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Journal of the American College of Nutrition, Vol. 20, No. 90005, 398S-402S (2001)
Published by the American College of Nutrition

The Role of Phytoestrogens in the Prevention and Treatment of Osteoporosis in Ovarian Hormone Deficiency

Bahram H. Arjmandi, PhD, RD

Department of Nutritional Sciences, Oklahoma State University, Stillwater, Oklahoma

Address reprint requests to: Bahram H. Arjmandi, PhD, RD, Department of Nutritional Sciences, 416 Human Environmental Sciences, Oklahoma State University, Stillwater, OK 74078. E-mail: arjmand{at}okstate.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 THE ROLE OF SOY...
 REFERENCES
 
Ovarian hormone deficiency is a major risk factor for osteoporosis in postmenopausal women. Hormone replacement therapy (HRT) is perhaps the most effective treatment, as it has been demonstrated to both reduce the rate of bone loss and risk of fracture, including hip fracture. However, not all women who may benefit from HRT are willing to initiate this treatment due to fear of cancer and contraindications. Other therapeutic agents currently available are also associated with certain adverse effects. As a result, postmenopausal women are more inclined to use natural remedies to alleviate postmenopausal symptoms and help reduce their risk for chronic diseases such as osteoporosis. Recent reports support the notion that certain bioactive constituents, e.g., phytoestrogens, in plants play a role in maintaining or improving skeletal health. The main consumable plant sources of phytoestrogens include isoflavones and lignans found mainly in soybeans and flaxseed, respectively. Although this paper primarily focuses on the effects of soy protein or its isoflavones on bone, additional statements regarding the role of flaxseed and dried plums, a rich source of polyphenols, with respect to bone will be made.

Key words: soy protein, isoflavones, flaxseed, dried plums, osteoporosis

Key teaching points:

• Isoflavones are a diverse group of compounds that have weak estrogen-like properties and are often referred to as phytoestrogens.

• Soybeans are a rich source of the isoflavones genistein and daidzein.

• Flaxseed is the richest source of mammalian lignan precursors, enterodiol and enterolactone.

• Dried plums are a good source of dietary fiber and contain a number of phenolic compounds that may act as powerful antioxidants.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
THE ROLE OF SOY...
 REFERENCES
 
Ovarian hormone deficiency is a major risk factor for osteoporosis in postmenopausal women [1–4]. Hormone replacement therapy (HRT) effectively alleviates postmenopausal symptoms and lowers the risk for coronary heart disease and osteoporosis. However, more than 80% of eligible women are unwilling to be placed on this therapy, either because of fear of increased risk of certain types of cancer or contraindications [5]. Medications that are categorically termed selective estrogen receptor modulators (SERMs) may hold promise as viable alternatives for postmenopausal therapy. SERMs are defined as a group of compounds behaving as estrogen agonists in certain tissues, while acting as antagonists in some other tissues [6]. Recent reports indicate that phytoestrogens exert their effects in a SERM-like manner [7]. Phytoestrogens are non-steroidal plant compounds of diverse structures found in many fruits, vegetables, and grains. Hence, food sources rich in phytoestrogens may provide postmenopausal women with yet an additional practical and safe alternative. The plant food sources high in phytoestrogens are numerous and include soybeans, flaxseeds, and certain other fruits and vegetables high in polyphenolic compounds.


   THE ROLE OF SOY OR ITS ISOFLAVONES ON BONE
TOP
 ABSTRACT
 INTRODUCTION
 THE ROLE OF SOY...
REFERENCES
 
Animal Studies
Among the earliest observations indicating the beneficial effects of soy protein on bone were those made by Kalu and colleagues [8]. These researchers reported that feeding soy protein instead of casein to old male rats prevented age-associated bone loss. This positive effect of soy protein on bone was credited to its amino acid pattern. Omi et al. [9] reported that rats fed soy milk had greater bone mineral density and mechanical bone strength than did casein-fed controls. The authors speculated that this beneficial effect might have been due to enhanced intestinal calcium absorption.

Since Type I, or postmenopausal, osteoporosis is by far the most common form of osteoporosis, we initiated a study in a rat model to evaluate the role of soy protein in preventing bone loss due to ovarian hormone deficiency. The findings of this study [10] indicate that replacement of casein by soy protein in the diet prevents bone loss due to ovariectomy with vertebral bone density similar to that of the estrogen-treated group. Nonspecific markers of bone formation (i.e., serum alkaline phosphatase activity) and bone resorption (i.e., serum tartrate-resistant acid phosphatase activity) were greater in ovariectomized rats consuming soy protein than in sham-operated control rats. Results from this study and similar studies [11,12] indicate that the beneficial effects of soy protein result from stimulation of bone formation rather than suppression of bone resorption.

To determine whether soy protein itself or its isoflavones exert beneficial effects on bone, we conducted a study using forty-eight, 95-day old Sprague-Dawley rats [13]. Animals were divided into four groups: sham-operated (sham), ovariectomized (ovx), ovx+soy protein with normal isoflavone content (soy), and ovx+soy protein with reduced isoflavone content (soy-). Sham and ovx groups were fed a casein-based diet. The soy groups were fed similar diets in which casein was replaced with soy with normal or reduced isoflavone content. The soy group had significantly greater femoral bone density (g/cm3 bone volume) than the ovx group, whereas soy- was similar to ovx (Fig. 1). Similar to our earlier findings [10], ovariectomy resulted in greater bone turnover, as indicated by higher serum alkaline phosphatase activity, serum insulin-like growth factor-I and insulin-like growth factor binding protein 3 concentrations, and urinary hydroxyproline. These increases were not affected by either soy with normal or reduced isoflavone content. Similarly, histomorphometry revealed a greater bone formation rate with ovariectomy, which was not ameliorated by the soy diets. Although it appears that the bone protective effects of soy protein are related to its non-protein constituents, isoflavones, the effects of other components such as saponins and phytic acid, which are also present in soy protein, cannot be ruled out.



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  		Fig. 1. Effects of soy protein with normal (Soy) or depleted (Soy-) isoflavones on femoral density of ovariectomized (ovx) rats. Bars represent mean ± SD; n = 12 rats per treatment group. Bars that do not share the same letters are significantly different (p < 0.05).

 
We carried out a study (unpublished data) in which two doses of 125 and 250 mg isoflavones/kg diet were added to casein-based diets of ovariectomized rats. These doses of mixed isoflavones delivered comparable amounts of genistein and diadzein which have been reported to produce positive effects on bone [12,14,15]. In this study, thirty-two 95-d old Sprague-Dawley rats were divided into four groups: sham-operated (sham), ovx, ovx+low-dose isoflavones (LD; 125 mg/kg diet) and ovx+high-dose isoflavones (HD: 250 mg/kg diet). As expected, ovx reduced 4th lumbar bone mineral density (p<0.006) in comparison with sham animals. This ovx-associated bone loss was not attenuated by either dose of isoflavones (Fig. 2). Other indices of bone turnover were not affected by these doses of isoflavones beyond that of ovariectomy. These results indicate that isoflavones may play an important role in protecting bone only in the context of soy protein.



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  		Fig. 2. Effects of two doses (D1; 125 and D2; 250 mg isoflavones/kg diet) on 4th lumbar bone density of ovariectomized (ovx) rats. Bars represent mean ± SD; n = 8 rats per treatment group.

 
Human Studies
To date, a limited number of small, short-term clinical studies have examined the effects of soy protein with normal or reduced isoflavone levels on bone mineral density (BMD) or indices of bone turnover. These studies have produced inconclusive results. A six-month study by Potter and colleagues [16], which was designed to examine the lipid-lowering properties of soy protein in postmenopausal women, reported that isoflavone-rich soy protein increased lumbar spine BMD and bone mineral content (BMC). In another study of similar duration, Alekel et al. [17] reported that the percentage change in lumbar spine BMD or BMC in perimenopausal women did not decline from baseline in the isoflavone-rich soy group, but significant losses in BMD and BMC occurred in the control group. Losses in lumbar spine BMD and BMC in subjects who received the isoflavone-poor supplement approached significance. The positive effects of soy supplementation on BMD and BMC could not be explained by changes in serum bone-specific alkaline phosphatase activity, a marker of bone formation, or urinary N-telopeptide (NTX), a marker of bone resorption, as these markers were not affected by treatment.

A recent study by Wangen et. al. [18] evaluated the effects of soy protein isolates with three levels of isoflavones on markers of bone turnover in 14 pre- and 17 postmenopausal women in a crossover design for over three months each. The authors concluded that the effects of soy isoflavones on markers of bone turnover were of small magnitude and unlikely to be clinically relevant. However, a study by Sheiber et al. [19] involving 50 postmenopausal women who received 60–70 mg of isoflavones in the form of soymilk for 12 weeks demonstrated a significant reduction in urinary NTX and an increase in serum osteocalcin. These findings indicate that while soy milk consumption reduces the rate of bone resorption, it concomitantly enhances the rate of bone formation. Our recent unpublished data support their findings. In our study, consumption of 40 g soy protein delivering 90 mg isoflavones daily for a period of three months significantly reduced urinary deoxypyridinoline (Dpd) excretion, a specific marker of bone resorption. At the same time, the soy protein significantly elevated serum IGF-I concentrations in women under or above age 65 regardless of their estrogen status.

There are numerous explanations for these inconsistencies, including the differences in age, menopausal status, and the relatively short duration of soy isoflavone treatment. The consensus, in general, is that significant changes in BMD in response to treatment require at least one year. All the clinical studies published so far do not come close to this time period. Additionally, although the isoflavone contents of the soy regimens provided to the study participants may be similar, the concentrations of individual isoflavones such as genistein and daidzein may vary from one extract to another, thereby exhibiting different biological activities on bone. Finally, in view of the favorable responses observed in the rat model, it should be noted that the doses of isoflavones used in the human studies are only about 5% to 10% of those used in rats when assessed per kilogram body weight. This may explain why the efficacious dose of ipriflavone, a synthetic isoflavone, for postmenopausal osteoporosis is 600 mg daily, which is several fold higher than the doses of isoflavones used in human studies. Therefore, dose-response studies are necessary to establish the most efficacious dose of isoflavones on bone. At this time, it should be noted that there are too few intervention studies in humans to enable us to draw any clear conclusions in regards to the role of isoflavones on bone.

FLAXSEED AND BONE
Among edible plant foods, flaxseed is by far the richest source of lignans, which are reported to have both weak estrogenic and anti-estrogenic activities [20]. Lignans are structurally similar to tamoxifen, which has beneficial effects on bone [21]. Flaxseed is also a rich source of polyunsaturated fatty acid (PUFA), especially {alpha}-linolenic acid (18:3 n-3) [22]. Alpha-linolenic acid may decrease the rate of bone resorption by inhibiting the biosynthesis of prostaglandins [23]. Lignans present in flaxseed may also possess antioxidant properties. Oxygen-derived free radicals, which are formed by a number of phagocytes including monocytes, macrophages, and neutrophils, have been reported to increase in chronic inflammatory diseases, aging, and osteoporosis. In vivo and in vitro findings indicate that free radicals generated in the bone environment enhance osteoclast formation and bone resorption. Hence, flaxseed may reduce the rapid rate of bone loss experienced by postmenopausal women, in part, by enhancing antioxidant status. We have previously reported [24] that flaxseed can potentially exert positive effects on bone of postmenopausal women. In a follow-up study, we assigned 60 postmenopausal women not on HRT to receive either 40 g flaxseed or a 40 g wheat-based comparative control supplement for three months. Early evaluation of the results from this study indicates no amelioration of serum and urinary biomarkers of bone metabolism. Whether a longer-term study using bioactive components of flaxseed such as lignans or its oil can exert a positive influence on BMD and BMC remains to be explored.

EVIDENCE FOR BENEFICIAL EFFECTS OF DRIED PLUMS ON BONE
Other plant food sources rich in phenolic compounds and flavonoids may also protect bone. Dried plums or prunes (Prunus domestica L.) are rich in phenolic compounds such as neochlorogenic acid and chlorogenic acid [25] and are ranked as having the highest oxygen radical absorbance capacity (ORAC) among the commonly consumed fruits and vegetables [26]. Hence, it is conceivable that antioxidants present in prunes may play an important role in protecting bone by scavenging free radicals and preventing oxidative damage to bone.

Dried plums are also a rich source of selenium and boron. Both of these trace elements are known to modulate bone metabolism [27–28] and play an important role in preserving bone mineral density (BMD) [28–29]. We have observed that inclusion of dried plums in the diet prevents the ovariectomy-induced bone mineral density (BMD) loss in rats [30]. The histomorphometric findings also confirm the efficacy of dried plums in preventing bone loss as indicated by significantly higher trabecular bone area and percent bone surface.

In a follow up study [31], we evaluated the ability of dried plums to reverse bone loss using osteopenic ovarian hormone deficient rats. Dried plums, as low as 5% of the diet, were able to bring the femoral bone density back to that of non-osteopenic rats. The same level of dried plums was also effective in increasing the 4th lumbar bone density; however, the increase was of smaller magnitude.

These observed effects of dried plums in the rat model were also confirmed in our unpublished findings in postmenopausal women. Dried plum supplementation for three months significantly increased bone-specific alkaline phosphatase activity, a marker of bone formation, by 6% while reducing the urinary marker of bone resorption by 11% in postmenopausal women not on HRT. These findings indicate that dried plums also have the ability to increase bone formation in postmenopausal women, thus decreasing the risk for osteoporotic fractures. The beneficial effects of dried plums on bone may be due to the presence of various components including phenolic compounds, sorbitol, boron, or their combination. A logical question is what component in dried plums exerts the beneficial effects on bone. Future studies are needed to answer this question and determine the mechanism(s) of action. Longer-term human studies are also necessary to confirm the positive effects of dried plums on bone mineral density.

CONCLUSION
Considering all of the animal and human data to date, soy protein may have modest effects on bone. However, it is premature to state whether it is soy protein or its isoflavones that prevent the bone loss in ovarian hormone deficiency. Future directives on the role of soy in bone health are to address numerous questions including whether isoflavones, independent of soy protein, are able to prevent ovarian hormone deficiency-associated bone loss. Another question is whether incorporating soy foods into the daily diet or intake of isoflavones on a regular basis is necessary to observe beneficial effects on bone.

We have just begun to address the health benefits of natural bioactive compounds in foods for humans. More studies are required to answer numerous questions regarding the potential skeletal benefits of these natural foods.


   ACKNOWLEDGMENTS
 
These studies have been supported, in part, by grants from NIH R03-AG16487-01, Illinois Soybean Program Operating Board, and California Dried Plum Board.

Received April 26, 2001.
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