Maturitas 42 (2002) 13 – 22

www.elsevier.com/locate/maturitas

Review

Polyunsaturated fatty acids. Is there a role in

postmenopausal osteoporosis prevention
Paola Albertazzi a,*, Keith Coupland b
a
Centre for Metabolic Bone Disease, H. S Brocklehurst Building, Hull Royal Infirmary, 220 -236 Anlaby Road, Hull HU3 2RW,
UK
b
Department of Chemistry, Lipid Research Centre, The Uni6ersity of Hull, Hull, UK
Received 21 June 2001; received in revised form 27 November 2001; accepted 7 February 2002

Abstract

Objecti6e: To review the effect of a diet supplemented with polyunsaturated fatty acids (PUFA) on prevention or
treatment of osteoporosis. Methods: MEDLINE (1966– April 2001), Allied Complementary Medicine (1985– 2001),
Cochrane Library and Database of Systematic Reviews (1st Quarter 2001) was searched. Five reviews and no
systematic reviews were found on this topic in the Cochrane Library. Eleven relevant in-vivo studies were identified
on the effect of these compounds on bone. Eight were animal studies and three were randomised control trials (RCT)
in human. Results: There are two classes of PUFA designated as n-3 and n-6 with alpha-linolenic acid (ALA). These
two different types of PUFA differently influence prostaglandin formation and hence modulate bone metabolism
differently. These are several in vitro and animal data suggesting that diet with a low n-6/n-3 ratio may have beneficial
effects on bone mineral density. Only three, short-term, small studies have been performed in human so far. Two
studies, one performed with bone markers and one with bone density showed a positive effect of PUFA on bone.
While a third study showed no effect. Conclusions: Preliminary, data have suggested that a diet with a low n-6/n-3
ratio may have beneficial effects on bone mineral density. Further studies are, however, required to fully assess the
dose and type of PUFA to be used for optimum bone effects. This may be useful particularly for the prevention of
disease in the elderly, since a diet rich in n-3 PUFA has been shown to have additional benefit on the cardiovascular,
central nervous system and joints. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Polyunsaturated fatty acids; Aging; Menopause

1. Introduction

The ageing of the population is one of the

* Corresponding author. Tel.: + 44-1482-675300; fax: + 44-
1482-675301.
E-mail address: p.albertazzi@medschool.hull.ac.uk (P. Al-
bertazzi).
major challenges of this century. Diet and lifestyle
play a crucial role in maintaining the health of
this growing portion of the community. A healthy
diet will not only prolong life (per se a doubtful
endpoint) but it is also crucial to disease preven-

0378-5122/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 3 7 8 - 5 1 2 2 ( 0 2 ) 0 0 0 2 2 - 1
14 P. Albertazzi, K. Coupland / Maturitas 42 (2002) 13–22
tion. Conditions such as cardiovascular disease,
dementia and osteoporosis together with cancer
dominate as leading causes of mortality and mor-
bidity in the elderly. Medications such as hor-
monal replacement therapy (HRT) are presently
used in postmenopausal women for the preven-
tion of osteoporosis, [1] cardiovascular disease, [2]
and Alzheimer’s disease and to improve cognitive
functions [3]. However, the non-acceptance and
non-continuation with these therapies is common,
and mainly due to proven or patient-perceived
side effects [4]. Food or food supplements consti-
tute a much more desirable alternative [5,6]. This
is evidenced by the rapid growth of the nutraceu-
tical industry and the vast interest expressed by
consumers. It is a commonly held view that food
or a food component can offer medical or health
benefits (including the prevention or treatment of
disease) above and beyond simple nutrition [7].
Marine oils are a good source of polyunsaturated
fatty acids (PUFA) and have traditionally been
used for the prevention of disease. Fish oils in-
cluding cod liver oil have been shown to have
several potential benefits in the postmenopausal
woman. Preliminary data have suggested that
they may help to reduce the risk of cardiovascular
disease [8], stroke [9], they have beneficial effects
on bone mineral density [10], on the central ner-
vous system [11], and on joints [12].
Japanese, consuming a traditional diet, have
been found to have a low incidence of breast and
prostate cancer, cardiovascular disease, os-
teoporosis, and in women of climacteric symp-
toms [13].
Soy alone is usually implicated in relation to
the health benefits of the traditional Japanese diet.
These diets are not exclusively soy of course and
fish is also a major component. Japanese fisher-
man who were found to eat approximately 180 g
of fish per day, and mainland Japanese with a
mean fish intake in the order of 90– 120 g daily
have also been found to have a remarkably low
incidence of cardiovascular disease [14]. Other
populations with a low prevalence of heart disease
such as the Greenland Eskimo have an estimated
intake of 400 g of seafood per day [15]. Fatty fish
consumption in Sweden has also been recently
associated with lower incidence of prostate cancer
[16]. It is conceivable, therefore, that fish or some
component in fish contributes to the overall
beneficial clinical effect. Fish oils are the richest
dietary sources of the metabolically active n-3
fatty acids derivatives eicosapentaenoic acid
(EPA) and docosahexaenoic acid (DHA). These
are the main compounds considered to be clini-
cally useful and most effective in preventing dis-
ease processes [17]. This review examines the
evidence supporting a role for supplementing the
diet with PUFA to prevent postmenopausal bone
loss.
2. Methods
We searched MEDLINE (1966–April 2001),
Allied Complementary Medicine (1985–2001),
Cochrane Library and Database of Systematic
Reviews (1st Quarter 2001). We combined the
medical subject headings; polyunsaturated fatty
acids, essential fatty acids, fish oil, with osteoporo-
sis, bone, bone mineral density, and menopause.
Additional articles were obtained from references
lists of relevant reviews. Five reviews and nine
primary data were identified. No systematic re-
views were found on this topic in the Cochrane
Library. Eleven relevant in-vivo studies were iden-
tified on the effect of these compounds on bone.
Eight were animal studies and three were ran-
domised control trials (RCT) in human.
2.1. The link between types of lipids and bone
The link between lipid, fat and bone is a tight
one. Adipocytes share a common mesenchymal
stem cell precursor with osteoblasts, chondro-
cytes, tenocytes and myeloblasts, which suggests a
link between lipid metabolism and connective tis-
sue [18]. Some factors favour differentiation in
either osteoblast or adipocyte but the link be-
tween cell types continues once differentiation has
taken place [19]. Cell expressing an osteoblastic
phenotype can be changes in vitro to adipocytes,
trabecular bone in human can express either phe-
notypes [20]. Statins given to patients for hyperc-
holesterolemia have anabolic effects on bone,
thereby indicating the mevalonate pathway is
 P. Albertazzi, K. Coupland / Maturitas 42 (2002) 13–22
common to both bone and lipid regulation [21].
Furthermore, there is evidence that lipids in the
circulation, in particular fatty acids, act as
metabolic substrates or as signalling molecules in
bone metabolism [22].
2.2. What are polyunsaturated fatty acids?
Fatty acids are unbranched hydrocarbon chains
with an even number of carbon ranging from
short chain fatty acids (four carbon atoms),
medium chain fatty acids (6– 12 carbon atoms)
and long chain fatty acids (14 or more carbon
atoms). Depending on the presence and number
of double bonds, fatty acids can be saturated (no
double bond) monounsaturated (one double
bond) or polyunsaturated (more than one double
bond). In animal diets, including that of humans,
the polyunsaturated fatty acids linoleic acid (18:2
n-6) and alpha-linolenic acids (18:3 n-3) are ‘es-
sential’ for normal growth and function. Human
biosynthetic enzymes can only insert a double
bond at the n-9 position or higher; but not in any
Fig. 1. Origin of n-3 and n-6 unsaturated fatty acids.
15
position closer to the methyl end such as position
6 or 3. Only plants and some fish are able to
synthesise these PUFA from shorter chain fats
(Fig. 1). Fatty acids vary in their chain length, as
well as the position of double bonds along the
hydrocarbon chain. The nomenclature used iden-
tifies the chemical structure of these compounds.
Hence linoleic acid (18:2 n-6) has an 18-carbon
chain, and two carbon–carbon double bonds, the
first of which is formed at carbon-6 when counted
from the methyl terminus. The EFA alpha-lino-
lenic acid (18:3 n-3) also has an 18-carbon back-
bone but with three double bonds beginning at
carbon 3. Both the letter ‘n’ or ‘v’ followed by a
number can be used interchangeably to indicate
the position of the first double bond. The latter is
specifically important as it indicates the essential-
ity of fatty acid. This chemical numbering is
useful to highlight fatty acids families, which are
related metabolically.
The essential fatty acid content of oils from
both plants and animal sources varies widely.
Short and medium chain fatty acids are found in
16 P. Albertazzi, K. Coupland / Maturitas 42 (2002) 13–22
Fig. 2. Formation of polyunsaturated fatty acids (PUFA).
vegetable oils and dairy fat, whereas fish oils and
certain plants contain fatty acids mainly of the
n-3 family. As a rule n-6 fatty acids are found in
vegetable fat and not in meat products, an excep-
tion being arachidonic acid (C20:4 n-6). (Fig. 1)
[17]. Plant-derived oils vary widely in composi-
tion, largely because of genetic and environmental
factors. In the case of animal fat, the composition
of the feed also affects fatty acid composition.
2.3. Sources of PUFA
The two classes of PUFA are designated n-3
and n-6 with alpha-linolenic acid (ALA) and
linoleic acid (LA) being the respective parent
members. LA is found in seeds of most plants
except coconut, cocoa, and palm and ALA is
found in the chloroplast of green leafy vegetables.
Both PUFA are metabolised to longer-chain fatty
acids of 20 and 22 carbon atoms. LA is converted
to arachidonic acid (AA) and ALA to eicosapen-
taenoic acid (EPA) and docosahexaenoic acid
(DHA). The chain length and degree of unsatura-
tion is increased by inserting extra double bonds
and by the addition of 2-carbon units to the
carboxyl group (Fig. 2). Humans can convert LA
to AA and ALA to EPA and DHA [23]. While
there is competition between n-3 and n-6 fatty
acids for the desaturation enzymes, the n-3 fatty
acids are better substrates for both the D-4 and
D-6 desaturases. Furthermore, there is some evi-
dence that D-6 desaturase activity decreases with
age [23] and with conditions such as hypertension
[24] and diabetes [25]. DHA and EPA can only be
obtained from the diet or by endogenous synthesis
from ALA.
2.4. The physiological role of PUFA n-6
(omega-6) 6 6ersus n-3 (omega-3)
Polyunsaturated fatty acids have two funda-
mental physiological functions. They are present
in high concentrations in all membranes as struc-
tural phospholipids and are the primary precur-
sors of the eicosanoids.
Arachidonic acid (C20:4 n-6), eicosapentaenoic
acid (C20:5 n-3) and docosahexaenoic acid (C22:6
n-3) are the most important and abundant long-
chain PUFA found in membrane phospholipids.
DHA predominates in the brain and in specialised
tissues such as retina and spermatozoa and is also
the most abundant component of the brain’s
structural lipids [26]. Adipose tissue contains fatty
acids of variable length.
The chain length and degree of unsaturation of
tissue fatty acids largely determines membrane
fluidity and other physical properties of mem-
brane phospholipids. These physical properties, in
turns, affect the ability of membrane phospho-
lipids to perform structural function, such as the
maintenance of normal activities of membrane
bound enzymes.
The heterogeneity and selectivity of PUFA with
respect to their tissue membrane distribution
among different organs may also be related to
their structural and functional role [27].
In addition to their structural role and their
movement across membranes, PUFA can also
affect cell function either by modulating intracel-
lular signal transduction or modulating cell–cell
interaction. These actions are initiated by phos-
pholipases such as phospholipase A2. PUFA re-
leased under the action of phospholipase are freed
extracellularly and act on other cells which pro-
duce mediators such as platelet activating factor
(PAF) and the eicosanoids.
 P. Albertazzi, K. Coupland / Maturitas 42 (2002) 13–22
Eicosanoids are produced from PUFA with
chain length of 20 carbon atoms. Eicosanoids
include the prostaglandins (PG), thromboxane
(TXA) and leukotrienes (LT). PG and TXA are
generated via cyclooxygenase (COX) enzymes,
whereas LT, hydroxy acids and lipoxins are pro-
duced from PUFA by lipoxygenase metabolism.
The two essential fatty acid families (n-3 and
n-6) are converted into two distinct families of
eicosanoids each with unique physiological prop-
erties. Competition between the two classes of
PUFA occurs in prostaglandin formation (Fig. 3).
Two n-6 EFA; di-homo-g-linolenic (20:3 n-6) and
arachidonic acid (20:4 n-6) and one n-3 EFA;
eicosapentaenoic acid (20:5 n-3) are eicosanoid
precursors (Fig. 3). Arachidonic acid is the pre-
ferred substrate for cyclooxygenase and is more
efficiently converted to eicosanoid than EPA.
PUFA of the n-6 family lead to the production of
PGE2, TXA2 (a potent platelet aggregator and
vasoconstrictor), LTB4 a pro-inflammatory ei-
cosanoid and powerful inducer of leukocyte
chemotaxis and adherence. EPA, however, tends
Fig. 3. Effects of n-6 and n-3 on prostaglandin formation.
17
to increase prostacyclins that are active vasodila-
tors and inhibitors of platelet aggregation. EPA
also increases LTB5, a weak inducer of both infl-
ammation and chemotacticity [28].
Thus diets rich in n-3 produce modulate ei-
cosanoids production towards products of blan-
der inflammatory potential. The prostaglandin E3
formed from EPA has milder inflammatory effects
compared with PGE2 derived from AA. The
leukotriene LTB5 derived from EPA is substan-
tially less pro-inflammatory and has a milder ef-
fect on neutrophils aggregation and chemotaxis
compared with the AA produced LTB4. Overpro-
duction of AA derived eicosanoids has thus been
implicated in many inflammatory and autoim-
mune disorders such as thrombosis, autoimmune-
inflammatory disease (e.g. arthritis, lupus,
nephritis), cancer and psoriatic skin lesion, among
others. PUFA from the n-3 family are anti-throm-
botic. EPA derived PGI3 has, in fact, anti-aggre-
gatory properties whereas the AA derived TXA2
is a powerful thrombogenic, vasoconstricting and
bronchoconstricting agent.
18 P. Albertazzi, K. Coupland / Maturitas 42 (2002) 13–22
2.5. Recommended intake
From epidemiological evidence, the estimated
desirable intake is of 35 g of fish daily. This
corresponds to two portions of fatty fish per
week, or 3 –4 g of standardised fish oil daily or
more specifically 1.25 g of a combination of EPA
(20:5 n-3)+DHA (22:6 n-3).
This is what the British Nutrition Foundation
recommended [29], and is far above mean con-
sumption in Western population that averages
that is presently about 0.25 g EPA+DHA [30].
The recommended dose of PUFA is associated
with a reduced risk of death from coronary heart
disease (CHD), especially myocardial infarction.
The optimal n-6/n-3 ratio in the diet is not yet
clear and may vary with the developmental stage,
the presence of long chain fatty acids and other
factors. Same authorities have suggested that the
n-6/n-3 essential fatty acid should be in the ratio
of 4:1–10:1; others believe optimal ratio should
be 4:1 or lower [31].
Dietary protein intakes also appear to have
strong influences on the activity of D-6 desaturase
and thus the amount of AA acid and DHA that is
formed from precursors [32].
3. PUFA effect on bone
3.1. Effects of eicosanoids on bone in-6i6o
The activity of bone formation and bone re-
sorption is regulated by systemic hormones and
local factors produced in bone. Amongst the lo-
calised compounds that act on bone cells ei-
cosanoids seems be the principle mediator.
Prostaglandin E2 is a potent stimulator of bone
resorption and the primary PG affecting bone
metabolism. Prostaglandins influence the synthe-
sis and action of insulin-like growth factors
(IGFs) that are major bone-derived growth fac-
tors [33]. PGE2 was reported to increase cortical
bone mass and intracortical bone remodelling in
both intact and ovariectomised rats, [34] and in-
crease proximal tibial metaphyseal bone area in
osteopenic ovariectomised rats [35]. On the other
hand Raisz and Fall reported that infusion of
PGE2 at high concentration depressed osteogene-
sis in rat calvaria [36]. Thus the effect of PGE2 on
bone formation may have a biphasic, dose-depen-
dent effect— stimulatory at low concentration but
inhibitory at high concentrations often associated
with inflammation [37]. Similarly to
prostaglandins, leukotrienes may also play an im-
portant role on bone metabolism. In particular
LTB4, LTC4, LTD4 and LTE4, that are all pro-
duced from n-6 PUFA (Fig. 3) have been shown
to increase bone resorption and osteoclast number
in vivo and in vitro [37].
Attenuation of PGE2 formation in human and
murine osteoblast cell culture increases markers of
bone formation [38,39]. In experiments on the
MC3T3-E1 osteoblast-like cell lines, EPA reduced
PGE2 and increased alkaline phosphatase activity
and osteocalcin compared with cell treated with
arachidonic acids and interleukin-1 (a cytokine
associated with bone resorption) [40].
3.2. Effects on animals
The importance of essential fatty acids in rela-
tion to calcium homeostasis was first reported in
1931 [41]. Other papers appeared after a gap of 20
years and reported that essential fatty acid defi-
ciency was associated with loss of normal synthe-
sis of bone connective tissue matrix, loss of
normal cartilage, and bone demineralisation [42].
Animal studies using different ratios of n-6 to n-3
PUFA as supplements to a semi-synthetic diet
showed that a low n-6/n-3 ratio such as 1:1 in-
creased bone calcification in both male and female
ovariectomised rat [43,44]. Dietary fish oil supple-
mentation adversely affected cortical bone in
growing rabbits [45]. Differences in lipid
metabolism between these animals and human
make this evidence difficult to interpret [46]. Male
rat fed different combination of PUFA in the
form of soy oil as a source of n-6 versus a
combination of menhaden and safflower oil that is
a good source of n-3 PUFA with and without
conjugated linolenic acid (CLA) showed a modu-
lation on IGF-I and prostaglandin production. In
particular rats fed soy oil had higher endogenous
production of PGE2 and lower ash weight per
millimeter of bone length in humeri compared
 P. Albertazzi, K. Coupland / Maturitas 42 (2002) 13–22
with rats fed an n-3 rich diet [47]. A similar diet
combination fed to male chicks produced a varia-
tion in eicosanoid production and the addition of
acetylsalicylic acid further modulated PGE2 pro-
duction. PUFA supplementation increases cal-
cium balance and absorption [48– 50]. EPA also
appeared to reduce phosphate excretion in rats,
[51] and pathological fractures have been shown
in animals after PUFA deficiency that could not
be prevented by Vitamin D supplementation [52].
3.3. Effects on human
So far only three studies have been performed
on the effects of PUFA on human for osteoporo-
sis prevention and treatment. These involved a
total of 190 women and using mixtures of evening
primrose oil (rich in n-6 GLA) together with n-3
rich fish oil. Results have been rather contradic-
tory (Table 1). Kruger et al. performed a ran-
domised placebo controlled study in 65
postmenopausal women with low bone mass (T
score between − 1 and −2.5). Women were fed 6
g per day of a mixture of evening primrose oil and
fish oil. These two oils would have provided
linoleic acid (60%), g-linolenic acid (8%), eicos-
apentaenoic acid (4%) and docosahexaenoic acid
(3%). After 18 months, women on the active
treatment maintained bone mass at the lumbar
spine while women on placebo lost about 3%.
Women on the active treatment had 1.3% increase
at the femoral neck while women on placebo had
a 2.1% decrease. Osteocalcin and deoxypyridino-
line levels fell in both groups possibly underlying
a decrease in bone turnover [53].
Vanpapendorp and colleagues [54] supple-
mented the diet of 40 osteoporotic patients with
evening primrose and fish oil or olive oil (placebo)
for 16 weeks. Patients supplemented with the
PUFA rich oils showed an improvement in cal-
cium absorption and an stimulation of osteoblas-
tic activity indicated by a rise in osteocalcin and
procollagen both markers of bone formation.
Bassey et al. [55] failed to show any effect in
total bone mineral density in 43 premenopausal
women and 42 postmenopausal women ran-
domised to either Efacal® or placebo for 12
months. Efacal® contained 4 g of primrose oil, 1 g
19
of calcium and 440 mg of marine fish oil per day.
No significant difference was observed also in
markers of bone turnover.
4. Conclusion
There is a strong interest in strategies that will
reduce the risk of osteoporosis and the related
health care cost. Furthermore, one of the con-
cerns is to maintain a high quality of life into old
age. Another concern is the continuous and explo-
sive growth in public health care costs. This has
lead to governmental measures that let people pay
relatively high self-contributions for medical treat-
ment. One of the results of these developments is
a growing trend toward self-medication. Since
drugs cannot be obtained without prescription,
consumers seek for natural products to fit their
need and expectation [56]. Furthermore, nutrition
is traditionally a critical component of risk reduc-
tion and treatment and must be included in clini-
cal and perspective services for women. There are
some in vivo and in vitro studies which indicate
that polyunsaturated fatty acids and, in particu-
lar, a diet rich in n-3 PUFA might be protective
against osteoporosis. The data in humans are
scanty. In vitro and animal data appear to suggest
that the effects of PUFA are mediated through
modulation of PGE2 production. Prostaglandins
particularly PGE2 have been widely implicated in
bone metabolism. Lower concentrations of PGE2
have been associated with bone formation while
higher concentrations have been shown to be
associated with resorption [57]. The eicosanoid
balance has been shown to depend on the fatty
acid precursors supplied with the diet. Diets rich
in n-3 lower the ratio of n-6 to n-3 and least in
animal studies have shown the most promising
results. Fish and fish oils are an easy way to add
n-3 fatty acids to the diet. Several problems,
however, prevent the widespread use of fish and
fish oil. To be effective fish oil has to be taken in
large doses that are both expensive and unpalat-
able. Furthermore, fish is presently not a sustain-
able resource and an alternative source of equally
clinically effective compounds needs to be found.
Further data on the optimal dose and source of
 20

Table 1
Effects of PUFA on bone human studies

Subjects Duration in Design PUFA Effect on bone P

months

[55] 42 pmw 18 Double blind placebo Efacal® 4 g evening primrose oil 440 mg marine BMD total body Ns
fish oil 1 g ca
[53] 65 pmw 18+18 (21 Double blind placebo for 6 g (60% A, 8% g ALA, 4% EPA 3% DHA)   1.3% BMD hip
BMD 0.037
patients only) first 18 months spine
[54] 40 osteoporotic 16 weeks Double blind RCT Evening primrose 9 fish oil   Osteocalcin,   serum Ca, 0.05
patients   procollagen
P. Albertazzi, K. Coupland / Maturitas 42 (2002) 13–22
 P. Albertazzi, K. Coupland / Maturitas 42 (2002) 13–22
n-3 fatty acids is warranted and the performance
of long-term human study is critical to obtain an
ideal form of supplementation that will be both
acceptable to consumers and effective to improve
bone density and resource the incidence of
osteoporosis.
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