Ipriflavone: Efficacy Trials
Ipriflavone: Efficacy Trials
September 2000; Volume 2; 67-70
By Adriane Fugh-Berman, MD
Ipriflavone (ip), a relatively benign synthetic drug marketed as a dietary supplement, is being heavily promoted as an effective therapy for preventing and treating osteoporosis. Although several trials indicate that IP increases vertebral and radial bone density, no trials have examined bone density at the hip, and no trials of adequate size have examined non-vertebral fractures as an endpoint. This article is a review of controlled trials of IP in naturally or surgically menopausal women.
Bone Mineral Density in Menopausal Women
A two-year, double-blind multicenter Italian randomized controlled trial, reported in 1997, enrolled 255 postmenopausal women ages 50-65 with bone mineral density (BMD) of the distal radius of at least one standard deviation (SD) below the mean for normal age-matched women (z-score) measured by dual photon absorptiometry (DPA).1 Women were randomized to 200 mg IP tid with meals or placebo. Both groups also received 1,000 mg/d elemental calcium. Distal radius BMD and markers of bone metabolism were measured at baseline and every six months.
One hundred ninety-six women completed the trial; of these, 155 (80 in the treatment group) were deemed "valid completers." Analyses were done according to valid completers (VC) and intention-to-treat (ITT) analyses, generally considered a more reliable analysis. VCs were defined as those "who completed the two-year treatment, had all scheduled measures done, and did not violate the protocol in a manner liable to influence the efficacy outcome." In both analyses, after two years, the treated group maintained radial BMD while the control group’s BMD declined; the difference between the two groups was significant at both one and two years.
Urinary hydroxyproline/creatinine (HOP/cr), markers of bone loss, were decreased in the IP group and increased in the placebo group, with a significant difference between groups at the end of the first and second year.
There was a high dropout rate in this trial. Thirty-one women (16 in the treatment group) dropped out because of adverse events, 24 for "personal reasons or a change in osteoporosis treatment by their general practitioner," and four because of illness. Reported side effects were primarily gastrointestinal and did not differ between groups.
A paper by Gennari et al, also published in 1997, reported the results of two multicenter studies;2 however, one of these is clearly a republication of the study above. The other study enrolled 198 women; entry criteria, treatment, duration, and analysis appeared identical to the study just described. However, BMD measurements were taken at the vertebra and dual-energy X-ray absorptiometry (DEXA) was used. These factors make this a better study; DEXA is a better modality for measuring BMD, which is site-specific; radial BMD is not useful for predicting fracture risk at other sites. Actually, even site-specific BMD is not a particularly good predictor for individual risk of fracture, but that’s a topic for another article.
In the ITT analysis, the placebo group lost 1.1% vertebral BMD at year 2 while there were no changes from baseline in the IP-treated group. It is not stated whether the between-group difference was significant. In the VC analysis, the IP group showed a 1.4% gain in vertebral bone density at the end of the first year; at two years this gain had dwindled to 0.4%.
At the two-year point, the placebo-treated group lost 1.2% in vertebral bone density. In this analysis, the between-group difference was significant (P < 0.05) for both groups. Side effects were minimal (mostly gastrointestinal) and similar between the two groups.
Another two-year study enrolled 56 postmenopausal Caucasian women with vertebral bone density (measured by DEXA) one SD below the age-matched mean and at least two other risk factors (low calcium intake, smoking, alcohol or caffeine "abuse," sedentary life style, or "familiarity with osteoporosis," which presumably means family history). Subjects were randomized to IP (200 mg tid) or placebo; both groups also received 1,000 mg calcium.3
Forty of 56 women completed the trial. In the ITT analysis, the placebo group experienced significant decrease in bone (-3.8%) and the IP group had no change (-1.2%); the between-group differences were significant only at year 2. In the VC analysis (including 38 women), vertebral bone density decreased significantly in the placebo group at two years (4.9% ± 1.1%) but did not change significantly in the IP group (-0.4%). A significant between-group difference was noted at the end of both the first and second years. Five patients (one patient in the IP group and four in the calcium group) experienced side effects, primarily gastrointestinal, that caused them to discontinue the study. No significant changes in serum alkaline phosphatase, serum osteocalcin, and urinary Ca/Cr were seen in any groups; urinary hydroxyproline decreased substantially in the IP group.
Fifty-seven postmenopausal women with osteopenia or osteoporosis were randomized to either 600 mg IP or 0.8 g/d calcium lactate for one year.4 In the IP group, lumbar BMD measured by DEXA decreased from 0.78 ± 0.12 g/cm2 before treatment to 0.77 after treatment; in the calcium group BMD decreased from 0.81 ± 0.07 to 0.79 ± 0.09. The authors state that the rate of reduction of BMD was significantly greater in the calcium group and that BMD was significantly decreased in the calcium group compared to baseline. Whether the difference between groups was significant is not stated, but it is hard to imagine that this difference was significant.
A double-blind study of 40 postmenopausal women treated with 600 mg/d IP or placebo (all received 1,000 mg/d calcium) found that after a year, BMD (measured by DEXA) in the spine and forearm, compared to baseline, was significantly reduced in the placebo group while BMD was stable in the IP treated group.5 No changes in bone markers were seen in either group.
Effect on Fractures
Two small, problematic studies published in small journals have looked at vertebral fracture endpoints. Both studies were double-blind, placebo-controlled studies of women over age 65 with vertebral fractures. Treated groups received 200 mg tid IP; all women also received 1,000 mg/d calcium.
The first study was published in the Italian Journal of Mineral and Electrolyte Research.6 Only 27 of 49 women completed the trial, a very high dropout rate. The treated group experienced an increase in radial BMD (measured by DPA), while BMD was unchanged in the placebo group; the between-group difference was significant at year 1 and 2.
HOP/cr ratio was significantly decreased in the treated group and unchanged on the placebo group. The secondary source states that four out of 20 in the treatment group had new vertebral fractures, compared to eight out of 20 in the placebo group; it is not stated in the secondary source whether this is significant, nor at what time point this was taken.7
In the second two-year randomized, double-blind study of 100 women (84 completed) over age 65 with osteoporosis and at least one previous vertebral fracture, researchers compared 200 mg IP tid to placebo (all received 1,000 mg/d calcium).8 A significant increase in radial BMD was seen in the treated group while a significant decrease was seen in the placebo group. Between-group differences were significant at 6, 12, and 24 months. Urinary HOP/cr decreased significantly in the treated and increased in the placebo group. Two new vertebral fractures occurred in the treated group and 11 new vertebral fractures occurred in the placebo group; it is not stated how many patients this represents nor whether this was statistically significant. Analgesic use decreased significantly in the IP group while it increased in the placebo group.
IP and 1a Vitamin D
Ninety-eight postmenopausal oophorectomized women ages 45-65 were randomized to 600 mg/d IP (n = 28), 1ag/d vitamin D (n = 15), both (n = 20), or neither (n = 35).9 No explanation is given for the lopsided allotment. Women were assessed at baseline and every six months for 18 months. Seventy-nine women completed the study. Vertebral BMD was measured by DEXA. All groups lost bone, but the IP/vitamin D combination significantly reduced bone loss at all time points compared to all other groups. At 18 months the combination group had lost 0.33%, the IP group lost 2.37%, the vitamin D group lost 1.15%, and the controls lost 3.70%.
IP and Estrogen
There is some evidence that IP may be helpful as an adjunct to estrogen in maintaining bone density, but studies are inconsistent.
A study in 116 recently oophorectomized Japanese women found that IP alone is inadequate to maintain bone density in this group, although it may be helpful in combination with estrogen. Women were randomized to placebo, 0.625 mg/d conjugated equine estrogens (CEE), 600 mg/d IP, or CEE and IP for 48 weeks.10 At the end of the study, vertebral BMD (measured by DEXA) was reduced significantly by 6.1% in the placebo group, 3.9% in the CEE group, and 5.1% in the IP group; but there was no significant change in the combined-therapy group (vertebral BMD decreased 1.2%).
At 48 weeks urinary pyridinoline decreased 49.5% in the estrogen group, 32% in the IP group, and 41.5% in the combined group; there was no change in the placebo group. Intact human osteocalcin (a marker of bone formation) decreased significantly in both groups that received estrogen; hOC was increased in the group receiving IP alone but not in the group receiving IP with estrogen. The researchers suggest that IP stimulates osteoblasts (while CEE is known to inhibit bone turnover).10
Agnusdei et al conducted a study on the combination of IP and low-dose estrogen replacement therapy (ERT).11 Eighty-three postmenopausal women underwent a double-blind, one-year multicenter study in which they were randomized to a double placebo (n = 24); placebo plus 0.3 mg/d CEE (n = 31), 0.3 mg/d CEE plus 200 mg tid IP (n = 28). Among "valid completers," the placebo group showed a decrease in forearm bone density (measured by DPA) at one year; the CEE group had an average bone loss of 1.4%, and the CEE plus IP group experienced increased BMD (+ 5.6%; P < 0.01); the difference was significant (P < 0.05). None of the treatments changed biochemical markers of bone turnover.
Another one-year study randomized 105 Caucasian early postmenopausal women to control (500 mg calcium), low-dose hormone-replacement therapy (HRT) (25 µg/d transdermal 17 b-estradiol plus 5 mg/d medrogestone for 12 days/month), high-dose HRT (50 µg/d transdermal 17 b-estradiol plus 5 mg/d medrogestone for 12 days/month), 600 mg/d IP, or IP combined with low-dose HRT.12 All were given a 1,490 cal/d diet which included 73 g protein, 50 g lipids, 187 g carbohydrates, and 1,550 mg calcium. Ninety-six subjects completed the study, and 81.8% observed the dietary regimen.
Compared to baseline, the only significant change in vertebral BMD (measured by DPA) was in the control group, in which vertebral BMD decreased 3.41%. Mean BMD increased 1.84% in the 50 mg HRT group, increased 0.11% in the IP group, and decreased 0.22% in the combined IP/HRT group. BMD was not significantly different in the 25 mg HRT group (decreased 0.55%). Compared to baseline, 24-hour plasma urinary HOP/cr excretion and bone Gla protein were significantly reduced in the high-dose HRT, IP, and IP/low-dose HRT groups.
Another study randomized 80 postmenopausal women ages 40-49 to 500 mg/d calcium, 200 mg tid IP, 0.3 mg/d CEE, or 400 mg IP plus 0.3 mg/d CEE (all treatment groups also received 500 mg/d calcium). Fifty-two women completed the trial (a high dropout rate). Compared to baseline, vertebral bone density (measured by DEXA) decreased significantly in the control and low-dose CEE groups and increased significantly in both IP groups at one and two years.13 The difference between both IP groups and the other two groups was significant. IP had no effect on vaginal maturation index, which predictably improved in both groups receiving CEE.
IP vs. Calcitonin
Forty postmenopausal women with BMD > 2 SD below the mean for age-matched controls were studied in a controlled but not blinded study comparing salmon calcitonin to IP over a year.14 Both treatments significantly increased BMD; 4.3% in the IP group and 1.9% in the calcitonin group (the between-group difference was significant). Four patients in the IP group experienced gastric pain; in the calcitonin group one patient reported pruritis and another epistaxis.
Summary
Seven placebo-controlled trials have looked at the effect of IP on bone density in menopausal women. Five of these (three using DEXA) showed that IP maintained BMD in vertebrae or radius. Two trials published in small journals showed an increase in radial BMD (by DPA); these are also the only trials that showed decreased vertebral fractures.
Two studies in oophorectomized women show that IP alone is not effective treatment; the combination of IP with estrogen or vitamin D reduces but does not eliminate bone loss. Two of three studies found a benefit of the addition of IP to low-dose estrogen. A small unblinded study found a benefit of IP over calcitonin.
Many of these trials have methodological problems. The most glaring problem with this literature is the lack of trials with fracture endpoints. More and better studies of IP are needed. At least one such trial is in progress.
The Ipriflavone Multicenter European Fracture Study (IMEFS) will include 460 Caucasian postmenopausal women, ages 45-75, treated with IP for at least 12 months. The primary endpoint is incidence of vertebral, non-traumatic fractures. BMD of the spine, hip, and distal radius, as well as serum and urinary markers of bone metabolism, will also be evaluated.15 Results of this trial are expected next year; clinicians should wait for the results of this or other adequately designed trials before recommending IP to patients.
References
1. Adami S, et al. Ipriflavone prevents radial bone loss in postmenopausal women with low bone mass over 2 years. Osteoporos Int 1997;7:119-125.
2. Gennari C, et al. Effect of chronic treatment with ipriflavone in postmenopausal women with low bone mass. Calcif Tissue Int 1997;61:19-22.
3. Gennari C, et al. Effect of ipriflavone—a synthetic derivative of natural isoflavones—on bone mass loss in the early years after menopause. Menopause 1998;5:9-15.
4. Ohta H, et al. Effects of 1-year ipriflavone treatment on lumbar bone mineral density and bone metabolic markers in postmenopausal women with low bone mass. Horm Res 1999;51:178-183.
5. Valente M, et al. Effects of 1-year treatment with ipriflavone on bone in postmenopausal women with low bone mass. Calcif Tissue Int 1994;54:377-380.
6. Passeri M, et al. Effects of 2-year ipriflavone in elderly women with established osteoporosis. Ital J Mineral Electrolyte Metab 1995;9:136-144.
7. Agnusdei D, Bufalino L. Efficacy of ipriflavone in established osteoporosis and long-term safety. Calcif Tissue Int 1997;61(Suppl 1):S23-S27.
8. Maugeri D, et al. Ipriflavone treatment of senile osteoporosis: Results of a multicenter, double-blind clinical trial of 2 years. Arch Gerentol Geriatr 1994;19:253-263.
9. Ushiroyama T, et al. Efficacy of ipriflavone and 1avitamin D therapy for the cessation of vertebral bone loss. Int J Gynaecol Obstet 1995;48:283-288.
10. Nozaki M, et al. Treatment of bone loss in oophorectomized women with a combination of ipriflavone and conjugated equine estrogen. Int J Gynaecol Obstet 1998;62:69-75.
11. Agnusdei D, et al. Prevention of early postmenopausal bone loss using low doses of conjugated estrogens and the non-hormonal, bone-active drug ipriflavone. Osteoporos Int 1995;5:462-466.
12. de Aloysio D, et al. Bone density changes in postmenopausal women with the administration of ipriflavone alone or in association with low-dose ERT. Gynecol Endocrinol 1997;11:289-293.
13. Gambacciani M, et al. Effects of combined low dose of the isoflavone derivative ipriflavone and estrogen replacement on bone mineral density and metabolism in postmenopausal women. Maturitas 1997;281:75-81.
14. Cecchettin M, et al. Metabolic and bone effects after administration of ipriflavone and salmon calcitonin in postmenopausal osteoporosis. Biomed Pharmacother 1995;49:465-468.
15. Reginster JY, et al. Design for an Ipriflavone Multicenter European Fracture Study. Calcif Tissue Int 1997;61(Suppl 1):S28-S32.
September 2000; Volume 2; 67-70
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