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Using a sequential in vitro/in vivo approach, we tested the ability of botanical extracts to influence biomarkers associated with bone resorption and bone formation. Pomegranate fruit and grape seed extracts were found to exhibit anti-resorptive activity by inhibiting receptor activator of nuclear factor-κB ligand (RANKL) expression in MG-63 cells and to reduce IL-1β-stimulated calvarial 45Ca loss. A combination of pomegranate fruit and grape seed extracts were shown to be effective at inhibiting bone loss in ovariectomised rats as demonstrated by standard histomorphometry, biomechanical and bone mineral density measurements. Quercetin and licorice extract exhibited bone formation activity as measured by bone morphogenetic protein-2 (BMP-2) promoter activation, increased expression of BMP-2 mRNA and protein levels, and promotion of bone growth in cultured mouse calvariae. A combination of quercetin and licorice extract demonstrated a potential for increasing bone mineral density in an intact female rat model as compared with controls. The results from this sequential in vitro/in vivo research model yielded botanical extract formulas that demonstrate significant potential benefits for bone health.