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Osteoporosis International
Published in: Osteoporosis International 5/2003

01-06-2003 | Review

Isoflavones and skeletal health: are these molecules ready for clinical application?

Authors: S. Migliaccio, J. J. B. Anderson

Published in: Osteoporosis International | Issue 5/2003

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Abstract

A review of the recent literature on the effects of isoflavones was undertaken to determine whether molecules such as genistein and daidzein, aglycone derivatives of soybeans, might have benefit in the prevention and treatment of osteoporosis. The current standard for science-based medicine is the documentation of efficacy of an agent under controlled, randomized, prospective conditions. A few short clinical investigations have been undertaken using isoflavones (along with soy protein), but they had limitations in study design, and the numbers of women studied were small. Other evidence from animal models, in vitro experiments, and epidemiological reports suggest that the isoflavones have skeletal benefits in women with little or no ovarian estrogen production. A clear need exists for prospective human trials, using the required conditions of randomized clinical trials and designs, to satisfy objectively the needs for science-based medicine and for appropriate clinical applications.
Literature
1.
Moule GR, Braaden AWH, Lamond DR (1963) The significance of oestrogens in pasture plants in relation to animal production. Anim Breed Abstr 31:139–157
2.
Anderson JJB, Anthony M, Messina M, Garner SC (1999) Effects of phyto-oestrogens on tissues. Nutr Res Rev 12:75–116
3.
Adlercreutz H (1991) Diet and sex metabolism. In: Rowland IR (ed) Nutrition, Toxicity and Cancer. CRC Press, Boca Raton, pp 37–195
4.
Adlercreutz H, Fotsis T, Bannwart C et al (1986) Determination of urinary lignans and phytoestrogen metabolites, potential antiestrogens and anticarcinogens, in urine of women on various habitual diets. J Steroid Biochem 25:791–797
5.
King RA, Bursill DB (1998) Plasma and urinary kinetics of the isoflavones daidzein and genistein after a single soy meal in humans. Am J Clin Nutr 67:867–872
6.
Setchell KD, 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. J Nutr 131:1362S-1375S
7.
McLachlan JA (2001) Environmental signaling: what embryos and evolution teach us about endocrine disrupting chemicals. Endocri Rev 22:319–341
8.
Day AJ, Canada FJ, Diaz JC, Kroon PA, McLauchlan R, Faulds CB, Plumb GW, Morgan MRA, Williamson G (2000) Dietary flavonoid and isoflavone glycosides are hydrolyzed by the lactose site of lactase phlorizin hydrolase. FEBS Letters 468:166–170
9.
Hur HG, Lay JO Jr, Beger RD, Freeman JP, Rafi F (2000) Isolation of human intestinal bacteria metabolizing the natural isoflavone glycosides daidzein and genistein. Arch Microbiol 174:422–428
10.
Vehare M, Ohta A, Sakai K, Suzuki K, Watanabe S, Adlercreutz H (2001) Dietary fructooligosaccharides modify intestinal bioavailability of a single dose of genistein and daidzein and affect their urinary excretion and kinetics in blood of rats. J Nutr 131:787–795
11.
Beato M, Klug J (2000) Steroid hormone receptors: an update. Hum Reprod Update 6:225–236
12.
Kuiper GCJM, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson J-A (1996) Cloning of a novel human estrogen receptor expressed in prostate and ovary. Proc Natl Acad Sci USA 93:5925–5930
13.
Mosselman S, Polman J, Dijkema R (1996) ERβ: identification and characterization of a novel human estrogen receptor. FEBS Lett 392:49–53
14.
Tremblay GB, Tremblay A, Copeland NG, Gilbert DJ, Jenkins NA, Labrie F, Giguere V (1997) Cloning, chromosomal localization and functional analysis of the murine estrogen receptor β. Mol Endocrinol 11:353–365
15.
Kuiper GGJM, Carlsson B, Gardien K, Enmark E, Haggblad J, Nilsson S and Gustafsson J-A (1997) Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and β. Endocrinology 138:863–870
16.
Arts J, Kuiper GG, Janssen JMMF, Gustafsson J-A, Lowik CW,GM, Pols HAP, van Leeuwen JPTM (1997) Differential expression of estrogen receptor α and β mRNA during differentiation of human osteoblast SV-HFO cells. Endocrinology 38:5067–5070
17.
Bodine PV, Henderson RA, Green J, Aronow M, Owen T, Stein GS, Lian JB, Komm BS (1998) Estrogen receptor α is developmentally regulated during osteoblast differentiation and contributes to selective responsiveness of gene expression. Endocrinology 139:2048-2057
18.
Barkhem T, Carlsson B, Nilsson Y, Enmark E, Gustafsson J, Nilsson S (1998) Differential response of estrogen receptor α and estrogen receptor β in the presence of a partial estrogen agonist/antagonist. Mol Pharmacol 54:105–102
19.
Pike AC, Brzozowski AM, Hubbard RE, Bonn T, Thorsell AG, Engstrom O, Ljunggren J, Gustaffon JA, Carlquist M (1999) Structure of the ligand-binding domain of oestrogen receptor β in the presence of a partial agonist and a full antagonist. EMBO J 18:4608–4618
20.
Messina MJ (1999) Legumes and soybeans: overview of their nutritional profiles and health effects. Am J Clin Nutr 70:439S-450S
21.
Kousteni S, Bellido T, Plotkin LI, O'Brien CA, Bodenner DL, Han L, Han K, DiGregorio GB, Katzenellenbogen JA, Katzenellenbogen BS, Roberson PK, Weinstein RS, Jilka RL, Manolagas SC (2001) Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell 104:719–730
22.
Lu D, Giguere V (2001) Requirement of Ras-dependent pathways for activation of the transforming growth factor β3 promoter by estradiol. Endocrinology 142:751–759
23.
Endoh H, Sasaki H, Maruyama K, Takeyama K, Waga I, Shimizu T, Kato S, Kawashima H (1997) Rapid activation of MAP kinase by estrogen in the bone cell line. Biochem Biophys Res Commun 235:99–102
24.
Ignar-Trowbridge DM, Hughes AR, Putney JW Jr, McLachlan JA, Korach KS (1991) Diethylstilbestrol stimulates persistent phosphatidylinositol lipid turnover by an estrogen receptor-mediated mechanism in immature mouse uterus. Endocrinology 129:2423–2430
25.
Migliaccio S, Wetsel WC, Fox WM, Washburn TF, Korach KS (1993) Endogenous protein kinase C activation in osteoblast-like cells modulates estrogen responsiveness and estrogen receptor levels. Mol Endocrinol 7:1133–1143
26.
Akiyama T, Ishida I, Nakagawa S, Ogawara H, Watanabe S, Itoh N, Shibuya M, Fuami Y (1987) Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem 262:5592–5595
27.
Barnes S, Peterson TG (1995) Biochemical targets of the isoflavone genistein in tumor cell lines. Proc Soc Exp Biol Med 208:103–108
28.
Peterson TG (1995) Evaluation of the biochemical targets of genistein in tumor cell. J Nutr 125:784S-789S
29.
Polkowski K, Skierski JS, Mazurek AP (2000) Anticancer activity of genistein-piperazine complex. In vitro study with HL-60 cells. Acta Pol Pharm 57:223–32
30.
Chan WH, Yu JS (2000) Inhibition of UV irradiation-induced oxidative stress and apoptotic biochemical changes in human epidermal carcinoma A431 cells by genistein. J Cell Biochem 78:73–84
31.
Coward L, Kirk M, Albin N, Barnes S (1996) Analysis of plasma isoflavones by reversed-phase HPLC-multiple reaction ion monitoring-mass spectrometry. Clin Chim Acta 247:121–142
32.
Gao YH, Yamaguchi M (1999) Suppressive effect of genistein on rat bone osteoclasts: apoptosis is induced through calcium signaling. Biol Pharm Bull 22:805–809
33.
Gao YH, Yamaguchi M (2000) Suppressive effect of genistein on rat bone osteoclasts: involvement of protein kinase inhibition and protein tyrosine phosphatase activation. Int J Mol Med 5:261–267
34.
Yoon HK, Chen K, Baylink DJ, Lau KH (1998) Differential effects of two protein tyrosine kinase inhibitors, tyrphostin and genistein, on human bone cell proliferation as compared with differentiation. Calcif Tissue Int 63:243–249
35.
Migliaccio S, Davis VL, Gibson MK, Gray TK, Korach KS (1992) Estrogens modulate the responsiveness of osteoblast-like cells (ROS 17/2.8) stably transfected with the estrogen receptor. Endocrinology 130:2617–2624
36.
Anderson JJB, Garner SC (1998) Phytoestrogens and bone. Bailliere's Clin Endocrinol Metab 12:543-557
37.
Makela S, Davis VL, Tally WC (1994) Dietary estrogens act through estrogen receptor mediated processes and show no antiestrogenicity in cultured breast cancer cells. Environ Health Perspect 102:572–578
38.
De Launoit Y, Veilleux R, Dufour M, Simard J, Labrie F (1991) Characteristics of the biphasic action of androgens and of the potent antiproliferative effects of the new pure antiestrogen EM-139 on cell cycle kinetic parameters in LNCaP human prostatic cancer cells. Cancer Res 51:5165–5170
39.
Hayashi T, Ishikawa T, Yamada K, Kuzuya M, Naito M, Hidaka H, Iguchi A (1994) Biphasic effect of estrogen on neuronal constitutive nitric oxide synthase via Ca (2+)-calmodulin dependent mechanism. Biochem Biophys Res Commun 203:1013–1019
40.
Taranta A, Teti A, Brama M, De Luca V, Agnusdei D, Spera G, Scandurra R, Termine JD and Migliaccio S (2002) The selective estrogen receptor modulator raloxifene regulates osteoclast and osteoblast activity in vitro. Bone 30:368–376
41.
Chen XW, Garner, SC, Anderson, JJB. (2002) Isoflavones regulate interleukin-6 and osteoprotegerin synthesis during osteoblast cell differentiation via an estrogen-receptor-dependent pathway. Biochem Biophys Res Commun 295:417–22
42.
Oreffo RO, Kusec V, Virdi AS, Flanagan AM, Grano M, Zambonin-Zallone A, Triffit JT (1999) Expression of estrogen receptor-a in cells of the osteoclastic lineage. Histochem Cell Biol 111:125–133
43.
Fiorelli G, Martineti V, Gori F, Benvenuti S, Frediani U, Formigli L, Zecchi S, Brandi ML (1997) Heterogeneity of binding sites and bioeffects of raloxifene on the human leukaemic cell line FLG 29.1. Biochem Biophys Res Commun 240:573–579
44.
Bord S, Horner A, Beavan S, Compston J (2001) Estrogen receptors alpha and beta are differently expressed in developing human bone. J Clin Endocrinol Metab 86:2309–2314
45.
Shevde NK, Bendixen AC, Dienger KM, Pike JW (2000) Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-jun repression. Proc Natl Acad Sci USA 97:7829–7834
46.
Tsutsumi N (1995) Effect of coumestrol on bone metabolism in organ culture. Biol Pharmacol Bull 18:1012–1015
47.
Anderson JJB, Ambrose WW, Garner SC (1995) Orally dosed genistein from soy and prevention of cancellous bone loss in two ovariectomized rat models. J Nutr 125:799S
48.
Turner KJ, Sharpe RM (1997) Environmental oestrogens—present understanding. Rev Reprod 2:69–73
49.
Omi N, Aoi S, Murata K, Ezawa I (1994) Evaluation of the effects of soybean milk peptide on bone metabolism in the rat model with ovariectomized osteoporosis. J Nutr Sci Vitaminol 40:201–211
50.
Fanti P, Monier-Fauger MC, Geng Z, Schmidt J, Morris PE, Cohen D, Malluche HH (1998) The phytoestrogen genistein reduces bone loss in short term ovariectomized rats. Osteoporos Int 8:274–281
51.
Anderson JJB, Ambrose WW, Garner SC (1998) Biphasic effects of genistein on bone tissue in the ovariectomized, lactating rat model. Proc Soc Exp Biol Med 217:345–350
52.
Jayo MJ, Anthony MS, Register TC, Rankin SE, Vest T, Clarkson TB (1997) Dietary soy isoflavones and bone loss in ovariectomized monkeys. FASEB J 11:S228
53.
Ishimi Y, Miyaura C, Ohmura M, Onoe Y (1999) Selective effects of genistein, a soybean isoflavone, on B-lymphopoiesis and bone loss caused by estrogen deficiency. Endocrinology 140:1893–1900
54.
Arjmandi BH, Alekel L, Hollis BW, et al (1996) Dietary soybean protein prevents bone loss in ovariectomized rat model of osteoporosis. J Nutr 126:161–167
55.
Arjmandi BH, Birnbaum R, Goyal NV, et al (1998) Bone-sparing effect of soy protein in ovarian hormone deficient rats is related to its isoflavone content. Am J Clin Nutr 68:1364–1368
56.
Bell NH, Termine JD (2001) Treatment and prevention of osteoporosis: future directions. J South Carolina Med Assoc 97:99–101
57.
Kass-Annese B (2000) Alternative therapies for menopause. Clin Obstet Gynecol 43:162–183
58.
Anderson JJB, Anthony MS, Cline JM, Washburn SA, Garner SC (1999) Health potential of soy isoflavones for menopausal women. Public Health Nutr 2:489–504
59.
Scheiber MD, Rebar RW (1999) Isoflavones and postmenopausal bone health: a viable alternative to estrogen. Menopausa 6:233–241
60.
Potter SM, Baum JA, Teng H, Stillman RJ, Shay NF, Erdman JW (1998) Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women. Am J Clin Nutr 68:1375–1379
61.
Alekel DL, St Germain A, Peterson CT, Hanson KB, Stewart JW, Toda T (2000) Isoflavone-rich soy protein isolate attenuates bone loss in the lumbar spine of perimenopausal women. Am J Clin Nutr 72:844–852
62.
Glazier MG, Bowman MA (2001) A review of the evidence for the use of phytoestrogens as replacement for traditional estrogen replacement therapy. Arch Intern Med 161:1161–1172
63.
Carusi D (2000) Phytoestrogens as hormone replacement therapy: an evidence-based approach. Prim Care Update Ob Gyn 7:253–259
64.
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. J Bone Miner Res 16:1362–1366
65.
Horiuchi T, Onouchi T, Takahashi M, Ito H, Orimo H (2000) Effect of soy protein on bone metaboliosm in postmenopausal Japanese women. Osteoporos Int 11:721–724
66.
Greendale GA, FitzGerald G, Huang M-H, Sternfeld B, Gold E, Seeman T, Sherman S, Sowers MF (2002) Dietary soy isoflavones and bone mineral density: results from the Study of Women's Health Across the Nation. Am J Epidemiol 155:746–754
67.
Mei J, Yeung SSC, Kung AWC (2001) High dietary phytoestrogen intake is associated with higher bone mineral density in postmenopausal but not premenopausal women. J Clin Endocrinol Metab 86:5217–5221
68.
Clifton-Bligh PB, Baber R, Fulcher GR, Nery M-L, Moreton T (2001) The effect of isoflavones extracted from red clover (Rimostil) on lipid and bone metabolism. Menopause 8:259–265
69.
Anderson JJB, Chen XW, Boass A, Symons M, Kohlmeier M, Renner JB, Garner SC (2002) Soy isoflavones: no effects on bone mineral content and bone mineral density in healthy, menstruating young adult women after one year. J Am Coll Nutr 21:388–393
70.
Dalais FS, Rice GE, Wahlqvist ML, Bell RJ (1998) Effects of dietary phytoestrogens in postmenopausal women. Climacteric 1(2):124–129
71.
Baird DD, Umbach DM, Lansdell L, Hughes CL, Setchell KD, Weiberg CR, Haney AF, Wilcox AJ, McLachlan JA (1995) Dietary intervention study to assess estrogenicity of dietary soy among postmenopausal women. J Clin Endocrinol Metab 80:1685–1690
72.
Wangen KE, Duncan AM, Merz-Demlow BE, Xu X, Marcus RE, Phipps WR, Kurzer MS (2000) Effects of soy isoflavones on markers of bone turnover in premenopausal and postmenopausal women. J Clin Endocrinol Metab 85:3043–3048
73.
Anon.(2000) The role of isoflavones in menopausal health: consensus opinion of The North American Menopause Society. Menopause 7:215–229
74.
Humfrey CD (1998) Phytoestrogens and human health effects: weighing up the current evidence. Natural Toxins 6:51–59
75.
This P, De la Rochefordiere A, Clough K, Fourquet A, Magdelenat H (2001) Phytoestrogens after breast cancer. Endocrine Related Cancer 8:129–134
76.
Alexandersen P, Toussaint, Christiansen C, Devogelear JP, Roux C, Fechtenbaum J, Gennari C, Reginster JY (2001) Ipriflavone in the treatment of postmenopausal osteoporosis: a randomized controlled trial. JAMA 285:1482–1488
Metadata
Title
Isoflavones and skeletal health: are these molecules ready for clinical application?
Authors
S. Migliaccio
J. J. B. Anderson
Publication date
01-06-2003
Publisher
Springer-Verlag
Published in
Osteoporosis International / Issue 5/2003
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI
https://doi.org/10.1007/s00198-002-1372-1

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