Journal of Osteoporosis as glucosides or as aglycones, the glucosides being readily hydrolyzed in the gut to their aglycones. The aglycones are easily transported across intestinal epithelial cells [13]. Genistein 2 has one-third the potency of estradiol 1 when it interacts with ERβ, and one thousandth of the potency of estradiol 1 when it interacts with ERβ as determined by expression of luciferase reporter gene construct in kidney cells that had been cotransfected with ERα and ERβ [25]. Genistein 2 can induce similar responses in breast, ovarian, endometrial, prostate, vascular, and bone tissues and cell lines as estradiol-1 [19, 26]. Genistein 2 can act as an estrogen antagonist in some tissues. Soy isoﬂavones have an inﬂuence not only on sex hor- mone metabolism, but also possess other biological activities including cholesterol-lowering properties, anti-carcinogenic eﬀects and more recently their protective role in bone health [27, 28]. Results of many studies on the protective role of soy protein, its isoﬂavones, or their combination on bone in ovarian hormone deﬁcient models of osteoporosis are inconsistent. In these studies, the rate of bone formation and bone resorption, as assessed by biochemical markers are unchanged, decreased, or increased. Analogous to animal ﬁndings, the eﬀect of soy and its isoﬂavones on bone in humans are also conﬂicting. Furthermore, it is not clear whether the bone protective eﬀect of soy protein is due to its amino acid composition [29], nonprotein constituents such as isoﬂavones [30, 31], or a combination of these factors [31]. Animal studies using the ovariectomized rat model per- formed by Arjmandi et al. [30] showed that the soy diet with isoﬂavones was more eﬀective in preventing ovariectomy- induced loss of bone density than either the casein or the soy protein, depleted of its isoﬂavones, diet. Using an osteopenic rat model, Arjmandi et al. [31] demonstrated a slight reversal of the ovarian hormone deﬁciency-induced loss of bone with soy protein diets with either normal or reduced isoaﬂvone content. Although animal ﬁndings [30, 31], so far, indicate the importance of isoﬂavones in preserving bone, it is still not clear whether isoﬂavones can exert similar bone protective eﬀects independently of soy protein. Findings by Picherit et al. [32] support the bone protective role of isoﬂavones independent of soy protein. These authors reported that isoﬂavones dose-dependently prevented ovariectomy-induced bone loss in a rat model. However, the same group of investigators did not ﬁnd similar beneﬁcial eﬀects of isoﬂavones in reversing bone loss in ovariectomized osteopenic rats [33], even though the rate of bone turnover was reduced. Hence, one can speculate that a longer treatment period with isoﬂavones would have reversed bone loss. Whether the magnitude of eﬀects of isoﬂavones on bone in these animal studies by Picherit [32, 33] would have been greater had isoﬂavones been given in conjunction with soy protein still remains to be answered? On the other hand, studies investigating the eﬀects of individual soy isoﬂavones, genistin and daidzin, support the important role of these naturally occurring compounds in bone health regardless of the dietary protein source. For instance, two weeks of a genistin-rich treatment (1.0 mg/day) in lactating ovariectomized rats was eﬀective in maintaining 3 trabecular bone tissue in comparison with ovariectomized control animals [34]. Furthermore, in the same report, genistin stimulated alkaline phosphatase activity of an osteoblast-like cell line, suggesting a positive eﬀect on bone formation. In another study, Fanti et al. [35] reported that genistein (5 mg/kg body weight) maintained both cortical and trabecular bones in ovariectomized rats, and the bone- sparing eﬀect of genistein appeared to be biphasic. Although it is believed that genistin is the most potent of all the soy isoﬂavones, study by Picherit et al. [36] reported that daidzin, is more eﬃcient than genistin in preventing the ovariectomy-induced increase in bone turnover and decrease in bone mineral density. Clearly, this demonstrates that there are uncertainties as to which isoﬂavone plays a more important role in skeletal health. Use of a single isoﬂavone may not necessarily be the approach to be taken and future studies should address whether the combination of isoﬂavones exerts a more pronounced eﬀect on bone. To study the relation between soy isoﬂavone intake and bone mineral density (BMD), Greendale et al. [37] analyzed baseline data from the Study of Women’s Health Across the Nation, a US community-based cohort study of women aged 42–52 years. Their 1996-1997 analysis included African- American (n = 497), Caucasian (n = 1,003), Chinese (n = 200), and Japanese (n = 227) participants. Genistein and daidzein intakes were highly correlated (r = 0.98); therefore, analyses were conducted by using genistein. Median intakes of genistein (measured in micrograms/day) by African Americans and Caucasians were too low to pursue relational analyses further. For Chinese and Japanese women, median genistein intakes were 3,511 and 7,151 μg/day, respectively. Ethnic-speciﬁc, linear models were used to predict BMD as a function of energy-adjusted tertile of intake, controlled for relevant covariates. For Chinese women, no association between genistein and BMD was found. Premenopausal, but not perimenopausal, Japanese women whose intakes were greater had higher spine and femoral neck BMD. Adjusted mean spinal BMD of those in the highest tertile of intake was 7.7% greater than that of women in the lowest tertile (P = .02); femoral neck BMD was 12% greater in the highest versus the lowest tertile (P < .0001). Most of the studies suggest that Phytoestrogens are somewhat eﬀective in maintaining bone mineral density in postmenopausal women [38, 39]. A double blind placebo controlled study of postmenopausal women showed signif- icant increase in BMD at the femoral neck after 12 months of daily administration of 54 mg genistein, isolated from soy, although a signiﬁcant increase in osteocalcin and bone speciﬁc alkaline phosphatase (BAP) was also observed [39]. In contrast 17β-estradiol 1 increased BMD with a signiﬁcant decrease in osteocalcin and bone alkaline phospatase (BAP) levels [39]. In a 24-week study comparing isoﬂavone rich soy protein (80.4 mg aglycone isoﬂavones/day) and isoﬂavone poor soy protein (4.4 mg aglycone isoﬂavones/day) in perimenopausal women, both BMD and bone mineral content (BMC) were signiﬁcantly higher with the diet high in isoﬂavones [38]. There was no signiﬁcant change in the BMD or BMC of the lumbar spine over the 24 weeks for the women on either the