Soy phytoestrogens: Impact on postmenopausal bone loss and mechanisms of action

Nutrition Reviews

Volumn 66, Issue 7, 2008, Pages 359-374

  Poulsen, Raewyn C ^a   Kruger, Marlena C ^a  

^a MASSEY UNIVERSITY   (New Zealand)

Author keywords

Daidzein; Genistein; Isoflavones; Osteoblast; Osteoclast; Osteoporosis

Indexed keywords

4 ETHYLPHENOL; AGLYCONE; DAIDZEIN; EQUOL; ESTRADIOL; GENISTEIN; GLYCOSIDE; ISOFLAVONE AGLYCONE; ISOFLAVONE DERIVATIVE; O NORANGOLENSIN; OSTEOCLAST DIFFERENTIATION FACTOR; PENTETATE CALCIUM; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; PHYTOESTROGEN;

BONE DENSITY; BONE DEVELOPMENT; BONE MINERAL; DIET SUPPLEMENTATION; DIETARY INTAKE; DRUG ACTIVITY; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG EXCRETION; DRUG MECHANISM; DRUG METABOLISM; DRUG RECEPTOR BINDING; HUMAN; IN VITRO STUDY; NONHUMAN; OSTEOBLAST; OSTEOCLAST; POSTMENOPAUSE; POSTMENOPAUSE OSTEOPOROSIS; REVIEW; SOYBEAN; SOYBEAN MILK; TREATMENT DURATION;

ANIMALS; BONE AND BONES; BONE DENSITY CONSERVATION AGENTS; CLINICAL TRIALS AS TOPIC; DISEASE MODELS, ANIMAL; DOSE-RESPONSE RELATIONSHIP, DRUG; FEMALE; HUMANS; MIDDLE AGED; OSTEOPOROSIS, POSTMENOPAUSAL; PHYTOESTROGENS; SOYBEANS;

ANIMALIA; MAMMALIA;

EID: 47349132821     PISSN: 00296643     EISSN: None     Source Type: Journal    
DOI: 10.1111/j.1753-4887.2008.00046.x     Document Type: Review

References (135)

1. Fraser WD. The burden of osteoporosis and the case for disease management. Dis Manag Health Out. 2004 12 : 409 418.
2. Consensus Development Conference. Prophylaxis and treatment of osteoporosis. Am J Med. 1991 90 : 107 110.
3. Bonewald L. Mechanosensation and transduction in osteocytes. BoneKEy. 2006 3 : 7 15.
4. Roodman GD. Cell biology of the osteoclast. Exp Hematol. 1999 27 : 1229 1241.
5. Aubin J. Regulation of osteoblast formation and function. Rev Endocr Metab Disord. 2001 2 : 81 94.
6. Riggs B. Endocrine Causes of Age-Related Bone Loss and Osteoporosis. West Sussex : John Wiley & Sons Ltd 2002.
7. Chan SDH, Chiu DKH, Atkins D. Oophorectomy leads to a selective decrease in 1,25-dihydroxycholecalciferol receptors in rat jejunal villous cells. Clin Sci. 1984 66 : 745 748.
8. Arts J, Kuiper GGJM, Janssen JMMF, et al. Differential expression of estrogen receptors {alpha} and {beta} mRNA during differentiation of human osteoblast SV-HFO cells. Endocrinology. 1997 138 : 5067 5070.
9. Batra GS, Hainey L, Freemont AJ, et al. Evidence for cell-specific changes with age in expression of oestrogen receptor (ER) alpha and beta in bone fractures from men and women. J Pathol. 2003 200 : 65 73.
10. Mundy G. Bone Remodeling and Its Disorders. London : Martin Dunitz 1995.
11. Fitzpatrick L, Bilezikian J. Actions of parathyroid hormone. In : Bilezikian J, Raisz L, Rodan G, eds. Principles of Bone Biology. San Diego : Academic Press 1996 : 339 346.
12. Lindsay R, Cosman F. The pharmacology of estrogens in osteoporosis. In : Bilezikian J, Raisz LG, Rodan G, eds. Principles of Bone Biology. San Diego : Academic Press 1996 : 1063 1067.
13. Pfeilschifter J, Koditz R, Pfohl M, Schatz H. Changes in proinflammatory cytokine activity after menopause. Endocr Rev. 2002 23 : 90 119.
14. Coldham N, Darby C, Hows M, King L, Zhang A, Sauer M. Comparative metabolism of genistin by human and rat gut microflora: detection and identification of the end-products of metabolism. Xenobiotica. 2002 32 : 45 62.
15. Setchell KDR, Brown NM, Lydeking-Olsen E. The clinical importance of the metabolite equol - A clue to the effectiveness of soy and its isoflavones. J Nutr. 2002 132 : 3577 3584.
16. Heinonen S, Wahala K, Adlercreutz H. Identification of isoflavone metabolites dihydrodaidzein, dihydrogenistein, 6'-OH-O-dma, and cis-4-OH-equol in human urine by gas chromatography-mass spectroscopy using authentic reference compounds. Anal Biochem. 1999 274 : 211 219.
17. Mueller SO, Simon S, Chae K, Metzler M, Korach KS. Phytoestrogens and their human metabolites show distinct agonistic and antagonistic properties on estrogen receptor {alpha} (ER{alpha}) and ER{beta} in human cells. Toxicol Sci. 2004 80 : 14 25.
18. Woclawek-Potocka I, Acosta TJ, Korzekwa A, et al. Phytoestrogens modulate prostaglandin production in bovine endometrium: cell type specificity and intracellular mechanisms. Exp Biol Med. 2005 230 : 326 333.
19. Woclawek-Potocka I, Bah MM, Korzekwa A, et al. Soybean-derived phytoestrogens regulate prostaglandin secretion in endometrium during cattle estrous cycle and early pregnancy. Exp Biol Med. 2005 230 : 189 199.
20. Woclawek-Potocka I, Bober A, Korzekwa A, Okuda K, Skarzynski DJ. Equol and para-ethylphenol stimulate prostaglandin F2alpha secretion in bovine corpus luteum: intracellular mechanisms of action. Prostaglandins Other Lipid Mediat. 2006 79 : 287 297.
21. Woclawek-Potocka I, Okuda K, Acosta TJ, Korzekwa A, Pilawski W, Skarzynski DJ. Phytoestrogen metabolites are much more active than phytoestrogens themselves in increasing prostaglandin F-2 alpha synthesis via prostaglanin F-2 alpha synthase-like 2 stimulation in bovine endometrium. Prostaglandins Other Lipid Mediat. 2005 78 : 202 217.
22. Sebastian A. Isoflavones, protein, and bone. Am J Clin Nutr. 2005 81 : 733 735.
23. Mei J, Yeung SSC, Kung AWC. High dietary phytoestrogen intake is associated with higher bone mineral density in postmenopausal but not premenopausal women. J Clin Endocrinol Metab. 2001 86 : 5217 5221.
24. Greendale GA, FitzGerald G, Huang M-H, et al. Dietary soy isoflavones and bone mineral density: results from the study of women's health across the nation. Am J Epidemiol. 2002 155 : 746 754.
25. Ho SC, Woo J, Lam S, Chen Y, Sham A, Lau J. Soy protein consumption and bone mass in early postmenopausal Chinese women. Osteoporosis Int. 2003 14 : 835 842.
26. Horiuchi T, Onouchi T, Takahashi M, Ito H, Orimo H. Effect of soy protein on bone metabolism in postmenopausal Japanese women. Osteoporosis Int. 2000 11 : 721 724.
27. Kim MK, Chung BC, Yu VY, et al. Relationships of urinary phyto-oestrogen excretion to BMD in postmenopausal women. Clin Endocrinol. 2002 56 : 321 328.
28. Xu X, Harris KS, Wang H-J, Murphy PA, Hendrich S. Bioavailability of soybean isoflavones depends upon gut microflora in women. J Nutr. 1995 125 : 2307 2315.
29. Maskarinec G, Oshiro C, Morimoto Y, Henbshi S, Novotny R, Franke AA. Urinary isoflavone excretion as a compliance measure in a soy intervention among young girls: a pilot study. Eur J Clin Nutr. 2005 59 : 369 375.
30. Rowland I, Wiseman H, Sanders T, Adlercreutz H, Bowey E. Interindividual variation in metabolism of soy isoflavones and lignans: influence of habitual diet on equol production by the gut microflora. Nutr Cancer. 2000 36 : 27 32.
31. Rowland I, Faughnan M, Hoey L, Wahala K, Williamson G, Cassidy A. Bioavailability of phyto-oestrogens. Br J Nutr. 2003 89 (Suppl S45 S58.
32. Song KB, Atkinson C, Frankenfeld CL, et al. Prevalence of daidzein-metabolizing phenotypes differs between Caucasian and Korean American women and girls. J Nutr. 2006 136 : 1347 1351.
33. Kritz-Silverstein D, Goodman-Gruen DL. Usual dietary isoflavone intake, bone mineral density, and bone metabolism in postmenopausal women. J Womens Health Gend Based Med. 2002 11 : 69 78.
34. Anderson JJB, Chen X, Boass A, et al. 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. 2002 21 : 388 393.
35. Geppert J, Baier S, Zehn N, et al. Short-term effects of high soy supplementation on sex hormones, bone markers, and lipid parameters in young female adults. Eur J Nutr. 2004 43 : 100 108.
36. Wangen KE, Duncan AM, Merz-Demlow BE, et al. Effects of soy isoflavones on markers of bone turnover in premenopausal and postmenopausal women. J Clin Endocr Metab. 2000 85 : 3043 3048.
37. Jones G, Dwyer T, Hynes K, Dalais FS, Parameswaran V, Greenaway TM. A randomized controlled trial of phytoestrogen supplementation, growth and bone turnover in adolescent males. Eur J Clin Nutr. 2003 57 : 324 327.
38. Alekel DL, Germain AS, Peterson CT, Hanson KB, Stewart JW, Toda T. Isoflavone-rich soy protein isolate attenuates bone loss in the lumbar spine of perimenopausal women. Am J Clin Nutr. 2000 72 : 844 852.
39. Gallagher JC, Satpathy R, Rafferty K, Haynatzka V. The effect of soy protein isolate on bone metabolism. Menopause. 2004 11 : 290 298.
40. Uesugi T, Fukui Y, Yamori Y. Beneficial effects of soybean isoflavone supplementation on bone metabolism and serum lipids in postmenopausal Japanese women: a four-week study. J Am Coll Nutr. 2002 21 : 97 102.
41. Yamori Y, Moriguchi EH, Teramoto T, et al. Soybean isoflavones reduce postmenopausal bone resorption in female Japanese immigrants in Brazil: a ten-week study. J Am Coll Nutr. 2002 21 : 560 563.
42. Chen YM, Ho SC, Lam SSH, Ho SSS, Woo JLF. Soy isoflavones have a favorable effect on bone loss in Chinese postmenopausal women with lower bone mass: a double-blind, randomized, controlled trial. J Clin Endocr Metab. 2003 88 : 4740 4747.
43. Brooks JD, Ward WE, Lewis JE, et al. Supplementation with flaxseed alters estrogen metabolism in postmenopausal women to a greater extent than does supplementation with an equal amount of soy. Am J Clin Nutr. 2004 79 : 318 325.
44. Chiechi LM, Secreto G, D'Amore M, et al. Efficacy of a soy rich diet in preventing postmenopausal osteoporosis: the Menfis randomized trial. Maturitas. 2002 42 : 295 300.
45. Morabito N, Crisafulli A, Vergara C, et al. Effects of genistein and hormone-replacement therapy on bone loss in early postmenopausal women: a randomized double-blind placebo-controlled study. J Bone Miner Res. 2002 17 : 1904 1912.
46. Albertazzi P, Steel SA, Bottazzi M. Effect of pure genistein on bone markers and hot flushes. Climacteric. 2005 8 : 371 379.
47. Spence LA, Lipscomb ER, Cadogan J, et al. The effect of soy protein and soy isoflavones on calcium metabolism in postmenopausal women: a randomized crossover study. Am J Clin Nutr. 2005 81 : 916 922.
48. Koyama I, Shimanuki S, Tezuka M, et al. Effects of natto (fermented soybean; made from isoflavone-rich soybean) supplemented with zinc and calcium on bone density and bone metabolic markers of postmenopausal women. J Nutr. 2004 134 (Suppl S1288 S1289.
49. Uesugi S, Watanabe S, Ishiwata N, Uehara M, Ouchi K. Effects of isoflavone supplements on bone metabolic markers and climacteric symptoms in Japanese women. Biofactors. 2004 22 : 221 228.
50. Potter S, Baum J, Teng H, Stillman R, Shay N, Erdman Jr J. Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women. Am J Clin Nutr. 1998 68 (Suppl S1375 S1379.
51. Roughead ZK, Hunt JR, Johnson LK, Badger TM, Lykken GI. Controlled substitution of soy protein for meat protein: effects on calcium retention, bone, and cardiovascular health indices in postmenopausal women. J Clin Endocr Metab. 2005 90 : 181 189.
52. Scheiber M, Liu J, Subbiah M, Rebar R, Setchell K. Dietary inclusion of whole soy foods results in significant reductions in clinical risk factors for osteoporosis and cardiovascular disease in normal postmenopausal women. Menopause. 2001 8 : 384 392.
53. Lydeking-Olsen E, Beck-Jensen JE, Setchell KDR, Holm-Jensen T. Soymilk or progesterone for prevention of bone loss - a 2 year randomized, placebo-controlled trial. Eur J Nutr. 2004 43 : 246 257.
54. Ye YB, Su YX, Verbruggen M. A prospective clinical trial of soy germ isoflavone extract attenuating bone loss in postmenopausal women. J Nutr. 2004 134 (Suppl S1243 S1243.
55. Kreijkamp-Kaspers S, Kok L, Grobbee DE, et al. Effect of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women - a randomized controlled trial. JAMA. 2004 292 : 65 74.
56. Brink E, Coxam V, Robins S, et al. Long-term consumption of isoflavone-enriched foods does not affect bone mineral density, bone metabolism, or hormonal status in early postmenopausal women: a randomized, double-blind, placebo controlled study. Am J Clin Nutr. 2008 87 : 761 770.
57. Harkness L, Fiedler K, Sehgal A, Oravec D, Lerner E. Decreased bone resorption with soy isoflavone supplementation in postmenopausal women. J Womens Health. 2004 13 : 1000 1007.
58. Nikander E, Metsa-Heikkila M, Ylikorkala O, Tiitinen A. Effects of phytoestrogens on bone turnover in postmenopausal women with a history of breast cancer. J Clin Endocr Metab. 2004 89 : 1207 1212.
59. Dalais FS, Ebeling PR, Kotsopoulos D, McGrath BP, Teede HJ. The effects of soy protein containing isoflavones on lipids and indices of bone resorption in postmenopausal women. Clin Endocrinol. 2003 58 : 704 709.
60. Atkinson C, Compston JE, Day NE, Dowsett M, Bingham SA. The effects of phytoestrogen isoflavones on bone density in women: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr. 2004 79 : 326 333.
61. Setchell KDR, Brown NM, Desai P, et al. Bioavailability of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements. J Nutr. 2001 131 (Suppl S1362 S1375.
62. Frankenfeld C, Atkinson C, Thomas W, et al. Familial correlations, segregation analysis and nongenetic correlates of soy isoflavone-metabolising phenotypes. Exp Biol Med. 2004 229 : 902 913.
63. Bowey EA, Adlercreutz H, Rowland IR. Metabolism of isoflavones and lignans by the gut microflora: a study in germ-free and human flora associated rats. Food Chem Toxicol. 2003 41 : 631 636.
64. Simmering R, Pforte H, Jacobasch G, Blaut M. The growth of the flavonoid-degrading intestinal bacterium, Eubacterium ramulus, is stimulated by dietary flavonoids in vivo. FEMS Microbiol Ecol. 2002 40 : 243 248.
65. Ibarreta D, Daxenberger A, Meyer HHD. Possible health impact of phytoestrogens and xenoestrogens in food. APMIS. 2001 109 : 161 184.
66. Nettleton JA, Greany KA, Thomas W, Wangen KE, Adlercreutz H, Kurzer MS. Plasma phytoestrogens are not altered by probiotic consumption in postmenopausal women with and without a history of breast cancer. J Nutr. 2004 134 : 1998 2003.
67. Slavin J, Karr S, Hutchins A, Lampe J. Influence of soybean processing, habitual diet, and soy dose on urinary isoflavonoid excretion. Am J Clin Nutr. 1998 68 (Suppl S1492 S1495.
68. Tokunaga T. Novel physiological function of fructooligosaccharides. Biofactors. 2004 21 : 89 94.
69. Mathey J, Puel C, Kati-Coulibaly S, et al. Fructooligosaccharides maximize bone-sparing effects of soy isoflavone-enriched diet in the ovariectomized rat. Calcif Tissue Int. 2004 75 : 169 179.
70. Gnudi S, Giardino R, Mongiorgi R, et al. Evaluation of an experimental model of osteoporosis induced in the female rat through ovariectomy. Boll Soc Ital Biol Sper. 1993 69 : 453 460.
71. Giardino R, Fini M, Giavaresi G, Mongiorgi R, Gnudi S, Zati A. Experimental surgical model in osteoporosis study. Boll Soc Ital Biol Sper. 1993 69 : 453 460.
72. Arjmandi B, Getlinger M, Goya N, et al. Role of soy protein with normal or reduced isoflavone content in reversing bone loss induced by ovarian hormone deficiency in rats. Am J Clin Nutr. 1998 68 (Suppl S1358 S1363.
73. Arjmandi B, Birnbaum R, Goyal N, et al. Bone-sparing effect of soy protein in ovarian hormone-deficient rats is related to its isoflavone content. Am J Clin Nutr. 1998 68 (Suppl S1364 S1368.
74. Fanti P, Monier-Faugere M, Geng Z, et al. The phytoestrogen genistein reduces bone loss in short-term ovariectomised rats. Osteoporosis Int. 1998 8 : 274 281.
75. Deyhim F, Stoecker BJ, Brusewitz GH, Arjmandi BH. The effects of estrogen depletion and isoflavones on bone metabolism in rats. Nutr Res. 2003 23 : 123 130.
76. Kim MS, Lee YS. Effects of soy isoflavone and/or estrogen treatments on bone metabolism in ovariectomized rats. J Med Food. 2005 8 : 439 445.
77. Lee YB, Lee HJ, Kim KS, et al. Evaluation of the preventive effect of isoflavone extract on bone loss in ovariectomized rats. Biosci Biotechnol Biochem. 2004 68 : 1040 1045.
78. Ishimi Y, Arai N, Wang XX, et al. Difference in effective dosage of genistein on bone and uterus in ovariectomized mice. Biochem Biophys Res Commun. 2000 274 : 697 701.
79. Ward WE, Kim S, Chan D, Fonseca D. Serum equol, bone mineral density and biomechanical bone strength differ among four mouse strains. J Nutr Biochem. 2005 16 : 743 749.
80. Wu J, Wang XX, Chiba H, et al. Combined intervention of soy isoflavone and moderate exercise prevents body fat elevation and bone loss in ovariectomized mice. Metabolism. 2004 53 : 942 948.
81. Cai DJ, Zhao YD, Glasier J, et al. Comparative effect of soy protein, soy isoflavones, and 17 beta-estradiol on bone metabolism in adult ovariectomized rats. J Bone Min Res. 2005 20 : 828 839.
82. Picherit C, Bennetau-Pelissero C, Chanteranne B, et al. Soybean isoflavones dose-dependently reduce bone turnover but do not reverse established osteopenia in adult ovariectomised rats. J Nutr. 2001 131 : 723 728.
83. Picherit C, Chanteranne B, Bennetau-Pelissero C, et al. Dose-dependent bone-sparing effects of dietary isoflavones in the ovariectomised rat. Br J Nutr. 2001 85 : 307 316.
84. Blum S, Heaton S, Bowman B, Hegsted M, Miller S. Dietary soy protein maintains some indices of bone mineral density and bone formation in aged ovariectomised rats. J Nutr. 2003 133 : 1244 1249.
85. Picherit C, Coxam V, Bennetau-Pelissero C, et al. Daidzein is more efficient than genistein in preventing ovariectomy-induced bone loss in rats. J Nutr. 2000 130 : 1675 1681.
86. James P, Sabatier JP, Bureau F, et al. Influence of dietary protein and phyto-oestrogens on bone mineralization in the young rat. Nutr Res. 2002 22 : 385 392.
87. Hotchkiss C, Weis C, Blaydes B, Newbold R, Delclos K. Multigenerational exposure to genistein does not increase bone mineral density in rats. Bone. 2005 37 : 720 727.
88. Nakai M, Black M, Jeffery EH, Bahr JM. Dietary soy protein and isoflavones: no effect on the reproductive tract and minimal positive effect on bone resorption in the intact female Fischer 344 rat. Food Chem Toxicol. 2005 43 : 945 949.
89. Register TC, Jayo MJ, Anthony MS. Soy phytoestrogens do not prevent bone loss in postmenopausal monkeys. J Clin Endocr Metab. 2003 88 : 4362 4370.
90. Picherit C, Coxam V, Bennetau-Pelissero C, et al. Daidzein is more effective than genistein in preventing ovariectomy-induced bone loss in rats. J Nutr. 2000 130 : 1675 1681.
91. Kalu D. The ovariectomised rat model of postmenopausal bone loss. Bone Miner. 1991 15 : 175 191.
92. Turner R, Maran M, Lotinun S, et al. Animal models for osteoporosis. Rev Endocr Metab Disord. 2001 2 : 117 127.
93. Setchell K. Phytoestrogens: the biochemistry, physiology and implications for human health of soy isoflavones. Am J Clin Nutr. 1998 68 (Suppl S1333 S1346.
94. Migliaccio S, Anderson JJB. Isoflavones and skeletal health: are these molecules ready for clinical application? Osteoporosis Int. 2003 14 : 361 368.
95. Committee on Toxicity of Chemicals in Food Consumer Products and the Environment. Phytoestrogens and Health. London : Food Standards Agency 2003.
96. De Wilde A, Lieberherr M, Colin C, Pointillart A. A low dose of daidzein acts as an ER beta-selective agonist in trabecular osteoblasts of young female piglets. J Cell Physiol. 2004 200 : 253 262.
97. Adlercreutz H, Mazur W. Phyto-oestrogens and Western diseases. Ann Med. 1997 29 : 95 120.
98. Szkudelski T, Nogowski L, Pruszynska-Oszmalek E, Kaczmarek P, Szkudelska K. Genistein restricts leptin secretion from rat adipocytes. J Steroid Biochem Mol Biol. 2005 96 : 301 307.
99. Cotter AA, Jewell C, Cashman KD. The effect of oestrogen and dietary phyto-oestrogens on transepithelial calcium transport in human intestinal-like Caco-2 cells. Br J Nutr. 2003 89 : 755 765.
100. Arjmandi BH, Khalil DA, Hollis BW. Soy protein: its effects on intestinal calcium transport, serum vitamin D, and insulin-like growth factor-I in ovariectomized rats. Calcif Tissue Int. 2002 70 : 483 487.
101. Ge YB, Chen DW, Xie LP, Zhang RQ. Enhancing effect of daidzein on the differentiation and mineralization in mouse osteoblast-like MC3T3-E1 cells. Yakugaku Zasshi. 2006 126 : 651 656.
102. Pan W, Quarles LD, Song LH, et al. Genistein stimulates the osteoblastic differentiation via NO/cGMP in bone marrow culture. J Cell Biochem. 2005 94 : 307 316.
103. Ducy P. Cbfa1: a molecular switch in osteoblast biology. Dev Dynam. 2000 219 : 461 471.
104. Sant'Anna EF, Leven RM, Virdi AS, Sumner DR. Effect of low intensity pulsed ultrasound and BMP-2 on rat bone marrow stromal cell gene expression. J Orthopaed Res. 2005 23 : 646 652.
105. Abe E. Function of BMPs and BMP antagonists in adult bone. Ann NY Acad Sci. 2006 1068 : 41 53.
106. Federici E, Garrett R, Quintin A, et al. Soybean extract and its isoflavones, genistein and daidzein, stimulate BMP-2 expression and bone formation by inhibiting the mevalonate pathway in osteoblast cells. Bone. 2004 34 (Suppl S4 S4.
107. Jia TL, Wang HZ, Xie LP, Wang XY, Zhang RQ. Daidzein enhances osteoblast growth that may be mediated by increased bone morphogenetic protein (BMP) production. Biochem Pharmacol. 2003 65 : 709 715.
108. Chang H, Jin TY, Jin WF, Gu SZ, Zhou YF. Modulation of isoflavones on bone-nodule formation in rat calvaria osteoblasts in vitro. Biomed Environ Sci. 2003 16 : 83 89.
109. Dang ZC, Audinot V, Papapoulos SE, Boutin JA, Lowik C. Peroxisome proliferator-activated receptor gamma (PPAR gamma) as a molecular target for the soy phytoestrogen genistein. J Biol Chem. 2003 278 : 962 967.
110. Dang ZC, Lowik C. The balance between concurrent activation of ERs and PPARs determines daidzein-induced osteogenesis and adipogenesis. J Bone Miner Res. 2004 19 : 853 861.
111. Heim M, Frank O, Kampmann G, et al. The phytoestrogen genistein enhances osteogenesis and represses adipogenic differentiation of human primary bone marrow stromal cells. Endocrinology. 2004 145 : 848 859.
112. Manuel H, Pennimpede T, Kampmann G, et al. The phytoestrogen genistein represses PPAR gamma activity in human osteoblast cells via an ER alpha-mediated pathway. FASEB J. 2003 17 : A724 A725.
113. Kim S, Shin HJ, Kim SY, et al. Genistein enhances expression of genes involved in fatty acid catabolism through activation of PPAR alpha. Mol Cell Endocrinol. 2004 220 : 51 58.
114. Yamaguchi M, Ono R, Ma ZJ. Prolonged intake of isoflavone- and saponin-containing soybean extract (nijiru) supplement enhances circulating gamma-carboxylated osteocalcin concentrations in healthy individuals. J Health Sci. 2001 47 : 579 582.
115. Sliwinski L, Folwarczna J, Janiec W, Grynkiewicz G, Kuzyk K. Differential effects of genistein, estradiol and raloxifene on rat osteoclasts in vitro. Pharmacol Rep. 2005 57 : 352 359.
116. Palacios VG, Robinson LJ, Borysenko CW, Lehmann T, Kalla SE, Blair HC. Negative regulation of RANKL-induced osteoclastic differentiation in RAW264.7 cells by estrogen and phytoestrogens. J Biol Chem. 2005 280 : 13720 13727.
117. Yasuda H, Shima N, Nakagawa N, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Nat Acad Sci. 1998 95 : 3597 3602.
118. Nakagawa N, Kinosaki M, Yamaguchi K, et al. RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochem Biophys Res Commun. 1998 253 : 395 400.
119. Udagawa N, Takahashi N, Jimi E, et al. Osteoblasts/stromal cells stimulate osteoclast activation through expression of osteoclast differentiation factor/RANKL but not macrophage colony-stimulating factor. Bone. 1999 25 : 517 523.
120. Udagawa N. The mechanism of osteoclast differentiation from macrophages: possible roles of T lymphocytes in osteoclastogenesis. J Bone Min Metab. 2003 21 : 337 343.
121. Hsu HL, Lacey DL, Dunstan CR, et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Nat Acad Sci. 1999 96 : 3540 3545.
122. Fuller K, Wong B, Fox S, Choi Y, Chambers TJ. TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J Exp Med. 1998 188 : 997 1001.
123. Theoleyre S, Wittrant Y, Tat SK, Fortun Y, Redini F, Heymann D. The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling. Cytokine Growth Factor Rev. 2004 15 : 457 475.
124. Rassi CM, Lieberherr M, Chaumaz G, Pointillart A, Cournot G. Down-regulation of osteoclast differentiation by daidzein via caspase 3. J Bone Miner Res. 2002 17 : 630 638.
125. Yamagishi T, Otsuka E, Hagiwara H. Reciprocal control of expression of mRNAs for osteoclast differentiation factor and OPG in osteogenic stromal cells by genistein: evidence for the involvement of topoisomerase II in osteoclastogenesis. Endocrinology. 2001 142 : 3632 3637.
126. Crisafulli A, Altavilla D, Squadrito G, et al. Effects of the phytoestrogen genistein on the circulating soluble receptor activator of nuclear factor kappa B ligand-osteoprotegerin system in early postmenopausal women. J Clin Endocr Metab. 2004 89 : 188 192.
127. Collin-Osdoby P, Rothe L, Anderson F, Nelson M, Maloney W, Osdoby P. Receptor activator of NF-kappa B and osteoprotegerin expression by human microvascular endothelial cells, regulation by inflammatory cytokines, and role in human osteoclastogenesis. J Biol Chem. 2001 276 : 20659 20672.
128. Katagiri T, Takahashi N. Regulatory mechanisms of osteoblast and osteoclast differentiation. Oral Dis. 2002 8 : 147 159.
129. Huang YF, Cao SM, Nagamani M, Anderson KE, Grady JJ, Lu LJW. Decreased circulating levels of tumor necrosis factor-alpha in postmenopausal women during consumption of soy-containing isoflavones. J Clin Endocr Metab. 2005 90 : 3956 3962.
130. Li BB, Yu SF. Genistein prevents bone resorption diseases by inhibiting bone resorption and stimulating bone formation. Biol Pharm Bull. 2003 26 : 780 786.
131. Chen XW, Garner SC, Quarles LD, Anderson JJB. Effects of genistein on expression cell of bone markers during MC3T3-E1 osteoblastic differentiation. J Nutr Biochem. 2003 14 : 342 349.
132. Chen XW, Garner SC, Anderson JJB. Isoflavones regulate interleukin-6 and osteoprotegerin synthesis during osteoblast cell differentiation via an estrogen-receptor-dependent pathway. Biochem Biophys Res Comm. 2002 295 : 417 422.
133. Suh KS, Koh G, Park CY, et al. Soybean isoflavones inhibit tumor necrosis factor-alpha-induced apoptosis and the production of interleukin-6 and prostaglandin E-2 in osteoblastic cells. Phytochemistry. 2003 63 : 209 215.
134. Okamoto F, Okabe K, Kajiya H. Genistein, a soybean isoflavone, inhibits inward rectifier K+ channels in rat osteoclasts (Abstract). Jap J Physiol. 2001 51 : 501 509.
135. Hwang CS, Kwak HS, Lim HJ, et al. Isoflavone metabolites and their in vitro dual functions: They can act as an estrogenic agonist or antagonist depending on the estrogen concentration. J Steroid Biochem Mol Biol. 2006 101 : 246 253.