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

Clin Oral Investig. 2017 Apr;21(3):771-778. doi: 10.1007/s00784-016-1842-z. Epub 2016 May 12.


Objectives: 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.

Results: 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.

Conclusions: 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.

Keywords: Angiogenesis; BP-ONJ; Bisphosphonate; Geranylgeraniol; Isoprenoid; Osteonecrosis.

MeSH terms

  • Bisphosphonate-Associated Osteonecrosis of the Jaw / drug therapy*
  • Bone Density Conservation Agents / adverse effects*
  • Bone Density Conservation Agents / pharmacology*
  • Diphosphonates / adverse effects*
  • Diphosphonates / pharmacology*
  • Diterpenes / pharmacology*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • In Vitro Techniques
  • Microvessels / drug effects*
  • Neovascularization, Pathologic / drug therapy*


  • Bone Density Conservation Agents
  • Diphosphonates
  • Diterpenes
  • geranylgeraniol