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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 3 1207-1212
Copyright © 2004 by The Endocrine Society

Effects of Phytoestrogens on Bone Turnover in Postmenopausal Women with a History of Breast Cancer

Eini Nikander, Merja Metsä-Heikkilä, Olavi Ylikorkala and Aila Tiitinen

Department of Obstetrics and Gynecology (E.N., M.M.-H., O.Y., A.T.), Helsinki University Central Hospital, FIN-00029 HUS, Helsinki, Finland; and Department of Obstetrics and Gynecology (E.N.), Jorvi Hospital, FIN-02740 Espoo, Finland

Address all correspondence and requests for reprints to: Dr. Eini Nikander, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, P.O. Box 140, FIN-00029 HUS, Helsinki, Finland. E-mail: eini.nikander{at}pp.fimnet.fi.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
High phytoestrogen intake among Asian women has been thought to explain the low risk of bone fractures in these populations. In a randomized placebo-controlled trial we studied the effects of isoflavonoids on urinary output of the N-terminal cross-linked telopeptide of type I collagen, pyridinoline (Pyr), and deoxypyridinoline (Dpyr) (bone resorption markers) and serum levels of bone-specific alkaline phosphatase and N-terminal and C-terminal procollagen type I (bone formation markers). Fifty-five postmenopausal women with a history of breast cancer used phytoestrogens (114 mg of isoflavonoids) or placebo tablets daily for 3 months; the treatment regimens were then crossed over after a 2-month washout period. The markers were measured before and on the last day of each treatment period.

Bone resorption was reduced during phytoestrogen use, as reflected in falls in the urinary output of Pyr (9%; P = 0.001) and Dpyr (5%; P = 0.008). Compared with the placebo group, the fall in Dpyr was significant (P = 0.022) and the falls in Pyr (P = 0.084) and N-terminal cross-linked telopeptide of type I collagen (P = 0.082) showed a trend toward significance. Bone formation markers were not affected by this regimen.

Thus, isoflavonoid-induced inhibition of bone resorption may contribute to the low risk of osteoporosis in Asian women.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
OSTEOPOROSIS IN POSTMENOPAUSAL women is a common but often preventable disease. Bisphosphonates and raloxifene have been approved by the Food and Drug Administration for prevention and treatment of osteoporosis, and calcitonin only for treatment of the condition (1). PTH is a promising agent for treatment of osteoporosis as well (2). There is also substantial epidemiological evidence that estrogen/hormone replacement therapy (HRT) protects against bone fractures (3, 4). However, randomized placebo-controlled HRT trials have given contradictory results, showing no bone protection (5) or a significant reduction in the risk of hip fractures (6). However, in the latter trial (6), the health risks (breast cancer, thromboembolism, and occlusive arterial disease) outweighed the health benefits (decreased risk for colon cancer, or hip fracture). Clearly, new bone preservation options are needed, and an ideal one could be part of the everyday diet.

In Asia, the incidence of osteoporosis-related fractures is low compared with that in Western countries (7, 8). This phenomenon might have many explanations, e.g. those related to anatomic differences, but one explanation could be a high intake of phytoestrogens (9). Indeed, Asian populations consume soy, a major source of isoflavones, 10–20 times more than women in Western societies do (10). Isoflavones, such as genistein and daidzein, have been shown to exert bone benefits in animals (11, 12, 13, 14). However, human data are inconsistent, showing a potential benefit in some (15, 16) but not in all studies (17). It is also known that a high dietary intake (55 mg/d) and high urinary excretion of isoflavones are associated with high bone mineral density (BMD) in Chinese (18), Japanese (19), and Korean (20) postmenopausal women. Isoflavonoids may stimulate estrogen ß-receptors, which are present in osteoblasts (11, 21), and they may also promote calcium absorption (22).

A bone-preserving drug or regimen should ultimately prevent bone fractures. However, to demonstrate this effect takes decades, and that is why various surrogate markers, reflecting the risk of fracture, are commonly used. One of the most established predictors is BMD as assessed by dual x-ray absorptiometry (23). However, even this method may take up to 2 yr before a significant change in BMD can be detected (23, 24). Therefore, various biochemical markers reflecting bone resorption and formation, which respond to various treatments in shorter time periods, have been commonly used in clinical trials on the effect on bone of a given agent (25, 26, 27, 28, 29, 30).

We decided to study the effects of phytoestrogens on bone metabolism in postmenopausal women surviving breast cancer. This population was selected because even though they suffer from hot flashes and other typical climacteric symptoms, they often are advised against the use of HRT (31).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

With the permission of the local ethical committee, we studied 64 postmenopausal women who had been treated for breast cancer 8 months to 22 yr earlier (mean 5 yr). After the women had received thorough written and verbal information on the purpose and conduct of the study, informed written consent was obtained from all of them. Thirteen women had received chemotherapy, at a mean of 5 yr before recruitment. Two of these women had already been postmenopausal, whereas chemotherapy triggered the onset of menopause in the other 11. Before the diagnosis of breast cancer, 22 of the 56 women completing the study (39.3%) had used some form of HRT for 6 months to 20 yr (mean 5.5 yr). Three women had used tamoxifen for 2 months to 4 yr, but this treatment had been discontinued 5 months to 4 yr before recruitment. Each woman was devoid of any metastasis at recruitment, which was carried out between September 1, 1999, and October 10, 2000. The inclusion criteria were 1) lack of residual malignant disease; 2) incapacitating climacteric complaints such as hot flashes, night sweats, and sleeplessness; and 3) a level of FSH exceeding 30 U/liter. The exclusion criteria were 1) use of sex steroids (including tamoxifen); 2) use of natural products with possible estrogenic activity; 3) use of drugs possibly affecting climacteric symptoms, metabolism, or absorption of phytoestrogens (e.g. antibiotics during the previous 3 months); and 4) history of any thromboembolic or hepatic event. Six women used thyroxine and were considered euthyreotic. Ten women had undergone hysterectomy, six with their ovaries conserved. No woman was considered to be osteoporotic on clinical grounds, although no BMD assessments were routinely carried out.

Protocol

After a double-blind, crossover technique, the women were treated in computer-randomized order either with phytoestrogens or a similar looking placebo. Each treatment lasted 3 months, and the treatment phases were interrupted by a 2-month washout period. Phytoestrogen tablets and similar looking placebo tablets were to be taken every 12 h (3 tablets) with a glass of water. Phytoestrogen tablets (Bonette, Novomed, Helsinki, Finland) (19 mg of isoflavonoids) consisted of glycitein (11 mg, 58%), daidzein (7 mg, 36%), and genistein (1 mg, 6%) (32). The subjects were seen at the research center immediately before and on the last day of each treatment period. General and pelvic examinations were performed, and appropriate blood, urine, and other samples collected.

During the study the women were encouraged to lead normal lives with no changes in dietary habits, alcohol consumption, or physical activity, which were all recorded by means of questionnaires before and at the end of each treatment period. Based on these reports, our study group was regarded to represent average Finnish postmenopausal women whose diets contain approximately 300-1000 mg calcium a day (33). We did not provide calcium or vitamin D supplementation, but eight women used calcium supplementation and three women took vitamin D supplements; they were advised to continue these during the trial. The women kept weekly diaries concerning their general health, bleeding, use of antibiotics or any other concomitant drugs, and possible side effects. Compliance with use of the study medication was confirmed by checking the diaries and by analyzing the serum levels of daidzein, genistein, and equol, as reported before (32).

Laboratory assays

Blood and urine samples were collected after an overnight fast immediately before the start of the regimen and on the last day of each treatment period. Serum was separated by centrifugation, and samples of serum and urine were stored frozen (-20 C) until assayed.

Bone resorption

Bone resorption was evaluated by assay of the urinary cross-linked N-telopeptide of type I collagen (NTx) and urinary pyridinoline (Pyr) and deoxypyridinoline (Dpyr). Concentrations of NTx were assessed by an ELISA (Ostex International, Medix Scientific Laboratory, Kauniainen, Finland); the intra- and interassay coefficients of variation of this method were 8 and 13%, respectively. Urinary Pyr and Dpyr concentrations were assessed by reversed-phase HPLC (Medix); the intra- and interassay coefficients of variation of this method were 9 and 11%, respectively. To avoid the possible source of error arising from different urine dilutions, NTx, Pyr, and Dpyr data were expressed against millimoles of creatinine, which was assessed by a routine laboratory method.

Bone formation

Bone formation was evaluated by measuring the serum levels of bone-specific alkaline phosphatase (BAP), procollagen type I N-terminal propeptide (PINP) and procollagen type I C-terminal propeptide (PICP). Serum BAP levels were assessed by chemiluminescent immunoassay (Beckman Coulter, Inc., Limbach, Germany); the intra- and interassay coefficients of variation of this method were both 5%. Concentrations of PINP and PICP were measured by RIAs (Orion Diagnostica, Medix Diacor, Espoo, Finland). The intra- and interassay coefficients of variation of the PINP assay were both 6%, and for the PICP assay they were 8 and 13%, respectively.

Phytoestrogens

Daidzein, genistein, and equol concentrations in serum were assessed by time-resolved fluoroimmunoassay, and the data have been reported before (32).

Statistical analysis

The data are presented as mean ± SD except in Fig. 1Go, where the data are presented as mean ± SE. As we used the crossover design, the possibility of a period effect was tested by the Mann-Whitney test, where we compared the differences between the periods in the two groups of patients (those beginning with the phytoestrogen and those beginning with the placebo). No period effect was detected. The possibility of a treatment-period interaction was also investigated by the Mann-Whitney test, where we compared the average responses to the two treatments and found patients’ average responses to the two treatments to be the same regardless of the order of treatments. As there was no carryover effect detected in any bone marker, a nonparametric test (the Wilcoxon signed ranks test) could be used to determine any changes (difference between posttreatment and baseline values) in the main variables. This test was also used to compare the effects of the two treatments. Correlations between variables were calculated by means of Spearman’s nonparametric correlation analysis. Levels at baseline were compared by using either the unpaired t test or the Mann-Whitney U test. Statistical analyses were performed by using an SPSS 10.0 statistical package (SPSS Institute, Inc., Chicago, IL). A P value < 0.05 was considered significant. Due to the lack of prospective data on the effect of isoflavonoids on bone markers at the time of the design of our study, we assumed for the power analysis that phytoestrogens would be equally as effective as HRT, which reduces bone resorption markers in 3 months by approximately 20–30%. With this efficacy, our study group of 55 women would give an 80% power to detect this difference.



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  		FIG. 1. Percent changes in the urinary output of NTx, Pyr, and Dpyr (mean ± SE) in women using phytoestrogens or placebo for 3 months.

 

   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Of the 64 screened women, two were excluded; one because her serum FSH level was <30 U/liter and the other because she had taken a course of antibiotics within 3 months of the study. Of the 62 randomized women, 32 were to start with phytoestrogens and 30 with placebo. Six women discontinued the trial during the first treatment regimen: four in the phytoestrogen group (two because of stomach ache, one for personal reasons, and one because of recurrence of breast cancer) and two in the placebo group (one because of lack of effect and one because of vaginal bleeding). Thus, 56 women completed the study (Table 1Go). One woman was excluded from the final analysis because she had used alendronate.


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  		TABLE 1. Clinical characteristics at baseline of the 56 women completing the study

 
All the data were first analyzed separately for the first and second treatment phase, and because the order of treatment was not a confounding factor, the data were pooled to form a single phytoestrogen and a single placebo group.

Age, years spent in menopause, previous use of HRT (22 of 56 women, 39.3%), chemotherapy, use of antiestrogens, body mass index, smoking, and blood pressure were not determinants of the basal value of any bone marker. However, the concentrations of all bone resorption and formation markers at baseline (except for Pyr in relation to PICP) were in positive relationships to each other (P < 0.05; detailed data not shown). The 10 hysterectomized women showed a trend toward higher NTx output compared with nonhysterectomized women (82.5 ± 30.0 vs. 67.9 ± 45.4 nmol/mmol creatinine; P = 0.053) and a significantly higher mean basal BAP level (69.3 ± 26.0 vs. 50.1 ± 19.6 µg/liter; P = 0.018). Four of the 10 hysterectomized women were also ovariectomized and had significantly higher NTx excretion (83.50 ± 1.7 vs. 70.4 ± 45.7 nmol/mmol creatinine; P = 0.033) and PINP levels (91.3 ± 24.3 vs. 51.0 ± 19.0 µg/liter; P = 0.005) than women with an intact uterus and ovaries and higher PINP levels than only hysterectomized women (91.3 ± 24.3 vs. 54.7 ± 14.9 µg/liter; P = 0.017).

The phytoestrogen regimen failed to affect the urinary output of NTx significantly, although it resulted in a trend toward its reduction (Table 2Go; Fig. 1Go). The outputs of Pyr and Dpyr were reduced from baseline after the phytoestrogen regimen by 9 and 5%, respectively. Compared with the placebo group, the fall in Dpyr was more profound (P = 0.022), and it showed a trend as regards Pyr (Table 2Go). The higher the value of any biochemical bone marker at baseline, the larger the reduction during the phytoestrogen regimen (P < 0.01).


View this table:
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  		TABLE 2. Urinary output of the N-terminal cross-linked telopeptide of type I collagen (NTx), Pyr and Dpyr and serum levels of BAP, PINP and PICP before and after phytoestrogen or placebo treatment for 3 months.

 
Phytoestrogens did not affect the serum levels of BAP, PINP, and PICP when analyzed in regard to changes from basal values or when compared with changes in the placebo group (Table 2Go).

Individual changes in the urinary output of Pyr during the phytoestrogen regimen were in direct correlation with changes in NTx and Dpyr (Spearman’s correlation coefficient = 0.299, P = 0.032, and Spearman’s correlation coefficient = 0.854, P < 0.01, respectively), as were the changes in the levels of BAP and PINP (Spearman’s correlation coefficient = 0.395; P = 0.003) and PINP and PICP (Spearman’s correlation coefficient = 0.550; P < 0.01).

The use of phytoestrogens led to 19- to 106-fold rises in the serum levels of daidzein, genistein, and equol, whereas the placebo regimen had no effect (32). The increases in genistein and equol levels did not correlate with changes in the concentrations of any bone resorption or formation marker, whereas elevation of the serum daidzein level was in direct correlation with falls in the concentrations of Pyr (Spearman’s correlation coefficient = 0.315; P = 0.024), PINP (Spearman’s correlation coefficient = 0.272, P = 0.047) and PICP (Spearman’s correlation coefficient = 0.272; P = 0.047). There were no statistical changes in body weights during the study and individual changes in body weight did not correlate with changes in any bone turnover markers (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We studied the effects of phytoestrogens on bone metabolism in postmenopausal women who had a history of breast cancer. Eleven women had received chemotherapy while they were premenopausal, and this may have prompted the onset of menopause in these individuals. These women had similar levels of bone markers at baseline as did the women who did not receive chemotherapy, suggesting that chemotherapy had not caused any long-lasting effects in bone metabolism. In addition, three subjects had used tamoxifen, which strengthens bone (26, 34, 35), but because tamoxifen had been discontinued 5 months to 4 yr before our trial, we feel that bone metabolism was probably also normal in these women. Therefore, we believe that our subjects were rather representative of healthy postmenopausal women, as regards bone metabolism, although we did not measure BMD; no clinical signs implied osteoporosis or osteopenia. Furthermore, we did not measure BMD during the trial because it takes up to 2 yr to demonstrate significant changes, at least in nonosteoporotic women (24). It is known that at least bone resorption markers respond within 2–6 weeks to HRT (24, 36) and alendronate (25, 36), and therefore 3 months’ exposure to phytoestrogens was likely to be long enough to reveal any major effect on bone if it existed. We feel that the total dose of phytoestrogens, which, in fact, was twice as great as used in some other studies (15, 16), was adequate, because the levels of isoflavonoids rose profoundly in serum (32). However, even this dosage failed to relieve hot flashes and other climacteric symptoms in our subjects (32).

The hysterectomized women (10 of 56), whether ovariectomized (4 of 10) or not (6 of 10), displayed significantly higher levels of several bone turnover markers than did the subjects with an intact uterus and ovaries, indicating stimulation of bone turnover. It is known that hysterectomy may induce an early onset of menopause, perhaps as a result of ovarian blood flow deficiency (37), and this may be one explanation for accelerated bone loss in hysterectomized women, as seen in our study and also in a previous one (38).

To assess bone resorption we assayed three different markers (NTx, Pyr, and Dpyr), all of which illustrate the breakdown of bone collagen, although each slightly differently (29). The use of three markers was an advantage, because, at least in theory, phytoestrogens may affect various sites of bone collagen destruction. However, linear correlations between the urinary concentrations of NTx, Pyr, and Dpyr at baseline suggest that they reflect bone resorption similarly. Phytoestrogen treatment resulted in falls of 5–9% from baseline in bone resorption markers, and this effect was most conspicuous as regards Dpyr, which was reduced significantly more after the phytoestrogen treatment than after placebo treatment. However, the falls in the concentrations of bone resorption markers in our study were not as marked as reported in some other trials; e.g. genistein (54 mg/d) decreased Pyr levels by 54% and Dpyr levels by 55% in 6 months (30). Whole soy foods containing isoflavones (60 mg/d) have been reported to result in a 14% decrease in NTx levels in 3 months (39). However, in some other trials on isoflavones, at 47 mg/d (40) or 80 mg/d (15), lasting 3–6 months, no changes in NTx have been observed. The discrepant data on bone resorption markers during phytoestrogen use may be explained by different bone status at baseline, various exposure times, and differences in study populations; genetic, lifestyle, and environmental factors may well play a role in the response of bone to phytoestrogens. However, our data, collected during a 3 months’ trial, imply that our phytoestrogen regimen inhibits the normal bone resorption that occurs in postmenopausal women using no estrogen/HRT or other bone-strengthening regimen. We like to emphasize that due to the rather modest changes in bone markers in 3 months, our study may have been underpowered to detect small changes, which may, however, be clinically significant.

We assessed bone formation by measuring the serum concentrations of BAP and two collagen propeptides, which in combination may give a more reliable index of bone formation than a single analyte alone. A bone-preserving regimen would be expected to reduce them all. However, the phytoestrogen regimen did not affect the levels of these markers in 3 months. The data are in line with the results of a previous study where isoflavones (80 mg/d) had no effect on bone formation in 6 months (16), but they are in contrast to some others where isoflavonoids (130 mg/day) for 3 months decreased BAP concentrations by approximately 10% (41), and genistein (54 mg/d) for 6 months increased BAP levels by 23% (30). It is known that bone formation markers need longer exposure times than 3 months (29), and thus the 3-month duration of phytoestrogen use in our study was possibly too short to affect bone formation.

There could be several mechanisms of action by which phytoestrogens affect bone metabolism. Osteoblasts abundantly express estrogen ß-receptors, which bind phytoestrogens. Thus, the effect on bone of phytoestrogens may closely resemble that of estrogen (11, 21). Other mechanisms of action include promotion of calcium absorption (22) and increased production of IGF-1, which is known to enhance osteoblastic activity and correlate with bone formation (42, 43). Soy protein with isoflavones increases the levels of IGF-1 (43). It is also known that genistein without soy protein stimulates the production of osteoprotegerin by osteoblasts, which prevents bone resorption (44).

Our data do not allow us to deduce which component (or components) included in our regimen (daidzein, genistein, or glycitein) was responsible for the inhibition of bone resorption we found. The tablets mainly contained glycitein (66.1 mg/day), and no data exist on the effect of glycitein alone on bone. Thus, it is possible that this isoflavonoid is relatively ineffective toward bone. We also gave daidzein (41.1 mg/day) and genistein (6.8 mg/d), both of which, when given alone, have been shown to have bone-sparing activity (30, 45). Because we gave all three isoflavonoids concomitantly, it is also possible that one isoflavonoid counteracted, or stimulated, the effect of another in bone cells; this concept is in line with the selective estrogen receptor modulator principle. Therefore, in additional trials, the effects on bone of each isoflavonoid should ideally be studied first when given alone and then when given in combination with other isoflavonoids. Only then could one find an optimal single isoflavonoid or a combination for bone preservation. Furthermore, soy protein itself may be of importance for the action of phytoestrogens (46), and therefore, purified isoflavonoids, as we gave, may be less effective.

In summary, the use of isoflavonoids for 3 months by postmenopausal women inhibited bone resorption, and this effect, if persistent during more prolonged use, may be one explanation for the reduced risk of osteoporosis in women consuming relatively plenty of isoflavonoids in their diets.


   Footnotes
 
This work was supported by grants from research funds of Jorvi Hospital and Helsinki University Central Hospital and the Juho Vainio Foundation.

Abbreviations: BAP, Bone-specific alkaline phosphatase; BMD, bone mineral density; Dpyr, deoxypyridinoline; HRT, hormone replacement therapy; NTx, cross-linked N-terminal telopeptide of type I collagen; PICP, procollagen type I C-terminal propeptide; PINP, procollagen type I N-terminal propeptide; Pyr, pyridinoline.

Received July 8, 2003.

Accepted November 21, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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