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Osteologie 2012; 21(03): 186-192
DOI: 10.1055/s-0037-1621684
Osteonekrose des Kiefers
Schattauer GmbH

Pathophysiologie des Knochenstoffwechsels bei Osteonekrosen im Zusammenhang mit starker antiresorptiver Therapie

Pathophysiology of bone metabolism in osteonecrosis associated with antiresorptive treatment
F. Jakob
1   Orthopädisches Zentrum für Muskuloskelettale Forschung, Universität Würzburg
,
L. Seefried
1   Orthopädisches Zentrum für Muskuloskelettale Forschung, Universität Würzburg
,
R. Ebert
1   Orthopädisches Zentrum für Muskuloskelettale Forschung, Universität Würzburg
› Author Affiliations
Further Information

Publication History

eingereicht: 13 July 2012

angenommen: 18 July 2012

Publication Date:
04 January 2018 (online)

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Zusammenfassung

Osteonekrosen des Kiefers sind mit der hoch dosierten Langzeittherapie von Knochenmetastasen mit Bisphosphonaten und Denosumab, selten auch mit der niedriger dosierten Therapie der Osteoporose als unerwünschte Ereignisse assoziiert. Wahrscheinlich müssen die beiden starken Antiresorptiva als einer von mehreren Risikofaktoren gelten, die im Zusammenwirken die Zerstörung von Infek tionsbarrieren begünstigen und die Regeneration des betroffenen Gewebes verhindern. Mechanische Verletzung bei der Nahrungsaufnahme oder bei oralchirurgischen Eingriffen und medikamentöse Einflüsse wie Chemotherapie zerstören die Epithelbarriere, gefolgt von medikamentöser Beeinträchtigung und Abtötung der Zellen für die verschiedenen immunologischen Verteidigungslinien, das „innate immune system” (Monozyten/Makrophagen und Granulozyten) und das adaptive Immunsystem (B-und T-Zellen). Osteoklasten als Abräumer des knöchernen Gewebsdetritus werden ebenso beeinträchtigt wie möglicherweise Osteoblastenvorläufer und Endothelien als Ausgangspunkt der knöchernen Regeneration. Der Anteil der Bisphosphonate an den genannten Vorgängen beinhaltet die Einleitung der Apoptose von Monozyten und Osteoklasten und kann theoretisch – so genügend hohe Konzentrationen erreicht werden – auch zur Apoptose osteoblastärer, epithelialer und endothelialer Zellen beitragen. Chemotherapeutika und Immunsuppressiva haben besonders starke Einflüsse auf die Zellen des innate und adaptiven Immunsystems. Letztlich erscheint die Osteonekrose des Kiefers als eine facettenreiche Erkrankung, zu der starke Antiresorptiva wie Bisphosphonate und Denosumab nur einen Teil beitragen, der allerdings im Zusammenhang mit anderen Risikofaktoren nicht unwesentlich ist. Weitere Forschung ist erforderlich für die Klärung der Frage, ob die Biologie des Kieferknochens aufgrund der entwicklungsbiologischen Abstammung Besonderheiten aufweist, welche die Suszeptibilität begünstigen, oder ob die ausgesprochen hohe Exposition dieser Region zu Bakterien und Pilzen im Kontext mit ernsthaft eingeschränkten Immunund Gewebereparaturfunktionen der ausschlaggebende Faktor ist.

Summary

Osteonecroses of the jaw are adverse events associated with high dose and long term bisphosphonate and denosumab treatment regimens of bone metastases and may rarely occur in low dose indications like osteoporosis. Both bisphosphonates and denosumab as strong antiresorptive agents are obvious risk factors besides others which favor destruction/ alterations of infection barriers and impairment of tissue regeneration. Mechanical injury during nutrition or due to oral surgery as well as treatment associated factors during chemotherapy destroy the epithelial barrier, which is followed by destruction of cells active in various lines of defense against infection, e. g. the innate immune system (monocytes/ macrophages and granulocytes) and the adaptive immune system (T-and B-cells). Osteoclasts which remove bone detritus are impaired, as are osteoblast precursors and endothelial cells, being the sources of bone regeneration. Factors that can be exaggerated by bisphosphonates are induction of apoptosis in monocytes and osteoclasts and – given very high bisphosphonate concentrations can be achieved in the microenvironment – also osteoblastic, osteocytic, epithelial and endothelial cells can be forced into apoptosis. Chemotherapeutic and immunosuppressive compounds clearly influence the cells of the adaptive immune system. In conclusion osteonecrosis of the jaw appears to be a multifaceted disease which is only partly, but substantially propagated by antiresorptives like bisphosphonates and denosumab. Clearly further research is needed to unravel questions like to what extend the developmental biology of bone derived from the neural crest confers a special susceptibility to the disease or if the preference for maxillary bone simply is due to their comparably high exposure to bacteria and fungi in the context of severely impaired immune and repair functions.

Schlüsselwörter

Knochenstoffwechsel - Osteonekrose - antiresorptive Therapie - Bisphosphonate - Denosumab

Keywords

Bone turnover - osteonecrosis - anti resorptive therapy - bisphosphonates - Denosumab
 

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