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By Nicole Nisly, MD and Teresa Klepser, PharmD
Osteoporosis is a major public health problem occurring primarily among postmenopausal women (PMW). A diet rich in legumes, especially soy, has been linked to a lower risk of fractures in Asian women, despite their lower bone density, when compared with Caucasian women.1 Hormone replacement therapy (HRT) is effective in maintaining bone and reducing susceptibility to osteoporotic fractures associated with menopause, but the negative potential effects of HRT make it unacceptable to many women, and adherence is poor.2 To identify substances that may provide the benefits of estrogen therapy without some of its negative effects, attention has been given to plant-derived phytoestrogens.
Definition and Classification
Phytoestrogens are nonsteroidal plant compounds structurally resembling estradiol (E2), that are shown to have both estrogenic and anti-estrogenic activities in both humans and animals.3 Phytoestrogens are found in many fruits, vegetables, and grains, but leguminous seeds are especially rich in these compounds.4
There are three main classes of phytoestrogens: flavonoids, coumestans, and resorcyclic acid lactones. Isoflavones have the most potent hormonal-like activity and an extensive range of biological activities in the body. More than 1,000 isoflavonoids are known, and they are exclusively found in leguminous seeds (such as soybeans, chickpeas, lentils, and beans). The most important isoflavones are genistein, daidzein, glycetin, formonetin, and biochanin (the last two are 4-methyl ether derivatives of genistein and daidzein, respectively).
Soybean is a rich source of isoflavones, especially daidzein and genistein.4 In some individuals, daidzein may be converted into equol,5 a potent mammalian isoflavone metabolite. Clover sprouts also contain the isoflavone formonetin, which is metabolized in the gut via daidzein into equol. Despite its weak estrogenic activity (equol is about 1,000 times less potent than estradiol), its urinary excretion in humans eating a soy-rich diet can greatly exceed the concentration of urinary endogenous estrogens, enhancing the plausibility of human health effects.5
Ipriflavone (7-isopropoxyisoflavone) is a synthetic isoflavone derivative used in several countries in Europe, in particular Italy, and in Japan, for prevention and treatment of osteoporosis. In the United States, ipriflavone (IP) is available as a dietary supplement.
In nature, isoflavones are sugar-bound (glycoside) and are not biologically active. To transform these inactive compounds into their free active form (aglycone), they must be metabolized in the bowel.6
The extent of this metabolism appears to be highly variable, and is influenced by diet and microflora, including the use of antibiotics.7 Like endogenous estrogens, isoflavones undergo enterohepatic circulation and are secreted in the bile. Estrogens are strongly protein bound, so that less than 5% circulate free. Isoflavones are less avidly bound; equol has about tenfold less affinity for serum protein than estradiol, theoretically increasing equol’s effectiveness.
Mechanism of Action
Like estrogen, isoflavone molecules are complex with estrogen receptors (ER), particularly ER beta,8 which predominates in bone, heart, and bladder. In normal reproductive women, these phytoestrogens behave as anti-estrogens, but in hypo-estrogenic PMW, isoflavones behave as weak estrogens. Isoflavones have also been found to interface with transforming growth factor beta9 and to inhibit tyrosine kinase,10 which may explain some of their non-estrogenic activity on bone. Similarly to estrogen, isoflavones decrease post-menopausal bone loss and in high doses may increase bone density.
Ipriflavone structurally resembles soybean’s isoflav-ones.11 One of its metabolites is daidzein. It does not possess estrogenic activity,12 affecting bone remodeling by inhibiting bone resorption and possibly stimulating bone formation.13
Selected Animal Studies
Preclinical studies suggest cytostatic activity against human mammary cancer cell lines and the ability to suppress carcinogen-induced mammary cancer in murine models. Case-control studies show reduced risk for pre-menopausal and post-menopausal breast cancers.14 Clinical studies are lacking to confirm these beneficial effects.
Potter et al studied the effects of soy protein with moderate and greater isoflavone content on bone mineral density in 66 PMW with hypercholesterolemia, during a six-month, parallel group, double-blind trial.15 The incidence of osteoporosis on the study subjects was not reported. The women were randomly assigned to three sources of protein: milk protein, medium isoflavone content soy (55.6 mg/d), or high isoflavone isolated soy protein (90 mg/d). Dual energy x-ray absorptiometry bone density studies were performed of lumbar spine, proximal femur, and total body at the beginning of the study and six months later. The hypothesis was that the three groups would maintain similar bone density levels. The high isoflavone group experienced a 2% increase in bone density of the vertebral bone (P < 0.05), with similar trends noted for other skeletal areas (not statistically significant). No other significant differences were noted among the three groups. This is the only well-designed human study available in the literature on soy and bone density.
Experiments in animals on the effect of IP on the treatment of bone diseases related to bone mass loss started in 1974, when this isoflavone analog was selected among several similar compounds because of its observed activity on bone and lack of estrogenic activity. Human studies began in 1981.11 As of 1997, 2,769 patients have been treated with IP in 60 clinical trials: Many are randomized control trials (RCTs).16 Two small studies have shown fewer vertebral fractures after two years of treatment with IP than without it.16
Gennari and colleagues17 conducted two multicenter randomized, placebo-controlled, two-year studies in Italy, evaluating the efficacy and tolerability of IP in PMW with low bone mass. Four hundred fifty-three PMW aged 50-65 years with vertebral (study A) or radial (study B) bone mineral density decrease (one SD below age matched peers) were randomly selected to receive IP 200 mg tid or matching placebo. All patients received 1 g of oral calcium daily (amount of elemental calcium not specified). At the end of the two-year treatment, patients receiving IP plus calcium maintained their bone density on both spine (trabecular bone) and distal radius (cortical bone) whereas significant bone loss occurred in the control group. A slight trend toward reduction of bone turnover rate was noted in the IP treated group. IP seemed to prevent axial and peripheral bone loss in PMW and was well tolerated.
Side effects of IP may include gastrointestinal complaints and allergic reactions. A meta-analysis of the 60 trials conducted on IP revealed an incidence of ADR of 14.5% vs. 16.1% ADR on the placebo group.16 GI complaints accounted for 77.9% of the reported ADR on the IP group (placebo 81.8%) and allergic reactions accounting for 9.1% (7.4 % on the placebo group). The effects of overdosage in humans are unknown. Animals exposed to high levels (80 mg/kg) of isoflavones show evidence of hyper-estrogenization, including both temporary and permanent infertility.18
Based on company information on the isoflavone concentrate Promensil, acute and chronic toxicity tests in animals (3,000 mg/kg in single dose and daily for 28 days) did not reveal any abnormalities. Six clinical trials, including two RCTs, were performed by this company in humans. No significant side effects were observed with doses varying from 40-160 mg/d. The pooled number of participants in these studies was 110 PMW.19
Several human studies on IP revealed an excellent side effect profile.16 The recommended dose should be adjusted for renal failure, as follows: creatine clearance of 40-80 ml/min, 400 mg/d; less than 40 ml/min, 200 mg/d.16
Contraindications and Precautions
There are concerns in the literature with the use of high doses of isoflavones by patients with hormone-sensitive cancers and in pregnancy. In animal studies, genistein in high doses (14-70 mg/kg) was associated with decreased anogenital distance at birth,20 delayed onset of puberty, and decreased birth weight. Genistein should be avoided in pregnancy and lactation. Until use in cancer patients is more carefully evaluated, concentrated supplements should be taken with caution.
When used in conjunction with estrogens, isoflavone concentrates may potentially cause competitive inhibition. Until data are available, concomitant use of isoflavone concentrates with estrogenic preparations should be discouraged and practitioners should monitor PMW for decreased HRT effectiveness. Competitive inhibition has not been demonstrated with IP, which acts synergistically with estrogen,21 preserving bone density. Individuals treated with proton pump inhibitors or H2 antagonists may not attain maximal benefits with isoflavone use because of decreased absorption of aglycone isoflavones. Similarly, antibiotics may reduce isoflavone metabolism by changing bowel flora. Potential elevation of serum theophylline levels may occur with IP through inhibition of cytochrome P450 enzymes.16 IP has increased anticoagulant activity and prolonged prothrombin time, when administered with coumadin.16
Use in Lactation and Pregnancy
Use of isoflavone dietary supplements in pregnancy and lactation is not recommended. Isoflavones are secreted in breast milk. Infants fed soy-based formulas will receive equivalent or higher doses of isoflavones than those fed breast milk. IP has not been evaluated in this population.
Dosage and Formulation
Isoflavone consumption in Eastern countries is in the order of 20-150 mg/d (average 40 mg/d),22,23 as compared with 2-5 mg/d in Western countries. In adults consuming 50 mg/d total isoflavones (such as found in the traditional Japanese diet) a plasma isoflavone concentration of 50-800 ng/ml may be achieved, far exceeding normal plasma estradiol concentrations (40-80 pg/ml).7
Persons with risk factors for osteoporosis should consume about 14 servings of soy protein per week.24 This would provide an average of approximately 16-20 g of soy protein/d with 32-40 mg of isoflavones/d. Persons with osteoporosis should consume 21 servings of soy protein per week, which would yield about 24-30 g of soy protein and 48-60 mg of isoflavones daily.
The average dose recommendation of isoflavone dietary supplements is 40 mg/d of aglycone isoflavones. Doses of 40-160 mg/d have been used in humans with a favorable side effect profile.19 The usual dose of IP is 200 mg tid. (See Table 1 for protein and isoflavone concentration in soy foods.)
|Table 1-Estimated protein and isoflavone concentration in soy foods|
|Serving Size||Protein g/100 g||Genistein mg/100g||Daidzein mg/100 g||Total Isoflavone* mg/serving|
|Mature soybeans (uncooked)||1/2 cup||37.0||73.76||46.64||175.6|
|Roasted soybeans||1/2 cup||35.2||65.88||52.04||167.0|
|Soy flour||1/4 cup||37.8||96.83||71.19||43.8|
|Textured soy protein||1/4 cup||18.0||78.90||59.62||27.8|
|Green soybeans (uncooked)||1/2 cup||16.6||72.51||67.79||70.1|
|Soy milk||1 cup||4.4||6.06||4.45||20.0|
|Tempeh (uncooked)||4 oz||17.0||24.85||17.59||60.5|
|Tofu (uncooked)||4 oz||15.8||13.60||9.02||38.3|
|Soy isolate (dry)||1 oz||92.0||59.62||33.59||56.5|
|Soy concentrate (dry)||1 oz||63.6||5.33||6.83||12.4|
|Soy cheese||1 oz||7.0||20.08||11.24||31.3|
|Adapted from: Anderson JW. American Dietetic Association 80th Annual Meeting and USDA — Iowa State University Database on Isoflavone Content of Foods. 1999.|
|*The above isoflavone content is a mean estimate. It varies widely among soybean varieties and manufacturers.|
Isoflavone consumption may reduce the risk for osteoporosis and have therapeutic value for persons with it.15 However, before firm conclusions can be drawn, long-term human studies need to be conducted on the effects of isoflavones on bone density and fracture risk. The use of standardized isoflavone concentrates19 needs to be further studied, but small human studies conducted in Australia by one of the manufacturers reveal an excellent safety profile and promising data. IP is widely used in Europe and Japan for osteoporosis prevention and treatment, with good evidence of safety and efficacy.16
IP should be considered for patients at risk for or diagnosed with osteoporosis, who cannot tolerate or decline the use of HRT, raloxifene, or alendronate and who are unable to increase their dietary consumption of isoflavones. The use of standardized isoflavone preparations within the dosing guidelines and following the precautions summarized above may be considered for women at risk for or diagnosed with osteoporosis, who cannot or will not use HRT, raloxifene, or alendronate, and who are unable to increase their dietary isoflavone consumption to the levels found to be beneficial.
Dr. Nisly is Assistant Professor, Department of Internal Medicine, University of Iowa College of Medicine, and Dr. Klepser is Assistant Professor, Division of Clinical and Administrative Pharmacy, University of Iowa College of Pharmacy.
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