After 8 weeks, both the hops group and the placebo group had significant improvement in outcome measures compared to the baseline and actually higher average reductions in the placebo group. After 16 weeks however, only the group that was on the hops extract in the second 8 weeks had a reduction in all outcome measures whereas the placebo group in the second 8 weeks had an increase for all outcome measures. Although the overall treatment efficacy of the hops treatment compared with the placebo did not show a significant effect, the time specific uses did indicate significant reductions in the KI and the VAS for the hops group, and a marginal reduction in symptoms for the MRS after 16 weeks.

Commentary: This is the second study on an oral hops extract for menopause symptoms that I am aware of. The German Commission E (the German agency similar to our FDA), has approved hops for mood issues such as anxiety and restlessness, and for sleep disruptions. In the previous randomized, double-blind, placebo-controlled study, 67 menopausal women were given either a placebo or a 100 mcg or 250 mcg standardized hops extract for 12 weeks.[i] At 6 weeks, the 100 mcg dose was significantly superior to placebo, but not after 12 weeks. Even so, there was a more rapid decrease in menopause symptoms scored for both doses of hops extract , especially the hot flush score. The higher dose was not any better than the lower dose. Both the current study and this previous study, used a standardized hops extract at 100 mcg 8-prenylnaringenin. The current study used the lower 100 mcg dose.

This hops standardized extract may provide a useful herb for women suffering from common menopause symptoms such as hot flashes/night sweats. I have been using it in my clinical practice for approximately two years, usually along with one or more of the following: Black cohosh, St. John’s wort, Maca extract or a combination botanical of Dong Quai/burdock root/ wild yam root/ licorice root/motherwort. Hops do contain phytoestrogens and this is the likely mechanism of action.

Reference:

[i] Heyerick A, Vervarcke S, Depypere H, et al. A first prospective, randomized, double blind, placebo-controlled study on the use of a standardized hop extract to alleviate menopausal discomforts. Maturitas 2006;54:164-175.

Soybeans contain a class of compounds called phytoestrogens, comprising mostly genistein, daidzein and glycitein, all of which have a biochemical structure similar to 17- beta estradiol.  The binding of isoflavones to estrogen receptors is preferential for the estrogen receptor beta and thus indicates that soy isoflavones act as selective estrogen modulators.  Daidzein is similar in shape to a drug called Ipriflavone, which is used in Europe to treat osteoporosis.  In the U.S., Ipriflavone is available as a nutritional supplement. 

Bone mineral density (BMD) is the gold standard for determining fracture risk due to non-traumatic events.  Bone turnover is an independent predictor of fracture risk.  While research on the effects of soy on bone metabolism has been inconsistent, many positive studies do exist that suggest a role for soy in slowing bone turnover and increasing bone density in women.  Soy appears to have an estrogenic effect on bone in some experimental evaluations. The bone density of ovariectomized rats was evaluated in a study in which soy replaced casein in the diet and compared to another group that received estrogen. The addition of soy inhibited bone loss, although not to the same extent as was achieved with the estrogen treatment.  Another study of ovariectomized rats also reported a positive effect of the soy phytoestrogen, genistein in maintaining bone.  These authors also reported that genistein suppresses osteoclasts, the cells responsible for bone resorption, both in the test tube and in vivo.  Arjmandi also did a double-blind, randomized, and controlled trial using 40g of soy protein containing isoflavones over 3 months in postmenopausal women.  Bone resorption was decreased, when compared to milk protein.

Several human studies have provided further insight and comfort in the possible role of soy in our bone health. A study conducted at the University of Illinois found that menopausal women had an increase in mineral levels and density in their lumbar spines after taking 55-90 mg of soy isoflavones for six months.  The placebo group showed the lowest bone density and the greatest bone loss, while the estrogen group showed the highest bone density and the slowest bone loss. What was surprising was that the isoflavone diet was effective in preventing bone loss in the fourth lumbar vertebra and, although less so, in the right hip. Soy isoflavones seem to have more of an effect on trabecular bone (more predominant in the spine) than on cortical bone (more predominant in the hip). The soy did not show as great of ability in preventing bone loss as the estrogen group, but the positive effect it showed is encouraging. 

An analysis of the relationship of soy isoflavone intake and bone mineral density was conducted from the Study of Women’s Health Across the Nation, a US cohort study of women aged 42-52 years.  For African-American and Caucasian women, median intakes of genistein were too low to pursue analyses. For Chinese women, no association between genistein and bone mineral density was found. Premenopausal, but not perimenopausal Japanese women whose intakes were greater had a higher bone density of the spine and femoral neck. The mean spinal bone density of those women in the highest group was 7.7% greater than that of women in the lowest group. Bone density of the femoral neck was 12% greater in the highest intake group versus the lowest.
 
Other positive studies on soy and bone density also give some credence to the role of soy and bone health. In a study estimating the daily intakes of soy isoflavones in the diets of 478 postmenopausal Japanese women who reported soy consumption, high consumption of soy products was associated with increased bone mass.

A recent meta-analysis further increases our optimism about using soy to inhibit bone resorption.  Nine studies with a total of 432 menopausal women were evaluated in this meta-analysis.  Amount of soy intake varied amongst the nine studies from 37 mg of isoflavones per day to 118 mg of isoflavones per day. Testing for urinary peptides (deoxypyridinoline), a marker of bone turnover, demonstrated that those who consumed isoflavones had a decrease in these biomarkers of -2.08nmol/mmol, when compared to those who did not consume isoflavones.  In five of the studies where isolated soy protein was used there was no significant effect on urinary deoxypyridinoline.  In the current analysis, a significant reduction in urinary deoxypyridinoline was not observed in those studies with isoflavones of less than 90 mg/day.  In a review of the research in 2003, the author concluded that 90 mg of isoflavones per day is required to achieve benefits on bone health.

In contrast to the positive studies, several clinical trials using a variety of soy protein isolate formulations found no clinically important effects of soy on bone metabolism and bone turnover markers.  Further inconsistent research can be seen with several clinical trials using soy protein or isoflavones demonstrating a positive effect on BMD, while others have not had positive findings.

I mentioned variations in dosing, duration, soy formulations used, and different study populations as possible reasons for inconsistent results on the effects of soy isoflavones on bone turnover and bone density.  But, another significant consideration may be due to how the isoflavones are metabolized in the gut.  In the meta-analysis mentioned above which analyzed nine studies the significant effects on urinary peptides occurred in Asian women but not Caucasian women.  This may be due to the conversion of daidzein into its active metabolite equol by intestinal flora, and by the fact that only one-third of Caucasian women can metabolize isoflavones into equol, whereas more than half of Asian women possess this ability. 

Soy isoflavones may also have more of an effect in post-menopausal women than in pre or perimenopausal women.  In one study, 53.3 mg of isoflavones per day was associated with an increase in bone density in postmenopausal women, but not pre-menopausal women.

A nutritional influence of soy foods that may be overlooked is the amount of calcium in some of these foods or in diets that contain soy foods. A diet that includes greater amounts of soy products can account for a meaningful amount of calcium, and some soy foods can offer as much, or more, calcium than a serving of dairy products.
 

CALCIUM CONTENT OF SELECTED SOY FOODS

With the inconsistent research, it is difficult to draw confident conclusions about the role of soy in bone health.  My clinical advice is to increase soy foods as part of a regular diet in prevention strategies for all pre, peri and postmenopausal women.  For all women who have significant risk factors for osteoporosis, I would in addition, recommend soy supplementation so that their total daily soy isoflavone intake would deliver approximately 90 mg of soy isoflavones per day.  For treatment of peri and postmenopausal women who already have osteoporosis, I would not consider soy an adequate treatment alone.  For these women who already have osteoporosis, I am in favor of proven conventional therapies to reduce fracture risk in addition to the 90 mg per day of soy isoflavones and typical supplementation including calcium, vitamin D and other potential nutrients (K, boron, magnesium, manganese, and more), and dietary and exercise advice.

References
  Weaver C, Cheong J.  Soy isoflavones and bone health: the relationship is still unclear.  J Nutr 2005; 135:1243-1247.

  Setchell K.  Soy isoflavones-benefits and risk from nature’s selective estrogen receptor modulators (SERMS).  J Am Coll Nutr 2001; 20: 354S-362S.

  Garnero P, Hausherr E, Chapuy M, et al.  Markers of bone resorption predict hip fracture in elderly women: the EPIDOS Prospective Study.  J Bone Miner Res 1996; 11:1531-1538.

  Arjmandi B, Alekel L, Hollis B, Amin D, Stacwicz-Sapuntzakis M, Guo, Kukreja S.  Dietary soybean protein prevents bone loss in an ovariectomized rat model of osteoporosis.  J Nutr 1996;126:161-167.

  Blair H, Jordan S, Peterson T, Barnes S.  Variable effects of tyrosine kinase inhibitors on avian osteoclastic activity and reduction of bone loss in ovariectomized rats. J Cell Biochem  1996;61:629-637.

  Arjmandi B, Khalil D, Smith B, 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. J Clin Endocrinol Metab  2003; 88: 1048-1054.

  Erdman J, Stillman R, Lee K, Potter S.  Short-term effects of soybean isoflavones on bone in postmenopausal women.  Program and Abstract Book, Second International symposium on the Role of Soy in Preventing and Treating Chronic Disease.  Brussels, Belgium, 1996.

  Greendale G, FitzGerald G, Huang M, et al.  Dietary soy isoflavones and bone mineral density: Results from the study of women’s health across the nation. Amer J Epidemiology 2002;155(8):746-754.

  Somekawa Y, Chiguchi M, Ishibashi T, Takeshi A. Soy intake related to menopausal symptoms, serum lipids, and bone mineral density in postmenopausal Japanese women. Obstet Gynecol  2001;97:109-115.

  Ma DF, Qin LQ, Want P-Y, Katoh R.  Soy isoflavone intake inhibits bone resorption and stimulates bone formation in menopausal women:  meta-analysis of randomized controlled trials.  European J of Clinical Nutrition 2008; 62:155-161.

  Branca F.  Dietary phyto-oestrogens and bone health.  Proc Nutr Soc 2003; 62: 877-887.

  Wangen K, Duncan A, Merz-Demlow B, et al.  Effects of soy isoflavones on markers of bone turnover in premenopausal and postmenopausal women.  J Clin Endocrinol Metab 2000; 85:3043-3048.

  Knight D, Howes J, Eden J, Howes L.  Effects of menopausal symptoms and acceptability of isoflavone-containing soy powder dietary supplementation. Climacteric 2001; 4:13-18.

  Dalais F, Ebeling P, Kotsopoulos D, McGrath B, Teede H.  The effects of soy protein containing isoflavones on lipids and indices of bone resorption in postmenopausal women.  Clin Endocrinol 2003; 58:704-709.

  Potter S, Baum J, Teng H, et al.  Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women.  Am J Clin Nutr 1998; 68:1375S-1379S.
  Alekel D, Germain A, Peterson C, et al.  Isoflavone-rich soy protein attenuates bone loss in the lumbar spine of perimenopausal women.  Am J Clin Nutr 2000; 72:844-852.

  Morabito N, Crisafulli A, Vergara C, et al.  Effects of genistein and hormone-replacement therapy on bone loss in early postmenopausal women:  a randomized double-blind placebo controlled study. J Bone Miner Res 2002; 17:1904-1912.

  Chen Y, Ho S, Lam S, Ho S, Woo J.  Soy isoflavones have a favorable effect on bone loss in Chinese postmenopausal women with lower bone mass: a double-blind, randomized, controlled trial. J Clin Endocrinol Metab 2003;88:4740-4747.

  Lydeking-Olsen E, Beck-Jensen J, Setchell K, Holm-Jensen T.  Soymilk or progesterone for prevention of bone loss: a 2 year randomized, placebo-controlled trial. Eur J Nutr 2004;43:246-257.

  Gallagher J, Satpathy R, Rafferty K, Haynatzka V.  The effect of soy protein on bone metabolism.  Menopause 2004; 11:290-298.

  Kreijkamp-Kaspers S, Kok L, et al.  Effects of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women.  JAMA 2004; 292:65-74.

  Mei J, Yeung S, Kung A.  High dietary phytoestrogen intake is associated with higher bone mineral density in postmenopausal but not premenopausal women. J Clin Endocrinol Metab 2001; 86:5217-5221.

Compared with the placebo group, symptoms of hot flashes and excessive sweating significantly reduced after 3 months and weakness, palpitations, limb paresthesias and total symptoms significantly decreased after 6 months, (P< 0.05) but only in the equol producers. At 3 months, total scores had decreased by 66% in the EP group, 54% in the non-EP group and 59% in the placebo group. At 6 months, symptom scores had decreased by 84% in the EP group, 58%in the non-EP group and 66 % for the placebo group.

Jou H-J, Wu S-S, Change F-W, Ling P-Y, Chue K, Wu W-H. Effect of intestinal production of equol on menopausal symptoms in women treated with soy isoflavones. Intl J Gynecology and Obstetrics (2008), doi: 10.1016/j.ijgo. 2008.01.028

Commentary: The research on soy’s ability to relieve menopause symptoms has produced quite mixed results. Differences in study doses, different proportions of genistein and daidzein used in the study medication, and differences in the study population have been used to explain the discrepancies. Study populations who may have a higher percentage of women who are equol producers have been previously suspected to be the determining factor in the effectiveness of soy isoflvaones, but the current study seems to be the first to demonstrate more clearly that a woman’s ability to produce equol determines her response to soy isoflavone supplementation. Daidzein and genestien are the two most significant phytoestrogens in soy. Daidzein is converted to equol, a metabolite of daidzein, by bacterial flora in the gut. It may be appropriate to test for equol production prior to treatment of perimenopausal and menopausal women to achieve the most success, and/or improve gut flora so that the individuals can more easily transform soy isoflavones to equol. This can be done with improving one’s diet to whole foods nutrition, reducing sugar to a minimum, consuming mostly unsaturated fats, and possibly taking probiotics as a nutritional supplement or in quality yogurts.

389 postmenopausal women aged 49 to 67 with a femoral neck bone mineral density (BMD) of less than 0.795 g/cm2 received either genistein or placebo. All women received calcium and vitamin D. After 2 years, BMD at the femoral neck increased in the group that received the genistein and declined in the women who received placebo. A mean change of 0.035 gm/cm2 for genistein vs – 0.037 gm/cm2 for placebo. A smaller positive change was seen at the lumbar spine for genistein and a smaller loss in the placebo group.

Bone turnover decreased significantly in the women who received genistein, and bone-specific alkaline phosphatase and IGF-1 also significantly increased. None of these markers changed in the placebo group. Genistein did not significantly change the endometrial thickness but did reduce the mean number of hot flashes. Side effects included gastrointestinal symptoms and the withdrawal rate from the study due to these side effects was 19% in the genistein group vs 8% in the placebo group.

Marini H, Minutoli L, Polito F, et al. Effects of phytoestrogen genistein on bone metabolism in osteoenic postmenopausal women: a randomized trial. Ann Intern Med 2007;146:839-847.

Comments: Previous studies have reported that women with high soy diets had a lower risk for osteoporosis. The current report provides additional compelling evidence that 54 mg of genistein per day, along with 500 mg of calcium and vitamin D 400 IU for 2 years can increase the BMD of the lumbar spine and femoral neck. Further evidence is provided by the decreased urinary markers for bone resorption and the increase in circulating levels of the bone formation markers.

More than twice as many women had side effects in the genistein group and discontinued treatment because of these symptoms. That said, these side effects are considerably less than those reported for many women who utilize bisphosphanates for bone loss. Although I would not consider genistein an adequate treatment for women with osteoporosis, I would consider genistein an important treatment in women with osteopenia, especially up to the age of 65, prior to higher age related risks for fracture.

Three hundred and eighty nine postmenopausal women aged 49 to 67 with a femoral neck bone mineral density (BMD) of less than 0.795 g/cm2 received either genistein or placebo. All women received calcium and vitamin D. After 2 years, BMD at the femoral neck increased in the group that received the genistein by 0.035 gm/cm2 and declined in the women who received placebo by – 0.037 gm/cm2. A smaller positive change was seen at the lumbar spine for genistein and a smaller loss in the placebo group.

Bone turnover decreased significantly in the women who received genistein, and bone-specific alkaline phosphatase and IGF-1 increased significantly. None of these markers changed in the placebo group. Genistein did not significantly change the endometrial thickness but did reduce the mean number of hot flashes.Side effects included gastrointestinal symptoms. The withdrawal rate from the study due to these side effects was 19% in the genistein group vs 8% in the placebo group.

Marini H, Minutoli L, Polito F, et al. Effects of phytoestrogen genistein on bone metabolism in osteopenic postmenopausal women: a randomized trial. Ann Intern Med 2007;146:839-847.

Comments: Previous studies have reported that women with high soy diets had a lower risk for osteoporosis. This current report provides additional compelling evidence demonstrating that 54 mg of genistein per day, along with 500 mg of calcium and 400 IU of vitamin D for 2 years can increase the BMD of the lumbar spine and femoral neck. Further evidence is provided by, the decreased urinary markers for bone resorption and the increased circulating levels of bone formation markers.

More than twice as many women had side effects in the genistein group and discontinued treatment because of these symptoms. That said, these side effects are considerably less than those reported for many women who utilize bisphosphanates for bone loss. Although I would not consider genistein an adequate treatment for women with osteoporosis. I would consider genistein an important treatment for osteopeninic women under 65, before they arrive at the age where they are at increased risk of age related fractures.