Open access peer-reviewed chapter

Evidence for the Effectiveness of Soy in Aging and Improving Quality of Life

Written By

Bahram Herman Arjmandi and Elizabeth Marie Foley

Submitted: December 15th, 2018 Reviewed: March 5th, 2019 Published: June 20th, 2019

DOI: 10.5772/intechopen.85664

From the Edited Volume

Aging

Edited by Robert J. Reynolds and Steven M. Day

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Abstract

Soy is a highly nutritious yet widely underutilized food. Because of the controversy surrounding soy, individuals with chronic disease states that may benefit from soy or soy isoflavone consumption may avoid this food. The relationship of soy to estrogen, breast cancer, osteoarthritis, and other chronic disease states is discussed. Osteoarthritis is a specific focus, as the immobility brought about by this disease state may lead to other chronic diseases that are also positively affected by soy consumption, and because there is no clear etiology or cure for this debilitating disease. Conclusions and future directions for soy research as it relates to healthy aging are also discussed.

Keywords

  • soy
  • osteoarthritis
  • aging
  • breast cancer
  • longevity

1. Introduction

Globally, life expectancy has increased by nearly 20 years in both sexes since the 1950s [1]. In the United States (US) in 2015, life expectancy at birth was calculated to be almost 79 years old for both males and females [2]. While these numbers are encouraging, the quality of life of these individuals has not increased along with this increased life expectancy [3]. There are many factors that can influence quality of life but chronic diseases such as osteoporosis, osteoarthritis, heart disease, sarcopenia, type 2 diabetes (T2D), and dementia all play a role in the quality of life (QOL) of aging individuals.

Many chronic diseases are highly preventable and are generally treatable through diet and exercise. Indeed, poor diet and inadequate physical activity are two of the three most common risk factors for several chronic diseases, and addressing these factors in addition to the third risk factor, smoking, reduces the risk of cardiovascular disease (CVD), stroke, and T2D by 80% [4]. A 2013 study which analyzed the effect of physical inactivity on chronic disease estimated that, worldwide, physical inactivity is linked to 6–10% of chronic diseases that included CVD, T2D, breast cancer, and colon cancer, and that inactivity is associated 9% of premature deaths [5].

Knee osteoarthritis (OA) has been ranked as one of the top contributors to global disabilities in the world [6]. Osteoarthritis is a degenerative disorder of synovial joints characterized by focal loss of articular cartilage with reactive changes in subchondral and marginal bone, synovium and para-articular structures [7]. These degenerative changes lead to the primary complaints of pain with movement, stiffness, instability, and loss of function, particularly in those with knee OA [8]. The World Health Organization (WHO) estimates that about 10% of individuals 60 years or older have OA, an estimate that will only increase as the world’s population continues to age due to longer life expectancies [9]. The conclusive etiology of this disease is unknown, but injury to the joint, age, gender, and obesity are all known factors to contribute to the development of OA [10]. There is also mounting evidence that leptin may play a key role in the pathophysiology of OA. Leptin concentration in the serum is positively correlated with Body Mass Index (BMI) [11, 12]. This finding is significant as it helps to explain why obesity is a risk factor for OA, even in non-weight bearing joints such as hands.

Because individuals with OA are in constant pain, they are likely to stop exercising or to engage in any physical activity, thus increasing their risk of morbidity. It may also lead to other chronic diseases, both as a result of the lack of exercise, and the possibility of weight gain and the risks associated with excess weight. In fact, T2D has been shown to be a risk factor for knee OA progression [13], indicating that these disease states feed off of each other. While exercise is incredibly important for health, nutrition may be a much more helpful and significant treatment for individuals with chronic diseases, specifically OA, because the source of many of these diseases is underlying inflammation [14] and treating the inflammation through dietary change may result in the treatment of multiple disease states.

Although OA affects a large number of Americans, there are no proven therapies for preventing or halting its progression. In the normal joint, there is a balance between synthesis and degradation of cartilage. In inflammatory conditions such as OA, and other chronic diseases, catabolic molecules are upregulated, thereby interrupting the function of anabolic molecules [15]. Catabolic cytokines also induce the production of specific matrix degrading metalloproteases, causing cartilage degradation [16]. This finding has been confirmed by the increased level of these cytokines in people with OA [17]. Unregulated or excess production of these molecules may play a detrimental role in the pathophysiology of OA [16, 18].

The development of OA is also accompanied by increased production of prostaglandins (PGs), molecules that may contribute to joint damage, pain, and inflammation [19]. Cyclooxygenase (COX) is responsible for the production of PGs and exists as two distinct isoforms, COX-1, and COX-2. Increased expression of COX-2 has been demonstrated in synovial tissues suggesting that COX-2 expression mediates the inflammatory response in OA [20]. COX-2 is undetectable in most tissues, but is increased in inflammation leading to overproduction of PGE2 [21, 22]. Inhibition of these enzymes by non-steroidal anti-inflammatory drugs (NSAID) and selective COX-2 inhibitors reduces the levels of PGs, resulting in a reduction in pain and inflammation.

Finding nutritional interventions to target the COX-2 pathway while allowing other necessary inflammatory pathways to function would significantly increase quality of life as well as functionality of individuals with OA. It may also inadvertently target unregulated inflammation that has been associated with other chronic disease states, and allow for affected individuals to exercise thus further decreasing their risk for the aforementioned chronic diseases.

Soy appears to be a promising treatment for those with OA, and has many other health benefits. Soy protein is low in saturated fat, contains all of the essential amino acids, and is also a good source of fiber, iron, calcium, zinc, and B vitamins [23]. This book chapter will focus on soy and its relationship to OA and other chronic diseases.

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2. Nutrition profile of soy

Soy is a very nutritious plant, and the only complete plant protein. Protein in soy is not only high, but comparable in quality to animal protein regarding amino acid content and digestibility [24]. The carbohydrate content of soybeans is not only low, but poorly digested by intestinal enzymes, and thus behaves as a prebiotic for beneficial bacteria [25]. The fat content is highly variable among different soybean varieties, but includes 10–15% saturated fat, 19–41% monounsaturated fat, and 46–62% polyunsaturated fat [26].

Most notably, soybeans contain isoflavones. The three main isoflavones present in soybeans include genistein (50% of isoflavones), daidzein (40% isoflavones) and glycitein (10% of isoflavones) [27]. Isoflavones are also classified as phytoestrogens because of their similar structure to estrogen (Figures 1 and 2). Isoflavones are more bioactive in their unconjugated (aglycon) form than their conjugated form, which must be hydrolyzed in the intestine to release the aglycons [28]. Additionally, fermented soy has more unconjugated isoflavones, thus making fermented soy foods more pharmacokinetically beneficial [29]. Soy isoflavones are also metabolized by gut bacteria, which leads to many different metabolites, the most biologically active being euqol [30]. Equol is structurally similar to estrogen, but inhibits growth of mammary tumors and may act as a selective estrogen receptor modulator (SERM) [31]. Isoflavones have anti-oxidative and anti-inflammatory properties, as well as the ability to alter gene expression, specifically in estrogen-responsive genes [32]. It is this ability that often leads health practitioners to believe that soy may be dangerous for certain populations, specifically breast cancer, which will be later discussed in this chapter. However, these SERM like capabilities are responsible for many of soy’s positive effects on health.

Figure 1.

Similarity of isoflavones to estrogens.

Figure 2.

Structure of estrogen and isoflavones.

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3. Soy, estrogen, and breast cancer

Breast cancer is one of the most common cancers diagnosed in women in the United States, and is the second leading cause of death after lung cancer in women [33]. Breast cancer is strongly linked to ovarian hormones and estrogen levels [34]. Factors like high endogenous estrogen levels and hormone therapy have been implicated in increasing breast cancer risk [35]. Indeed, 2/3 of breast cancer cases are estrogen receptor (ER) positive [36].

Because soy isoflavones closely resemble estrogen, many health practitioners warn against soy consumption in women, women with breast cancer, and post-menopausal women for fear that soy will behave like an estrogen molecule. In our opinion, this idea is misconceived, as soy isoflavones would likely compete with endogenous estrogen for binding receptor sites in the breast, thereby reducing estrogen-stimulated growth and proliferation in the breast tissue, and may reduce endogenous estrogen concentrations [37]. Indeed, it has been shown that soy isoflavones may act as an estrogen antagonist in estrogen rich environments, and an estrogen agonist in low estrogen environments [38]; there is also evidence that the bioavailability of soy isoflavones may be inversely related to estrogen levels [39].

Epidemiological studies have shown that soy isoflavones do exert a protective effect on breast cancer risk, indicating a 16% risk reduction per 10 mg of daily isoflavone consumed [40]. A Dutch study [41] found that high levels of plasma genistein were associated with up to a 32% decreased risk of breast cancer. A 2009 study [42] that investigated soy food intake and breast cancer survival found that soy food consumption was associated with a marked decreased risk of both mortality and recurrence of breast cancer.

A 1997 study [43] found that genistein is a potent estrogen agonist and exhibited cell growth-inhibitory actions in breast cancer cells in vitro. A more recent study [44] also found that genistein works to inhibit topoisomerase II activity, thus resulting in the inhibition of breast cancer growth. Davis et al. [45] investigated the radioprotective effects of genistein by injecting female mice with the isoflavone 24 h prior to receiving a toxic dose of radiation, and found that genistein treated mice expressed fewer DNA damage responsive and cell cycle checkpoint genes than untreated mice. Magee et al. [46] investigated the effect of coumestrol, glycitein, daidzein, and the metabolites equol and O-desmethylangolensin on MDA-MB-231 cells, finding that each inhibited invasion by approximately 30% at the lowest dose, while genistein and coumestrol exerted the most potent inhibitory effects on invasion at the highest dose.

A clinical trial by Shike et al. [47] supplementing soy isoflavones in women with breast cancer found that soy consumption did alter gene expression in breast cancer tumors, specifically in FANCC and UGT2A1 which have both been implicated in the development of breast cancer tumors. There was a subset of tumors with upregulated FGFR2 expression, which is a marker of poor prognosis in breast cancer patients, and overall soy intake did not significantly change cell proliferation and apoptosis indices compared with the placebo group. While this initially sounds discouraging, the article points out that the clinical ramifications of this minor upregulation have yet to be determined.

Another common concern about soy supplementation in post-menopausal women, specifically, is that it causes lymphocytopenia, which is the condition of having low levels of lymphocytes in the blood. Some of these concerns stem from a multicenter study [48] published in 2001 where postmenopausal women supplemented 600 mg of ipriflavone, a synthetic isoflavone, for 3 years. Out of 234 women, 13.2% developed subclinical lymphocytopenia (<0.5 × 103/mm3). Another 2 year study [49] found that 3% of their participants also developed abnormal lymphocyte numbers. Another study by Ben-Hurt et al. [50] found that post-menopausal women also had higher monocyte levels, indicating that menopause definitively alters hematological parameters.

A rat study [51] by our lab refutes these results. Our study not only found that ovariectomy increased lymphocyte, monocyte, eosinophil, and basophil differential counts, but that soy isoflavones retuned leukocyte counts to pre-surgery levels. To test the truth of this in human populations, our lab also investigated the extent to which 1 year of 25 g soy protein containing 60 mg isoflavones supplementation alters lymphocyte counts in postmenopausal women [52]. This study indicated no effect on total and differential white blood cell counts in postmenopausal women, which may be due to the fact that the estimated isoflavone content of the soy protein was lower than the pharmacological dose at 60 mg.

Because leukocyte counts tend to go up with menopause, it is not necessarily a bad side effect for pharmaceutical doses of soy to bring down white blood cell counts. Additionally, the supplementation of soy protein did not have a significant impact on leukocyte levels, indicating that soy supplementation is generally safe for healthy postmenopausal populations.

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4. Soy, estrogen, and OA

Interestingly, OA is often seen in postmenopausal women, and is three times more likely to be a problem for postmenopausal women rather than men [53]. Cartilage is an estrogen sensitive tissue, which may, in part, explain the gender disparity. Because postmenopausal women experience a severe drop in the production of estrogen, it stands to reason that estrogen may be protective against the development of OA. Some studies [54, 55, 56] have found an association between hysterectomy and OA, while others [57, 58] have found no association. A study by Gao et al. [59] found that estradiol (E2) deficiency as well as changes in estrogen metabolites are involved in the pathogenesis of OA. Increased cartilage and bone turnover has been found in multiple animal models of menopause [60], but contrary to a general belief that lack of estrogen in women is the cause of OA, Tsai and colleagues [61] have suggested that excessive level of synovial fluid estrogen is responsible for the development of OA in both men and women. Indeed, some studies have found that the direct administration of estrogen to the knee joint has increased OA instance and progression [62, 63]. Intraarticular estradiol injection to ovariectomized rabbits both upregulated ER and ultimately caused further cartilage degeneration [64].

Soy isoflavones are often referred to as phytoestrogens, and may be helpful in relieving some symptoms of OA, and possibly prevent its progression. The conformational binding of soy isoflavones is similar to that of a SERM, which have been shown to be effective estrogen agonists or antagonists [65]. Genistein is the most potent of the isoflavones, and can therefore hypothetically produce positive effects on cartilage by blocking the action of estrogen. In addition to the possibility of modulating ERs, soy isoflavones may be able to increase IGF-1 production and decrease inflammation while also acting as an antioxidant. IGF-1 is thought to slow cartilage degradation [66]. Because soy isoflavones may serve as a natural modulator of IGF-1 production, it is probable that consumption of soy would benefit people suffering from OA.

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5. Soy, leptin, and OA

Leptin is of particular interest in the pathology of OA, as the severity of OA is associated with both weight and BMI [67, 68], and leptin is generally elevated in obese individuals [69]. Leptin is a hormone secreted by adipocytes and is involved with energy homeostasis, namely through its ability to cross the blood brain barrier to decrease orexigenic neuropeptides and increase anorexigenic neuropeptides [70]. In healthy individuals, leptin is secreted in proportion adipose tissue and energy intake [71]. Leptin is generally thought of as a satiety hormone, although many obese individuals have “leptin resistance” [72] where the secretion of leptin in these individuals does not suppress appetite or lead to reduced energy intake.

The role of leptin may extend beyond energy homeostasis. BMI and plasma leptin levels in OA patients correlate positively [70]. Plasma leptin concentrations have also been found to be 3 times higher in premenopausal women than men [73]. Bao et al. [74] found that injecting the knee with leptin caused significant degradation of the cartilage. Additionally, leptin taken from the synovial joint has been found to be higher than plasma leptin concentrations [75].

Results from our research group, corroborates previous findings [76]. In this study, we examined the relationship between serum and synovial fluid concentrations of leptin in both males and females with varying degrees of OA. Serum and synovial fluid samples were obtained from 20 men (mean age = 68.4 ± 10.8 years) and 20 women (mean age = 61.6 ± 12.4 years) with varying degrees of OA who underwent arthroscopic or total knee replacement surgery. We found that leptin concentrations in both the serum and synovial fluid of patients with knee OA increased according to disease severity. That is, as the level of OA became more severe, the leptin concentration also increased, in both men (Figure 3A) and women (Figure 3B). We also found a significant correlation between serum and synovial fluid leptin concentration and BMI in both men (Figure 4A and B) and women (Figure 5A and B) with OA. These findings indicate that leptin may in part play a role in the increased risk of OA related to obesity.

Figure 3.

The relationship between serum and synovial fluid concentrations of leptin and severity of OA in both men (A) and women (B).

Figure 4.

The correlation between serum (A) and synovial fluid (B) leptin concentration and BMI in men with OA.

Figure 5.

The correlation between serum (A) and synovial fluid (B) leptin concentration and BMI in women with OA.

The mechanism by which leptin may contribute to the pathophysiology of OA is likely due to its place in the cytokine family [72]. Leptin may trigger immune responses by increasing the expression of adhesion molecules, likely through a pro-inflammatory cytokine pathway [77]. Additionally, mice without a working leptin gene (ob/ob) demonstrated decreased secretion of inflammatory cytokines, while the administration of leptin to these mice restored inflammatory secretions [78]. Additionally, leptin receptors are present in the cartilage suggesting a direct action on this tissue. There is evidence [79] that leptin stimulates inflammatory markers Interlukin-6 (IL-6), Interlukin-8 (IL-8), nitric oxide, Interlukin-1 β (IL-1β), Tumor Necrosis Factor-alpha (TNFα), COX2, and PGE 2 in the joint thereby contributing to cartilage matrix breakdown.

Because of isoflavones’ role in inflammation, the negative action of excess leptin levels on cartilage may be suppressed by isoflavones. For example, rats fed a high fat soy diet, or regular soy diet, were found to have lower serum leptin concentrations than those fed a high fat casein, or regular fat casein diet [80]. Their study [80] also found that the expression of inflammatory genes decreased along with the expression of leptin. Niwa et al. [81] also found that soy isoflavones decreased leptin secretion in the adipocytes of mice, and a study by Llaneza et al. [82] found that the consumption of 200 mg of soy isoflavone extract in postmenopausal women resulted in decreased leptin levels, as well as TNFα. Another study in overweight and obese subjects found that after 12 weeks of black soy peptide supplementation, serum leptin concentrations were significantly reduced from baseline [83].

These studies and our observations so far suggest that soy and its isoflavones are likely very efficacious in alleviating pain associated with OA and its symptoms, in part due to its ability to decrease inflammatory responses. Soy’s ability to mediate leptin and inflammatory immune responses may also be integral in both preventing OA, halting its progression, and improving the QOL of individuals affected.

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6. Soy and OA

The main soy isoflavones include genistein, daidzein, and glycetine [84]. Genistein is structurally similar to ipriflavone [84], a synthetic isoflavone. SERMs such as tamoxifen [85] and ipriflavone [86] have both been shown to influence cartilage metabolism and reduce or alleviate the symptoms associated with OA. Therefore, it is conceivable to also expect that genistein similarly influences cartilage metabolism.

Our in vitrostudy [87] found that genistein had the capacity to reduce inflammation in human chondrocytes. Indeed, in chondrocytes treated with LPS to induce inflammation, genistein significantly decreased COX-2 production (Figure 6), but did not have an effect on COX-1 production (Figure 7) [87]. This is of particular interest, as NSAIDs are thought to inhibit inflammation via COX-1 and COX-2 dependent pathways, but are thought to cause damage because of the inhibition of COX-1, an important enzyme that regulates normal cellular processes and is expressed in most tissues [88]. This inhibited synthesis caused by most NSAIDS can negatively affect the maintenance and integrity of the gastric and duodenal mucosa, as well as lead to kidney issues [89, 90]. COX-2, however, is generally unexpressed by most tissues and is upregulated specifically by inflammation [91]. The seemingly selective inhibition of COX-2 by genistein provides a promising alternative to those who experience gastric distress due to the use of NSAIDs.

Figure 6.

COX-2 levels in cytosolic fraction of chondrocytes. LPS, lipopolysaccharides; and GEN, genistein. Bars represent mean ± SE, n = 3 per treatment group. Bars with different letters are significantly different from each other (P < 0.05).

Figure 7.

COX-1 levels in cytosolic fraction of chondrocytes. LPS, lipopolysaccharides; and GEN, genistein. Bars represent mean ± SE, n = 3 per treatment group.

IL-1β, an inflammatory cytokine, was also measured in this study and was found to be lower in both the high and low doses of genistein (Figure 8) [87]. More importantly, YKL-40, a marker of human cartilage glycoprotein degradation [92], was found to be suppressed in genistein treated groups (Figure 9); however, the difference between the LPS and genistein groups did not reach statistical significance [87].

Figure 8.

IL-1β level in culture supernatant measured via ELISA kit. LPS, lipopolysaccharides; and GEN, genistein. Bars represent mean ± SE, n = 4 per treatment group.

Figure 9.

YKL-40 level in culture supernatant which was measured via ELISA kit. LPS, lipopolysaccharides; and GEN, genistein. Bars represent mean ± SE, n = 4 per treatment group.

An animal study by Borzan et al. [93] also supports our clinical findings on soy. The aim of the aforementioned study was to determine if a soy diet could reduce the pain behaviors and inflammation induced by the intraplantar administration of complete Freund’s adjuvant. They reported that neuropathic pain following partial sciatic nerve injury was attenuated in rats fed a soy protein diet [93], indicating that soy may be effective in attenuating pain symptoms, including those of OA.

Lymphocytes and monocytes are often seen at sites of injury and inflammation [51]. Our lab investigated the effect of soy isoflavone supplementation on ovariectomy induced lymphopoiesis in rats. In this animal study [94], we observed that ovariectomy-induced increases in peripheral blood total lymphocyte and monocyte counts were returned to the levels of sham-operated rats after soy isoflavone supplementation (Figure 10A and B). Forty-eight 12-month-old Sprague-Dawley rats were either sham-operated (sham; 1 group) or OVX (3 groups) and were fed a standard semi-purified diet for 120 days. Thereafter, the OVX groups received one of the three doses of isoflavones: 0 (OVX), 500 (ISO500), or 1000 (ISO1000) mg/kg diet for 100 days. Ovariectomy significantly (P < 0.05) increased the total leukocyte, lymphocyte, monocyte, eosinophil, and basophil counts. Isoflavones at 500 and 1000 mg/kg diet returned the total leukocyte counts as well as leukocyte subpopulations to levels comparable to that of sham. These findings indicate that isoflavones are capable of normalizing circulating levels of inflammatory cells that produce many proinflammatory mediators, which may prove effective for the synovial joint.

Figure 10.

(A and B) Indicate effects of isoflavones (ISO) on lymphocyte and monocyte counts. Values are mean ± SE(n = 12). Bars that do not share the same superscript are significantly different (P < 0.05).

Our lab also carried out a three-month double-blind randomized clinical trial [95] to investigate the effects of soy supplementation on symptoms associated with knee OA. About 135 free-living individuals (64 men, mean age = 55.8 ± 13.6 years; and 71 women, mean age = 59.3 ± 12.0 years) with knee OA were randomly assigned to receive 40 g of either soy protein or milk protein daily. This study indicated that soy protein regimen containing 88 mg isoflavones improved (P < 0.05) knee range of motion and ability to climb several flights of stairs, and reduced (P < 0.05) the intensity, frequency, severity of pain, hindrance to activities (Figure 11A), and use of pain medications (Figure 11B). The improvement in self-described pain parameters due to soy supplementation became more pronounced as the treatment duration progressed. Additionally, the soy regimen significantly improved circulating levels of IGF-I which suggests that isoflavones may exert anabolic effects on the cartilage.

Figure 11.

(A) represents self-reported pain limiting physical activities with scores ranging from 1 to 2; (1) referring to no limitation and (2) referring to pain as causing limitation in physical activity. (B) indicates the use of pain medications (mean + SE). A lower score reflects less use of pain medication and a higher score reflects more frequent use of pain medication.

In the same study, serum IGF-I as well as human cartilage glycoprotein 39 (YKL-40), a marker of joint destruction [92], were assessed. Results indicated that protein supplementation had significantly lowered mean serum concentration of YKL-40 in men, implying that soy can slow down cartilage degradation. Although both proteins, as expected, increased (P < 0.05) circulating levels of IGF-I, soy protein had a more pronounced effect compared to milk protein. We have repeatedly shown [84, 96] that soy has the ability to uniquely enhance serum IGF-I in comparison with milk protein, indicating that this effect may be due to its isoflavone content rather than merely protein.

The findings of our three-month study indicate that soy protein supplementation significantly reduced the intensity and frequency of pain. By comparison, milk protein only reduced pain intensity indicating that the reduction in the frequency of pain and discomfort are specific to soy and not the control protein. Our findings also indicate a reduced need for pain medication. The increased serum IGF-I level with soy supplementation suggests that isoflavones may exert anabolic effects on the cartilage, and decreased YKL-40 levels which is associated with cartilage degeneration, support our hypothesis that soy can improve symptoms and severity of OA. The authors suggest that people with no contraindications to soy isoflavones use ipriflavone, a synthetic isoflavone, for decreasing the symptoms of OA. However, this is just a suggestion and further research must be done to assess the potency of isoflavone usage for symptomatic control of OA.

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7. Soy and cardiovascular disease

As mentioned previously, soy isoflavones are phytoestrogens. Estrogen is known to be cardioprotective, so it stands to reason that soy may also be cardioprotective. Many of the clinical trials investigating the effect of soy supplementation on heart health focus mainly on cholesterol levels. This may be due to the fact that the phytosterols, like those found in soy, compete with cholesterol for intestinal absorption [97]. A 2015 study [98] investigated the effect of 8 weeks of standard soymilk supplementation against the effect of 2 g/day of phytosterols and 10 g/day of inulin-enriched soymilk supplementation. While both groups did see a reduction in LDL-C in both groups, the study group supplementing with the extra phytosterols and inulin saw significantly better results. TC was also significantly reduced in the study group, compared to the control of regular soymilk.

Soy can be beneficial in many forms beyond that of soymilk. A study [99] that supplemented whole soy foods (3–4 servings per day) for 12 weeks found that the soy intervention significantly reduced total cholesterol, LDL-C, non-HDL cholesterol, and apoB even though BMI did not decrease. An earlier study [100] also found that soy protein supplementation resulted in decreased cholesterol levels. Prehypertensive women who supplemented 40 g of soy flour saw decreases in LDL-C and well as high sensitivity C-Reactive Protein (CRP), a marker of inflammation [101]. Interestingly, another study found that 1 month of soy nut supplementation modestly reduced arterial stiffness but did not improve inflammatory biomarkers [102]. Additionally, Lucas et al. [103] found that soy isoflavones prevented both hyperlipidemia and atherosclerotic lesions in ovariectomized Golden Syrian Hamsters.

While there are still gaps in the research for CVD and soy consumption, research generally points to a positive effect of soy on heart health, irrespective to its effect on cholesterol. Finding that soy significantly decreased the development of atherosclerotic lesion in a hamster model of postmenopausal CVD is particularly important since CVD remains the leading cause of death in the US.

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8. Soy and osteoporosis

Just as OA greatly affects women more so than men, osteoporosis is a particularly concerning problem for the aging female population. Because intestinal cells contain ER, and because estrogen enhances calcium transport [104], it stands to reason that phytoestrogens like soy may increase intestinal calcium transport. There have been multiple studies researching intestinal transport of calcium and soy, as well as the effect of soy on animal models of osteoporosis, and human studies. A study by our lab in 2001 [104] confirmed that not only does ovariectomy decrease rates of calcium transport, but that soy isoflavones in soy protein promoted calcium absorption in a manner analogous to estrogen without any of the side effects/risk. Pawlowski et al. [105] also found that soy isoflavones were effective in increasing calcium retention in bone, and Arjmandi et al. [84] found that women not on hormone replacement therapy who supplemented soy protein experienced reduced urinary calcium excretion.

Animal studies have yielded positive results for isoflavone’s bone sparing properties. A 1998 study [106] by our lab compared casein protein and soy protein in ovariectomized (OVX) rats, and found that soy protein with higher levels of isoflavones spared the femoral bone density decreases brought about by ovariectomy. Our 2006 study [107] found that soy positively affected tibial architectural properties of OVX rats, including trabecular thickness, separation, and number without preserving BMD. Another study by our lab [108] found that soy protein with or without isoflavones did not preserve BMD in a male rat model of osteoporosis, but did positively affect the biomechanical properties of bone including yield and ultimate force which are measures of elasticity and plasticity in bone. Multiple other studies have concluded that any bone sparing effects of soy consumption are likely due to soy isoflavone content, which increases bone formation and improves the architectural properties of bone [109, 110, 111, 112].

Interestingly, while animal studies have been promising for moderate prevention of bone loss, a 2-year Thai study [113] found that soy isoflavones did not significantly reduce bone loss. Similarly, a 3-year study [114] that gave postmenopausal women soy isoflavones did not find significant bone sparing effects, except for the femoral neck which was still only modestly affected by supplementation. The same lab then evaluated the safety of soy isoflavone supplementation by evaluating effects on hormones, endometrial thickness, and any adverse events, finding no negative evidence of treatment effect on this population, once again indicating that soy supplementation is safe. Wong et al. [115] found that 120 mg of soy isoflavones did reduce whole body BMD loss, but did not positively affect common female fracture sites. Studies by our lab [96, 116], and others [117], generally find that soy supplementation for the treatment of osteoporosis generally has little to no effect on BMD, but may still positively affect bone metabolism as well as bone quality.

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9. Conclusions and future directions

Although the role of soy in CVD, lowering cholesterol, and improving bone has been questioned, there is ample evidence to suggest that soy improves symptoms of OA by at least three mechanisms, including (1) acting as a SERM, thereby modulating estrogen receptors; (2) increasing circulating levels of IGF-1, thereby regenerating cartilage and/or preventing further damage; (3) and inhibiting production of inflammatory molecules, such as COX-2, TNF-α. The authors believe that soy plays an important role in the healthy aging process by decreasing the incidence of OA, and allowing those who are afflicted to achieve greater mobility, thus decreasing their chances of developing other chronic diseases that would have resulted from decreased mobility. Therefore, we suggest that consumption of soy and soy isoflavones is crucial for healthy aging and improved QOL throughout the aging process.

We have demonstrated that both leptin and estrogen have a significant role in the etiology, progression, and treatment of OA, but the specifics of that role remain uncertain. The above studies also indicate a positive effect of soy supplementation on cartilage metabolism, inflammation, and indices of pain, likely through the modulation of the aforementioned factors. Soy appears to be promising in the treatment of OA symptoms, but its ability to prevent the disease is questionable. While isoflavones are known to act as SERMs, it is reasonable to suspect that the protein content of soy as a whole in conjunction with isoflavone content is responsible for positive effects in this population. Though the literature indicates that soy supplementation may be helpful in decreasing usage of NSAIDs, slow cartilage degradation, and increase functionality in individuals afflicted with OA, determining the safety as well as the efficacy of soy or its isoflavones as a long-term OA intervention is the next logical step. Any intervention that can improve the QOL of individuals afflicted with OA is worth pursuing, but it is paramount that researchers uncover the exact etiology of the disease so as to prevent future occurrences.

The literature referenced here also indicates that soy can be promising for other chronic disease states, without necessarily posing a risk for increased instance of breast cancer. However, there is still much confusion about which populations are at higher risk for breast cancer when consuming soy. The multiple health benefits appear to outweigh breast cancer risk for most women, even decreasing the chance of breast cancer, but further interventional, rather than strictly epidemiological and cell culture studies, need to be established.

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Acknowledgments

We want to thank Dr. Shirin Hooshmand and Jenna Schmidt for collecting and analyzing part of the data.

Conflict of interest

The authors have no conflict of interest to declare.

References

  1. 1. Collaborators GM. Global, regional, and national age-sex-specific mortality and life expectancy, 1950-2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1684-1735. DOI: 10.1016/S0140-6736(18)31891-9. Epub 2018/11/08. PubMed PMID: 30496102; PubMed Central PMCID: PMCPMC6227504
  2. 2. Xu J, Murphy SL, Kochanek KD, Arias E. Mortality in the United States, 2015. NCHS Data Briefs. 2016;267:1-8. PubMed PMID: 27930283
  3. 3. Brown GC. Living too long: The current focus of medical research on increasing the quantity, rather than the quality, of life is damaging our health and harming the economy. EMBO Reports. 2015;16(2):137-141. DOI: 10.15252/embr.201439518. Epub 2014/12/18. PubMed PMID: 25525070; PubMed Central PMCID: PMCPMC4328740
  4. 4. Shlisky J, Bloom DE, Beaudreault AR, Tucker KL, Keller HH, Freund-Levi Y, et al. Nutritional considerations for healthy aging and reduction in age-related chronic disease. Advances in Nutrition. 2017;8(1):17-26. DOI: 10.3945/an.116.013474. Epub 2017/01/17. PubMed PMID: 28096124; PubMed Central PMCID: PMCPMC5227979
  5. 5. Nunan D, Mahtani KR, Roberts N, Heneghan C. Physical activity for the prevention and treatment of major chronic disease: An overview of systematic reviews. Systematic Reviews. 2013;2:56. DOI: 10.1186/2046-4053-2-56. Epub 2013/07/10. PubMed PMID: 23837523; PubMed Central PMCID: PMCPMC3710239
  6. 6. Cross M, Smith E, Hoy D, Nolte S, Ackerman I, Fransen M, et al. The global burden of hip and knee osteoarthritis: Estimates from the global burden of disease 2010 study. Annals of the Rheumatic Diseases. 2014;73(7):1323-1330. DOI: 10.1136/annrheumdis-2013-204763. Epub 2014/02/19. PubMed PMID: 24553908
  7. 7. Day JS, Van Der Linden JC, Bank RA, Ding M, Hvid I, Sumner DR, et al. Adaptation of subchondral bone in osteoarthritis. Biorheology. 2004;41(3-4):359-368. PubMed PMID: 15299268
  8. 8. Felson DT, Naimark A, Anderson J, Kazis L, Castelli W, Meenan RF. The prevalence of knee osteoarthritis in the elderly. The Framingham osteoarthritis study. Arthritis and Rheumatism. 1987;30(8):914-918. PubMed PMID: 3632732
  9. 9. Pereira D, Peleteiro B, Araújo J, Branco J, Santos RA, Ramos E. The effect of osteoarthritis definition on prevalence and incidence estimates: A systematic review. Osteoarthritis and Cartilage. 2011;19(11):1270-1285. DOI: 10.1016/j.joca.2011.08.009. Epub 2011/08/24. PubMed PMID: 21907813
  10. 10. Heidari B. Knee osteoarthritis prevalence, risk factors, pathogenesis and features: Part I. Caspian Journal of Internal Medicine. 2011;2(2):205-212. PubMed PMID: 24024017; PubMed Central PMCID: PMCPMC3766936
  11. 11. Paul RF, Hassan M, Nazar HS, Gillani S, Afzal N, Qayyum I. Effect of body mass index on serum leptin levels. Journal of Ayub Medical College, Abbottabad. 2011;23(3):40-43. PubMed PMID: 23272432
  12. 12. Al Maskari MY, Alnaqdy AA. Correlation between serum leptin levels, body mass index and obesity in Omanis. Sultan Qaboos University Medical Journal. 2006;6(2):27-31. PubMed PMID: 21748132; PubMed Central PMCID: PMCPMC3074914
  13. 13. Eymard F, Parsons C, Edwards MH, Petit-Dop F, Reginster JY, Bruyère O, et al. Diabetes is a risk factor for knee osteoarthritis progression. Osteoarthritis and Cartilage. 2015;23(6):851-859. DOI: 10.1016/j.joca.2015.01.013. Epub 2015/02/03. PubMed PMID: 25655678
  14. 14. Minihane AM, Vinoy S, Russell WR, Baka A, Roche HM, Tuohy KM, et al. Low-grade inflammation, diet composition and health: Current research evidence and its translation. The British Journal of Nutrition. 2015;114(7):999-1012. DOI: 10.1017/S0007114515002093. Epub 2015/07/31. PubMed PMID: 26228057; PubMed Central PMCID: PMCPMC4579563
  15. 15. Brooks P. Inflammation as an important feature of osteoarthritis. Bulletin of the World Health Organization. 2003;81(9):689-690. Epub 2003/11/14. PubMed PMID: 14710513; PubMed Central PMCID: PMCPMC2572543
  16. 16. Poole AR, Nelson F, Dahlberg L, Tchetina E, Kobayashi M, Yasuda T, et al. Proteolysis of the collagen fibril in osteoarthritis. Biochemical Society Symposium. 2003;70:115-123. PubMed PMID: 14587287
  17. 17. Brenner SS, Klotz U, Alscher DM, Mais A, Lauer G, Schweer H, et al. Osteoarthritis of the knee—Clinical assessments and inflammatory markers. Osteoarthritis and Cartilage. 2004;12(6):469-475. DOI: 10.1016/j.joca.2004.02.011. PubMed PMID: 15135143
  18. 18. Ishiguro N, Kojima T, Poole AR. Mechanism of cartilage destruction in osteoarthritis. Nagoya Journal of Medical Science. 2002;65(3-4):73-84. PubMed PMID: 12580533
  19. 19. Nakamura H, Shibakawa A, Tanaka M, Kato T, Nishioka K. Effects of glucosamine hydrochloride on the production of prostaglandin E2, nitric oxide and metalloproteases by chondrocytes and synoviocytes in osteoarthritis. Clinical and Experimental Rheumatology. 2004;22(3):293-299. PubMed PMID: 15144122
  20. 20. Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of the effects of soy protein intake on serum lipids. The New England Journal of Medicine. 1995;333(5):276-282. DOI: 10.1056/NEJM199508033330502. PubMed PMID: 7596371
  21. 21. Lu S, Nishimura K, Hossain MA, Jisaka M, Nagaya T, Yokota K. Regulation and role of arachidonate cascade during changes in life cycle of adipocytes. Applied Biochemistry and Biotechnology. 2004;118(1-3):133-153. PubMed PMID: 15304745
  22. 22. Tamura M, Deb S, Sebastian S, Okamura K, Bulun SE. Estrogen up-regulates cyclooxygenase-2 via estrogen receptor in human uterine microvascular endothelial cells. Fertility and Sterility. 2004;81(5):1351-1356. DOI: 10.1016/j.fertnstert.2003.09.076. PubMed PMID: 15136101
  23. 23. Montgomery KS. Soy protein. The Journal of Perinatal Education. 2003;12(3):42-45. DOI: 10.1624/105812403X106946. PubMed PMID: 17273351; PubMed Central PMCID: PMCPMC1595159
  24. 24. Hughes GJ, Ryan DJ, Mukherjea R, Schasteen CS. Protein digestibility-corrected amino acid scores (PDCAAS) for soy protein isolates and concentrate: Criteria for evaluation. Journal of Agricultural and Food Chemistry. 2011;59(23):12707-12712. DOI: 10.1021/jf203220v. Epub 2011/11/16. PubMed PMID: 22017752
  25. 25. Bang MH, Chio OS, Kim WK. Soyoligosaccharide increases fecal bifidobacteria counts, short-chain fatty acids, and fecal lipid concentrations in young Korean women. Journal of Medicinal Food. 2007;10(2):366-370. DOI: 10.1089/jmf.2005.096. PubMed PMID: 17651076
  26. 26. Slavin M, Kenworthy W, Yu LL. Antioxidant properties, phytochemical composition, and antiproliferative activity of Maryland-grown soybeans with colored seed coats. Journal of Agricultural and Food Chemistry. 2009;57(23):11174-11185. DOI: 10.1021/jf902609n. PubMed PMID: 19950996
  27. 27. Messina M. Soy and health update: Evaluation of the clinical and epidemiologic literature. Nutrients. 2016;8(12):1-42. DOI: 10.3390/nu8120754. Epub 2016/11/24. PubMed PMID: 27886135; PubMed Central PMCID: PMCPMC5188409
  28. 28. Setchell KD, Brown NM, Zimmer-Nechemias L, Brashear WT, Wolfe BE, Kirschner AS, et al. Evidence for lack of absorption of soy isoflavone glycosides in humans, supporting the crucial role of intestinal metabolism for bioavailability. The American Journal of Clinical Nutrition. 2002;76(2):447-453. DOI: 10.1093/ajcn/76.2.447. PubMed PMID: 12145021
  29. 29. Nakajima N, Nozaki N, Ishihara K, Ishikawa A, Tsuji H. Analysis of isoflavone content in tempeh, a fermented soybean, and preparation of a new isoflavone-enriched tempeh. Journal of Bioscience and Bioengineering. 2005;100(6):685-687. DOI: 10.1263/jbb.100.685. PubMed PMID: 16473782
  30. 30. Setchell KDR. The history and basic science development of soy isoflavones. Menopause. 2017;24(12):1338-1350. DOI: 10.1097/GME.0000000000001018. PubMed PMID: 29189602
  31. 31. Charalambous C, Pitta CA, Constantinou AI. Equol enhances tamoxifen's anti-tumor activity by induction of caspase-mediated apoptosis in MCF-7 breast cancer cells. BMC Cancer. 2013;13:238. DOI: 10.1186/1471-2407-13-238. Epub 2013/05/15. PubMed PMID: 23675643; PubMed Central PMCID: PMCPMC3661348
  32. 32. Lecomte S, Demay F, Ferrière F, Pakdel F. Phytochemicals targeting estrogen receptors: Beneficial rather than adverse effects? International Journal of Molecular Sciences. 2017;18(7):1-19. DOI: 10.3390/ijms18071381. Epub 2017/06/28. PubMed PMID: 28657580; PubMed Central PMCID: PMCPMC5535874
  33. 33. DeSantis C, Ma J, Bryan L, Jemal A. Breast cancer statistics, 2013. CA: A Cancer Journal for Clinicians. 2014;64(1):52-62. DOI: 10.3322/caac.21203. Epub 2013/10/01. PubMed PMID: 24114568
  34. 34. Iversen A, Thune I, McTiernan A, Emaus A, Finstad SE, Flote V, et al. Ovarian hormones and reproductive risk factors for breast cancer in premenopausal women: The Norwegian EBBA-I study. Human Reproduction. 2011;26(6):1519-1529. DOI: 10.1093/humrep/der081. Epub 2011/04/05. PubMed PMID: 21467202; PubMed Central PMCID: PMCPMC3096559
  35. 35. Samavat H, Kurzer MS. Estrogen metabolism and breast cancer. Cancer Letters. 2015;356(2 Pt A):231-243. DOI: 10.1016/j.canlet.2014.04.018. Epub 2014/04/28. PubMed PMID: 24784887; PubMed Central PMCID: PMCPMC4505810
  36. 36. Roodi N, Bailey LR, Kao WY, Verrier CS, Yee CJ, Dupont WD, et al. Estrogen receptor gene analysis in estrogen receptor-positive and receptor-negative primary breast cancer. Journal of the National Cancer Institute. 1995;87(6):446-451. PubMed PMID: 7861463
  37. 37. Douglas CC, Johnson SA, Arjmandi BH. Soy and its isoflavones: The truth behind the science in breast cancer. Anti-Cancer Agents in Medicinal Chemistry. 2013;13(8):1178-1187. PubMed PMID: 23919747
  38. 38. Anderson JJ, Anthony MS, Cline JM, Washburn SA, Garner SC. Health potential of soy isoflavones for menopausal women. Public Health Nutrition. 1999;2(4):489-504. PubMed PMID: 10656468
  39. 39. Kulkarni KH, Yang Z, Niu T, Hu M. Effects of estrogen and estrus cycle on pharmacokinetics, absorption, and disposition of genistein in female Sprague-Dawley rats. The Journal of Agricultural and Food Chemistry. 2012;60(32):7949-7956. DOI: 10.1021/jf204755g. Epub 2012/08/03. PubMed PMID: 22757747; PubMed Central PMCID: PMCPMC4030716
  40. 40. Wu AH, Yu MC, Tseng CC, Pike MC. Epidemiology of soy exposures and breast cancer risk. The British Journal of Cancer. 2008;98(1):9-14. DOI: 10.1038/sj.bjc.6604145. Epub 2008/01/08. PubMed PMID: 18182974; PubMed Central PMCID: PMCPMC2359677
  41. 41. Verheus M, van Gils CH, Keinan-Boker L, Grace PB, Bingham SA, Peeters PH. Plasma phytoestrogens and subsequent breast cancer risk. Journal of Clinical Oncology. 2007;25(6):648-655. DOI: 10.1200/JCO.2006.06.0244. Epub 2007/01/02. PubMed PMID: 17200150
  42. 42. Shu XO, Zheng Y, Cai H, Gu K, Chen Z, Zheng W, et al. Soy food intake and breast cancer survival. Journal of the American Medical Association. 2009;302(22):2437-2443. DOI: 10.1001/jama.2009.1783. PubMed PMID: 19996398; PubMed Central PMCID: PMCPMC2874068
  43. 43. Zava DT, Duwe G. Estrogenic and antiproliferative properties of genistein and other flavonoids in human breast cancer cells in vitro. Nutrition and Cancer. 1997;27(1):31-40. DOI: 10.1080/01635589709514498. PubMed PMID: 8970179
  44. 44. Mizushina Y, Shiomi K, Kuriyama I, Takahashi Y, Yoshida H. Inhibitory effects of a major soy isoflavone, genistein, on human DNA topoisomerase II activity and cancer cell proliferation. International Journal of Oncology. 2013;43(4):1117-1124. DOI: 10.3892/ijo.2013.2032. Epub 2013/07/23. PubMed PMID: 23900272
  45. 45. Davis TA, Mungunsukh O, Zins S, Day RM, Landauer MR. Genistein induces radioprotection by hematopoietic stem cell quiescence. International Journal of Radiation Biology. 2008;84(9):713-726. DOI: 10.1080/09553000802317778. PubMed PMID: 18821385
  46. 46. Magee PJ, McGlynn H, Rowland IR. Differential effects of isoflavones and lignans on invasiveness of MDA-MB-231 breast cancer cells in vitro. Cancer Letters. 2004;208(1):35-41. DOI: 10.1016/j.canlet.2003.11.012. PubMed PMID: 15105043
  47. 47. Shike M, Doane AS, Russo L, Cabal R, Reis-Filho JS, Gerald W, et al. The effects of soy supplementation on gene expression in breast cancer: A randomized placebo-controlled study. Journal of the National Cancer Institute. 2014;106(9):1-12. DOI: 10.1093/jnci/dju189. Epub 2014/09/04. PubMed PMID: 25190728; PubMed Central PMCID: PMCPMC4817128
  48. 48. Alexandersen P, Toussaint A, Christiansen C, Devogelaer JP, Roux C, Fechtenbaum J, et al. Ipriflavone in the treatment of postmenopausal osteoporosis: A randomized controlled trial. Journal of the American Medical Association. 2001;285(11):1482-1488. PubMed PMID: 11255425
  49. 49. Agnusdei D, Bufalino L. Efficacy of ipriflavone in established osteoporosis and long-term safety. Calcified Tissue International. 1997;61(Suppl 1):S23-S27. PubMed PMID: 9263613
  50. 50. Ben-Hur H, Mor G, Insler V, Blickstein I, Amir-Zaltsman Y, Sharp A, et al. Menopause is associated with a significant increase in blood monocyte number and a relative decrease in the expression of estrogen receptors in human peripheral monocytes. American Journal of Reproductive Immunology. 1995;34(6):363-369. PubMed PMID: 8607941
  51. 51. Soung DY, Khalil DA, Arquitt AB, Smith BJ, Hammond LJ, Droke EA, et al. Soy isoflavones prevent the ovarian hormone deficiency-associated rise in leukocytes in rats. Phytomedicine. 2004;11(4):303-308. DOI: 10.1078/0944711041495164. PubMed PMID: 15185842
  52. 52. Soung DY, Patade A, Khalil DA, Lucas EA, Devareddy L, Greaves KA, et al. Soy protein supplementation does not cause lymphocytopenia in postmenopausal women. Nutrition Journal. 2006;5:12. DOI: 10.1186/1475-2891-5-12. Epub 2006/04/11. PubMed PMID: 16608514; PubMed Central PMCID: PMCPMC1481570
  53. 53. Martín-Millán M, Castañeda S. Estrogens, osteoarthritis and inflammation. Joint Bone Spine. 2013;80(4):368-373. DOI: 10.1016/j.jbspin.2012.11.008. Epub 2013/01/23. PubMed PMID: 23352515
  54. 54. Inoue K, Ushiyama T, Kim Y, Shichikawa K, Nishioka J, Hukuda S.Increased rate of hysterectomy in women undergoing surgery for osteoarthritis of the knee. Osteoarthritis Cartilage. 1995;3(3):205-209. PubMed PMID: 8581750
  55. 55. Spector TD, Brown GC, Silman AJ. Increased rates of previous hysterectomy and gynaecological operations in women with osteoarthritis. BMJ. 1988;297(6653):899-900. PubMed PMID: 3140970; PubMed Central PMCID: PMCPMC1834435
  56. 56. Spector TD, Hart DJ, Brown P, Almeyda J, Dacre JE, Doyle DV, et al. Frequency of osteoarthritis in hysterectomized women. Journal of Rheumatology. 1991;18(12):1877-1883. PubMed PMID: 1795326
  57. 57. Richette P, Corvol M, Bardin T. Estrogens, cartilage, and osteoarthritis. Joint Bone Spine. 2003;70(4):257-262. PubMed PMID: 12951307
  58. 58. Stöve J, Stürmer T, Kessler S, Brenner H, Puhl W, Günther KP. Hysterectomy and patterns of osteoarthritis. The Ulm Osteoarthritis Study. Scandinavian Journal of Rheumatology. 2001;30(6):340-345. PubMed PMID: 11846052
  59. 59. Gao W, Zeng C, Cai D, Liu B, Li Y, Wen X, et al. Serum concentrations of selected endogenous estrogen and estrogen metabolites in pre- and post-menopausal Chinese women with osteoarthritis. The Journal of Endocrinological Investigation. 2010;33(9):644-649. DOI: 10.1007/BF03346664. Epub 2010/03/25. PubMed PMID: 20339312
  60. 60. Roman-Blas JA, Castañeda S, Largo R, Herrero-Beaumont G. Osteoarthritis associated with estrogen deficiency. Arthritis Research and Therapy. 2009;11(5):241. DOI: 10.1186/ar2791. Epub 2009/09/21. PubMed PMID: 19804619; PubMed Central PMCID: PMCPMC2787275
  61. 61. Tsai CL, Liu TK, Chen TJ. Estrogen and osteoarthritis: A study of synovial estradiol and estradiol receptor binding in human osteoarthritic knees. Biochemical and Biophysical Research Communications. 1992;183(3):1287-1291. PubMed PMID: 1567405
  62. 62. Rosner IA, Malemud CJ, Goldberg VM, Papay RS, Getzy L, Moskowitz RW. Pathologic and metabolic responses of experimental osteoarthritis to estradiol and an estradiol antagonist. Clinical Orthopaedics and Related Research. 1982;(171):280-286. PubMed PMID: 7140079
  63. 63. Ng MC, Harper RP, Le CT, Wong BS. Effects of estrogen on the condylar cartilage of the rat mandible in organ culture. Journal of Oral and Maxillofacial Surgery. 1999;57(7):818-823. PubMed PMID: 10416629
  64. 64. Tsai CL, Liu TK. Up-regulation of estrogen receptors in rabbit osteoarthritic cartilage. Life Sciences. 1992;50(22):1727-1735. PubMed PMID: 1588803
  65. 65. Setchell KD. Soy isoflavones—Benefits and risks from nature's selective estrogen receptor modulators (SERMs). Journal of the American College of Nutrition. 2001;20(5 Suppl):354S-362S; discussion 81S–83S. PubMed PMID: 11603644
  66. 66. Zhang Z, Li L, Yang W, Cao Y, Shi Y, Li X, et al. The effects of different doses of IGF-1 on cartilage and subchondral bone during the repair of full-thickness articular cartilage defects in rabbits. Osteoarthritis Cartilage. 2017;25(2):309-320. DOI: 10.1016/j.joca.2016.09.010. Epub 2016/09/20. PubMed PMID: 27662821
  67. 67. Foley E, Browne J, Akhavan N, George K, Muños J, Siebert S, et al. Relationship between inflammation, oxidative damage, weight, and severity of knee osteoarthritis. ASN 2018. Abstract. 2018
  68. 68. Akhavan NS, Ormsbee L, Johnson SA, George KS, Foley EM, Elam ML, et al. Functionality in middle-aged and older overweight and obese individuals with knee osteoarthritis. Healthcare (Basel). 2018;6(3):1-12. DOI: 10.3390/healthcare6030074. Epub 2018/07/04. PubMed PMID: 29973574
  69. 69. Ahima RS. Revisiting leptin’s role in obesity and weight loss. The Journal of Clinical Investigation. 2008;118(7):2380-2383. DOI: 10.1172/JCI36284. PubMed PMID: 18568083; PubMed Central PMCID: PMCPMC2430504
  70. 70. Scotece M, Mobasheri A. Leptin in osteoarthritis: Focus on articular cartilage and chondrocytes. Life Sciences. 2015;140:75-78. DOI: 10.1016/j.lfs.2015.05.025. Epub 2015/06/19. PubMed PMID: 26094910
  71. 71. Farr OM, Gavrieli A, Mantzoros CS. Leptin applications in 2015: What have we learned about leptin and obesity? Current Opinion in Endocrinology Diabetes and Obesity. 2015;22(5):353-359. DOI: 10.1097/MED.0000000000000184. PubMed PMID: 26313897; PubMed Central PMCID: PMCPMC4610373
  72. 72. Vuolteenaho K, Koskinen A, Moilanen E. Leptin—A link between obesity and osteoarthritis: Applications for prevention and treatment. Basic and Clinical Pharmacology and Toxicology. 2014;114(1):103-108. DOI: 10.1111/bcpt.12160. Epub 2013/11/20. PubMed PMID: 24138453
  73. 73. Rosenbaum M, Nicolson M, Hirsch J, Heymsfield SB, Gallagher D, Chu F, et al. Effects of gender, body composition, and menopause on plasma concentrations of leptin. Journal of Clinical Endocrinology and Metabolism. 1996;81(9):3424-3427. DOI: 10.1210/jcem.81.9.8784109. PubMed PMID: 8784109
  74. 74. Bao JP, Chen WP, Feng J, Hu PF, Shi ZL, Wu LD. Leptin plays a catabolic role on articular cartilage. Molecular Biology Reports. 2010;37(7):3265-3272. DOI: 10.1007/s11033-009-9911-x. Epub 2009/10/30. PubMed PMID: 19876764
  75. 75. Presle N, Pottie P, Dumond H, Guillaume C, Lapicque F, Pallu S, et al. Differential distribution of adipokines between serum and synovial fluid in patients with osteoarthritis. Contribution of joint tissues to their articular production. Osteoarthritis Cartilage. 2006;14(7):690-695. DOI: 10.1016/j.joca.2006.01.009. Epub 2006/03/09. PubMed PMID: 16527497
  76. 76. Schmidt J, Shirin H, Arjmandi B. Relationship between serum and synovial fluid concentration of leptin and degree of osteoarthritis. FASEB Journal. Abstract. 2011
  77. 77. La Cava A, Matarese G. The weight of leptin in immunity. Nature Reviews Immunology. 2004;4(5):371-379. DOI: 10.1038/nri1350. PubMed PMID: 15122202
  78. 78. Siegmund B, Lehr HA, Fantuzzi G. Leptin: A pivotal mediator of intestinal inflammation in mice. Gastroenterology. 2002;122(7):2011-2025. PubMed PMID: 12055606
  79. 79. Iikuni N, Lam QL, Lu L, Matarese G, La Cava A. Leptin and Inflammation. Current Immunology Reviews. 2008;4(2):70-79. DOI: 10.2174/157339508784325046. PubMed PMID: 20198122; PubMed Central PMCID: PMCPMC2829991
  80. 80. Frigolet ME, Torres N, Uribe-Figueroa L, Rangel C, Jimenez-Sanchez G, Tovar AR. White adipose tissue genome wide-expression profiling and adipocyte metabolic functions after soy protein consumption in rats. Journal of Nutritional Biochemistry. 2011;22(2):118-129. DOI: 10.1016/j.jnutbio.2009.12.006. Epub 2010/05/14. PubMed PMID: 20471815
  81. 81. Niwa T, Yokoyama S, Osawa T. Effect of the genistein metabolite on leptin secretion in murine adipocytes in vitro. Food Chemistry. 2013;138(1):122-125. DOI: 10.1016/j.foodchem.2012.09.108. Epub 2012/11/08. PubMed PMID: 23265465
  82. 82. Llaneza P, González C, Fernández-Iñarrea J, Alonso A, Díaz F, Pérez-López FR. Soy isoflavones improve insulin sensitivity without changing serum leptin among postmenopausal women. Climacteric. 2012;15(6):611-620. DOI: 10.3109/13697137.2011.631062. Epub 2011/12/23. PubMed PMID: 22191384
  83. 83. Kwak JH, Ahn CW, Park SH, Jung SU, Min BJ, Kim OY, et al. Weight reduction effects of a black soy peptide supplement in overweight and obese subjects: Double blind, randomized, controlled study. Food and Function. 2012;3(10):1019-1024. DOI: 10.1039/c2fo10244g. Epub 2012/06/28. PubMed PMID: 22739624
  84. 84. Arjmandi BH, Khalil DA, Smith BJ, Lucas EA, Juma S, Payton ME, et al. Soy protein has a greater effect on bone in postmenopausal women not on hormone replacement therapy, as evidenced by reducing bone resorption and urinary calcium excretion. Journal of Clinical Endocrinology and Metabolism. 2003;88(3):1048-1054. DOI: 10.1210/jc.2002-020849. PubMed PMID: 12629084
  85. 85. Ye F, Wu J, Dunn T, Yi J, Tong X, Zhang D. Inhibition of cyclooxygenase-2 activity in head and neck cancer cells by genistein. Cancer Letters. 2004;211(1):39-46. DOI: 10.1016/j.canlet.2004.03.043. PubMed PMID: 15194215
  86. 86. Liang YC, Huang YT, Tsai SH, Lin-Shiau SY, Chen CF, Lin JK. Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related flavonoids in mouse macrophages. Carcinogenesis. 1999;20(10):1945-1952. PubMed PMID: 10506109
  87. 87. Hooshmand S, Soung DY, Lucas EA, Madihally SV, Levenson CW, Arjmandi BH. Genistein reduces the production of proinflammatory molecules in human chondrocytes. Journal of Nutritional Biochemistry. 2007;18(9):609-614. DOI: 10.1016/j.jnutbio.2006.11.006. Epub 2007/03/21. PubMed PMID: 17368882
  88. 88. Zidar N, Odar K, Glavac D, Jerse M, Zupanc T, Stajer D. Cyclooxygenase in normal human tissues—Is COX-1 really a constitutive isoform, and COX-2 an inducible isoform? Journal of Cellular and Molecular Medicine. 2009;13(9B):3753-3763. DOI: 10.1111/j.1582-4934.2008.00430.x. Epub 2008/07/24. PubMed PMID: 18657230; PubMed Central PMCID: PMCPMC4516524
  89. 89. Dubois RW, Melmed GY, Henning JM, Bernal M. Risk of upper gastrointestinal injury and events in patients treated with cyclooxygenase (COX)-1/COX-2 nonsteroidal antiinflammatory drugs (NSAIDs), COX-2 selective NSAIDs, and gastroprotective cotherapy: An appraisal of the literature. Journal of Clinical Rheumatology. 2004;10(4):178-189. DOI: 10.1097/01.rhu.0000128851.12010.46. PubMed PMID: 17043507
  90. 90. Hörl WH. Nonsteroidal anti-inflammatory drugs and the kidney. Pharmaceuticals (Basel). 2010;3(7):2291-2321. DOI: 10.3390/ph3072291. Epub 2010/07/21. PubMed PMID: 27713354; PubMed Central PMCID: PMCPMC4036662
  91. 91. Hawkey CJ. COX-1 and COX-2 inhibitors. Best Practice and Research Clinical Gastroenterology. 2001;15(5):801-820. DOI: 10.1053/bega.2001.0236. PubMed PMID: 11566042
  92. 92. Volck B, Johansen JS, Stoltenberg M, Garbarsch C, Price PA, Ostergaard M, et al. Studies on YKL-40 in knee joints of patients with rheumatoid arthritis and osteoarthritis. Involvement of YKL-40 in the joint pathology. Osteoarthritis Cartilage. 2001;9(3):203-214. DOI: 10.1053/joca.2000.0377. PubMed PMID: 11300743
  93. 93. Borzan J, Tall JM, Zhao C, Meyer RA, Raja SN. Effects of soy diet on inflammation-induced primary and secondary hyperalgesia in rat. The European Journal of Pain. 2010;14(8):792-798. DOI: 10.1016/j.ejpain.2009.12.002. Epub 2010/01/08. PubMed PMID: 20060762; PubMed Central PMCID: PMCPMC2891824
  94. 94. Hurtubise J, McLellan K, Durr K, Onasanya O, Nwabuko D, Ndisang JF. The different facets of dyslipidemia and hypertension in atherosclerosis. Current Atherosclerosis Reports. 2016;18(12):82. DOI: 10.1007/s11883-016-0632-z. PubMed PMID: 27822682
  95. 95. Arjmandi BH, Khalil DA, Lucas EA, Smith BJ, Sinichi N, Hodges SB, et al. Soy protein may alleviate osteoarthritis symptoms. Phytomedicine. 2004;11(7-8):567-575. DOI: 10.1016/j.phymed.2003.11.001. PubMed PMID: 15636169
  96. 96. Khalil DA, Lucas EA, Juma S, Smith BJ, Payton ME, Arjmandi BH. Soy protein supplementation increases serum insulin-like growth factor-I in young and old men but does not affect markers of bone metabolism. Journal of Nutrition. 2002;132(9):2605-2608. DOI: 10.1093/jn/132.9.2605. PubMed PMID: 12221217
  97. 97. Katan MB, Grundy SM, Jones P, Law M, Miettinen T, Paoletti R, et al. Efficacy and safety of plant stanols and sterols in the management of blood cholesterol levels. Mayo Clinic Proceedings. 2003;78(8):965-978. DOI: 10.4065/78.8.965. PubMed PMID: 12911045
  98. 98. Kietsiriroje N, Kwankaew J, Kitpakornsanti S, Leelawattana R. Effect of phytosterols and inulin-enriched soymilk on LDL-cholesterol in Thai subjects: A double-blinded randomized controlled trial. Lipids in Health and Disease. 2015;14:146. DOI: 10.1186/s12944-015-0149-4. Epub 2015/11/09. PubMed PMID: 26553006; PubMed Central PMCID: PMCPMC4640379
  99. 99. Ruscica M, Pavanello C, Gandini S, Gomaraschi M, Vitali C, Macchi C, et al. Effect of soy on metabolic syndrome and cardiovascular risk factors: A randomized controlled trial. The European Journal of Nutrition. 2018;57(2):499-511. DOI: 10.1007/s00394-016-1333-7. Epub 2016/10/18. PubMed PMID: 27757595
  100. 100. Harland JI, Haffner TA. Systematic review, meta-analysis and regression of randomised controlled trials reporting an association between an intake of circa 25 g soya protein per day and blood cholesterol. Atherosclerosis. 2008;200(1):13-27. DOI: 10.1016/j.atherosclerosis.2008.04.006. Epub 2008/04/15. PubMed PMID: 18534601
  101. 101. Liu ZM, Ho SC, Chen YM, Ho S, To K, Tomlinson B, et al. Whole soy, but not purified daidzein, had a favorable effect on improvement of cardiovascular risks: A 6-month randomized, double-blind, and placebo-controlled trial in equol-producing postmenopausal women. Molecular Nutrition and Food Research. 2014;58(4):709-717. DOI: 10.1002/mnfr.201300499. Epub 2013/11/24. PubMed PMID: 24273218
  102. 102. Reverri EJ, LaSalle CD, Franke AA, Steinberg FM. Soy provides modest benefits on endothelial function without affecting inflammatory biomarkers in adults at cardiometabolic risk. Molecular Nutrition and Food Research. 2015;59(2):323-333. DOI: 10.1002/mnfr.201400270. Epub 2014/12/05. PubMed PMID: 25351805; PubMed Central PMCID: PMCPMC4451218
  103. 103. Lucas EA, Lightfoot SA, Hammond LJ, Devareddy L, Khalil DA, Daggy BP, et al. Soy isoflavones prevent ovariectomy-induced atherosclerotic lesions in Golden Syrian hamster model of postmenopausal hyperlipidemia. Menopause. 2003;10(4):314-321. DOI: 10.1097/01.GME.0000051509.84118.FD. PubMed PMID: 12851514
  104. 104. Arjmandi BH, Khalil DA, Hollis BW. Soy protein: Its effects on intestinal calcium transport, serum vitamin D, and insulin-like growth factor-I in ovariectomized rats. Calcified Tissue International. 2002;70(6):483-487. DOI: 10.1007/s00223-001-1100-4. Epub 2002/06/01. PubMed PMID: 27695965
  105. 105. Pawlowski JW, Martin BR, McCabe GP, McCabe L, Jackson GS, Peacock M, et al. Impact of equol-producing capacity and soy-isoflavone profiles of supplements on bone calcium retention in postmenopausal women: A randomized crossover trial. The American Journal of Clinical Nutrition. 2015;102(3):695-703. DOI: 10.3945/ajcn.114.093906. Epub 2015/08/05. PubMed PMID: 26245807; PubMed Central PMCID: PMCPMC4548170
  106. 106. Arjmandi BH, Birnbaum R, Goyal NV, Getlinger MJ, Juma S, Alekel L, et al. Bone-sparing effect of soy protein in ovarian hormone-deficient rats is related to its isoflavone content. The American Journal of Clinical Nutrition. 1998;68(6 Suppl):1364S-1368S. DOI: 10.1093/ajcn/68.6.1364S. PubMed PMID: 9848500
  107. 107. Devareddy L, Khalil DA, Smith BJ, Lucas EA, Soung DY, Marlow DD, et al. Soy moderately improves microstructural properties without affecting bone mass in an ovariectomized rat model of osteoporosis. Bone. 2006;38(5):686-693. DOI: 10.1016/j.bone.2005.10.024. Epub 2006/01/10. PubMed PMID: 16406762
  108. 108. Juma SS, Ezzat-Zadeh Z, Khalil DA, Hooshmand S, Akhter M, Arjmandi BH. Soy protein with or without isoflavones failed to preserve bone density in gonadal hormone-deficient male rat model of osteoporosis. Nutrition Research. 2012;32(9):694-700. DOI: 10.1016/j.nutres.2012.08.001. Epub 2012/09/23. PubMed PMID: 23084642
  109. 109. Soung DY, Devareddy L, Khalil DA, Hooshmand S, Patade A, Lucas EA, et al. Soy affects trabecular microarchitecture and favorably alters select bone-specific gene expressions in a male rat model of osteoporosis. Calcified Tissue International. 2006;78(6):385-391. DOI: 10.1007/s00223-005-0069-9. Epub 2006/07/21. PubMed PMID: 16830200
  110. 110. Devareddy L, Khalil DA, Korlagunta K, Hooshmand S, Bellmer DD, Arjmandi BH. The effects of fructo-oligosaccharides in combination with soy protein on bone in osteopenic ovariectomized rats. Menopause. 2006;13(4):692-699. DOI: 10.1097/01.gme.0000195372.74944.71. PubMed PMID: 16837891
  111. 111. Khalil DA, Lucas EA, Smith BJ, Soung DY, Devareddy L, Juma S, et al. Soy isoflavones may protect against orchidectomy-induced bone loss in aged male rats. Calcified Tissue International. 2005;76(1):56-62. DOI: 10.1007/s00223-004-0018-z. Epub 2004/11/04. PubMed PMID: 15549639
  112. 112. Hooshmand S, Juma S, Arjmandi BH. Combination of genistin and fructooligosaccharides prevents bone loss in ovarian hormone deficiency. Journal of Medicinal Food. 2010;13(2):320-325. DOI: 10.1089/jmf.2009.0059. PubMed PMID: 20132047
  113. 113. Tai TY, Tsai KS, Tu ST, Wu JS, Chang CI, Chen CL, et al. The effect of soy isoflavone on bone mineral density in postmenopausal Taiwanese women with bone loss: A 2-year randomized double-blind placebo-controlled study. Osteoporosis International. 2012;23(5):1571-1580. DOI: 10.1007/s00198-011-1750-7. Epub 2011/09/08. PubMed PMID: 21901480; PubMed Central PMCID: PMCPMC3332377
  114. 114. Alekel DL, Van Loan MD, Koehler KJ, Hanson LN, Stewart JW, Hanson KB, et al. The soy isoflavones for reducing bone loss (SIRBL) study: A 3-y randomized controlled trial in postmenopausal women. The American Journal of Clinical Nutrition. 2010;91(1):218-230. DOI: 10.3945/ajcn.2009.28306. Epub 2009/11/11. PubMed PMID: 19906801; PubMed Central PMCID: PMCPMC2793109
  115. 115. Wong WW, Lewis RD, Steinberg FM, Murray MJ, Cramer MA, Amato P, et al. Soy isoflavone supplementation and bone mineral density in menopausal women: A 2-y multicenter clinical trial. The American Journal of Clinical Nutrition. 2009;90(5):1433-1439. DOI: 10.3945/ajcn.2009.28001. Epub 2009/09/16. PubMed PMID: 19759166; PubMed Central PMCID: PMCPMC2762163
  116. 116. Arjmandi BH, Lucas EA, Khalil DA, Devareddy L, Smith BJ, McDonald J, et al. One year soy protein supplementation has positive effects on bone formation markers but not bone density in postmenopausal women. Nutrition Journal. 2005;4:8. DOI: 10.1186/1475-2891-4-8. Epub 2005/02/23. PubMed PMID: 15727682; PubMed Central PMCID: PMCPMC554088
  117. 117. Levis S, Strickman-Stein N, Ganjei-Azar P, Xu P, Doerge DR, Krischer J. Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms: A randomized, double-blind trial. Archives of Internal Medicine. 2011;171(15):1363-1369. DOI: 10.1001/archinternmed.2011.330. PubMed PMID: 21824950

Written By

Bahram Herman Arjmandi and Elizabeth Marie Foley

Submitted: December 15th, 2018 Reviewed: March 5th, 2019 Published: June 20th, 2019