Caco-2 cells responded to genistein and daidzein similarly to 17β-estrogen with no effect on calbindinD9k, an intestinal Ca transport protein [43]. Furthermore, increasing levels of soy isoflavones had no effect on Ca absorption in postmenopausal women [44,45].
On the other hand, it has been shown that isoflavones reach the bone tissue [46]. Low-dose daidzein induced nucleus ERβ, while 17β-estrogen increased ERα in young piglet bone cells [47]. Genistein also increased ERβ expression in rat mandibular subchondrial bone [41]. By binding to ERβ in osteoblastic cells in vitro, phytoestrogens induce production of osteoprotegerin (OPG). OPG competes with RANKL and prevents maturation of pre-osteoclasts and thus, resorption [48]. In piglets, daidzein increased osteoblast differentiation, secretion of OPG and RANKL, and bone mineralization more potently than the same dose of 17β-estrogen [47]. In porcine bone marrow, daidzein suppressed 1,25(OH)2D-induced TRAP-positive multi-nucleated cell formation, decreased resorption activity, and increased ER expression and apoptosis through caspase-8 and caspase-3 fragmentation in mono-nucleated cells [49]. In humans, genistein supplementation for 1 and 2 years in osteopenic post-menopausal women resulted in a greater decrease in soluble RANKL/OPG by increasing OPG and decreasing soluble RANKL [50]. These evidences imply that genistein and daidzein induce ERβ transcription and binding and reduce mature osteoclastogenesis, and hence bone resorption.