Ipriflavone: An Important Bone-Building
Kathleen A. Head, N.D.
Ipriflavone, an isoflavone synthesized from the
soy isoflavone daidzein, holds great promise in the prevention and
treatment of osteoporosis and other metabolic bone diseases. It
has been widely studied in humans and found effective for inhibiting
bone resorption and enhancing bone formation, the net result being
an increase in bone density and a decrease in fracture rates in
osteoporotic women. While ipriflavone appears to enhance estrogen's
effect, it does not possess intrinsic estrogenic activity, making
it an attractive adjunct or alternative to conventional hormone
replacement therapy. Preliminary studies have also found ipriflavone
effective in preventing bone loss associated with chronic steroid
use, immobility, ovariectomy, renal osteodystrophy, and gonadotrophin
hormone-releasing hormone agonists. In addition, it holds promise
for the treatment of other metabolic diseases affecting the bones,
including Paget's disease of the bone, hyperparathyroidism, and
tinnitus caused by otosclerosis. (Altern Med Rev 1999;4(1):10-22)
Ipriflavone (chemical structure: 7-isopropoxyisoflavone),
derived from the soy isoflavone, daidzein, holds great promise for
osteoporosis prevention and treatment. Ipriflavone (IP) was discovered
in the 1930s but has only recently begun to be embraced by the medical
community in this country. Over 150 studies on safety and effectiveness,
both animal and human, have been conducted in Italy, Hungary, and
Japan. As of 1997, 2,769 patients had been treated a total of 3,132
IP is metabolized mainly in the liver and excreted
in the urine. Food appears to enhance its absorption. When given
to healthy male volunteers, 80 percent of a 200 mg dose of IP was
absorbed when taken after breakfast.2 IP appears to be extensively
metabolized. In dogs and rats, seven metabolites were identified
in the plasma, labeled MI-MVII. In humans, however, only MI, MII
(daidzein), MIII, and MV seem to predominate. The mean excretion
half-life in healthy human volunteers was 9.8 hours for ipriflavone
and ranged from 2.7-16.1 hours for its metabolites. Ipriflavone
metabolism was not found to be significantly different in elderly
osteoporotic or mild kidney failure patients than in younger, healthy
subjects.3 Studies using labeled IP in rats found it concentrated
primarily in the gastrointestinal tract, liver, kidneys, bones,
and adrenal glands.3
Review Of Bone Remodeling
Bone is subject to continual remodeling; i.e., the
bone is renewed through a process of resorption of old bone by osteoclasts
and formation of new bone by osteoblasts. Osteoclastic activity
is stimulated by parathyroid hormone when serum calcium levels are
low. Conversely, calcitonin is secreted from the thyroid in response
to hypercalcemia, and antagonizes the bone-resorptive effects of
parathyroid hormone. This process occurs in discrete sections called
basic multicellular units (BMUs). This interaction between osteoclasts
and osteoblasts is a coupled process.
Mechanisms of Action
Ipriflavone appears to have several mechanisms of
action, all of which enhance bone density, making IP seemingly superior
to many of the other treatments available for osteoporosis prevention
and treatment. While it has been popular to label osteoporosis drugs
as primarily either anti-resorptive or bone-forming, this does not
take into account the fact these two processes are coupled. Because
of this coupling, substances which have a beneficial effect on prevention
of bone resorption by osteoclasts may also prevent osteoblastic
activity when taken long-term. Treatments which are primarily anti-resorptive
include estrogen, calcium, bisphosphonates, and calcitonin, while
sodium fluoride, anabolic fragments of parathyroid hormone, and
insulin-like growth factor demonstrate mainly bone forming activity.4-5
While IP is considered to be primarily an anti-resorptive, it also
possesses bone forming properties.
Anti-resorptive mechanisms: An animal study found
IP inhibited parathyroid hormone-, vitamin D-, PGE2- and interleukin
1ß-stimulated bone resorption.6 Bonnuci et al found parathyroid-stimulated
osteoclastic activity and resulting hypercalcemia were inhibited
in a dose-dependent manner by IP supplementation in rats.7
Ipriflavone metabolites have also been found to
inhibit bone resorption. An in vitro study on fetal rat long bones
found all metabolites capable of inhibiting parathyroid-stimulated
bone resorption.8 MIII was the strongest inhibitor, approximately
three times more potent than MII; MI and MV were the least potent.
Azria et al observed no inhibition of bone resorption
of incubated bone slices or changes in rat osteoclast motility at
IP concentrations greater than 100 times peak blood concentrations
after a standard therapeutic dose.9
On the contrary, Notoya et al found ipriflavone
to inhibit bone resorption by mouse osteoclasts. The mechanisms
involved included inhibition of both the activation of mature osteoclasts
and the formation of new osteoclasts.10 When IP was combined with
vitamin K in cell media, an additive inhibition of bone resorption
was noted. In this respect, vitamin K and ipriflavone appear to
have similar mechanisms of action. However, ipriflavone, but not
vitamin K, was found to stimulate alkaline phosphatase activity,
an indicator of new bone formation. The authors concluded the inhibitory
effects of IP on bone resorption are similar to those of vitamin
K, while mechanisms for osteoblastic activity are different.11
Other in vitro studies of isolated osteoclasts using
bone resorption assays and measurements of intraosteoclastic calcium
found ipriflavone inhibited osteoclastic activity (motility and
resorptive activity) by modulating intracellular free calcium. These
results were achieved at concentrations mimicking the plasma concentrations
reached from typical oral IP dosages in vivo.12 Other researchers
confirmed the effect of ipriflavone on calcium influx in chicken,
rat, and rabbit osteoclasts and preosteoclasts.13 The effect of
calcium influx into osteoclasts has not been clearly elucidated.
Miyauchi et al found IP increased intracellular calcium in osteoclasts
and pre-osteoclasts, and that osteoclast maturation was inhibited.
These findings suggest the high calcium concentration in precursor
cells inhibit osteoclastic maturation.
Bone-forming mechanisms: An in vitro examination
of the osteoblastic effect of IP and its metabolites resulted in
some interesting findings. Ipriflavone and metabolite II stimulated
cell proliferation of an osteoblast-like cell line (UMR-106a
a cell line often used to determine the effect of various hormones
and drugs on bone metabolism). IP and metabolite I increased alkaline
phosphatase activity, metabolite V enhanced collagen formation,
and IP alone inhibited parathyroid hormone activity.14
Bone marrow osteoprogenitor cells and trabecular
bone osteoblasts were isolated from human donors and incubated with
IP and its metabolites. These substances were found to regulate
osteoblastic differentiation by enhancing the expression of important
bone-matrix proteins and facilitating mineralization.15
Further evidence of ipriflavone's direct action
on osteoblastic activity was provided by Sortino et al, who found
IP to affect intracellular messenger systems in UMR-106a cells by
inhibiting both calcium influx into osteoblasts and phosphoinositide
hydrolysis. Both calcitonin and estrogen act to preserve bone in
a similar manner.16
Bonucci et al found in vitro IP applications stimulated
osteoblast-like cell proliferation and inhibited both parathyroid-induced
bone degeneration and preosteoclastic cell proliferation. The researchers
concluded the inhibition of resorption may be an indirect effect,
mediated by osteoblasts.17
Effect on Advanced Glycation End Products (AGE):
AGE (proteins nonenzymatically reacted with sugar) have been implicated
in a number of chronic degenerative conditions especially related
to diabetes and aging. AGE have also been implicated in bone resorption
around amyloid deposits in dialysis-related amyloidosis. Both ipriflavone
and calcitonin were found, in vitro, to inhibit this AGE-associated
bone resorption.18 This may have implications for age- and diabetes-related
osteoporosis as well.
Lack of Estrogen Effect: One of the benefits of
ipriflavone in the treatment of osteoporosis is its lack of estrogenic
effect. Melis et al administered ipriflavone or placebo to a group
of 15 postmenopausal women. Leutinizing hormone, follicle-stimulating
hormone, prolactin, and estradiol were measured after a single oral
dose of 600 or 1000 mg, and after 7, 14, and 21 days of treatment
with 600 or 1000 mg doses. No differences in endocrine effect were
noted between the ipriflavone and placebo groups. To examine the
neuroendocrine effect, the women received a naloxone infusion (to
block the opioid effect of estrogen) before and after 21 days of
treatment with ipriflavone, conjugated estrogens (0.625 mg/day),
or placebo. There was no evidence of central nervous system opioid
effect with IP or placebo; whereas, estrogen therapy restored the
opioidergic activity, with a decrease in climacteric symptoms. Vaginal
cytology was unchanged after 21 days of IP or placebo compared to
a significant increase in superficial vaginal cells in the estrogen
In vitro investigation of the interaction between
ipriflavone and preosteoclastic cell lines found it was not mediated
by direct interaction with estrogen receptors.20 Instead, unique
binding cites for ipriflavone were identified in the nucleus of
preosteoclastic cells. The presence of IP binding sites was confirmed
by Miyauchi et al. They identified two classes of binding sites
in chicken osteoclasts and their precursors.13 Similar IP binding
sites have been identified in human leukemic cells, a line with
similar characteristics to osteoclast precursors.
IP metabolites were also tested and the only one
which exhibited any affinity for estrogen receptor binding, although
weak, was metabolite II (daidzein, a known soy isoflavone phytoestrogen).
Daidzein's effect was not strong enough to influence growth or functional
characteristics of the preosteoclastic cell line.20
While IP does not have a directly estrogenic effect,
it appears to potentiate estrogen's effect. Calcitonin secretion
is modulated by estrogen, the levels of calcitonin significantly
dropping in ovariectomized rats. Estrogen replacement returned calcitonin
levels to normal after three weeks. While ipriflavone alone did
not enhance calcitonin levels, it acted synergistically with estrogen,
necessitating lower doses of estrogen to achieve normal calcitonin
secretion. It appears IP increases the sensitivity of the thyroid
gland to estrogen-stimulated calcitonin secretion.21
Cecchini et al found ipriflavone inhibited bone
resorption, in a manner similar to estrogen, in both intact and
ovariectomized rats, without a uterotropic effect.22 The compound
appears to have a selective effect on bone but not reproductive
tissue, suggesting it may behave as a selective estrogen receptor
modulator, similar to raloxifene and droloxifene, without the potential
harmful effects associated with this new class of drugs.
In another animal study, ipriflavone was found to
have a uterotropic effect on intact but not ovariectomized rats.
However, when administered simultaneously with estrone and estradiol
to the ovariectomized animals, it potentiated the effect of the
estrogens. This seems to again point to the lack of direct estrogenic
effect of IP while augmenting existing estrogenic effects.23
Effect on Crystalline Structure: Certain osteoporosis
medications, such as sodium fluoride, increase bone density but
change the crystalline structure, making the bone actually more
fragile.24 A study using high doses of ipriflavone (200-400 mg/kg/day)
in rats for 12 weeks found no change in the crystalline structure
of the bone. The researchers concluded "the positive effect
of ipriflavone on bone mineral density appears to be associated
with an increased apatite crystal formation rather than an increase
of crystal size."25 A study on rat long bones found ipriflavone
increased the resistance to fracture by 50 percent without changing
mineral composition or bone crystallinity.26
Ipriflavone and Osteoporosis: The Clinical Evidence
In the last decade there have been over 60 human
studies many double-blind and placebo-controlled on
the use of ipriflavone for the prevention and reversal of bone loss.
An overview of these studies follows.
A two-year, double-blind, placebo-controlled trial
was conducted in nine Italian centers. Postmenopausal women (n=196
completers) aged 50-65 with established primary osteoporosis were
randomly assigned to receive either ipriflavone (200 mg TID with
meals) or placebo; subjects in both groups also received one gram
calcium daily (in the forms of gluconolactate and carbonate). Inclusion
criteria included a bone mineral density (BMD) of the distal radius
at least one standard deviation below the mean and x-ray evidence
of osteopenia. BMD was measured by dual photon absorptiometry (DPA).
After two years the IP-treated group had demonstrated insignificant
increases in BMD while the placebo group experienced a decline in
bone mineral density, with an average difference between the placebo
and IP groups of 3.5 percent.27
A similarly designed double-blind study evaluated
453 postmenopausal women age 50-65 with either radial (measured
by DPA) or lumbar vertebral bone density (determined by dual x-ray
absorptiometry DEXA) at least one standard deviation below
the mean and x-ray evidence of osteopenia. They were randomly assigned
to receive either ipriflavone (200 mg TID) plus one gram calcium
or placebo plus calcium. At the end of the two-year study, those
women on ipriflavone maintained bone mass in both the spine, which
is primarily trabecular bone, and the distal radius, where cortical
bone predominates. While density of the hip and pelvis were not
evaluated, since they are a combination of cortical and trabecular
bone, it is not unreasonable to assume protection in this area as
well. A significant decrease in BMD was noted in the placebo group.
Metabolic markers of bone loss were also affected by ipriflavone.
Serum bone Gla-protein (BGP) and urinary hydroxyproline/creatinine
(HPO/Cr), signs of bone turnover, were measured every six months
during the study and found to be significantly elevated after one
year in the placebo group. The IP group had no change in BGP and
a decrease in HPO/Cr.28
In addition to helping prevent bone loss, IP can
also contribute to increased bone density. A study of 198 women,
designed exactly like the two studies cited above, found a one percent
increase in vertebral bone density after two years on ipriflavone,
while the placebo group experienced significant bone loss.29
A double-blind study on 40 women, using the same
protocol, found similar results. After 12 months the placebo group
experienced a 2.2-percent decrease in bone density in the spine
and 1.2-percent decrease in the forearm, while BMD increased in
the IP group by 1.2 percent in the spine and 3 percent in the forearm.30
An interesting Hungarian study was conducted on
91 postmenopausal women age 47-70 who were given either IP (200
mg TID) or placebo; both groups received calcium. For analysis the
researchers divided the groups into an early menopause group (menopause
< 5 years) and a late menopause group (> 5 years). There were
no statistically significant differences between the placebo and
treatment groups in the early menopause group; however, the late
menopause group and the total study population had a statistically
significant increase in BMD at the lumbar spine after six months
compared to the placebo group who experienced a decrease. While
both the placebo and IP groups experienced an initial increase followed
by a decrease in bone density at the femoral neck, the decrease
reached statistical significance only in the placebo group. Interestingly,
the peak effect of ipriflavone in this study was reached after six
months of treatment. Thereafter, significant differences between
the two groups were not observed. This led the researchers to speculate
whether the most positive clinical results might be achieved with
intermittent IP therapy.31 A cyclic approach to treatment with ipriflavone
remains to be investigated.
It appears ipriflavone may be particularly effective
for treatment of so-called "senile osteoporosis" (osteoporosis
in women or men over age 65) as evidenced by the results of two
studies in seven Italian centers. In one double-blind, two-year
study of 28 elderly (age 65-79) osteoporotic women with x-ray evidence
of at least one vertebral fracture, subjects received either 200
mg ipriflavone three times daily or placebo, plus one gram calcium.
The IP treated group demonstrated a significant increase in BMD
(6 percent after one year). The placebo group experienced a small
but statistically insignificant decrease. In addition, urinary hydroxyproline
was significantly decreased in the IP group, suggesting a decrease
in bone turnover. Subjective reports of decreased bone pain and
use of analgesics were noted.32
Another study, designed exactly as the one above,
found similar results. In 84 subjects a 4-percent increase in radial
bone density was noted after two years in the IP group and a statistically
significant 3-percent decrease in the placebo (calcium only) group.
The most clinically relevant finding was a decrease in fracture
rates in the IP group (2 of 41 patients experienced fractures in
the IP group, whereas 11 of 43 experienced fractures in the placebo
Ipriflavone Combined with Other Nutrients or
Some studies have combined ipriflavone with other
bone-preserving supplements or medications. A Japanese study examining
the effect of combining ipriflavone with 1a vitamin D (a form commonly
used in Japan for osteoporosis) found a decrease in vertebral bone
density in the vitamin D (1 mcg/day), ipriflavone (600 mg/day) and
placebo groups, but a maintenance of bone density in the combined
A number of studies have examined the effect of
ipriflavone and estrogen for the treatment of osteoporosis. While
low doses of conjugated estrogen (0.15-0.30 mg/day) typically are
high enough to prevent hot flashes and other neurovegetative symptoms
of menopause, a somewhat higher dose (0.625 mg/day or higher) is
generally necessary for bone protection. Some studies, however,
found when combining ipriflavone and estrogen, lower doses of estrogen
An Italian study examined 133 healthy postmenopausal
women at risk for developing osteoporosis because of family history,
smoking, low calcium intake, etc. Subjects, all receiving one gram
calcium daily, were divided into five groups: 1) placebo; 2) placebo
plus conjugated estrogen (CE) (0.15 mg/day); 3) placebo plus CE
(0.30 mg/day; 4) 600 mg/day ipriflavone plus CE (0.15 mg/day); or
5) 600 mg IP plus CE (0.30 mg/day). After 12 months insignificant
bone loss was noted in the placebo and both estrogen-plus-placebo
groups. By contrast, an increase in BMD was reported in both estrogen-plus-IP
groups, reaching statistical significance only in the IP-plus-0.30
mg CE. Symptoms of hot flashes were relieved in all groups except
the placebo control group.34
Gambacciani et al studied 80 menopausal women (age
40-49) randomly divided into four groups, with 52 subjects completing
the two-year study: 1) 500 mg/day calcium; 2) ipriflavone 600 mg/day
plus 500 mg calcium; 3) 0.30 mg/day conjugated estrogens plus 500
mg calcium; 4) lower dose IP (400 mg/day), CE (0.3 mg/day) plus
500 mg calcium. Both the control and CE-treated groups experienced
statistically significant decreases in vertebral bone density at
24 months (average of -3.7 percent in the control group and -2.2
percent in the CE group), while both the IP and IP-plus-CE groups
experienced a small but significant (P<0.05) increase of 1.2
percent in both groups after 24 months.35
In another double-blind, placebo-controlled one-year
study, 83 postmenopausal women were divided into three groups: 1)
double placebo; 2) placebo plus CE (0.3 mg/day); or 3) CE ( 0.3
mg/day) plus IP (600 mg/day). After 12 months, those in the double
placebo group demonstrated a progressive decrease in bone density;
those in the CE group maintained their BMD for six months, but showed
a 1.4 percent bone loss at the end of 12 months; and those in the
CE-plus-IP group showed a significant increase in BMD after one
year (+5.6 %; p<0.01).36
Not all studies have found ipriflavone protective
from bone loss when combined with low dose estrogen. In a study
comparing several protocols: 1) 500 mg calcium (controls); 2) 25
mcg transdermal estradiol plus five mg medroxyprogesterone (12 days);
3) 50 mcg transdermal estradiol plus five mg medroxyprogesterone
(12 days); 4) 600 mg IP; or 5) 600 mg IP, 25 mcg transdermal estradiol,
and 5 mg medroxyprogesterone, only the group taking the higher estrogen
dose showed any significant increase in bone density (+1.84%). The
IP group showed slightly improved bone density (+0.11%), while the
IP-plus-25 mcg estradiol group actually experienced a slight decrease
Many practitioners in their search for safer forms
of estrogen replacement have turned to the weaker estrogen, estriol.
However, its use for the prevention of osteoporosis remains controversial.38
A Japanese study compared the use of ipriflavone alone or with estriol.39
Seventy-nine postmenopausal women receiving ipriflavone (600 mg/day)
alone or in combination with 1 mg estriol daily were compared to
controls who received nothing. After one year, the controls demonstrated
a 4-5 percent decrease in bone density. Both the IP and the IP-plus-estriol
groups maintained bone density over the course of the study, with
no significant difference between the latter two groups. This study
points to the efficacy of ipriflavone but not low-dose estriol in
bone preservation. It is possible a higher dose of estriol would
prove more efficacious.
An open, controlled 12-month trial compared ipriflavone
with salmon calcitonin in 40 postmenopausal women. Significant increases
in bone density were observed in both groups after 12 months: a
4.3-percent increase in BMD in the ipriflavone group and a 1.9-percent
increase in the calcitonin group. Markers of bone loss (serum osteocalcin,
alkaline phosphatase, urinary calcium, and hydroxyproline/calcium
ratio) were significantly reduced in both groups.40
Ipriflavone in the Prevention of Surgical or
Gonadotropin hormone-releasing hormone agonists
(GnRH-A) such as Lupronâ are used to induce hypogonadism,
for the treatment of such conditions as uterine fibroids and endometriosis.
These drugs induce a temporary menopause-like condition characterized
by rapid bone loss as well as hot flashes and other symptoms of
menopause. Researchers examined the effect of ipriflavone in restraining
bone loss induced by these drugs. In a double-blind, placebo-controlled
trial, 78 women treated with GnRH-A (3.75 mg leuproreline every
30 days for six months) were randomly assigned to receive either
ipriflavone (600 mg/day) or placebo; both groups received 500 mg
calcium daily. In placebo subjects, markers of bone turnover (urinary
hydroxyproline and plasma bone Gla) were significantly elevated
while BMD decreased significantly after six months. Conversely,
there were no changes in BMD or bone markers in the ipriflavone-treated
group. Although BMD improved in the placebo group after withdrawal
of leuproreline, it was still below baseline values at 12 months
(six months after discontinuation of the drug).41
Typically an ovariectomy results in rapid bone loss.
In order to examine the effect of ipriflavone in the prevention
of this bone loss, 32 recently ovariectomized women received either
500 mg calcium or 600 mg ipriflavone in addition to the calcium
for 12 months. In the calcium-only group, markers of bone loss (urinary
hydroxyproline, serum alkaline phosphatase, and plasma bone Gla)
increased significantly and BMD significantly decreased six months
after surgery. On the other hand, radial bone density and biochemical
markers in the ipriflavone group showed no significant changes,
indicating ipriflavone appeared to protect women from the sudden
bone loss often experienced after ovariectomy.42
Researchers examined the effect of a combination
of ipriflavone and conjugated estrogen in preventing rapid bone
loss after ovariectomy. Estrogen had been previously tested (at
a dose of 0.625 mg/day), and was found to be ineffective in this
population for preventing acute post-surgical bone loss. Women (n=116),
post-ovariectomy, were divided into four groups: 1) placebo; 2)
CE (0.625 mg/day); 3) 600 mg ipriflavone; or 4) CE plus IP. Vertebral
bone density was measured by the DEXA method and two biochemical
markers of bone turnover, urinary pyridinoline and serum osteocalcin,
were measured before, 24, and 48 weeks after beginning treatment.
BMD was reduced in all groups after 48 weeks of treatment (6.1,
3.9, and 5.1 % in groups 1-3, but only 1.2 % in group 4 the
estrogen-plus-ipriflavone group). In this study, concomitant use
of estrogen plus ipriflavone significantly slowed bone loss.43
Ipriflavone may be effective in preventing osteoporosis
associated with long-term steroid use. An animal study found ipriflavone,
administered orally to rats with steroid-induced osteoporosis, was
able to increase bone density and mechanical strength of the tibia
and femur. Human studies in this population are warranted.44
Osteoporosis may occur as a result of long-term
immobilization of a limb. Two rat studies have found ipriflavone
to either increase bone density45 or slow bone loss46 in this population.
Studies on human populations are indicated.
Ipriflavone in the Treatment of Other Conditions
Paget's Disease: Several other pathological conditions
involving bone may be helped by ipriflavone. Paget's disease of
the bone is characterized by specific areas of rapid bone turnover
with both increased osteoclastic and osteoblastic activity. This
results in abnormal bone, increased fracture rate, and perhaps most
distressingly, bone pain which can be quite severe. A small study
of 16 patients with Paget's disease randomly allocated subjects
to one of two cross-over regimes, either 600 mg or 1200 mg IP daily
for 30 days with a 15-day washout period between each regime. Serum
alkaline phosphatase and urinary hydroxyproline/creatinine, generally
elevated in Paget's disease, were reduced during both sequences,
alkaline phosphatase by an average of 31.5 percent and HOP/Cr by
an average of 25 percent. Bone pain scores were reduced in both
treatment groups with the most significant decrease in the 1200/600
mg daily regime.47
Hyperparathyroidism: Because in vitro studies have
found ipriflavone to inhibit parathyroid-stimulated bone resorption,
a small preliminary study tested its effectiveness in inhibiting
bone loss associated with hyperparathyroidism. Nine patients with
primary hyperparathyroidism, six females and three males age 34-72,
were treated for 21 days with 1200 mg daily ipriflavone in three
divided doses. In five patients the treatment was prolonged for
42 days. Statistically significant reductions in markers of bone
turnover (urinary Ca/Cr and HOP/Cr) were observed in all patients
after 21 days. By day 42 there was a trend toward increases in alkaline
phosphatase and serum osteocalcin. The researchers explained this
phenomenon as a positive uncoupling of osteoclastic and osteoblastic
activity, since bone formation seemed not to be affected by the
treatment. In other words, they postulated the increase in alkaline
phosphatase was a result of increased bone formation rather than
due to bone resorption.48 The study was quite small and short-term,
bearing further investigation.
Otosclerosis: Tinnitus, predominantly low tone,
is a common symptom of otosclerosis. A small, double-blind study
of 16 patients tested the effectiveness of ipriflavone or placebo
in combination with stapedectomy in the treatment of tinnitus due
to otosclerosis. Subjects were treated for three months preoperatively
and three months postoperatively with 200 mg ipriflavone or placebo
four times daily. During the preoperative phase, while ipriflavone
resulted in no improvement in hearing loss, tinnitus was arrested
in four of nine patients. One of seven in the placebo group experienced
relief of tinnitus. Postoperatively, all patients in the ipriflavone
group but only 50 percent of the patients in the placebo group experienced
relief of tinnitus.49 The exact reason for ipriflavone's benefit
in otosclerosis remains to be determined.
Renal Osteodystrophy: Chronic renal failure results
in abnormalities of calcium, phosphorus, vitamin D, and parathyroid
metabolism. The eventual outcome is a decrease in bone mineralization.
Twenty-three hemodialysis patients with decreased bone mineralization
due to renal failure (renal osteodystrophy) were administered ipriflavone
(400-600 mg daily) and observed for a period of 1-9 months. Alkaline
phosphatase levels significantly decreased with IP treatment, while
calcitonin was significantly increased after one month compared
with levels prior to treatment. Serum IP levels before and after
hemodialysis were not much greater than for patients with normal
kidney function. Ipriflavone increased serum calcitonin levels to
a greater extent in these patients than in patients with normally
functioning kidneys. There were no instances of adverse effects,
indicating that, while this report is preliminary, ipriflavone may
be a safe, effective supplement for patients in renal failure suffering
Oxygen-sparing: Experimental studies on the cardiological
effects of ipriflavone in rabbits, dogs, and rats have found IP
decreases cardiac oxygen consumption, a phenomenon which was more
pronounced in anoxic conditions. Significant decreases in lactic
acid concentrations in myocardial tissue, especially in areas of
ischemia, were also observed. Ipriflavone also counteracted calcium
accumulation in the mitochondria induced by coronary ligation. Overall,
ipriflavone seemed to have an oxygen-sparing effect, positively
influencing mitochondrial energetics.51
Safety of Ipriflavone
In general, ipriflavone appears to be quite safe
and well tolerated. As of 1997, long-term safety of ipriflavone
(for periods ranging from 6-96 months) had been assessed in 2,769
patients for a total of 3,132 patient years in 60 human studies
in Hungary, Japan, and Italy.1 The incidence of adverse reactions
in the IP-treated patients was 14.5 percent, while the incidence
in the placebo groups was 16.1 percent. Side-effects were mainly
gastrointestinal (GI). Since the placebo groups in most studies
received calcium, it is not unreasonable to assume calcium may have
as much to do with GI effects as ipriflavone. Other symptoms observed
to a lesser extent included skin rashes, headache, depression, drowsiness,
and tachycardia. Minor transient abnormalities in liver, kidney,
and hematological parameters were documented in a small percent
A reduction in theophylline metabolism and increased
serum theophylline was observed in a patient being treated with
ipriflavone.52 Animal studies indicated this may be due to inhibition
of certain cytochrome p450 enzymes, resulting in diminished elimination
of the drug via the liver.53-54
While ipriflavone was found to have potential for
treatment of renal osteodystrophy and short-term use was without
side-effects, pharmacokinetic studies have revealed elevated levels
of ipriflavone and its metabolites in the serum of patients with
moderate to severe renal failure.55 Patients with mild renal disease
seem to tolerate ipriflavone at doses similar to those of healthy
subjects. Researchers recommend lower doses (200-400 mg/day) in
patients with more advanced renal failure. Further study of its
safety in this population is warranted.
The therapeutic benefits of ipriflavone in the prevention
and treatment of osteoporosis have been well researched. IP appears
to restrain bone loss in postmenopausal women and in some cases,
particularly in elderly populations, stimulates new bone growth
and decreases fracture rates. It has also been found to enhance
the effect of low-dose estrogen on bone preservation. Ipriflavone
appears to be effective in prevention of acute bone loss after surgery
or GnHR-As, and may protect from steroid-induced osteoporosis as
well. Preliminary studies have pointed to its effectiveness in the
treatment of other conditions involving bone pathology, including
Paget's disease, hyperpara-thyroidism, renal osteodystrophy, and
tinnitus due to otosclerosis. Ipriflavone appears to exert its bone
protective effects by inhibition of osteoclastic and enhancement
of osteoblastic activity without having a direct estrogenic effect.
While fracture rate was decreased by about 50 percent in some preliminary
trials, longer term studies are indicated, particularly to evaluate
ipriflavone's effectiveness in decreasing hip fracture rate. The
Ipriflavone Multicenter European Fracture Study began in 1997; results
will not be available until 2001.
1. Agnusdei D, Bufalino L. Efficacy of ipriflavone
in established osteoporosis and long-term safety. Calcif Tissue
2. Saito AM. Pharmacokinetic study of ipriflavone
(TC80) by oral administration in healthy male volunteers. Jpn Pharm
Ther J 1985;13:7223-7233.
3. Reginster JYL. Ipriflavone pharmacological properties
and usefulness in postmenopausal osteoporosis. Bone Miner 1993;23:223-232.
4. Gennari C. Proceedings of the satellite symposium
on ipriflavone: a new non-hormonal therapeutic agent in osteoporosis.
Bone Miner 1992;19:S81-S82.
5. Sibilia V, Netti, C. Current therapies and future
directions in osteoporosis management. Pharmacol Res 1996;34:237-245.
6. Tsutsumi N, Kawashima K, Nagata H, et al. Effects
of KCA-098 on bone metabolism: comparison with those of ipriflavone.
Jpn J Pharmacol 1994;65:343-349.
7. Bonucci E, Ballanti P, Martelli A, et al. Ipriflavone
inhibits osteoclast differentiation in parathyroid transplanted
parietal bone of rats. Calcif Tissue Int 1992;50:314-319.
8. Giossi M, Caruso P, Civelli M, Bongrani S. Inhibition
of parathyroid hormone-stimulated resorption in cultured fetal rat
long bones by the main metabolites of ipriflavone. Calcif Tissue
9. Azria M, Behhar C, Cooper S. Lack of effect of
ipriflavone on osteoclast motility and bone resorption in vitro
and ex vivo studies. Calcif Tissue Int 1993;52:16-20.
10. Notoya K, Yoshida K, Taketomi S, et al. Inhibitory
effect of ipriflavone on osteoclast-mediated bone resorption and
new osteoclast formation in long-term cultures of mouse infractionated
bone cells. Calcif Tissue Int 1993;53:206-209.
11. Notoya K, Yoshia K, Shirakawa Y, et al. Similarities
and differences between the effects of ipriflavone and vitamin K
on bone resorption and formation in vitro. Bone 1995;16:S349-S353.
12. Albanese CV, Cudd A, Argentino L, et al. Ipriflavone
directly inhibits osteoclastic activity. Biochem Biophys Res Commun
13. Miyauchi A, Notoya K, Taketomi S, et al. Novel
ipriflavone receptors coupled to calcium influx regulate osteoclast
differentiation and function. Endocrinology 1996;137:3544-3550.
14. Benvenuti S, Tanini A, Frediani U, et al. Effects
of ipriflavone and its metabolites on a clonal osteoblastic cell
line. J Bone Miner Res 1991;6:987-996.
15. Cheng SL, Zhang SF, Nelson TL, et al. Stimulation
of human osteoblast differentiation and function by ipriflavone
and its metabolites. Calcif Tissue Int 1994;55:356-362.
16. Sortino MA, Aleppo G, Scapagnini U, Canonico
PL. Ipriflavone inhibits phosphoinositide hydrolysis and Ca2+ uptake
in the osteoblast-like UMR-106 cells. Eur J Pharmacol 1992;226:273-277.
17. Bonucci E, Silvestrini P, Ballanti P, 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:S15-S25.
18. Miyata T, Notoya K, Yoshida K, et al. Advanced
glycation end products enhance osteo-clast-induced bone resorption
in cultured mouse unfractionated bone cells and in rats implanted
subcutaneously with devitalized bone particles. J Am Soc Nephrol
19. Melis GB, Paoletti AM, Cagnacci L, et al. Lack
of any estrogenic effect of ipriflavone in postmenopausal women.
J Endocrin Invest 1992;15:755-761.
20. Petilli M, Fiorelli G, Benvenuti U, et al. Interactions
between ipriflavone and the estrogen receptor. Calcif Tissue Int
21. Yamazaki I, Kinoshita M. Calcitonin secreting
property of ipriflavone in the presence of estrogen. Life Sci 1986;38:1535-1541.
22. Cecchini MG, Fleisch H, Muhlbauer RC. Ipriflavone
inhibits bone resorption in intact and ovariectomized rats. Calcif
Tissue Int 1997;61:9-11.
23. Yamazaki I. Effect of ipriflavone on the response
of uterus and thyroid to estrogen. Life Sci 1986;38:757-764.
24. Riggs BL, Hodgson SF, O'Fallon WM. Effects of
fluoride treatment on the fracture rate in postmenopausal women
with osteoporosis. N Engl J Med 1990;322:802-809.
25. Ghezzo C, Civettelli R, Cadel S, et al. Ipriflavone
does not alter bone apatite crystal structure in adult male rats.
Calcif Tissue Int 1996;59:496-499.
26. Civitelli R, Abbasi-Jarhomi SH, Halstead LR,
Dimargonas A. Ipriflavone improves bone density and biomechanical
properties of adult male rat bones. Calcif Tissue Int 1997;61:12-14.
27. Adami S, Bufalino L, Cervetti R, et al. Ipriflavone
prevents radial bone loss in postmenopausal women with low bone
mass over 2 years. Osteoporos Int 1997;7:119-125.
28. Gennari C, Adami S, Agnusdei D, et al. Effect
of chronic treatment with ipriflavone in postmenopausal women with
low bone mass. Calcif Tissue Int 1997;61:S19-S22.
29. Agnusdei D, Crepaldi G, Isaia G, et al. A double
blind, placebo-controlled trial of ipriflavone for prevention of
postmenopausal spinal bone loss. Calcif Tissue Int 1997;61:142-147.
30. Valente M, Bufalino L, Castiglione GN, 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.
31. Kovacs A. Efficacy of ipriflavone in the prevention
and treatment of postmenopausal osteoporosis. Agents Actions 1994;41:86-87.
32. Passeri M, Biondi M, Costi D, et al. Effect
of ipriflavone on bone mass in elderly osteo-porotic women. Bone
33. Ushiroyama T, Okamura S, Ikeda A, Ueki M. Efficacy
of ipriflavone and 1a vitamin D therapy for the cessation of vertebral
bone loss. Int J Gynaecol Obstet 1995;48:283-288.
34. Melis GB, Paoletti AM, Bartolini R, et al. Ipriflavone
and low doses of estrogen in the prevention of bone mineral loss
in climac-terium. Bone Miner 1992;19:S49-S56.
35. Gambacciani M, Ciaponi M, Cappagli B, 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.
36. Agnusdei D, Gennari C, Bufalino L. Prevention
of early postmenopausal bone loss using low doses of conjugated
estrogens and the non-hormonal, bone-active drug ipriflavone. Osteoporos
37. de Aloysio D, Gambacciani M, Altieri P, et al.
Bone density changes in postmenopausal women with the administration
of ipriflavone alone or in association with low-dose ERT. Gynecol
38. Head K. Estriol: safety and efficacy. Altern
Med Rev 1998;3:101-113.
39. Hanabayashi T, Imai A, Tamaya T. Effects of
ipriflavone and estriol on postmenopausal osteoporotic changes.
Int J Gynaecol Obstet 1995;51:63-64.
40. Cecchettin M, Bellometti S, Cremonesi G, et
al. Metabolic and bone effects after administration of ipriflavone
and salmon calcitonin in postmenopausal osteoporosis. Biomed Pharmacother
41. Gambacciani M, Cappagli B, Piagessi L, et al.
Ipriflavone prevents the loss of bone mass in pharmacological menopause
induced by GnRH-agonists. Calcif Tissue Int 1997;61:15-18.
42. Gambacciani M, Spinetti A, Cappagli B, et al.
Effects of ipriflavone administration on bone mass and metabolism
in ovariectomized women. J Endocrinol Invest 1993;16:333-337.
43. Nozaki M, Hashimoto K, Inoue Y, et al. Treatment
of bone loss in oophorectomized women with a combination of ipriflavone
and conjugated equine estrogen. Int J Gynaecol Obstet 1998;62:69-75.
44. Yamazaki I, Shino A, Shimizu Y, et al. Effect
of ipriflavone on glucocorticoid-induced osteoporosis in rats. Life
45. Notoya K, Yoshia K, Tsukuda R, et al. Increase
in femoral bone mass by ipriflavone alone and in combination with
1a-hydroxyvitamin D3 in growing rats with skeletal unloading. Calcif
Tissue Int 1996;58:88-94.
46. Foldes I, Rapcsak M, Szoor A, et al. The effect
of ipriflavone treatment on osteoporosis induced by immobilization.
Acta Morphologica Hungarica 1988;36:79-93.
47. Agnusdei D, Camporeale A, Gonnelli S, et al.
Short-term treatment of Paget's disease of bone with ipriflavone.
Bone Miner 1992;19:S35-S42.
48. Mazzuoli G, Romagnoli E, Carnevale V, et al.
Effects of ipriflavone on bone remodeling in primary hyperparathyroidism.
Bone Miner 1992;19:S27-S33.
49. Sziklai I, Komora V, Ribari O. Double-blind
study of the effectiveness of a bioflavonoid in the control of tinnitus
in otosclerosis. Acta Chirurgica Hungarica 1992-93;33:101-107.
50. Hyodo T, Ono K, Koumi T, et al. A study of the
effects of ipriflavone administration in hemodialysis patients with
renal osteodystrophy: preliminary report. Nephron 1991;58:114-115.
51. Feuer L, Barath P, Strauss I, Kekes E. Experimental
studies on the cardiological effects of ipriflavone on the isolated
rabbit heart and in rat and dog. Arzneim-Forsch/Drug Res 1981;31:953-958.
52. Takahashi J, Kawakatsu K, Wakayama T, Sawaoka
H. Elevation of serum theophylline levels by ipriflavone in a patient
with chronic obstructive pulmonary disease. Eur J Clin Pharmacol
53. Monostory K, Vereczky L, Levai F, Szatmari I.
Ipriflavone as an inhibitor of human cytochrome p450 enzymes. Br
J Pharmacol 1998;123:605-610.
54. Monostory K, Vereczkey L. Interaction of theophylline
and ipriflavone at the cytochrome p450 level. Eur J Drug Metab Pharmacokinet
55. Rondelli I, Acerbi D, Ventura P. Steady-state
phamacokinetics of ipriflavone and its metabolites in patients with
renal failure. Int J Clin Pharm Res 1991;11:183-192.