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Original Research Communications |
1 From the Department of Food Science and Human Nutrition, Human Metabolic Unit, Center for Designing Foods to Improve Nutrition, the Department of Statistics, Iowa State University, Ames, and the Research and Development Laboratory, Fujicco Co, Ltd, Kobe Hyogo, Japan.
See corresponding editorial on page679.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONADDENDUMREFERENCES |
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Objective: Our objective was to determine the effects of 24 wk of consumption of soy protein isolate with isoflavones (80.4 mg/d) in attenuating bone loss during the menopausal transition.
Design: Perimenopausal subjects were randomly assigned, double blind, to treatment: isoflavone-rich soy (SPI+; n = 24), isoflavone-poor soy (SPI-; n = 24), or whey (control; n = 21) protein. At baseline and posttreatment, lumbar spine bone mineral density (BMD) and bone mineral content (BMC) were measured by using dual-energy X-ray absorptiometry. At baseline, midtreatment, and posttreatment, urinary N-telopeptides and serum bone-specific alkaline phosphatase (BAP) were measured.
Results: The percentage change in lumbar spine BMD and BMC, respectively, did not differ from zero in the SPI+ or SPI- groups, but loss occurred in the control group (-1.28%, P = 0.0041; -1.73%, P = 0.0037). By regression analysis, SPI+ treatment had a positive effect on change in BMD (5.6%; P = 0.023) and BMC (10.1%; P = 0.0032). Baseline BMD and BMC (P 
0.0001) negatively affected the percentage change in their respective models; baseline body weight (P = 0.0036) and bone-free lean weight (P = 0.016) contributed positively to percentage change in BMD and BMC, respectively. Serum BAP posttreatment was negatively related to percentage change in BMD (P = 0.0016) and BMC (P = 0.019). Contrast coding using analyses of covariance with BMD or BMC as the outcome showed that isoflavones, not soy protein, exerted the effect.
Conclusion: Soy isoflavones attenuated bone loss from the lumbar spine in perimenopausal women.
Key Words: Soy • isoflavones • bone density • lumbar vertebrae • biochemical markers • menopause • bone mineral content • perimenopausal women
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONADDENDUMREFERENCES |
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Isoflavones, found predominantly in soy products, are estrogen-like substances structurally and functionally similar to 17 ß-estradiol (4). On the basis of evidence primarily from animal and in vitro studies, isoflavones are thought to exert both estrogenic and antiestrogenic effects, depending on the tissue in which they act (5). Isoflavones may exert a weak antagonistic effect on the estrogen receptor (5), thereby having an antiestrogenic effect on uterine and breast tissue (6), where excess estrogen may stimulate synthesis. Alternatively, isoflavones may combine with the estrogen receptor, albeit with lower affinity than 17 ß-estradiol (7), and stimulate estrogen activity, thus having an estrogenic effect on bone (5) and blood vessels (8). Recent observations indicate that soy or soy isoflavones have a positive effect on bone and other tissues, but the mechanism of action is unclear. Soybean milk–based diets were shown to increase calcium absorption in rats (9) and the isoflavones in soy protein isolate (10) were shown to prevent femoral (10, 11) and vertebral (11) bone loss in rats. In addition, soy protein isolate increased bone formation by stimulating insulin-like growth factor I messenger RNA synthesis in rats (12) or moderately increasing bone turnover, with formation being greater than resorption (10–12).
One published study designed to examine lipid-related effects also showed that soy protein isolate rich in isoflavones increased the lumbar spine bone mineral density (BMD) in a heterogeneous (with respect to time since menopause) group of postmenopausal women (13). That study was one of the first to examine the effect of isoflavone-rich soy protein on bone or bone turnover in humans. If studies indicate that isoflavone-rich soy attenuates bone loss, then soy supplementation could serve as an alternative or adjuvant treatment during menopause for women who either are poor candidates for HRT or choose not to receive it. The purpose of this study was to examine the hypothesized bone-sparing effect of isoflavone-rich soy protein isolate on BMD and bone mineral content (BMC) of the lumbar spine in perimenopausal women. Biochemical markers of bone resorption [urinary cross-linked N-telopeptides (N-Tx)] and of bone formation [serum bone-specific alkaline phosphatase (BAP)] were also measured.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONADDENDUMREFERENCES |
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2.09 MJ (500 kcal) and 650 mg Ca/d regardless of treatment, the subjects were instructed to consume these as a meal replacement and not a supplement. Women in each treatment group were instructed to avoid food items that contained soy isoflavones throughout the study. The subjects were required to cease taking any of their own supplements before inclusion in the study but were provided a nonprescription daily vitamin and mineral supplement containing 160 mg Ca. Before baseline testing began, an informational meeting was conducted at which the subjects signed a consent form, were assured that participation was completely voluntary, and were given a medical release form to be signed by their physician. The women came to the Human Metabolic Unit every 6 wk for testing and supply replenishment. They were also required to keep a 5-d food diary before baseline, week 12, and week 24 and to collect a 24-h urine sample before each visit.
Subject screening, selection, and characteristics
Subjects were recruited throughout the state of Iowa and communities near the Iowa border through bulletin board and newspaper advertisements, feature articles in local newspapers, and local television news stories. Potential subjects were screened initially via telephone to ensure that they were nonsmoking perimenopausal women experiencing 
10 hot flashes or night sweats per week and irregular menstrual periods, were free from chronic disease (such as known osteoporosis or cardiovascular disease), were taking no medications long-term, were not receiving HRT or ERT at the time of the study or for 12 mo previously, were not exercising excessively [<10.46 MJ (2500 kcal) expenditure/wk], had one or both ovaries remaining, had a body mass index (BMI; in kg/m2) between 20 and 31, and were willing to be randomly assigned to 1 of 3 treatment groups. Because another purpose of the study was to assess the effect of isoflavone-rich soy protein in alleviating menopausal symptoms, women with vasomotor symptoms were selected.
Women who met these criteria had blood drawn to ensure that their follicle-stimulating hormone (FSH) concentrations were 30 IU/L, because the postmenopausal range is considered to be 34–96 IU/L (14). One hundred two women were initially recruited and met the screening criteria. However, 22 women were dropped because they failed to meet the subsequent criterion for FSH concentration (15); another 11 women dropped out for reasons such as the inability to tolerate treatment (n = 6), death (n = 1), death of a family member (n = 1), medical conditions preventing their continuance (n = 2), and noncompliance (n = 1).
The protocol and consent forms were approved by the Iowa State University Human Subjects Review Committee (IRB no. 01; Assurance ID no. M1361). Because of the difficulty in obtaining a sufficient number of symptomatic women who met our strict criteria, we had 4 cohorts of women, with treatments equally represented in each. The cohorts began in January 1997, May 1997, September 1997, and March 1998.
Data collection and measurement
Trained interviewers administered questionnaires to obtain individual information on health and medical history, physical activity and dietary habits, and reproductive and menopausal history. Estrogen exposure (in y) was calculated for each subject by subtracting her age at menarche from her age at her last menstrual cycle. Eleven women who entered the study had undergone hysterectomies (one subject at age 18 y) but had intact ovaries. The average time since the last menstrual cycle for all subjects combined was used to calculate estrogen exposure for women who had had hysterectomies. A health and medical questionnaire (16) was used in conjunction with the telephone screening to rule out women with chronic or acute conditions and diseases, women who chronically used various prescription (including hormones) and nonprescription medications or illegal drugs, and women who were not experiencing regular hot flashes. The questionnaire also included information on smoking history, bone health, weight history, and overall health.
Lifetime use of cigarettes was expressed as pack-years, calculated by multiplying the average number of cigarette packs smoked/d by smoking history in y. The Paffenbarger physical activity recall (17) was used to obtain information on the previous year's activity, including walking or climbing stairs, sports and recreational activity, rate of exertion with exercise, and the time spent daily on activities ranging from sleeping to aerobic activity. Each recreational activity was summed to provide an estimate of weekly energy expenditure. The nutrition history questionnaire (16) was used to elicit usual intake patterns. It included adherence to modified or specialized diets; intake of fats and oils; usual caffeine, alcohol, and sodium intakes; calcium intake from milk and yogurt throughout life; vitamin and mineral supplement use; and a typical 24-h dietary intake to clarify information obtained from the food records. Three-dimensional food models (Nasco, Fort Atkinson, WI) were used to approximate portion sizes reported in the 24-h intake. The subjects were required to complete a consecutive 5-d food record at baseline, midtreatment, and posttreatment, which each subject recorded in a different 5-d block of time to ensure inclusion of each day of the week twice during the study. Two-dimensional food portion visual aids (Morgan/Posner, 1981; Nutrition Consulting Enterprises, Framingham, MA) were provided to assist subjects in quantifying portion sizes. Diet records are considered the best method for assessing usual dietary intake (18) and were thus used to assess change in energy or nutrient intake throughout the study and to assess typical mean intakes of energy, macronutrients, dietary fiber, alcohol, caffeine, and a variety of vitamins and minerals (in addition to calcium) at baseline. The 5-d food records were analyzed by nutrition students using the NUTRITIONIST IV computerized nutrient database program (version 4.1, 1995; First DataBank, Inc, San Bruno, CA). These analyses did not include the vitamin and mineral supplements we provided the subjects.
Subjects collected 24-h urine samples in polyethylene containers the day before each visit. After the first morning void, all urine was collected, including the next morning's first void. The total volume of urine samples was measured to an accuracy of 10 mL and recorded. A urinalysis was performed by using Multistix (Bayer Corp, Elkhart, IN) reagent strips. Aliquots were frozen at -80°C for subsequent analysis. Aliquots for each subject at each time point were shipped to Fujicco Co Ltd (Kobe, Japan) and analyzed for urinary isoflavones to monitor compliance. Urinary isoflavone (genistein and daidzein) concentrations were determined in each subject's sample by using reversed-phase HPLC. Duplicate 1-mL samples of urine were incubated with sulfatase (EC 3.1.6.1; Sigma Chemical Co, St Louis) and ß-glucuronidase (EC 3.2.1.31; Wako Pure Chemical Industries, Ltd, Osaka, Japan) at 37°C for 2 h to release the aglycones of the isoflavones; this was followed by purification of reactants using a Sep-Pak C18 cartridge (Waters Corp, Milford, MA).
Urinary isoflavones were separated at ambient temperature by reversed-phase HPLC on a 4.6 mm x 25 cm Zorbax octadecylsilane column (Hewlett-Packard Co, Palo Alto, CA) using a Waters 600 multisolvent delivery system with a WISP 710B autosampler and a model 490 programmable multiwavelength detector (Waters Corp). Elution was performed at a flow rate of 1 mL/min with a nonlinear gradient of acetonitrile solution (10–35%) containing a constant 0.1% acetic acid. The absorbance of urinary daidzein and genistein was measured at 254 nm. To estimate urinary genistein and daidzein concentrations, peak areas were compared with areas of corresponding isoflavone standards. Known concentrations of isoflavones were used to supplement some samples to determine recovery. For standards, commercially available daidzein and genistein (Fujicco Co Ltd) were used.
Quantitative, colorimetric determination of creatinine in urine was done at 500 nm according to the manufacturer's guidelines (creatinine procedure no. 555; Sigma Diagnostics, St Louis). Urinary cross-linked N-Tx were measured at baseline, midtreatment, and posttreatment by using a competitive enzyme-linked immunosorbent assay according to the manufacturer's guidelines (Osteomark; Ostex International, Inc, Seattle) and plates were read by using an automated microtiter plate reader (ELx800; Bio-Tek Instruments, Inc, Winooski, VT). Assay values were standardized to an equivalent amount of bone collagen, which is expressed as nmol bone collagen equivalents (BCE) of N-Tx immunoreactivity/mmol creatinine. The intra- and interassay variability was 7.5% and 5.7%, respectively, for N-Tx.
Fasting blood samples were collected at baseline, midtreatment, and posttreatment to measure serum BAP (Tandem-Microplate Ostase, Hybritech Inc) concentrations. This bone formation marker is measured by using a monoclonal antibody with a solid phase, immunoenzymetric method according to manufacturer's guidelines. The Ostase kits were donated by Hybritech to our laboratory for this study. The plates were washed by using an ELx50 automated stripwasher (Bio-Tek Instruments, Inc) and read by using the automated microtiter plate reader. The intraassay variability was 3.2% and the interassay variability was 3.5%. Quest Diagnostics (St Louis), a certified clinical laboratory, performed the serum reproductive hormone analyses at baseline, midtreatment, and posttreatment.
Dual-energy X-ray absorptiometry via QDR 2000+ (Hologic, Inc, Waltham, MA) was used to assess overall body composition (lean and fat mass) and lumbar spine (vertebrae L1–L4) BMD and BMC at baseline and posttreatment. The same 2 researchers, who were trained and certified by Hologic, Inc, performed the scans. A trained research assistant completed the spine analysis following guidelines from the Hologic QDR 2000+ operator's manual (1992 version). The procedure involved selecting the vertebral region (L1–L4) and marking the space between each vertebra with a horizontal line. The posttreatment scans were analyzed by using the compare mode. Our laboratory's short-term within-subject in vivo reproducibility CVs of lumbar spine BMD and BMC are 0.71% and 0.86%, respectively.
Power analysis and statistical analyses of data
This study focused on BMD of the lumbar spine and hence power analysis was based on this outcome in a multiple regression model. Because our sample size (n = 69) was smaller than desired, the effect size of 0.0895 was smaller than expected, and the power to detect a change in spine BMD in this study was 0.57. The power for the overall spine BMD regression model was 0.99 (19).
Statistical analyses were performed with PC SAS, version 6.12 (20). Descriptive statistics include means for normally distributed data (bone, BMI, and total dietary calcium intake), medians for data that were not normally distributed (biochemical markers of bone, serum reproductive hormone concentrations, reproductive history, calcium intake from dairy products throughout life, usual alcohol intake, and urinary isoflavone excretion), and frequencies (reproductive history and smoking history). Percentage change in lumbar spine BMD and BMC and body weight were calculated ([(posttreatment - baseline values)/baseline values] x 100) for each group. To determine whether change over the course of treatment was significantly different from zero in each group, paired t tests were performed. Analysis of covariance (ANCOVA) was used to determine the effect of treatment on BMD and BMC, taking cohort and baseline measures of BMD and BMC, respectively, into account. To determine the effect of cohort, treatment, and time-by-treatment interactions on serum BAP and urinary N-Tx, repeated-measures ANCOVA was used. Residual analysis indicated nonconstancy of error variance (it increased with greater ^Yi values) for N-Tx as the outcome variable in a regression model (using the above-mentioned covariates as regressors); thus, N-Tx values were log-transformed for the repeated-measures ANCOVA.
Stepwise multiple regression analysis was used to determine the effect of treatment and contributors to percentage change in BMD and BMC from baseline to posttreatment. Classes of variables in modeling the outcomes of baseline BMD and BMC included the best index of baseline body size (weight or BMI), body composition (bone-free lean body mass or fat mass), estrogen exposure, posttreatment values of reproductive hormones (17 ß-estradiol, estrone, or FSH), change in physical activity, posttreatment values of biochemical markers of bone turnover (serum BAP or urinary N-Tx), percentage change of dietary intake of selected nutrients (energy, protein, or calcium), typical weekly alcohol intake, and smoking history (pack-years). Residual analyses indicated that the model assumptions of independence of residuals, normality of error terms, and homogeneity of residual variance were satisfied for these regression models, indicating no violation of model assumptions. The variance inflation factor option in the regression analysis (19) did not reveal notable multicollinearities among independent variables.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONADDENDUMREFERENCES |
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0.0001) different among the 3 groups when the Kruskal-Wallis chi-square approximation test was used. The control group had negligible urinary isoflavone excretion throughout the study. Midtreatment and posttreatment median values (mg/L), respectively, for each of the 3 groups were SPI+, 0.99 and 2.10; SPI-, 0.14 and 0.27; and control, 0.05 and 0.08. Most subjects indicated that they perceived they were in the active treatment group (SPI+), suggesting that they could not distinguish by taste among the 3 treatments. Eighty-seven percent (60 of 69 women) reported consuming 100% of the muffins and 84% (58 of 69) reported consuming 100% of the powder throughout the study. During the 168 d of treatment in the SPI+ group, 4 women missed an average of 1 muffin and 7 d of powder; in the SPI- group, 3 women missed an average of 2 muffins and 5 women an average of 8 d of powder; in the control group, 2 women missed an average of 1 muffin and 2 d of powder. Sporadically, subjects neglected to consume their muffins or powder because of lack of convenience rather than because of any reported adverse effects. Compliance was not an issue in this study.
Subject characteristics
The median age of these perimenopausal women was 50.6 y. The highest level of education completed as reported by the subjects was high school for 26%, college for 49%, and postcollege for 25%. Three of the women (2 in the SPI- group, 1 in the control group) were taking medication for hypothyroidism at the time of the study, but they were well controlled and euthyroid. Nonprescription medications used by these women included antacids by 10 (4 in the SPI+ group, 2 in the SPI- group, 4 in the control group), aspirin by 1 (in the SPI+ group), and ibuprofen by 2 (1 in the SPI+ group, 1 in the control group). These women were instructed and agreed to discontinue regular and continual use of these medications during the course of the study and to particularly avoid their use 1–2 d before blood draws. Prescription medications used by the women included albuterol inhalers by 2 (1 in the SPI+ group, 1 in the control group), a steroid nasal spray by 2 (1 in the SPI+ group, 1 in the control group), antidepressants by 2 (1 in the SPI- group, 1 in the control group), and a nonsteroidal antiinflammatory agent sporadically by 1 in the SPI- group. Additional baseline characteristics of the subjects are presented in Table 1
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30 IU/L; however, 3 of the subjects with values <30 IU/L (22.2, 26.7, and 27.6 IU/L) at baseline were nonetheless included in the study because of recent menstruation and a presumed decline postovulation causing lower FSH values at the time of this blood draw. Baseline reproductive history and serum hormone concentrations among the groups were not significantly different; self-reported smoking history and current alcohol intake as assessed from the nutrition history were not significantly different. Calcium intake from milk and yogurt varied throughout life, with the highest intakes during childhood; calcium intake usually tapered off during adulthood. One woman had a weekly energy expenditure of 16.736 MJ (4000 kcal) from recreational activities because she managed a health club and engaged in extensive moderate activity. Each group experienced a significant gain in body weight (SPI+, 2.2%; SPI-, 1.5%; control, 2.5%) during the course of treatment but treatment per se was not related (P = 0.69) to weight gain as determined by ANCOVA, taking baseline weight (P = 0.17) and cohort (P = 0.37) into account. Moreover, dietary intake of energy or physical activity was not related to body weight gain on the basis of various regression analyses that included absolute values, percentage change, or change from baseline to posttreatment values for energy intake and physical activity.
Lumbar spine response to treatment
Mean (±SEM) percentage change in lumbar spine BMD or BMC (Figure 1) did not decline in the SPI+ or SPI- groups; however, significant losses occurred in the control group. Descriptive results for BMD and BMC are presented in Table 2. Absolute values for bone at baseline and posttreatment were not significantly different among the 3 treatment groups. Results of ANCOVA indicated that treatment had a significant effect on percentage change in BMC (P = 0.021) but not on percentage change in BMD (P = 0.25). However, when various contributing factors were taken into account by using multiple regression analyses (Table 3), the SPI+ treatment had a significant positive treatment effect on the percentage change (loss) in both BMD (5.6%; P = 0.023) and BMC (10.1%; P = 0.0032), whereas the other treatments had no effect. After adjustment for all covariates, there were significant differences in BMD between the SPI+ and the control group (P = 0.014), the SPI+ group and the SPI- plus control groups (P = 0.019), and the SPI+ plus SPI- groups and the control group (P = 0.046). Likewise, after adjustment for all covariates, there were significant differences in BMC between the SPI+ group and the control group (P = 0.0027), the SPI+ group and the SPI- plus control groups (P = 0.0028), the SPI+ plus SPI- groups and the control group (P = 0.021), and the SPI+ group and the SPI- group (P = 0.028).
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0.0001) to percentage change in BMD and BMC (Table 3
). In contrast, baseline body weight (P = 0.0036) and bone-free lean weight (P = 0.016) contributed positively to percentage change in BMD and BMC, respectively. Serum BAP posttreatment was negatively associated with percentage change in BMD (P = 0.0016) and BMC (P = 0.019), indicating that serum BAP was higher with greater loss in spine bone mass. Urinary N-Tx and serum reproductive hormones did not meet the entry criterion (P 0.15) in either lumbar spine regression model. The only dietary variable that remained was energy intake (P = 0.062) posttreatment for BMD, but it was not significant. In both models of percentage change, cohort was not significant and hence is not presented in the table; however, cohort is included in each bone model to provide correct error degrees of freedom, parameter estimates, percentage variances, P values, and variance inflation factors. Thus, initial bone mass, bone turnover, body mass or composition, and SPI+ treatment were significant contributors to percentage change in lumbar spine BMD and BMC.
Biochemical markers of bone
Given that only 4 of the 9 groups (3 treatments at 3 time points) of urinary N-Tx values whereas 7 of the 9 groups of serum BAP values were normally distributed, median values for these variables are presented in a scatter plot (Figure 2). Baseline values for serum BAP were significantly different (P = 0.036) among the groups; the SPI+ group had higher values than did the control group. Log-transformed N-Tx values were used for the repeated-measures ANCOVA, whereas residual analysis using serum BAP as the outcome in a regression model (and using the same covariates mentioned above) indicated constancy of error variance and thus BAP data were not log-transformed for the ANCOVA. Repeated-measures ANCOVA indicated that both time (P 0.005) and baseline value (P 0.0001) were significant, whereas treatment per se had no significant effect on either N-Tx (P = 0.12) or BAP (P = 0.32) values. Also, cohort had a significant effect on N-Tx (P = 0.0089) but not on BAP (P = 0.56) value, suggesting that cohort may reflect a seasonal effect on bone resorption.
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DISCUSSION |
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It was the bone-free lean body mass at baseline rather than gain in mass or final mass that contributed significantly to percentage change in BMC. Some studies showed that lean body mass is related to bone mass, whereas others showed that fat mass is more important. Glauber and et al (21) concluded that in postmenopausal women, the effect of weight on BMD at weight-bearing sites is a direct result of mass rather than adiposity per se; rather, at non-weight-bearing sites, adiposity is more important. In contrast, Reid et al (22) concluded that in postmenopausal women, fat mass was a factor in predicting BMD. Thus, the relative contribution of fat compared with lean body mass to BMD in peri- and postmenopausal women remains controversial.
Our positive results, in conjunction with those of ipriflavone studies, suggest that dietary isoflavones may be effective in preventing vertebral bone loss due to ovarian hormone deficiency. Several human studies showed that ipriflavone, a synthetic isoflavone, is effective in preventing and treating osteoporosis. Yet, the mechanisms of action of ipriflavone and isoflavones are unclear. Agnusdei et al (23) showed that ipriflavone prevented bone loss in postmenopausal women with established osteoporosis. Recently, Gennari et al (24) found that 600 mg ipriflavone/d prevented rapid bone loss and reduced bone turnover during early menopause in 28 women with low vertebral BMD. Ipriflavone, combined with estrogen, improves the therapeutic bone response, above that of estrogen or ipriflavone alone (25).
Serum BAP posttreatment was negatively related to percentage change in both BMD and BMC, reflecting the fact that those with more lumbar spine loss during the study had higher BAP concentrations. Subjects with greater bone mass may have higher bone turnover, reflected by higher BAP, simply because of their greater skeletal mass. Notably, baseline spine BMD or BMC was a highly significant negative contributor to percentage change in each respective model, suggesting that those with higher initial bone mass had greater bone loss during the 24 wk, as reported previously (26). Accordingly, Ravn et al (27) concluded that high bone turnover is associated with low bone mass and spinal fractures in postmenopausal women. Our results may simply illustrate the fact that BAP is a marker of bone turnover rather than of bone formation per se. It may also be that BAP is not affected by seasonal variation in the same manner as N-Tx because bone resorption is greater during the months of minimal sun exposure (28). To lessen this seasonal variation, each of the 4 cohorts began at different times of the year, spanning 2 seasons. Assuming that cohort was a surrogate for seasonal effect, there was no effect of cohort on BAP, but there was a significant effect of cohort on N-Tx. Hence, seasonal variation may very well have been a confounding factor, clouding the relation between bone loss and N-Tx concentrations.
Repeated-measures ANCOVA of the data presented in the scatter plot (Figure 2) indicated an overall effect of time but not of treatment on BAP and N-Tx. It appears that serum BAP declined slightly in each group from baseline to posttreatment, whereas urinary N-Tx declined midtreatment but then returned to baseline posttreatment. These changes in bone markers reflect a relative increase in resorption compared with formation during the menopausal transition (29), suggesting that the overriding effect was due to the hormonal milieu. The failure of SPI+ treatment to affect bone resorption or formation implies that the reported bone-sparing effect of soy isoflavones may be different from that of estrogen and other antiresorptive agents.
A potential confounder in isoflavone feeding studies is the heterogeneity in bioavailability and metabolism; some subjects are high, some low, and some moderate metabolizers of soy isoflavones (30). Despite the fact that we provided the subjects in the active treatment group with the same dose of isoflavones, variable responses are probable (31). Although the subjects were instructed to consume the muffins and protein powder as a meal replacement and to decrease their protein intake from other sources, dietary intake changed from baseline to posttreatment in each group, with an overall increase in energy and protein and a decrease in dietary fiber. Nonetheless, treatment per se was not related to weight gain. Also, physical activity did not explain the variability in bone loss, which is not necessarily consistent with current research (32).
Compliance of our subjects was excellent, as reflected by isoflavone excretion and self-reported intake of muffins and powder. Yet, a limitation of the study was a smaller than desired sample size as a result of problems recruiting symptomatic women who met the inclusion criteria. Nonetheless, we detected a significant treatment effect in this homogenous group of white women. More subjects are needed to provide greater statistical power to substantiate the bone-sparing effect of soy isoflavones while accounting for confounding factors. Because a bone-remodeling cycle ranges from 30 to 80 wk (33), this 24-wk preliminary study cannot answer the question of whether these bone-sparing effects would be sustained over a longer period. From these results, we cannot determine whether the reported bone-sparing effect is due to treatment, is a transient artifact of bone remodeling, or is simply a result of physiologic changes during menopause (30). A longer study is necessary to determine whether soy isoflavones will affect the remodeling balance, tipping it in favor of bone formation rather than resorption.
In summary, the results of this study suggest that isoflavones attenuated bone loss from the lumbar spine in estrogen-deficient perimenopausal women, who may otherwise be expected to lose 2–3% of bone/y. This attenuation of loss, particularly if continued throughout the postmenopausal period, could translate into a decrease in lifetime risk of osteoporosis. The most important contributors to the percentage change in lumbar spine BMD and BMC were their respective baseline spine BMD and BMC measurements, with the isoflavone-rich treatment contributing significantly to bone mass. Thus, it is possible that the inclusion of isoflavone-containing soy products in the diets of perimenopausal women could serve as an alternative or adjunct treatment for women at risk of osteoporosis. This may be especially important for women who are poor candidates for HRT or choose not to receive it. To advance our basic knowledge and to pave the way for finding alternatives to steroid hormone therapy for postmenopausal women, a long-term dose-response study in humans designed to corroborate these findings and to examine potential mechanisms is needed.
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ADDENDUM |
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0.0001). Urinary calcium exerted a positive effect (P = 0.011) on bone and explained an additional 6.7% and 6.9% of the variability in BMD and BMC, respectively. When urinary calcium is included, the effect of SPI+ treatment on BMD (6.0%; P = 0.016) and BMC (10.3%; P = 0.0019) is slightly higher than what is reported in Table 3 for BMD (5.6%; P = 0.023) and BMC (10.13%; P = 0.0032).
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ACKNOWLEDGMENTS |
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REFERENCES |
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 L. M Ritland, D L. Alekel, O. A Matvienko, K. B Hanson, J. W Stewart, L. N Hanson, M. B Reddy, M. D Van Loan, and U. Genschel Centrally located body fat is related to appetitive hormones in healthy postmenopausal women. Eur. J. Endocrinol., June 1, 2008; 158(6): 889 - 897. [Abstract] [Full Text] [PDF]
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 R. C. Poulsen, P. J. Moughan, and M. C. Kruger Docosahexaenoic Acid and 17{beta}-Estradiol Co-Treatment Is More Effective Than 17{beta}-Estradiol Alone in Maintaining Bone Post-Ovariectomy Experimental Biology and Medicine, May 1, 2008; 233(5): 592 - 602. [Abstract] [Full Text] [PDF]
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J. Mardon, J. Mathey, S. Kati-Coulibaly, C. Puel, M.-J. Davicco, P. Lebecque, M.-N. Horcajada, and V. Coxam Influence of Lifelong Soy Isoflavones Consumption on Bone Mass in the Rat Experimental Biology and Medicine, February 1, 2008; 233(2): 229 - 237. [Abstract] [Full Text] [PDF]
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 M. A. Farag, D. V. Huhman, R. A. Dixon, and L. W. Sumner Metabolomics Reveals Novel Pathways and Differential Mechanistic and Elicitor-Specific Responses in Phenylpropanoid and Isoflavonoid Biosynthesis in Medicago truncatula Cell Cultures Plant Physiology, February 1, 2008; 146(2): 387 - 402. [Abstract] [Full Text] [PDF]
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J. M. K. Cheong, B. R. Martin, G. S. Jackson, D. Elmore, G. P. McCabe, J. R. Nolan, S. Barnes, M. Peacock, and C. M. Weaver Soy Isoflavones Do Not Affect Bone Resorption in Postmenopausal Women: A Dose-Response Study Using a Novel Approach with 41Ca J. Clin. Endocrinol. Metab., February 1, 2007; 92(2): 577 - 582. [Abstract] [Full Text] [PDF]
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L. N Hanson, H. M Engelman, D L. Alekel, K. L Schalinske, M. L Kohut, and M. B Reddy Effects of soy isoflavones and phytate on homocysteine, C-reactive protein, and iron status in postmenopausal women. Am. J. Clinical Nutrition, October 1, 2006; 84(4): 774 - 780. [Abstract] [Full Text] [PDF]
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 J. E. Kerstetter, D. E. Wall, K. O. O'Brien, D. M. Caseria, and K. L. Insogna Meat and Soy Protein Affect Calcium Homeostasis in Healthy Women J. Nutr., July 1, 2006; 136(7): 1890 - 1895. [Abstract] [Full Text] [PDF]
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T. A Ryan-Borchers, J. S. Park, B. P Chew, M. K McGuire, L. R Fournier, and K. A Beerman Soy isoflavones modulate immune function in healthy postmenopausal women Am. J. Clinical Nutrition, May 1, 2006; 83(5): 1118 - 1125. [Abstract] [Full Text] [PDF]
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 A. M. Whelan, T. M Jurgens, and S. K Bowles Natural Health Products in the Prevention and Treatment of Osteoporosis: Systematic Review of Randomized Controlled Trials Ann. Pharmacother., May 1, 2006; 40(5): 836 - 849. [Abstract] [Full Text] [PDF]
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 F. M. Sacks, A. Lichtenstein, L. Van Horn, W. Harris, P. Kris-Etherton, M. Winston, and for the American Heart Association Nutrition Commi Soy Protein, Isoflavones, and Cardiovascular Health: An American Heart Association Science Advisory for Professionals From the Nutrition Committee Circulation, February 21, 2006; 113(7): 1034 - 1044. [Abstract] [Full Text] [PDF]
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G. R Mundy Nutritional modulators of bone remodeling during aging Am. J. Clinical Nutrition, February 1, 2006; 83(2): 427S - 430S. [Abstract] [Full Text] [PDF]
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M. Reimann, J. Dierkes, A. Carlsohn, D. Talbot, M. Ferrari, J. Hallund, W. L. Hall, K. Vafeiadou, U. Huebner, F. Branca, et al. Consumption of Soy Isoflavones Does Not Affect Plasma Total Homocysteine or Asymmetric Dimethylarginine Concentrations in Healthy Postmenopausal Women J. Nutr., January 1, 2006; 136(1): 100 - 105. [Abstract] [Full Text] [PDF]
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 X. Zhang, X.-O. Shu, H. Li, G. Yang, Q. Li, Y.-T. Gao, and W. Zheng Prospective Cohort Study of Soy Food Consumption and Risk of Bone Fracture Among Postmenopausal Women Arch Intern Med, September 12, 2005; 165(16): 1890 - 1895. [Abstract] [Full Text] [PDF]
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C. M. Weaver and J. M. K. Cheong Soy Isoflavones and Bone Health: The Relationship Is Still Unclear J. Nutr., May 1, 2005; 135(5): 1243 - 1247. [Abstract] [Full Text] [PDF]
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L. A Spence, E. R Lipscomb, J. Cadogan, B. Martin, M. E Wastney, M. Peacock, and C. M Weaver The effect of soy protein and soy isoflavones on calcium metabolism in postmenopausal women: a randomized crossover study Am. J. Clinical Nutrition, April 1, 2005; 81(4): 916 - 922. [Abstract] [Full Text] [PDF]
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S. Dodin, A. Lemay, H. Jacques, F. Legare, J.-C. Forest, and B. Masse The Effects of Flaxseed Dietary Supplement on Lipid Profile, Bone Mineral Density, and Symptoms in Menopausal Women: A Randomized, Double-Blind, Wheat Germ Placebo-Controlled Clinical Trial J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1390 - 1397. [Abstract] [Full Text] [PDF]
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G. Williamson and C. Manach Bioavailability and bioefficacy of polyphenols in humans. II. Review of 93 intervention studies Am. J. Clinical Nutrition, January 1, 2005; 81(1): 243S - 255S. [Abstract] [Full Text] [PDF]
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Z. K. Roughead, J. R. Hunt, L. K. Johnson, T. M. Badger, and G. I. Lykken Controlled Substitution of Soy Protein for Meat Protein: Effects on Calcium Retention, Bone, and Cardiovascular Health Indices in Postmenopausal Women J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 181 - 189. [Abstract] [Full Text] [PDF]
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Y. Zheng, S.-O. Lee, M. A. Verbruggen, P. A. Murphy, and S. Hendrich The Apparent Absorptions of Isoflavone Glucosides and Aglucons Are Similar in Women and Are Increased by Rapid Gut Transit Time and Low Fecal Isoflavone Degradation J. Nutr., October 1, 2004; 134(10): 2534 - 2539. [Abstract] [Full Text] [PDF]
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M. Fujioka, M. Uehara, J. Wu, H. Adlercreutz, K. Suzuki, K. Kanazawa, K. Takeda, K. Yamada, and Y. Ishimi Equol, a Metabolite of Daidzein, Inhibits Bone Loss in Ovariectomized Mice J. Nutr., October 1, 2004; 134(10): 2623 - 2627. [Abstract] [Full Text] [PDF]
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E. Nikander, M. Metsa-Heikkila, O. Ylikorkala, and A. Tiitinen Effects of Phytoestrogens on Bone Turnover in Postmenopausal Women with a History of Breast Cancer J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1207 - 1212. [Abstract] [Full Text] [PDF]
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J. D Brooks, W. E Ward, J. E Lewis, J. Hilditch, L. Nickell, E. Wong, and L. U Thompson Supplementation with flaxseed alters estrogen metabolism in postmenopausal women to a greater extent than does supplementation with an equal amount of soy Am. J. Clinical Nutrition, February 1, 2004; 79(2): 318 - 325. [Abstract] [Full Text] [PDF]
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C. Atkinson, J. E Compston, N. E Day, M. Dowsett, and S. A Bingham The effects of phytoestrogen isoflavones on bone density in women: a double-blind, randomized, placebo-controlled trial Am. J. Clinical Nutrition, February 1, 2004; 79(2): 326 - 333. [Abstract] [Full Text] [PDF]
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R. C. Muhlbauer, A. Lozano, A. Reinli, and H. Wetli Various Selected Vegetables, Fruits, Mushrooms and Red Wine Residue Inhibit Bone Resorption in Rats J. Nutr., November 1, 2003; 133(11): 3592 - 3597. [Abstract] [Full Text] [PDF]
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Y.-M. Chen, S. C. Ho, S. S. H. Lam, S. S. S. Ho, and J. L. F. Woo 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., October 1, 2003; 88(10): 4740 - 4747. [Abstract] [Full Text] [PDF]
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Y. Zheng, J. Hu, P. A. Murphy, D. L. Alekel, W. D. Franke, and S. Hendrich Rapid Gut Transit Time and Slow Fecal Isoflavone Disappearance Phenotype Are Associated with Greater Genistein Bioavailability in Women J. Nutr., October 1, 2003; 133(10): 3110 - 3116. [Abstract] [Full Text] [PDF]
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K. D. Setchell and E. Lydeking-Olsen Dietary phytoestrogens and their effect on bone: evidence from in vitro and in vivo, human observational, and dietary intervention studies Am. J. Clinical Nutrition, September 1, 2003; 78(3): 593S - 609. [Abstract] [Full Text] [PDF]
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T. C. Register, M. J. Jayo, and M. S. Anthony Soy Phytoestrogens Do Not Prevent Bone Loss in Postmenopausal Monkeys J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4362 - 4370. [Abstract] [Full Text] [PDF]
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 C. E. Piersen Phytoestrogens in Botanical Dietary Supplements: Implications for Cancer Integr Cancer Ther, June 1, 2003; 2(2): 120 - 138. [Abstract] [PDF]
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M. S. Kurzer Phytoestrogen Supplement Use by Women J. Nutr., June 1, 2003; 133(6): 1983S - 1986. [Abstract] [Full Text] [PDF]
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 W. Cabot Phytoestrogens J. Am. Acad. Ortho. Surg., May 1, 2003; 11(3): 153 - 156. [Full Text] [PDF]
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S. C. Blum, S. N. Heaton, B. M. Bowman, M. Hegsted, and S. C. Miller Dietary Soy Protein Maintains Some Indices of Bone Mineral Density and Bone Formation in Aged Ovariectomized Rats J. Nutr., May 1, 2003; 133(5): 1244 - 1249. [Abstract] [Full Text] [PDF]
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B. H. Arjmandi, D. A. Khalil, B. J. Smith, E. A. Lucas, S. Juma, M. E. Payton, and R. A. Wild Soy Protein Has a Greater Effect on Bone in Postmenopausal Women Not on Hormone Replacement Therapy, as Evidenced by Reducing Bone Resorption and Urinary Calcium Excretion J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1048 - 1054. [Abstract] [Full Text] [PDF]
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R. A. Dixon and L. W. Sumner Legume Natural Products: Understanding and Manipulating Complex Pathways for Human and Animal Health Plant Physiology, March 1, 2003; 131(3): 878 - 885. [Full Text] [PDF]
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Y. Yamori, E. H. Moriguchi, T. Teramoto, A. Miura, Y. Fukui, K.-i. Honda, M. Fukui, Y. Nara, K. Taira, and Y. Moriguchi Soybean Isoflavones Reduce Postmenopausal Bone Resorption in Female Japanese Immigrants in Brazil: A Ten-Week Study J. Am. Coll. Nutr., December 1, 2002; 21(6): 560 - 563. [Abstract] [Full Text] [PDF]
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K. D. R. Setchell, N. M. Brown, and E. Lydeking-Olsen The Clinical Importance of the Metabolite Equol--A Clue to the Effectiveness of Soy and Its Isoflavones J. Nutr., December 1, 2002; 132(12): 3577 - 3584. [Abstract] [Full Text] [PDF]
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 C.-J. Liu, J. W. Blount, C. L. Steele, and R. A. Dixon Bottlenecks for metabolic engineering of isoflavone glycoconjugates in Arabidopsis PNAS, October 29, 2002; 99(22): 14578 - 14583. [Abstract] [Full Text] [PDF]
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J. J. B. Anderson, X. Chen, A. Boass, M. Symons, M. Kohlmeier, J. B. Renner, and S. C. Garner Soy Isoflavones: No Effects on Bone Mineral Content and Bone Mineral Density in Healthy, Menstruating Young Adult Women after One Year J. Am. Coll. Nutr., October 1, 2002; 21(5): 388 - 393. [Abstract] [Full Text] [PDF]
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D. A. Khalil, E. A. Lucas, S. Juma, B. J. Smith, M. E. Payton, and B. H. Arjmandi Soy Protein Supplementation Increases Serum Insulin-Like Growth Factor-I in Young and Old Men but Does Not Affect Markers of Bone Metabolism J. Nutr., September 1, 2002; 132(9): 2605 - 2608. [Abstract] [Full Text] [PDF]
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J. H Swain, D L. Alekel, S. B Dent, C. T Peterson, and M. B Reddy Iron indexes and total antioxidant status in response to soy protein intake in perimenopausal women Am. J. Clinical Nutrition, July 1, 2002; 76(1): 165 - 171. [Abstract] [Full Text] [PDF]
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A. Ohta, M. Uehara, K. Sakai, M. Takasaki, H. Adlercreutz, T. Morohashi, and Y. Ishimi A Combination of Dietary Fructooligosaccharides and Isoflavone Conjugates Increases Femoral Bone Mineral Density and Equol Production in Ovariectomized Mice J. Nutr., July 1, 2002; 132(7): 2048 - 2054. [Abstract] [Full Text] [PDF]
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L. K. Boker, Y. T. Van der Schouw, M. J. J. De Kleijn, P. F. Jacques, D. E. Grobbee, and P. H. M. Peeters Intake of Dietary Phytoestrogens by Dutch Women J. Nutr., June 1, 2002; 132(6): 1319 - 1328. [Abstract] [Full Text] [PDF]
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 G. A. Greendale, G. FitzGerald, M.-H. Huang, B. Sternfeld, E. Gold, T. Seeman, S. Sherman, and M. Sowers Dietary Soy Isoflavones and Bone Mineral Density: Results from the Study of Women's Health Across the Nation Am. J. Epidemiol., April 15, 2002; 155(8): 746 - 754. [Abstract] [Full Text] [PDF]
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M. Messina, C. Gardner, and S. Barnes Gaining Insight into the Health Effects of Soy but a Long Way Still to Go: Commentary on the Fourth International Symposium on the Role of Soy in Preventing and Treating Chronic Disease J. Nutr., March 1, 2002; 132(3): 547S - 551. [Abstract] [Full Text] [PDF]
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J. Mei, S. S. C. Yeung, and A. W. C. Kung High Dietary Phytoestrogen Intake Is Associated with Higher Bone Mineral Density in Postmenopausal but Not Premenopausal Women J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5217 - 5221. [Abstract] [Full Text] [PDF]
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 S. A. Atkinson and W. E. Ward Clinical nutrition: 2. The role of nutrition in the prevention and treatment of adult osteoporosis Can. Med. Assoc. J., November 1, 2001; 165(11): 1511 - 1514. [Full Text] [PDF]
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K. D. R. Setchell Soy Isoflavones--Benefits and Risks from Nature's Selective Estrogen Receptor Modulators (SERMs) J. Am. Coll. Nutr., October 1, 2001; 20(90005): 354S - 362. [Abstract] [Full Text]
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B. H. Arjmandi The Role of Phytoestrogens in the Prevention and Treatment of Osteoporosis in Ovarian Hormone Deficiency J. Am. Coll. Nutr., October 1, 2001; 20(90005): 398S - 402. [Abstract] [Full Text]
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S. B. Dent, C. T. Peterson, L. D. Brace, J. H. Swain, M. B. Reddy, K. B. Hanson, J. G. Robinson, and D. L. Alekel Soy Protein Intake by Perimenopausal Women Does Not Affect Circulating Lipids and Lipoproteins or Coagulation and Fibrinolytic Factors J. Nutr., September 1, 2001; 131(9): 2280 - 2287. [Abstract] [Full Text] [PDF]
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B. Anderson; Soy Phytoestrogens, Lipid Reductions, and Atherosclerosis Delay in Ovariectomized Primates J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 39 - 40. [Full Text]
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J. W Erdman Jr, R. J Stillman, and R. A Boileau Provocative relation between soy and bone maintenance Am. J. Clinical Nutrition, September 1, 2000; 72(3): 679 - 680. [Full Text] [PDF]
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 J. An, C. Tzagarakis-Foster, T. C. Scharschmidt, N. Lomri, and D. C. Leitman Estrogen Receptor beta -Selective Transcriptional Activity and Recruitment of Coregulators by Phytoestrogens J. Biol. Chem., May 18, 2001; 276(21): 17808 - 17814. [Abstract] [Full Text] [PDF]
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; n = 24), and whey (control: 
; n = 21) protein. Lumbar spine bone mass was determined by using dual-energy X-ray absorptiometry. *Significantly different from baseline (paired t tests with Bonferroni adjustment; P values noted).