Estrogen deficiency is known to induce bone mineral loss – which correlates to the development of osteoporosis frequently observed in postmenopausal women with low estrogen levels. However, despite some discrepancy in this matter it is apparently not the classical estrogen receptor alpha (ER-α) which is responsible for the hormonal effect of estrogen on bone mineral density, but the protective ER-beta system. This ER-β system is also activated to a certain degree by isoflavones, which contributes to the bone-protective effects observed with a higher dietary intake of soy food and isoflavone supplements. Such bone-protective effects of isoflavones have not only been confirmed in animal experiments, but also in clinical observations (Wu et al. 2006; Zhang et al. 2005).
Beneficial effects of soy food and of isoflavone in general are known from epidemiological studies. In Asian countries with a high consumption of soy the risk of hip fracture is distinctly lower than in Western countries with no dietary habit of soy food (Koh et al. 2009). Most intriguingly, the intake of calcium is rather low in Asian countries – in Western countries calcium (next to vitamin D) is perceived as one of the most important factors for the prevention of bone mineral loss.
Menopausal women seem to profit best from the improved bone structure, although the results of the clinical observations are heterogeneous. The bioavailability of the isoflavones may play an important role when it comes to differences in study outcomes (Ikeda et al. 2006). In a large examination in 75,000 pre- and postmenopausal women a distinct protection from bone fractures was correlated with soy consumption and the intake of isoflavones. The risk of bone fractions was reduced by 50 % especially in early menopause (Zhang et al. 2005).
The benefits of isoflavones for bone structure could not be demonstrated in all clinical trials. E.g., a one-year double-blind study of isoflavone effects (110 mg daily as aglycones) on bone mineral density, bone metabolism and hormonal status in 237 healthy postmenopausal women failed to demonstrate changes in parameters of bone mineral density and markers of bone formation and resorption (Brink et al. 2008). Discrepancies between study outcomes have been explained by the intestinal isoflavone metabolism, mainly the transformation of daidzein into equol by the intestinal flora – although this was explicitly excluded in the study of Brink et al. (2008). Equol seems to have stronger effects than genistein or daidzein, a phenomenon also observed in animal studies (Kolios et al. 2009). Possibly the less pronounced overall results in European women are related to the inability to produce equol upon isoflavone ingestion (Wu et al. 2006), maybe also to the question of the contribution of life-long exposure in Asian countries. Despite the studies with negative outcome the benefits of sufficiently high doses of isoflavones (≥ 90 mg/day for at least 12 weeks) have been confirmed in a meta-analysis of randomized controlled trials, where isoflavone intake clearly promoted bone regeneration (Ma et al. 2008a; Ma et al. 2008b).
Starting from the natural isoflavones a semisynthetic derivative, ipriflavone, has been developed. Ipriflavone is administered against osteoporosis based on its bone-sparing and bone-regenerating effects (Sharan et al. 2009). Such effects have also been shown with isolated genistein: a placebo-controlled three-year study in 389 postmenopausal women confirmed an increase of the bone mineral density of the lumbar spine and the femoral neck upon daily ingestion of 54 mg of genistein – without any safety issues with respect to potential hormonal effects, e.g. on mammographic breast tissue density or endometrial thickness (Marini et al. 2008).
The validity of the clinical data on bone-sparing effects of isoflavones has been questioned by the German food authorities because of the lack of end-point studies. The existing studies have focused on surrogate parameters of bone resorption and bone regeneration, but no study to date has measured the frequency of bone fractures after prolonged intake of isoflavones. Such a position seems, however, rather dubious, as long term end-point studies can only be performed when the use of a certain active constituent has been accepted based on studies with surrogate parameters. Thus, drugs with anti-osteoporotic activity (incidentally the problem is identical for any other long-term preventive measure, e.g. the relation between lipid lowering and cardiovascular disease) will be prescribed long before robust end-point studies are available. In the case of soy there is a positive signal from epidemiological studies, and the potential benefits of a simple dietetic measure should not simply be discarded because there is still research performed on the topic. Overall, the existing data points to such benefits, with at the same time an excellent safety profile.
References
Brink, E., Coxam, V., Robins, S., Wahala, K., Cassidy, A., and Branca, F. (2008). 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. 87 (3): 761-770.
Ikeda, Y., Iki, M., Morita, A., Kajita, E., Kagamimori, S., Kagawa, Y., and Yoneshima, H. (2006). Intake of fermented soybeans, natto, is associated with reduced bone loss in postmenopausal women: Japanese Population-Based Osteoporosis (JPOS) Study. J. Nutr. 136 (5): 1323-1328.
Koh, W. P., Wu, A. H., Wang, R., Ang, L. W., Heng, D., Yuan, J. M., and Yu, M. C. (2009). Gender-specific associations between soy and risk of hip fracture in the Singapore Chinese Health Study. Am. J. Epidemiol. 170 (7): 901-909.
Kolios, L., Sehmisch, S., Daub, F., Rack, T., Tezval, M., Stuermer, K. M., and Stuermer, E. K. (2009). Equol but not Genistein Improves Early Metaphyseal Fracture Healing in Osteoporotic Rats. Planta Med 75 (5): 459-465.
Ma, D. F., Qin, L. Q., Wang, P. Y., and Katoh, R. (2008a). Soy isoflavone intake increases bone mineral density in the spine of menopausal women: meta-analysis of randomized controlled trials. Clin Nutr. 27 (1): 57-64.
Ma, D. F., Qin, L. Q., Wang, P. Y., and Katoh, R. (2008b). Soy isoflavone intake inhibits bone resorption and stimulates bone formation in menopausal women: meta-analysis of randomized controlled trials. Eur. J. Clin Nutr. 62 (2): 155-161.
Marini, H., Bitto, A., Altavilla, D., Burnett, B. P., Polito, F., Di, Stefano, V, Minutoli, L., Atteritano, M., Levy, R. M., D'Anna, R., Frisina, N., Mazzaferro, S., Cancellieri, F., Cannata, M. L., Corrado, F., Frisina, A., Adamo, V., Lubrano, C., Sansotta, C., Marini, R., Adamo, E. B., and Squadrito, F. (2008). Breast Safety and efficacy of genistein aglycone for post-menopausal bone loss: A follow-up study. J. Clin Endocrinol. Metab 93 (12): 7487-7496.
Sharan, K., Siddiqui, J. A., Swarnkar, G., Maurya, R., and Chattopadhyay, N. (2009). Role of phytochemicals in the prevention of menopausal bone loss: evidence from in vitro and in vivo, human interventional and pharma-cokinetic studies. Curr. Med Chem. 16 (9): 1138-1157.
Wu, J., Oka, J., Higuchi, M., Tabata, I., Toda, T., Fujioka, M., Fuku, N., Teramoto, T., Okuhira, T., Ueno, T., Uchiyama, S., Urata, K., Yamada, K., and Ishimi, Y. (2006). Cooperative effects of isoflavones and exercise on bone and lipid metabolism in postmenopausal Japanese women: a randomized placebo-controlled trial. Metabolism 55 (4): 423-433.
Zhang, X., Shu, X. O., Li, H., Yang, G., Li, Q., Gao, Y. T., and Zheng, W. (2005). Prospective cohort study of soy food consumption and risk of bone fracture among postmenopausal women. Arch. Intern. Med. 165 (16): 1890-1895.
Clinical effects 