Der Einfluss von Bortezomib auf den Knochenstoffwechsel beim multiplen Myelom

Zusammenfassung

Die erhöhte Knochenresorption ist ein Hauptmerkmal des multiplen Myeloms und kann die Lebensqualität der Patienten maßgeblich beeinträchtigen. Bei der überwiegenden Mehrzahl der Myelompatienten sind Osteolysen festzustellen, die Schmerzen auslösen und ein erhöhtes Frakturrisiko verursachen. Die Knochendestruktion entsteht beim multiplen Myelom durch ein gestörtes Gleichgewicht der Aktivität der knochenaufbauenden Osteoblasten und der knochenabbauenden Osteoklasten. Die zellulären Interaktionen sowie Dysregulation von Zytokinen im Knochenmarkmikroenvironment sind an der Knochendestruktion beteiligt. Die Behandlung mit Bisphosphonaten hemmt zwar die osteoklasteninduzierte Knochenresorption, ist aber nicht in der Lage, die beim multiplen Myelom beobachtete Hemmung der Differenzierung der mesenchymalen Stammzellen zu Osteoblasten auszugleichen. Bortezomib ist die wirksamste Einzelsubstanz in der Therapie des multiplen Myeloms. Präklinische Untersuchungen zeigen, dass der Proteasominhibitor Bortezomib darüber hinaus der myelominduzierten Knochendestruktion entgegenwirken kann. Bortezomib hemmt einerseits die Osteoklastenaktivität und fördert andererseits die Osteoblastenfunktion und weist somit Eigenschaften auf, die für die Therapie der Knochenbeteiligung beim multiplen Myelom ideal erscheinen. Bortezomib könnte somit nicht nur in der Behandlung gegen die Tumorzellen, sondern auch in der Behandlung der Knochendestruktion eine wesentliche Rolle spielen. Klinische Studien sind jedoch notwendig, um diese Effekte hinsichtlich ihrer klinischen Relevanz zu untersuchen. Internationale prospektive klinische Studien wurden begonnen, um dies in einem randomisierten Studiendesign zu untersuchen.

Abstract

Increased bone resorption is one of the main characteristics of multiple myeloma and can considerably impair the quality of life of the patients. The vast majority of myeloma patients have lytic bone lesions which lead to pain and an increased risk of fractures. Bone destruction in multiple myeloma patients is caused by an imbalance of the activity of bone-building osteoblasts and bone-resorbing osteoclasts. Cellular interactions, as well as dysregulation of cytokines in the bone marrow microenvironment are involved in bone destruction. Treatment with bisphosphonates inhibits osteoclast-induced bone resorption, but it cannot compensate for the inhibited differentiation of mesenchymal stem cells into osteoblasts observed in multiple myeloma patients. Bortezomib is the most efficient single substance for the treatment of multiple myeloma. Preclinical tests show that the proteasome inhibitor Bortezomib can furthermore counteract the myeloma-induced bone destruction. On the one hand, Bortezomib inhibits osteoclast activity and, on the other hand, promotes osteoblast function and thus has properties that seem to be ideal for the therapy of bone disease in multiple myeloma patients. Bortezomib might play an important part not only in the treatment against the tumour cells, but also in the treatment of bone destruction. However, clinical studies have to be carried out in order to examine these effects with a view to their clinical relevance. International prospective randomized clinical trials have already been started.

Schlüsselwörter

Bortezomib - Knochen - multiples Myelom - Osteoblasten - Osteoklasten - Proteasom

Key words

Bortezomib - bones - multiple myeloma - osteoblasts - osteoclasts - proteasome

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