Die Wirkung der antiresorptiven Therapie am Knochen

Zusammenfassung

Die meisten aktuellen Ansätze zur medikamentösen Behandlung des systemischen Knochenverlustes bei Osteoporose–wie Östrogene und SERM, aber vor allem Bisphosphonate und Denosumab – zielen auf eine Inhibition der Osteoklasten, der den Knochen abbauenden Zellen, ab. Stickstoffhaltige Bisphosphonate wirken durch ihre starke Bindung an der Knochenoberfläche und eine Hemmung der Osteoklastenfunktion vorwiegend über die Inhibierung der Farnesyl-Pyrophosphat-Synthase. Denosumab als vollhumaner monoklonaler Antikörper bewirkt hingegen eine gezielte Hemmung von RANK-Ligand und damit der Osteoklastendifferenzierung und -aktivierung sowie letztlich eine Reduktion der Osteoklastenzahl an der Knochenoberfläche. Bisphosphonate wie Alendronat, Risedronat, Ibandronat und Zoledronat sowie eben auch Denosumab zeigten in klinischen Studien robuste Ergebnisse bezüglich einer signifikanten Reduktion des Frakturrisikos. Ein grundlegendes Wissen um die unterschiedliche Wirkungsweise ist Voraussetzung, um einen potenziell kausalen Zusammenhang zwischen Antiresorptiva und Kieferosteonekrosen (ONJ) verstehen und daraus differenzierte und effektive Präventions- und Therapiestrategien entwickeln zu können.

Summary

In order to treat systemic bone loss in osteo - porosis, most approaches target the osteoclasts – the cells resorbing bone. Drugs inhibiting the differentiation, activity and/or survival of osteoclasts have, thus, become a fundamental option for the prevention and treatment of osteoporosis. In general, this class includes estrogens and selective estrogen receptor modulators, but, first of all, bisphosphonates and denosumab. Bisphosphonates are currently the most widely used antiresorptive therapy. They act by binding to bone and interfering with osteoclast function. The nitrogen-containing bisphosphonates act as inhibitors of farnesyl-pyro - phosphate synthase, which leads to inhibition of the prenylation of intracellular proteins. The recent discovery of the RANK/RANKL/OPG system and its essential role in the osteoclast differentiation, activity and survival, have led to the development of denosumab – an innovative treatment option. This fully human monoclonal antibody acts by binding to and inhibiting RANK-Ligand (RANKL), leading to the inhibition of osteoclast differentiation, its activity and survival and, finally, to a loss of osteoclasts from bone surfaces. Bisphosphonates, such as alendronate, risedronate, ibandronate and zoledronate, as well as the RANKLinhibitor denosumab have been approved for the treatment of osteoporosis and have shown robust efficacy data in reference to fracture prevention. The key pharmacological differences between denosumab and bisphosphonates are a result of the distribution of the drugs within bone and their effects on precursors and mature osteoclasts. This may explain differences in the degree of reduction of bone resorption, their potential differential effects on trabecular and cortical bone, and the reversibility of their actions. Basic knowledge of the differences in mode of action of these drugs is also essential to understanding of their potential association with osteonecrosis of the jaw (ONJ) and to development of differentiated and sufficient ONJ prevention and treatment strategies.

Schlüsselwörter

Osteoklasten - Antiresorptiva - Bisphosphonate - Denosumab

Keywords

Osteoclasts - antiresorptive therapy - bisphosphonates - denosumab

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