by Thomas Incledon, PhD(c), RD, LD/LN, RPT, NSCA-CPT, CSCS
Brief Background
Ipriflavone (IP) is an isoflavone that has some interesting properties.The Europeans and Japanese use it as an anti-osteoporotic agent. Recent claims by supplement companies state that IP is a bone builder and can also increase lean body mass.We searched through 141 abstracts and several patents (1-4), singled out the important research studies, and put together this review.
The history of IP begins in 1969 with Chinoin Pharmaceutical and ChemicalWorks Co. Ltd., Budapest, Hungary. The scientists focused on developing an isoflavone derivative that maximized the anabolic actions and minimized the estrogenic actions of the agent (5). Ipriflavone was first used as a feed additive for animals, then later as an anti-anginal agent, and finally registered and launched as an anti-osteoporotic agent in Japan in 1988.
Ipriflavone is also known as 7-isopropoxy-isoflavone.A careful review of the scientific studies published to date reveals that almost all of the studies are supported by either Chiesi Farmaceutici SpA, Parma, Italy; Chinoin Pharmaceutical and Chemical Works Co. Ltd., Budapest, Hungary; and/or Takeda Chemical Industries Ltd.,Tokyo, Japan. This fact is pointed out because most of the patents on IP and its uses are owned by one of these three companies.
Metabolism of Ipriflavone
Before we discuss the human and animal studies that have been published on IP, some key differences in its metabolism should be pointed out. In humans, IP administered orally appears to be well absorbed and metabolized (6,7). In tablet form, 6 out of 12 subjects had undetectable levels of IP in their blood while all 12 subjects had detectable levels for the capsule form (7). It appears that a dosage of 300 mg capsules taken twice daily is preferred to a dosage of 200 mg tablets taken three times daily for maintaining blood levels. Ipriflavone is metabolized into different metabolites that are simply referred to as M1,M2,M3,M4,M5,M6, and M7.M5 (7-(1-carboxy-ethoxy)- isoflavone) appears to be the main metabolite in humans (6, 7).There are no gender differences in the metabolism of IP in human studies.
After ingesting a 200-mg tablet, about 40% is excreted in the feces. The rest of the ingested IP is absorbed into the blood via the small intestine. 57% of the ingested dose is metabolized and recoverable in the urine as metabolites (6). In the blood, 94-99% of IP and its metabolites are reversibly bound primarily to albumin. There appears to be a strong first pass effect on IP (8). Since the liver oxidizes or conjugates most of the IP, very little may be detected in the blood. This explains why other studies have reported difficulty in measuring IP. The absorption of this agent could be improved and it is important to note that there are patents for the use of “oily vehicles” (1) and cyclodextrins (3) as delivery agents for IP. Both of these delivery methods would enable greater absorption and uptake of IP. At the time of writing this article, neither form has been seen on the commercial market in the US. Keep in mind, though, that most of the published evidence to date has been done using tablets and not capsules or any other forms of IP.
Anabolic Actions vs Lack of Evidence
In contrast to humans, animals appear to absorb IP much more effectively and the primary metabolite is M1 (7-hydroxy-isoflavone).This is pointed out because while animals absorb it better and are generally given higher dosages, no direct evidence could be found in the scientific literature that IP increased body weight. So let’s say this again: after searching through all the published studies on IP, nothing in the scientific literature indicates that IP would increase body weight or lean body mass.
However, there is a patent for IP indicating that it has anabolic activity (4). In this patent, dosages of 150-mg IP tablets administered three times per day resulted in 2-3 kilograms (4.4-6.6 pounds) of weight gain in patients. These patients are referred to as having some type of “pathological thinness.” To say that they gained weight and, therefore, normal healthy people will, is a stretch of science. Other sections discuss dosage ranges of 50- 1000 mg per day with 300-600 mg per day being preferred. Here is the problem, though. While patent information can be helpful, it doesn’t describe things in the same detail that peer-reviewed studies do.With all the studies done on animals and humans that have been published, at least one would have shown or reported an increase in body weight or lean body mass if IP was truly anabolic. However, this has not yet occurred.
Anecdotal reports, mostly from Europe, continue to indicate that IP is anabolic and promotes weight gain. While we can not find any scientific evidence of this currently, we would also like to point out that research is underway that will help determine if this isoflavanoid is anabolic. This data should be revealed within the next year (2000). Based on the available evidence, it would seem that while there is a lack of scientific data to support the use of IP for gains in lean body mass in normal, healthy people, it may work for some pathological conditions. More research is certainly needed in this area.
Anti-Osteoporotic Agent
If the anabolic actions of IP are highly suspect at this time then why would anyone want to take it?The answer is that most people taking IP are not taking it for its effects on lean body mass. For diseases where there is a loss of bone mineral such as osteoporosis and Paget’s disease, IP may prove useful in attenuating the rate of bone loss. Some studies have reported that IP treatment increased vertebral bone mineral density (9, 14) and forearm bone mineral density (15, 16). Others studies report that it just maintained distal radius bone density (12), reduced bone loss (10, 16, 19), or prevented the loss of bone mass in pharmacological menopause induced by GnRH-agonists (17). In addition, its actions may be increased when combined with 1-alpha-vitamin D (10) and estrogens (11, 13, 18, 20).
While over 60 clinical studies on 2769 patients have been performed in Italy, Japan, and Hungary on the effectiveness of IP as an counteragent for osteoporosis, we will only describe a few here.One study compared the effects of IP with that of a placebo for 198 postmenopausal women (aged 50-65 years).These women had a vertebral bone density below the average value for normal, age-matched, postmenopausal subjects (14). From the original 198, only 134 subjects completed the two-year study. All subjects were randomly assigned to a 2-year treatment with oral IP (200 mg three times daily) or a matching placebo, following a double-blind, parallel group design. In addition, all subjects also received an oral daily calcium supplement of 1 g as calcium carbonate. At baseline and every 6 months, vertebral bone density and other markers of bone turnover were measured. Before and after the treatment period complete routine checks of liver and kidney functions were conducted. The IP-treated women had a significant increase in vertebral bone density of +1.4% after 1 year, and +1% at the end of treatment period (P < 0.05). In contrast, the placebo group had a significant decrease of vertebral bone density after 2 years of treatment (P < 0.05). Markers of bone metabolism, like skeletal alkaline phosphatase, serum bone Gla-protein, and urinary hydroxyproline/creatinine ratio significantly decreased in IP-treated women.This data suggests that IP has an inhibitory effect on bone turnover rate in postmenopausal women aged 50-65 years.
The results of two multi-center, double-blind, placebo-controlled, 2-year studies to evaluate the efficacy and tolerability of IP in 453 postmenopausal women (aged 50-65 years) has also been published (16). These women had an average vertebral or radial mineral density value 1 standard deviation below age-matched controls. Subjects were randomly selected to receive oral IP (200 mg three times daily with meals) or a matching placebo, plus 1 g oral calcium daily.Vertebral bone density (studyA) was measured by dual X-ray absorptiometry and radial bone density (study B) was measured by dual photon absorptiometry. In addition, serum bone Gla-protein (BGP), and urinary hydroxyproline/creatinine (HOP/Cr) were measured every 6 months. Both studies showed a maintenance of bone mass in IP-treated women, whereas in the placebo group, bone mineral density was significantly decreased.After 2 years there was a bone-sparing effect of 1.6% in study A, and of 3.5% in study B. Biochemical markers of bone turnover decreased in patients treated with IP, thus suggesting a reduction of bone turnover rate.
While research supports the efficacy of IP in the treatment of postmenopausal osteoporosis after 2 years (12), there are some practical considerations. For instance the cost of IP vs other forms of treatment. Perhaps more importantly though is the end results of IP treatment. Older women don’t take IP to make their bones stronger per se rather they take IP to decrease their chances of developing a fracture. While IP may maintain bone density and possibly increase bone density, does it reduce the frequency of fractures? The latest evidence is that it may not (21). This is where all the scientific evidence can be misleading. After all the studies done on the effects of IP treatment, few have actually examined whether or not it decreases the incidence of fractures. This is not an easy task to do because there are difficulties in defining what will be counted as a fracture and as a control for the initial fracture status of the subjects. For instance, if a woman has an existing fracture and it heals would that count as a decrease, or if a woman has an existing fracture and it worsens would that be an increase? Fortunately, the Ipriflavone Multi-center European Fracture Study was performed.This was a three-year, double-blind, placebo-controlled, parallel group study using 460 Caucasian, nonobese, postmenopausal women, 45-75 years old. The study was reported to run from August 1995 to August 1998. The data is expected to be available in the near future. The speculation at this time by most scientists is that IP will decrease the incidence of fractures. However, the companies holding patents on IP and its uses employ these scientists.
Side Effects of IpriflavoneTreatment
Reports of adverse events are generally mild and do not differ between IP and placebo groups (11, 12, 14). The incidence of adverse reactions in IP-treated patients (14.5%) was reported to be similar to subjects receiving a placebo (16.1%) (15). Side effects are usually gastrointestinal (15). Few patients presented reversible modifications of laboratory parameters. The data from the above studies show that long-term treatment with IP may be considered safe. There is one case report that links IP administration to a gastric ulcer (22). However, the woman was 81 and had a positive history for gastric ulcers and stopped taking her H2 antagonists while she was taking IP. In addition, the researchers reported that “the formation of the fistula between the stomach and the jejunum seemed to have been facilitated by the patient being very lean and having minimal mesenteric adipose tissue.”
Theophylline metabolism and excretion are decreased by IP (30). In vitro work indicates that this is due to an inhibitory effect of IP or its metabolite, 7-hydroxy-isoflavone, on the liver enzyme CYP1A2 (30). All factors considered it doesn’t appear that IP poses any problems for most people. People prone to ulcers or taking medications with caffeine or theophylline should pay careful attention to how their body is responding to IP treatment.
Actions of Ipriflavone
If you wanted to develop an anti-osteoporotic drug, it would have to be cost effective, decrease net bone resorption (the breaking done of bone cells to release calcium), increase bone density without altering bone structure, be well tolerated for long periods of administration, not interact with other drugs and/or hormones in the body, and have minimal side effects. The reason why IP is being researched even though other agents may work better acutely, is that it comes pretty close to meeting all of these objectives. But how does it do this? The answer is rather complex, but we will try to explain it in steps to make it easy to follow.
Ipriflavone and its metabolite (MIII) inhibit bone resorption by acting directly on preosteoclasts and inhibiting their proliferation (29). This effect may be due to the inhibition of nitric oxide release (26). In vitro evidence from mice indicates that the inhibitory effect of IP may be enhanced by the addition of vitamin K2 (31). Estrogen replacement therapy is effective in the prevention of postmenopausal osteoporosis, and a direct action of 17-beta-estradiol on osteoblastic and osteoclastic cells has been demonstrated, so a comparison of estrogen vs IP for estrogenic activity seemed inevitable (23). 600-1000 mg of IP was unable to exert the same effects that estrogens do in postmenopausal women (23). Since IP inhibits bone resorption, yet is devoid of estrogenic properties, and is active in potentiating the effects of estrogen on bone tissue, perhaps its actions are the result of one or more of its metabolites. To address this theory, the molecular interactions of IP and its four main in vivo metabolites (I, II, III, andV) with the estrogen receptor in the human preosteoclastic cell line FLG 29.1 and the human breast cancer cell line MCF7 were studied (24). Binding sites for IP were found in the nuclear fraction of FLG 29.1 cells. 17-beta-estradiol and other steroid compounds failed to displace IP from its receptor. Not only does IP not bind to the estrogen receptor, it also does not bind to the type II estrogen binding site that tamoxifen and some flavonoids can bind to (25). Subsequent work on mouse, rat, and human estrogen receptor subtypes, alpha and beta, indicates that of the phytoestrogens tested, IP has one of the lowest abilities to induce transcription (27). It appears that from the above research that IP may initiate its actions by binding to an independent site.
Practical Recommendations
While the data strongly suggests that IP can prevent bone loss, it does not provide adequate support for a decrease in the rate of fractures.This may be difficult to establish in human research. In addition, most patients would be unlikely to take IP until the later stages of osteoporosis where interventions have minimal impact because the bone density is very low. Preventative programs where IP intake is initiated early in menopause may prove useful in decreasing the incidence of risk fractures.The impact of IP in cases of very low bone mineral density has not been studied as well as cases just one standard deviation below the mean.While beyond the scope of this article, weight-bearing activity initiated pre-menopause and maintained throughout postmenopause may also serve as a preventative aid.
An interesting point from one study is that while compliance was high (intake more than 80% after 2 years in 92.5% of patients treated with IP and 92.8% of patients treated with placebo) it was not 100% (14).To interpret this practically, lower dosages of IP may also be effective then the typical 600 mg dose. In fact, some evidence indicates that 450 mg may be all that is needed for benefits (4). Given the positive interactions of IP with Vitamins 1-alpha-D and K2, it may be prudent to take them with calcium for maximum protection against bone loss. So while all the evidence is still not in for IP and its effects on lean body mass, it may be a beneficial anti-osteoporotic supplement for postmenopausal women.
References:
(1) Chiesi, et al. United States Patent # 5,504,105. Pharmaceutical compositions containing ipriflavone, process for the preparation thereof and relative therapeutic use Inventors: Chiesi; Paolo (Parma, IT); Pavesi; Luciana (Parma, IT). Assignee: Chinoin Pharmaceutical and Chemical Works Co. Ltd. (Budapest, HU).April. 2, 1996.
(2) Csanyi, et. al. United States Patent # 5,110,720. Dental composition and a process for the preparation thereof. Inventors:Csanyi; Endre (Budapest,HU);Csanyi;Gabor (Budapest,HU);Balogh; Tibor (Budapest,HU);Nagy; Laszlo (Budapest, HU).Assignee: Reanal Einomvegyszergyar (Budapest, HU).May 5, 1992.
(3) Stadler nee Szoke, et al. United States Patent # 4,826,963. Inclusion complex of 7-isopropoxyisoflavon formed with cyclodextrin, the preparation thereof and pharmaceutical compositions containing these compounds as active ingredient. Inventors: Stadler nee Szoke; Agnes (Budapest, HU); Szejtli; Jozsef (Budapest,HU); Weiszfeiler; Viktor (Budapest,HU);Vargay;Zoltan (Budapest,HU); Kaloy; Katalin (Budapest, HU); Gergely;Vera (Budapest, HU); Szuts;Tamas (Budapest, HU) Assignee: Chinoin Gyogyszer esVegyeszeti Termekek Gyara, R.T. (Budapest, HU). September 10, 1986
4) Feuer et al. United States Patent # 3,949,085. Anabolic weight-gain promoting compositions containing isoflavone derivatives and method using same. Inventors: Feuer, Laslo; Nogradi, Mihaly; Gottsegen, Agnes;Vermes, Borbals; Strelisky, Janos;Wolfner, Andreas; Farkas, Lorant; Antus, Sandor; Kovaks, Maria. Assignee: Chinoin Gyogyszer es Vegyeszeti Termekek Gyara, R.T. (Budapest, HU). August 15, 1974.
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24) Petilli M. Fiorelli G. Benvenuti S. Frediani U. Gori F. Brandi ML. Interactions between ipriflavone and the estrogen receptor. Calcified Tissue International. 56(2): 160 165, 1995 Feb.
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28) Shibano K.Watanabe J. Iwamoto M. Ogawa R. Kanamura S. Culture of stromal cells derived from medullary cavity of human long bone in the presence of 1,25-dihydroxyvitamin D3, recombinant human bone morphogenetic protein-2, or ipriflavone. Bone. 22(3): 251-258, 1998 Mar.
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