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Division of Foods and Nutrition and Division of Radiobiology, University of Utah, Salt Lake City, UT and * School of Human Ecology, Louisiana State University, Baton Rouge, LA
2To whom correspondence and reprint requests should be addressed. E-mail: scott.miller{at}hsc.utah.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • soy protein • bone formation • bone density • rats • ovariectomy
Osteoporosis is an age-related disease characterized by loss of bone mass and deterioration of the architecture of bone tissue, resulting in increased bone fragility (1 ,2 ). Postmenopausal women are most at risk for osteoporosis, and the loss is associated with reductions in estrogen levels as the result of the cessation of menses (3 ). Hormone replacement therapy (HRT) has been used for many years to slow the development of osteoporosis and help alleviate other menopausal symptoms. Traditional HRT can be quite effective in reducing the loss of bone at all skeletal sites, particularly within the first few years after menopause (4 ,5 ). There is, however, mounting evidence that HRT may be linked with greater risks for some diseases including cancer, coronary vascular disease (6 ) and thromboembolism (7 ). For these reasons, alternatives to traditional HRT are sought.
The consumption of plant-based foods rich in "phytoestrogens," more specifically the isoflavones and their derivatives, may provide an alternative to traditional HRT. The largest concentrations of naturally occurring isoflavones are found in common legumes, particularly soy. The consumption of soy is reported to have beneficial cardiovascular effects including improved lipid profiles and reduced cholesterol in both clinical (8 ) and animal (9 ) studies. Additionally, the consumption of isoflavone-rich foods or soy extract has also been associated with a reduction in postmenopausal hot flashes and vaginal dryness (10 ,11 ).
The consumption of soy may also have beneficial effects on skeletal tissues. Dietary soy was found to slow the rate of bone loss after ovariectomy in rats (12 ,13 ), but was unable to restore lost bone mass in established osteopenia in the same animal model (14 ). The tissue mechanisms for the partial preservation of bone mass after ovariectomy were not studied directly, but the authors suggested that the mechanisms might be different than those known for estrogen, perhaps including increases in bone formation. Another study reported improvements in bone strength with dietary soy and attributed this to an increased efficiency of the intestine to absorb calcium (15 ). The conservation of calcium with dietary soy compared with other protein sources may be due to a reduction in the urinary excretion of calcium (16 ).
An increasing number of studies conducted in women have demonstrated increases in bone density or attenuation of bone loss with consumption of greater amounts of soy protein (17 –21 ). In a recent cross-sectional study, for example, women with the highest intake of dietary isoflavones also had the highest bone mineral density (BMD) measured in the spine (20 ). However, improvements in bone health have not been observed in all studies [reviewed in (22 )]. Additionally, some beneficial effects of dietary soy on serum lipids were reported (23 ,24 ). This has led to considerable discussion whether soy or components of soy, for example, genistein, might be effective alternatives to HRT (25 ). Although the mechanisms of putative bone gains and/or preservation with soy in humans are not well understood, some shorter-term studies have demonstrated decreased urinary markers of resorption associated with soy consumption (19 ,24 ,26 ). Unlike estrogen, which is known to suppress bone formation and resorption (27 ), some human studies have shown that the consumption of soy is associated with increases in serum markers of bone formation (24 ,26 ).
The purpose of the present study was to determine the effects of dietary soy on indices of bone mass, density, and bone formation and resorption in a rat model of aging and menopause. Thus, diets enriched with soy proteins were fed to aged, retired breeder rats that were either sham operated or ovariectomized. The ovariectomized rat is a model of peri- and postmenopausal bone loss and replicates many aspects of the changes observed in humans (28 ). Because there is biochemical evidence in some animal models and humans that dietary soy may stimulate bone formation, emphasis was placed on the direct tissue measurements of bone formation in both cancellous and cortical bone.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Female, retired breeder Sprague-Dawley rats (Harland Sprague-Dawley, Indianapolis, IN) were used in this study. The rats had 9 previous reproductive cycles and were 
11 mo of age at the beginning of the study. The rats were fed a casein or soy diet (Table 1) based on the AIN rodent diet (AIN-93M) (#110951, DYETS, Bethlehem, PA) (29
). The vitamin mix used in both diets was the AIN-93 mix (#310025, DYETS,). The AIN-93M mineral mix was used for the casein diet (#210050, DYETS,) whereas a mineral mix adjusted for the mineral content of soy protein was used in the soy diet (#210057, DYETS,). The soy-based diet was a gift from Protein Technologies, San Diego, CA.
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The remaining rats were divided into 4 groups (n = 9/group). The rats in two of the groups were ovariectomized and the rats in the other 2 groups were sham operated. The absence of ovarian tissue and atrophy of the uterine horns later confirmed the success of the ovariectomy (Ovx). The rats were further divided into the following groups: sham rats fed the casein-based diet (Sham Casein), sham rats fed the soy-based diet (Sham Soy), ovariectomized rats fed the casein-based diet (Ovx Casein) and ovariectomized rats fed the soy diet (Ovx Soy). The rats were fed the diets and tap water and the study continued for 14 wk. Food consumption and body weight were measured every week.
At 12 and 2 d before necropsy, all of the rats were given calcein and tetracycline as bone markers, respectively, as described above for the baseline group. At necropsy, the uterus, abdominal fat, tibias, humerii and femurs were collected. The length and weight of the uterus and weight of the abdominal fat were measured. The weight of the uterus was normalized to its length.
Preparation of skeletal tissues.
The femurs and humerii were wrapped in saline-soaked gauze and immediately frozen and stored at -70°C. The tibias were cut in half through the mid-diaphyseal shaft and fixed for 24 h in 0.1 mol/L phosphate buffered formalin. The tissues were then dehydrated in ethanol and embedded in methyl methacrylate. Frontal sections of the proximal tibia and cross sections at the tibiofibular junction were cut on a low speed saw (Isomet, Buehler, Lake Bluff, IL), mounted on plastic slides and ground to 30 µm in thickness.
Dual X-ray absorptiometry.
To measure BMD, the frozen femurs and humerii were scanned using a peripheral dual energy X-ray absorptiometer (Norland Medical Systems, Fort Atkinson, WI). The BMD was determined for the entire femur, the proximal and distal femur, mid-diaphysis of the femur, the entire humerus and the proximal humerus. The CV on repeated scans and standards was <1.0%.
Histomorphometry of cortical bone.
Cortical bone histomorphometric indices were measured at the tibiofibular junction as previously described (30 ). The primary indices included the total periosteal and endocortical perimeter, bone area, cortical width, marrow area, periosteal and endocortical single- and double-labeled surface, interlabel width and endocortical resorption (eroded) surface. Calculated from these measurements were the percentage of double-labeled surface, mineral apposition rates and surface-referent bone formation rates. The bone formation rates were calculated using the double-labeled surface. The histomorphometric nomenclature conforms with recommendations by Parfitt et al. (31 ).
Histomorphometry of cancellous bone.
Structural and dynamic histomorphometric data were measured in the cancellous bone of the proximal tibial metaphysis, as previously described (32 ). A 6-mm2 area of cancellous bone in the proximal tibial metaphyseal secondary spongiosa was quantified using a digitizing tablet and histomorphometry software (KSS Scientific Consultants, Magna, UT). The proximal boundary of the measured area was the junction of the primary and secondary spongiosa. The primary indices included the trabecular bone perimeter, trabecular area, single- and double-labeled surface, and interlabel width. From these measurements, the percentage of double-labeled surface, the percentage of mineralizing surface, mineral apposition rate, and surface- and volume-referent bone formation rates were calculated. The mineral apposition rate was corrected for obliquity (33 ), and bone formation calculations were made using the double-labeled surface (31 ).
Statistical analyses.
The baseline group was included to determine the influence of aging and Ovx during the study and to provide basal values of bone mass, structure and dynamics. The baseline, casein control (Sham casein) and casein ovariectomy (Ovx Casein) groups were first compared by an ANOVA followed by Fishers protected least significant difference post-hoc test (StatView, Cary, NC). The specific effects of soy compared with the casein diet control were compared independently in the Ovx groups (Ovx Soy compared with Ovx Casein) and sham groups (Sham Soy compared with Sham Casein) using a one-tailed Student’s t test. Statistical significance was considered at P < 0.05, but statistical trends (P < 0.10) are also indicated. The data are expressed as the means ± SEM.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The ability of dietary soy to increase and/or maintain indices of bone formation in rats has been suggested in some studies, but not measured directly. Arjmandi et al. (12 ,14 ) suggested that a stimulation and/or sustained maintenance of bone formation rather than inhibition of bone resorption may be responsible for positive changes in bone mass in ovariectomized rats fed soy protein. The results from the present study support this. This same group also showed that the synthetic phytoestrogen, ipriflavone, protected bone mass in ovariectomized rats perhaps by increasing the rates of bone formation (34 ). Ipriflavone is reported to have some bone-sparing properties in postmenopausal women (35 ). Genistein is one of the primary phytoestrogens in soy; when it is given by subcutaneous injection to ovariectomized rats, it slowed the rate of bone loss and promoted bone formation rates (36 ). Increases in serum indices of bone formation with dietary soy have been observed in some (19 ,26 ) but not all (37 ) human studies. The findings that soy and some of its components may stimulate bone formation are supported by several in vitro studies. Choi et al. (38 ) reported that soybean extracts promote anabolic functions of osteoblast-like cells, and Yamaguchi et al. (39 ) reported that genistein and daidzein stimulated protein synthesis in osteoblastic-like cells in vitro. Recently, phosphorylated genistein and daidzein were reported to be anabolic for bone tissues in vitro (40 ).
The ability of dietary soy to sustain and/or increase some indices of bone formation, as demonstrated in the present study and supported by other animal, human and in vitro studies, differs from the normal actions of estrogens in mammalian bone. Estrogen administration suppresses bone formation and resorption in the ovariectomized rat model (41
) and is also associated with suppressed bone turnover in humans (27
). Additionally, estrogen also suppresses endochondral bone elongation (41
), and no effects of soy on endochondral growth were observed in the present study. Other investigators have noted some differences between the skeletal effects of "phytoestrogens" and classical estrogen effects and have suggested that these may act through different mechanisms in bone (13
). The finding in the present study that dietary soy appears to increase and/or maintain some indices of bone formation indicates a different tissue-level mechanism of action than the classical estrogen effects in bone. That phytoestrogens and estrogen may act differently in bone is supported by some molecular studies that have examined the binding of soy components to the estrogen receptor (ER). The ER is thought to exist as two subtypes, ER-ß and ER-
. These subtypes differ in the C-terminal and the N-terminal ligands. Studies have found that some phytoestrogens, including genistein, are ER-ß selective and bind to ER-ß with a greater affinity than estradiol, indicating that the phytoestrogens may exert their effects through actions separate and distinct from those of classical estrogens (42
). This is supported by a study that showed that the binding of genistein to the ER differed from estradiol but was nearly identical to selective ER modulators (SERM) (43
). These findings led to the recent suggestion that soy isoflavones should not be considered as "phytoestrogens," but rather as natural SERM (44
).
The aged, retired-breeder rats used in this study had been through multiple reproductive cycles, which can have profound effects on bone structure and dynamics in female rats (45 ). For example, after a reproductive cycle, there is a period of intense bone formation at certain bone envelopes to reconstitute the skeletal mass lost during lactation. The higher rates of periosteal bone formation, for example, in the Baseline group compared with the Sham Casein control, can be attributed to the more recent recovery from lactation in the Baseline rats. This would also explain the smaller endocortical eroded (resorption) surfaces in the Baseline compared with the Sham Casein rats. The periosteal bone formation rates in the Sham Soy group were significantly greater than their Sham Casein controls, but were less than those observed in the Baseline group. Thus, in this case, dietary soy may have maintained the elevated bone formation rates that are associated with recovery from the reproductive cycle.
Ovx is also associated with transient increases of bone formation and bone turnover at different bone envelopes (46 ). On endosteal surfaces, increases in bone formation are countered by greater increases in bone resorption, resulting in decreased bone mass. The soy-based diet resulted in significantly greater bone formation rates at the endocortical and endosteal surfaces in the Ovx rats than in their casein diet counterparts. Because Ovx can increase bone formation rates at these surfaces, the soy diet maintained the elevated bone formation rates or perhaps actually increased these rates. Ovx is also associated with a transient increase in bone resorption that exceeds bone formation. In the present study, no significant differences in eroded surfaces were observed at the end of the study (14 wk), but a longitudinal study would be required to determine whether soy could blunt the increase in bone resorption that occurs soon after Ovx. That dietary soy may blunt bone resorption is supported by clinical measurements from several relatively shorter-term human studies (24 ,26 ). Thus, the ability of soy to blunt increases in bone resorption after Ovx and contribute to the maintenance of bone mass cannot yet be excluded.
In conclusion, this study demonstrates some beneficial effects of dietary soy on skeletal tissues in a model of estrogen-deficiency bone loss. The feeding of soy protein for 14 wk had a beneficial but not complete effect on maintaining cortical and cancellous BMD after Ovx in the aged, retired breeder rat. Dietary soy was also associated with modest, but significantly greater indices of bone formation in certain bone envelopes in both intact and Ovx rats. The ability of dietary soy to increase and/or maintain bone formation rates is a mechanism of action that is different from classical estrogen effects in bone, suggesting that phytoestrogens act through different mechanisms in bone than estrogen. The results from this study support previous animal and humans studies that dietary soy has some beneficial effects on skeletal mass and metabolism and may offer an alternative to traditional HRT. It would be of interest to further define those components of soy that promote the bone formation/maintenance response observed in this study.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: BMD, bone mineral density; ER, estrogen receptor; HRT, hormone replacement therapy; Ovx, ovariectomy; SERM, selective estrogen receptor modulator.
Manuscript received 26 December 2002. Initial review completed 28 January 2003. Revision accepted 14 February 2003.
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