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Journal of the American College of Nutrition, Vol. 21, No. 6, 560-563 (2002)
Published by the American College of Nutrition

Soybean Isoflavones Reduce Postmenopausal Bone Resorption in Female Japanese Immigrants in Brazil: A Ten-Week Study

Yukio Yamori, MD, PhD, FACN, Emilio H. Moriguchi, MD, PhD, Takanori Teramoto, MS,, Ayako Miura, MS, Yutaka Fukui, MS, Kei-ich Honda, MS, Masakazu Fukui, MS, Yasuo Nara, PhD, Kazuhiko Taira, MD and Yukio Moriguchi, MD, PhD

WHO Collaborating Center for Research on Primary Prevention of Cardiovascular Diseases, Kyoto (Y.Y.)
Fujicco Co., Ltd., Kobe (T.T., Y.F., K.H., M.F.)
Department of Life Long Health Promotion Faculty of Education, University of the Ryukyus, Nishihara (A.M., K.T.)
Division of Life Science, Graduate School of Integrate Science and Art University of East Asia, Shimonoseki (Y.N.), JAPAN
Institute of Geriatrics and Gerontology, Pontifical Catholic University of Rio Grande do Sul, Rio de Janeiro, BRAZIL (E.M., Y.M.)

Address reprint requests to: Yukio Yamori MD, PhD, FACN, WHO Collaborating Center for Research on Primary Prevention of Cardiovascular Diseases, Kokusaikenju Bldg, 86, Shimobanba-cho, Joudoji, Sakyo-ku, Kyoto 6068431, JAPAN. E-mail: Yukio.Yamori{at}ma3.seikyou.ne.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 REFERENCES
 
Objective: Some human studies and animal models of experimental osteoporosis have shown that soy isoflavones may be effective on bone health. In this study, we carried out an intervention study to explore the effects of dietary isoflavone on bone metabolism.

Methods: Forty healthy female postmenopausal Japanese immigrants living in Brazil were divided into two groups: isoflavone-administered (n = 20) or placebo (n = 20). Subjects in the isoflavone-administered group ingested 37.3 mg per day for 10 weeks. The collection of 24-hour urine and the measurement of bone stiffness were performed at 0 and 10 weeks. Urinary excretion of isoflavones and bone resorption markers were analyzed.

Results: Urinary isoflavone excretion in the isoflavone-administered group was significantly increased at weeks 3 and 10. Urinary excretion of bone resorption markers was reduced in the isoflavone-administered group, while the placebo group did not show any significant reduction. Differences in levels of urinary isoflavones and bone resorption markers between the two groups were significant.

Conclusion: This study demonstrated that the bone resorption was associated with the intake of soy isoflavones in postmenopausal women, and continuous dietary intake of isoflavone may inhibit postmenopausal osteoporosis.

Key words: isoflavones, bone resorption, pyridinoline, deoxypyridinoline, postmenopausal women


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 REFERENCES
 
Soy isoflavones with weak estrogen-like activities has already been shown to have possible inhibitory effects on carcinogenesis in breast and prostate, cardiovascular diseases, and may also benefit bone metabolism [1]. It is well known that isoflavone glycosides, daidzin, genistin and glycitin, and their acylates and malonylates are abundant in soybeans and are metabolized to their aglycons [2]. Glucuronate and sulfate conjugates of isoflavones are detectable in both blood and urine. Xu et al. reported that isoflavones are excreted into the urine over 24 hours at a rate of 15% to 20% for daidzein and 10% for genistein [3,4].

The relationships between soybean isoflavones and bone tissue have been studied for less than decade. Data from several animal studies have demonstrated that soy isoflavones had bone-conserving effects in the retention of bone mass following ovariectomy [5,6]. A possible role for soy isoflavones in modifying human bone mass has been suggested by Potter et al. [7] and Alekel et al. [8]. They found that soy protein supplements enriched in isoflavones attenuated bone loss in postmenopausal and perimenopausal women. Some in vitro studies have suggested that isoflavones had biphasic effects, bone formation [9,10] and bone resorption [11].

Pyridinoline and deoxypyridinoline, nonreducible crosslinks released from bone tissue during bone resorption, are known to be one of the specific bone resorption markers [12]. At the clinical level, the urinary concentrations of these markers have been shown to correlate inversely with individual bone mass in postmenopausal patients [13, 14].

In this study, we examined the effects of the consumption of soy isoflavones on bone metabolism, especially bone resorption, in postmenopausal Japanese immigrants in Brazil.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 REFERENCES
 
Subjects
The randomized double-blind, placebo-controlled clinical study was conducted in Campo Grande, Brazil, under the supervision of the WHO Collaborating Centre for Research on Primary Prevention of Cardiovascular Diseases. Informed consent was obtained from all subjects based on the Ethical Committee of the Pontifical University of Rio Grande do Sul. Forty healthy postmenopausal women, aged 45 to 59, were recruited from among 200 Japanese immigrants from Okinawa. Twenty subjects were assigned randomly to receive an isoflavone diet, and the remaining 20 subjects were assigned to receive a placebo diet.

Diets
A mixture of roasted hypocotyl (germ) of soybean and sesame (1:2 w/w) was used as a source of isoflavones. Subjects ingested two spoonfuls of this mixture (approximately 6 g) per day for 10 weeks. Total daily isoflavones in this diet was 37.3 mg (Table 1). Subjects in the placebo group ingested the diet composed only of the sesame. The dietary restriction during the study period was not completely carried out.


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  		Table 1. Components of the administered sample (6 g/day)

 
Urine Analyses
Twenty-four hour urine specimens were collected at weeks 0, 3 and 10 in order to measure the excretion of isoflavones, bone resorption markers (pyridinoline and deoxypyridinoline) and creatinine. Analytical methods of these components were described by Uesugi et al. [15].

Bone Stiffness
The stiffness value as an index of bone density was determined using an Achilles ultrasound bone densitometer (Achilles A-1000, Lunar Corp., Madison, WI). Right calcaneal bone stiffness was measured at the beginning of the study and 10 weeks later.

Statistical Methods
Differences between the means for the two groups were evaluated by using Student’s t test. Changes within each group were evaluated by using Student’s paired t test, and differences between the changes observed in each groups were evaluated by using repeated ANOVA. Differences in the means were considered statistically significant when p < 0.05. StatView-j Version 4.11 (Abacus Concepts, Inc., Berkeley, CA) was utilized for statistical analysis.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
REFERENCES
 
There were no significant differences as regards baseline characteristics including age, year after menopause, height, weight and body mass index, between the test (isoflavone supplemented) and placebo group (Table 2).


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  		Table 2. Baseline characteristics

 
The changes of urinary isoflavones excretion during the test period are shown in Table 3. In the test group, urinary daidzein excretion was significantly increased at 3 and 10 weeks in comparison with the baseline or the placebo group. In the placebo group, for the contrariety, it was significantly decreased in comparison with the baseline at 10 weeks. The increase in urinary genistein excretion by administration could not be recognized except at 3 weeks.


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  		Table 3. Effects of isoflavone supplementation on urinary markers and bone stiffness

 
The changes of urinary excretion of bone resorption parameters, pyridinoline and deoxypyridinoline are shown in Table 3. In the test group, pyridinoline was significantly decreased at weeks 3 and 10 from the baseline level, and deoxypyridinoline was significantly decreased in comparison with the placebo group. The significant changes of bone resorption markers during the test period could not be recognized in the placebo group.

Bone stiffness did not significantly change within or between the two groups during the 10 weeks of this study (Table 3).


   DISCUSSION
 
The present study examined the effects of soy isoflavones consumption (37.3 mg per day) on bone stiffness and urinary bone resorption markers, pyridinoline and deoxypyridinoline, in postmenopausal Japanese immigrants in Brazil.

It was confirmed that the urinary isoflavone excretion significantly increased by the isoflavone administration in this examination. This means that the testing diets were appropriately taken, indicating the good compliance of the test group. On the other hand, the placebo group had the low level of urinary isoflavone excretion throughout the study period. Though Japanese generally have habitually high intake of dietary isoflavones [16], it is considered that dietary isoflavone intake decreased in Japanese women who immigrated to Brazil.

The isoflavone intake for 3 or 10 weeks was proven to decrease the excretion of urinary bone resorption markers, reversed with the increase in the excretion of urinary isoflavone. Stock et al. reported that the estrogenic effects on the bone might appear in a short period because the administration of estrogen for two weeks could change the bone metabolic parameters in postmenopausal women [17]. Animal studies demonstrated that isoflavones, daidzin, genistin or glycitin, as well as estrogen, had prospective effects against bone loss and bone resorption accentuation after ovariectomy [18,19]. These data indicate that the isoflavone effect observed in this study on bone metabolism was due to the weak estrogenic effect that isoflavones possessed.

Uesugi et al. demonstrated that the intake of soy isoflavones (61.8 mg per day) for four weeks was associated with a significant reduction in the excretion of bone resorption markers, pyridinoline and deoxypyridinoline, in postmenopausal Japanese women [15]. The subjects in that previous study had customarily high isoflavone intake. Our present study targeted postmenopausal Japanese women without habitual intake of dietary isoflavones and was designed to test whether or not the reduced dose of isoflavones (37.3 mg per day) has a similar effect on bone at that recognized in the previous report. From the knowledge of studies of Asian women, Anderson et al. suggested a benefit of soy consumption on the skeletal tissue, with average intakes as high as 30 g per day providing almost 40 mg of isoflavones a day [20]. Their suggestion about the effective isoflavone quantity for the bone seems to agree well with our results given in this study. It should be further examined whether the comparatively low dose of isoflavones such as that in this study has any effect in Japanese who are taking isoflavones habitually.

No significant changes in the stiffness value, an index of bone density, were noted in this ten-week study. Potter et al. reported that daily intake of a soy protein diet with 90 mg isoflavones for six months was associated with increased bone mineral density and content [7]. Alekel et al. also reported that the daily intake of a soy protein diet with 80.4 mg isoflavones for six months was associated with increased bone mineral density and content [8]. These studies showed the positive effects on bone health of the longer isoflavone intake in comparison with our study, and the effectiveness on the bone proven in these studies was not at the calcaneal bone but at the lumbar spine only. The longer intake period or an investigation of the lumbar spine, even in this study, might give a beneficial skeletal effect since we could detected the beneficial preventive effects on the bone resorption.

Based on these date about isoflavone intake and bone health, we conclude that continuous dietary isoflavone intake should reduce bone resorption and may thus contribute to the prevention of postmenopausal osteoporosis.

Received May 31, 2002. Accepted July 9, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 REFERENCES
 

  1. Adlercreutz HCT, Goldin BR, Gorbach SL, Hockerstedt KAV, Watanabe S, Hamalainen EK, Markkanen MH, Makela TH, Wahala KT, Hase TA, Fotsis T: Soybean phytoestrogen intake and cancer risk.J Nutr125 :757S –770S,1995 .
  2. Setchell KDR, Adlercreutz H:Mammalian lignans and phyto-oestrogens recent studies on their formation, metabolism and biological role in health and disease In Rowland IR (ed): "Role of the Gut Flora in Toxicity and Cancer." San Diego: Academic Press, pp315 –345,1988 .
  3. Xu X, Wang HJ, Murphy PA, Cook L, Hendrich S: Daidzein is a more bioavailable soymilk isoflavone than is genistein in adult women.J Nutr124 :825 –832,1994 .
  4. Xu X, Harris KS, Wang HJ, Murphy PA, Hendrich S: Bioavailability of soybean isoflavones depends upon gut microflora in women.J Nutr125 :2307 –2315,1995 .
  5. Arjmandi BH, Alekel L, Hollis BW, Amin D, Stacewicz-Sapuntzakis M, Guo P, Kukreja SC: Dietary soybean protein prevents bone loss in an ovariectomized rat model of osteoporosis.J Nutr126 :161 –167,1996 .
  6. Ishida H, Uesugi T, Hirai K, Toda T, Nukaya H, Yokotsuka K, Tsuji K: Preventive effects of the plant isoflavones, daidzin and genistin, on bone loss in ovariectomized rats fed a calcium-deficient diet.Biol Pharm Bull21 :62 –66,1998 .[Medline]
  7. Potter SM, Baum JA, Teng H, Stillman RJ, Shay NF, Erdman JW: Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women.Am J Clin Nutr68 :1375S –1379S,1998 .[Abstract]
  8. 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 Nutr72 :844 –852,2000 .[Abstract/Free Full Text]
  9. Yamaguchi M, Gao YH: Anabolic effect of daidzein on cortical bone in tissue culture: Comparison with genistein effect.Mol Cell Biochem194 :93 –97,1999 .[Medline]
  10. Yoshida H, Teramoto T, Ikeda K, Yamori Y: Glycitein effect on suppressing the proliferation and stimulating the differentiation of osteoblastic MC3T3-E1 cells.Biosci Biotechnol Biochem65 :1211 –1213,2001 .[Medline]
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  12. Kent GN: Markers of bone resorption and their application in metabolic bone disease.Clin Biochem Rev16 :4 –10,1995 .
  13. Garnero P, Shin WJ, Gineyts E, Karpf DB, Delmas PD: Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment.J Clin Endocrinol Metab79 :1693 –1700,1994 .[Abstract]
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  15. 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 Nutr21 :97 –102,2002 .[Abstract/Free Full Text]
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