Clinical Oral Investigations

, Volume 21, Issue 3, pp 771–778 | Cite as

The influence of geranylgeraniol on microvessel sprouting after bisphosphonate substitution in an in vitro 3D-angiogenesis assay

  • A. M. PabstEmail author
  • M. Krüger
  • K. Sagheb
  • T. Ziebart
  • C. Jacobs
  • S. Blatt
  • E. Goetze
  • C. Walter
Original Article



Recent studies focused on angiogenesis in the pathophysiology of bisphosphonate-associated osteonecrosis of the jaws (BP-ONJ) and identified geranylgeraniol (GGOH) as a feasible option for BP-ONJ therapy. This study investigated the influence of GGOH on microvessel sprouting after BP-incubation in vitro.

Materials and methods

Ten experimental set-ups were randomly designed in an in vitro 3D-angiogenesis assay. Two groups included HUVEC cell spheroids with and without (±) GGOH substitution as controls and eight groups pairwise contained either clodronate or the nitrogen-containing bisphosphonates (N-BP) ibandronate, pamidronate, and zoledronate ± GGOH. The size of the cell spheroids including the outbranching sprouts (SpS) as well as the density (SpD) and length of the sprouts (SpL) were analyzed by a grid system after 0, 24, 48, and 72 h.


For controls and NN-BP clodronate, no significant differences at any tested parameter and any point of measurement could be detected within the experimental set-ups ± GGOH (p each ≥0.05). For N-BP ibandronate, the experimental set-ups +GGOH showed a significantly increased SpS, SpD, and SpL after 48 and 72 h (p each ≤0.002) compared to the experimental set-ups −GGOH. For N-BPs pamidronate and zoledronate, the experimental set-ups + GGOH demonstrated a significantly increased SpS, SpD, and SpL after 24, 48, and 72 h (p each ≤0.001) compared to the experimental set-ups −GGOH.


The strong negative influence of N-BPs on microvessel sprouting could be significantly reversed by GGOH.

Clinical relevance

Since supportive therapeutic options for BP-ONJ are lacking, GGOH might be a promising substitute for BP-ONJ prevention and therapy.


Bisphosphonate BP-ONJ Osteonecrosis Isoprenoid Geranylgeraniol Angiogenesis 



The authors give special thanks to Kathy Taylor for proof-reading and language checking.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


No fundings were received for this study. The work was supported by the Department of Oral and Maxillofacial Surgery, University Medical Center, Augustusplatz 2, 55131 Mainz, Germany.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this type of study, formal consent is not required.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • A. M. Pabst
    • 1
    • 2
    Email author
  • M. Krüger
    • 2
  • K. Sagheb
    • 2
  • T. Ziebart
    • 3
  • C. Jacobs
    • 4
  • S. Blatt
    • 2
  • E. Goetze
    • 2
  • C. Walter
    • 2
  1. 1.Department of Oral and Maxillofacial SurgeryFederal Armed Forces HospitalKoblenzGermany
  2. 2.Department of Oral and Maxillofacial SurgeryUniversity Medical CenterMainzGermany
  3. 3.Department of Oral and Maxillofacial SurgeryUniversity ClinicMarburgGermany
  4. 4.Department of OrthodonticsUniversity Medical CenterMainzGermany

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