Zusammenfassung
Die Entwicklung der Bisphosphonate basierte auf unseren Untersuchungen in den 1960er Jahren zum Mechanismus der Verkalkung. Es erwies sich, dass biologische Flüssigkeiten Hemmkörper der Verkalkung enthielten, die wir dann als anorganisches Pyrophosphat identifizierten.
Pyrophosphat, das schon seit langem (wie auch längere Polyphosphate) als Wasserenthärter gebraucht wurde, um die Kalziumkarbonatbildung zu hemmen, hatte die Eigenschaft auch die Kalziumphosphatkristallbildung und -auflösung zu hemmen. Falls parenteral (aber nicht wenn oral) verabreicht, hemmten sie auch experimentell erzeugte Verkalkungen in vivo beim Tier. Die fehlende Wirkung bei oraler Applikation und auf die Knochenzerstörung wurde auf ihre enzymatische Spaltung im Körper zurückgeführt. Somit suchten wir nach Analogen, die ähnliche Eigenschaften besaßen, aber biologisch nicht abgebaut würden. Die Bisphosphonate, die statt einer P-O-P- eine P-C-P-Gruppe aufweisen, erfüllten diese Kriterien. Auch sie wurden industriell u. a. als Wasserenthärter gebraucht und sind seit der Mitte des 19. Jahrhunderts bekannt. Sie binden sich wie Pyrophosphat an Kalziumphosphatkristallen und hemmen sowohl die Kalziumphosphatbindung und -zerstörung. In vivo hemmen sie die Mineralisation wie auch die Knochenzerstörung.
Während die 1. Wirkung durch einen physikalisch-chemischen Mechanismus erklärt ist, ist die 2. zellulär bedingt – sie besteht in der Hemmung der Bildung, Lebensdauer und Aktivität der Osteoklasten. Der molekulare Mechanismus hängt von der Struktur der Bisphosphonate ab. Die strukturell einfacheren (ohne Stickstoff) inkorporieren die P-C-P-Verbindung in ATP-enthaltende Moleküle und werden für die Osteoklasten toxisch. Die aktiveren, Stickstoff enthaltenden Bisphosphonate hemmen den Mevalonat-Stoffwechsel in Folge einer spezifischen Hemmung von Farnesylpyrophosphatsynthase. Dies führt zur Verminderung von Geranylgeranylpyrophosphat, das für den Osteoklasten lebenswichtig ist.
Abstract
The development of bisphosphonates is based on our studies in the 1960s on the mechanism of mineralization. It was shown that biological fluids contained mineralization inhibitors which we identified as inorganic pyrophosphate.
Pyrophosphate, which, along with longer polyphosphates, has long been known as a water softener due to its inhibition of calcium carbonate formation, also has the ability to inhibit calcium phosphate crystal formation as well as dissolution. When given parenterally (but not orally), they also inhibit experimentally induced mineralization in vivo in animals. Their lack of effectiveness on oral application, as well as for bone destruction, is due to enzymatic cleavage in the body. We therefore sought analogues which had similar properties but were not biologically degraded. The bisphosphonates, which have a P-C-P instead of a P-O-P bond, fulfilled these criteria. Theyhave been known since the middle of the 19th century and have also been used industrially as water softeners. We discovered that they bind to calcium phosphate crystals in the same way as pyrophosphate and inhibit calcium phosphate binding as well as its dissolution. In vivo, they inhibit mineralization as well as bone destruction.
While the first process can be explained by a physicochemical mechanism, the second is cellular and involves the inhibition of the formation, lifespan and activity of osteoclasts. The molecular mechanism is dependent on the structure of the bisphosphonate. The structurally more simple molecules without nitrogen incorporate the P-C-P bond in ATP containing molecules and become toxic to the osteoclasts. The more active nitrogen containing bisphosphonates inhibit mevalonate metabolism due to the specific inhibition of farnesyl pyrophosphate synthase. This leads to a reduction in geranylgeranyl pyrophosphate, which is necessary for osteoclast survival.
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Fleisch, H. Einführung in die Bisphosphonate. Orthopäde 36, 103–109 (2007). https://doi.org/10.1007/s00132-006-1040-9
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DOI: https://doi.org/10.1007/s00132-006-1040-9