TABLE 3.

The effects of GGOH on osteoblasts.

GGOH alone
Authors (years)	Study design	Major findings
Yoshida et al. (2009)	MC3T3-E1 pre-osteoblastic cells were cultured with GGOH with geranylgeranyl transferase I inhibitor in serum-deprived media	GGOH (10−5 M) ↓ caspase-3 activity and cell death induced by geranylgeranyl transferase I inhibitor but not Rho kinase inhibitor
Hagelauer et al. (2015)	Commercialised human osteogenic cells treated with zoledronate, GGOH, farnesol or other isoprenoids	GGOH alone: High dose (5 × 10−5–1 × 10−4 M) ↓ cell viability, no effects on migration (10−5–10−4 M)
GGOH in the presence of BPs
Still et al. (2003)	Bone marrow cells from Wistar rats were harvested and incubated with various bisphosphonates and with or without GGOH.	GGOH (10−3 M) ↑ colony formation in culture exposed/unexposed to suppressed by alendronate (10−5 M) and risedronate (10−5 M)
Ziebert et al. (2011)	Commercially available human osteogenic cells cultured with BPs with or without GGOH for 72 h. All BP at 5 × 10−5 M, GGOH at ×10−5 M	GGOH ↑ the viability suppressed by ibandronate, pamidronate, zoledronate
		GGOH ↑ cell migration suppressed by zoledronate
		GGOH reversed cytoskeletal distortion in all cells caused by ibandronate, pamidronate, zoledronate
Hagelauer et al. (2015)	Commercialised human osteogenic cells treated with zoledronate, GGOH, farnesol or other isoprenoids	GGOH alone: High dose (5 × 10−5–1 × 10−4 M) ↓ cell viability, no effects on migration (10−5–10−4 M)
		GGOH + zoledronate: ↑ cell viability and migration suppressed by zoledronate acid at all concentrations (10−5–10−4 M)
		GGOH reverses destructive cellular morphology induced by zoledronate
		Other isoprenoids including farnesol show no similar antagonism
Zafar et al. (2016)	Human osteoblasts from the mandibular alveolar bone of three healthy women were cultured with zoledronate and geranylgeraniol for 72 h	GGOH (5 × 10−5 M) ↑ cell viability, migration, nodule formation suppressed by zoledronate
		GGOH preserves cell morphology in cells exposed to zoledronate
Fliefel et al. (2019)	Commercialised human osteoblasts treated with zoledronate (1 × 10−7, 2.5 × 10−5, 1 × 10−4 M) and GGOH (1 × 10−5–8 × 10−5 M) for 7 days	GGOH alone ↑ cell viability at low doses (1 × 10−5–4 × 10−5 M), ↓ it at high dose (8 × 10−5 M) with or without zoledronate
		GGOH ↑ Rap1A/B protein expression suppressed by zoledronate
Fliefel et al. (2020)	Commercialised human mesenchymal stem cells were treated with zoledronate, GGOH or both for 7 days	At high dose (8 × 10−5 M), GGOH alone or with zoledronate at high dose ↓ cell viability
		At low dose (1 × 10−5–4 × 10−5 M), GGOH ↑ cell viability suppressed by zoledronate
Mungpayabarn and Patntirapong (2021)	MC3T3 cells were treated with alendronate (10−5 M) and GGOH (5 × 10−5 M)	GGOH added at early time points ↑ mineralisation suppressed by alendronate
		GGOH preserves cellular morphology in cells exposed to GGOH
		GGOH ↑ FGF2, VEGF, VEGFR2, COL1, OPN expressions in cells exposed to alendronate. OPN and VEGF upregulations are sustained for up to 7 days
Patntirapong et al. (2021)	MC3T3-E1 was treated with alendronate (5 × 10−6, 1 × 10−5, 5 × 10−5 M) and GGOH (1 × 10−5, 5 × 10−5 M)	GGOH alone did not affect cell viability but ↑ viability and ↓ apoptosis in cells exposed to alendronate
		GGOH relieves G2/M phase accumulation due to alendronate
		GGOH preserves actin stress fibre and destructive cell morphology caused by alendronate
		GGOH alone or with alendronate ↑ mineralisation
Singhatanadgit et al. (2021)	Commercialised human mesenchymal stem cells were cultured with zoledronate (0–5 × 10−5 M) with or without GGOH (0–10−4 M)	GGOH ↑ viability, mineralisation and ↓ cell cycle arrest through reactivation of Rho and YAP in mesenchymal stem cells exposed to zoledronate

Abbreviation↓, decrease; ↑, increase; COL1, type I collagen; GGOH, geranylgeraniol; FGF2, fibroblast growth factor-2; OPN, osteopontin; VEGF, vascular endothelial growth factor; VEGFR2, vascular endothelial growth factor receptor 2.