Menopause Live (10 October, 2011) from IMS

Tai and colleagues [1] have recently reported that treatment with 300 mg/day of isoflavones (aglycone equivalents) (172.5 mg genistein + 127.5 mg daidzein) for 2 years failed to prevent lumbar spine and total proximal femur bone mineral density (BMD) from declining, as compared with the placebo group. This randomized, double-blind, two-arm-designed study was conducted in a clinical sample of 431 postmenopausal women aged 45–65 years in three centers of Taipei (Taiwan). Each participant also ingested 600 mg of calcium and 125 IU of vitamin D per day. The BMD of the lumbar spine and total proximal femur were measured using dual-energy X-ray absorptiometry at baseline and every half-year thereafter. Serum bone-specific alkaline phosphatase, urinary N-telopeptide of type 1 collagen/creatinine, and other safety assessments were examined regularly. Serum concentrations of isoflavone metabolites, genistein and daidzein, in the intervention group were remarkably elevated following intake of isoflavones (p < 0.001). However, differences in the mean percentage changes of BMD throughout the treatment period were not statistically significant (lumbar spine, p = 0.42; total femur, p = 0.39) between the isoflavone and placebo groups. A significant time trend of bone loss was observed at both sites following repeated measurement of BMD (p < 0.001). Differences in bone marker levels were not significant between the two treatment groups. The authors concluded that treatment with 300 mg/day isoflavones (aglycone equivalents) failed to prevent a decline in BMD in the lumbar spine or total femur compared with the placebo group.

Comment
The results of the current randomized, double-blind, placebo-controlled study indicated that a daily intake of 300 mg isoflavones for 2 years generated no difference in the rate of bone loss at the lumbar spine or total femur. Contrasting with these results, several previous studies and meta-analyses [2,3] have shown many beneficial effects of soy isoflavones on bone. However, most of the studies included only small sample sizes, there was no control of compliance by assessing isoflavones in blood, and there may have been biases, or short follow-up periods, and therefore long-term effects could not be evaluated. A recent meta-analysis on the effects of supplementation with soy isoflavone extract with an average of 82 mg (47–150 mg) (aglycone equivalents) on BMD [3] showed an increase in lumbar spine BMD by 2.4% after 6–12 months. However, no significant change of proximal femur BMD could be found [3]. It is noteworthy that recent reports have demonstrated the absence of the supposed beneficial effects of isoflavones on bone, supporting the results of this large study by Tai and colleagues [4,5]. This controversy may be the result of differences in dosage, product forms, length of observations, ethnic dietary habits, or other factors related to the high variability in the soy isoflavone compounds. Interestingly, the results within each center were analyzed separately and did not show any trend of effects. 

The main challenge with this study was that the sample size was not sufficient to establish the real effects of isoflavones on fracture incidence. However, the fracture rate reported by Tai and colleagues was higher than the previously reported rate in a large prospective cohort [6] and, in view of the 64% increase in bone fracture rate in the isoflavone arm compared with that of the placebo arm, more cautious monitoring in this regard is mandatory.

Camil Castelo-Branco
Ob Gyn Senior Consultant, Hospital Clínic Barcelona, and Full Professor, University of Barcelona, Spain

References
1. Tai TY, Tsai KS, Tu ST, et al. The effect of soy isoflavone on bone mineral density in postmenopausal Taiwanese women with bone loss: a 2-year randomized double-blind placebo-controlled study. Osteoporos Int 2011 Sep 8. Epub ahead of print
http://www.ncbi.nlm.nih.gov/pubmed/21901480
2. Taku K, Melby MK, Kurzer MS, Mizuno S, Watanabe S, Ishimi Y. Effects of soy isoflavone supplements on bone turnover markers in menopausal women: systematic review and meta-analysis of randomized controlled trials. Bone 2010;47:413–23.
http://www.ncbi.nlm.nih.gov/pubmed/20452475
3. Taku K, Melby MK, Takebayashi J, et al. Effect of soy isoflavone extract supplements on bone mineral density in menopausal women: meta-analysis of randomized controlled trials. Asia Pac J Clin Nutr 2010;19:33–42.
http://www.ncbi.nlm.nih.gov/pubmed/20199985
4. Kenny AM, Mangano KM, Abourizk RH, et al. Soy proteins and isoflavones affect bone mineral density in older women: a randomized controlled trial. Am J Clin Nutr 2009;90:234–42.
http://www.ncbi.nlm.nih.gov/pubmed/19474141
5. Alekel DL, Van Loan MD, Koehler KJ, et al. The soy isoflavones for reducing bone loss (SIRBL) study: a 3-y randomized controlled trial in postmenopausal women. Am J Clin Nutr 2010;91:218–30.
http://www.ncbi.nlm.nih.gov/pubmed/19906801
6. Zhang X, Shu XO, Li H, et al. Prospective cohort study of soy food consumption and risk
http://www.ncbi.nlm.nih.gov/pubmed/16157834