2 relation between phytoestrogens and osteoporosis risk was generated from observations of signiﬁcantly lower numbers of hip fractures in Asian women, relative to Caucasian women [6]. Numerous observational studies relating soy intake of pre- and postmenopausal women to BMD have generally reported signiﬁcant positive associations [7], with only some studies reporting no association [8]. Some studies assessing BMD have found positive eﬀects of soy and soy isoﬂavones speciﬁcally on BMD of the lumbar spine [8]. Studies assessing biomarkers of bone formation and resorption have been less consistent, with some reporting beneﬁcial eﬀects with respect to bone health [9] while others have reported no signiﬁcant eﬀects [10] or eﬀects too small to be of clinical relevance [11]. Selective estrogen receptor modulators (SERMs), for example, raloxiﬁne have been shown to be eﬀective in preventing bone loss or increasing bone mass. SERMs are a group of chemically diverse non-steroidal compounds that bind to and interact with the estrogen receptors. Soy isoﬂavones, have been characterized as naturally occurring SERMs with similar beneﬁcial eﬀects to raloxifene on bone without its side eﬀects [12]. This paper focuses on the role of soy protein and soy phytoestrogens, especially, isoﬂavones as well as the synthetic isoﬂavone—ipriﬂavone on the prevention and management of osteoporosis. 2. Dietary Sources of Isoﬂavonoids and Their Biopotency Isoﬂavonoids from legumes, including genistein 2 and daidzein, are the most studied phytoestrogens. They can exist 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]. Although isoﬂavones are non-steroidal compounds, they are structurally similar to naturally occurring estrogens, syn- thetic estrogens and anti-estrogens. The structural similarity of phytoestrogens to endogenous estrogens has prompted the hypothesis that phytoestrogens exert hormonal or anti- hormonal eﬀects relevant to the risk of hormone-dependent disease and/or their suitability as a dietary alternative to hormone replacement therapy. Isoﬂavones are found in highest amounts in soybeans and soy foods, although they are also present in other beans and legumes. Soy foods generally contain 1.2–3.3 mg isoﬂavones/g dry weight, with the precise amount depending on numerous factors, including the type of soy food [14, 15] as well as soybean variety, harvest year and geographical location [14, 15]. Table 1 below shows the dietary sources of isoﬂavones. Studies have estimated typical isoﬂavone intakes to be 30–50 mg/day for Asians [14, 15] and less than 1 mg/day for postmenopausal women living in the USA [16]. The plasma concentrations of genistein 2 have been found to range from 0.1–10 mM in the Asian population [17]. The major isoﬂavones present in soy foods include genistein and daidzein and, to a lesser extent, glycitein. Genistein and daidzein are derived from genistin and daidzin Journal of Osteoporosis Table 1: Isoﬂavonoid content of selected legumes and soy-based foods [16]. Food Soy-based infant formula Soy milk Soybeans, mature Tofu Beans Chick peas Genistein 2 (mg/100 g) 1.6–15 1.1–11.3 1.1–150 5.0–42.1 0.007–0.5 0.07–0.2 ∗Including formomonetin and biochanin. Daidzein (mg/100 g) 0.8–9.7 1.1–9.8 0.5–91 0.6–25.6 0.008–0.04 0.01–0.2 Total isoﬂavonoids (mg/100 g)∗ 2.6–31 1.3–21 1.7–221 3.6–67.5 0.015–0.5 1.1–3.6 as the result of the action of gut microﬂora. They occur in soy conjugated to sugar moieties as glycosides, termed genistin, daidzin and glycitin. Genistein 2 has one-third the potency of estradiol 1 when it interacts with estrogen receptor-β (ERβ), and one thousandth of the potency of estradiol 1 when it interacts with ERα. Genistein 2 can induce similar responses in breast, ovarian, endometrial, prostate, vascular, and bone tissues and cell lines as estradiol 1 [18, 19]. Although fermentation of soy can reduce the amount of isoﬂavonoids present by a factor of 2-3 [15, 16], bioavail- ability of isoﬂavonoids is higher in fermented products, so urinary excretion rates are similar for people consuming fermented and unfermented products. Even though genistein 2 has relatively low potency compared to estradiol 1, high concentrations in plasma may be suﬃcient to cause a variety of physiological eﬀects. 3. Bone-Modulating Effects of Soy Protein and Soy Isoﬂavones Estrogen plays an important role in maintaining bone density by regulating the formation and resorption of bone [20]. Since lower circulating estradiol-1 levels are found during menopause, calcium is lost from the bone into blood plasma, leading to osteoporosis [21]. One of the aims of hormone replacement therapy (HRT) is to prevent or lower the incidence of osteoporosis in postmenopausal women. Prior to the turn of the twentieth century it was assumed that estrogens were exclusively produced by animals. How- ever, the principle that plants can also produce estrogen- like molecules was established by 1966 [22]. Now, it is recognized that certain plants and plant products contain phytoestrogens. One group of such compounds reported to have estrogenic activity is the ﬂavonoids [23, 24]. Flavonoids are a large chemical class that are formed through the phenylpropanoid-acetate biodemial pathway via chalcone synthase and condensation reactions with malonyl CoA. Isoﬂavonoids are a subclass of ﬂavonoids, where one phenolic ring has migrated from C-3 to C-2. The isoﬂavonoids from legumes, including genistein 2 and daidzein, are the most studied phytoestrogens. They can exist