Benzylideneacetone Derivatives Inhibit Osteoclastogenesis and Activate Osteoblastogenesis Independently Based on Specific Structure–Activity Relationship

(E)-3,4-Dihydroxybenzylidene­acetone (compound 1) inhibited receptor activator of NF-κB ligand-induced
osteoclastogenesis of C57BL/6 bone marrow monocyte/macrophages with
IC50 of 7.8 μM (IC50 of alendronate, 3.7
μM) while stimulating the differentiation of MC3T3-E1 osteoblastic
cells, accompanied by the induction of Runt-related transcription
factor 2, alkaline phosphatase, and osteocalcin. (E)-4-(3-Hydroxy-4-methoxyphenyl)-3-buten-2-one (compound 2c) showed a dramatically increased osteoclast-inhibitory potency with
IC50 of 0.11 μM while sustaining osteoblast-stimulatory
activity. (E)-4-(4-Hydroxy-3-methoxyphenyl)-3-buten-2-one
(compound 2g) stimulated alkaline phosphatase production
2-fold at 50 μM without changing osteoclast-inhibitory activity,
compared with compound 1. Oral administration of compounds 1, 2c, and 2g prevented ovariectomy-induced
osteoporosis in ddY mice to a degree proportional to their osteoclastogenesis-inhibitory
potencies. The administration of 1 (mg/kg)/d compound 2c ameliorated histomorphometry of osteoporotic bone to a degree comparable
with 10 (mg/kg)/d alendronate. Conclusively, the in vitro capacity
of a few benzylideneacetone derivatives to inhibit osteoclastogenesis
supported by independent osteoblastogenesis activation was convincingly
reflected in in vivo management of osteoporosis, suggesting a potential
novel therapeutics for osteopenic diseases.