Ipriflavone
For Bone - Not!
by Michael
Mooney February, 2001, with update December, 2003
www.medibolics.com
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.
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.
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.)
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.)
Because of these controversies, I continued to conduct in-depth research on
ipriflavone to learn more about the truth.
This is what I found.
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."
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. |
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.
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."
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.)
www.medibolics.com
Can you please enlighten me?
Thank you,
J. D.
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.