Ipriflavone for Prevention of Osteoporosis
Ipriflavone for Prevention of Osteoporosis
December 2000; Volume 3; 133-137
By Judith L. Balk, MD, FACOG
Osteoporosis is a decrease in bone mass leading to an in-creased frequency of fractures that occur with minimal trauma. An expensive disease, osteoporosis costs roughly $10-20 billion annually in the United States.1 It causes significant morbidity and mortality, with the death rate within one year of an osteoporotic hip fracture being approximately 20%.2 Hormone replacement therapy (HRT) often is recommended as a treatment for osteoporosis, but many women cannot or do not wish to take HRT. Non-hormonal agents are being developed and studied as osteoporosis treatments. One such agent is ipriflavone, which is approved for treatment of osteoporosis in European and Asian countries.
Source and Identification
Ipriflavone, chemical structure 7-isopropoxyisoflavone, also is known as 7-isoproxy-3-phenyl-4H-1-Benzopyran-4-one. It is a derivative of the naturally occurring class of isoflavones found mainly in soy. Ipriflavone has been reported to exist in trace amounts in bee propolis, though most commonly it is chemically synthesized.
Pharmacology and Metabolism
Ipriflavone is metabolized into seven metabolites, one of which is daidzein, an isoflavone that is produced via soy metabolism. Metabolism occurs mainly in the liver and excretion occurs through the kidneys. Food seems to enhance absorption. In rats, labeled ipriflavone is concentrated in the bones, gastrointestinal tract, liver, kidneys, and adrenal glands.4 Ipriflavone and metabolites are completely eliminated from the body within 120 hours. No accumulation occurs in any body compartment, including bone.5
Mechanisms of Action
Bone mass is determined by two main factors: the rate of bone resorption and the rate of bone growth. Bone resorption is the function of the osteoclasts, whereas bone growth is the function of the osteoblasts. Both inhibition of bone resorption and stimulation of bone formation have been demonstrated for ipriflavone. Figure 1 demonstrates the mechanisms of action of ipriflavone on the bone remodeling process.
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Inhibition of Bone Resorption. Ipriflavone receptors have been identified in both osteoclast precursor cells and mature osteoclasts. These receptors appear to be distinct from other known calcium-regulating receptors, because other modulators of osteoclast function, such as estradiol, do not displace ipriflavone binding. These distinct receptors could provide a mechanism to regulate osteoclast differentiation and function.6 Ipriflavone appears to inhibit new osteoclast formation and bone resorption at the cellular level.7 Human studies also show a decrease in bone resorption, as indicated by markers of bone turnover.8,9
Stimulation of Bone Growth. Ipriflavone and metabolites stimulate human osteoblast differentiation and function, enhancing expression of matrix proteins and facilitating the mineralization process.10 Pretreatment of osteoblasts with ipriflavone demonstrated effects on parathyroid hormone (PTH) response, collagen synthesis, and cell proliferation, again indicating a modulation of synthetic and growth properties of bone.11
Estrogenic Effects? Ipriflavone may bind to estrogen receptors and elicit its effects based on estrogenic activity. Ipriflavone and some of its metabolites were not able to displace estradiol binding to MCF-7 cells or to the estrogen receptor in a preosteoclastic cell line, again suggesting different receptors. However, one metabolite, the phytoestrogen daidzein, showed weak displacement activity, and thus could demonstrate estrogenic activity. Several authors conclude that effects on bone likely are not mediated by a direct interaction with the estrogen receptor.
Animal Studies
Animal studies demonstrate successful treatment of osteoporosis with ipriflavone. For instance, glucocorticoid-induced osteoporosis in rats was treated successfully with ipriflavone. Ipriflavone increased bone density and inhibited decreases in mechanical strength and breaking strain.12
Clinical Trials
Ipriflavone has been shown to protect against bone loss in early menopause,13 during treatment with gonadotropin-releasing hormone agonist,14 after recent oophorectomy,15 in postmenopausal women with low bone mass,16 and in elderly osteoporotic women.5 The majority of these studies found that bone mass was not increased in the ipriflavone group, but it was decreased in the control group, with significant between-group differences. Urinary hydroxyproline ratios indicated reduction of bone turnover.
One study compared five different groups for one year: calcium alone (500 mg/d), low-dose HRT, higher-dose HRT, ipriflavone alone, and ipriflavone plus
low-dose HRT.8 The control group lost the most bone, 3.41%. Low-dose HRT lost 0.55%, which was not statistically significantly different from the control group, and low-dose HRT plus ipriflavone lost 0.22% bone, which was different from baseline. Ipriflavone and higher-dose HRT both gained bone, 0.11% and 1.84%, respectively. Urinary hydroxyproline/creatinine ratios decreased in both the ipriflavone and the higher-dose HRT groups, implying inhibition of resorption rather than a stimulation of bone formation.
Low-dose estrogen therapy may not be as protective on bone as higher-dose HRT. A study investigated the addition of ipriflavone to low-dose estrogen therapy.17 Both placebo and low-dose estrogen, either 0.15 or 0.3 mg conjugated estrogens (CE), had no significant changes in the bone mass after one year. In the estrogen plus ipriflavone groups, only the 0.3 mg CE group had a significant bone mass increase, and this was significantly different than the 0.3 mg CE alone. In this study, all 56 women were postmenopausal; side effects were not different between groups, but breast pain and vaginal bleeding were some of the side effects noted.
A two-year study randomized 80 postmenopausal women to one of four treatment groups: calcium alone, ipriflavone alone, low-dose estrogen therapy (0.3 mg CE), or low-dose estrogen plus ipriflavone.18 In this study, both the calcium and the estrogen only groups lost bone; both of the ipriflavone groups gained mass. Importantly, vaginal cytology changed in both of the estrogen groups and was unchanged in both the calcium group and the ipriflavone group. Thus, ipriflavone appears to cause little or no estrogenic stimulation to the vagina.
Ipriflavone also has been studied and found to have beneficial effects in Paget’s disease of bone19 and in primary hyperparathyroidism.20
The Ipriflavone Multicentre European Fracture Study is an ongoing large study of 460 non-obese postmenopausal women with low bone density. This three-year, randomized, double-blind, placebo-controlled, parallel group study is evaluating the efficacy of ipriflavone in preventing vertebral non-traumatic fractures. Secondary endpoints are changes in bone density. No results have been published. No clinical trials have studied fracture as an endpoint.
Adverse Effects
Any time an analog of estrogen is synthesized, effects on hormonally sensitive tissue become important. Animal studies have shown no effects on the uterus with ipriflavone alone.21 However, human studies evaluating direct effects of ipriflavone on the breast and endometrium are lacking. Short-term studies are suggestive of a lack of significant hormonal effects, as evidenced by testing in 15 postmenopausal women treated with ipriflavone, placebo, or estrogen for 21 days.22 It is unknown whether an enhancement of estrogenic activity may be harmful.
From the 1980s to 1997, a total of 3,132 patient-years were studied, with 2,769 patients treated with ipriflavone for six to 96 months. The incidence of adverse reactions was not different from that of placebo, with the most common complaints being gastrointestinal.5 However, the two-year studies do not look specifically for changes that may be related to estrogenic activity.5,16 In a two-year study of postmenopausal treatment, some patients had increases in liver function tests and decreases in white blood cell counts that normalized after ipriflavone discontinuation. However, the numbers of patients with these blood changes were not given.16
Drug Interactions
Ipriflavone and one metabolite inhibited the major pathway of theophylline metabolism, leading to decreased theophylline clearance and elevation of serum theophylline concentrations.23 Ipriflavone should be used with caution in those with liver or kidney disease24 or in those taking theophylline. Increased anticoagulant activity was noted when acenocoumarol was administered with ipriflavone,5 so those taking coumarin need to be cautious. For those who choose to take ipriflavone, calcium and vitamin D supplementation may enhance the effects of the ipriflavone. Vitamin D increases calcium absorption and hence inhibits PTH-mediated bone resorption; vitamin D plus ipriflavone is better at preventing bone loss than either agent alone.25
Formulation and Dosage
The typical dosage used in most studies is 200 mg tid, for a total daily dosage of 600 mg, although a 300 mg tablet bid appears to have the same bioavailability as the 200 mg tid dosage.26 An adjusted dosage schedule is recommended for those with renal disease: If creatinine clearance is between 80-40 ml/min, the dose is 400 mg/d; with severe renal impairment (< 40 ml/min), the dose is 200 mg/d. Ipriflavone is available on the Internet, through mail-order catalogs, in health food stores, and through numerous compounding pharmacies.
Conclusion
Ipriflavone appears to be safe and effective for maintenance of bone mass. It has been shown to be a useful therapy for treatment and prevention of osteoporosis. Ipriflavone has a long history of use in other countries, and has been studied extensively. It appears to work both by inhibiting bone turnover and by stimulating bone formation. Although ipriflavone may not have direct estrogenic effects, its metabolites may. Potentiation of estrogen may be problematic for those with hormone-dependent cancers.
| Table 1-Ipriflavone price and formulation comparison | |||
| Product/Manufacturer | Formulation per Dose | Manufacturer's Recommended Dose | Price/Quantity |
| Ultra Bone-Up Jarrow Formulas |
1000 mg elemental calcium, 500 mg phosphorus, 300 mg glucosamine HCl, 600 mg ipriflavone, 100 mg MSM (methylsulfonylmethant), 200 mg vitamin C, 600 IU vitamin D3, 100 µg vitamin K1, 600 mg magnesium oxide, 10 mg zinc, 1 mg copper, 3 mg manganese citrate, 3 mg boron |
2 tablets tid with meals |
$29.95/120 tablets |
| Iprical Plus Natural Balance |
200 IU vitamin D, 75 µg vitamin K, 500 mg calcium, 200 mg magnesium, 1 mg zinc, 250 µg copper, 500 µg manganese, 50 µg DynaChrome chromium, 50 µg molybdenum, 500 µg boron, 300 mg ipriflavone (7-isopropoxy-isoflavone) |
3 tablets bid with meals |
$25.99/90 tablets |
| Ipriflavone 200 Jarrow Formulas |
200 mg ipriflavone (7-isopropoxyflavone) | 1-3 capsules/d with meals |
$23.95/60 capsules |
| Ipriflavone/Advanced Physician Products |
300 mg ipriflavone (7-isopropoxy isoflavone) from soy | 1 capsule bid | $23.37/120 capsules |
| Source: Online mail-order companies | |||
Recommendation
Those with known breast and endometrial cancers, and those who are pregnant or breast-feeding should avoid ipriflavone until more research is completed. Given the lack of adverse effects found in previous studies, ipriflavone could be considered for prevention of bone loss. If one chooses to try ipriflavone, taking it with vitamin D and calcium is recommended. For women already taking full-dose HRT, ipriflavone may cause enhancement of the estrogenic effect and probably is not recommended. For women who take low-dose HRT, ipriflavone may be helpful for bone loss prevention. Monitoring of blood work may be necessary because changes in blood chemistries have been noted in those taking ipriflavone. However, no clear guidelines are available at this time. More research is necessary to fully understand the indications, contraindications, and side effects of ipriflavone.
Dr. Balk is Assistant Professor of Obstetrics and Gynecology at the University of Pittsburgh.
References
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2. Barrett-Connor E. The economic and human costs of osteoporotic fracture. Am J Med 1995;98(Suppl 2A):3S-8S.
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S3-S14.
4. Reginster JY. Ipriflavone: Pharmacological properties and usefulness in postmenopausal osteoporosis. Bone Miner 1993;23:223-232.
5. Agnusdei D, Bufalino L. Efficacy of ipriflavone in established osteoporosis and long-term safety. Calcif Tissue Int 1997;61(Suppl 1):S23-S27.
6. Miyauchi A, et al. Novel ipriflavone receptors coupled to calcium influx regulate osteoclast differentiation and function. Endocrinology 1996;137:3544-3550.
7. Morita I, et al. Ipriflavone inhibits murine osteoclast formation in vitro. Calcif Tissue Int 1992;51(Suppl 1):
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8. 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.
9. Agnusdei D, et al. Effects of ipriflavone on bone mass and bone remodeling in patients with established postmenopausal osteoporosis. Curr Ther Res 1992;51:
82-91.
10. Cheng SL, et al. Stimulation of human osteoblast differentiation and function by ipriflavone and its metabolites. Calcif Tissue Int 1994;55:356-362.
11. Benvenuti S, et al. Effects of ipriflavone and its metabolites on a clonal osteoblastic cell line. J Bone Miner Res 1991;6:987-996.
12. Yamazaki I, et al. Effect of ipriflavone on glucocorticoid-induced osteoporosis in rats. Life Sci 1986;38:
951-958.
13. 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.
14. Gambacciani M, et al. Ipriflavone prevents the loss of bone mass in pharmacological menopause induced by GnRH-agonists. Calcif Tissue Int 1997;61(Suppl 1):
S15-S18.
15. Gambacciani M, et al. Effects of ipriflavone administration on bone mass and metabolism in ovariecto-mized women. J Endocrinol Invest 1993;16:333-337.
16. Gennari C, et al. Effect of chronic treatment with ipriflavone in postmenopausal women with low bone mass. Calcif Tissue Int 1997;61:S19-S22.
17. Melis GB, et al. Ipriflavone and low doses of estrogens in the prevention of bone mineral loss in climacterium. Bone Miner 1992;19(Suppl 1):S49-S56.
18. 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;28:75-81.
19. Agnusdei D, et al. Short-term treatment of Paget’s disease of bone with ipriflavone. Bone Miner 1992;
19(Suppl 1):S35-S42.
20. Mazzuoli G, et al. Effects of ipriflavone on bone remodeling in primary hyperparathyroidism. Bone Miner 1992;19(Suppl 1):S27-S33.
21. Arjmandi B, et al. The synthetic phytoestrogen, ipriflavone, and estrogen prevent bone loss by different mechanisms. Calcif Tissue Int 2000;66:61-65.
22. Melis G, et al. Lack of any estrogenic effect of ipriflavone in postmenopausal women. J Endocrinol Invest 1992;15:755-761.
23. Monostory K, Vereczkey L. The effect of ipriflavone and its main metabolites on theophylline biotransformation. Eur J Drug Metab Pharmacokinet 1996;21:
61-66.
24. Rondelli I, et al. Steady-state pharmacokinetics of ipriflavone and its metabolites in patients with renal failure. Int J Clin Pharmacol Res 1991;11:183-192.
25. Ushiroyama T, et al. Efficacy of ipriflavone and 1-alpha vitamin D therapy for the cessation of vertebral bone loss. Int J Gynaecol Obstet 1995;48:283-288.
26. 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.
December 2000; Volume 3; 133-137
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