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CC BY 4.0 · Osteologie 2020; 29(04): 302-310
DOI: 10.1055/a-1233-9812
Originalarbeit

Genetische Ursachen und Therapie der Osteogenesis imperfecta

Pathophysiology and therapeutic options in osteogenesis imperfecta
Oliver Semler
1   Universität zu Köln, Medizinische Fakultät und Uniklinik Köln, Klinik und Poliklinik für Kinder- und Jugendmedizin, Köln, Deutschland
,
Uwe Kornak
2   Institut für Humangenetik, Universitätsmedizin Göttingen, Germany
,
Ralf Oheim
3   Universitätsklinikum Hamburg-Eppendorf, Institut für Osteologie und Biomechanik, Hamburg, Deutschland
,
Lothar Seefried
4   Experimentelle und Klinische Osteologie, Lehrstuhl Orthopädie und Orthopädische Klinik König-Ludwig-Haus, Würzburg, Deutschland
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Zusammenfassung

Die Osteogenesis imperfecta (OI) ist die häufigste angeborene Erkrankung, die zu einer erhöhten Fragilität des Skelettsystems führt. Die Variabilität des Phänotyps kann nicht vollständig durch die ursächlichen genetischen Veränderungen erklärt werden. Die meisten Formen werden durch Mutationen in Genen verursacht, die die Kollagen-Synthese/-Prozessierung verändern, wobei die meisten Patientinnen und Patienten von Mutationen in den Genen COL1A1/A2 betroffen sind. Das bessere Verständnis der Pathophysiologie bei seltenen rezessiven Formen der Erkrankung hat bereits in zwei Fällen zu neuen therapeutischen Ansätzen geführt. Bei OI Typ VI, verursacht durch Mutationen in SERPINF1, kommt es zu einer Überaktivierung von Osteoklasten über den OPG/RANKL-pathway. Hier konnte gezeigt werden, dass eine Behandlung mit dem Osteoklasten-Antikörper Denosumab effektiver ist als eine antiresorptive Therapie mit Bisphosphonaten. Bei Patientinnen und Patienten, bei denen die ursächliche Mutation im Gen WNT1 liegt, bietet sich eine osteoanabole Behandlung mit Antisklerostin-Antikörpern an. Neben der medikamentösen Therapie sind die Bereiche der Rehabilitation und Orthopädie unverzichtbare Bestandteile einer interdisziplinären Behandlung.

Abstract

Osteogenesis imperfecta (OI) is the most common hereditary disease causing an increased bone fragility. The wide variability of the phenotype can not be explained by the genotype. Most forms are caused by mutations in genes influencing synthesis and posttranslational modification of collagen. Most patients are affected by mutations in the genes COL1A1/A2. The increased knowledge about underlying genetic alteration and pathophysiology in some rare recessive forms has led to new therapeutic strategies. OI VI is caused by mutations in SERPINF1 leading to an increased activity of osteoclasts via the OPG/RANKL-pathway. In these patients a medical treatment with denosumab has been proven to be more effective as antiresorptive treatment compared to the former therapy with bisphosphonates. In patients affected by mutations in WNT1 an osteoanabolic treatment might be more suitable than an antiresorptive therapy. Pharmacological treatment has to be included in an interdisciplinary therapeutic concept in combination with physiotherapy and surgical treatment.

Schlüsselwörter

Osteogenesis imperfecta - Therapie - Pathophysiologie - Bisphosphonate

Key words

Osteogenesis imperfecta - Therapy - Pathophysiology - Bisphosphonates


Publikationsverlauf

Artikel online veröffentlicht:
02. September 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/)

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  • Literatur

  • 1 Marini JC, Forlino A, Bächinger HP. et al. Osteogenesis imperfecta. Nat Rev Dis Primers 2017; 3: 17052 . doi: 10.1038/nrdp.2017.52
    Google Scholar
  • 2 Rauch F, Glorieux FH. Osteogenesis imperfecta. Lancet 2004; 363 (9418): 1377-1385
    CrossrefPubMedGoogle Scholar
  • 3 Kashii M, Kanayama S, Kitaoka T. et al. Development of scoliosis in young children with osteogenesis imperfecta undergoing intravenous bisphosphonate therapy. J Bone Miner Metab 2019; 37 (03) : 545-553 . doi: 10.1007/s00774-018-0952-x
    CrossrefPubMedGoogle Scholar
  • 4 Hoyer-Kuhn H, Rehberg M, Semler O. Angeborene Skeletterkrankungen. Monatsschrift Kinderheilkunde 2017; 165 (08) : 663-671
    CrossrefGoogle Scholar
  • 5 Land C, Rauch F, Montpetit K. et al. Effect of intravenous pamidronate therapy on functional abilities and level of ambulation in children with osteogenesis imperfecta. J Pediatr 2006; 148 (04) : 456-460 . doi: 10.1016/j.jpeds.2005.10.041
    CrossrefPubMedGoogle Scholar
  • 6 Glorieux FH, Bishop NJ, Plotkin H. et al. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med 1998; 339 (14) : 947-952 . doi: 10.1056/NEJM199810013391402
    CrossrefPubMedGoogle Scholar
  • 7 Gatti D, Antoniazzi F, Prizzi R. et al. Intravenous neridronate in children with osteogenesis imperfecta: a randomized controlled study. J Bone Miner Res 2005; 20 (05) : 758-763 . doi: 10.1359/JBMR.041232
    CrossrefPubMedGoogle Scholar
  • 8 Kumar C, Panigrahi I, Somasekhara Aradhya A. et al. Zoledronate for Osteogenesis imperfecta: evaluation of safety profile in children. J Pediatr Endocrinol Metab 2016; 29 (08) : 947-952 . doi: 10.1515/jpem-2015-0351
    CrossrefPubMedGoogle Scholar
  • 9 Land C, Rauch F, Munns CF. et al. Vertebral morphometry in children and adolescents with osteogenesis imperfecta: effect of intravenous pamidronate treatment. Bone 2006; 39 (04) : 901-906 . doi: 10.1016/j.bone.2006.04.004
    CrossrefPubMedGoogle Scholar
  • 10 Hoyer-Kuhn H, Bartz-Seel J, Blickheuser R. et al. Diagnostik und Therapie der Osteogenesis imperfecta. Monatsschrift Kinderheilkunde 2016; 165 (04) : 333-346 . doi: 10.1007/s00112-016-0189-5
    CrossrefGoogle Scholar
  • 11 Bishop N, Adami S, Ahmed SF. et al. Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebo-controlled trial. Lancet 2013; 382: (9902): 1424-1432 . doi: 10.1016/S0140-6736(13)61091-0
    CrossrefGoogle Scholar
  • 12 Hoyer-Kuhn H, Franklin J, Allo G. et al. Safety and efficacy of denosumab in children with osteogenesis imperfect–a first prospective trial. J Musculoskelet Neuronal Interact 2016; 16 (01) : 24-32
    PubMedGoogle Scholar
  • 13 Trejo P, Rauch F, Ward L. Hypercalcemia and hypercalciuria during denosumab treatment in children with osteogenesis imperfecta type VI. J Musculoskelet Neuronal Interact 2018; 18 (01) : 76-80
    PubMedGoogle Scholar
  • 14 Vahle JL, Sato M, Long GG. et al. Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1–34) for 2 years and relevance to human safety. Toxicol Pathol 2002; 30 (03) : 312-321 . doi: 10.1080/01926230252929882
    CrossrefPubMedGoogle Scholar
  • 15 Orwoll ES, Shapiro J, Veith S. et al. Evaluation of teriparatide treatment in adults with osteogenesis imperfecta. J Clin Invest 2014; 124 (02) : 491-498 . doi: 10.1172/JCI71101
    CrossrefPubMedGoogle Scholar
  • 16 Glorieux FH, Devogelaer JP, Durigova M. et al. BPS804 anti-sclerostin antibody in adults with moderate osteogenesis imperfecta: results of a randomized phase 2a trial. J Bone Miner Res 2017; 32 (07) : 1496-1504 . doi: 10.1002/jbmr.3143
    CrossrefPubMedGoogle Scholar
  • 17 Tauer JT, Abdullah S, Rauch F. Effect of anti-TGF-beta treatment in a mouse model of severe osteogenesis imperfecta. J Bone Miner Res 2019; 34 (02) : 207-214
    CrossrefPubMedGoogle Scholar
  • 18 Maines E, Tadiotto E, Morandi G. et al. Hypocalcemia following neridronate administration in pediatric patients with osteogenesis imperfecta: a prospective observational study. J Pediatr Genet 2020; 9 (02) : 93-100 . doi: 10.1055/s-0039-1700972
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 19 Plante L, Veilleux LN, Glorieux FH. et al. Effect of high-dose vitamin D supplementation on bone density in youth with osteogenesis imperfecta: a randomized controlled trial. Bone 2016; 86: 36-42 . doi: 10.1016/j.bone.2016.02.013
    CrossrefPubMedGoogle Scholar
  • 20 Wirth T. Osteogenesis imperfecta. Orthopade. 2012; 41 (09) : 773-782 ; quiz 83-4.
    CrossrefPubMedGoogle Scholar
  • 21 Mueller B, Engelbert R, Baratta-Ziska F. et al. Consensus statement on physical rehabilitation in children and adolescents with osteogenesis imperfecta. Orphanet J Rare Dis 2018; 13 (01) : 158 . doi: 10.1186/s13023-018-0905-4
    CrossrefPubMedGoogle Scholar
  • 22 Forlino A, Marini JC. Osteogenesis imperfecta. Lancet 2016; 387 (10028): 1657-1671
    Google Scholar
  • 23 Pollitt R, McMahon R, Nunn J. et al. Mutation analysis of COL1A1 and COL1A2 in patients diagnosed with osteogenesis imperfecta type I-IV. Hum Mutat 2006; 27 (07) : 716 . doi: 10.1002/humu.9430
    CrossrefPubMedGoogle Scholar
  • 24 Van Dijk FS, Sillence DO. Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment. Am J Med Genet A 2014; 164A (06) : 1470-1481
    CrossrefPubMedGoogle Scholar
  • 25 Mrosk J, Bhavani GS, Shah H. et al. Diagnostic strategies and genotype-phenotype correlation in a large Indian cohort of osteogenesis imperfecta. Bone 2018; 110: 368-377 . doi: 10.1016/j.bone.2018.02.029
    CrossrefPubMedGoogle Scholar
  • 26 Lindert U, Cabral WA, Ausavarat S. et al. MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta. Nat Commun 2016; 7: 11920 . doi:10.1038/ncomms11920
    CrossrefPubMedGoogle Scholar
  • 27 Semler O, Garbes L, Keupp K. et al. A mutation in the 5ʹ-UTR of IFITM5 creates an in-frame start codon and causes autosomal-dominant osteogenesis imperfecta type V with hyperplastic callus. Am J Hum Genet 2012; 91 (02) : 349-357 . doi: 10.1016/j.ajhg.2012.06.011
    CrossrefPubMedGoogle Scholar
  • 28 Breslau-Siderius EJ, Engelbert RH, Pals G. et al. Bruck syndrome: a rare combination of bone fragility and multiple congenital joint contractures. J Pediatr Orthop B 1998; 7 (01) : 35-38
    CrossrefPubMedGoogle Scholar
  • 29 Tauer JT, Robinson ME, Rauch F. Osteogenesis imperfecta: new perspectives from clinical and translational research. JBMR Plus 2019; 3 (08) : e10174
    CrossrefPubMedGoogle Scholar
  • 30 Glorieux FH, Ward LM, Rauch F. et al. Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect. J Bone Miner Res 2002; 17 (01) : 30-38 . doi: 10.1359/jbmr.2002.17.1.30
    CrossrefPubMedGoogle Scholar
  • 31 Becker J, Semler O, Gilissen C. et al. Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta. Am J Hum Genet 2011; 88 (03) : 362-371 . doi:10.1016/j.ajhg.2011.01.015
    CrossrefPubMedGoogle Scholar
  • 32 Akiyama T. , Dass CR, Shinoda Y et al. PEDF regulates osteoclasts via osteoprotegerin and RANKL. Biochem Biophys Res Commun 2010; 391 (01) : 789-794 . doi: 10.1016/j.bbrc.2009.11.139
    CrossrefPubMedGoogle Scholar
  • 33 Li F, Na S, Tombran-Tink J. et al. Pigment epithelium-derived factor enhances differentiation and mineral deposition of human mesenchymal stem cells. Stem Cells 2013; 31 (12) : 2714-2723
    CrossrefPubMedGoogle Scholar
  • 34 Keupp K, Beleggia F, Kayserili H. et al. Mutations in WNT1 cause different forms of bone fragility. Am J Hum Genet 2013; 92 (04) : 565-574 . doi: 10.1016/j.ajhg.2013.02.010
    CrossrefPubMedGoogle Scholar
  • 35 Nusslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature 1980; 287 (5785): 795-801
    CrossrefPubMedGoogle Scholar
  • 36 Nusse R, Varmus HE. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 1982; 31 (01) : 99-109
    CrossrefPubMedGoogle Scholar
  • 37 Saito-Diaz K, Chen TW, Wang X. et al. The way Wnt works: components and mechanism. Growth Factors 2013; 31 (01) : 1-31 . doi: 10.3109/08977194.2012.752737
    CrossrefPubMedGoogle Scholar
  • 38 McMahon AP, Bradley A. The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain. Cell 1990; 62 (06) : 1073-1085
    CrossrefPubMedGoogle Scholar
  • 39 Thomas KR, Capecchi MR. Targeted disruption of the murine int-1 proto-oncogene resulting in severe abnormalities in midbrain and cerebellar development. Nature 1990; 346 (6287): 847-850
    CrossrefPubMedGoogle Scholar
  • 40 Joeng KS, Lee YC, Jiang MM. et al. The swaying mouse as a model of osteogenesis imperfecta caused by WNT1 mutations. Hum Mol Genet 2014; 23 (15) : 4035-4042 . doi: 10.1093/hmg/ddu117
    CrossrefPubMedGoogle Scholar
  • 41 Luther J, Yorgan TA, Rolvien T. et al. Wnt1 is an Lrp5-independent bone-anabolic Wnt ligand. Sci Transl Med 2018; 10: 466 . doi:10.1126/scitranslmed.aau7137
    CrossrefPubMedGoogle Scholar
  • 42 Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell 2012; 149 (06) : 1192-1205
    CrossrefPubMedGoogle Scholar
  • 43 Tamai K, Semenov M, Kato Y. et al. LDL-receptor-related proteins in Wnt signal transduction. Nature 2000; 407: (6803): 530-535 . doi:10.1038/35035117
    CrossrefGoogle Scholar
  • 44 Bovolenta P, Esteve P, Ruiz JM. et al. Beyond Wnt inhibition: new functions of secreted frizzled-related proteins in development and disease. J Cell Sci 2008; 121: (Pt 6): 737-746 . doi: 10.1242/jcs.026096
    CrossrefGoogle Scholar
  • 45 Balemans W, Patel N, Ebeling M. et al. Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet 2002; 39 (02) : 91-97 . doi: 10.1136/jmg.39.2.91
    CrossrefPubMedGoogle Scholar
  • 46 van Dinther M, Zhang J, Weidauer SE. et al. Anti-Sclerostin antibody inhibits internalization of Sclerostin and Sclerostin-mediated antagonism of Wnt/LRP6 signaling. PLoS One 2013; 8 (04) : e62295 . doi: 10.1371/journal.pone.0062295
    CrossrefPubMedGoogle Scholar
  • 47 Cosman F, Crittenden DB, Achadi JD. et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 2016; 375 (16) : 1532-1543 . doi: 10.1056/NEJMoa1607948
    CrossrefPubMedGoogle Scholar