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POSTMENOPAUSAL OSTEOPOROSIS
years off treatment, while it increased further on
continuing treatment. Finally, the BMD of hip
sites showed some decrease, but not back to
baseline. Similarly, in the FLEX study, patients
who received placebo after 5 years of alendronate
therapy showed a 25% increase in urinary NTx
(cross-linked N-telopeptides of type I collagen)
that remained stable during the following 5 years
without bisphosphonate
31
. Changes in BMD
were similar to those in the extension of the
phase III study, with the exception of total hip
BMD, which reached pretreatment values after 5
years off treatment.
USE OF BISPHOSPHONATES AT
INTERVALS LONGER THAN
1 WEEK
Intermittent administration of bisphosphonates
to patients with osteoporosis has been used for
many years, but studies have generally failed to
show concrete evidence of antifracture efficacy.
Interest in this form of treatment has recently
been renewed with the development of more
potent bisphosphonates that can be given at
intervals longer than 1 week, either orally at safe
doses or intravenously in convenient ways either
by injection or by short-term infusion. Such reg-
imens are thought to offer patient convenience,
contributing to better long-term adherence to
treatment. These administration regimens usu-
ally induce a fast decrease in the level of bone
resorption, which reaches a nadir within a few
days. The exact nadir reached depends on the
sampling schedule, and it is greater than that of
daily regimens since the dose size used in inter-
mittent regimens is usually higher than that
reached by daily treatments. Thereafter, bone
resorption starts to increase again toward base-
line until the administration of the next dose.
The result is a fluctuating level of bone resorp-
tion. All such regimens can lead to some
increases in BMD, but, until recently no clear-cut
antifracture efficacy has been shown, suggesting
that dose size or dosage interval may have been
incorrect. A typical example of this is the intra-
venous injection of ibandronate 0.5 or 1.0 mg
every 3 months to osteoporotic women. These
doses increased BMD by about 3% after 3 years,
but led to a non-significant reduction in the risk
of new vertebral fractures
37
. The results sug-
gested that a higher dose or a shorter dose inter-
val might be needed for antifracture efficacy. In
further phase II studies, intravenous ibandronate
injections, 2 mg every 3 months, were associated
with larger decreases in bone resorption and
larger increases in BMD
38
. On the other hand, a
single infusion of zolendronate 4 mg in patients
with osteoporosis suppressed bone resorption
during 1 year to a constant level, with a long-
term pattern similar to that observed during
daily oral administration of other bisphospho-
nates
39
. Similar data have previously been
reported with intravenous alendronate (7.5 mg
on four consecutive days) at a dose equivalent to
about 430 days of treatment with 10 mg/day
orally
40
. Of particular interest was a treatment
regimen with oral ibandronate, given with a
drug-free interval of longer than 2 months, that
suppressed bone resorption significantly, with a
response pattern similar to that induced by daily
treatment. This was the first time that an inter-
mittent bisphosphonate regimen was shown to
have antifracture efficacy in a prospective, con-
trolled trial
23
. These results opened the way to
explore other treatment regimens with this
bisphosphonate, such as once-monthly oral
administration.
CONCLUSIONS
Bisphosphonates, because of their efficacy and
safety, are generally accepted as first-line therapy
for osteoporosis, and current research focuses on
issues related to their optimal clinical use. Despite
progress in our understanding of their action to
reduce fracture risk and their long-term effects on
bone, there are still questions regarding their
long-term use that remain to be addressed. These
focus mainly on the clinical question of length of
treatment, and to potential differences among
bisphosphonates. Will it be possible to offer to
our patients ‘drug holidays’ with a bisphos-
phonate? Such a therapeutic approach can have
substantial economic benefits, is more patient-
friendly and may enhance adherence to treatment.
214
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BISPHOSPHONATES IN MANAGEMENT OF OSTEOPOROSIS
best use bisphosphonates in combination with
other agents for the management of the rather
small, but clinically very important, group of
patients with severe disease? The first steps to
answer this question have already been taken.
Ongoing research is expected to provide more
information that will help in the optimal man-
agement of the individual patient with osteo-
porosis with bisphosphonates.
215
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bone mass: results of the FOSIT study. Fosamax
Can long-term results obtained with one bispho-
sphonate be extrapolated to the whole class?
There are suggestions that this may not be the
case. A number of ongoing studies are expected
to provide more insight into these issues. When
will efficacious regimens with intermittent
administration of bisphosphonates either orally or
parenterally become available? Current data
indicate that this will be soon. Finally, how can we
https://t.me/med1917
POSTMENOPAUSAL OSTEOPOROSIS
International Trial study group. Osteoporos Int
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17. Harris ST, Watts NB, Genant HK, et al. Effects
of risedronate treatment on vertebral and non-
vertebral fractures in women with post-
menopausal osteoporosis: a randomized con-
trolled trial. Vertebral Efficacy with Risedronate
Therapy (VERT) Study Group. J Am Med Assoc
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18. Reginster JY, Minne HW, Sorensen OH, et al.
Randomized trial of the effects of risedronate on
vertebral fractures in women with established
postmenopausal osteoporosis. Vertebral Efficacy
with Risedronate Therapy (VERT) study group.
Osteoporos Int 2000; 11: 83–91
19. McClung MR, Geusens P, Miller PD, et al. Hip
Intervention Program Study Group. Effect of
risedronate on the risk of hip fracture in elderly
women. N Engl J Med 2001; 344: 333–40
20. Sorensen OH, Crawford GM, Mulder H, et al.
Long-term efficacy of risedronate: a 5-year
placebo-controlled clinical experience. Bone
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21. Brumsen C, Papapoulos SE, Lips P, et al. Daily
oral pamidronate in women and men with osteo-
porosis: a 3-year randomized, placebo-controlled
clinical trial with a 2-year open extension. J Bone
Miner Res 2002; 17: 1057–64
22. McCloskey E, Selby P, Davies M, et al. Clo-
dronate reduces vertebral fracture risk in women
with postmenopausal osteoporosis: results of a
double-blind, placebo-controlled 3-year study. J
Bone Miner Res 2004; 19: 728–36
23. Chesnut Ch III, Skag A, Christiansen C, et al.
Effects of oral ibandronate administered daily or
intermittently on fracture risk in postmenopausal
osteoporosis. J Bone Miner Res 2004; 19: 1241–9
24. Cranney A, Wells G, Willan A, et al. Meta-analy-
sis of alendronate for the treatment of post-
menopausal women. Endocr Rev 2002; 23: 508–16
25. Cranney A, Tugwell P, Adachi J, et al. Meta-
analysis of risedronate for the treatment of post-
menopausal osteoporosis. Endocr Rev 2002; 23:
517–23
26. Papapoulos SE, Quandt SA, Liberman UA, et al.
Meta-analysis of the efficacy of alendronate for
the prevention of hip fractures in postmenopausal
women. Osteoporos Int 2005; 16: 468–74
27. Dufresne TE, Chmielewski PA, Manhart MD, et
al. Risedronate preserves bone architecture in
early postmenopausal women in 1 year as meas-
ured by three-dimensional microcomputed
tomography. Calcif Tissue Int 2003; 73: 423–32
28. Recker R, Masarachia P, Santora A, et al. Trabec-
ular bone microarchitecture after alendronate
treatment of osteoporotic women. Curr Med Res
Opin 2005; 21: 185–94
29. Roschger P, Rinnerthaler S, Yates J, et al. Alen-
dronate increases degree and uniformity of min-
eralization in cancellous bone and decreases the
porosity in cortical bone of osteoporotic women.
Bone 2001; 29: 185–91
30. Boivin GY, Chavassieux PM, Santora AC, et al.
Alendronate increases bone strength by increasing
the mean degree of mineralization of bone tissue
in osteoporotic women. Bone 2000; 27: 687–94
31. Borah B, Dufresne TE, Chmielewski PA, et al.
Risedronate preserves bone architecture in post-
menopausal women with osteoporosis as meas-
ured by three-dimensional microcomputed
tomography. Bone 2004; 34: 736–46
32. Black D, Schwartz A, Ensrud K, et al. A 5 year
randomized trial of the long-term efficacy and
safety of alendronate: the FIT long-term exten-
sion (FLEX). J Bone Miner Res 2004; 19 (Suppl 2):
S45
33. McClung MR, Wasnich RD, Hosking DJ, et al.
Prevention of postmenopausal bone loss: six-year
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89: 4879–85
34. Wasnich RD, Bagger YZ, Hosking DJ, et al.
Early Postmenopausal Intervention Cohort Study
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drawal. Menopause 2004; 11: 622–30
35. Bagger YZ, Tanko LB, Alexandersen P, et al.
Alendronate has a residual effect on bone mass in
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after treatment withdrawal. Bone 2003; 33:
301–7
los SE. Skeletal metabolism in patients with
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BISPHOSPHONATES IN MANAGEMENT OF OSTEOPOROSIS
osteoporosis after discontinuation of long-term
treatment with oral pamidronate. J Clin
Endocrinol Metab 1995; 80: 3465–8
37. Recker R, Stakkestad JA, Chesnut CH III, et al.
Insufficiently dosed intravenous ibandronate
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38. Adami S, Felsenberg D, Christiansen C, et al.
Efficacy and safety of ibandronate given by
intravenous injection once every 3 months. Bone
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39. Reid IR, Brown JP, Burckhardt P, et al. Intra-
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Bone Miner Res 1997; 10: 1700–7
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compounds with weak estrogenic or antiestro-
genic activity toward mammals. Of particular
interest in relation to human health are these
plant-derived estrogens, or phytoestrogens,
which embody several groups of non-steroidal
estrogens widely distributed within the plant
kingdom. Although in vitro and animal studies
provide preliminary plausible mechanisms to
explain how phytoestrogens act, the application
of diets rich in such compounds and their con-
sequent biological effects still need to be fully
examined, tested and confirmed through tradi-
tional scientific experimental pathways (Table 1).
Phytoestrogens are strikingly similar in chemical
structure to the mammalian estrogen, estradiol,
and bind to estrogen receptors (ERs) with a pref-
erence for ER
β
2
. This suggests that these com-
pounds may exert tissue-specific effects, besides
other non-receptor-mediated biological activi-
ties, such as antioxidant capacity and antiprolif-
erative/antiangiogenic effects.
Natural estrogens are involved in a multiplic-
ity of programmed events in target tissues such
as the uterus, breast, pituitary gland and hor-
mone-responsive tumors. The initiation of estro-
gen action by all of the estrogens is considered to
be the same in each target tissue. Estrogen first
binds to the nuclear ER, then an estrogenic lig-
and causes a conformational change that encour-
ages dimerization and interaction with either
specific DNA sequences or a protein–protein
interaction with activator protein-1 (AP-1) or
specificity protein 1 (SP1) sites in the promoter
region of estrogen-responsive genes
3
. These
events herald the biological effects of estrogen in
the specific target tissue or tumor. A small per-
centage (2–3%) of ERs are located on the cell
membrane and contribute to non-genomic
Phytoestrogens: food or drug?
L. Bacciottini, A. Falchetti, B. Pampaloni, E. Bartolini, A. M. Carossino and
M. L. Brandi
24
Medical sciences Food sciences
Drugs
Bioactive
compounds
(phytoestrogens)
Foods
Functional foods
Nutritional sciences
Figure 1 Phytoestrogens: scientific research areas
INTRODUCTION
Within the past several years, the relationship
between diet and health has been accepted by
the mainstream nutrition community and, in this
connection, interest in the physiological role of
bioactive compounds present in plants has dra-
matically increased over the last decade. As a
complex mixture of chemicals, foods provide
essential nutrients, requisite calories and other
physiologically active constituents that may be
useful for life and health. A new paradigm for
‘optimal nutrition’ may be evolving that would
identify physiologically active components that
contribute to disease prevention. Thus, the
functional foods concept unifies the medical,
nutritional and food sciences (Figure 1). Collect-
ively, plants contain several different families of
natural bioactive products, among which are
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phytochemicals or polyphenols. These are the
largest category of phytochemicals and the most
widely distributed in the plant kingdom
7
.
Polyphenols in plants show a multiple func-
tion: they act as antioxidants (protection against
ultraviolet (UV) light), exert a protective action
against insects, fungi, viruses and bacteria, and a
visual attention–pollinator attraction (they are
responsible for plant and flower colors), and they
can also serve as feed-repellents and plant hor-
mone controllers.
The study of phytoestrogens started in the
1950s when it was realized that some plant-
derived substances could cause an estrogenic
effect. Sheep that were grazing on pastures con-
taining red clover had multiple fertility prob-
lems, and it was shown that the clover present in
these pastures had high amounts of isoflavones
8
,
in particular formononetin and biochanin A.
The classification of phytoestrogens is contro-
versial; however, currently we can subdivide the
phytoestrogens into four main classes: flavonoids
(flavonols and isoflavones), lignans, coumestans
and stilbenes (Table 3).
Flavonoids
These are the largest group of plant phenols,
including more than 4000 different compounds,
which are the most studied phytochemicals. The
basic flavonoid structure allows a multitude of
variations in chemical structure, giving rise to
flavonols (quercetin, kaempferol, myricetin),
flavones (apigenin, luteolin), flavanones (catechin,
220
effects of estrogen
4
. Two ERs are currently
known, ER
α and ERβ. Although the two ERs
can be localized within the same cell, they vary in
tissue distribution and can have different effects
on mixed agonist and antagonist molecules.
Phytoestrogens include a wide variety of
structurally diverse compounds such as
isoflavones, mainly found in soy, lignans founds
in grains and stilbenes found in the skins of
grapes. Other less investigated compounds
include flavones, flavans, isoflavanes and
coumestans
5
. The estrogenic or antiestrogenic
activity of any chemical depends on the ability of
the compound to interact with the ERs (ER
α,
ER
β).
The aim of this chapter is to describe the sub-
stances that, up to date, have been validated
from a pharmacological point of view for their
estrogenicity or antiestrogenicity.
PHYTOESTROGEN-RICH FOODS
Phytoestrogens are present in many human food-
stuffs including fruits (plums, pears, apples,
grapes, berries, etc.), vegetables (beans, sprouts,
cabbage, spinach, soybeans, grains, hops, garlic,
onions, etc.), wines and teas, and have been
identified in a number of botanical dietary sup-
plements (Table 2). Plants vary both intra- and
inter-species in the types and concentrations of
phytoestrogens, due to variables in plant growth,
soil, weather conditions and the age of the
plant. Chemically, phytoestrogens are phenolic
Table 1 Research needed to clarify possible roles of phytoestrogens in health. Modified from reference 1
Identify the specific types of phytoestrogens that provide health benefits
Characterize the sources, dietary or supplemental
Define the effective dose of phytoestrogens that provides protection against a specific symptom
Determine the concentration at which pharmacologic doses become a toxicologic problem
Identify new mechanisms by which the phytoestrogens produce protective effects
Identify specific binding proteins
Identify specific metabolites
Determine the effects of phytoestrogens on cell differentiation
Establish the pharmacokinetics of delivered doses
Identify the proportion of the population likely to respond positively to phytoestrogens
Examine more closely the dietary components relative to the diet as whole
POSTMENOPAUSAL OSTEOPOROSIS
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epicatechin), antocyanidins and isoflavonoids
(genistein, daidzein)
9
. An important effect of
flavonoids is the scavenging of oxygen-derived
free radicals. The major source of isoflavonoids in
the diet is from soy-based foods. The isoflavo-
noids from legumes, including genistein and
daidzein, are the most studied phytoestrogens.
They can exist as glycosides or as aglycones, the
glucosides being readily hydrolyzed in the gut as
their aglycones. The aglycones are easily trans-
ported across intestinal epithelial cells. Genistein
has one-third the potency of estradiol when it
interacts with ER
β, and one-thousandth the
potency of estradiol when it interacts with ER
α,
as determined by the expression of luciferase
reporter gene construct in kidney cells that have
221
Table 2 Levels of isoflavones and lignans in various food sources. Values (in nanomoles per gram dry weight)
were determined by isotope dilution gas chromatography–mass spectrometry with selected ion monitoring
6
Plant species
(common name) Genistein Daidzein Secoisolariciresinol Matairesinol
Soybean 993–3115 413–2205 < 1–8 < 1
Kidney bean < 1–19 < 1–2 2–4 < 1
American groundnut 4–30 < 1 < 1–2 < 1
Chickpea 3–8 < 1–8 < 1 0
Pea < 1 < 1<1<1
Lentil < 1 < 1 <1 <1
Kudzu root 467 7283 < 1 < 1
Flaxseed 0 0 10–247 30
Sunflower seed <1 6 2 17
Peanut 2 1 8 <1
Wheat bran < 1 < 1 3 0
Barley < 1 < 1 2 0
Rye bran 0 445
Strawberry 0 0 33 < 1
Cranberry 0 0 29 0
Blueberry 0 0 23 0
Raspberry 0 0 4 0
Red cabbage < 1 < 1 4 <1
Broccoli < 1 < 1 11 < 1
Garlic 0 0 11 <1
Zucchini 0 0 23 < 1
Carrot 0 0 10 < 1
Beetroot 0 0 3 < 1
Black tea trace trace 73 12
Green tea trace trace 75 5
PHYTOESTROGENS: FOOD OR DRUG?
Table 3 Main chemical categories of phytoestrogens
Lignans Flavonols Coumestans Isoflavones Stilbenes
Enterolactone quercetin coumestrol glycitein resveratrol
Enterodiol rutin genistein
daidzein
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POSTMENOPAUSAL OSTEOPOROSIS
been cotransfected with ERα and ERβ
10
. Genis-
tein may produce similar effects to estradiol in
several different tissues such as breast, ovary,
endometrium, prostate, vascular tissue, bone tis-
sue and cell lines
11,12
. Furthermore, genistein
also induces responses that are not associated
with the ER, such as the inhibition of tyrosine
kinase and DNA topoisomerase
13
. Such an effect
is produced even in the presence of antiestrogen,
revealing a non-genomic action that could
explain a part of the difference between genistein
and estradiol.
In vitro experimental systems have also shown
that flavonoids possess anti-inflammatory, antial-
lergic, antiviral and anticarcinogenic proper-
ties
14
, and various of these molecules, notably
isoflavonoids, are identified as phytoestrogens
being able to bind estrogen receptors, and pos-
sess estrogenic or antiestrogenic activities
15,16
.
Lignans
These are constituents of higher plants, such as
whole-grains, legumes, vegetables and seeds,
with exceptionally high concentrations of lignans
found in flaxseed. Although previously thought
to be present only in higher plants, mammalian
lignans have been detected in the biological flu-
ids of humans and animals. The chemical struc-
ture of plant lignans is very different from that of
mammalian lignans, and most of the changes
occur in the colon, liver and small intestine.
Enterolactone and enterodiol are metabolites of
the plant lignans matairesinol and secoisolari-
ciresinol, respectively
17
. A clinical study showed
that excretion of the lignans enterodiol and
enterolactone was significantly higher during a
carotenoid (carrot and spinach) and cruciferous
(broccoli and cauliflower) vegetable diet than
during a vegetable-free diet
18
.
Coumestans
Legumes are the main source of coumestrol, the
coumestan showing the highest estrogenic activ-
ity, and low levels of coumestrol have also been
found in brussels sprouts and spinach, while the
highest concentrations are reported in clover and
in soybean sprouts.
Stilbenes
Recently, the stilbene resveratrol has also been
identified as a phytoestrogen. Resveratrol is a
natural compound produced by some plants,
such as grapevines, in response to injury. Peanuts
are rich in resveratrol too. Polygonium cuspidatum
roots, which have long been used in traditional
oriental medicine, have been identified as the
major active source of stilbene phytoalexins.
Trans-resveratrol was first detected in grapevines
in 1976 by Langcake and Pryce, who found that
this compound was synthesized by leaf tissues in
response to Botrytis cinerea fungal infection or
exposure to UV light
19
.
The biological activity of resveratrol was
attested about 15 years ago by the health bene-
fits obtained with orally administred resveratrol.
An experimental study suggested that an aver-
age drinker of wine may, in the long term, absorb
a quantity of resveratrol sufficient to explain the
beneficial effect of red wine on human health
20
.
Resveratrol possesses anticancer properties and
antioxidant activity, and some observations have
challenged the protective effects of resveratrol
against atherosclerosis thus preventing cardio-
vascular disease. As a phytoestrogen it may
favorably influence several physiological pro-
cesses, and, given that resveratrol has a different
structure, its mechanism of action might differ
somewhat from that of other flavonoids
19,20
.
HEALTH-BENEFICIAL EFFECTS OF
PHYTOESTROGENS
In the past two decades, many clinical and epi-
demiological studies have been performed to test
the health effects of foods and supplements rich
in phytoestrogens. A recent review summarizes
the main results from scientific studies
21
. The
effects of phytoestrogen administration are eval-
uated on different clinical end-points as listed in
Table 4.
Cardiovascular health
Estrogen may affect the vascular system both
directly through the ERs located on vascular
tissue, and indirectly through altering the
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lipoprotein profile
22
. Initial epidemiologic stud-
ies showed that women taking hormone replace
therapy (HRT) were 50% less likely to experi-
ence severe cardiovascular disease (CVD) than
women not taking HRT
23
. Lately, a more com-
prehensive study performed by the Women’s
Health Initiative has demonstrated a significant
increase in CVD in the first year of HRT use,
which is still elevated after 5 years of continued
use
24–26
. There are several clinical studies that
have examined the effect of phytoestrogens on
CVD. Isoflavonoids or soy/soy protein and
flaxseed have the ability to lower total choles-
terol
27,28
and low-density lipoprotein (LDL) cho-
lesterol
27,29
, and to raise high-density lipoprotein
(HDL) cholesterol
30,31
. In contrast, other studies
have shown no effect of isoflavonoids derived
from soy or red clover on serum cholesterol lev-
els or plasma lipids
32,33
.
Although no clinical studies have shown that
resveratrol improves cardiovascular function, the
consumption of red wine has been linked to the
‘French paradox’, a phenomenon observed in
French people who have a diet similar to the
North American diet, with a significantly lower
rate of CVD
34
.
Cancer
There is a large body of evidence coming from
epidemiologic studies showing that people who
consume high amounts of isoflavonoids in their
diets have lower rates of occurrence of several
cancers, including breast, prostate and colon
cancer
35
.
The protective effect of phytoestrogens on
cancer may be due to their role in lowering cir-
culating levels of unconjugated sex hormones.
Estrogens mainly circulate as inactive conjugates
of sex hormone-binding globulin (SHBG) or
albumin
36
. Dietary supplementation with soy
isoflavonoids or lignans produced an increase of
the levels of SHBG in postmenopausal women,
lowering the serum levels of estradiol
37,38
. Fur-
thermore, higher intakes of soya products and
flaxseed produced a significant decrease of the
urinary excretion of genotoxic estrogen metab-
olites
39
. Moreover, the role of phytoestrogens in
preventing cancer in women may be related to
changes in menstrual cycle length
40
. Increases in
menstrual cycle length together with eating a
diet rich in phytoestrogens correlate with a
decreased rate of hormone-dependent cancer
development, including endometrial, ovarian
and breast cancers
41
.
Menopausal symptoms
Epidemiological studies show that Asiatic
women experience less severe, less frequent hot
flushes than Western women, 20% vs. 80%,
respectively.
Diet has been included among the various
reasons proposed to explain such a proven differ-
ence. Indeed, the Asian diet is known to be rich
in phytoestrogens, and, even though only a few
clinical trials have been conducted to evaluate
the role of these bioactive substances in regulat-
ing menopausal symptoms, most data from ran-
domized studies indicate a significant drop in the
severity and frequency of such symptoms. How-
ever, women given placebo also demonstrated a
decline in menopausal symptoms
42,43
. The vari-
ability in frequency and severity of hot flushes
and the high placebo-response rate make these
clinical trials difficult to interpret, and, currently,
they are not sufficient to demonstrate the
223
Table 4 Summary of phytoestrogen clinical studies.
Modified from reference 21
Clinical end-points Positive results (n) Total (n)
Maintaining bone 11 15
density
Relief of menopausal 4 17
symptoms
Cardiovascular benefit 25 38
Cancer prevention 7 13
Hormone levels/ 12 19
menstrual cycle
Effect of hormones 0 1
in men
Immune system 1 1
Neurological 5 5
Total
*
64 105
*
Totals are less than the sum of the studies since some
studies examined several clinical end-points
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