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Dietary phyto-oestrogens and bone health

Published online by Cambridge University Press:  07 March 2007

Francesco Branca
Francesco Branca*
Affiliation:
Istituto Nazionale di Ricerca per gli Alimenti e la Nutrizione (INRAN), Via Ardeatina 546, 00178, Rome, Italy
*
Corresponding author: Professor Francesco Branca, fax+39 06 51494 550, email F. Branca@agora.it
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Abstract

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The use of dietary phyto-oestrogens as a possible option for the prevention of osteoporosis has raised considerable interest because of the increased concern about the risks associated with the use of hormone-replacement therapy. However, the evidence in support of a bone-sparing effect in post-menopausal women is still not sufficiently convincing. Most studies have been performed on soyabean isoflavones (genistein and daidzein), either in the purified form or as a soyabean-based product or extract. In vitro studies using primary cell cultures or stabilised cell lines indicate that treatment with genistein may lead to a reduction in bone resorption, but effects on bone formation have also been shown. Investigations using animal models have provided convincing evidence of major improvements in bone mass or bone turnover following soyabean feeding. Cross-sectional observations in South-East Asian populations with moderately high intakes of soyabean isoflavones (50 mg/d) have shown that women in the high quartile of intake have higher bone mineral density (BMD) and reduced bone turnover, an effect that has not been shown in populations with low average intakes. Human trials have given an indication of a possible effect on lumbar spine BMD, although they have been either short term (<6 months) or methodologically weak. Unresolved issues are: the optimal dose compatible with safety; the individual differences in response that can be related to diet and genotypes; the duration of exposure. Furthermore, there needs to be an evaluation of the relative biological effects of phyto-oestrogens other than isoflavones (lignans, resorcylic acid lactones, flavanols, coumestans) that are also present in European diets.

Keywords

Phyto-oestrogensOsteoporosisSoyabean
Type
Meeting Report
Information
Proceedings of the Nutrition Society , Volume 62 , Issue 4 , November 2003 , pp. 877 - 887
Copyright
Copyright © The Nutrition Society 2003

References

Alekel, DL, Germain, AS, Peterson, CT, Hanson, KB, Steward, JW & Toda, T (2000) Isoflavone-rich soy protein isolate attenuate bone loss in the lumbar spine of perimenopausal women. American Journal of Clinical Nutrition 72, 844–852.CrossRefGoogle ScholarPubMed
Anderson, JJB, Adlercreutz, H, Barnes, S, Bennink, MR, Clarkson, T, Jeffrey, E, Kurzer, MS, Murphy, P, Setchell, K, Weaver, CM & Hasler, CM (2000) Appropriate isoflavone food fortification levels: results of a consensus conference. Experimental Biology 2000, San Diego, CA: Publishers?Google Scholar
Batra, GS, Hainey, L, Freemont, AJ, Andrew, G, Saunders, PTK, Hoyland, JA & Braidman, IP (2003) Evidence for cell-specific changes with age in expression of oestrogen receptor (ER) α and β in bone fractures from men and women. Journal of Pathology 200, 65–73.CrossRefGoogle ScholarPubMed
Berrino, F, Secreto, G, Bellati, C, Camerini, E, Pala, V, Panico, S, Allegro, G & Kaaks, R (2001) Reducing bio-available sex hormones through a comprehensive change in dietary composition: the DIANA randomised trial. Cancer Epidemiology Biomarkers and Prevention 10, 25–33.Google Scholar
Bonnelye, E, Kung, V, Laplace, C, Galson, DL & Aubin, JE (2002) Estrogen receptor-related receptor α impinges on the estrogen axis in bone: potential function in osteoporosis. Endocrinology 143, 3658–3670.CrossRefGoogle ScholarPubMed
Braidman, IP, Davenport, LK, Carter, DH, Selby, PL, Mawer, EB & Freemont, AJ (1995) Preliminary in-situ identification of estrogen target cells in bone. Journal of Bone and Mineral Research 10, 74–80.CrossRefGoogle ScholarPubMed
Braidman, IP, Hainey, L, Batra, G, Selby, PL, Saunders, PTK & Hoyland, JA (2001) Localization of estrogen receptor beta protein expression in adult human bone. Journal of Bone and Mineral Research 16, 214–220.CrossRefGoogle ScholarPubMed
Camper-Kirby, D, Welch, S, Walker, A, Shiraishi, I, Setchell, KDR, Schaefer, E, Kajstura, J, Anversa, P & Sussman, MA (2001) Myocardial Akt activation and gender increased nuclear activity in females versus males. Circulation Research 88, 1020–1027.Google Scholar
Chiechi, LM, Secreto, G, D'Amore, M, Fanelli, M, Venturelli, E, Cantatore, F, Valerio, T, Laselva, G & Loizzi, P (2002) Efficacy of a soy rich diet in preventing postmenopausal osteoporosis: the Menfis ranomised trial. Maturitas 42, 295–300.Google Scholar
Clifton-Bligh, PB, Barber, RJ, Fulcher, GR, Nery, ML & Moreton, T (2001) The effect of isoflavones extracted from red clover (Rimostril) on lipid and bone metabolism. Menopause 8, 259–265.Google Scholar
Cotroneo, MS, Wang, J, Eltoum, IA & Lamartiniere, CA (2001) Sex steroid receptor regulation by genistein in the prepubertal rat uterus. Molecular and Cellular Endocrinology 173, 135–145.Google Scholar
Coxam, V (2003) Prevention of osteopaenia by phyto-oestrogens: animal studies. British Journal of Nutrition 89, Suppl. 1, S75–S85.Google Scholar
Dalais, FS, Rice, GE, Wahlqvist, ML, Grehan, M, Murkies, AL, Medley, G, Ayton, R & Strauss, BJ (1998) Effects of dietary phytoestrogens in postmenopausal women. Climacteric 1, 124–129.Google Scholar
Di Leo, C, Tarolo, GL, Bestetti, A, Tagliabue, L, Del Sole, A, Aliberti, G, Cestaro, B & Pepe, L (2000) Osteoporosi e fitoestrogeni: valutazione della densita minerale ossea mediante Tomografia Computerizzata quantitativa periferica nelle donne lattoovovegetariane nella premenopausa (Osteoporosis and phytoestrogens: an assessment of bone mineral density via quantitative peripheral computed tomography in milk-egg-vegetarian women in the premenopause). Radiologica Medica (Torino) 99, 250–257.Google Scholar
Eden, JA (1998) Phytoestrogen study design. Climacteric 1, 243–244.Google ScholarPubMed
Food and Drug Administration (1994) Guidelines for Preclinical and Clinical Evaluation of Agents Used in the Prevention or Treatment of Postmenopausal Osteoporosis. Rockville, MD: FDA.Google Scholar
Food Standards Agency (2002) Report of the COT Working Group on Phytoestrogens; available at http://www.food.gov.uk/ multimedia/pdfs/phytoestrogenreport.pdfGoogle Scholar
Fotsis, T, Pepper, M, Adlercreutz, H, Fleischman, G, Hase, T, Montesano, R & Schweigerer, L (1993) Genistein, a dietaryderived inhibitor of in vitro angiogenesis. Proceedings of the National Academy of Sciences USA 90, 2690–2694.CrossRefGoogle ScholarPubMed
Frey, RS & Singletary, KW (2003) Genistein activates p38 mitogenactivated protein kinase, inactivates ERK1/ERK2 and decreases Cdc25C expression in immortalized human mammary epithelial cells. Journal of Nutrition 133, 226–231.CrossRefGoogle ScholarPubMed
Gao, YH & Yamaguchi, M (1999) Inhibitory effect of genistein on osteoclast-like cell formation in mouse marrow cultures. Biochemical Pharmacology 58, 767–772.Google Scholar
Greendale, GA, Fitzgerald, G, Huang, MH, Sternfeld, B, Gold, E, Seeman, T, Sherman, S & Sowers, M (2002) Dietary soy isoflavones and bone mineral density: results from the study of women's health across the nation. American Journal of Epidemiology 155, 746–754.Google Scholar
Guo, TL, McCay, JA, Zhang, LX, Brown, RD, You, L, Karrow, NA, Germolec, DR, Ehite, KL Jr (2001) Genistein modulates immune responses and increases host resistance to B16F10 tumor in adult female B6C3F1 mice. Journal of Nutrition 131, 3251–3258.CrossRefGoogle ScholarPubMed
Hall, JM, Couse, JF & Korach, KS (2001) The multifaceted mechanisms of estradiol and estrogen receptor signaling. Journal of Biological Chemistry 276, 36869–36872.CrossRefGoogle ScholarPubMed
Han, DH, Denison, MS, Tachibana, H & Yamada, K (2002) Relationship between estrogen receptor-binding and estrogenic activities of environmental estrogens and suppression by flavonoids. Bioscience Biotechnology Biochemistry 66, 1479–1487.CrossRefGoogle ScholarPubMed
Hegsted, M, Warner, S, Heaton, S, Bowman, B & Miller, SC (1999) Soy diet increases tibial cortical bone formation in ovariectomized retired breeder rats. Journal of Bone and Mineral Research 14, S531.Google Scholar
Hertog, MGL, Feskens, EJM & Kromhout, D (1997) Antioxidant flavonols and coronary heart disease risk: ten year follow-up of the Zutphen Elderly Study. Lancet 349, 699.Google Scholar
Ho, SC, Chan, SG, Yi, Q, Wong, E & Leung, PC (2001) Soy intake and the maintenance of peak bone mass in Hong Kong Chinese women. Journal of Bone and Mineral Research 16, 1363–1369.Google Scholar
Horcajada-Molteni, MN, Crespy, V, Coxam, V, Davicco, MJ, Remesy, C & Barlet, JP (2000) Rutine inhibits ovariectomy-induced osteopenia in rats. Journal of Bone and Mineral Research 15, 2251–2258.Google Scholar
Horiuchi, T, Onouchi, T, Takahashi, M, Ito, H & Orimo, H (2000) Effect of soy protein on bone metabolism in postmenopausal Japanese women. Osteoporosis International 11, 721–724.Google Scholar
Hsu, C-S, Shen, WW, Hsueh, YM & Yeh, SL (2001) Soy isoflavone supplementation in postmenopausal women. Journal of Reproductive Medicine 42, 221–226.Google Scholar
Hughes, DE, Dai, A, Tiffee, JC, Li, HH, Mundy, GR & Boyce, BF (1996) Estrogen promotes apoptosis of murine osteoclasts mediated by TGFβ. Nature Medicine 2, 1132–1136.CrossRefGoogle ScholarPubMed
Hunter, I, McGregor, DP, Robins, SP (2001) Caspase-dependent cleavage of cadherins and catenins during osteoblast apoptosis. Journal of Bone and Mineral Research 16, 466–477.Google Scholar
Ishida, H, Uesugi, T, Toda, T & Tsuji, K (2000) Effect of soy isoflavones, daidzein, genistein and glycitein on bone loss and lipid metabolic pathway in ovariectomized rats. Journal of Nutrition 130, Suppl., 685S.Google Scholar
Kardinaal, AFM, Morton, MS, Bruggermann-Rotgans, IEM & Van Beresteijn, ECH (1998) Phytoestrogen excretion and rate of bone loss in postmenopausal women. European Journal of Clinical Nutrition 52, 850–855.CrossRefGoogle ScholarPubMed
Kim, MK, Chung, BC, Yu, VY, Nam, JH, Lee, HC, Huh, KB & Lim, SK (2002) Relationships of urinary phyto-oestrogen excretion to BMD in postmenopausal women. Clinical Endocrinology 56, 321–328.CrossRefGoogle ScholarPubMed
Kritz-Silverstein, D & Goodman-Gruen, DL (2002) Usual dietary isoflavone intake, bone mineral density, and bone metabolism in postmenopausal women. Journal of Womens' Health and Gender Based Medicine 11, 69–78.CrossRefGoogle ScholarPubMed
Kuhnau, J (1976) The flavonoids: a class of semi-essential food components: their role in human nutrition. World Review of Nutrition and Dietetics 24, 117–191.Google Scholar
Kuiper, GGJM, Carlsson, B, Grandien, K, Enmark, E, Haggblad, J, Nilsson, S & Gustafsson, JA (1997) Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 138, 863–870.Google Scholar
Lamartiniere, CA, Cotroneo, MS, Fritz, WA, Wang, J, Mentor-Marcel, R & Elgavish, A (2002) Genistein chemoprevention: Timing and mechanisms of action in murine mammary and prostate. Journal of Nutrition 132, 552S–558S.CrossRefGoogle ScholarPubMed
Leth, T & Justesen, U (1998) Analysis of flavonoids in fruits, vegetables and beverages by HPCL-UV and LC-MS and estimation of the total daily flavonoid intake in Denmark. In Polyphenols in Food, pp. 39–40. [Amado, R, Andersson, H, Bardocz, S, Serra, S, editors]. Luxembourg: Official Publications of the European Communit.Google Scholar
Lieberherr, M, Cournot, G & Robins, SP (2003) Guidelines for using in vitro methods to study the effects of phyto-oestrogens on bone. British Journal of Nutrition 89, Suppl. 1, S59–S73.CrossRefGoogle Scholar
Lorenzetti, S, Germani, D, Farini, D, Paterno, A, Branca, F & Cianfarani, S (2002) Inhibitory effects of 17β-estradiol, phytoestrogens and IGF-I peptides on murine and human osteoclastogenesis. Hormone Research 58, Suppl. 2, 112.Google Scholar
Lucas, EA, Wild, RD, Hammond, LJ, Khalil, DA, Juma, S, Daggy, BP, Stoecker, BJ & Arjmandi, BH (2002) Flaxseed improves lipid profile without altering biomarkers of bone metabolism in postmenopausal women. Journal of Clinical Endocrinology and Metabolism 87, 1527–1532.Google Scholar
Lydeking-Olsen, E, Jensen, J-BE, Setchell, KDR, Damhus, M & Jensen, TH (2002) Isoflavone-rich soymilk prevents bone-loss in the lumbar spine of postmenopausal women. A 2 year study. Journal of Nutrition 132, 581S.Google Scholar
Matsukawa, Y, Marui, N, Sakai, T, Satomi, Y, Yoshida, M, Matsumoto, K, Nishino, H & Aoike, A (1993) Genistein arrests cell cycle progression at G2M. Cancer Research 53, 1328–1331.Google Scholar
Mazur, WM, Uehara, M, Wahala, K & Adlercreutz, H (2000) Phytooestrogen content of berries, and plasma concentrations and urinary excretion of enterolactone after a single strawberry-meal in human subjects. British Journal of Nutrition 83, 381–387.Google Scholar
Mei, J, Yeung, SSC & Kung, AWC (2001) High dietary phytoestrogen intake is associated with higher bone mineral density in postmenopausal but not premenopausal women. Journal of Clinical Endocrinology and Metabolism 86, 5217–5221.Google Scholar
Molteni & Coxam V (2001)Google Scholar
Morabito, N, Crisafulli, A, Vergara, C, Gaudio, A, Lasco, A, Frisina, N, D'Anna, R, Corrado, F, Pizzoleo, MA, Cincotta, M, Altavilla, D, Ientile, R & Squadrito, F (2002) Effects of genistein and hormonereplacement therapy on bone loss in early postmenopausal women: a randomized double-blind placebo-controlled study. Journal of Bone and Mineral Research 17, 1904–1911.Google Scholar
Morton, MS, Matos-Ferreira, A, Abranches-Monterio, L, Correia, R, Blacklock, N, Chan, PSF, Cheng, C, Lloyd, S, Chieh-Ping, W & Griffiths, K (1997) Measurement and metabolism of isoflavonoids and lignans in human male. Cancer Letters 114, 145–151.CrossRefGoogle ScholarPubMed
Murkies, AL, Lombard, C, Strauss, BJG, Wilcox, G, Burger, HG & Morton, MS (1995) Dietary flour supplementation decreases post-menopausal hot flushes: effect of soy and wheat. Maturitas 21, 189–195.CrossRefGoogle ScholarPubMed
Mühlbauer, RC & Li, F (1999) Effects of vegetables on bone metabolism. Nature 401, 343–344.Google Scholar
Nagata, C, Shimizu, H, Takami, R, Hayashi, M, Takeda, N & Yasuda, K (2002) Soy product intake and serum isoflavonoid and estradiol concentrations in relation to bone mineral density in postmenopausal Japanese women. Osteoporosis International 13, 200–204.CrossRefGoogle ScholarPubMed
National Institutes of Health (2000) National Institutes of Health Consensus Development Conference statement. Osteoporosis Prevention, Diagnosis, and Therapy, vol. 17 Bethesda, MD: National Institutes of Health.Google Scholar
Nilsson, S, Makela, S, Treuter, E, Tujague, M, Thomsen, J, Andersson, G, Enmark, E, Pettersson, K, Warner, M & Gustafsson, JA (2001) Mechanisms of estrogen action. Physiological Reviews 81, 1535–1565.Google Scholar
Oreffo, RO, Kusec, V, Virdi, AS, Flanagan, AM, Grano, M, Zambonin-Zallone, A & Triffitt, JT (1999) Expression of estrogen receptor-alpha in cells of the osteoclastic lineage. Histochemistry Cell Biology 111, 125–133.Google Scholar
Paech, K, Webb, P, Kuiper, GGJM, Nilsson, S, Gustafsson, JA, Kushner, PJ & Scalan, TS (1997) Differential ligand activation of estrogen receptors ERαand ERβat AP1 sites. Science 277, 1508–1510.Google Scholar
Picherit, C, Bennetau-Pelissero, C, Chanteranne, B, Lebecque, P, Davicco, MJ, Barlet, JP & Coxam, V (2001) Soybean isoflavones dose-dependently reduce bone turnover but do not reverse established osteopenia in adult ovariectomized rats. Journal of Nutrition 131, 723–728.CrossRefGoogle Scholar
Pike, AC, Brzozowski, AM, Hubbard, RE, Bonn, T, Thorsell, AG, Engstrom, O, Ljunggren, J, Gustafsson, JA & Carlquist, M (1999) Structure of the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist. EMBO Journal 18, 4608–4618.Google Scholar
Potter, SM, Baum, JA, Teng, H, Stillman, RJ, Shay, NF & Erdman, JW (1998) Soy protein and isoflavones: effects on blood lipids and bone density in postmenopausal women. American Journal of Clinical Nutrition 68, 1375S–1379S.CrossRefGoogle ScholarPubMed
Rassi, CM, Lieberherr, M, Chaumaz, G, Pointillart, A & Cournot, G (2002) Down-regulation of osteoclast differentiation by daidzein via caspase 3. Journal of Bone and Mineral Research 17, 630–638.Google Scholar
Rickard, DJ, Monroe, DG, Ruesink, TJ, Khosla, S, Riggs, BL & Spelsberg, TC (2003) Phytoestrogen genistein acts as an estrogen agonist on human osteoblastic cells through estrogen receptors alpha and beta. Journal of Cell Biochemistry 89, 633–646.Google Scholar
Ross, JA & Kasum, CM (2002) Dietary flavonoids: bioavailability, metabolic effects, and safety. Annual Review of Nutrition 22, 19–34.Google Scholar
Rowland, I, Faughnan, M, Hoey, L, Wahala, K, Williamson, G & Cassidy, A (2003) Bioavailability of phyto-oestrogens. British Journal of Nutrition 89, Suppl. 1, S45–S58.Google Scholar
Saarinen, N, Joshi, SC, Ahotupa, M, Li, X, Ammala, J, Makela, S & Santti, R (2001) No evidence for the in vivo activity of aromatase-inhibiting flavonoids. Journal of Steroid Biochemistry and Molecular Biology 78, 231–239.Google Scholar
Scambia, G, Mango, D, Signorile, PG, Angeli, RA, Palena, C, Bombardelli, E, Morazzoni, P, Riva, A & Mancuso, S (1999) Clinical effects of a standardised soy extract in postmenopausal women: a pilot study. Menopause 6, 233–241.Google Scholar
Scheiber, MD, Liu, JH, Subbiah, MTR, Rebar, RW & Setchell, KDR (2000) Dietary soy isoflavones favorably influence lipids and bone turnover in healthy postmenopausal women. Journal of Nutrition 130, 668S.Google Scholar
Setchell, KDR, Brown, NM, Desai, P, Zimmer-Nechemias, L, Wolfe, BE, Brashear, WT, Kirschner, AS, Cassidy, A & Heubi, JE (2001) Bioavailability of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements. Journal of Nutrition 131, 1362S–1375S.Google Scholar
Setchell, KD, Brown, NM, Lydeking-Olsen, E (2002 a) The clinical importance of the metabolite equol – a clue to the effectiveness of soy and its isoflavones. Journal of Nutrition 132, 3577–3584.Google Scholar
Setchell, KDR, Brown, NM, Zimmer-Nechemias, L, Brashear, WT, Wolfe, BE, Kirschner, AS, Heubi, JE, (2002 b) Evidence for lack of absorption of soy isoflavone glycosides in humans, supporting the crucial role of intestinal metabolism for bioavailability. American Journal of Clinical Nutrition 76, 447–453.CrossRefGoogle ScholarPubMed
Setchell, KDR, Zimmer-Nechemias, L, Cai, J & Heubi, JE (1998) Isoflavone content of infant formulas and the metabolic fate of those phytoestrogens in early life. American Journal of Clinical Nutrition 68, 1453S–1461S.CrossRefGoogle ScholarPubMed
Somekawa, Y, Chiguchi, M, Ishibashi, T & Aso, T (2001) Soy intake related to menopausal symptoms, serum lipids, and bone mineral density in postmenopausal Japanese women. Obstetrics and Gynecology 97, 109–115.Google Scholar
Srivastava, S, Weitzmann, MN, Kimble, RB, Rizzo, M, Zahner, M, Milbrandt, J, Ross, FP & Pacifici, R (1998) Estrogen blocks MCSF gene expression and osteoclast formation by regulating phosphorylation of Egr-1 and its interaction with Sp-1. Journal of Clinical Investigation 102, 1850–1859.CrossRefGoogle ScholarPubMed
Tsuchida, K, Mizushima, S, Toba, M & Soda, K (1999) Dietary soybeans intake and bone mineral density among 995 middleaged women in Yokohama. Journal of Epidemiology 9, 14–19.Google Scholar
Uesugi, T, Fukui, Y & Yamori, Y (2002) Beneficial effects of soybean isoflavone supplementation on bone metabolism and serum lipids in postmenopausal Japanese women: a four-week study. Journal of the American College of Nutrition 21, 97–102.Google Scholar
Upmalis, DH, Lobo, R, Bradley, L, Warren, M, Cone, FL & Lamia, CA (2000) Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter, double blind, randomized, placebo-controlled study. Menopause 7, 236–242.Google Scholar
Valtueña, S, Cashman, K, Robins, SP, Cassidy, A, Kardinaal, A & Branca, F (2003) Investigating the role of natural phytooestrogens on bone health in postmenopausal women. British Journal of Nutrition 89, Suppl. 1, S87–S99.CrossRefGoogle Scholar
van Erp-Baart, A-MJ, Brants, HAM, Keily, M, Mulligan, A, Turrini, A, Sermoneta, C, Kilkkinen, A & Valsta, LM (2003) Isoflavone intake in four different European countries: the VENUS approach. British Journal of Nutrition 89, Suppl. 1, S25–S30.Google Scholar
Wangen, KE, Duncan, AM, Merz-Demlow, BE, Xu, X, Marcus, R, Phipps, WR & Kurzer, MS (2000) Effects of soy isoflavones on markers of bone turnover in premenopausal and postmenopausal women. Journal of Clinical Endocrinology and Metabolism 85, 3043–3048.Google ScholarPubMed
Washburn, S, Burke, GL, Morgan, T & Anthony, M (1999) Effect of soy protein supplementation on serum lipoproteins, blood pressure, and menopausal symptoms in perimenopausal women. Menopause 6, 7–13.Google ScholarPubMed
Writing Group for the Women's Health Initiative Investigators (2002) Risks and benefits of estrogen plus progesterone in healthy post-menopausal women. Journal of the American Medical Association 288, 321–333.Google Scholar
Yamaguchi, M & Gao, YH (1997) Anabolic effect of genistein on bone metabolism in the femoral-metaphyseal tissues of elderly rats is inhibited by the anti-estrogen tamoxifen. Research in Experimental Medicine 197, 101–107.Google Scholar
Yamaguchi, M & Gao, YH (1998) Anabolic effect of genistein and genistin on bone metabolism in the femoral-metaphyseal tissues of elderly rats: the genistein effect is enhanced by zinc. Molecular and Cellular Biochemistry 178, 377–82.Google Scholar
Yamaguchi, M & Sugimoto, E (2000) Stimulatory effect of genistein and daidzein on protein synthesis in osteoblastic MC3T3-E1 cells: activation of aminoacyl-tRNA synthetase. Molecular and Cellular Biochemistry 214, 97–102.Google Scholar
Zand, RS, Jenkins, DJ & Diamandis, EP (2000) Steroid hormone activity of flavonoids and related compounds. Breast Cancer Research and Treatment 62, 35–49.Google Scholar