CONTEXT: Data on the efficacy and safety of ipriflavone for prevention of postmenopausal bone loss are conflicting.

OBJECTIVES: To investigate the effect of oral ipriflavone on prevention of postmenopausal bone loss and to assess the safety profile of long-term treatment with ipriflavone in postmenopausal osteoporotic women.

DESIGN AND SETTING: Prospective, randomized, double-blind, placebo-controlled, 4-year study conducted in 4 centers in Belgium, Denmark, and Italy from August 1994 to July 1998.

PARTICIPANTS: Four hundred seventy-four postmenopausal white women, aged 45 to 75 years, with bone mineral densities (BMDs) of less than 0.86 g/cm(2).

INTERVENTIONS: Patients were randomly assigned to receive ipriflavone, 200 mg 3 times per day (n = 234), or placebo (n = 240); all received 500 mg/d of calcium.

MAIN OUTCOME MEASURES: Efficacy measures included spine, hip, and forearm BMD and biochemical markers of bone resorption (urinary hydroxyproline corrected for creatinine and urinary CrossLaps [Osteometer Biotech, Herlev, Denmark] corrected for creatinine), assessed every 6 months. Laboratory safety measures and adverse events were recorded every 3 months.

RESULTS: Based on intent-to-treat analysis, after 36 months of treatment, the annual percentage change from baseline in BMD of the lumbar spine for ipriflavone vs placebo (0.1% [95% confidence interval (CI), -7.9% to 8.1%] vs 0.8% [95% CI, -9.1% to 10.7%]; P =.14), or in any of the other sites measured, did not differ significantly between groups. The response in biochemical markers was also similar between groups (eg, for hydroxyproline corrected for creatinine, 20.13 mg/g [95% CI, 18.85-21.41 mg/g] vs 20.67 mg/g [95% CI, 19.41-21.92 mg/g]; P =.96); urinary CrossLaps corrected for creatinine, 268 mg/mol (95% CI, 249-288 mg/mol) vs 268 mg/mol (95% CI, 254-282 mg/mol); P =.81. The number of women with new vertebral fracture was identical or nearly so in the 2 groups at all time points.

Lymphocyte concentrations decreased significantly (500/L (0.5 x 10(9)/L]) in women treated with ipriflavone. Thirty-one women (13.2%) in the ipriflavone group developed subclinical lymphocytopenia, of whom 29 developed it during ipriflavone treatment. Of these, 15 (52%) of 29 had recovered spontaneously by 1 year and 22 (81%) of 29 by 2 years.

CONCLUSIONS: Our data indicate that ipriflavone does not prevent bone loss or affect biochemical markers of bone metabolism. Additionally, ipriflavone induces lymphocytopenia in a significant number of women.