By Lynn Keegan, RN, PhD, HNC, FAAN, and Gerald T. Keegan, MD, FACS
Lynn Keegan, Director of Holistic Nursing Consultants in Port Angeles, WA, is on the Editorial Advisory Board of Alternative Therapies in Women's Health. Gerald T. Keegan is Emeritus Staff, Scott & White Clinic and Hospital, and former Professor of Surgery (Urology), Texas A&M University School of Medicine.
As the percentage of the U.S. population age 65 and older continues to increase every year, osteoporosis and osteopenia (low bone density) progressively are becoming more important public health problems. It is estimated that at least 10 million people in the United States have osteoporosis, and another 34 million have osteopenia, which places these individuals at significant risk for osteoporosis and related bone fractures. Eighty percent of the 10 million Americans estimated to have osteoporosis are women. One in two women and one in four men older than age 50 will have an osteoporosis-related fracture in her/his remaining lifetime.1
History of the Disease
Osteoporosis develops as a result of defective bone remodeling and an imbalance in the dynamic interaction of osteoclasts and osteoblasts. Osteoclasts, the cells that resorb bone, respond to many signals, the most important of which is osteoprotegerin ligand. Osteoblasts, the cells that build bone, respond to a variety of factors including estrogens, vitamin D, cytokines, and growth factors. Risk factors for osteoporosis include age, female sex, family history, white race, estrogen deficiency, medications including steroid use, low calcium intake, tobacco use, physical inactivity, and low body weight.
Hormone replacement therapy commonly has been used in postmenopausal patients. Estrogenic compounds increase osteoblastic activity and lead to enhanced pro-collagen production and increased alkaline phosphatase production and thus inhibit bone loss. The Women’s Health Initiative (WHI) studies demonstrated a 33% decrease in hip fractures and a 24% decrease in total fractures in postmenopausal women treated with estrogens.2 However, recent results from the WHI2 and the long-term follow-up of the Heart and Estrogen/progestin Replacement Study3 show an increased risk of both cardiovascular disease and breast cancer among those women randomized to the hormonal therapy group.4 For this reason, many women are seeking alternatives to prescribed estrogen/progestin compounds and have started using dietary supplements containing phytoestrogens derived from soy protein and red clover.5,6
Plant-derived phytoestrogens have been a focus of research for osteoporosis treatment. Their estrogenic activity generally is much less than that of human estrogens. Whether phytoestrogens have any effect at all in human patients is debated and the data are still unclear. However, the protective effects of soy protein on bone health may be somewhat encouraging.7
Constituents and Metabolism
Soybean is an annual legume of the Fabaceae or Legumenosae family (Glycine max.). This bean, which originated in Asia, has been cultivated widely for more than 2,000 years.8 Soybeans contain a number of active substances in addition to protein, including several classes of phytoestrogens. The three main classes of phytoestrogens are the isoflavones, coumestans, and lignans.9 Some of these agents are thought to have antioxidant, anti-inflammatory, antibacterial, antiangiogenic, antiproliferative, and antiparasitic effects, but only four agents (genistein, daidzein, biochanin, and formononetin) have potent phytoestrogenic activity.9 There are limited data on the quantitative absorption, protein-binding, or the specific metabolism of dietary estrogens. Dietary phyto- estrogens are metabolized by intestinal bacteria, absorbed then conjugated in the liver, circulated in the plasma, and excreted in the urine.10
Proposed Mechanisms of Action
Multiple mechanisms may play distinctive and separate roles in the protective effect of soy products on bone health. The substitution of soy protein for animal protein may have less of a calciuric effect, perhaps related to an insulin-modulated effect at the renal level.11 The retardation of the excretion of calcium in the urine may preserve the body’s calcium stores.12
Another postulated mechanism involves the direct effect of phytoestrogens on bone remodeling. Isoflav- ones are polyphenolic compounds that are structurally related to estrogens. These so-called phytoestrogens have been shown to bind to estrogen receptors,13 and have greater affinity for estrogens-receptor beta than alpha.14 Because isoflavones bind to estrogen receptors, they are considered to be possible estrogen receptor modulators. However, isoflavones also can exert biological effects independent of their phytoestrogenic activities.15 Isoflavones have been found to affect bone cells in culture.7 Both daidzein and genistein have been found to suppress osteoclastic activity. Genistein has been discovered to have a stimulatory effect on osteoblasts in vitro as well as anabolic effects on bone in animal models.16
A third postulated mechanism is based on the anti-inflammatory effects of soy. Both animal and human studies have indicated that an increased intake of n-6 fatty acids from vegetable oils elevates prostaglandin E(2) levels as well as pro-inflammatory cytokines. It also has been found that lack of estrogen increases the production of these cytokines by immune cells and thereby activates osteoclasts during the perimenopausal period.
In a study assessing the use of n-3 fatty acids and soy protein, the authors postulate that the anti-inflammatory effect might protect against bone loss by decreasing osteoclast activation and subsequent bone resorption. One of the mechanisms appears to be decreasing the receptor activator of NF-kappaB ligand on T cells, which has been found to increase osteoclast activation along with increasing pro-inflammatory cytokines in ovariectomized (OVX) mice.17
Much of the evidence suggesting a beneficial effect of soy products in preventing bone loss in the environment of estrogen deficiency is derived from experimental animal studies. A recent study in aged OVX rats demonstrated that dietary soy had a beneficial effect on the preservation of bone mineral density (BMD) associated with estrogen-deficiency bone loss. These data also show that at the tissue level, soy functions in a manner different from estrogen by increasing or sustaining elevated bone formation rates after ovariectomy.18
Although soybean isoflavones may reduce bone turnover, they do not reverse established osteopenia. A study in France that assessed the dose-dependent effects of daily soybean isoflavone consumption in reversing bone loss in adult OVX rats found neither BMD nor cancellous bone area was greater in soy phytoestrogen-fed rats than in OVX rats.19
A study of soy phytoestrogens compared with conjugated equine estrogen (Premarin) in postmenopausal monkeys concluded that there was no beneficial effect of soy phytoestrogens on bone mass.20
Human Clinical Studies
The results of the human clinical studies are somewhat difficult to interpret, especially because of the lack of adequate control groups, the mostly homogeneous populations in which the studies have been performed with their lifetime consumption of soy products, and the various types of soy/isoflavone products that were evaluated.
Isoflavones. A recent review of 15 clinical trials examined the effects of isoflavones or isoflavone-rich soy protein on BMD. Although there were inconsistencies, the results in general suggested that isoflavones reduce bone loss in younger postmenopausal women. Similarly, limited epidemiologic data show that among Asian populations isoflavone intake is associated with higher BMD. The authors conclude that although soy foods and isoflavones cannot be viewed as substitutes for established anti-osteoporotic medications, health professionals can feel justified in encouraging postmenopausal women concerned about bone health to incorporate soy foods into their diet.21
A study from China examined whether the associations between isoflavone supplementation and rates of change in bone mineral content (BMC) could be modified by years since menopause, body weight (BW), and dietary calcium intake. A group of 203 postmenopausal women between ages 48 and 62 were randomly assigned to three treatment groups: placebo (0 mg/d isoflavones), mid-dose (40 mg/d isoflavones); and high-dose (80 mg/d isoflavones). All groups also took 500 mg/d calcium. Both univariate and multivariate analyses observed significant favorable effect of isoflavone supplementation on rates of change in BMC at the total hip and trochanter among later postmenopausal women (> 4 y), in women with lower BW (< median, 55.5 kg), or among women with lower level of calcium intake (< median, 1,095 mg/d).22
These same researchers conducted a double-blind, placebo-controlled, randomized trial examining the effects of soy isoflavones on bone loss in 203 postmenopausal Chinese women, ages 48-62 years. Subjects were randomly assigned to three treatment groups with daily doses of placebo (1 g starch), mid-dose (0.5 g starch, 0.5 g soy extracts, and approximately 40 mg isoflavones), and high-dose (1.0 g soy extracts and approximately 80 mg isoflavones). All were given 500 mg calcium and 125 IU vitamin D(3). Both univariate and multivariate analyses showed that women in the high-dose group had mild, but statistically significant, favorable change rate in BMC compared with the placebo and mid-dose groups. Further stratified analyses revealed that the positive effects of soy isoflavone supplementation were observed only among women with lower initial baseline BMC (median or less). The authors conclude that soy isoflavones have a mild, but significant, independent effect on the maintenance of hip BMC in postmenopausal women with low initial bone mass.23 Another study from the same group reported the results of the baseline cross-sectional analysis of the association between dietary soy protein intake and BMD/BMC in a population-based study of more than 400 healthy Chinese women within the first 12 years of postmenopause. This study demonstrated that soy protein/isoflavone intake had a modest but significant association with hip BMD as well as total body BMC among women after the initial few years of postmenopause.24
In a two-year study in Denmark, postmenopausal Caucasian women with established osteoporosis or at least three risk factors for osteoporosis were randomly assigned to one of four treatment groups: soy milk containing isoflavones (soy+), transdermal progesterone (TDP+), the combination of soy+ and TDP+, or placebo (isoflavone-poor soy milk, soy- and progesterone-free cream). The investigators found that the percentage change in lumbar spine BMD and BMC did not differ from zero in the soy+ and TDP+ groups, but significant bone loss occurred in the control and combined treatment groups. The authors concluded that drinking two glasses of soy milk containing 76 mg isoflavones prevented lumbar spine bone loss in postmenopausal women. Transdermal progesterone had bone-sparing effects, but when combined with soy milk, a negative interaction between the two treatments occurs, resulting in bone loss to a greater extent than either treatment alone.25
Soy protein. A 15-month pilot study designed to investigate the effect of soy protein isolate with varying concentrations of isoflavones on early postmenopausal bone loss and lipids concluded that there was no significant positive effect of soy protein isolate supplemented with isoflavones on BMD and the serum lipid profile in early postmenopausal women.26
One of the above postulated mechanisms for preservation of calcium in bone was the selective retention of calcium in soy protein as opposed to animal protein diets. This theory is challenged to some extent by a study examining the effects of substituting 25 g soy protein for meat on calcium retention and bone biomarkers. Thirteen postmenopausal women ate similar diets, but in one diet 25 g high-isoflavone soy protein was substituted for an equivalent amount of meat protein for seven weeks. Despite a 15-20% lower renal acid excretion during the soy protein diet, urinary calcium loss was unaffected by diet. The authors concluded that substituting high-isoflavone soy protein for meat, in the presence of typical calcium intakes, did not improve or impair calcium retention or other indicators of bone health in postmenopausal women.27
Ipriflavone. Daidzein is a metabolite of ipriflavone (IP), a synthetic derived from soy protein. In animals, daidzein contributes to bone sparing. Early studies with this agent combined with calcium in women ages 65 and older showed significant increase in BMD.28 Some studies have demonstrated that IP reduces bone mass loss caused by glucocorticoids29 and gonadotropin-releasing hormone agonists used in producing pharmacological menopause in women.30 IP may prevent bone loss by an anti-inflammatory effect.31 IP has been found in some studies to be anti-resorptive and possibly mildly stimulatory on bone in the treatment of osteopenic and osteoporotic postmenopausal women.32 The bone-sparing effects of this substance have been noted primarily at the lumbar spine, but it has also been noted to affect radial bone and femoral neck density as well.
A randomized placebo-controlled study in Japan evaluated the effect of IP against bone loss in premenopausal OVX women and postmenopausal women. Thirty-seven Japanese women who underwent premenopausal bilateral ovariectomy within three months (early-stage group) and 52 Japanese women who were ovariectomized or who had undergone menopause more than three years before the start of the study (late-stage group) were enrolled. The first group received 600 mg/d IP; the second received placebo. In the early-stage group, the IP group showed a 6.7% decrease in BMD from baseline levels, whereas the placebo group showed a 10.7% decrease at 12 months of treatment; the two groups showed 7.1% and 12.6% decreases at 24 months, respectively. In the late-stage group, there was a 0.3% increase in BMD in the IP group and a 2.3% decrease in the placebo group at six months of treatment. Similar changes were seen at 18 months (1.4% increase and 3.9% decrease). IP suppressed bone loss compared with placebo; however, it did not prevent acute bone loss in the early stage following ovariectomy. The effect of IP alone on bone loss in the early stage is not sufficient to reduce the risk of osteoporosis in later life.33
The American Heart Association recommends 20-50 g/d of soy protein. Isoflavone supplements should contain about 50 mg/d and should not exceed 100 mg/d. IP is administered as 200 mg tid, and if used should be combined with both calcium and vitamin D supplements.
Other non-prescription medication treatment options for bone health include calcium supplementation (1,500 mg/d) from dietary dairy products with added calcium citrate, vitamin D supplementation (800 IU in high-risk patients), exercise, and abstaining from tobacco smoking.
Adverse Effects of Soy Products
Synthetic IP is contraindicated in pregnant and lactating women and very cautious use should be counseled in patients with liver or kidney disease.34 IP also potentiates the toxic effects of theophylline. Although there are reports of a reversible lymphocytopenia in human patients using IP,35 the effect of this phenomenon on immunological status is unknown. Animal studies in OVX mice showed that the increased lymphopoesis and subsequent leucocytosis produced by ovarian hormone deficiency was restored to normal levels by the use of this agent.36
Although basic research indicates that dietary soy products may have definitive effects in protecting estrogen-deficient animals from the development of osteoporosis and osteopenia, there is little clear evidence that these products will work in treatment of already established osteopenia. The human clinical studies are inconclusive and lack adequate controls and specificity as to product, dosage, and duration of treatment. In addition, most of the positive human studies are in populations that have a life-long use of soy products. Interpretation of data must be taken in this light.
Although human studies do not indicate an unequivocal effect of consumption of soy products on the development of osteoporosis in postmenopausal women, there seems little harm and probably some distinct benefits in recommending diets high in soy products, especially when substituted for the animal fat and protein so common in the Western diet. In many cases osteoporosis can be considered as a pediatric disease with geriatric manifestations, and as such any preventive modalities need to begin in youth and continued through the teenage years into adulthood to be effective.
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