Genetische Ursachen und therapeutische Optionen bei Osteoporose im Kindes- und Jugendalter

Zusammenfassung

In den letzten Jahren hat sich die Diagnose “Osteogenesis imperfecta” (OI) von einem klar definierten, aber unvollständig verstandenen Krankheitsbild, zu einem heterogenen Symptomenkomplex gewandelt. Die meisten Patienten sind von einer Mutation in den Genen COL1A1 oder COL1A2 betroffen, die zu einem quantitativen oder qualitativen Mangel an Kollagen I führt. In den vergangenen Jahren wurde das pathophysiologische Verständnis durch neue molekulargenetische Erkenntnisse detaillierter. Mutationen, die Störungen der posttranslationalen Modifikation von Kollagen I bewirken, verursachen genauso den Phänotyp einer OI, wie Störungen der Osteoblastendifferenzierung. Das klinische Bild der OI kann aber über einen anderen pathophysiologischen Weg, wie z. B. der Überaktivierung von Osteoklasten (Mutationen im Gen SERPINF1), hervorgerufen werden. Trotz dieses erweiterten Wissens ist die Therapie weiterhin symptomatisch und beruht auf chirurgisch/orthopädischen und physiotherapeutischen Maßnahmen sowie auf der Behandlung mit Bisphosphonaten. Nur durch eine koordinierte Betreuung in einem Spezialzentrum kann den Kindern die bestmögliche Perspektive für ein Leben mit Glasknochen gegeben werden.

Summary

Osteogenesis imperfecta (OI) as a rare disease (incidence 1 : 20.000) is characterized by a complex of symptoms and signs of reduced bone mass, increased bone fragility, dwarfism and extra-skelettal signs as blue sclera, dentinogenesis imperfecta, reduced connective tissue stability and muscle weakness. In most of the cases (80–90 %) it is caused by autosomal dominant inherited mutations in the collagen genes COL1A1 or COL1A2, which lead to loss of function of the osteo blasts with a quantitative or qualitative collagen deficiency. Additionally, autosomal recessive mutations in the genes CRTAP, LEPRE 1 PPIB, SERPINH1, FKBP10, SP7/OSX, BMP1 and WNT1 lead to qualitative deficiency in the collagen production by the osteo blasts due to different mechanisms of posttranslational modification. Recently the genes leading to OI type V and VI were described. The description of these genes brought a new understanding for the pathophysiology of the disease. In patients suffering from SERPINF 1 mutations (OI VI) an increased activity of the osteoclasts cause the disease. In most cases diagnosis is made clinically. Laboratory examinations of the calcium-phosphate-metabolism, lateral x-ray of the spine and measurement of bone mass are instruments to objectify the diagnosis. There is no clear genotype phenotype association. The therapy is based on three different approaches. Bisphosphonates are used to reduce fracture rates and skeletal pain. Intensive muscle training is essential to achieve independency of the patients and to create a sufficient osteoanabol stimulus for the osteoblasts. In case of fractures and deformities surgical treatment becomes necessary. Offering a multidisciplinary concept to patients with OI might lead to further improvement in the care of these patients. Further research is mandatory to develop an individual translational treatment approach even in patients with a rare disease as OI.

Schlüsselwörter

Osteogenesis imperfecta - Kollagen - Bisphosphonate - genetische Diagnostik

Keywords

Osteogenesis imperfecta - collagen - bisphosphonates - genetic diagnostics

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