The main purpose of the SPARE study is to determine the effectiveness of soy isoflavones 200 mg daily in attenuating or preventing the rapid bone loss that usually occurs in the first years of menopause. A total of the 248 women were randomized into this trial, which includes a large proportion of white Hispanic women. A limitation of the study is the relatively high BMI of the study population which could impact the rate of bone loss over the course of the trial [39
Although persons volunteering for a clinical trial could represent a self-selected group, we believe the characteristics of our participants represent those of the general local population. Clinical characteristics found during the screening of this multiethnic group of recently menopausal women anticipate potential medical problems that might arise as they age. Remarkably, almost 18% of the women who failed the screening process did so because of osteoporosis; 61% of the women screened were either overweight or obese, and 25% were hypertensive. In addition, 47% of the women participating in the study had measurable isoflavone levels in urine at baseline. Although the levels were low, they reflect the ubiquitous presence of isoflavones in the food supply [40
It is usually women in the initial years of menopause who seek to prevent the consequences of estrogen depletion, including bone loss and menopausal symptoms. The WHI results stopped many menopausal women from starting or continuing hormone replacement and many resorted to soy isoflavone products expecting to obtain the benefits but none of the adverse effects of estrogens. Previous soy studies assessing the effects of soy isoflavones in menopausal women have had multiple limitations and reported conflicting results [18
It is estimated that about 40% of all women will suffer an osteoporotic fracture in their lifetime [41
]. Earlier studies have reported up to 50% trabecular bone loss and 30% loss of cortical bone loss during a woman’s lifetime [42
]. Women experience the most severe menopausal symptoms immediately following the last menses and more than 10% of their bone mass can be lost in the initial 5 years of menopause [39
]. Thus, until recently estrogen replacement was the first-line treatment for prevention of menopausal symptoms and early postmenopausal bone loss. The beneficial skeletal effects of estrogens have been extensively documented in observational studies and in prospective studies assessing surrogate markers for fracture risk, such as BMD and markers of bone turnover. The WHI was the first large-scale prospective clinical trial to assess the effectiveness of estrogen replacement, with and without progestin, in preventing fractures. Although the WHI did not address specifically early postmenopausal bone loss, the study showed a 24% decreased risk of fractures in menopausal women on estrogen therapy, with or without progestin [45
]. After a mean use of hormone therapy for 5.2 years, the trial also demonstrated a 37% decreased risk of colon cancer, but a 26% increased risk of breast cancer and a 22% increase in cardiovascular events. Because of these concerns, many menopausal women stopped using estrogens and searched for natural alternatives that would provide skeletal benefits and relief from menopausal symptoms as estrogens but none of the potential adverse effects of estrogens.
Soy products have been actively sought by menopausal women because of their isoflavone content. In addition to protein, the soy bean contains isoflavones, natural phytoestrogens that activate estrogen receptors. The two major isoflavone glucosides in the soybean are genistin and daidzin. Once ingested, isoflavone glucosides are metabolized in the bowel by β-glucosidases of microbial and intestinal origin into the aglycones genistein and daidzein, respectively [46
]. These compounds are absorbed as free isoflavones and also metabolized by the intestinal flora into other metabolites, such as equol which is derived from daidzein and is the most potent soy metabolite [47
]. The metabolism of isoflavones in the intestine varies significantly among individuals, depending largely on the microflora, diet, and the use of antibiotics. Only about one third of the population has the ability to produce equol. The isoflavone molecules resemble that of 17-beta estradiol and bind to the estrogen receptor (ER) alpha and beta, exerting partial or full agonistic or antagonistic effects. Isoflavones have a weaker effect than estradiol. The relative affinities of these compounds for the ER vary and are lower than for estradiol, i.e., genistein has greater affinity for ER-beta than ER-alpha and equol has 10- to 100-fold greater affinity to ERs than daidzein [48
It is still not clear how isoflavones influence bone remodeling in humans and evidence suggests that it might be through different mechanisms than estradiol [50
]. At the time of menopause, low estrogen levels result in increased osteoclastic activity and rapid bone loss. Estrogen replacement protects from the rapid bone loss that accompanies menopause by decreasing the function and life span and inducing apoptosis of the osteoclast. Studies suggest that isoflavones act on both osteoclasts and osteoblasts [51
]. Genistein appears to have an anabolic effect on bone, by acting directly on osteoblasts and some of these effects might not be through the ER [50
Epidemiological studies strongly suggest that phytoestrogens have a beneficial skeletal effect. Among Chinese women, those on diets with higher isoflavone content have higher BMD and lower markers of bone turnover [53
]. A prospective population-based study of Chinese women reported an inverse relationship between the consumption of soy foods and fracture risk [54
]. Postmenopausal Japanese women and Japanese-American premenopausal women also show a significant positive association between isoflavone intake and BMD [30
]. The consumption of soy products among women in the US varies significantly and is generally very low. Not surprisingly, a study of peri- and postmenopausal women in California did not find any association between soy intake and BMD [56
Although animal studies demonstrate a clear skeletal benefit, prospective trials of soy isoflavones on bone in postmenopausal women, whether using soy foods or soy supplements, show conflicting results. Problems with most of these trials include their study design, small sample size, short duration (12 months or less), use of low doses, variation in isoflavone formulation (soy foods, soy supplements, isolated isoflavones), and high drop-out rates [20
]. In addition, some trials have enrolled women who had recent treatment with bone-active drugs and most included women in a wide age range or who were several years into menopause, not women in the initial postmenopausal years, the most likely users of soy products [7
]. In contrast, the SPARE study includes a large sample size, it enrolled multiethnic group of women in the first 5 postmenopausal years, has a 2-year duration, utilizes a large dose of isoflavones of a defined composition, and measures isoflavone metabolites, including equol, to correlate each participant’s biological response to her serum estradiol in addition to serve as an objective indicator of compliance. The results of the SPARE study will provide a wide range of information on the effectiveness of soy that is particularly important to a growing number of women, a number that continues to rise as the “baby boom” generation reaches menopause.
Based on the large sample size and multiethnic study population, the trial will be able to evaluate differences and similarities in the response to soy isoflavones among several racial and ethnic groups. In addition, the SPARE study is the first long-term prospective clinical trial simultaneously examining the effect of soy on multiple other outcomes associated to menopausal changes.