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1 From the Department of Pediatrics, Clinical Mass Spectrometry, Children’s Hospital Medical Center, Cincinnati (KDRS), and the Institute for Optimum Nutrition, Copenhagen (EL).
2 Presented at the Fourth International Congress on Vegetarian Nutrition, held in Loma Linda, CA, April 8–11, 2002. Published proceedings edited by Joan Sabaté and Sujatha Rajaram, Loma Linda University, Loma Linda, CA. 3 Address reprint requests to KDR Setchell, Clinical Mass Spectrometry, Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229. E-mail: kenneth.setchell{at}chmcc.org.
ABSTRACT
Impressive data from the many studies on cultured bone cells and rat models of postmenopausal osteoporosis support a significant bone-sparing effect of the soy isoflavones genistein and daidzein. Translating this research to the clinic has been more challenging, and thus far only a few clinical studies have attempted to tease out the influence of phytoestrogens on bone from the many other components of the diet. Human studies have shown promising although variable results. Studies have been mostly of short duration and with relatively small sample sizes, making it difficult to observe significant and accurate changes in bone. Levels of intake of the soy protein and isoflavones are varied, and the optimal isoflavone intake for bone-sparing effects remains to be determined. Clinical studies thus far performed can be broadly divided into those that have assessed biochemical evidence of reduced bone turnover from measurement of surrogate markers of osteoblast and osteoclast activity, and those that have examined changes in bone mineral density. There are no studies examining effects on fracture rate. This review focuses specifically on the potential influence of phytoestrogens on bone by examining the evidence from 17 in vitro studies of cultured bone cells, 24 in vivo studies of animal models for postmenopausal osteoporosis, 15 human observational/epidemiologic studies, and 17 dietary intervention studies. On balance, the collective data suggest that diets rich in phytoestrogens have bone-sparing effects in the long term, although the magnitude of the effect and the exact mechanism(s) of action are presently elusive or speculative.
Key Words: Phytoestrogens • bone • isoflavones • soy • osteoporosis
INTRODUCTION
Osteoporosis is now a major public health threat, and its prevalence is expected to rise dramatically in the coming decades. Figures from the National Osteoporosis Foundation indicate that about 44 million Americans are at risk for the disease by virtue of having low bone mineral densities. Presently 10 million adults have osteoporosis, and while the majority of these patients are women, it is not a sex-exclusive disease. Nationally, the direct expenditure on treating the 1.5 million fractures that occur each year associated with osteoporosis runs at approximately $47 million every day and, alarmingly, almost a quarter of the patients over the age of 50 y die within 1 y of their hip fracture.
Estrogen deficiency is generally not listed as one of the main risk factors for osteoporosis, but it is indirectly and strongly associated with the many recognized risk factors: being female, being thin, being of advanced age, being postmenopausal, having amenorrhea, and using alcohol excessively. In the 1940s, Fuller Albright first highlighted the importance of estrogen with clinical descriptions of osteoporosis in ovariectomized women and how estrogen improved calcium status (1–3). However, it was not until the 1970s and only after it became possible to directly measure bone density that the full impact of estrogen was realized (4, 5). Although adequate dietary calcium is important in the prevention of osteoporosis (6, 7), acute ovarian deficiency accounts for the loss of 20% of bone mass in the first 5–7 y of the postmenopausal period (8). Innumerable studies attest to the importance of estrogen in bone remodeling, evident from the fact that hormone replacement therapy (HRT) administered in a dose-dependent manner effectively prevents bone loss in postmenopausal women (5, 9) and reduces the incidence of fractures (10–13). Unfortunately, few women are likely to reap the bone-sparing benefits of HRT long term because of poor compliance due partly to the fear of increased risk for breast and endometrial cancers (14, 15) and because of unwanted side effects associated with these powerful steroids. Recent results from the Women’s Health Initiative Study showing an unexpected lack of cardioprotective effects of HRT (14) will undoubtedly serve to increase the search for alternative and natural strategies for menopausal estrogen deficiency, including ways of managing the prevention of osteoporosis with aging. Of all the natural alternatives currently under investigation, phytoestrogens appear to offer the most potential for the prevention of bone loss. Investigations of the bone-conserving properties of isoflavones have been justified by the following lines of tantalizing circumstantial evidence:
IN VITRO STUDIES OF PHYTOESTROGENS ON BONE CELLS
Bone remodeling is the function of the activity of 2 different cell lines. Osteoblasts, responsible for bone formation, respond to changes in the activity of osteoclasts, the bone resorbing cells. Many hormones, growth factors, and cytokines play a regulatory role in maintaining bone homeostasis (35–38) by their effects on these 2 cell lines, and estrogen in particular is responsible for suppressing osteoclast activity and thereby preventing bone resorption. However, in acute ovarian estrogen deficiency, as occurs in surgical or natural menopause, the rate of bone resorption due to increased osteoclast activity exceeds the rate at which osteoblasts are capable of forming new bone. The net result is depletion of calcium, collagen, and protein from bone, and increased porosity and accompanying risk for fracture. Estrogen receptors ER and ERß are both found in human osteoblasts, although the expression of these subtypes varies considerably during differentiation (28, 39). The greatly increased expression of ERß during bone mineralization (27) is particularly pertinent to the potential hormonal effects of phytoestrogens because compounds such as genistein show a much higher affinity for ERß than for ER (40, 41). For example, genistein at physiologic concentrations is a relatively good "estrogen" where ERß is concerned, and its transcriptional activity is actually almost twice that of estradiol on ER and ERß (40).
The first in vitro studies of the action of a number of phytoestrogen classes predated any clinical studies of the actions of phytoestrogens on bone. One of the earliest studies of phytoestrogens found that the coumestan, coumestrol, not only inhibited bone resorption of 9-d-old chick embryo femur explants (42) but also negated the bone resorption effects of parathyroid hormone, vitamin D, and prostaglandin at doses that were 10-5 mol/L (43). Some years later, it was reported that the potent antiestrogen tamoxifen blocked the inhibitory actions of genistein on parathyroid-induced bone resorption in tissue culture (44). Numerous in vitro studies with human and animal osteoblasts or osteoblast-like cell lines, and with osteoclasts, have been carried out, with consistent observations of direct effects of phytoestrogens and related compounds on both cell types (42, 45–59). These are summarized in Table 1. Daidzein and genistein have been found to have a stimulatory effect on protein synthesis and on alkaline phosphatase release by various types of osteoblast cells in vitro (60–62). This effect is blocked by the addition of actinomycin or cycloheximide, suggesting that these isoflavones influence transcriptional or translational events. Osteoprotegerin (OPG), a member of the tumor necrosis factor receptor superfamily, prevents bone resorption by a paracrine mechanism (63). It is now apparent that osteoclast activity is modulated through osteoblasts via OPG. The cytokine receptor/activator of nuclear factor-K (RANKL) (64) stimulates osteoclast differentiation and function with higher levels of RANKL expression leading to increased bone resorption. OPG is a ligand for this cytokine and blocks its expression. Ovariectomy, or the pure antiestrogen ICI 182 780 decreases, and estrogen increases expression of OPG mRNA and protein by human fetal osteoblastic cell line (hFOB/ER-9) transfected with ER (56). More recently, genistein has been found to stimulate the production of osteoprotegerin by human paracrine osteoblasts, providing a further mechanism for the bone-sparing effects of soy isoflavones. It is apparent that in addition to osteoblast and osteoclast activities being coupled, the actions of isoflavones on osteoclasts could also be independent of their effects on osteoblasts because estrogen receptors appear not to be present in the nucleus of these cells. Genistein and daidzein both suppress osteoclast activity by a number of possible mechanisms, including induction of apoptosis, activation of protein tyrosine phosphatase, inhibition of cytokines, changes in intracellular Ca++, and membrane depolarization (45, 46, 51, 65, 66), further highlighting the level of complexity in mechanism of estrogens and phytoestrogens in bone turnover.
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TABLE 1 . In vitro studies on phytoestrogens and bone effects1
While the mechanism of action for isoflavones remains elusive, it is evident from the many lines of evidence that there are probably multiple pathways, genomic and nongenomic, that conserve the integrity and activity of these 2 cell lines to maintain stable bone mass in adults. Certainly the presence of estrogen receptors in bone (27, 28) and the wide-ranging biological properties of these nonsteroidal dietary estrogens (67–70) provide good rationale for thinking that dietary phytoestrogens should play a role in bone remodeling.
IN VIVO EFFECTS OF PHYTOESTROGENS IN ANIMAL MODELS OF POSTMENOPAUSAL BONE LOSS
While in vitro studies provide useful insight into possible actions of isoflavones on individual bone cells, in vivo studies offer the advantage of an intact system that takes account of any coupling effects between osteoblasts and osteoclasts and their progenitor or precursor cells, while also allowing for metabolic events that might influence the efficacy of a candidate compound. For phytoestrogens and most phytochemicals, intestinal metabolism plays a crucial role in their bioavailability and biological activity (71).
Most of the bone studies of phytoestrogens have been performed in rodents that have been ovariectomized, although limited data exist for nonhuman primate species (72) and for pigs (53). The models are accepted models for postmenopausal osteoporosis in that acute ovarian estrogen deficiency leads to rapid and measurable loss of bone mass; however, they are often highly stressed with regard to calcium requirement. With few exceptions (73–76), soy isoflavones have mainly been investigated. Armandji et al first reported that soy protein isolate was as effective as estradiol in retarding bone loss following ovariectomy (77). The earliest studies examined the effects of soy milk (78) and of soy protein isolate (77, 79) compared with casein, and all found BMD in rats to be highest in the soy-fed animals relative to controls. In total, we can document 22 rodent studies on phytoestrogens and bone (45, 72, 80–99), mostly isoflavones; the study designs, specific models used, and the main findings of each are summarized in Table 2. Not all of these studies have been published in detail or subjected to peer review publication, and in some cases data have been taken from published abstracts from recent presentations at national and international congresses. Collectively the study designs are in principle similar, but among individual studies there is high variability. For example, subcutaneous injection, gavage, or oral feeding has been the chosen route of administration of phytoestrogens; the source has been usually isoflavones, either pure compounds (mainly genistein) or soy proteins, with or without their isoflavones; and the control comparisons have been with casein or semipurified diets. In a number of the studies, the effect of phytoestrogens has been compared with conjugated estrogen (Premarin) or estradiol. Primary endpoints generally measured have been bone mass of trabecular and/or cortical bone after ashing, BMD, and mechanical strength, and secondary measures often included surrogate markers of bone turnover and effects on uterine weight. The latter is aimed at addressing the estrogenic effectiveness of the treatment and drawing some conclusions on possible negative effects on the uterus.
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TABLE 2 . Animal research regarding soy, isoflavones, and bone effects1
As with the findings on ipriflavone, almost without exception phytoestrogens universally influence both trabecular and/or cortical bone in ovariectomized rodents (Table 2). Interestingly, the one exception, a study by Draper et al, found no effect of a red clover isoflavone supplement on BMD of ovariectomized rats (74), yet a recent clinical study reported that a commercial red clover isoflavone supplement increased BMD in postmenopausal women by a surprising (given the physiologically slow rate of bone turnover) 4.1% in 6 mo with no observed dose-response effect (100). Single studies of ovariectomized monkeys (72) and growing pigs (53) have also found no effects of soy isoflavones on bone, so there may be species differences in responsiveness to soy isoflavones. Teasing out the specific component(s) of soy that may be responsible for the bone-sparing effects observed in these animal models is not simple or straightforward, as it is evident that where whole foods or soy protein extracts are concerned there must be multiple effects that collectively contribute. For example, the controversial role of the protein on bone (101–103) should not be discounted because vegetable protein, such as soy, is less hypercalciuric than animal protein (104, 105) and some soy foods, such as soy milk, can reduce calcium bioavailability in adults (106). It should be pointed out that many soymilks are, however, fortified with calcium, and overall the effect of soy protein foods is to reduce urinary calcium excretion and enhance net calcium retention, independent of isoflavones (107). Nevertheless, there is ample evidence from the animal model studies for the effectiveness of isoflavones in conserving bone. To our knowledge, Blair et al (45) were the first to test pure genistein added to the diet, as opposed to an isoflavone-rich soy protein, in ovariectomized Sprague-Dawley rats and found that it increased BMD by 12% over a 30-d period following surgery. This observation was subsequently confirmed by others working with the pure isoflavones, and dose-response effects were noted for daidzin and genistin (87), including a biphasic response reported by Anderson et al (81) in which a low dose of genistein (0.5 mg/d) was considerably more effective than higher doses (> 1.6 mg/d) and comparable to Premarin’s effects on bone in a lactating, ovariectomized, and calcium-stressed rat model. Also of interest was the finding that delaying administration of genistein until long after ovariectomy was less effective in conserving bone than if it was given immediately on loss of ovarian estrogen (84). This isolated observation may have implications for humans because what is not yet known is whether the timing of administration of isoflavones affects the ultimate outcome for bone. For example, can having early intakes better prevent postmenopausal osteoporosis rather than waiting for menopausal bone loss to be initiated? Overall, the animal studies on phytoestrogens convincingly support in vitro studies showing that isoflavones modulate bone turnover and retard bone loss in acute estrogen deficiency.
CLINICAL AND DIETARY EFFECTS OF PHYTOESTROGENS ON BONE
Short-term human studies of surrogate markers of bone turnover
A number of observational and dietary intervention studies (Table 3) confirm the general findings from the in vitro effects of phytoestrogens on bone cells in culture. Thus far, 9 observational or epidemiologic studies (108–116) and 9 dietary intervention studies (117–125) have shown significant relationships between phytoestrogens and surrogate markers for bone turnover that are indirectly consistent with reduced bone turnover (Table 4). Markers indicative of osteoblast and osteoclast activity that have been measured include urinary calcium, magnesium and phosphorous, hydroxyproline, and collagen cross-links, while serum measures have included bone-specific alkaline phosphatase, tartarate-resistant acid phosphatase, osteocalcin, insulin-like growth factor I (IGF-I), and interleukin 6. One advantage of using these sensitive markers is that biochemical events occurring in bone can be detected long before significant changes in BMD or bone mineral content (BMC) can be measured, or fractures occur.
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TABLE 3 . Human observational studies regarding usual soy/phytoestrogen intake, bone and bone metabolism1
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TABLE 4 . Human intervention studies with phytoestrogen and bone in peri- and postmenopausal women1
Most of the observational studies on bone markers have been performed in women living in countries where the indigenous population have a relatively high phytoestrogen intake, largely because of the consumption of isoflavones in soy protein foods. Typical intakes, estimated at 15–50 mg/d (125–129), however, never approach the high levels currently being adopted in most clinical intervention studies being performed in the Western countries, or for that matter advocated for the prevention of osteoporosis. Notwithstanding the limitations of using bone markers, observational studies have consistently found a significant inverse correlation between isoflavone intake or urinary excretion and the excretion of the bone resorption markers pyridinoline and deoxypyridinoline cross-links for postmenopausal women living in Japan, Korea, and China (109–111, 114), while one study of whites in the United States found urinary NTx to be 18% lower in women with the highest intake of dietary genistein (114).
The acute effects of phytoestrogen-rich diets on bone markers is also revealed in a number of intervention studies summarized in Table 4. There is little consistency in the design among these human studies, and a variety of soy foods have been tested with differing levels of isoflavones. Nevertheless, most studies have found that when soy foods containing substantial levels of isoflavones are substituted in the diet of postmenopausal women, urinary pyridinoline cross-links are reduced (117–120, 122–124) consistent with reduced bone resorption. One study of 12 postmenopausal women fed about 1 L of soymilk each day for 4 mo actually observed an increase in deoxypyridinoline cross-links (124). To our knowledge, only one study in men has been described; this found that 40 g/d of soy protein as compared with casein fed over a 3-mo period increased serum IGF-I (121), a marker associated with bone formation, but found no changes in urinary hydroxyproline, deoxypyridinoline magnesium, calcium, or phosphorus were detected. Overall, the encouraging findings from the short-term bone marker studies and the vast amount of positive data from in vitro and in vivo studies have given sufficient justification for longer-term clinical studies investigating more fully the role of phytoestrogens on bone.
Epidemiologic and dietary intervention studies of phytoestrogens and bone
Much of the early justification for investigating phytoestrogens, and particularly soy isoflavones, as candidates for preventing bone loss came from the wealth of positive data on the bone-sparing effects of the synthetic isoflavone ipriflavone (19). This pharmacologic OTC agent was found to suppress bone resorption, increase Ca++ retention in bone, and augment the action of estrogen on bone and was deemed a rational alternative to HRT in preventing bone loss in acute and ovarian-deficient states and in postmenopausal women. One of its metabolites, coincidentally, is the soy isoflavone daidzein (18, 130). The drug became approved in a number of countries, but a recent large 3-y multicenter clinical study found it to be no better than placebo in preventing bone loss, and reports of lymphocytopenia have raised concerns about its use (21).
Human studies to elucidate the role of phytoestrogens in preventing bone loss can be broadly separated into epidemiologic studies and dietary intervention trials. It is outside the scope of this article to review all the factors that pertain to differences in BMD and fracture rates among Asian and Western populations, but it is evident that these are multifactorial. Even within Asian populations, several observational studies now show that postmenopausal women consuming the highest amounts of soy foods, and hence isoflavones, have the highest femoral and/or lumbar spine BMD (109, 113, 114), an observation also confirmed in 2 studies of Japanese-Americans (109, 112) (Table 3). With regard to premenopausal women, only 4 studies have been reported, and it is not possible to draw conclusions regarding the impact of phytoestrogens on bone earlier in life (114, 131–133). Interestingly, a recent study of Chinese women found that those who consumed the most soy foods as adolescents had the lowest risk for breast cancer as adults; soy food intake as adolescents was assessed from dietary recall questionnaires administered to the study subjects, and the accuracy of recall was confirmed by their surviving mothers (134). Whether this type of early exposure effect could also occur in relation to osteoporosis risk is uncertain, as no prospective studies of soy and BMD, or fracture rates, have been performed to date. Data are limited, so it is difficult to draw conclusions on the relationship between phytoestrogen intake and bone density or fracture rate in adults living in Western countries (108, 115, 135), especially given that phytoestrogen intake is generally negligible in such countries.
Overall, it is difficult to discern whether it is the intake of phytoestrogens or other components of the diet, including lifestyle, that account for what appear to be positive associations between soy food or isoflavones and bone density, but the data are tantalizing enough to warrant clinical investigations. In this regard, only a few dietary intervention studies have been completed thus far (Table 4), and the results have been variable and conflicting (136). Perhaps the biggest problem with these studies is that they are all of different design and of relatively too short a duration to accurately detect significant changes in BMD given the slow rate of bone turnover. The landmark publication of Potter et al (137), which found a significant bone-sparing effect (BMD increased 2.2%) at the lumbar spine of a soy protein diet with an intake of 90 mg/d isoflavones over a 6-mo period but not with 45 mg/d, set the benchmark for the choice of "dosing" in subsequent studies. It should be noted that an intake of 45 mg/d of isoflavones from soy foods had previously been shown to have endocrine-modulating effects on the menstrual cycle of healthy premenopausal women (138). On the issue of dosing, it is not always clear how the isoflavone intake is calculated because the absolute level of isoflavone is considerably higher if expressed as total isoflavones (inclusion of the glycoside portion) as compared with aglycons only. Note that 90 mg of total isoflavone is really equivalent to only 50–55 mg of isoflavones after removal of the glycoside moiety by intestinal bacteria (71), and this is the true maximal bioavailable fraction of the molecule. Nevertheless, there does appear from the few dietary intervention studies thus far performed to be a threshold level of intake below which changes in BMD have been undetectable in the short term. Whether this implies that there are no effects of low doses of isoflavones in the diet, or whether it is a case of low doses taking a very long time to be effective in preventing bone loss, remains to be determined. Certainly, the typical isoflavone intake of Japanese and Chinese women consuming traditional diets [estimated at 15–50 mg/d (126–129)] does not approach the levels being tested in clinical intervention studies. This again poses the question of how important early exposure to phytoestrogens might be in the longer term for bone health. This question could be answered only by long-term intervention studies of premenopausal women.
Since the work of Potter et al (137), there have been 3 dietary intervention studies in postmenopausal women that were of 9-mo duration or less with soy (139–141), and one study that used a red clover supplement rather than soy foods as the source of isoflavones (100). Of these, 2 studies showed no changes in BMD with soy foods containing isoflavones when compared with a placebo or control diets (140, 141), one showed a bone-sparing effect where BMD remained unchanged whereas the control group consuming whey protein significantly lost bone (139), and one showed a surprising 4.1% increase in BMD measured at the proximal radius and ulna (100) with a dose of 57 mg/d of red clover isoflavones. The magnitude of this increase over 6 mo in the latter study seems improbable given the slow physiologic rate of bone gain, while the lack of a dose-response effect is also difficult to reconcile if isoflavones have bone-sparing effects (100). Problems seem apparent with the study by Dalais et al (140), which indicated a 5.2% increase in BMC over a 3-mo period with various phytoestrogen-rich diets yet no change in BMD. This change in whole-body BMC would by our calculations imply the equivalent of a gain of 115–125 g in BMC—seemingly improbable over a 3-mo period.
Only 2 long-term studies in postmenopausal women have been reported to date, both of 2-y duration; these also revealed somewhat conflicting data with regard to isoflavones (144, 145). In one study, the Food and Drug Administration–approved level of 25 g of soy protein for heart health was used, and it was varied with regard to its isoflavone content; 3 different levels of isoflavones—5, 42, and 58 mg/d—were tested. Total-body BMD did not differ among the 3 groups, and only minimal bone loss was observed, suggesting that soy protein had some bone-sparing effects independent of isoflavones (144). By contrast, a 2-y study from our group of 108 postmenopausal women consuming 500 mL of soy milk (18 g soy protein) containing 85 mg isoflavones (aglycon equivalents) as compared with the same amount of soy milk with < 1 mg/d isoflavones prevented bone loss in the lumbar spine, with only minimal change in the femur regardless of isoflavone level (145). BMD and BMC showed 1.1% and 2.2% increases, respectively, and this change was not significantly different from baseline values in those women consuming soy milk with isoflavones, while women who consumed the same amount of soy protein lacking isoflavones lost 4.2% and 4.3%, respectively, in lumbar spine BMD and BMC (P < 0.01 for both measures). This magnitude of change is typical of the usual physiologic loss of bone anticipated in the first 2 y of menopause in the absence of any therapeutic intervention, and it should be mentioned that the bone-sparing effect was unrelated to dietary calcium or protein composition, which was identical in all women. Interestingly, interim analysis of the study data failed to find any significant effects of soy isoflavones on BMD after 1 y as measured by dual-energy X-ray absorptiometry, emphasizing our contention that more long-term studies are needed before definitive conclusions can be reached regarding the effectiveness of phytoestrogens on bone.
More interestingly, we have found that the extent of intestinal metabolism of isoflavones may be the single most important clue to the clinical efficacy of soy foods in preventing bone loss (146). Equol, a specific bacterial metabolite of daidzein (147), and an isoflavone not found in soy, was formed in only 45% of the postmenopausal women studied (145), but in those capable of making equol, referred to as "equol producers," lumbar spine BMD increased by 2.4% (P < 0.001 compared with control group), while there was no significant change in BMD in the "non-equol producers." Equol has a much higher affinity for the estrogen receptor than daidzein, its precursor phytoestrogen, and of all the isoflavones it has the highest antioxidant capacity (146), factors that could account for the greater effects observed in equol producers in this bone study (145). The ability to "bacteriotype" individuals for their ability to produce equol now seems crucial in the design of future clinical studies of soy foods, and the failure to do this in all of the previously reported studies may explain the variances in reported findings on phytoestrogens and bone. It is evident there are 2 distinct subpopulations for which soy isoflavones may show different efficacy (146). In some ways, this could be considered analogous to the differences in responses to calcium seen by genotyping for the vitamin D receptor (VDR). Although the finding is controversial, calcium supplementation may have greater benefit on BMD in women with the BB genotype rather than the bb or Bb alleles for the VDR (148, 149). The role of the many other components of the diet, including but not restricted to vitamin K and vitamin D, and the possibility of nutrient interactions need also to be considered along with lifestyle issues that orchestrate the quality of bone earlier in life. For example, moderate consumption of tea, which contains flavonoids closely related to soy isoflavones, has been found to be associated with higher BMD in men and women (150, 151) and lower rates of fracture (152, 153), while caffeine intake has opposing effects in certain VDR genotypes (154). It is not always clear whether such factors are considered in the dietary intervention studies of soy isoflavones or in the observational studies of soy intake and bone in the Asian studies.
SUMMARY
As Erdman et al (136) stated recently, the results from the few studies of phytoestrogens, in particular soy isoflavones and bone health, are provocative and too few to draw definitive conclusions. A wealth of supporting data from many in vitro mechanistic studies of bone cell lines and in vivo studies of models of osteoporosis convincingly shows bone-sparing effects from dietary phytoestrogens. The data are, however, sufficiently tantalizing to justify large-scale clinical dietary intervention studies of phytoestrogens. The timing of intervention, however, is an important consideration because it is possible that soy isoflavones may offer the maximum benefit for prevention rather than treatment of osteoporosis. Ultimately, a prospective study of the impact of phytoestrogen-rich diets on fracture rate would provide definitive answers to the efficacy of phytoestrogen-rich diets and their value as a possible alternative to pharmacologic treatments of what will likely become a disease of epidemic proportions in the future.
ACKNOWLEDGMENTS
The authors had no conflict of interest.
REFERENCES