Ipriflavone For Bone - Not!

by Michael Mooney February, 2001, with update December, 2003

The Newsletter for Program For Wellness Restoration

I recommend that people with HIV should avoid the use of the popular bone-building dietary supplement called ipriflavone. I also recommend that anyone, whether HIV(+) or HIV(-), who is concerned with long-term health and healthy immune function should consider its use carefully as a new four-year, double blind, placebo-controlled study gives cause for concern.

In October, in answer to questions, I sent out a Nutrition Email Update to my list that stated that the popular bone-building supplement ipriflavone is not natural. As documented later in this article, I received confirmation from professional chemists that components in the ipriflavone molecule are “not known to occur in nature.”

I had several people contact me to question my statement that ipriflavone is not found in nature. One of them asked a research person associated with their company, and was told that ipriflavone is found in soy, alfalfa, and propolis. However, the research person provided no references to studies that verified that this is true. In fact, a search of medical databases showed that there are none that appear in peer-reviewed journals or any journals that are available on Medline.

I have been told that there are two studies in Chinese and Japanese medical journals. I was also told, however, that the only evidence of this are two sentences translated by a person who works for one of the main vendors of ipriflavone.

When I requested more information from an ipriflavone vendor, a translated statement that was sent me from a study by Kawai et al., said, "The laboratory of the Chinoin Company perceived that one of the growth factors of the alfalfa plant for fodder is flavonoid." The word "flavonoid," it seems, is used to refer to ipriflavone. Chinoin is a drug company that sells ipriflavone in Europe.

It is standard practice in the world of science to require confirmation from at least one independent source before accepting statements like this from vendors of a product.

The first question that should be answered is what method of analysis "perceived" this? Scientists would want to know what method of evaluation was used in considering validity. But more important is that only an analysis from an independent source, not a company that sells a product, would be considered as a basis for credibility, especially since to date, no researcher has published confirmation of detection of ipriflavone in a plant source or in a source that is found in nature in a well-recognized medical journal, such as a peer-reviewed journal that is available on Medline.

Certainly, the possibility that this is true could only be accepted after independent scientists confirm it in a study published in a recognized peer-reviewed journal.

This is an especially important consideration since, as I said in my original email regarding ipriflavone, a recent study, which is one of the most comprehensive studies ever done on ipriflavone, showed that ipriflavone decreased lymphocytes significantly. (Lymphocytes are immune system cells.)

This four year double-blind, placebo-controlled study of 474 women, which was recently published in the Journal of the American Medical Association, also showed that it took 2 years for 81% of the women who experienced a decrease in lymphocytes to regain normal lymphocyte levels. The study did not show that there were more infections, like colds and flu, related to the decrease in lymphocytes, so the researchers called for more studies to evaluate this. (Click here to read the study abstract.)

While this is not conclusive data, it should be of concern to anyone who is involved with public health, and especially to people with immune system problems like HIV.

To read an article by Dr. Joseph Mercola that details this, click here.

Regarding Safety
Other published data give cause for concern about possible negative effects from the use of ipriflavone. In 1997 when researchers Agnusdei and Bufalino looked at long term-safety of ipriflavone, they found that in 2769 elderly osteoporotic women, almost 13 percent showed variations from normal blood ranges in 33 standard blood tests up to 4 percent out of range. (Note: 13 percent is 1 out of 8 women.)

Furthermore, while some researchers state that the side effects are mostly gastrointestinal and stop after treatment is over, this study evaluated the frequency of various side effects and the results are not easy to dismiss.

Of 554 women, almost all of them had one or more of the following side effects.

-- 77.9% experienced heartburn, nausea, vomiting, gastric pain, abdominal pain, constipation, diarrhea.
-- 9.1% experienced rashes, itching, erythema.
-- 9.5% experienced headaches, depression, drowsiness.
-- 3.75% experienced asthenia, fatigue, tachycardia.
(See: Agnusdei D, Bufalino L. Efficacy of ipriflavone in established osteoporosis and long-term safety. Calcif Tissue Int (United States), 1997, 61 Suppl 1:S23-S27.)

While some researchers and journalists did not appear to be concerned about the long-term effects of these perhaps moderate abnormalities, it is more prudent to “do no harm,” and consider any potential for adverse effects carefully.

Still another study showed a more serious effect, in that ipriflavone may cause abnormally high blood concentration of some asthma drugs because it can reduce the liver’s ability to process them. (See: Monostory K. The effect of ipriflavone and its main metabolites on theophylline biotransformation. Eur J Drug Metab Pharmacokinet (Switzerland), Jan-Mar 1996, 21(1):61-66.)

Certainly, this study indicates that labels for products containing ipriflavone should contain a warning that, “Ipriflavone may increase blood levels of asthma drugs.”

Because of these controversies, I continued to conduct in-depth research on ipriflavone to learn more about the truth.

This is what I found.

Chemist Patrick Arnold’s Comments

I contacted Patrick Arnold, the professional research chemist who first introduced ipriflavone to the United States in 1994. Arnold had discovered ipriflavone in Europe as a drug used to improve bone density. At that time it appeared that ipriflavone might also have some potential muscle-building properties, which would make it valuable in the bodybuilding supplement market, Arnold’s primary business. Arnold soon determined, though, that any potential to affect muscle, was “not readily apparent,” so he stopped working with it.

Arnold told me explicitly that ipriflavone is not found in nature. As a professional chemist, he said, "Ipriflavone contains an isopropyl-ether group in the molecule. Flavonoid isopropyl-ether groups are not known to occur in nature, so it is extremely unlikely that ipriflavone can occur in nature. There are no quality studies that show ipriflavone occurring in soy, alfalfa, or propolis, although I have heard well-meaning people assert these things."

Although Patrick Arnold is a nutritional researcher who is known for his accuracy, I checked further.

I learned that ipriflavone was synthesized in a laboratory in 1969 by Dr. Lazlo Peuer, who was working for Sanofi Pharmaceuticals, a European drug manufacturer. Dr. Peuer was working with other scientists to create new (artificial) flavones that had anabolic properties with no estrogenic properties. (See: Lanyi G, et al. The Ipriflavone Story, Acta Pharmaceutica Hungarica 1995;65:191-194.)

The scientists worked together to synthesize the ipriflavone molecule and about 200 other artificial flavones in their laboratories, and began testing them in 1974 in animals and in 1981 in humans. (See: Gennari C. Ipriflavone: Background. Calcif Tissue Int (1997) 61:S3-S4.)

When ipriflavone is used as a search term on Medline, numerous studies appear that specifically refer to ipriflavone as "synthetic."

  Sample of a few studies that refer to ipriflavone as synthetic.

  Gennari C, Agnusdei D, Crepaldi G, et al.
  Effect of ipriflavone--a synthetic derivative of natural isoflavones--on
  bone mass loss in the early years after menopause. Menopause (United
  States), Spring 1998, 5(1) p9-15

  Arjmandi BH, Khalil DA, Hollis BW
  Ipriflavone, a synthetic phytoestrogen, enhances intestinal calcium
  transport in vitro. Calcif Tissue Int (United States), Sep 2000, 67(3) p225-9

  Arjmandi BH, Birnbaum RS, Juma S, et al.
  The synthetic phytoestrogen, ipriflavone, and estrogen prevent bone loss by 
  different mechanisms. Calcif Tissue Int (United States), Jan 2000, 66(1):61-5

After I sent out my email about ipriflavone, another retailer called to say that he was under the impression that ipriflavone occurred in natural products including propolis, and referred me to a book called The Osteoporosis Solution that stated that ipriflavone occurred in propolis.

I obtained a study by Bankova that The Osteoporosis Solution derived its information from and found that Bankova's study does not say that ipriflavone occurs naturally in propolis. On page 139, in Table IV, the study lists ipriflavone as a comparative chemical, but when the complete study is analyzed it is clear that the study does not assert in any way that ipriflavone naturally occurs in propolis. (See: Bankova VS, et al. High-performance liquid chromatographic analysis of flavonoids from propolis. Journal of Chromatography, 1982;242:135-143.) Click here to read my analysis of the study.

Patrick Arnold also stated that one of the reasons many people assume that ipriflavone is natural is because various journalists, lecturers, authors, and manufacturers have misinterpreted its use as a chemical listed in the Bankova study, thinking that Bankova was stating that ipriflavone was contained in propolis. Arnold agreed with me that this is clearly not the case.

Arnold also stated, "No studies of ipriflavone have shown that it is contained in soy or any other natural product. Indeed, the market's eagerness for new, natural flavone products has allowed ipriflavone, an artificial flavone, to gain popularity."

When I talked to another leading researcher in the dietary supplement industry about ipriflavone he said that another study had recently been published by the same authors (Alexandersen and Reginster) that also stated that ipriflavone caused a significant decrease in lymphocytes. While more study is needed to confirm whether this effect on lymphocytes is conclusively true, he thought that for the time being manufacturers would be most prudent if they considered including a warning statement on the labels of products that contain ipriflavone that states something that means, in effect, “Some data indicate that ipriflavone may decrease lymphocytes. Have your doctor monitor your lymphocyte counts if you decide to take ipriflavone."

Notably, in the two new studies that showed that ipriflavone use was associated with decreased lymphocytes (immune system cells) in senior women over a time period of three years, it took a full year for 52 percent of the women to recover normal lymphocyte production and, as I said previously, 2 years for 81 percent of the women to regain full lymphocyte counts. If this is proven to be true in other studies, it will be a serious consideration over the long-term.

While no one has a perfect conclusion about this yet, vendors who sell ipriflavone should consider including warnings with sales of ipriflavone products until there is scientific conclusion that there is no problem.

When I did a quick Medline search of "flavones and lymphocytes," I found several studies that show that certain common flavones have immunomodulatory effects, so potential positive and negative effects are possible. This lends a little substance to the idea that these new studies that say that ipriflavone can decrease lymphocytes may have merit. (Read the studies below.)

Of course, any possibility of harm deserves our responsible caution and consideration.

Michael Mooney


Dear Michael,

I just started using ipriflavone, as I have osteoporosis and do not trust the drug Fosamax. Calcium and magnesium supplements did not help me enough.

What do you recommending instead of ipriflavone for bone protection AND new growth.
Can you please enlighten me?
Thank you,
J. D.

To Read My Answer To J.D. Click Here

Return to Medibolics Main Page: Dietary Supplement Alerts 

Two studies that show that common flavones can have effects on lymphocytes.

Effects of genistein on the growth and cell cycle progression of normal human lymphocytes and human leukemic MOLT-4 and HL-60 cells. Cancer Res 1992 Nov 15;52(22):6200-6208. Traganos F; Ardelt B; Halko N; Bruno S; Darzynkiewicz Z

Abstract: Genistein (GEN) is an isoflavone known to inhibit both tyrosine protein kinases and DNA topoisomerase II. The effects of GEN on cell proliferation and cell cycle kinetics of human myelogenous leukemia HL-60 and lymphocytic leukemia MOLT-4 cell cultures were studied, and the data were compared to results obtained with normal human lymphocytes stimulated to proliferate with phytohemagglutinin. GEN concentrations greater than 50 micrograms/ml (185 microM) were cytotoxic to HL-60 and MOLT-4 cells following exposure for 24 h; in HL-60 cell cultures, a population of cells with decreased DNA content and nuclear fragmentation characteristic of apoptosis was observed within 8 h. The 50% inhibition concentration after 24 h of exposure for HL-60 and MOLT-4 cells was 8.5 and 13.0 micrograms/ml, respectively. Normal proliferating lymphocytes survived a 24-h exposure of up to 200 micrograms/ml GEN. Short-term (4-8 h) exposures of MOLT-4 or HL-60 cells to 5-20 micrograms/ml GEN resulted in a suppression of cell progression through S or through both S and G2 phases, respectively, while equivalent treatment had no effect on proliferating lymphocytes. A stathmokinetic experiment using MOLT-4 cells revealed that as little as 5 micrograms/ml GEN suppressed cell exit from S to G2 phase by 40%, with a terminal point of action at or near the S-G2 border. Cell progression through the very early portion of G1 phase (G1A, characterized by postmitotic chromatin decondensation) was also suppressed by approximately 40%, whereas cell advancement through the remainder of the G1 phase was not markedly affected. Longer (24 h) exposure of proliferating lymphocytes to 20 micrograms/ml GEN led to an S-phase arrest, while similar treatment of leukemic cells caused cell arrest in G2 phase and an increase in the number of cells entering the cycle at higher DNA ploidy. The mitogen-induced transition of lymphocytes from G0 to G1 phase was extremely sensitive to inhibition by GEN; the 50% inhibition concentration was 1.6 micrograms/ml. The chemotherapeutic value of GEN may be due to the fact that, in terms of cytotoxicity, this agent is more active against proliferating leukemic cells than against normal proliferating lymphocytes. The sensitivity of the G0 to G1 transition in normal lymphocyte cultures and the suppressive effect of GEN on the G1A exit in MOLT-4 cells both suggest that protein kinases involved in chromatin decondensation may be a target of this drug. In light of the observation that lymphocyte stimulation is sensitive to the presence of GEN, the drug is expected to be a strong immunosuppressant.

The phytoestrogens coumoestrol and genistein induce structural chromosomal aberrations in cultured human peripheral blood lymphocytes. Arch Toxicol 1999 Feb;73(1):50-54.
Kulling SE; Rosenberg B; Jacobs E; Metzler M

Abstract: The clastogenic potential of the phytoestrogens coumoestrol (COUM), genistein (GEN) and daidzein (DAI) has been studied in human peripheral blood lymphocytes in vitro. After exposure of the cultured lymphocytes to 50 to 75 microM COUM or 25 microM GEN for 6 h, a clear induction of structural chromosomal aberrations was observed by cytogenetic analysis. The major alterations were chromatid breaks, gaps and interchanges. In contrast, DAI did not induce chromosome aberrations even at 100  microM. These results, together with previously published reports on the induction of micronuclei and DNA strand breaks in cultured Chinese hamster V79 cells by COUM and GEN, but not DAI, suggest that some but not all phytoestrogens have the potential for genetic toxicity.