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
