Clinical Briefs
With Comments from John La Puma, MD, FACP
Ipriflavone for Osteoporosis
July 2001; Volume 4; 84
Source: Alexandersen P, et al. Ipriflavone in the treatment of postmenopausal osteoporosis: A randomized controlled trial. JAMA 2001;285:1482-1488.
Data on the efficacy and safety of ipriflavone for prevention of postmenopausal bone loss are conflicting. 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, we conducted a prospective, randomized, double-blind, placebo-controlled, four-year study in four centers in Belgium, Denmark, and Italy from August 1994 to July 1998.
We enrolled 474 postmenopausal white women, ages 45 to 75 years, with bone mineral densities (BMDs) of less than 0.86 g/cm2. Patients were randomly assigned to receive 200 mg ipriflavone tid (n = 234) or placebo (n = 240); all received 500 mg/d of calcium. 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 six months. Laboratory safety measures and adverse events were recorded every three months.
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 = 0.14), or in any of the other sites measured, did not differ significantly between groups. The response in biochemical markers also was similar between groups (e.g., 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 = 0.96); 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 = 0.81. The number of women with new vertebral fractures was identical or nearly so in the two groups at all time points. Lymphocyte concentrations decreased significantly (500/microliters [0.5 x 109/L]) in women treated with ipriflavone. Thirty-one women (13.2%) in the ipriflavone group developed subclinical lymphocytopenia; 29 developed it during ipriflavone treatment. Of these, 15 (52%) of 29 had recovered spontaneously by one year and 22 (81%) of 29 by two years.
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.
Comment
Ipriflavone, a derivative of the naturally occurring class of isoflavones, found mainly in soy, is marketed and approved in Europe to prevent bone loss. The Ipriflavone Multicentre European Fracture Study (IMEFS) is a large study of nonobese postmenopausal women with low bone density. The design is a three-year, randomized, double-blind, placebo-controlled, parallel group study. Its primary purpose is to evaluate the efficacy of ipriflavone in preventing vertebral non-traumatic fractures.
Although only 292 of 492 individuals completed the study, the results were unfavorable. Postmenopausal women with established osteoporosis but without vertebral fractures did not have better bone density, though this claim is not usually made for ipriflavone. Balk notes, "The majority of the (previous ipriflavone) studies found that bone mass was not increased in the ipriflavone group, but that it was decreased in the control group, with significant between-group differences." (See Alternative Medicine Alert, December 2000, pp. 133-137.) The IMEFS did not have sufficient power to detect an effect of ipriflavone on fracture incidence. Studies of bisphosphonates or raloxifene typically attempt to enroll hundreds or even thousands of patients to detect such an incidence.
Previously noted lymphocytopenia was indicated here as well. The women remained immunologically healthy, and it is unknown whether the lymphocyte subpopulations CD4 and CD8 were affected equally. Still, one of eight study women was determined to be lymphocytopenic—certainly a finding that needs verification.
Does this mean ipriflavone doesn’t work in this population? Not yet, though this is the best evidence we have. The dosage may have been suboptimal, the power inadequate to detect statistically significant differences, or the study population too osteoporotic. Ipriflavone appears not to increase bone density in nonobese, postmenopausal osteoporotic women, but whether it improves fracture incidence is still uncertain.
Recommendation
These data do not support the use of ipriflavone to prevent bone density loss, but they are not the final word. Women with hematological and immune disorders and hormone-dependent cancers, and women who are breast feeding or pregnant should avoid ipriflavone, as its metabolites may have estrogenic effects.
July 2001; Volume 4; 84
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