The phytoestrogen genistein reduces bone loss in short-term ovariectomizedrats

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 phy toestrogen, or vehicle (Veh) and killed '1 days after surgery. As expected, ovariectomy resulted in loss of bone mineral density (BMD) and in uterine atrophy. However, administration of 5 mu g GEN per gram body weight (b.w.) ameliorated the ovariectomy-induced loss of BMD (189 +/- 2 mg/cm(2) in OVX and 192 +/- 2 in OVX with 5 mu g 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 mu g and 25 mu g GEN per gram body weight were statistically not differe nt. A trend toward reduced uterine atrophy (21% reduction) was noted with t he 25 mu g GEN dose, but not with the 1 mu g and 5 mu g doses. A separate e xperiment with 2 x 2 factorial design was conducted to elucidate the mechan ism by which GEN ameliorates ovariectomy-induced bone loss. fn this experim ent, 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 wi th 5 mu g GEN per gram per day (3.3 +/- 0.2% of total bone volume in OVX-Ve h 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 r esorption were not affected by GEN. The concentration of serum osteocalcin and the urinary excretion of deoxypyridinoline provided corroborating resul ts. Since production of proinflammatory cytokines is intimately involved in the pathogenesis of postmenopausal osteoporosis, the effect of GEN on lips polysaccharide-induced in vitro production of Tumor necrosis factor-alpha ( TNF alpha) was tested in monocytic cells from the same four rat groups. Pro duction 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 mts. This study shows that GEN reduces both trabecular and compact bone loss after ovariectomy a nd that this protective effect differs from that of estrogen, since it depe nds on stimulation of bone formation rather than on suppression of bone res orption. Lack of action of GEN on uterine atrophy supports the possibility that this GEN dose affects target tissues via non-estrogenic mechanisms. Mo dulation of cytokine production may be involved in the effect of GEN on bon e.