The results of the current randomized, double-blind, placebo-controlled study indicated that a daily intake of 300-mg isoflavones (aglycone equivalents) for 2 years generated no difference in the rate of bone loss at the lumbar spine or total femur. The two bone turnover markers examined, serum BAP and urinary NTx/creatinine, similarly showed no significant difference between the two groups throughout the course of treatment. In terms of time trend, isoflavone treatment in this study failed to change bone turnover biomarkers and failed to prevent lumbar spine or total femur BMD from declining (Tables , , and ). Additionally, the examined serum genistein and daidzein concentrations testified to the high compliance of participants as well as the high bioavailability of isoflavones.
Unlike the results in this study, several previous studies [8
] and two meta-analyses [24
] showed a number of beneficial effects of soy isoflavones on bone. Most of them included only small sample sizes (
175 subjects) and may have been biases, or short follow-up periods (
12 months), so that true long-term effects could not be assessed, and most of these studies did not measure the serum levels of isoflavones. The two recent meta-analyses (both by Taku et al.) analyzed the overall effects of soy isoflavone supplements on bone turnover markers and BMD separately [24
]. There was only a modest overall decrease of urinary deoxypyridinoline, whereas the other bone turnover markers including osteocalcin, BAP, and other bone resorption markers did not show a significant change [24
]. Meta-analysis on the effects of supplementation with soy isoflavone extract with an average of 82 (47–150) mg (aglycone equivalents) on BMD showed an increase in lumbar spine BMD by 2.4% after 6 to 12 months. However, no significant change of proximal femur BMD could be found [25
]. Taken together, these results were different from those of conventional estrogen therapy, making it difficult to obtain a clear picture of the mechanism behind the action of isoflavone, a phytoestrogen, on bones. On the other hand, several recent reports have demonstrated the absence of beneficial effects of isoflavones on bone [26
], supporting our findings. This controversy may be the result of differences in dosage, product forms, length of observations, ethnic dietary habits, or other factors. To further complicate the issue, a number of reports have claimed antagonistic activities of various isoflavones [35
], or the need for the presence of soy protein for isoflavones to exert their effects on BMD [8
]. For example, Morabito et al. and Marini et al. reported that the ingestion of single isoflavone-genistein 54 mg/day for 1 [10
] and 2 years [23
] resulted in a decline of bone resorption markers and an increase in bone formation markers and BMD of the lumbar spine and femoral neck. These outcomes were totally different from ours. Because each subject in the isoflavone arm of the current study consumed 172.5-mg genistein and 127.5-mg daidzein/day, whether the discrepancy between our results and those of aforementioned authors is due to the antagonistic activities of various isoflavones requires further clarification. We administered a relatively large dose of a common aglycone combination (57.5% genistein and 42.5% daidzein, without soy protein) and measured bone turnover markers and BMD both at the lumbar spine and proximal femur every 6 months. Our results did not show any significant effects throughout the 24 months, in the presence of markedly elevated serum levels of genistein and diadzein of the isoflavone-treated group. Thus, our results strongly suggest that soy isoflavones in the form and dosage used in this study have no transient or long-term effect on bone in postmenopausal women.
One of the participants in the isoflavone arm was diagnosed with breast cancer in the study period. According to the statistics of Taiwan Cancer Registry, Department of Health, Executive Yuan for the year 2006, the incidence rate of breast cancer in the entire female population aged 45–64 years in Taiwan was 141.9/100,000 person-year, which was apparently lower than the incidence rate of breast cancer in the isoflavone group of this study (230.4/100,000 person-year). This subject was treated with estrogen and progesterone for 3–4 years after menopause and discontinued for more than 1 year prior to randomization in this study. The breast cancer of this subject might be incidental, and the causal relationship remains unclear.
This study may have shortcomings. (1) The baseline serum levels of genistein and daidzein were higher than those reported in the Caucasian population [31
], which may mask the effects of the supplement. Nonetheless, the baseline levels were far lower than the post-treatment levels of the isoflavone-treated subjects, making this possibility less likely. (2) The supplement of vitamin D (125 IU of vitamin D3
daily) in this study may have been suboptimal. We did not measure plasma 25(OH)D level in this study. Consequently, the possibility of vitamin D deficiency or insufficiency and their impact on the effects of isoflavones could not be completely ruled out. However, all our participants were ambulatory. A previous study on the nutritional status of vitamin D among ambulatory women aged 40 to 75 of Taipei City reported that vitamin D deficiency was very rare [39
], and it was further supported by the report that dietary vitamin D intakes were relatively adequate in this population [40
]. Thus, vitamin D insufficiency or deficiency may not have been a major factor for the lack of effects of isoflavones. (3) We did not collect data on hot flashes that could have served as a reflection of the biological effect and the appropriateness of the dosage of the isoflavones used in this study, in addition to the serum levels of isoflavones. (4) We used three different models of instruments from three different manufacturers to measure BMD. The variations among the three instruments may have masked the effects of soy isoflavones. However, we performed BMD measurements according to the International Society of Clinical Densitometry guidelines. The instruments had daily quality checks and were operated by the same technologists throughout the period of study. The results within each center were analyzed separately and did not show any trend of effects. (5) A lack of total proximal femur BMD data from one center may have reduced the power to estimate the effect of soy isoflavones. However, it is difficult to perceive how isoflavone treatment could improve proximal femur BMD while providing no benefit in preventing bone loss at the lumbar spine. (6) Our sample size was not sufficient to analyze the effects of soy isoflavone on fracture rates. The fracture incidence in our study appeared higher than the results reported by a prospective study in Shanghai, China [41
]. It should be noted that our study included only osteopenic or osteoporotic women, whereas the study in Shanghai included a cohort from the general population. However, in view of 64% increase in bone fracture rate in the isoflavone arm compared with that of the placebo arm, more cautious monitoring in this regard is warranted in the future studies.