Endocrine care

doi: 10.4183/aeb.2012.67
DOES OBESITY PROTECT POSTMENOPAUSAL WOMEN
AGAINST OSTEOPOROSIS?

S.Oros1, O. Ianas1, S.Vladoiu1, M. Giurcaneanu1, L. Ionescu 1, E. Neacsu 1,

G.Voicu1, M. Stoiceanu 1, R. Rosca 2, C. Neamtu2, C. Badiu2, C. Dumitrache2

1C.I.Parhon National Institute of Endocrinology - Research Dpt., Bucharest,

Romania, 2 C.I. Parhon National Institute of Endocrinology Clinical Department,
Bucharest, Romania
Abstract
Introduction. Obesity was considered
to protect against osteoporosis. Recent
studies indicate the opposite.
The study aimed to see if adipose
tissue has a protective effect on bone mass
and if adipocytokines can explain the
relationship between obesity and
osteoporosis.
Subjects and methods
We designed a study enrolling 83
postmenopausal women, aged over 60,
without diagnosed or treated osteoporosis
and no secondary osteoporosis. We formed
3 groups- group 1- osteoporosis and
metabolic syndrome (MetSyn), group 2-
osteoporosis, group 3- MetSyn.
We evaluated the hematological,
biochemical profile, bone turnover markers
and adipocytokines. DXA of the spine and
the hip (left) was performed on all the
enrolled women. Insulin resistance was
appreciated using HOMA index. Metsyn
was defined using the International Diabetes
Federations criteria.
Results were statistically analyzed
using SPSS program, version 15.
Results. All groups were vitamin D
insufficient with lower vitamin D,
osteocalcin and adiponectin levels in the
groups with MetSyn and higher leptin
levels. BMI correlated positively with spine
BMD, while leptin correlated positively
with hip BMD, pointing out to the
protective effect of obesity against
osteoporosis due to leptins involvement.
Conclusion. Obesity seems to have a
protective effect against osteoporosis,
probably due to leptin.
Key words: osteoporosis, obesity,
metabolic syndrome, adipocytokines.
INTRODUCTION
Obesity and osteoporosis are major
health problems, considered until now
to be two unrelated diseases, studied
intensively in order to explain their
physiological relationship (1).
A substantial body of evidence (2)
indicates that fat mass may have

*Correspondence to: Sabina Oros, MD, C.I. Parhon National Institute of Endocrinology -
Research Dpt., Aviatorilor 34-36, Bucharest 011863, Romania, Email: sabinaoros@yahoo.com
Acta Endocrinologica (Buc), vol. VIII, no. 1, p. 67-76, 2012

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 S.Oros et al.
beneficial effects on the bone, while
contrasting studies (3) reported that
increased visceral fat is associated with
reduced lumbar spine BMD (bone
mineral density) in men and that
excessive fat mass may not protect
against osteoporosis or osteoporotic
fracture.
The relationship between body
weight and BMD is complex and not
completely understood. Possible
explanations for the protective bone
effects of increased body weight include
increased aromatization of androgens to
estrogen in adipose tissue, mechanical
loading, lower levels of sex hormone-
binding globulin, and increased bone
formation due to high circulating insulin
levels (4,5). In normal pre- and
postmenopausal women, total body fat is
positively related to BMD throughout the
skeleton and that rapid bone losers have
significantly lower fat mass than the slow
bone losers (1).
Menopause has also been associated
with increased bone loss, increased fat
mass and decreased lean mass. When the
mechanical loading effect of total body
weight is statistically removed, fat mass is
negatively correlated with bone mass,
suggesting that fat mass has actually a
detrimental effect on the bone (1).
Studies of adipocyte function have
revealed that adipose tissue expresses and
secretes estrogen, resistin, leptin,
adiponectin, and interleukin-6 (IL-6) that
affect human energy homeostasis and
may be involved in bone metabolism.
In obese postmenopausal women,
increased extragonadal estrogen synthesis
caused by high fat mass has been
suggested as one of the potential
protective mechanisms.
68
Adiponectin and its receptors are
expressed in primary human osteoblasts,
suggesting a link between adiponectin and
bone. In vivo and in vitro studies indicate
that adiponectin actually increases bone
mass by suppressing osteoclastogenesis
and by activating osteoblastogenesis (1),
while another study showed that
adiponectin increases osteoclast formation
by stimulating the production of receptor
activator of nuclear factor- B ligand
(RANKL) that stimulates osteoclast
differentiation and activity and by
inhibiting the production of
osteoprotegerin (OPG), an inhibitor of
osteoclastogenesis, in osteoblasts (1,6).
The fact that leptin, a hormone
released from fat tissue, can regulate bone
mass first came to prominence in 2000.
Increased leptin during obesity (7,8) may
represent a mechanism for enlarging bone
size and thus bone resistance to cope with
increased body weight. The role of leptin
in bone turnover and osteoporosis is not
completely understood. In vitro data
suggest that leptin stimulates bone
formation possibly by acting on human
marrow stromal cells to enhance
osteoblast and inhibit adipocyte
differentiation. Leptin also inhibits
osteoclastogenesis by decreasing the
receptor activator of nuclear factor-B
(RANK) and its ligand (RANKL) and
increasing the production of
osteoprotegerin. In a prospective study of
postmenopausal women, plasma leptin
was positively correlated with BMD at
the lumbar spine, femoral neck and total
body (5).
Resistin, another adipokine
discovered some years ago, was identified
as an adipose tissue-specific secreted
factor, as a protein found in inflammatory
 Obesity and osteoporosis
zone 3 (FIZZ3), and as a hormone that
potentially linked obesity to diabetes.
Thommesen (9) showed that
resistin may play a role in bone
remodeling. Their study indicates that
resistin is expressed in mesenchymal
bone marrow stem cells, osteoblasts,
and osteoclasts and that resistin
increases osteoblast proliferation and
cytokine release, as well as osteoclast
differentiation.
AIM
To see if adipose tissue and the
presence of metabolic syndrome have a
protective effect on bone mass and if
adipokines and cytokines can be
involved in adipose-bone tissue
communication.
SUBJECTS AND METHODS
We designed a study enrolling
postmenopausal women, aged over 60,
without diagnosed osteoporosis. Women
with secondary causes for osteoporosis
and women receiving already
osteoporosis treatment were excluded.
In order to see the influence of
adipose tissue on bone mass we formed
three groups: group 1- women with
osteoporosis and MetSyn; group 2-
women with osteoporosis without
MetSyn; group 3- women with MetSyn
without osteoporosis
The patients were informed about
the study protocol (approved by the Ethic
Committee of the institute), number of
visits and the possibility to receive free
treatment for osteoporosis in The National
Osteoporosis Treatment Program.
Blood samples were taken early in
the morning after a 12 hours fasting
period, in order to evaluate their
hematological, biochemical profile, bone
turnover markers (PTH, 25 OH vitamin
D, osteocalcin and crosslaps) and
adipocytokines (adiponectin, leptin,
resistin, CRP, TNF and IL6). We used
R&D System ELISA commercial kits,
provided by Cybermed. Normal ranges
were for adiponectin: 8.65-214.24 ng/mL,
for leptin:3.87-77.27 ng/mL, for resistin:
1.287-5.28ng/mL, for TNF alpha: <15.6
pg/mL, for IL6: 3.12-12.5 pg/mL and for
CRP: 0.0-0.5 mg/dL.
Dual-emission X-ray absorptio-
metry (DXA) of the spine and the hip
(left) was performed on all the enrolled
women using the same DXA machine.
Insulin resistance was appreciated using
the formula:
HOMA-IR= (Insulin x glucose x
0.05551) / 22.5.
Metsyn was defined using the
International Diabetes Federations
criteria.
Results were statistically analyzed
using SPSS program, version 15; results
are expressed as means standard error.
We used t-test to compare
means between groups and Pearsons
coefficient for correlations and logistic
regressions to predict risk factors. They
are considered statistically significant if
p is 0.05.
RESULTS
Eighty-three postmenopausal
women without known osteoporosis were
enrolled after signing a written consent.
They were divided into 3 groups due to
DXA results and the presence of MetSyn-
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 S.Oros et al.

group 1- 16 postmenopausal women with group 1.

osteoporosis and MetSyn, group 2- 16
postmenopausal women with
osteoporosis without MetSyn and group
3- 51 postmenopausal women with
MetSyn without osteoporosis.
We compared mean values and we
Adiponectin mean values were in
the normal range (Table 2) with lower
levels in group 3 when compared with
group 1(p=0.007), and p=0.001- when
compared to group 2 (Table 2). There was
a tendency towards lower adiponectin

Figure 1. 25 OH vitamin D mean values in Figure 2. mean values in group 1 (red

group 1 (red column), group 2 ( blue column), group 2 ( blue column), group 3
column), group 3 (green column) . (green column) (p<0.001 group 3 vs
group1; p=0.001-group 3 vs group 2).

found higher left hip BMD in group 3
when compared to group 1 and 2
(p<0.001)- see Table 1; 25 OH vitamin
D levels in the insufficiency domain for
all three groups with lower vitamin D
levels in group 1 when compared to
group 3 (p=0.045) and even lower
vitamin D levels in group 1 when
compared with group 2 (p=0.003) (table
2 and Fig. 1). 25 OH vitamin D mean
values in groups 2 and 3 did not differ
statistically significant.
The lowest osteocalcin mean values
were in group 3 (p=0.001- versus group 1;
p<0.001- versus group 2- Table 2, Fig. 2),
with a tendency to higher osteocalcin
values in group 2 when compared to
values in group 1 when compared to
group 2, but without statistical difference
(Fig. 3).
Leptin mean values were higher in
group 3 when compared to group 2
(p=0.001), suggesting the protective
effect of leptin on bone mass (Fig. 4).
The highest CRP levels were in
group 3 when compared to group 1
(p=0.001), while crosslaps were the
highest in group 1 when compared with
group3 (p=0.037, Table 2).
In group 1, BMI correlated
positively with spine BMD (p=0.031,
Fig. 5), leptin (p=0.022); insulinemia
correlated positively with osteocalcin
(p=0.004); crosslaps correlated positively

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 Obesity and osteoporosis

Table 1. Mean values of physical variables of study groups

Variables Group Group 1 Group 2
1 vs 2 vs 3 vs 3
Mean SEM p Mean SEM p Mean SEM p
left hip BMD 0.719 0.03 0.471 0.72 0.03 <0.001 0.75 0.03 <0.001
g/cm2 0.746 0.03 0.471 0.90 0.02 <0.001 0.90 0.02 <0.001
spine T score -2.789 0.22 0.697 -2.89 0.22 <0.001 -3.01 0.20 <0.001
-3.01 0.20 0.697 -0.91 0.15 <0.001 -0.91 0.15 <0.001
spine z score -1.58 0.23 0.899 -1.58 0.23 <0.001 -1.53 0.25 <0.001
-1.53 0.25 0.899 0.02 0.16 <0.001 0.02 0.16 <0.001
left hip T score -2.26 0.20 0.483 -2.26 0.20 <0.001 -2.06 0.21 <0.001
-2.06 0.21 0.483 -1.04 0.12 <0.001 -1.04 0.12 <0.001
left hip Z score -0.58 0.26 0.896 -0.58 0.26 0.011 -0.63 0.20 0.003
-0.63 0.20 0.896 0.08 0.12 0.034 0.08 0.12 0.006
BMI 28.03 1.05 0.012 28.03 1.05 0.029 24.10 1.03 <0.001
(kg/m2) 24.10 1.03 0.013 31.62 0.87 0.012 31.62 0.87 <0.001
Waist circumfe 90.75 2.22 0.021 90.75 2.22 0.002 81.63 2.99 <0.001
rence
(cm) 81.63 2.99 0.02 101.68 1.81 0.001 101.68 1.81 <0.001
Hip 104.94 2.11 0.026 104.94 2.11 0.008 97.56 2.32 <0.001
circum
ference
(cm) 97.56 2.32 0.026 114.12 1.78 0.002 114.12 1.78 <0.001
SBP 125.00 2.62 0.131 125.00 2.62 0.413 117.81 3.79 0.036
(mmHg) 117.81 3.79 0.129 129.20 2.75 0.274 129.20 2.75 0.021

with HOMA-IR (p=0.005). Adiponectin suggesting that in the absence of

correlated negatively with cholesterol
(p=0.048) and LDL-cholesterol
(p=0.006). TNF correlated positively
with years post menopause (p=0.024),
PTH (p=0.031), while IL6 correlated
positively only with years post
menopause (p=0.007).
In women with osteoporosis
without MetSyn, BMI did not correlate
statistically significant with BMD;
waist circumference and hip
circumference correlated positively
with osteocalcin (p=0.02; p=0.021),
MetSyn, adipose tissue can influence
positively bone formation.
TNF correlated positively with
years post menopause as in group 1
(p=0.011) and with PTH (p=0.02).
Adiponectin presented some
interesting correlations in this group,
positively with hip BMD (p=0.039), with
left hip T score (p=0.035) and negatively
with leptin as we expected (p=0.028).
In the MetSyn group, BMI
correlated positively with left hip BMD
(p=0.05, chart 6), waist circumference

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 S.Oros et al.

Table 2. Mean values of metabolic variables of study groups

Variables Group Group 1 Group

1 vs 2 vs 3 2 vs 3
Mean SEM p Mean SEM p Mean SEM p
Glucose 92.92 2.77 0.419 92.92 2.77 0.054 89.72 2.75 0.021
(mg/dL) 89.72 2.75 0.419 108.29 4.28 0.004 108.29 4.28 0.001
Triglyceride 144.05 17.41 0.024 144.05 17.41 0.896 97.15 8.47 0.013
(mg/dL) 97.15 8.47 0.022 141.52 9.30 0.899 141.52 9.30 0.001
HDL-C 53.09 2.16 0.006 53.09 2.16 0.404 63.34 2.66 <0,001
(mg/dL) 63.34 2.66 0.006 50.31 1.70 0.319 50.31 1.70 <0,001
Insulinemia 11.94 5.00 0.345 11.94 5.00 0.345 6.70 2.01 0.212
(mU/mL) 6.70 2.01 0.34 9.00 0.80 0.572 9.00 0.80 0.303
HOMA-IR 2.73 1.07 0.323 2.73 1.07 0.411 1.51 0.54 0.207
1.51 0.54 0.309 2.15 0.22 0.605 2.15 0.22 0.289
Vit D 11.00 0.79 0.003 11.00 0.79 0.045 15.06 0.94 0.471
(ng/mL) 15.06 0.94 0.003 13.98 0.77 0.011 13.98 0.77 0.384
cross laps 0.52 0.06 0.451 0.52 0.06 0.037 0.46 0.06 0.26
(ng/mL) 0.46 0.06 0.453 0.38 0.03 0.043 0.38 0.03 0.299
osteocalcin 29.19 3.52 0.871 29.19 3.52 0.001 29.88 2.39 <0.001
(ng/mL) 29.88 2.39 0.869 18.70 1.16 0.012 18.70 1.16 <0.001
CRP 0.25 0.03 0.39 0.25 0.03 0.201 0.60 0.39 0.429
(mg/dL) 0.60 0.39 0.466 1.07 0.38 0.042 1.07 0.38 0.388
HBA1C 5.45 0.34 0.502 5.45 0.34 0.165 4.97 0.49 0.025
(%) 4.97 0.49 0.459 5.91 0.12 0.302 5.91 0.12 0.287
TNFalfa 2.75 0.56 0.121 2.75 0.56 0.299 1.47 0.56 0.148
(pg/mL) 1.47 0.56 0.124 2.23 0.22 0.398 2.23 0.22 0.23
IL6 2.88 1.07 0.464 2.88 1.07 0.677 4.67 2.11 0.457
(pg/mL) 4.67 2.11 0.435 3.43 0.64 0.665 3.43 0.64 0.587
Resistin 1.55 0.13 0.276 1.55 0.13 0.127 1.89 0.26 0.898
(ng/mL) 1.89 0.26 0.241 1.86 0.10 0.072 1.86 0.10 0.915
Adiponectin 122.04 20.40 0.632 122.04 20.40 0.007 137.75 24.84 0.001
(ng/mL) 137.75 24.84 0.627 76.07 6.61 0.053 76.07 6.61 0.039
Leptin 108.34 42.52 0.099 201.79 42.52 0.205 108.34 32.73 0.018
(ng/mL) 201.79 32.73 0.11 291.79 35.85 0.118 291.79 35.85 0.001

correlated positively with leptin effect of adipose tissue on bone mass.

(p<0.001), while hip circumference
correlated positively with left hip BMD
(p=0.039) and positively with leptin
(p<0.001, Fig. 7), pointing that leptin
might be responsible for the protective
Using logistic regression we found out
that higher BMI (p<0.001) and higher
leptin values (p=0.012) are associated
independently with a lower osteoporosis
risk, when comparing group 3 with 2.

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 Obesity and osteoporosis

Figure 3. Adiponectin mean values (p=0.001 Figure 4. Leptin mean values (p=0.018
group 3 vs 2, p=0.007 group 3 vs 1). group 2 vs 3).
HOMA- IR and insulinemia BMI (p=0.01) and with IL6 (p=0.008) in
correlated positively with leptin (p=0.004; group 3, positively with diastolic blood
p=0.012); HOMA-IR correlated pressure in group 1 (p=0.026) and
positively with TNF (p=0.048) and negatively with HDL-cholesterol
negatively with adiponectin (p=0.034). (p=0.023) in group 2, suggesting its
Logistic regressions showed a higher risk involvement more in inflammation and
for osteoporosis due to higher insulin cardiovascular risk, than in bone
resistance (p=0.004) when comparing metabolism.
group 2 with 3.
Resistin correlated positively with

Figure 5. BMI-spine BMD correlation in Figure 6. BMI-hip BMD correlation in

group 1 (p=0.031). group 3 (p=0.05).

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 S.Oros et al.
DISCUSSION
Regarding adipocytokines, we had
only two very different groups
(phenotypes)- the osteoporotic group
with the lowest leptin and the highest
adiponectin mean values and the
MetSyn group (opposite to the
osteoporotic group).
Figure 7. Leptin-hip BMD correlation in group 3 (p<0.001).
Adiponectin mean values were the
lowest in the MetSyn group without
osteoporosis and the positive correlation
with hip BMD in group 2 provide a partial
explanation for the protective effects of fat
on bone (cortical bone). Some consider
that reducing levels of adiponectin,
associated with obesity in conjunction
with inverse correlations between
adiponectin levels and BMD, may be in
favor of the protective effects of fat on
bone (1,10).
74
It would be reasonable to anticipate
that a rise in adiponectin levels caused by
fat reduction should have a beneficial
effect on BMD. Leptin mean values were
the highest in the MetSyn group and
correlated positively with hip BMD
suggesting leptins role in the protective
effect of adipose tissue on bone. This is
augmented by the lowest leptin mean
values in the osteoporotic group. Leptin
deficiency may have a greater effect on
hip BMD compared to spine BMD (1).
Data is similar with literature, presenting
reduced levels of leptin associated with
reduced bone formation and increased
bone resorption (1). In a study of leptin-
deficient mice, cortical thinning was
observed, while trabecular volume was
increased compared to control mice. In
addition, adipocyte infiltration was seen in
the femoral marrow, but not the vertebral
 Obesity and osteoporosis
marrow of the leptin-deficient mice.
The positive correlations of BMI
and hip circumference with left hip BMD
and of leptin with waist and hip
circumference suggest that adipose tissue
has a protective effect on bone mass and
leptin may be responsible. In
postmenopaual women without MetSyn,
BMI did not correlate with BMD, waist
circumference and hip circumference
correlated positively with osteocalcin
suggesting that in the absence of insulin
resistance, adipose tissue can influence
positively bone formation.
We aimed to see why the MetSyn
group were not osteoporotic? We think
that leptin and adiponectin both are
involved in bone protection.
Insulin resistance leads to
inflammation, as the higher CRP mean
values and the positive correlation
between HOMA-IR and TNF in the
MetSyn group point an insulin resistance
and inflammation not imbalanced by the
low adiponectin values.
The tendency towards higher resistin
values directly correlated with the
excessive adipose mass and its
correlations in our studied groups suggest
its involvement more in inflammation and
cardiovascular risk, than in bone
metabolism.
TNF and IL6 correlated with the
number of years since menopause,
pointing to the state of inflammation in
postmenopausal women. TNF
correlated also positively with PTH in
both osteoporotic groups and in
connection with high cross laps values
show their involvement in bone
resorption.
All our recruited postmenopausal
women were vitamin D insufficient,
suggesting that no attention is accorded to
vitamin D levels, or the adherence to a
prophylactic treatment is low.Even lower
25 OH vitamin D mean values in
postmenopausal women with
osteoporosis and MetSyn that in
osteoporotic women point that the
presence of MetSyn augments vitamin D
insufficiency (11,12).
It was easier for us to find
postmenopausal women with MetSyn
aged over 60 without osteoporosis, than
women with osteoporosis and MetSyn or
women with osteoporosis that were not
treated, suggesting that in our country
postmenopausal women are diagnosed
early and treated for osteoporosis, so we
admit that our osteoporotic groups are
quite small and results are limited
regarding statistical significance. We hope
that our in vitro studies (co-cultures of
adipocytes and osteoblasts) will explain
better the bone-adipose relationship.
In conclusion, adipose tissue seems
to have a protective effect on bone mass
and can be explained partially through
higher leptin mean values. The
postmenopausal women we enrolled were
vitamin D insufficient, with even lower 25
OH vitamin D in the groups associating
MetSyn suggesting the involvement of
vitamin D in MetSyn and emphasizing the
importance of optimal vitamin D levels.
Osteocalcin and adiponectin levels,
although in normal range, were the lowest
in postmenopausal women with MetSyn,
without ostoporosis, pointing out to them
as being markers of insulin sensitivity.
This study is funded by the research
project PN II-RU-PD 97/2010.
Conflict of interest.
The authors declare that there is no conflict
of interest.
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 S.Oros et al.
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