Pathophysiologie der Primären Osteoporose

Zusammenfassung

Osteoporose ist eine polygenetische Erkrankung, deren Manifestation in hohem Maße durch Umwelt und Lebensweise determiniert wird. Erniedrigte Knochenmasse und gestörte Mikroarchitektur führen zu erhöhter Frakturneigung. Die Spitzenknochenmasse wird bis zum Ende der 3. Lebensdekade erreicht, danach nimmt sie kontinuierlich ab. Knochen wird durch Osteoblasten mesenchymaler Abstammung und Osteoklasten myeloischer Herkunft in einem komplizierten Wechselspiel aufgebaut und ständig remodelliert. Die Differenzierung und Funktion dieser beiden Zellarten wird durch eine Reihe von Transkriptionsfaktoren, Hormonen und anderen Signalsubstanzen gesteuert (z. B. Parathormon, Vitamin D-Hormon, Sexualsteroide, Kortikosteroide, Extrazellulärmatrix-Proteine, Zytokine). Diese wiederum sind in die systemische Regulation des Kalzium-Stoffwechsels eingebunden. Die adäquate Aufnahme und ein adäquater Metabolismus von Kalzium, Phosphat, Vitamin D und Vitamin K sind für eine ungestörte Funktion des Knochenstoffwechsels wichtig. Vitamin D₃ wird zu mehr als der Hälfte des Bedarfs in der Haut unter dem Einfluss von UV Sonnenlicht produziert. In der Leber entsteht 25(OH)-Cholecalciferol, in der Niere wird dies an Position 1α hydroxyliert und dadurch zur hormonell wirksamen Substanz aktiviert. Das Secosteroidhormon 1,25-Dihydroxycholecalciferol (Vitamin D-Hormon) ist unabdingbar für die Kalziumaufnahme im Dünndarm. Sexualsteroide wirken antiresorptiv und ihr Mangel oder Verlust hat eine negative Bilanz des Knochens zur Folge. Regelmäßige Belastung des Skeletts ist essenziell für den Aufbau der Spitzenknochenmasse und für den Erhalt des Knochens. Alle Systeme für die Regulation der Knochenmasse unterliegen Störungsmöglichkeiten durch äußere Umstände und die Lebensweise. Die gleichen Systeme können aber auch durch genetische Polymorphismen verändert sein, wobei nach heutigen Erkenntnissen mildere Störungen in mehreren Genen zugrunde liegen. Die bunte Mischung der exogenen Einflüsse auf einem unterschiedlich starken genetischen Hintergrund kann zur Osteoporose führen. Die bislang beschriebenen genetischen Polymorphismen haben alle einen relativ geringen Einfluss auf die Risikokonstellation und werden vermutlich in ihrer Summe wirksam. Möglicherweise führen neue Erkenntnisse über die Linkage bislang nicht charakterisierter Genbereiche mit der Osteoporose in naher Zukunft dazu, dass unbekannte Gene mit großem Einfluss auf die Knochenmasse charakterisiert werden können. Auch die Entdeckung neuer Regulationsmechanismen wie die hypothalamische Steuerung der Knochenmasse wird zum besseren Verständnis der Pathophysiologie der Osteoporose beitragen.

Pathophysiology of Primary Osteoporosis

Osteoporosis is a polygenetic disease, the onset of which is strongly influenced by factors of environment and life style. Low bone mass and altered bone microarchitecture are the basis of a high fracture incidence. At the end of the third decade of life a persons peak bone mass is achieved, which thereafter steadily decreases. Bone is built up and remodelled by mesenchyme derived osteoblasts and myeloid osteoclasts in complex interaction. The differentiation and function of both cell types is regulated by a series of transcription factors, hormones and other signalling substances (e. g. parathyroid hormone, vitamin D-hormone, sex steroids, corticosteroids, growth factors, extracellular matrix proteins, cytokines). These factors are integrated into the systemic regulation of calcium metabolism. The adequate intake and metabolism of calcium, phosphate, vitamin D and vitamin K are important for unaltered mechanisms of bone metabolism. More than 50 % of our daily requirements of vitamin D₃ are produced from 7-dehydrocholesterol in the skin under the influence of UV sun light. 25(OH)-vitamin D₃ is produced by the liver and is subsequently 1α-hydroxylated in the kidney. The latter event is the critical step where the hormonally active secosteroid 1,25-dihydroxycholecalciferol is produced. This hormone is indispensable for calcium absorption in the gut. Sex steroids are anabolic and antiresorptive hormones. Sex hormone deficiency or loss is followed by a negative balance of bone metabolism mainly due to enhanced bone resorption. Continuous influence of gravity, weight bearing and physical forces are essential to achieve an adequate peak bone mass and for the maintenance of bone mass. All bone mass regulatory systems may be altered by factors of the environment and life style. These identical systems may however as well be altered by genetic polymorphisms. Thus a mixed variety of exogenous factors on a variable genetic background may produce osteoporosis. To our present knowledge a series of relatively mild alterations in several genes may in summary be responsible for the genetic background. New data about linkage of so far unknown gene loci with osteoporosis will possibly lead to the characterization of new genes with a high impact on bone mass in the near future. The same holds through for data on new regulatory systems like the hypothalamic control of bone mass.

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