Effects of the Phytoestrogen Genistein on Bone Metabolism in Osteopenic Postmenopausal Women A Randomized Trial Herbert Marini, MD; Letteria Minutoli, MD; Francesca Polito, PhD; Alessandra Bitto, MD; Domenica Altavilla, PhD; Marco Atteritano, MD; Agostino Gaudio, MD; Susanna Mazzaferro, MD; Alessia Frisina, MD; Nicola Frisina, MD; Carla Lubrano, MD; Michele Bonaiuto, MD; Rosario D’Anna, MD; Maria Letizia Cannata, MD; Francesco Corrado, MD; Elena Bianca Adamo, MD; Steven Wilson, PhD; and Francesco Squadrito, MD Background: Observational studies and small trials of short dura- tion suggest that the isoflavone phytoestrogen genistein reduces bone loss, but the evidence is not definitive. Objective: To assess the effects of genistein on bone metabolism in osteopenic postmenopausal women. Design: Randomized, double-blind, placebo-controlled trial. Setting: 3 university medical centers in Italy. Patients: 389 postmenopausal women with a bone mineral density (BMD) less than 0.795 g/cm 2 at the femoral neck and no signifi- cant comorbid conditions. Intervention: After a 4-week stabilization period during which par- ticipants received a low-soy, reduced-fat diet, participants were randomly assigned to receive placebo (n = 191) or 54 mg of genistein (n = 198) daily for 24 months. Both the genistein and placebo tablets contained calcium and vitamin D. Measurements: The primary outcome was BMD at the antero- posterior lumbar spine and femoral neck at 24 months. Secondary outcomes were serum levels of bone-specific alkaline phosphatase and insulin-like growth factor I, urinary excretion of pyridinoline and deoxypyridinoline, and endometrial thickness. Data on adverse events were also collected. Results: At 24 months, BMD had increased in genistein recipients and decreased in placebo recipients at the anteroposterior lumbar spine (change, 0.049 g/cm 2 [95% CI, 0.035 to 0.059] vs. -0.053 g/cm 2 [CI, -0.058 to -0.035]; difference, 0.10 g/cm 2 [CI, 0.08 to 0.12]; P  0.001) and the femoral neck (change, 0.035 g/cm 2 [CI, 0.025 to 0.042] vs. -0.037 g/cm 2 [CI, -0.044 to -0.027]; dif- ference, 0.062 g/cm 2 [CI, 0.049 to 0.073]; P  0.001). Genistein statistically significantly decreased urinary excretion of pyridinoline and deoxypyridinoline, increased levels of bone-specific alkaline phosphatase and insulin-like growth factor I, and did not change endometrial thickness compared with placebo. More genistein re- cipients than placebo recipients experienced gastrointestinal side effects (19% vs. 8%; P = 0.002) and discontinued the study. Limitations: The study did not measure fractures and had limited power to evaluate adverse effects. Conclusion: Twenty-four months of treatment with genistein has positive effects on BMD in osteopenic postmenopausal women. Ann Intern Med. 2007;146:839-847. www.annals.org For author affiliations, see end of text. ClinicalTrials.gov registration number: NCT00355953. P ostmenopausal osteoporosis is caused by a sharp de- crease in estrogen levels that leads to an increased rate of bone remodeling (1–3). Currently available treatments for postmenopausal osteoporosis include hormone replace- ment therapy; calcitonin; bisphosphonates; and selective estrogen receptor modulators, such as raloxifene (4, 5). Although hormone replacement therapy is effective in reducing postmenopausal bone loss (6 – 8), it is associated with a higher risk for breast, endometrial, and ovarian can- cer; cardiovascular disease; venous thromboembolism; and stroke (8 –10). Epidemiologic data indicate that women who ingest high amounts of phytoestrogens, particularly isoflavones in soy products, have less risk for osteoporosis than do those who consume a typical Western diet (11– 13). Consequently, many women use phytoestrogens to maintain bone density. Genistein, an isoflavone phytoestrogen that is abun- dant in soybean products, structurally resembles 17-estra- diol (14). As a natural selective estrogen receptor modula- tor, genistein may positively regulate bone cell metabolism without harmful estrogenic activity in the breast and uterus. This safe profile results from the greater affinity of genistein for estrogen receptor-, which is more abundant in bone, than for estrogen receptor-, which is abundant in reproductive tissue. Observational studies suggest that postmenopausal Asian women who consume diets high in isoflavones have a lower rate of fracture than that in other groups (15, 16). However, the mechanism of action of genistein on bone is not yet fully understood. In postmenopausal women, treatment with genistein (54 mg/d) increased bone mineral density (BMD) at the lumbar spine and femoral neck with no clinically signifi- cant adverse effects on the breast and uterus (17). In the same cohort, genistein decreased the ratio of soluble recep- See also: Print Editors’ Notes ............................. 840 Summary for Patients ....................... I-34 Web-Only Conversion of figures and tables into slides Annals of Internal Medicine Article © 2007 American College of Physicians 839