Elsevier

Metabolism

Volume 55, Issue 4, April 2006, Pages 423-433
Metabolism

Cooperative effects of isoflavones and exercise on bone and lipid metabolism in postmenopausal Japanese women: a randomized placebo-controlled trial

https://doi.org/10.1016/j.metabol.2005.10.002Get rights and content

Abstract

Cooperative effects of isoflavones and exercise on bone and lipid metabolism have been exhibited in estrogen-deficient animals; however, results from clinical trials have not been published. In this study, we determined the effects of isoflavone intake and walking and their interaction on bone and lipid metabolism in postmenopausal women over 24 weeks. The bioavailability and metabolism of isoflavones (daidzein in particular) were also examined to clarify the mechanism of their bone-protective effects in humans. One hundred twenty-eight subjects were randomly assigned to 4 groups: placebo; placebo combined with walking (3 times per week); isoflavone intake (75 mg of isoflavones conjugates per day); and isoflavone combined with walking. The subjects were classified by equol status (producers or nonproducers) as identified using production of equol from daidzein in fecal culture. Bone mineral density (BMD), body composition, and serum concentrations of isoflavones were assessed. Serum high-density lipoprotein cholesterol concentration significantly increased (6.1%, P = .03), and fat mass in the whole body significantly decreased (−4.3%, P = .0003) from the baseline in the combined intervention group. There were no significant differences in BMD between baseline and postintervention in any of the treatment groups. However, the percent changes in BMD in equol producers were −0.53% and +0.13% in the sub–whole body and total hip, respectively. This was significantly different compared with −1.35 and −1.77 for the sub–whole body and total hip, respectively, in nonproducers in the isoflavone group (P = .049 and .040, respectively). The mean serum equol concentration was significantly higher in equol producers than in nonproducers in the isoflavone groups, but not in the placebo group. The combination of isoflavones and exercise exhibited favorable effects on serum lipid and body composition of postmenopausal women. The findings of this study suggest that the preventive effects of isoflavones on bone loss depend on the individual's intestinal flora for equol production.

Introduction

Menopause is often associated with the incidence of several chronic diseases including osteoporosis, cardiovascular disease, and obesity [1], [2], [3], [4]. Hormone replacement therapy (HRT) is the effective regimen to prevent these diseases in postmenopausal women [5], [6]; however, it is accompanied by an increased risk of unfavorable outcomes [7].

Recently, phytoestrogens have received a great deal of attention for their potential role in preventive osteoporosis and hypercholesterolemia because they are not as likely as steroid hormones to cause undesirable side effects in estrogen-deficient animals and postmenopausal women [8], [9], [10], [11]. The predominant phytoestrogens found in plants are soybean isoflavones, including genistin, daidzin, and glycitin, which have structures similar to that of estrogen [12]. We previously reported that genistein dose-dependently inhibited bone loss in both female and male osteoporotic animal models without any adverse effects [13], [14], [15]. However, conflicting results have been reported in several observational clinical studies, even among Asians who consume 10 to 100 times more isoflavones than Westerners [16]. Setchell et al [17] have recently suggested that equol, a specific intestinal bacterial metabolite of the isoflavone daidzein, is the single most important factor influencing the clinical efficacy of soy isoflavones in preventing bone loss, and individual variation in production capability may explain the mixed results in many studies.

On the other hand, it is well established that exercise is also effective in preventing bone loss and hypercholesterolemia resulting from estrogen deficiency in both animal and human studies [18], [19], [20]. Although high-intensity exercise can be expected to increase bone mass in pre/postmenopausal women, it is also often associated with stress fractures, especially in fragile skeletons. Walking is a relatively safe and common exercise among elderly people. However, it has a relatively low impact on bones and is, therefore, insufficient for the prevention of bone loss in postmenopausal women [21]. Thus, in clinical research, it has been shown that a combination of estrogen with exercise is more effective in increasing trabecular bone mineral density (BMD) in older women as compared with either treatment alone [22]. In this context, we have recently demonstrated that, in the prevention of bone loss and fat gain in estrogen-deficient animals, a combined intervention of moderate-intensity exercise and isoflavone administration was more advantageous than either treatment alone [23], [24], [25]. To assess this issue in humans, we examined the cooperative effects of soy isoflavone intake and walking on bone and lipid metabolism in postmenopausal Japanese women. Furthermore, we stratified the subjects by equol status, which is dependent on the individual's intestinal flora, to determine the actual effects of soy isoflavone on bone loss in early postmenopausal women.

The following questions were addressed in the present study:

  • 1.

    Are there any cooperative effects of isoflavones and walking on bone and lipid metabolism and the body composition of humans?

  • 2.

    Is there a positive association between soy isoflavone intake and the concentrations of serum isoflavones, including daidzein and equol, based on equol status?

  • 3.

    Is there any difference in the effect of soy isoflavone intervention on the change in BMD between equol producers and nonproducers among postmenopausal Japanese women?

Section snippets

Subjects

Subjects were recruited for this study through advertisements in local newspapers, and those who met the following criteria were enrolled in the study. Healthy postmenopausal women aged 45 to 60 years who were within 5 years of natural menopause defined as at least 12 months since last menstrual cycle were enrolled for the study. The subjects had not previously used hormone therapy, lipid-lowering medications, antibiotics, or any other medication known to affect the skeleton. They provided

General

The physical characteristics, daily intake of nutrients, and activity levels of the subjects at baseline and at 6 months of intervention are shown in Table 1. There were no significant differences in age, years since menopause, height, weight, BMI, and daily intake of isoflavones, calcium, vitamin D, and total protein among the different treatments groups at baseline. Average daily intake of isoflavone from soy foods (except isoflavone capsules) in each group at baseline was 44.4 to 49.4 mg.

Discussion

This randomized placebo-controlled study shows that the combined intervention of soy isoflavone intake and walking is most effective in decreasing the body fat and increasing the serum HDL-C concentration in early postmenopausal women, although the significant main effect was found for walking alone. Although isoflavone intervention for 6 months did not show a significant bone-protective effect, there was a significant difference in the percent change in BMD in the sub–whole body and hip

Acknowledgments

This study was supported by grants from the National Institute of Health and Nutrition, Ministry of Health, Labor and Welfare, Japan; Fujicco Japan; and the Japan Health Science Foundation.

We are grateful for the expert technical assistance and support provided by Dr Hidemi Takimoto, Ms Tomoko Ito, Dr Gang Mu, Ms Kiho Sugimoto, and Ms Fumie Sugiyama. We thank Dr Melissa Melby and Dr Mariko Uehara for discussion and preparation of the manuscript. We also gratefully acknowledge the dedicated

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