Hindawi Publishing Corporation
Clinical and Developmental Immunology
Volume 2013, Article ID 575936, 6 pages
Postmenopausal Osteoporosis: The Role of Immune System Cells
Maria Felicia Faienza,1Annamaria Ventura,1Flaviana Marzano,2and Luciano Cavallo1
1Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, 70124 Bari, Italy
2Institute for Biomedical Technologies, National Research Council, 70126 Bari, Italy
Correspondence should be addressed to Maria Felicia Faienza; email@example.com
Received 3 April 2013; Accepted 10 May 2013
Academic Editor: Giacomina Brunetti
Copyright © 2013 Maria Felicia Faienza et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
In the last years, new evidences of the relationship between immune system and bone have been accumulated both in animal
models and in humans affected by bone disease, such as rheumatoid arthritis, bone metastasis, periodontitis, and osteoporosis.
Osteoporosis is characterized by low bone mass and microarchitectural deterioration of bone tissue with a subsequent increase in
osteoporosis. This review focuses on the role of immune system in postmenopausal osteoporosis and on therapeutic strategies
targeting osteoimmunology pathways.
In the last few years, there have been important advances in
understanding the processes that regulate physiological and
pathological bone turnover.
bone has long been speculated, as bone loss is a common
condition of autoimmune and inflammatory disorders [1–3].
In this respect, T cells have been recognized as key regulators
in different diseases, such as rheumatoid arthritis , bone
metastasis [5, 6], periodontitis [7, 8], congenital adrenal
hyperplasia (CAH) [9–11], and osteoporosis .
In this review we focus on the involvement of immune
system in the pathogenesis of osteoporosis with particular
regard to postmenopausal osteoporosis and on the new
therapeutic advances in its treatment.
To maintain a structural integrity, the skeleton needs to
constantly remodel and repair the microcracks that develop
both in cancellous bone, the “spongy” bone present in the
vertebrae, pelvis, and metaphyses of long bones, and in
cortical bone, the “compact” bone present in the diaphysis of
the long bones and surrounding the cancellous bone in the
vertebrae and pelvis.
Osteoporosis is a systemic skeletal disease characterized
by low bone mass and microarchitectural deterioration of
bone tissue with a subsequent increase in bone fragility and
susceptibility to fractures [13, 14].
Skeletal fragility can result from failure to produce a
skeleton of optimal mass and strength during growth;
excessive bone resorption resulting in decreased bone mass
and microarchitectural deterioration of the skeleton; or
inadequate response to increased resorption during bone
The process of bone remodeling occurs in basic multicel-
lular units (BMUs) which include OCs, OBs, and osteocytes
and begins with the activation of hematopoietic precursors
to become OCs, which normally requires an interaction with
cells of the OB lineage.
OCs are members of the monocyte-macrophage family
clear phagocyte, the OC precursors (OCPs), which circulate
in peripheral blood (PB) . These cells differentiate under
the influence of two cytokines, namely, macrophage colony
stimulating factor (M-CSF) and receptor activator of nuclear
factor k-B ligand (RANKL). RANKL expressed on OBs and
stromal cells as a membrane-bound protein and cleaved
2 Clinical and Developmental Immunology
into a soluble molecule (sRANKL) by metalloproteinase 
promotes differentiation and fusion of OCPs and activates
mature OCs to reabsorb bone by binding to its specific
receptor RANK. Osteoprotegerin (OPG), a soluble decoy
receptor secreted by OBs and bone marrow stromal cells,
competes with RANK in binding to RANKL, preventing its
osteoclastogenic effect .
Mature multinucleated bone resorbing OCs are recog-
nized by the expression of key OC markers including TRAP
, calcitonin receptors , cathepsin K , pp60c-src
, matrix metalloproteinase 9 (MMP9) , and the alpha
V beta 3 integrin chains [23, 24].
Because the resorption and reversal phases of bone re-
modeling are short and the period required for OB replace-
ment of the bone is long, any increase in the rate of
bone remodeling will result in a loss of bone mass .
Moreover, the larger number of unfilled Howship’s lacunae
and Haversian canals will weaken the bone, and excessive
resorption can also result in complete loss of trabecular
structures, preventing bone formation.
Aside from postmenopausal osteoporosis which affects
30% of woman, there are many causes of secondary osteo-
porosis which occurs in almost 30–60% of men and more
than 50% of premenopausal women . Osteoporosis in
(usually genetic in origin) or secondary due to an underlying
medical condition and/or its treatment. The most common
condition in the former category is osteogenesis imperfecta
in which there is an underlying abnormality in bone matrix
composition, usually due to defective synthesis of type I
Instead, osteoporosis circumscripta, characterized by
focal osteolytic lesions , is a peculiar condition of Paget’s
disease, a skeletal disorder which affects 1-2% of adults over
50 [27, 28].
The evaluation of subjects presenting with osteoporosis
should include a detailed history, physical exam, and labora-
tory testing for secondary causes of osteoporosis, according
to the guidelines of the American Association of Clinical
Endocrinologists (AACE) .
3. Postmenopausal Osteoporosis
The decline of ovarian function at menopause results in
decreased production of estrogen and a parallel increase in
FSH levels. The combined effects of estrogen deprivation and
raising FSH production cause a marked stimulation of bone
resorption and a period of rapid bone loss which is central
for the onset of postmenopausal osteoporosis . Several
risk factors are implicated in favoring postmenopausal bone
loss. Important nonmodifiable predictors of bone deminer-
alization are age, sex, period of amenorrhea [31, 32], and
are dietary calcium intake [34, 35], low body mass index [31,
36, 37], smoking [38–40], reduced physical activity [41, 42],
and high alcohol intake .
3.1. Estrogen Effects on Bone Remodeling. Estrogen is the
major hormonal regulators of bone metabolism in women
and men. Estrogen inhibits the activation of bone remod-
eling, most likely via the osteocytes, and also inhibits bone
resorption, largely by direct actions on OCs, but also by
modulation of OB/osteocyte and T-cell regulation of OC
formation and activity .
The direct effects of estrogen on OCs include the induc-
tion of OC apoptosis and the inhibition of OC forma-
tion. In particular, this hormone inhibits OC formation
decreasing the responsiveness of OCPs to the osteoclasto-
genic cytokine RANKL . Moreover, estrogen inhibits
RANKL-stimulated osteoclastic differentiation of human
monocytes by inducing estrogen receptor 훼 (ER훼) binding
to a scaffolding protein, BCAR1; the ER훼/BCAR1 complex
RANKL-induced osteoclastogenesis .
In addition to these direct effects on OCs, estrogen also
appears to regulate OC formation and activity indirectly.
estrogen suppresses RANKL production by OBs and T and B
cells  and also increases production of the decoy receptor
for RANKL, OPG .
In mouse models, estrogen modulates the production of
a number of bone-resorbing cytokines, including interleukin
then sequesters TNF receptor-associated factor 6 (TRAF6),
leading to decreased activation of NF-휅B and impaired
(IL)-1, IL-6, tumor necrosis factor-훼 (TNF-훼), M-CSF, and
OC development, and estrogen deficiency induces bone loss
by upregulating cytokine production in immune cells .
Regarding the role of estrogen on OBs, it has been
prostaglandins [49–53]. Thus, this indirect pathway may play
a more important role in regulating the effect of estrogen on
3.2. Estrogen-Deficiency Effects on Bone Remodeling: The
Role of Immune System. Estrogen deficiency increases OC
viding a larger recruited OCP pool [56–58]. The upregulated
enlarged resorption areas in trabecular surfaces [13, 14]. In
addition, estrogen depletion also increases the life span of
OCs, and this event leads to prolonged bone loss, deeper
resorption cavities, and trabecular perforation increasing the
period of bone wasting following acute phase of bone loss
. The bone loss is partly compensated by increase of
bone formation due to the increased osteoblastogenesis. This
event is fueled by increasing the number of mesenchymal
promotes proliferation of early OB precursors [56, 59, 60].
The net increase of bone formation, however, is limited by
increasing apoptosis of OBs induced by estrogen deprivation
bone remodeling intensity, there is an imbalance between
bone resorption and bone formation [15, 62]. However, the
mechanism by which estrogen deficiency induces bone loss
seems more complicated, and interplay between estrogen
Clinical and Developmental Immunology3
deficiency and immune cells may play a pivotal role in
regulating bone absorption in postmenopausal osteoporosis.
In fact, estrogen is a well-known regulator of the immune
system and T-cell functions [63, 64].
In this respect, studies on humans are few, and the
majority of the data have been derived from animal models
and cellular cultures, but no consensual picture has emerged
from these models.
In one of the most interesting studies surface RANKL
expression was quantified by two-color flow cytometry
on isolated bone marrow mononuclear cells derived from
premenopausal women, early postmenopausal women, and
age-matched, estrogen-treated postmenopausal women. The
surface concentration of RANKL per cell was increased
in postmenopausal women compared to premenopausal
women and estrogen-treated postmenopausal women by
two- to threefold for MSCs, T cells, B cells, and total RANKL
RANKL production by T cells and B cells may contribute
to bone loss during estrogen deficiency in humans, and it is
supported by a recent work on mouse model .
human postmenopausal bone loss.
This work reported that women with postmenopausal
osteoporosis exhibit an increased T-cell activity and elevated
production of TNF훼 and RANKL compared to healthy
percentage of OC precursors (CD14+/CD11b+/VNR+cells)
from peripheral blood mononuclear cells (PBMCs) of post-
menopausal women with osteoporosis than in the control
groups. The mean fluorescence intensity (MFI) of CD11b
and VNR was higher in patients than in samples from the
controlgroups,while the MFI of CD14 was higher in the pre-
menopausal controls and inversely correlated with age. This
finding suggests that OCPs in patients were more committed
toward osteoclastic lineage as compared to controls .
Recent clinical studies reported that postmenopausal
sclerostin than premenopausal women, and that serum scle-
rostin levels were inversely correlated with the free estrogen
index in postmenopausal women . In vivo and in vitro
postmenopausal controls inducing OC formation and activ-
ity . In particular, flow cytometry showed a higher
studies suggest that TNF-훼, which is increased in estrogen
deficiency, may stimulate the expression of sclerostin via the
MEF2 transcription factor. Thus, the increase of sclerostin
mediated by TNF-훼 may at least partially contribute to the
of Th17 cytokine—promotes bone loss by favoring OC pro-
duction and inhibiting OB differentiation, whose production
is under the negative regulation of estrogen . Moreover,
an inhibition of IL-17 having bone sparing effect under
ovariectomy by antibody approach could form the basis for
using humanized antibody against this cytokine towards the
treatment of postmenopausal osteoporosis .
pathogenesis of postmenopausal osteoporosis .
A recent study provides evidence that IL-17—a member
3.3. B Lymphocyte Alterations in Postmenopausal Osteoporo-
sis. B-cell alterations are well documented during aging and
estrogen deficiency, but less is known on B lymphocyte
status during osteoporosis. Recently, increasing evidence
emerged on an intimate link between B lymphocytes and
bone metabolism .
deficiency, only one third of them suffer from osteoporo-
sis. In a recent study, Breuil et al. studied the phenotypic
and functional characteristics of immune cells of 26 post-
menopausal women with osteoporotic fractures compared
to 24 healthy controls similar for age and estrogen level
. They observed, for the first time, a reduction of B
lymphocyte number (in particular: B lymphocytes (CD19+),
memory B lymphocytes (CD19+/CD27+), memory B lym-
phocytes expressing CD38 (CD19+/CD27+/CD5−/CD38+),
populations in osteoporotic women are the consequences of
the physical changes, which took place in the bone marrow
microenvironment, independently from age and estrogen
status. Moreover, as memory B lymphocytes play a major
role in the immune response to infections, the modifications
of B lymphocytes may partly contribute to the increased
morbidity and mortality observed after OP fracture .
and RANK+ memory B (CD19+/CD27+/RANK+) lympho-
cytes) in osteoporotic women negatively correlated with
4. Therapeutic Strategies of
The treatment of osteoporosis aims to reduce the incidence
of vertebral and nonvertebral fractures responsible for the
disease-associated morbidity  and stabilize or increase
bone mass and strength .
The two main pharmacological approaches to osteo-
porosis are the anticatabolic and anabolic therapy, which,
bone formation .
The anticatabolic agents comprise bisphosphonates: eti-
gen and the selective estrogen receptor modulator (SERM)
raloxifene; salmon calcitonin; and denosumab. The only
anabolic agent currently available is teriparatide . The
treatment with bisphosphonates reduces fracture risk, not
shown for other available agents. Bisphosphonates accumu-
late in the mineral phase of bone and reduce OC activity
by inhibiting farnesyl pyrophosphate synthase . They
can be administered orally (daily, weekly, or monthly) or
iv (quarterly or yearly). Since their initial introduction in
the United States in 1995, questions have been raised about
their association with possible side effects (osteonecrosis
of the jaw, musculoskeletal pain, atrial fibrillation, atypical
fractures, and esophageal cancer) that appear to be rare
and may not be causally related . However, for most
the risks. A new therapeutic advance in the treatment
of osteoporosis is denosumab, a fully human monoclonal
antibody to soluble RANKL . Denosumab is the newest
antiresorptive agent, with a novel mechanism of action .
It acts like OPG, preventing RANKL from binding to OC
4 Clinical and Developmental Immunology
action are inhibited and bone resorption decreases. Unlike
bisphosphonates, denosumab does not accumulate in bone.
other monoclonal antibodies, the clearance of denosumab is
through the reticuloendothelial system and does not depend
on renal clearance .
In the last years, many studies has been made to understand
how the immune system impacts and regulates the skeleton
in physiological and pathological conditions through the
immunoskeletal interface. Although the majority of data
derived from studies on animal models, recently new evi-
dence of the crosstalk between immune system and bone
has been accumulated in humans in many disease such as
These data demonstrate that bone loss induced by estro-
gen deficiency in menopause is a complex effect of a mul-
titude of pathways and cytokines working in a cooperative
Among these cytokines, RANKL and TNF훼 seem to play
inhibiting OB differentiation.
to soluble RANKL, represents a new therapeutic advance
in the treatment of osteoporosis with a novel mechanism
of action that leads to the decrease of bone resorption and
a central role inducing OC formation and activity, while
IL-17 promotes bone loss by favoring OC production and
Conflict of Interests
The authors declare that they have no conflict of interests.
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