Soy Effects on Osteoporosis

Source: Ho SC, et al. Soy protein consumption and bone mass in early postmenopausal Chinese women. Osteoporos Int 2003;14: 835-842.

Abstract: Recent interest has been shown in the potential beneficial effects of phytoestrogens on bone health. As the early years of menopause are a period of rapid bone loss and the risk for osteoporosis increases substantially, the habitual intake of soy protein and isoflavones may play a role in the retardation of bone loss. This paper reports the results of the baseline cross-sectional analysis of the association between dietary soy protein intake and bone mineral density/content in a population-based study of Chinese women. The sample comprised 454 healthy Chinese women (mean age 55.1 ± 3.57 years) within the first 12 years of postmenopause. The authors estimated the dietary intake of soy protein and isoflavones and other key nutrients, including dietary protein and calcium, using the quantitative food-frequency method. Bone mineral density (BMD) and content (BMC) at the spine, hip, and total body were measured with a dual energy X-ray densitometer (Hologic 4500A). Stratified analyses were carried out among women within or at least four years postmenopausal. The authors observed few differences in BMD/BMC values among the intake quartiles in women within the first four years of menopause. However, among the later postmenopausal women, they noted a dose-response relationship with increasingly higher BMD values at the trochanter, intertrochanter as well as the total hip and total body with increasing soy protein intake quartiles (P < 0.05 from tests for trend). The BMD values differed by about 4-8% between the first and fourth soy protein intake quartiles. Though women from the fourth intake quartile had a 2.9% higher BMD value compared with those from the first intake quartile, the difference was not statistically significant. Stepwise multiple linear regression analyses showed the association between soy intake quartiles and hip BMD as well as total body BMC values remained after adjusting for body weight, which was retained in the final model. Analyses based on soy isoflavones content yielded similar results. This study demonstrated that among women after the initial few years postmenopausal, soy protein/isoflavones intake had a modest but significant association with hip BMD as well as total body BMC. The effects of soy protein and soy isoflavones on bone health should be further explored in populations with habitual dietary soy intake.

Source: Chen YM, et al. 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 Endocrinol Metab 2003;88:4740-4747.

Abstract: Animal studies have shown that soy isoflavones have an effect in preventing estrogen-related bone loss, but few data are available in humans, especially in Asian populations. This double-blind, placebo-controlled, randomized trial examines the effects of soy isoflavones on bone loss in postmenopausal Chinese women, aged 48-62 years. Two hundred and three eligible subjects were randomly assigned to three treatment groups with daily doses of placebo (1 g starch; n = 67), mid-dose (0.5 g starch, 0.5 g soy extracts, and approximately 40 mg isoflavones; n = 68), and high dose (1.0 g soy extracts and approximately 80 mg isoflavones; n = 68). All were given 12.5 mmol (500 mg) calcium and 125 IU vitamin D. BMD and BMC of the whole body, spine, and hip were measured using dual energy X-ray absorptiometry at baseline and one year post-treatment. Both univariate and multivariate analyses showed that women in the high-dose group had mild, but statistically significantly, higher favorable change rate in BMC at the total hip and trochanter (P < 0.05) compared with the placebo and mid-dose groups, even after further adjustments for potential confounding factors. Further stratified analyses revealed the positive effects of soy isoflavone supplementation were observed only among women with lower initial baseline BMC (median or less). In conclusion, soy isoflavones have a mild, but significant, independent effect on the maintenance of hip BMC in postmenopausal women with low initial bone mass.

Comments by Mary L. Hardy, MD

Osteoporosis—low bone mass or density—is a common sequela of aging that can have devastating effects on morbidity and mortality, especially in older women. Ten million women and men have osteoporosis currently. By 2010, that number is expected to grow to 12 million. An additional 55% of the population 50 years or older is at risk of developing osteoporosis and subsequently will be at higher risk for developing hip, wrist, and vertebral fractures.1 Effective medical therapy exists for this condition, but issues of cost, difficulty of use, and side effects limit use and patient acceptance. Therefore, there is interest in determining what dietary and lifestyle factors can promote bone health.

Soybeans contain a number of active constituents, specifically protein, isoflavones, and lignans. Also referred to as phytoestrogens, isoflavones are a class of phenolic compounds that are believed to exert weak estrogen-like effects, either through direct action on estrogen receptors or through modulating the effect of the much stronger endogenous estrogens.2 Although results for use of soy foods and isolated isoflavones for the reduction of vasomotor symptoms of menopause have been disappointing, the literature for the maintenance of bone health has been more hopeful.3 Two recent trials examining the effects of phytoestrogens on bone health have been performed on postmenopausal Chinese women.

A group of healthy Chinese women in Hong Kong who had been in menopause for 12 years or less were questioned regarding their soy food intake in the previous 12 months using a validated food-frequency questionnaire.4 A number of strategies were used to improve recall, such as including lists of specific soy foods and food types available in local markets (tofu pudding, curd sheets, tofu-rope) and including photos in the food portion control instrument. All women were given adequate calcium and vitamin D supplementation. Soy isoflavone and protein amounts were measured using standard food composition tables. Bone mineral density (BMD) and bone mineral content (BMC) were measured using dual energy X-ray densitometry at the left lumbar area and left hip. No laboratory measure of soy isoflavone intake, such as urinary isoflavones, was performed. Women in the lowest quartile approximated soy consumption of American women with a rate of 1.4 g/d, with average soy intake by the whole group recorded as 8 g/d. Women in the highest quartile of soy consumption had a mean soy intake of 19 g/d, but the range of consumption was huge (from 10-77 g/d). Isoflavone content of these foods followed the amounts of protein (approximately 0.2% of protein weight), but was not reported separately in the analysis.

The lack of urinary isoflavone levels to validate reports of oral soy intake is a limitation of this trial, but despite this there are interesting data to consider. Results showed little difference in early menopause (first four years) between the bone density and soy intake of the women in this cohort. However, for women who had been menopausal for longer periods (n = 185), there was a dose-response relationship between soy protein intake and higher BMD at the hip, but not at the spine (P < 0.05). Women in the highest quartile of use had a BMD almost 3% greater than women in the lowest quartile. The trend approached but did not exceed the level of statistical significance. Finally, a statistical method was applied to identify and remove the contribution to the effect of all confounding and interdependent variables (stepwise multiple linear regression analysis). Even after this analysis was performed, the positive association for BMD at the hip remained.

A follow-up clinical trial was performed by the same research group on a similar population of Chinese women in Hong Kong.5 In this randomized, double-blind, controlled trial, the effects of one year’s supplementation with a high or a low dose of soy isoflavones was tested in 203 postmenopausal women. The low dose of soy delivered 0.5 g/d of protein and 40 mg/d of isoflavones; the high dose contained 1 g/d of protein and 80 mg/d of isoflavones. The specific product tested was a little unusual in that it was a soy germ extract, not a soybean extract. The ratio of isoflavones in the current product (46% daidzein, 39% glycetein, 15% genistein) is different than usual soybean extracts. Bone density was measured as it was in the previous trial. No urinary measure of isoflavones was performed. Without the collection of urinary isoflavones, no independent assessment of compliance, with either diet or supplement, was made (a weakness of this trial). A dietary assessment of soy protein and total protein intake was performed by questionnaire. Women were not asked to modify their dietary soy intake, so this supplementation occurred on a background of relatively high soy dietary intake.

After one year of treatment, women in the high-dose group were shown to have a mild, but statistically significant, increase in BMC at the hip, but not the spine. This result remained even after statistical analysis designed to adjust for the effect of potential confounding factors (protein intake, weight, calcium use, baseline BMC) was removed. The strength of these data is called into question by the fact that BMD decreased in the hip rather than increased. Both BMD and BMC of the spine decreased; the rate of decline was not significantly slower than for the placebo or low-dose groups. It also should be noted that the supplement group reported minor side effects including abdominal distention (n = 14), constipation (n = 6), and breast disorder (n = 6). These complaints were not separated from placebo. Although the exact complaints from the placebo group were not reported, the researchers were told that there was no statistically significant difference in complaints between the two groups.

Although these results are modest and are not seen for all anatomical sites, they are encouraging. Both food sources and supplements appear to help maintain BMC/ BMD at the hip at least. It may be difficult to generalize these results to less ethnically similar populations who do not have a lifetime habit of soy consumption. In addition, it is possible that the type of soy products eaten in China are different from those eaten in the United States. For example, the most common U.S. soy product is soy milk, which is less common in China. The soy isoflavone product tested in the second trial contains different isoflavones than those previously tested, and this variation may have affected the results either positively or negatively.

To put these data and reservations in context, it is necessary to look at a broader survey of the literature on the effect of soy on bone health.3 A recent review by Setchell and Lydeking-Olsen collected data from in vitro and animal trials as well as observational and experimental human studies. The preclinical data suggest a biologically plausible mechanism for soy and its constituents to positively affect bone health. Isoflavones affect bone cells in culture; ovariectomized rats conserve bone with added soy in diet; and soy constituents genistein and daidzen have weak estrogenic activity in binding studies. Regarding the human studies, the results were mixed, but on balance this author concludes that the data are good enough to proceed to large, well-controlled trials.

For clinicians in practice: While we wait for these large trials, it seems reasonable to encourage the use of soy food, at a level to deliver 20-25 g/d of soy protein and 40 mg/d of isoflavones. The safety of this intervention is good. The food source is high-quality and healthy for the heart and could very well be a significant addition to a good osteoporosis prevention program, along with calcium supplementation and exercise. This intervention should be started even before the onset of menopause in order to maximize benefit. Use of isolated isoflavones has less supportive data and lacks the value of the soy protein component. 

Dr. Hardy, Medical Director Cedars-Sinai Integrative Medicine Medical Group Los Angeles, CA, is on the Editorial Advisory Board of Alternative Therapies in Women’s Health.

References

1. National Osteoporosis Foundation: Disease statistics. Available at: www.nof.org/osteoporosis/stats.htm. Accessed Jan. 15, 2004.

2. Duncan AM, et al. Phyto-oestrogens. Best Pract Res Clin Endocrinol Metab 2003;17:253-271.

3. Setchell KDR, Lydeking-Olsen E. Dietary phytoestrogens and their effect on bone: Evidence from in vitro and in vivo, human observational, and dietary intervention studies. Am J Clin Nutr 2003;78(suppl): 593S-609S.

4. Ho SC, et al. Soy protein consumption and bone mass in early postmenopausal Chinese women. Osteoporos Int 2003;14:835-842.

5. Chen YM, et al. 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 Endocrinol Metab 2003;88: 4740-4747.