar
• 39 Camacho PM, Mazhari AM, Wilczynski C. et al. Adult Hypophosphatasia Treated with Teriparatide: Report of 2 Patients and Review of the Literature. Endocr Pract 2016; 22 (08) : 941-950
  CrossrefPubMedGoogle Scholar
• 40 Schmidt T, Rolvien T, Linke C. et al. Outcome of Teriparatide Treatment on Fracture Healing Complications and Symptomatic Bone Marrow Edema in Four Adult Patients With Hypophosphatasia. JBMR Plus 2019; 3 (08) : e10215
  CrossrefPubMedGoogle Scholar
• 41 Whyte MP, Mumm S, Deal C. Adult hypophosphatasia treated with teriparatide. J Clin Endocrinol Metab 2007; 92 (04) : 1203-1208
  CrossrefPubMedGoogle Scholar
• 42 Laroche M. Failure of teriparatide in treatment of bone complications of adult hypophosphatasia. Calcif Tissue Int 2012; 90 (03) : 250
  CrossrefPubMedGoogle Scholar
• 43 Seefried L, Baumann J, Hemsley S. et al. Efficacy of anti-sclerostin monoclonal antibody BPS804 in adult patients with hypophosphatasia. J Clin Invest 2017; 127 (06) : 2148-2158
  CrossrefPubMedGoogle Scholar
• 44 Valenza G, Burgemeister S, Girschick H. et al. Analysis of the periodontal microbiota in childhood-type hypophosphatasia. Int J Med Microbiol 2006; 296 (07) : 493-500
  CrossrefPubMedGoogle Scholar
• 45 Hofmann C, Girschick HJ, Mentrup B. et al. Clinical aspects of hypophsophatasia: an update. Clinic Rev Bone Miner Metab 2013; 11: 60-70
  CrossrefGoogle Scholar
• 46 Collmann H, Mornet E, Gattenlöhner S. et al. Neurosurgical aspects of childhood hypophosphatasia. Childs Nerv Syst 2009; 25 (02) : 217-223
  CrossrefPubMedGoogle Scholar
• 47 Di Rocco F, Baujat G, Cormier-Daire V. et al. Craniosynostosis and hypophosphatasia. Arch Pediatr. 2017 24. (5s2): 5s89-5s92
  Google Scholar