Soy isoflavones not associated with reductions in bone loss, menopausal symptoms

Levis S. Arch Intern Med. 2011;171:1363-1369.

Newton KM. Arch Intern Med. 2011;171:1369-1370.

Daily administration of soy isoflavone tablets does not appear to reduce bone loss or menopausal symptoms in women within the first 5 years of menopause, according to a new report in the Archives of Internal Medicine.

“Estrogen therapy with or without progesterone prevents most of these changes. However, as a result of the Women’s Health Initiative findings suggesting that the overall risks outweigh the benefits, most menopausal women now decline estrogen therapy, increasingly seeking other alternatives,” Silvinia Levis, MD, and colleagues wrote. “Soy-derived products have been proposed to provide comparable benefits to estrogens but without the risks.”

Effects of an alternative therapy

The researchers conducted the NIH-funded, randomized controlled, double blind Soy Phytoestrogens as Replacement Estrogens (SPARE) trial from July 2004 to March 2009 to determine the effectiveness of soy isoflavone tablets in preventing bone loss and other menopausal symptoms. The study included 248 women aged 45 to 60 years. Women were eligible if they were within 5 years of menopause and had a bone mineral density T score of –2 or higher in the lumbar spine or total hip. A placebo tablet was randomly assigned to 126 women and a 200 mg soy isoflavone tablet to 122 women daily. The soy isoflavone dose was equivalent to approximately two times the highest intake through food sources in a typical Asian diet, according to the researchers.

During 2 years of follow-up, the soy isoflavone and placebo groups did not differ regarding BMD at the spine (–2% vs. –2.3%), the total hip (–1.2% vs. –1.4%) or the femoral neck (–2.2% vs. –2.1%), respectively.

The number of menopausal symptoms was comparable between the two groups at baseline and at 2 years, with the exception of hot flashes. At the end of the study, 48.4% of women in the soy isoflavones group and 31.7% in the placebo group reported hot flashes. In addition, a higher number of women in the soy isoflavones group reported constipation compared with women in the placebo group (31.2% vs. 20.6%); however, this finding was not statistically significant.

“Because of concerns regarding the risk of estrogens, a need exists for alternative interventions that could provide the beneficial effects of estrogens in bone and menopausal symptoms without the adverse effects on breast and cardiovascular health,” the researchers concluded. However, “we found that our population of women in the first 5 years of menopause, on average, had low rates of bone loss and that 200 mg of soy isoflavone tablets taken once daily does not prevent bone loss or reduce bone turnover or menopausal symptoms.”

Several limitations noted

About 80% of women will experience hot flashes and night sweats during the menopause transition, Katherine M. Newton, PhD, of the Group Health Research Institute, Group Health Cooperative, Seattle, and Deborah Grady, MD, MPH, of the University of California, San Francisco, and San Francisco VA Medical Center, wrote in an accompanying editorial.

Newton and Grady noted several limitations of the study, including a smaller study population than predicted and higher-than-expected dropout rates. However, even with the smaller sample size, “given the virtually identical results in the two groups, it is difficult to imagine that the results would have differed substantially with additional participants or better retention,” they wrote. “Overall, it does not appear that soy supplementation will play an important role in osteoporosis prevention.”

Newton and Grady said future efforts should be “directed away from the hope of a one-size-fits-all therapy for menopausal symptoms toward using existing treatments to target the symptoms that disturb patients most.”

Disclosure: The researchers and Drs. Newton and Grady report no relevant financial disclosures.

Wulf Utian, MD, PhD, DSC

I was a little surprised by the fact that the journal, in accepting the paper, didn't make the authors clarify their methodology and the limitations of their methodology in regard to the vasomotor symptoms. And, I was truly surprised by the media response. [The media] see - generally speaking - the abstract, maybe look at some of the discussion, but they really don't normally get into the methodology because it's scientific. In this particular instance, this was a secondary outcome in a study that really didn't - it came nowhere near being a vasomotor study. The FDA, when any pharmaceutical company or anyone is trying to get a new drug application or a new indication for a drug, has a guidance that companies have to follow in terms of setting pivotal studies - randomized, controlled, blinded studies. The FDA guidance requires at least 7-8 moderate to severe vasomotor symptoms per day or at least 50 per week, and it requires that the efficacy is present at 4 weeks and is present through 12 weeks. They also require that there is some valid instrument that they're using to actually quantify the number and severity of hot flashes. Usually this is a paper diary kept on a daily basis; they've become more lenient and allowed them to do it between weeks 3 and 4 and 11 and 12, compared with baseline, and look to see what's changed with those daily recordings. In this particular instance, they used something called the Women's Health Questionnaire - they asked in the beginning and maybe a few times throughout the course of the study. It's a single question in a multiple question questionnaire - are you bothered by your hot flashes? And women are saying yes or no. So a woman who may have had hot flashes at point A or the woman responding to the question of point A may be quite different from the woman who responded at point B, and much different from the woman responding at point C. So, they had no real way of knowing - and they had so many drop-outs in the study - who was saying what and therefore whether the soy was effective in individual women. It was a single question, and it was purely subjective with no precise measure.

The bottom line is they don't have a study about hot flashes, and yet I was amazed that the media picked it up and it got so much play saying that soy is useless for hot flashes without looking more deeply into it. Your follow-up now is crucial. I'm not going to be a proponent and say that soy is fantastic for hot flashes but I am going to say, as chair of the committee - the panel that NAMS set up to do its 2011 isoflavone support, we had a group of experts, we looked at the entire literature on the isoflavones - including individual studies as well as meta analyses - the bottom line we came to is that there is some evidence, that they actually do work. Do they work as well as hormones? Not at all. Are they worth trying as a first round, particularly with women with mild and moderate hot flashes? The NAMS panel thought yes. So I think to simply write them off on the basis of this one paper is premature and probably irresponsible.

Do I think that soy [tablets] are a treatment for women with severe hot flashes? No, I don't think they work. First of all they have a placebo effect, everything has a placebo effect, and if a woman gets a placebo effect and her flashes go from severe and intolerable to moderate or mild and she can tolerate them, then that's fine, she's going to be perfectly happy. But that's purely on a placebo response, which could happen with anything. I wish I knew how placebos worked; I would patent them and sell them. I'm not recommending that we prescribe placebos. [Soy tablets] work somewhere between the placebo and HT; they work about as well as the SSRIs, SNRIs and gabapentin. In other words, on a scale of 1-to-10, placebos are usually in the 4-to-5 range. The papers that have shown efficacy with soy and with the SSRIs, SNRIs and gabapentin are in the range of about 6 and hormones are in the rage of about 9.5. Clearly the gold standard for treatment remains HT, and clearly that is a problem because some women can't take it because of contraindication and others won't because they fear for side effects, potentially breast cancer.

- Wulf Utian, MD, PhD, DSC
Executive director emeritus of NAMS,
Consultant in women's health for Cleveland Clinic,
Professor emeritus at Case Western Reserve

Disclosure: Independent women's health consultant for Cleveland Clinic, Pfizer, Bayer, Pharmavite, Teva and Bionovo.