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Osteologie 2014; 23(04): 251-261
DOI: 10.1055/s-0037-1622029
Osteoonkologie
Schattauer GmbH

Moderne Osteoprotektion in der Onkologie

Current approaches to osteoprotection in oncology
I. J. Diel
1   Schwerpunktpraxis für Gynäkologische Onkologie, Mannheim
› Author Affiliations
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Publication History

eingereicht: 23 October 2014

angenommen: 27 October 2014

Publication Date:
02 January 2018 (online)

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Zusammenfassung

Knochenmetastasen zerstören den Knochen, dadurch dass Tumorzellen über parakrine Sekretion von osteotropen Substanzen den RANK/RANKL/OPG-Signalweg aktivieren, der zu einer gesteigerten Osteoklastenaktivierung führt. Bei der subsequenten Zerstörung der Knochenmatrix werden zuvor eingelagerte Wachstumsfaktoren freigesetzt, die zu einer Steigerung der proliferativen Aktivität der Tumorzellen beitragen können (Circulus vitiosus, maligner Dialog). Antiosteolytische Substanzen hemmen die Neubildung und/ oder Aktivierung von Osteoklasten und reduzieren so das Ausmaß der skelettalen Zerstörung. Das Ziel aller Therapiemaßnahmen bei Knochenmetastasen ist die Reduktion so - genannter skelettaler Komplikationen, wie Knochenschmerz, pathologische Frakturen, spinale Kompressionssyndrome und hyperkalzämische Episoden, um die Lebensqualität der Patienten zu verbessern und deren Überlebenszeit zu verlängern. Nicht nur die Therapie kann im Rahmen einer Tumorerkrankung zu einer Osteoporose führen, auch die Grundkrankheit selbst kann durch reduzierte körperliche Aktivität, Immobilisierung, Nausea, Mangel ernährung und direkte Effekte des Tumors zu einer Reduktion der Knochenmasse führen. Als eigenständiger Risikofaktor gilt jedoch insbesondere die medikamentöse Therapie. Zahlreiche Chemotherapeutika können den Knochen direkt, auch ohne Ausschaltung der gonadalen Aktivität, schädigen. Weitaus nachhaltiger wird der Knochen durch den Hypogonadismus beeinträchtigt, der bei Patienten mit hormonempfindlichen Tumoren erwünschtes Therapieziel ist. Zur Behandlung und Prophylaxe der Osteoporose gibt es zahlreiche medikamentöse Möglichkeiten, aber mit keiner anderen Substanzklasse liegen bei der tumortherapieinduzierten (TTI) Osteoporose so gute Resultate vor wie zu den Bisphosphonaten. Zumindest gleich gute Ergebnisse erzielt man mit der Anwendung von Denosumab bei Mammakarzinompatientinnen mit Aromatasehemmer-induzierter Osteopenie und bei Männern mit Prostatakarzinom und Androgenblockade. Kaum eine Einsatzmöglichkeit von osteoprotektiven Substanzen ist in den vergangenen Jahren so kontrovers diskutiert worden wie die Option zur Vermeidung von Knochenmetastasen. Das liegt zum größten Teil an den sehr divergenten Ergebnissen der einzelnen Studien, insbesondere zum Einsatz von Clodronat oder Zoledronat adjuvant. Nach einer kürzlich erschienenen Metaanalyse verbessern Bisphosphonate signifikant das knochenmetastasenfreie und das Gesamtüberleben – und das trotz Unterschieden in Applikationsweise, Patientenkollektiven und Einschlusskriterien der jeweiligen Studien. Es gibt also berechtigte Hinweise, diese Indikation weiter zu untersuchen, um herauszufinden wer von einem adjuvanten Einsatz profitiert und wer nicht. Nach derzeitigem Wissensstand sind es Patientinnen mit hohem Rezidivrisiko, aktiviertem Knochenstoffwechsel (Östrogen - depletion, postmenopausal) und/oder Tumorzellen im Knochenmark.

Summary

Bone metastases destroy the bone through paracrine secretion of osteotropic substances by tumour cells. Those substances lead to a higher activity of osteoclasts by influencing the RANK/RANKL/OPG signal path. The subsequent destruction of the osseous matrix releases growth factors which were previously stored within the bone and which can increase the proliferating activity of the tumorous cells (vicious cycle). Antiosteolytical drugs reduce the fusion and/or activation of osteoclasts and lower the degree of skeletal damage. All measures of therapy against bone metastases aim at the reduction of so called skeletal complications (events). The most important thing that is ought to be fought is bone pain, followed by pathological fractures, spinal cord compression and hypercalcemic episodes. The avoidance of such complications does not merely lead to an improvement in quality of life but can also prolong the survival time by lowering the level of immobility and decreasing the hospitalization rate in some individuals. It is by no means only the therapy that can lead to osteoporosis in patients with a tumour disease, it can also be caused by the disease itself. A lack of physical activity, immobilization, nausea, malnutrition and direct influences of the tumour can all contribute to a reduction of bone mass. But particularly the medication has to be seen as a separate and distinct risk factor. A wide range of chemotherapeutics socan harm the bone directly, even without neutralizing hormonal activity. Also the impairing effect of hypogonadism on the bone can be vast – even though hypogonadism is one of the specific goals in the treatment of patients with hormone sensitive tumours. The therapy and prophylaxis of primary and secondary osteoporosis aim mainly at the prevention of fractures and bone loss in order to sustain patients quality of life. Even though there are plenty of different pharmaceutical options in the treatment and prophylaxis of tumour-therapy-induced osteoporosis, no other medication shows better or even similar results to bis phosphonates. There are numerous studies on different bisphosphonates (Clo, Pam, Ale, Ris, Iba, Zol) that investigated the effectiveness of those substances in prevention and treatment of TTI-osteoporosis in patients with breast and prostate cancer. All substances were supposed to increase the bone density as a main therapy goal and all substances reached that. Denosumab brings results which are at least of the same quality as bisphosphonates, when applied to patients with breast cancer, whose osteopenia was triggered by the usage of aromatase-inhibitors. Almost all women who received this antibody experienced an increase in bone density. But since the studies had a fairly low number of patients, it was impossible to recognize a difference in the occurrence rate of fractures, in contrast to patients with prostate cancer and androgen-blockade. Few discussions of the last years were as controverse as the one about whether osteoprotective substances could be used as an option to prevent from bone metastases. Part of the reason is, that the results of all studies were quite divergent especially those that investigated the usage of Clodronate and Zoledronate as an adjuvant drug. But in a recent meta-analysis of studies it was clearly shown, that bisphosphonates increase the bone-metastases-free and the total survival rate of postmenopausal breast cancer patients significantly, despite the fact that the way of application, patients collective and criterias of participation differed vastly, throughout the investigated studies. So there are plenty of reasons to study the indication further and to find out which patients have an advantage of an adjuvant usage and which does not. According to our current knowledge, those patients are the ones with a high risk of a relapse, an activated bonemetabolism and/or tumour cells in the bone marrow.

Schlüsselwörter

Knochenmetastasen - RANK/RANKL/OPGSignalweg - Bisphosphonate - Denosumab

Keywords

Bone metastases - RANK/RANKL/OPG signal path - bisphosphonates - denosumab
 

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