Soy isoflavones and markers of bone health
Numerous studies have investigated the relationship between one or more isolated soy isoflavones and markers of bone health. Presented here are the conflicting results from the two longest-term studies reported to date [Alekel et al. 2010
; Atteritano et al. 2009
; Messina et al. 2009
; Marini et al. 2007
] and the results of several meta-analyses addressing this topic [Taku et al. 2010
; Liu et al. 2009
; Ma et al. 2008a
]. In the Soy Isoflavones for Reducing Bone Loss Study, a double-blind randomized controlled trial, 224 healthy postmenopausal women were treated with placebo or 80 or 120 mg/day isoflavones for 36 months. All participants received 500 mg calcium and 600 IU vitamin D3
daily and had BMD declines of the spine, femur, neck, and whole body. In both intent-to-treat and compliant analyses, the results did not show a bone-sparing effect of extracted soy isoflavones [Alekel et al. 2010
These results are in contrast to the findings of a study conducted at three medical centers in Italy. The trial was originally designed to last 2 years. In it, 389 postmenopausal osteopenic women, who were otherwise healthy, were randomly assigned to either placebo plus calcium and vitamin D or 54 mg/day genistein plus calcium and vitamin D. In this study, genistein treatment prevented bone loss and improved quantitative ultrasound parameters [Atteritano et al. 2009
; Marini et al. 2007
]. In a 1 year continuation with the 138 women who agreed to continue, spinal and hip BMD increased by approximately 8% and 9%, respectively, in the treated group (n
= 71) while BMD decreased at those sites by 12% and 8%, respectively, in controls (n
= 67) [Messina et al. 2009
]. Because the findings are so dramatically different between these two trials, researchers are trying to understand which factors in experimental design or study populations might account for these discrepancies. One possible explanation is the difference in isoflavone preparations; perhaps genistein is more effective than mixed isoflavone supplements [Messina et al. 2009
Similarly, recent meta-analyses of data on BMD from the randomized controlled trials came to contradictory conclusions. In one that included 10 randomized controlled trials with a total of 896 women, which lasted at least 1 year and had a mean dose of soy isoflavones of 87 mg per day, treatment did not significantly affect BMD changes in the hip or the spine [Liu et al. 2009
]. In the other, also a meta-analysis of 10 trials, in a total of 608 women consuming between 4.4 and 150 mg soy isoflavones per day for at least 3 months, the authors found that isoflavone intervention significantly attenuated bone loss of the spine in menopausal women, as measured by BMD or bone mineral content. Stronger effects were seen with isoflavone doses of >90 mg/day and for treatment durations of 6 months or longer [Ma et al. 2008a
Two other meta-analyses studied the impact of isoflavone intervention on markers of bone resorption and bone formation. In one analysis, which included nine studies in a total of 432 women, the authors found that even at doses <90 mg/day and with shorter (<12 week) interventions that isoflavone treatment significantly inhibited bone resorption and stimulated bone formation [Ma et al. 2008b
]. In the other study, the effects of soy isoflavones on urinary deoxypyridinoline (10 studies, 887 participants), serum bone alkaline phosphatase (10 studies, 1210 participants), and serum osteocalcin (8 studies, 380 participants) were analyzed. The authors found a modest decrease in deoxypyridinoline, a bone resorption marker, but no effect on either bone alkaline phosphatase or osteocalcin, bone formation markers [Taku et al. 2010
So what is the bottom line?
Why are the results of the randomized controlled trials so mixed when the observational studies seem quite clear? Differences in study design are likely to explain some of the variations in the results of the randomized controlled trials. The studies varied in length (from 4 to 24 months), they utilized different types of ‘active ingredient’ (mixed isoflavone extracts, genistein extracts, soy protein powder, or soy milk, sometimes enriched with additional soy isoflavones) at different dosages of isoflavones (e.g. 4.4 mg/day to 118 mg/day) and participants were male, female or both (though most studies had female participants), and among women, menopausal status varied (though most studies were in postmenopausal women).
In addition, the race, ethnicity, culture and dietary norms varied across the observational and randomized controlled trials [Liu et al. 2009
; Ma et al. 2008a
]. In particular, the results linking soy foods to bone health outcomes in observational studies (cross-sectional and longitudinal) were largely seen with Asian populations in China, Japan, or the USA. In these populations, much of the soy eaten comes from traditional soy foods, whole soybeans, soy milk, fresh bean curd, and fermented bean curd and other fermented soy foods [Zhang et al. 2008
]. In the observational US studies, the soy was largely consumed as soy milk, soy-based vegetarian meat substitutes, tofu, soy sauce, soy-based protein powders, and miso soup. In the US studies, the Asian–American participants were more likely to have a higher intake of soy isoflavones than participants from other racial or ethnic backgrounds [Greendale et al. 2002
Furthermore, it is not known whether physical activity levels differed among these populations in such a way as to be able to explain the differences in soy food or soy isoflavone associations with markers of bone health. The study that directly compared race and ethnicity subgroups did control for physical activity levels within population groups, but soy food intake was not high enough to do a relational analysis in the African–American and White population groups, so between-group comparisons were not possible [Greendale et al. 2002
In the observational studies, dietary patterns rich in isoflavone-containing foods did tend to have positive associations with markers of bone health [Koh et al. 2009
; Song et al. 2008
; Ho et al. 2008
; Hirota et al. 2005
; Zhang et al. 2005
; Greendale et al. 2002
; Mei et al. 2001
; Horiuchi et al. 2000
]. In clear contrast, most of the 25 or more human trials have been conducted using soy extracts (isoflavone supplements) rather than soy foods [Messina, 2008]. For purposes of standardization and reducing treatment bias, researchers designed the controlled trials using some form of soy extract, and many of these studies (even with more stringent controls to help reduce noise due to variations in source, dose, etc.) did not find a link between soy isoflavones and markers of bone health. These divergent results raise several questions and possible alternative explanations. Are soy isoflavones the ‘active ingredient’? If so, do these compounds need to be combined with other substances in soy foods to exert their beneficial effects? Or is there something about a dietary pattern that is rich in soy foods that supports bone health (rather than a specific component in soy foods)?
Researching dietary patterns
Observational studies have limitations. Cross-sectional studies in which populations or groups are compared at one point in time are especially limited in that a causal relationship, a change over time, and the magnitude of the impact cannot be determined. Often, the best use of cross-sectional studies is for hypothesis development (i.e. determining what questions might be useful to address with other types of studies). The longitudinal prospective studies share some of these same limitations.
However, some of the limitations of observational studies may also be benefits. Many common chronic diseases have multifactorial causes and develop over a long period of time, often a decade or more. Osteoporosis is a case in point. Many factors, such as activity level, a variety of dietary constituents, medication use, other health conditions, other lifestyle choices, as well as environmental factors in an individual’s life over time, are likely to impact that person’s risk of hip fracture. Participants in longitudinal prospective studies are living their lives with only limited interference from researchers. This, of course, creates noise (variation) in the data that makes it more difficult to draw conclusions, but the conclusions drawn are more likely to be applicable to people in real-life situations.
In longitudinal prospective studies, researchers often try to draw conclusions about specific nutrients, behaviors, or dietary patterns and the risk of some disease or condition by categorizing individuals into strata based on estimating a particular behavior (e.g. consumption of soy foods). Estimations, for example, of dietary isoflavone intake, are often calculated from assessment tools that also have limitations. For example, food frequency questionnaires may only be given once or twice over a 2–10 year study. Isoflavone intake is calculated from a food frequency questionnaire by including some foods known to be rich in isoflavones on a long list of possible foods a person might consume (typically 100+), and asking participants to estimate how often they eat each food over a week, month or year. Then the isoflavone intake is estimated from the usual amounts of isoflavones in the servings of those foods consumed in a month or year. Of course, it would be easy to miss foods (protein bars, protein powders in smoothies in the USA for example) or dietary supplements containing isoflavones on a food frequency questionnaire. Of course, the way an individual might fill out a food frequency questionnaire is likely to vary to at least some degree with season, year, current activity level, and other life factors.
These limitations would make it more difficult to see an effect of a particular dietary or lifestyle factor on the outcome of interest, making it all the more interesting when it does happen. In an observational study, researchers can never completely separate the factor of interest from the person’s life. This means that even with very good assessment tools and strong statistical techniques to reduce bias, the factor in question (soy food or isoflavone intake) can only be said to be relevant in the context of the dietary and lifestyle patterns of the groups of people studied. But this may be a good thing. Perhaps the most useful information about the use of nutrients for health is that which is embedded in people’s lives as they are actually lived.
David R. Jacobs has written eloquently on the need to shift our thinking about nutritional research towards the study of dietary patterns. He states: ‘The evidence for health benefit appears stronger when foods are put together in a synergistic dietary pattern than for individual foods or food constituents.’ [Jacobs et al. 2009
]. And in trying to make sense of the contradictory finding from the Nurse’s Health Study and the Women’s Health Trial, that dietary fat intake is not linked to cancer risk, T. Colin Campbell, explains the problem with what he calls ‘reductionistic’ science: ‘As long as scientists study highly isolated chemicals and food components, and take the information out of context to make sweeping assumptions about complex diet and disease relationships, confusion will result.’ [Campbell and Campbell, 2004
Robust findings from longitudinal prospective studies, well-designed ecological studies and the results of clinical trials addressing dietary patterns offer support for a dietary pattern approach. The few clinical trials that have been done looking at dietary patterns have shown some very strong support for this concept. In the DASH Diet (Dietary Approaches to Stop Hypertension), blood pressure was lowered with a dietary pattern high in fruits and vegetables, containing low-fat dairy products, and limited in meat, total fat and saturated fat compared with a control diet [Appel et al. 1997
]. Similarly, low-fat, vegetarian, or vegan dietary patterns have been shown to reverse markers of coronary heart disease [Esselstyn, 1999
; Ornish et al. 1998
], diabetes [Barnard et al. 2009
], and postmenopausal overweight [Turner-McGrievy et al. 2007
], and to slow prostate cancer progression [Frattaroli et al. 2008
; Ornish et al. 2005
]. In a study in which the dietary pattern was optimized for cholesterol reduction, a low-fat vegetarian diet that included soy protein, soluble fiber, plant sterols, and almonds was found to be as effective for lowering cholesterol as a statin drug [Jenkins et al. 2006
Research on soy isoflavones indicates that overall dietary patterns may be more important to bone health and fracture risk reduction than the individual factors – soy isoflavones – alone. Other reports on diet and bone health support the view that dietary pattern may be more important to supporting bone health than any particular nutrient or active ingredient. For example, a dietary pattern rich in fruits and vegetables has been positively associated with markers of bone health [New, 2003
] while dietary pattern research also indicates that calcium consumed via food or supplements neither reduces fracture risk [Warensjö et al. 2011
; Bischoff-Ferrari et al. 2011
; Jackson et al. 2006
] nor improves bone health in children [Winzenberg et al. 2006
; Lanou et al. 2005
]. These studies provide evidence that neither dairy products nor supplemental calcium to the levels of the US recommended daily allowances are necessary for osteoporosis risk reduction or optimal bone health.
Perhaps most importantly for the question of whether soy foods are beneficial to bone is the body of research showing that diets high in animal protein are associated with higher fracture rates than those high in protein from plant sources [Sellmeyer et al. 2001
; Frassetto et al. 2000
; Abelow et al. 1992
]. Soy foods intake may indirectly enhance bone strength by replacing animal protein in the diet. Research has shown that diets high in animal protein increase calcium excretion [Barzel and Massey, 1998
] and that soy protein intake decreases calcium excretion in comparison with meat and dairy protein [Zemel, 1988
]. These studies indicate that plant-based dietary patterns support bone health. Soy foods are a useful plant-based source of dietary protein and may be consumed at higher levels in plant-based eating styles.