Soy isoflavone supplementation and bone mineral density in menopausal women: a 2-y multicenter clinical trial.

Multicenter, placebo-controlled 2-year clinical trial in healthy postmenopausal women in the United States. The active intervention arms randomized 135 women to 80 mg/day and 136 women to 120 mg/day of soy hypocotyl aglycone isoflavones; participants were nonosteoporotic, had BMI < 30, were not taking osteoporosis medications, and were asked to maintain their usual diet and exercise habits.

Healthy postmenopausal women were randomized in a 3-arm multicenter trial to oral soy hypocotyl aglycone isoflavone tablets at 80 mg/day or 120 mg/day, taken as 3 tablets daily for 24 months, versus placebo. All active-arm participants also received calcium carbonate 1000 mg/day (providing 400 mg calcium) and a one-a-day multivitamin with 400 IU vitamin D.

The 120 mg/day regimen produced a modest whole-body bone benefit, but the clinical impact was limited. Adjusted whole-body BMD was significantly higher for 120 mg/day vs placebo after 1 and 2 years (sequential Sidak-adjusted P = 0.04), whereas 80 mg/day was not significant (P = 0.13). Neither dose slowed bone loss at the lumbar spine or total hip, and bone turnover markers (osteocalcin, BAP, NTx) were not favorably altered. Serious adverse events were reported in both active arms, including one breast cancer in the 120 mg/day group and one stage 1B, grade III squamous carcinoma of the endometrium in the 80 mg/day group.

The benefit was small and confined to whole-body BMD, not the common fracture sites most relevant to clinical decision-making. The trial was only 2 years long, had relatively small per-arm sample sizes, and enrolled healthy postmenopausal women with BMI < 30, which limits generalizability. Long-term fracture-prevention benefit remains uncertain, and serious cancers occurred in both active-dose groups.