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Pathophysiology of osteoporosis

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DOI: 10.1007/s10354-009-0647-y · Source: PubMed

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Wien Med Wochenschr (2009) 159/9–10: 230–234

DOI 10.1007/s10354-009-0647-y

Springer-Verlag 2009
Printed in Austria

Pathophysiology of osteoporosis
Wolfgang Sipos1, Peter Pietschmann2,3, Martina Rauner4, Katharina Kerschan-Schindl5 and Janina Patsch3

1
Medical Clinic II, University of Veterinary Medicine Vienna, Vienna, Austria
2
Ludwig Boltzmann-Institute of Aging Research, Vienna, Austria
3
Center for Physiology, Pathophysiology and Immunology, Department of Pathophysiology,
Medical University of Vienna, Vienna, Austria
4
Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine III,
Technical University, Dresden, Germany
5
Department of Physical Medicine and Rehabilitation, Medical University of Vienna, Vienna, Austria

Received August 5, 2008, accepted after revision September 16, 2008

Pathophysiologie der Osteoporose Key words: Osteoporosis, bone remodeling, osteoblasts,

osteoclasts, osteoimmunology, pig
Zusammenfassung. Die Osteoporose ist eine klassische alter-
sassoziierte Erkrankung, welche Frauen h€ aufiger als M€anner
betrifft. Die Hypothese, daß die Osteoporose infolge einer Ös-
Introduction
trogendefizienz auftritt, wurde bereits 1941 von Albright et al. [1]
aufgestellt. Die molekularbiologischen Wirkungsmechnismen Osteoporosis is one of the major public health
der Östrogendefizienz postmenopausaler Frauen sowie €alterer problems associated with aging. It is currently defined
M€anner werden in einer Vielzahl laufender Studien untersucht.
Die Östrogendefizienz hat sowohl direkte als auch indirekte
as a skeletal disorder characterized by compromised
Einflüsse auf den Knochenmetabolismus, welche allesamt zu bone strength predisposing a person to an increased risk
einer intensivierten Osteoklastogenese führen. Diese Übersicht- of fracture. Bone strength is influenced by bone density
sarbeit beleuchtet sowohl die endokrinologischen als auch die and bone quality (Figs. 1, 2) [2]. There is a clear correla-
osteoimmunologischen Mechanismen, die zur Involutionsos-
tion between each standard deviation (SD) decrease in
teoporose führen.
bone mineral density and the risk of fracture. A BMD
Schlüsselwörter: Osteoporose, Knochenremodeling, Osteo- value between 1 and 2.5 SD below the mean value for
blast, Osteoklast, Osteoimmunologie, Schwein young adults is referred to as osteopenia. Osteoporosis is
defined as BMD more than 2.5 standard deviations
Summary. Osteoporosis is a classical age-related disease that below the adult mean value [3]. This classification
affects women more often than men. The hypothesis that osteo- originally has been proposed by the WHO in 1994 for
porosis is a consequence of estrogen deficiency, has been pro-
posed as early as 1941 by Albright and colleagues [1]. The exact the hip BMD of postmenopausal Caucasian women, but
mechanisms of this steroid hormone deficiency in postmenopau- in clinical practice is also used for DXA measurements at
sal women as well as in the elderly men are continuously being the lumbar spine as well as for men. It is well known that
unraveled. Collectively, estrogen deficiency has direct as well as involutional osteoporosis is primarily a consequence of
indirect impacts on bone metabolism all of which promote os-
teoclastogenesis. This review aims at shedding light on the endo-
estrogen deficiency, but it also has to be kept in mind,
crine and osteoimmunological mechanisms that lead to involu- that there is a huge bulk of additional factors that
tional osteoporosis. contribute to the pathogenesis of osteoporosis such as
genetic and life-style factors as well as nutrition and the
intake of medications. From a clinical point of view,
primary and secondary forms of osteoporosis can be
Correspondence: Wolfgang Sipos, DVM, Associate Professor, Medical distinguished. This review focuses on involutional
Clinic II, University of Veterinary Medicine Vienna, Veterin€arplatz 1,
1210 Vienna, Austria. osteoporosis, the most frequent form of primary
Fax: þþ43-1-25077 5297, E-mail: [email protected] osteoporosis.

230
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was attributed to aging processes including osteoblast

dysfunction.
In 1998 the type 1/type 2 model was revised and
from now on termed “unitary model of osteoporosis in
postmenopausal women and aging men” [5]. In the
unitary model, estrogen deficiency was proposed to be
the main cause of both phases of bone loss in post-
menopausal women and osteoporosis in elderly men.
The following section deals with the multiple ef-
fects of estrogens on bone cells and mineral home-
ostasis. Before that, the main cell types, which are
involved in bone remodeling, which is indispensable
for repairing microdamage, adapting the skeleton to
mechanical loading, and maintaining calcium and
phosphorus homeostasis, will be reviewed. The process
of bone remodeling is based upon the coupled action of
Fig. 1: Normal bone microarchitecture as assessed by high resolution peri- bone-resorbing cells (osteoclasts) and bone-forming
pheral QCT cells (osteoblasts). Osteoblasts, as well as many other
cell types such as adipocytes, chondrocytes, fibroblasts
and myoblasts, differentiate from mesenchymal stem
cells [6]. Osteoclasts, on the contrary, are derived from
the hematopoietic mononuclear lineage (Fig. 3). Two
cytokines, which are mainly produced by bone marrow
stromal cells and osteoblasts, are essential for osteo-
clastogenesis: macrophage colony-stimulating factor
(M-CSF) and receptor activator of nuclear factor-kB
ligand (RANKL), which belongs to the tumor necrosis
factor (TNF) superfamily. RANK is the receptor for
RANKL and is expressed on mononuclear osteoclast
precursors. Osteoprotegerin (OPG), which is also
produced by stromal cells and osteoblasts, is a natural
decoy receptor for RANKL and thus antagonizes the
osteoclastogenic action of RANKL. These interactions
are currently under investigation with regard to their
potential for the treatment of osteoporosis [for reviews
Fig. 2: Disturbed trabecular microarchitecture in a patient with osteoporosis see 7, 8].
(high resolution peripheral QCT)

In the early 1980s Riggs and Melton proposed the

existence of two discrete types of involutional osteo-
porosis: postmenopausal (type 1) and senile (type 2)
osteoporosis [4]. Postmenopausal women experience
both types, whereas men undergo type 2 osteoporosis.
At menopause, women experience an accelerated, tran-
sient phase (that may result in type 1 osteoporosis),
which is most apparent over the subsequent decade
after menopause and involves mainly trabecular bone.
The slow, continuous phase of bone loss in the elderly
men resembles the late, slow phase in postmenopausal
women and affects both trabecular and cortical bone.
While postmenopausal osteoporosis was recognized to Fig. 3: Osteoclasts (in this case an osteoclast generated from porcine bone
marrow) are defined as multinucleate, tartrate-resistant acid phosphatase
be caused by estrogen deficiency, senile osteoporosis (TRAP) positive cells that have the ability to form resorption pits on bone

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Bone homeostasis-related mechanisms impaired metabolism of vitamin D to its active form and
of estrogens a decrease in intestinal vitamin D receptors [20–22].
Estrogen treatment was found to increase both serum
Estrogen exhibits both skeletal and extraskeletal Vitamin D levels and calcium absorption in postmeno-
activities that – in case of their deficiency – contribute to pausal osteoporotic women [20].
the pathogenesis of osteoporosis. Skeletal activities may
be divided into direct and indirect ones. Direct skeletal
activites are based upon estrogen receptors on osteo- Osteoimmunology
blasts and osteoclasts [9–11], whereas indirect activites
of estrogens are mediated by estrogen receptors on Many of the indirect effects of estrogens or estro-
various other cell types including stromal cells, which gen deficiency on bone are mediated by immune cells
upregulate OPG upon estrogen exposure [12], and cells and consequently are subject of the field of osteoimmu-
of the immune system that influence bone homeostasis. nology, which analyses the interactions between bone
Immune cell-osteoblast/osteoclast interactions are in- and immune cells. As early as 1989 it has been known
vestigated in the field of osteoimmunology and will be that there are some correlations between estrogen treat-
described later. Estrogen deficiency in postmenopausal ment and systemic cytokine release [23]. Meanwhile, it
women leads to an upregulation of RANKL on bone is well known that the production of many different
marrow cells, which is an important determinant of cytokines and other inflammatory mediators, such as
increased bone resorption [13], whereas estrogen itself interleukin (IL)-1, IL-6, TNF-a, and prostaglandin E2,
stimulates OPG production in osteoblasts and thus are involved in the pathogenesis of osteoporosis.
exerts anti-resorptive effects on bone (Fig. 4) [14]. Effects Although most studies concentrated on the effects of
of extraskeletal estrogen deficieny are mainly based these mediators on osteoclastogenesis, fewer studies
upon increased renal calcium excretion and decreased described the effects on osteoblasts. Nevertheless, it is
intestinal calcium absorption [15–17]. Estrogen defici- also known since the late 1980s, that estrogen treatment
eny also goes hand in hand with a continuous increase in increases the production of insulin-like growth factor-1
serum parathyroid hormone (PTH) levels. This second- (IGF-1) and transforming growth factor (TGF)-b by
ary hyperparathyroidism is a compensatory mechanism osteoblastic cells [24, 25].
for net calcium losses in the aging body on the one hand More recent studies deal with the effects of estro-
while estrogen also seems to have a direct depressive gen deficiency on T cell function. It could be demon-
action on the parathyroid gland on the other hand strated that estrogen withdrawal results in increased
[5, 18]. Additionally, estrogen deficieny increases the production of IL-7, leading to T cell activation. This is
sensitivity of bone to PTH [19]. Other mechanisms that accompanied by an increased production of interferon
are responsible for inadequate intestinal calcium ab- (IFN)-g and TNF-a by T cells [26, 27]. One major action
sorption in the elderly are vitamin D deficiency, the of IFN-g is the upregulation of major histocompatibil-
ity complex (MHC) class II molecules on antigen pre-
senting cells, such as bone marrow macrophages and
dendritic cells. This leads to a further activation of T
cells, which now produce more RANKL and TNF-a. As
already mentioned, these two cytokines have a pro-
nounced osteoclastogenic activity. The effects of IFN-g
on bone metabolism are scientifically challenging, as
IFN-g acts as pro-osteoclastogenic cytokine in the con-
text of ovariectomy [28], whereas it is regarded as anti-
osteoclastogenic in general [7].
T cells in fact seem to notably contribute to the
pathogenesis of osteoporosis. Data from our laboratory
indicate that the CD8þ CD57þ subset is expanded in
women suffering from osteoporotic fractures [29].
Moreover, these cells produce the proinflammatory
cytokine TNF-a. Notably, the postmenopausal phase is
Fig. 4: A model of the effects of estrogen deficiency on bone loss, PGE2 accompanied by a progressive proinflammatory status,
prostaglandin E2, OPG osteoprotegerin, MHC II major histocompatibility
complex class II molecules which is evidenced by the increase of systemic IL-1, IL-6,

232 Sipos et al. – Pathophysiology of osteoporosis
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and TNF-a [30]. This proinflammatory status has also (1999) could demonstrate that PPARg2 concomitantly
been associated with aging in general and is referred to to inducing the differentiation of adipocytes inhibits
as “inflammaging” [31]. Data from our laboratory in- the differentiation of osteoblasts and therefore acts as a
dicate that “inflammaging” is gender specific: in elderly key regulator of osteoblast and adipocyte differentia-
women T cells produce more IFN-g when compared to tion [39]. Furthermore, it has been shown that ectopic
young women, whereas in men no effect of age on IFN-g expression of recombinant PPARg2 in osteoblastic cells
production was seen [32]. Similar to what has been irreversibly suppressed runx2/cbfa1 expression and the
observed with IFN-g, T cells unexpectedly also may be osteoblast phenotype and converted these cells into
highly bone-protective through interacting with B cells terminally differentiated adipocytes [40]. In a very recent
involving CD40-CD40 ligand co-stimulation, which is report, Taleb et al. demonstrated the supportive action
followed by a consecutively upregulated OPG produc- of the cysteine protease cathepsin S on adipocyte diffe-
tion by B cells [33]. rentiation and in fact proposed cathepsin S as a novel
Accumulating oxidative stress is a common feature biomarker of adiposity since the circulating levels of
of the aging organism. It has been demonstrated in cathepsin S were positively correlated with the body
ovariectomized mice, that estrogen deficiency also cau- mass index, body fat, and plasma triglyceride levels [41].
ses an accumulation of reactive oxygen species in the In conclusion, research on osteoporosis reoriented
bone marrow, leading to a proinflammatory state cau- from solely investigating osteoclast hyperactivity to the
sed by an increased production of TNF-a by activated T characterization of the mechanisms of impaired osteo-
cells through upregulation of the costimulatory mole- blast development in aging.
cule CD80 on dendritic cells [34]. In this experimental
setting, bone loss could be prevented by the treatment of
A porcine model of osteoporosis – a
mice with antioxidants or CTLA4-Ig, which is an inhibi-
chance for preclinical testing of novel
tor of the CD80/CD28-pathway of co-stimulation. This
goes in line with previous observations, that ovariecto-
antiresorptive drugs?
my increases the antigen-presenting potential of den-
Antiresorptive drugs, such as any of newly de-
dritic cells approximately 5 fold, whereas it enhances
veloped substances intended for pharmacological use
that of bone marrow macrophages approximately 2
have to be tested in animal models before they can be
fold [35].
approved for clinical studies. Since the US Food and
Drug Administration besides the commonly used
The fate of mesenchymal stem cells rodent (mice and rats) also require large animal
is essential for the pathogenesis models, scientists search for such models. Pigs are
increasingly used in different fields of biomedical
of osteoporosis
research due to many anatomical and physiological
analogies to humans. Our group is on the way to
As already mentioned, osteoblasts as well as adi-
establish a porcine osteoporosis model using ovariec-
pocytes originate from mesenchymal stem cells. This
tomized sows. In this project, we do not only focus on
becomes obvious when keeping in mind that red bone
(micro)structural analyses of selected bones of re-
marrow turns into yellow bone marrow with aging.
spective sows, but also concentrate on the search for
Even though aging has negative effects on osteoblast
basic pathophysiological similarities including osteo-
production and activity, it supports the development
immunological aspects between these animals and
and production of adipogenic cells. In contrast to the
postmenopausal women. If we succeed in estab-
hematopoietic bone marrow of neonatal mammals
lishing this model we will be able to provide an
where adipocytes are scarce, adipocyte number and
additional test system for establishing novel antire-
size increase with age and lead to the appearance of
sorptive drugs.
fatty marrow. Intracellular and extracellular signals
determine the fate of the mesenchymal stem cells to
differentiate into certain specialized cell types. The Conflict of interest
expression of runx2 (runt-related transcription factor,
also termed cbfa1 is essential for commitment to the Dr. Peter Pietschmann has received research sup-
osteoblast lineage, whereas PPARg2 (peroxisome pro- port and/or honoraria from Amgen GmbH, Eli Lilly
liferator-activated receptor gamma 2) induces the dif- GmbH, MSD Merck Sharp & Dohme GesmbH, Nycomed
ferentiation of adipocytes [36–38]. Lecka-Czernik Pharma, Roche Austria, Servier Austria, Sanofi Aventis.

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