Impact of equol-producing capacity and soy-isoflavone profiles of supplements on bone calcium retention in postmenopausal women: a randomized crossover trial

Abstract

Background: Postmenopausal estrogen depletion is a major contributing factor to bone loss. Soy isoflavones have variable effects on the prevention of postmenopausal bone loss, which is possibly related to the specific isoflavone content or the variable equol-producing capacity of individuals.

Objective: We aimed to determine the effects of the content of isoflavones in a soy supplement and the equol-producing ability of the individual on postmenopausal bone calcium retention.

Design: The study was a blinded, randomized, crossover intervention trial in 24 postmenopausal women who were prescreened for their ability to convert daidzein to equol. Women were equilibrated with (41)Ca before the intervention. Interventions were 5 soy isoflavone oral supplements (2 doses of a genistein-rich soy supplement and 3 doses of mixed isoflavones in various proportions) and a bisphosphonate (risedronate). Each intervention was given sequentially for 50 d followed by a 50-d washout period. The percentage of bone calcium retention was determined from the change in urinary (41)Ca:calcium.

Results: Interventions that ranged from 52 to 220 mg total isoflavones/d increased bone calcium retention between 3.4% and 7.6% (P < 0.05), which was a moderate effect compared with that of risedronate at 15.3% (95% CI: 7.1%, 22.7%; P = 0.0014). The most-effective soy intervention delivered 105.23 mg total isoflavones/d as genistein, daidzein, and glycitein in their natural ratios and increased bone calcium retention by 7.6% (95% CI: 4.9%, 10.2%; P < 0.0001). Genistein, at 52.85 mg/d, increased bone calcium retention by 3.4% (95% CI: 0.5%, 6.2%; P = 0.029); but there was no benefit at higher amounts (113.52 mg/d). There was no difference (P = 0.5) in bone calcium retention between equol producers and nonproducers.

Conclusion: Soy isoflavones, although not as potent as risedronate, are effective bone-preserving agents in postmenopausal women regardless of their equol-producing status, and mixed isoflavones in their natural ratios are more effective than enriched genistein. This trial was registered at clinicaltrials.gov as NCT00244907.

Keywords: 41Ca; bone resorption; equol; genistein; postmenopausal women; soy isoflavones.

FIGURE 1

Study design. Twenty-four healthy postmenopausal women were enrolled in the study with 8 equol producers and 16 nonproducers. Subjects were dosed with ⁴¹Ca, and baseline values were collected after a 150-d equilibration period. All subjects received Soy-low as the first intervention. After the intervention with Soy-low, subjects had the option to continue directly with risedronate therapy or to receive 4 randomized soy interventions followed by risedronate. *One subject dropped out during the randomized soy interventions and had low compliance with taking the supplements; therefore, this subject was excluded in all analyses. Gen-high, high-dose genistein; Gen-low, low-dose genistein; Soy-gen, soy isoflavones enriched in genistein; Soy-high, high-dose soy; Soy-low, low-dose soy.

FIGURE 2

Mean ± 95% CI effects of soy and risedronate interventions on bone calcium retention in postmenopausal women. A 95% CI that does not include zero indicates a significant change from baseline at α = 0.05 by using a linear regression model. Interventions with Gen-low (n = 14), Soy-low (n = 24), Soy-high (n = 14), Soy-gen (n = 14), and risedronate (n = 19) resulted in significant increases in bone calcium retention compared with baseline. the intervention with Gen-high (n = 14) did not result in a change in bone calcium retention compared with baseline. t tests were performed to determine differences between interventions with a Bonferroni-corrected α = 0.007 used to adjust for 7 multiple comparisons. The intervention with Soy-low resulted in a significantly greater bone calcium retention (P = 0.001) than the intervention with Gen-low. Gen-high, high-dose genistein; Gen-low, low-dose genistein; Soy-gen, soy isoflavones enriched in genistein; Soy-high, high-dose soy; Soy-low, low-dose soy.

FIGURE 3

Mean ± 95% CI effects of soy and risedronate interventions on fractional calcium absorption in postmenopausal women. Significant differences were determined by contrasts after 2-factor ANOVA. Fractional calcium absorption for pooled soy interventions (A; n = 77) was significantly lower than at baseline (B; n = 24; P = 0.0026) and with the risedronate intervention (C; n = 19; P = 0.0017). Fractional calcium absorption at baseline was significantly lower than with the risedronate intervention (P < 0.0001). Gen-high, high-dose genistein; Gen-low, low-dose genistein; Soy-gen, soy isoflavones enriched in genistein; Soy-high, high-dose soy; Soy-low, low-dose soy.

FIGURE 4

Five soy treatments were analyzed in a repeated-measures mixed model that included equol status, dietary intake of daidzein, and the interaction to examine the effect of equol status on serum equol. Equol producers are indicated by filled circles, and nonproducers are indicated by open circles. There was a significant (P = 0.0036) interaction; in equol producers, there was an increase of 0.0236 nM serum equol for each milligram of daidzein in the diet (P = 0.009), whereas the slope for nonproducers was NS (P = 0.13).