Soy, Old Bones... Genistein and Osteopenia

Abstract & Commentary

By Russell H. Greenfield, MD. Dr. Greenfield is Clinical Assistant Professor, School of Medicine, University of North Carolina, Chapel Hill, and Visiting Assistant Professor, University of Arizona, College of Medicine in Tucson. Dr. Greenfield reports no financial relationship relevant to this field of study.

Source: Marini H, et al. Effects of the phytoestrogen genistein on bone metabolism in osteopenic postmenopausal women. Ann Intern Med. 2007;146:839-847.

Marini and colleagues of this randomized, double-blind, placebo-controlled trial performed at three university centers were interested in determining whether or not the isoflavone genistein had a clinically significant effect on bone metabolism in osteopenic postmenopausal women. Subjects (n=389) were women between the ages of 49-67 who had been postmenopausal for at least 12 months, with a bone mineral density (BMD) < 0.795 g/cm2 (corresponds to a T score of – 1.0 SD) at the femoral neck and no significant comorbid conditions. Following a complete physical examination and laboratory evaluation, BMD was measured at the lumbar spine and femoral neck using dual-energy x-ray absorptiometry. During a 4-week stabilization period, subjects received a low-soy, reduced fat diet. They were then randomized to receive either 54 mg genistein (n=198) or placebo (n=191) daily for 24 months. Primary outcome was BMD at the anteroposterior (AP) lumbar spine and femoral neck at 24 months. Multiple secondary outcomes included serum levels of bone-specific alkaline phosphatase and insulin-like growth factor I, urinary excretion of pyridinoline and deoxypyridinoline, lipid profile, triglyceride levels, calcium levels, genistein levels, and endometrial thickness (the latter assessed at baseline, 1 and 2 years). Clinic visits occurred every 3 months, during which subjects were queried about symptoms, while blood tests were performed every 6 months.

At 24 months follow-up, BMD, at the AP lumbar spine, had increased in genistein recipients (+0.049 g/cm2) and decreased in placebo recipients (-0.053 g/cm2). The same was true for BMD at the femoral neck (+0.035 g/cm2 vs –0.037 g/cm2). Use of genistein significantly decreased urinary excretion of bone resorption markers (pyridinoline and deoxypyridinoline) and increased levels of bone formation markers (bone-specific alkaline phosphatase and insulin-like growth factor I). Genistein had no discernible effect on endometrial thickness compared with placebo, and body mass index did not change significantly between the 2 groups at trial's end. More subjects in the genistein group developed gastrointestinal complaints, however, and discontinued the study compared with the placebo group (19% vs. 8%). Marini and colleagues concluded that 24 months of pure genistein produces a net gain in bone mass after 1 and 2 years of therapy.

Commentary

Genistein is an isoflavone found is significant concentrations in soybeans, with a chemical structure similar to 17-beta estradiol. It appears to act as a plant-based estrogen, binding to both alpha and beta estrogen receptor sites, but with greater affinity for beta receptors. This is clinically important because beta estrogen receptor sites are more prevalent in bone, whereas alpha receptors are more common in reproductive organs. Genistein has been promoted as a natural selective estrogen receptor modulator (SERM), and many women have turned to soy isoflavones in the hope of supporting bone health later in life. Results of this trial support the use of purified genistein in this way in a manner methodologically sound. Indeed, while more research is warranted, especially as relates to fracture rates and bone loss due to other reasons (steroid use, for example), these results are exciting.

Confidence in Marini et al's conclusions is enhanced because of the sample size, as well as the inclusion of biomarker studies. The dropout rate was significant, however, with at least 10% of participants dropping out of each group every year. Marini et al are quick to point out that while genistein had a beneficial effect on biomarkers for bone metabolism, these results may not correlate well with fracture risk. It is also noteworthy that the tablets for each group contained both calcium carbonate (500 mg) and vitamin D (400 IU).

Another interesting outcome detected by the researchers is that women in the genistein group experienced a significant decrease in daily hot flashes, unlike the comparison group.

Multiple effective pharmaceutical options exist for the treatment of postmenopausal bone loss. It remains to be seen whether purified genistein could be safely combined with some of these existing therapies to enhance clinical response, or if genistein alone is a reasonable option for those women who do not tolerate medication well. It is important to remember that epidemiological data suggest that women with high dietary isoflavone intakes, notably from soy products, seem to have a lower risk for bone loss. The dose of 54 mg genistein per day employed in the study is comparable to the isoflavone content found in many vegetarian diets, and dietary intake of nutrients trumps supplementation unless the dosage needed cannot be met through diet alone. Based on these results, it seems reasonable to recommend moderate soy food intake or purified genistein as employed in this study for postmenopausal osteopenic women; however, even with no effect on endometrial thickness, most experts advise caution regarding phytoestrogens for women at high risk for hormonally-driven tumors.