Ipriflavone: Mechanism and Safety
Ipriflavone: Mechanism and Safety
September 2000; Volume 2; 65-67
By Nicole Nisly, MD
Osteoporosis is associated with significant morbidity, mortality, and financial burden. The ideal treatment for this condition should be well tolerated and effective as a prophylactic for young menopausal women as well as a treatment for women with established disease. It should have few contraindications or side effects and should not accumulate in the skeleton, where it could become detrimental to normal bone turnover. This article will discuss ipriflavone (IP), a synthetic isoflavone derivative, marketed for treatment of osteoporosis in more than 20 countries worldwide and available as a dietary supplement in the United States.1
Background
In the 1930s, an estrogenic effect was first noted in cattle consuming large quantities of clover; this effect was later traced to isoflavones. In 1969, a research project aimed at synthesizing isoflavone derivatives with androgenic, but not estrogenic, activity was created. About 200 new molecules were created and screened. In 1970, 7-isopropoxyisoflavone (IP) was selected because of its calcium-retaining effect in in vitro studies.2 In the early 1970s, experiments in the treatment of bone diseases related to bone mass loss in humans and other animals were conducted.
Mechanisms of Action
IP has several mechanisms of action that enhance bone density. Its anti-resorptive properties include a dose-dependent inhibition of bone resorption.3,4 IP also inhibits osteoclastic activity (motility and resorptive activity) by modulating intracellular free calcium.5,6 IP’s bone-forming mechanisms include stimulation of cell proliferation and maturation of osteoblasts by inhibiting calcium influx into osteoblasts and phosphoinositide hydrolysis.7,8 IP also inhibits the effect of advanced glycation end product on bone resorption.9 Despite similarities to estrogen, IP possesses no intrinsic estrogenic activity,10 but does potentiate estrogen.11 Importantly, IP does not change bone mineral composition or crystalline structure.12
IP has several metabolites: the most important is MI, which has low potency and which increases alkaline phosphatase levels (a marker of new bone formation). Other metabolites are: MII (daidzein), of medium potency and the only metabolite with estrogenic receptor affinity; MIII, the most potent inhibitor of parathyroid hormone-stimulated bone resorption; and MV, a low-potency metabolite, which has been shown to enhance collagen formation.13-15
Safety
Data from 60 studies performed in Italy, Japan, and Hungary with a total of 2,769 treated patients showed a similar incidence of adverse reactions for those treated with IP (14.5%) and those treated with placebo (16.1%).16 Most complaints—77.9% and 81.8% of adverse reactions observed in the treatment and placebo groups respectively—were gastrointestinal, and included heartburn, vomiting, abdominal pain, constipation, and diarrhea. Skin rashes, pruritis, headache, depression, drowsiness, fatigue, and tachycardia also were reported.
Laboratory abnormalities were noted in patients treated with both IP and placebo. An article that summarized IP safety data noted transient changes in liver and kidney function tests, as well as hematological parameters. A slight elevation of liver enzymes occurred in both the treated and control groups; however, the data on the control group were not presented.16 The percentage of patients with abnormal laboratory values ranged from 0.42% (total proteins) to 3.66% (leukocytes); however, lack of data on the placebo-treated patients rendered these numbers uninterpretable. A dosage reduction was recommended in patients with renal dysfunction (creatinine clearance 40-80 ml/min, 400 mg/d, < 40 ml/min to 200 mg/d).17
IP increases the anticoagulant effect of acenocoumarol but does not interact with oral hypo-glycemics.16 It also elevated serum levels of theophylline in one patient (withdrawal of IP resulted in a return of serum theophylline levels to previous levels).18 In vitro tests of liver microsomes indicate a possible inhibitory effect of IP on cytochrome P450 isoenzymes.19,20
Summary
IP has a good safety profile and is well tolerated. Fracture prevention data are still lacking, with results from a large multicenter study expected in 2001. Hormone replacement therapy also lacks adequate, non-vertebral fracture prevention data. In the United States, IP is marketed as a dietary supplement. Because dietary supplements are unregulated in this country, the reliability of various formulations currently available is unknown. IP may turn out to be a viable treatment option for the prevention and treatment of osteoporosis, but better clinical studies with fracture endpoints are needed. COLOR=black>
Dr. Nisly is Assistant Professor, Department of Internal Medicine at the University of Iowa College of Medicine in Iowa City.
References
1. Avioli LV. The future of ipriflavone in the management of osteoporotic syndromes. Calcif Tissue Int 1997;61(Suppl 1):S33-S35.
2. Gennari C. Ipriflavone: Background. Calcif Tissue Int 1997;61(Suppl 1):S3-S4.
3. Tsutsumi N, et al. Effects of KCA-098 on bone metabolism: Comparison with those of ipriflavone. Jpn J Pharmacol 1994;65:343-349.
4. Bonucci E, et al. Cytological and ultrastructural investigation on osteoblastic and preosteoclastic cells grown in vitro in the presence of ipriflavone: Preliminary results. Bone Miner 1992;19(Suppl 1):S15-S25.
5. Albanese CV, et al. Ipriflavone directly inhibits osteoclastic activity. Biochem Biophys Res Commun 1994;199:930-936.
6. Miyauchi A, et al. Novel ipriflavone receptors coupled to calcium influx regulate osteoclast differentiation and function. Endocrinology 1996;137:3544-3550.
7. Cheng SL, et al. Stimulation of human osteoblast differentiation and function by ipriflavone and its metabolites. Calcif Tissue Int 1994;55:356-362.
8. Sortino MA, et al. Ipriflavone inhibits phosphoinositide hydrolysis and Ca2+ uptake in the osteoblast-like UMR-106 cells. Eur J Pharmacol 1992;226:273-277.
9. Miyata T, et al. Advanced glycation end products enhance osteoclast-induced bone resorption in cultured mouse unfractionated bone cells and in rats implanted subcutaneously with devitalized bone particles. J Am Soc Nephrol 1997;8:260-270.
10. Cecchini MG, et al. Ipriflavone inhibits bone resorption in intact and ovariectomized rats. Calcif Tissue Int 1997;61(Suppl 1):S9-S11.
11. Yamazaki I. Effect of ipriflavone on the response of the uterus and thyroid to estrogen. Life Sci 1986;38:757-764.
12. Civitelli R, et al. Ipriflavone improves bone density and biomechanical properties of adult male rat bones. Calcif Tissue Int 1995;56:215-219.
13. Giossi M, et al. Inhibition of parathyroid hormone-stimulated resorption in cultured fetal rat long bones by the main metabolites of ipriflavone. Calcif Tissue Int 1996;58:419-422.
14. Benvenuti S, et al. Effects of ipriflavone and its metabolites on a clonal osteoblastic cell line. J Bone Miner Res 1991;6:987-996.
15. Petilli M, et al. Interactions between ipriflavone and the estrogen receptor. Calcif Tissue Int 1995;56:160-165.
16. Agnusdei D, Bufalino L. Efficacy of ipriflavone in established osteoporosis and long-term safety. Calcif Tissue Int 1997;61(Suppl 1):S23-S27.
17. Rondelli I, et al. Steady-state phamacokinetics of ipriflavone and its metabolites in patients with renal failure. Int J Clin Pharmacol Res 1991;11:183-192.
18. Takahashi J, et al. Elevation of serum theophylline levels in a patient with chronic obstructive pulmonary disease. Eur J Clin Pharmacol 1992;43:207-208.
19. Monostory K, Vereczky L. Interaction of theophylline and ipriflavone at the cytochrome p450 level. Eur J Drug Metab Pharmacokinet 1995;20:43-47.
20. Monostory K, et al. Ipriflavone as an inhibitor of human cytochrome p450 enzymes. Br J Pharmacol 1998;123:605-610.
September 2000; Volume 2; 65-67
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