The Phytoestrogen Genistein Reduces Bone Loss in Short-Term Ovariectomized Rats

Abstract

The incidence of fractures and of osteoporosis differs between Oriental and Western Caucasian women. This may depend, at least in part, on nutritional factors, including dissimilarities in dietary intake of phytoestrogens. To investigate this possibility, 2-month-old female rats were ovariectomized (OVX) or sham-operated (SHAM), fed a casein-based diet, injected daily with subcutaneous genistein (GEN), the most abundant and best characterized phytoestrogen, or vehicle (Veh) and killed 21 days after surgery. As expected, ovariectomy resulted in loss of bone mineral density (BMD) and in uterine atrophy. However, administration of 5 micrograms GEN per gram body weight (b.w.) ameliorated the ovariectomy-induced loss of BMD (189 +/- 2 mg/cm2 in OVX and 192 +/- 2 in OVX with 5 micrograms GEN/g b.w. per day; p < 0.05). One microgram GEN per gram body weight did not affect the BMD loss and the effect of the 5 micrograms and 25 micrograms GEN per gram body weight were statistically not different. A trend toward reduced uterine atrophy (21% reduction) was noted with the 25 micrograms GEN dose, but not with the 1 microgram and 5 micrograms doses. A separate experiment with 2 x 2 factorial design was conducted to elucidate the mechanism by which GEN ameliorates ovariectomy-induced bone loss. In this experiment, histomorphometry demonstrated a dramatic reduction in trabecular bone volume after ovariectomy (7.6 +/- 0.7% of total bone volume in SHAM-Veh vs 3.3 +/- 0.2% in OVX-Veh; p < 0.01) and less bone loss in OVX rats injected with 5 micrograms GEN per gram per day (3.3 +/- 0.2% of total bone volume in OVX-Veh vs 5.2 +/- 0.4% in OVX-GEN; p < 0.01). Administration of GEN was associated with higher bone formation rate per tissue volume and with a trend toward a higher number of osteoblasts per bone perimeter. The parameters of bone resorption were not affected by GEN. The concentration of serum osteocalcin and the urinary excretion of deoxypyridinoline provided corroborating results. Since production of proinflammatory cytokines is intimately involved in the pathogenesis of postmenopausal osteoporosis, the effect of GEN on lipopolysaccharide-induced in vitro production of Tumor necrosis factor-alpha (TNF alpha) was tested in monocytic cells from the same four rat groups. Production of TNF alpha was markedly elevated in OVX-Veh as compared with the SHAM-Veh rats, but this was blocked by GEN in the OVX rats. This study shows that GEN reduces both trabecular and compact bone loss after ovariectomy and that this protective effect differs from that of estrogen, since it depends on stimulation of bone formation rather than on suppression of bone resorption. Lack of action of GEN on uterine atrophy supports the possibility that this GEN dose affects target tissues via non-estrogenic mechanisms. Modulation of cytokine production may be involved in the effect of GEN on bone.

Bariatric surgery and bone disease: from clinical perspective to molecular insights

“…Estrogen acts through a variety of mechanisms to suppress bone resorption and increase bone formation. 64,112 As weight decreases and adipose stores are depleted, the levels of estrogen decrease in both men and women resulting in decreased impact of estrogen on bone. Estrogen may also affect bone metabolism by direct effects on vitamin D and calcium metabolism.…”

Design, Synthesis, and Osteogenic Activity of Daidzein Analogs on Human Mesenchymal Stem Cells

“…11 Recent studies have demonstrated that ovariectomyinduced bone loss in rats is rescued with the delivery of the isoflavones daidzein and genistein. 9,10 Epidemiological studies in humans have shown that high dietary phytoestrogen intake is associated with higher bone mineral density in postmenopausal women. 12 Daidzein is a potent estrogenic compound that has a beneficial effect on bone health, 11,12 but its clinical potential is limited by its low bioavailability, unfavorable metabolism, and uterine estrogenicity.…”

Evaluation of the Preventive Effect of Isoflavone Extract on Bone Loss in Ovariectomized Rats

“…16) There are several reports that genistein inhibits osteoclastic activity and can reduce bone loss in ovariectomized rats. 9,[17][18][19] Moreover, it has been found that genistein has an anabolic effect on bone formation and mineralization by cultured bone cells. 15,20) Genistein also inhibits bone resorption in femoral metaphyseal tissues obtained from elderly rats in vitro.…”