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High Dietary Phytoestrogen Intake Is Associated with Higher Bone Mineral Density in Postmenopausal but Not Premenopausal Women

Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China

Address all correspondence and requests for reprints to: Dr. A. W. C. Kung, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China. E-mail: awckung{at}hkucc.hku.hk

Abstract

Animal studies demonstrated that phytoestrogen had a protective effect against bone loss after ovariectomy. However, data on dietary phytoestrogen intake as well as its relationship with bone mineral density (BMD) in human are not available. Six hundred fifty southern Chinese women, aged 19 to 86 yr, were recruited to determine their dietary phytoestrogen intake by a food frequency questionnaire. BMDs at the lumbar spine and hip region were measured using dual energy x-ray absorptiometry.

The subjects were analyzed according to various tertiles of phytoestrogen intake. Among the postmenopausal women (n = 357), significant differences in the lumbar spine (L2–4) BMD (0.820 ± 0.145 vs. 0.771 ± 0.131 g/cm², P < 0.05) and Ward’s triangle BMD (0.450 ± 0.151 vs. 0.415 ± 0.142 g/cm²; P < 0.05) were found between the highest and lowest intake of isoflavone after adjusting for age, height, weight, years since menopause, smoking, alcohol consumption, HRT usage, and daily calcium intake. Women with the highest intake of isoflavone had significantly lower levels of serum PTH (19.38 ± 14.61 vs. 26.56 ± 11.19 pg/ml; P < 0.05), osteocalcin (4.95 ± 3.61 vs. 6.69 ± 5.05 mg/liter; P = 0.05), and urinary N-telopeptide (34.18 ± 25.31 vs. 49.66 ± 41.00 nmol bone collagen equivalents/mmol creatinine; P < 0.05) when compared with those with the lowest intake of isoflavone. No association between dietary phytoestrogen intake and BMDs was seen in the premenopausal women with high endogenous E (n = 293).

In conclusion, postmenopausal women with habitually high intake of dietary isoflavone are associated with higher BMD values at both the spine and hip region. Customarily high isoflavone intake may help to reverse the state of secondary hyperparathyroidism associated with E withdrawal and hence lower the rate of bone turnover in postmenopausal women.

OSTEOPOROSIS IS AN important metabolic bone disease affecting postmenopausal women. It was observed that the incidence of hip fractures has tripled over the past three decades in southern Chinese (1). Together with the rapid aging of the population in Asia, it is estimated that by the year 2050, 50% of the world’s hip fractures will occur in Asian women (2). Hormonal replacement therapy (HRT) should theoretically be the best choice for the prevention and treatment of postmenopausal osteoporosis (3). Unfortunately, due to the many side effects of HRT as well as cultural differences, acceptance of HRT is extremely low in Asian women. Less than 3% of Chinese postmenopausal women have ever used HRT (4). Nonhormonal therapy or alternative therapy may be more acceptable in Asian women for the treatment and prevention of osteoporosis.

Phytoestrogen, a group of nonsteroidal plant-derived compounds, is structurally similar to E and possesses both weak estrogenic and antiestrogenic effects (5, 6). Animal studies showed that phytoestrogen had a protective effect against bone loss due to E withdrawal. Consumption of a soybean protein-based diet with natural phytoestrogen instead of a casein-based diet had been shown to prevent bone loss in ovariectomized (OVX) rats (7, 8). Similarly, genistein, a classic phytoestrogen found predominantly in soy, prevented bone loss in OVX rats (9, 10, 11). These results from animal studies suggested that phytoestrogen might have a beneficial role in bone protection in postmenopausal women. However, limited data were available from human studies. Recent interventional studies with supplementation of phytoestrogen in postmenopausal women revealed inconsistent results (12, 13, 14).

Japanese and Chinese are known to consume relatively high intakes of soybean and soy products. Soy products such as tofu are traditional popular Chinese food items with a high content of phytoestrogen. Whether high habitual dietary phytoestrogen intake would influence BMD is unknown. The objective of this study was to examine the relationship between dietary phytoestrogen intake and BMD in southern Chinese women.

Subjects and Methods

Subjects

Six hundred fifty southern Chinese women in Hong Kong, aged 19–86 yr, were enrolled in the study to determine the genetic and environmental risk factors for osteoporosis in our population. These women were recruited from the community when they passed by a road show on osteoporosis held in six different parts of Hong Kong from November 1998 to October 2000. Women with underlying metabolic or genetic bone diseases, premature menopause (age <40 yr), bilateral ovariectomy, or drug use that could affect bone mineral metabolism were excluded. The protocol was approved by the Ethics Committee of the University of Hong Kong.

Phytoestrogen intake

All subjects were instructed by a trained research assistant to complete a questionnaire on diet, basic demographic characteristics, medical history, and the use of HRT. Dietary phytoestrogen was assessed with a food frequency questionnaire that consisted of 33 most frequently consumed food items. Among the various food items were nine soy items commonly consumed by the local Chinese population: soft tofu, firm tofu, fried tofu, dried soybean, canned soybean, soymilk skin (Foo jook), soybean sprout, soy milk, and soy drink. Subjects were asked to indicate the average frequency of consumption of each food item per day, week, or month, as well as the typical serving size. The standard portion size was specified in commonly used units or portions judged by a registered dietitian. The amounts of isoflavone (genistein + daidzein + formononetin + biochanin A), coumestrol, lignan (enterolactone + enterodiol + secoisolariciresinol + matairesinol), and flavonoid (quercetin + kaempferol + luteolin + apigenin + myricetin) were calculated on the basis of published databases (15, 16, 17).

Laboratory assays

Serum E2 was measured by competitive chemiluminescent immunoassay (Ortho-Clinical Diagnostics, Inc., Rochester, NY) with a sensitivity of 10 pmol/liter, intraassay coefficient of variation (CV) of 13.4% at 21 pmol/liter and 7.3% at 85 pmol/liter, respectively, and interassay CV of 16.5% at 23 pmol/liter and 8.8% at 87 pmol/liter, respectively. Serum intact PTH was measured with chemiluminescence immunometric assay (Corning Magic Lite, Chiron Corp., Medfield, MA) with intraassay and interassay CVs of 5.6 and 6.6%, respectively. Serum intact osteocalcin was measured by enzyme-linked immunosorbent assay with a commercial kit (Novocalcin, Metra Biosystems Inc., Mountain View, CA). The intraassay and interassay CVs were 8.8 and 10.1%, respectively. Serum calcium, phosphate, and total alkaline phosphatase were measured with a Hitachi 747 random access analyzer (Roche Molecular Biochemicals, Mannheim, Germany). Urinary creatinine was determined by colorimetric reaction with the Synchron CX5 (Beckman Coulter, Inc., Palo Alto, CA). Urinary N-telopeptide (NTx) was determined in a 2-h fasting morning urine sample and measured by enzyme-linked immunosorbent assay (Osteomark, Ostex International, Inc., Seattle, WA). The intraassay and interassay CVs were 8.7 and 10.9%, respectively. Due to financial constraints, bone markers and hormonal assays were only performed on 100 randomly selected postmenopausal women.

Bone densitometry

BMD was measured at lumbar spine (L2–4), femoral neck, trochanter, Ward’s triangle, and total hip using dual-energy x-ray absorptiometry (Hologic QDR 2000 Plus, Hologic, Inc., Waltham, MA). The in vivo precision of the machine in postmenopausal women for lumbar spine and femoral neck measurements was 1.2 and 1.5%, respectively.

Statistical analysis

The subjects were categorized into pre- and postmenopausal (defined as cessation of menses for 12 or more months) groups. The variables for total and individual phytoestrogen were categorized by tertiles of phytoestrogen intake. BMD measurements of the three groups of phytoestrogen intakes were compared with the general linear model procedure after adjusting for age, weight, height, years since menopause, smoking, alcohol consumption, HRT usage, and calcium intake. The data are presented as mean and SD. Comparisons of basic characteristics between the three groups were done using either one-way ANOVA or ² test. Individual comparisons between two groups were done by least significant difference (LSD) test. All analyses were conducted with SPSS for Windows software version 10.0 (SPSS, Inc., Chicago, IL). A P value of less than 0.05 was considered significant.

Results

Characteristics of the subjects

The characteristics of 650 participants are shown in Table 1. Among the 293 premenopausal women, 14 were considered to be perimenopausal because the cessation of menstruation was less than 1 yr. The average age was 37.5 ± 9.4 and 63.0 ± 8.3 yr for the pre- and postmenopausal women, respectively. The mean daily calcium intake was 575.1 ± 229.8 and 657.6 ± 242.6 mg/d for the pre- and postmenopausal women, respectively. The percentage of past and current HRT users was 4.5% in postmenopausal women.

The mean daily intakes of isoflavone, coumestrol, lignan, and flavonoid in all subjects were 25.4 ± 35.0 mg, 63.9 ± 34.3 µg, 1.9 ± 0.9 mg and 33.1 ± 17.7 mg (mean ± SD), respectively. The total daily phytoestrogen intake (sum of all individual phytoestrogen) was 60.5 ± 41.8 mg (Table 3). Premenopausal women had a higher isoflavone intake, whereas postmenopausal women had higher intakes of coumestrol and flavonoid.

The BMD measurements are showed in Table 4. Among the postmenopausal women, the BMD values at the lumbar spine L2–4 and Ward’s triangle in women with the highest isoflavone intake are 6.4% (0.820 ± 0.145 vs. 0.771 ± 0.131 g/cm²; P < 0.05) and 8.4% (0.450 ± 0.151 vs. 0.415 ± 0.142 g/cm²; P < 0.05) higher than those with the lowest isoflavone intake after adjusting for age, height, weight, years since menopause, smoking, alcohol consumption, HRT usage, and daily calcium intake, respectively. To exclude the possible influence of E supplementation, the data were reanalyzed after excluding past and current HRT users (n = 16). The results showed a similar protective effect of isoflavone at the lumbar spine and Ward’s triangle (both P < 0.05; data not shown). No association was found between BMDs and coumestrol, lignan, and flavonoid intake (data not shown).

Biochemical variables

The serum E2 levels were similar among the various groups of isoflavone intake. Women with the highest intake of isoflavone had significantly lower levels of serum PTH, osteocalcin, and urinary NTx excretion (all P 0.05) when compared with those with the lowest intake of isoflavone (Table 5).

We found that at similar endogenous E2 levels, postmenopausal women with high intake of isoflavone had significantly higher BMD values at the lumbar spine and Ward’s triangle than those with a low intake of isoflavone after adjusting for confounding factors. No association between dietary phytoestrogen intake and BMD values was seen in the premenopausal women. Previous studies done on food items instead of individual analyses of dietary phytoestrogen suggested an association between soybean intake frequency and BMD (18, 19). To our knowledge, this study is the first report of the association of habitual dietary phytoestrogen intake and BMDs in postmenopausal women. In agreement with the results observed in human intervention studies (12, 13), the effect was seen primarily at the lumbar spine, suggesting that isoflavone, as similar to E, exerts more protection on trabecular than cortical bone in postmenopausal women.

The cause for higher BMDs observed in the postmenopausal women with high isoflavone intake was likely due to a reduction in bone turnover, as evidenced by the decrease in biochemical markers for both bone formation and bone resorption. We also observed for the first time that postmenopausal women with a high intake of isoflavone had significantly lower serum PTH levels, suggesting that customary high isoflavone intake may help to reverse the state of secondary hyperparathyroidism associated with E deficiency and, hence, lower the rate of bone turnover in postmenopausal women. The action of isoflavone in suppressing secondary hyperparathyroidism has not been reported previously and awaits further validation.

The pathogenesis of postmenopausal osteoporosis is complex, but one of the major pathogenic mechanisms of E deficiency is a negative calcium balance leading to secondary hyperparathyroidism, which in turn contributes to an increase in bone turnover (20, 21, 22). HRT prevents postmenopausal osteoporosis by suppressing secondary hyperparathyroidism and bone turnover (23, 24). Furthermore, there is extensive evidence that E acts by binding to E receptors on the osteoblasts (25), directly modulating osteoblastic activity and indirectly regulating osteoclast formation to reduce bone turnover or inhibit bone resorption (26, 27, 28). The bone protective mechanism of phytoestrogen is observed to be similar to E. Isoflavone can combine with E receptor ß, and the binding affinity of genistein with E receptor ß is comparable to that of 17ß-estradiol (29). In vitro, isoflavone can stimulate osteoblast-like cell formation (30, 31) and also suppress osteoclast formation and induce osteoclast apoptosis (32, 33). Studies in OVX rats demonstrated that isoflavone treatment resulted in a reduction (11) or no alteration (8) in the markers of bone formation as well as a reduction in markers of bone resorption (34, 35, 36). A recent study in postmenopausal women also showed that high soy protein intake was associated with a lower level of bone resorption (19).

Overall, the dietary calcium intake of our population is low and may account partly for the secondary hyperparathyroidism seen in our subjects. Unfortunately, 25-hydroxy vitamin D results are not available in these women. However, previous studies on ambulatory southern Chinese did not show the presence of vitamin D deficiency (37, 38). It should be noted that soybean and soy products are also good sources of dietary calcium, with a calcium content range 20–190 mg/100 g. Because higher calcium intake was noted in those postmenopausal women with high isoflavone intake, it can be argued that high dietary calcium intake is one of the reasons for the higher BMDs observed in these women. However, even after adjusting for daily calcium intake, high isoflavone intake is still associated with higher BMD as well as lower PTH levels. Moreover, we did not find any significant association between BMDs and calcium intake when we analyzed the BMD results according to tertiles of calcium intake in these postmenopausal women, suggesting that higher BMDs in these women was not related to the higher calcium intake. Anyhow, it could be possible that with higher dietary intake of calcium, which can potentiate the effect of E on bone mass (39), the beneficial effect of isoflavone on suppressing secondary hyperparathyroidism, and hence increasing bone mass, may be less profound.

According to limited data, a supplementation dose of isoflavone at 70–90 mg/d may be needed for its bone protective action (12, 13). This amount of isoflavone would pose a challenge if we were to consume it from a natural dietary source. In our study, the bone protective effect of isoflavone could be seen at 53.3 mg/d, which was the mean value for the highest tertile of isoflavone intake. This suggests that a lesser amount but habitual long-term consumption of isoflavone may also exert a favorable effect on bone tissues.

Our present study did not reveal any significant association between BMD values and individual phytoestrogen intake in premenopausal women who have high endogenous E levels. It has been hypothesized that phytoestrogen may act as an E agonist under E-depleted circumstances to provide beneficial effects on bone and cardiovascular system but exert antagonistic activities under circumstances of high endogenous E (40, 41).

In conclusion, our results suggest that high habitual intake of isoflavone is associated with higher BMD at the lumbar spine and hip region in postmenopausal women. Customary high isoflavone intake may help to reverse the state of secondary hyperparathyroidism associated with E withdrawal and, hence, lower the rate of bone turnover in postmenopausal women.

Acknowledgments

We thank S. C. F. Tam and R. Pang for E2 and PTH estimation and K. S. Lau for technical support.

Footnotes

J. M. is a recipient of the Ivy Wu Fellowship of the University of Hong Kong.

Abbreviations: BMD, Bone mineral density; HRT, hormonal replacement therapy; LSD, least significant difference; NTx, N-telopeptide; OVX, ovariectomized.

Received February 28, 2001.

Accepted August 14, 2001.

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