Biphasic Effects of Genistein on Bone Tissue in the Ovariectomized, Lactating Rat Model

Abstract

The ovariectomized (OVX), lactating rat model has been used to investigate the skeletal effects of the plant estrogen, genistein, over a 14-day period. The OVX, lactating rat on a low-calcium diet loses slightly more than 50% of its bone mineral mass during the first 2 weeks of lactation, and we have demonstrated that estrogen treatment can significantly reduce the loss of femoral mass (ash weight). Following OVX, the rats were assigned to treatment or control groups (both placebo and positive control with estrogen replacement). The treatment groups received one of three doses of a genistein-rich preparation each day via the feed for 2 weeks, after which time the pups began to have an interest in solid feed. A positive control group received conjugated estrogen in the feed. The genistein doses were: low (0.5 mg/d); intermediate (1.6 mg/d); and high (5.0 mg/d). Measurements included ash weights of the femur, scanning electron microscopy (SEM) of the proximal tibia, and uterine weights. SEM results were as follows: (1) at the low dose genistein was approximately equally effective to estrogen in the retention of cancellous bone tissue, as reflected in the number and density of trabeculae in hemisections of the tibial subepiphyseal region, but at high doses genistein was less effective; and (2) rats treated with low-dose genistein, like estradiol, had rougher endosteal surfaces and smaller pores on these surfaces than untreated control rats. Mean ash weights of the entire femur were highest in the rats treated with the low dose compared to control rats (P < 0.05), and they were higher than ash weights of rats administered the intermediate or high doses of genistein. The mean ash weights of the femurs were consistent with the genistein effects on the tibias observed by SEM. In summary, a biphasic response to the genistein preparation was found in this OVX rat model. Interpretation of the results suggests that, at the low dose, genistein appears to be an agonist at the estrogen receptor locus, whereas at higher doses the genistein is less effective and may even have adverse effects on bone cells. These findings of a biphasic effect of genistein (i.e., an inverted U effect) are consistent with those of other recent reports in the literature on isolated bone cells and on reproductive tissues. In summary, lower doses of genistein from soy foods would be expected to act similarly to estrogens with a beneficial effect on bone tissue, but at high doses that are unlikely to be consumed in human diets, this soy derivative may have potentially adverse effects on bone cell functions and thereby on bone tissue.

Age-dependent variations of cancellous bone in response to ovariectomy in C57BL/6J mice

“…The ovariectomy (OVX) rat is the most commonly used animal model for evaluating the mechanisms underlying postmenopausal osteoporosis and therapeutic strategies for treating this disease (6)(7)(8)(9). However, compared with rats, mice may be a more effective model as they have a more easily manipulated genome and lower drug doses are required for treatment.…”

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.…”

Health potential of soy isoflavones for menopausal women

“…All three of the studies incorporated the phyto-oestrogencontaining preparation into the diet; however, the doses used are difficult to compare. The phytooestrogen content was not determined in the soy protein isolate in the Arjmandi et al 46 study, and the phyto-oestrogen preparation used by Anderson et al 47 was only partially purified.…”

“…Studies from three different laboratories using OVX rats have shown that treatment with the isoflavones present in soy, either unpurified 46 , partially purified 47 or purified 48 (as genistein) exerted significant improvement in bone mass and approximately the same per cent retention, which may approach the gain from treatment with replacement doses of oestradiol (Fig. 6).…”

“…Blair et al 48 used purified genistein at a single high dose. Only the study by Anderson et al 47 used more than one dose, and they reported that the lowest dose was the most effective, with less effect at the two higher doses, i.e. a biphasic response.…”