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Osteoporos Int (2007) 18:13191328

DOI 10.1007/s00198-007-0394-0


Glucocorticoid-induced osteoporosis: pathophysiology

and therapy
E. Canalis & G. Mazziotti & A. Giustina & J. P. Bilezikian

Received: 11 February 2007 / Accepted: 30 April 2007 / Published online: 14 June 2007
# International Osteoporosis Foundation and National Osteoporosis Foundation 2007

Abstract Glucocorticoid-induced osteoporosis (GIO) is the

most common form of secondary osteoporosis. Fractures,
which are often asymptomatic, may occur in as many as 30
50% of patients receiving chronic glucocorticoid therapy.
Vertebral fractures occur early after exposure to glucocorticoids, at a time when bone mineral density (BMD) declines
rapidly. Fractures tend to occur at higher BMD levels than in
women with postmenopausal osteoporosis. In human subjects, the early rapid decline in BMD is followed by a slower
progressive decline in BMD. Glucocorticoids have direct
and indirect effects on the skeleton. The primary effects are
on osteoblasts and osteocytes. Glucocorticoids impair the
replication, differentiation and function of osteoblasts and

This work was supported by Grant AR21707 (E. Canalis) from the
National Institute of Arthritis and Musculoskeletal and Skin Diseases,
Grants DK42424 and DK45227 (E. Canalis), and DK32333 (J.P.
Bilezikian) from the National Institute of Diabetes & Digestive &
Kidney Diseases and by MIUR and Centro di Ricerca
sullOsteoporosi-University of Brescia/EULO (A. Giustina).
E. Canalis
Saint Francis Hospital and Medical Center,
Hartford, CT 060105, USA
E. Canalis
University of Connecticut School of Medicine,
Farmington, CT 06030, USA
G. Mazziotti : A. Giustina (*)
Department of Internal Medicine, University of Brescia,
Brescia, Italy
J. P. Bilezikian
Department of Medicine, College of Physicians and Surgeons,
Columbia University,
New York, NY 10032, USA

induce the apoptosis of mature osteoblasts and osteocytes.

These effects lead to a suppression of bone formation, a
central feature in the pathogenesis of GIO. Glucocorticoids
also favor osteoclastogenesis and as a consequence increase
bone resorption. Bisphosphonates are effective in the
prevention and treatment of GIO. Anabolic therapeutic
strategies are under investigation.
Keywords Bone mineral density . Fractures .
Glucocorticoid-induced osteoporosis

Synthetic glucocorticoids are used in a wide variety of
disorders, including autoimmune, pulmonary, and gastrointestinal diseases, as well as in patients following organ
transplantation and with malignancies. Although the indications for glucocorticoids in these various conditions are
clear, their use is fraught with a host of potential side
effects. One organ system that has the potential to be
profoundly affected by glucocorticoids is the skeleton, and
glucocorticoid-induced osteoporosis (GIO) is the most
common form of secondary osteoporosis [1]. Despite the
fact that glucocorticoids can cause bone loss and fractures,
many patients receiving or initiating long-term glucocorticoid therapy are not evaluated for their skeletal health.
Furthermore, patients often do not receive specific preventive or therapeutic agents when indicated [24]. New
knowledge of the pathophysiological mechanisms underlying GIO has been accompanied by the availability of
effective strategies to prevent and treat GIO. This article
focuses on the cellular aspects of glucocorticoid action in
bone, highlighting the mechanisms that are responsible for
bone loss (Fig. 1) [5]. We also review current guidelines


Osteoporos Int (2007) 18:13191328

Fig. 1 Diagram showing the

direct and indirect effects of
glucocorticoids on bone leading
to glucocorticoid-induced osteoporosis and fractures







bone formation

Neuroendocrine system



Calcium Metabolism


intestinal absorption
Renal excretion

of myofibrils

GH/IGF-I sex steroids

bone resorption


Negative calcium

Bone Mass

Bone Quality


Increased risk of fracture

and therapeutic approaches for the prevention and treatment

of GIO.

Direct effects of glucocorticoids on bone cells

Glucocorticoids decrease the number and the function of
osteoblasts. These effects lead to a suppression of bone
formation, a central feature in the pathogenesis of GIO.
Glucocorticoids decrease the replication of cells of the
osteoblastic lineage, reducing the pool of cells that may
differentiate into mature osteoblasts [6, 7]. In addition,
glucocorticoids impair osteoblastic differentiation and maturation [5]. Under certain experimental conditions, on the
other hand, glucocorticoids have been reported to favor
osteoblastic differentiation [8]. In murine models, basal
levels of glucocorticoids seem to be required for cortical
bone acquisition and osteoblast differentiation [9]. However, the effects of glucocorticoids to favor osteoblast
differentiation seem to be highly dependent on experimental conditions, and do not reflect the loss of cells of the
osteoblastic lineage regularly seen following glucocorticoid
exposure [5].
In the presence of glucocorticoids, bone marrow stromal
cells, the precursors of osteoblasts, do not differentiate or are
directed, instead, toward cells of the adipocytic lineage [10
12]. Mechanisms involved in this redirection of stromal cells
include induction of nuclear factors of the CCAAT enhancer
binding protein family and the induction of peroxisome

risk of falls

Muscle weakness

proliferator-activated receptor 2 (PPAR 2), both of which

play essential roles in adipogenesis [5, 13, 14]. In
accordance with these observations, thiazolidinediones,
which are known to activate PPAR 2, inhibit osteoblastic
cell differentiation in murine models. Recent observations
in human subjects indicate that diabetic patients receiving
thiazolidinediones have a higher incidence of fractures [15].
An additional mechanism by which glucocorticoids
inhibit osteoblast cell differentiation is by opposing Wnt/
-catenin signaling [5, 16, 17]. Wnt signaling has emerged
as a key regulator of osteoblastogenesis. Wnt uses four
known signaling pathways, but in skeletal cells the
canonical Wnt/-catenin signaling pathway operates [18].
In this pathway, when Wnt is absent, -catenin is
phosphorylated by glycogen-synthase kinase-3 (GSK-3),
and then degraded by ubiquitination. When Wnt is present,
it binds to specific receptors, called frizzled, and to coreceptors, low density lipoprotein receptor related proteins
(LRP)-5 and -6, leading to inhibition of GSK-3 activity.
When GSK-3 is not active, stabilized -catenin translocates to the nucleus, where it associates with transcription
factors to regulate gene expression [19]. Deletions of either
Wnt or -catenin result in the absence of osteoblastogenesis,
and increased osteoclastogenesis [19, 20]. The Wnt pathway
can be inactivated by Dickkopf, an antagonist that prevents
Wnt binding to its receptor complex. Glucocorticoids
enhance Dickkopf expression and maintain GSK 3- in an
active state, leading ultimately to the inactivation of -catenin
[16, 17, 21].
In addition to inhibiting the differentiation of osteoblasts,
glucocorticoids inhibit the function of the differentiated

Osteoporos Int (2007) 18:13191328

mature cells. Glucocorticoids inhibit osteoblast-driven

synthesis of type I collagen, the major component of the
bone extracellular matrix, with a consequent decrease in
bone matrix available for mineralization [5]. The decrease
in type I collagen synthesis occurs by transcriptional and
post-transcriptional mechanisms [22].
Glucocorticoids have pro-apoptotic effects on osteoblasts
and osteocytes due to activation of caspase 3, a common
downstream effector of several apoptotic signaling pathways [23, 24]. Caspases are synthesized as proenzymes and
are activated through autocatalysis or a caspase cascade.
Active caspases contribute to apoptosis by cleaving target
cellular proteins. Caspase 3 is a key mediator of apoptosis
and is a common downstream effector of multiple apoptotic
signaling pathways [24]. The inhibitory effects of glucocorticoids on osteoblastic cell replication and differentiation
and the increased apoptosis of mature osteoblasts, all
contribute to the depletion of the osteoblastic cellular pool
and decreased bone formation.
Osteocytes serve as mechanosensors, and play a role in the
repair of bone microdamage [25]. Loss of osteocytes
disrupts the osteocyte-canalicular network resulting in a
failure to detect signals that normally stimulate processes
associated with the replacement of damaged bone [26].
Disruption of the osteocyte-canalicular network can disrupt
fluid flow within the network adversely affecting the
material properties of the surrounding bone, independent
of changes in bone remodeling or architecture [26].
Glucocorticoids affect the function of osteocytes, by
modifying the elastic modulus surrounding osteocytic
lacunae [27]. Glucocorticoids induce the apoptosis of
osteocytes [23]. As a result, the normal maintenance of
bone through this mechanism is impaired and the biomechanical properties of bone are compromised [27].
In human subjects, GIO occurs in two phases: a rapid, early
phase in which bone mineral density (BMD) is reduced,
presumably due to excessive bone resorption, and a slower,
progressive phase in which BMD declines due to impaired
bone formation [28]. Osteoclasts are members of the
monocyte/macrophage family of cells that differentiate
under the influence of two requisite cytokines, namely
macrophage colony stimulating factor (M-CSF) and receptor
activator of NF-B ligand (RANK-L) [29]. Glucocorticoids
increase the expression of M-CSF and RANK-L, and
decrease the expression of its soluble decoy receptor,
osteoprotegerin, in stromal and osteoblastic cells [30, 31].
Glucocorticoids also enhance the expression of Interleukin-6,


an osteoclastogenic cytokine, and suppress the expression

of interferon-beta, an inhibitor of osteoclastogenesis [32,
33]. Glucocorticoids decrease the apoptosis of mature
osteoclasts [34]. Consequently, there is increased formation
of osteoclasts with a prolonged life span explaining, at the
cellular level, the enhanced and prolonged bone resorption
observed in GIO. The direct effects of glucocorticoids on
osteoclasts also may contribute to an operational decline in
osteoblast function during glucocorticoid exposure [35].
Although the net effect of glucocorticoids is to enhance
osteoclast number, osteoclast function may be tempered
with cells that no longer spread and resorb mineralized
matrix normally. Osteoblast signals that depend upon
normal osteoclast function could, thus, be impaired [35].
However, these novel findings have been challenged by
studies demonstrating a primary effect of glucocorticoids
on cells of the osteoblastic lineage [34]. In accordance with
their effects on bone resorption, glucocorticoids enhance
the expression of selected matrix metalloproteinases
(MMP). Osteoblasts secrete MMP1 or collagenase 1 and
MMP13 or collagenase 3, and both cleave type I collagen
fibrils at neutral pH [36, 37]. Cortisol increases collagenase
3 synthesis by post-transcriptional mechanisms, by regulating specific cytosolic RNA binding proteins, and their
binding to specific RNA sequences [38]. Glucocorticoids
may also have effects on bone remodelling at the basic
multicellular unit (BMU) level, mainly manifested as a
reduction in wall width (reduced amount of bone formed
per BMU) [39, 40]. In addition, there is some evidence that
increased resorption depth (increased amount of bone
resorbed per BMU) may occur in the early stages of
therapy, particularly at high doses of glucocorticoids.
Effects of glucocorticoids on bone cells mediated
by growth factors
In addition to the direct actions of glucocorticoids on bone
target cells, other effects are mediated by changes in the
synthesis, receptor binding or binding proteins of growth
factors present in the bone microenvironment. Glucocorticoids
influence the expression of insulin-like growth factor
(IGF) I. IGF-I increases bone formation and the synthesis
of type I collagen, and decreases bone collagen degradation and osteoblast apoptosis [41]. Glucocorticoids suppress
IGF I gene transcription, but do not alter IGF I receptor
number or affinity in osteoblasts [5]. Glucocorticoids
decrease IGF II receptor number, but the skeletal functions
of the IGF II receptor have remained elusive [42]. The
activities of IGFs are regulated by six IGF binding proteins
(IGFBP), all of which are expressed by the osteoblast [43].
Of these, IGFBP-5 was reported to have anabolic effects for
skeletal cells, and its transcription is suppressed by
glucocorticoids [44]. The inhibition of IGFBP-5 synthesis


Osteoporos Int (2007) 18:13191328

by glucocorticoids is probably not key to the ultimate effect

of glucocorticoids on osteoblastic function, because transgenic mice overexpressing IGFBP-5 exhibit decreased, and
not increased bone formation [45]. The effects of glucocorticoids on IGF-I expression by the osteoblast are
reversed by parathyroid hormone (PTH), an observation
that may help explain why PTH may be effective in the
treatment of GIO [46].

inhaled corticosteroids, suggesting that inhaled steroids

may alter the synthesis or release of GH [59]. However,
the cause or consequence of this effect is not clear, since
serum levels of cortisol and of IGF-I are not suppressed [59].
Glucocorticoids inhibit the release of gonadotropins, and as a
result estrogen and testosterone production. This effect of
glucocorticoids on the gonadal axis may be an additional
factor playing a role in the pathogenesis of GIO [60].

Indirect effects of glucocorticoids on bone metabolism

Pathogenesis of fractures in GIO

Glucocorticoids inhibit calcium absorption from the gastrointestinal tract, by opposing vitamin D actions, and by
decreasing the expression of specific calcium channels in the
duodenum [47]. Renal tubular calcium reabsorption also is
inhibited by glucocorticoids [1]. As a consequence of these
effects, secondary hyperparathyroidism could exist in the
context of glucocorticoid use. But a hyperparathyroid state
does not explain the bone disorder observed in GIO. Most
patients with GIO do not exhibit serum levels of PTH that
are frankly elevated. Although vertebral and non-vertebral
fractures occur in GIO, this condition is associated with a
preferential loss of cancellous bone, whereas hyperparathyroidism, is associated with a preferential loss of cortical
bone [48, 49]. Moreover, bone histomorphometric analysis
demonstrates reduced bone turnover in GIO, in contrast to
the increased bone turnover that characterizes hyperparathyroidism [1, 28]. These observations indicate that
hyperparathyroidism does not play a central role in the
development of the skeletal manifestations of GIO. Nevertheless, there may be subtle, but important effects of
glucocorticoids on the secretory dynamics of PTH, with a
decrease in the tonic release of PTH and an increase in
pulsatile bursts of the hormone [50]. In healthy subjects,
PTH is secreted by low amplitude and high frequency
pulses superimposed upon tonic secretion. Pulsatile PTH
secretion may be important for the regulation of the actions
of the hormone on bone [51]. Abnormal PTH pulsatility is
found not only following glucocorticoid exposure, but also
in post-menopausal women and in acromegaly [52, 53].
Additionally, glucocorticoids may enhance the sensitivity of
skeletal cells to PTH, by increasing the number and affinity
of PTH receptors [54].
In addition to the direct effects of glucorticoids on
skeletal IGF-I, glucocorticoids decrease the secretion of
growth hormone (GH) and may alter the systemic GH/IGFI axis [55]. However, serum levels of IGF-I are normal in
GIO. GH secretion is blunted by glucocorticoids by an
increase in hypothalamic somatostatin tone, and GH
administration could reverse some of the negative effects
of chronic glucocorticoid treatment on bone [5658].
Secretion of GH is blunted in asthmatic patients receiving

Fractures may occur in as many as 3050% of patients

receiving chronic glucocorticoid therapy [6163]. They
occur more frequently in postmenopausal women and men
at sites enriched in cancellous bone, such as the vertebrae
and femoral neck [64, 65]. As with vertebral fractures
occurring in post-menopausal osteoporosis, vertebral fractures associated with glucocorticoid therapy often are
asymptomatic [63]. When assessed by X-ray-based morphometric measurements of vertebral bodies, 37% of
postmenopausal women on chronic (> 6 months) oral
glucocorticoid therapy sustain one or more vertebral
fractures [63]. Vertebral fractures occur early after exposure
to glucocorticoids, at a time when BMD declines rapidly
[66]. The early rapid loss of bone predisposes to fracture,
even in individuals whose T-scores are only in the
osteopenic range.
Although fractures can occur early in the course of
glucocorticoid therapy, their incidence is also related to the
dose and duration of glucocorticoid exposure. Doses as low
as 2.5 to 7.5 mg of prednisolone equivalents per day can be
associated with a 2.5-fold increase in vertebral fractures,
but the risk is greater at higher doses for prolonged periods
of time [1, 67]. Following the exposure to prednisone
equivalents of 10 mg daily for longer than 90 days, the risk
of fractures of the hip and spine is increased by 7- and 17fold, respectively [67]. The risk of fracture declines after
discontinuation of glucocorticoid therapy [1].
The reason for the individual heterogeneity in the
response to glucocorticoids is not known, but differential
responses may be associated with polymorphisms of the
glucocorticoid receptor gene. Glucocorticoid receptor polymorphisms are associated with differences in BMD and
body composition [6870]. Indeed, body composition and
risk of fracture during glucocorticoid treatment seem to be
closely related [71]. Another explanation for individual
variability in the response of patients exposed to glucocorticoids is related to peripheral enzymes that interconvert
active and inactive glucocorticoid molecules. 11-hydroxysteroid dehydrogenases regulate the interconversion between cortisone and hormonally active cortisol, and play a
role in the regulation of glucocorticoid activity [72]. Two

Osteoporos Int (2007) 18:13191328

11-hydroxysteroid dehydrogenase enzymes have been

described: 11-hydroxysteroid dehydrogenase type-1 is
primarily a glucocorticoid activator, converting cortisone
to cortisol, and 11-hydroxysteroid dehydrogenase type II
is an inhibitor enzyme expressed in mineralocorticoid target
tissues. The type I enzyme is widely expressed in
glucocorticoid target tissues, including bone, and its activity
and the potential to generate cortisol from cortisone in
human osteoblasts is increased by glucocorticoids [7275].
There seems to be an inverse relationship between 11hydroxysteriod dehydrogenase type I activity and osteoblast
differentiation [75]. An increase of 11-hydroxysteriod
dehydrogenase type I activity occurs with aging, possibly
providing an explanation for the enhanced sensitivity of the
elderly to the effects of glucocorticoids on the skeleton [75].
An important point that is often minimized in discussions about GIO is that many disorders for which the
glucocorticoids are prescribed are themselves causes of
osteoporosis. One has to take into account, therefore, the
underlying disease itself along with the use of glucocorticoids
when considering the management of GIO. Inflammatory
bowel disease, rheumatoid arthritis and chronic obstructive
pulmonary disease (COPD), for example, all are associated
with bone loss, independent of glucocorticoid treatment
[76, 77]. The systemic release of inflammatory cytokines,
which affect bone formation and bone resorption seem to
underlie the pathophysiology of the bone loss in these
settings [76, 77]. However, there are additional factors that
may play a role in the bone loss. In inflammatory bowel
disease, bone loss may be due, in part, to malabsorption of
vitamin D, calcium and other nutrients [76]. In COPD,
hypoxia, acidosis, reduced physical activity, and smoking

Fig. 2 Relationship between

bone mineral density (BMD)
at lumbar spine and femoral
neck and incidence of radiological spinal deformities in
post-menopausal women with
glucocorticoid-induced osteoporosis as compared with postmenopausal osteoporosis (from
Van Staa TP, et al. Arthritis
Rheum. 2003 [ref. 83], with


may all contribute to bone loss, independent of the use of

glucocorticoids [60, 78, 79].
A direct relationship between BMD and fracture risk in
GIO has not been established [8082]. It is likely to be
different from that established in postmenopausal osteoporosis because fractures in GIO occur at higher BMDs [83]
(Fig. 2). This point has to be considered when making
treatment decisions in GIO. The Royal College of Physicians recommends a vertebral T-score of 1.5 as the
intervention threshold. The American College of Rheumatology (ACR) recommends a more stringent therapeutic
intervention at a T-score of 1. These scores are higher
than the treatment threshold T-Scores of 2.0 to 2.5, often
used in the management guidelines for post-menopausal
osteoporosis [84]. The reasons for the altered relationship
between BMD and risk of fracture are complex [85, 86]. In
addition to the rapid decline in BMD that occurs following
glucocorticoid exposure (the faster the bone loss, the
greater the risk), other factors influence bone strength and
fracture risk in GIO. These include the underlying disease
for which patients receive glucocorticoids, and multiple
cellular events that lead to structural changes in bone [87].
In GIO, the negative effects of glucocorticoids on osteoblasts and osteocytes affect adversely the architecture of
cancellous bone. However, these changes often are not
translated into a decrease in BMD. Reductions in trabecular
thickness, number, and connectivity cannot be determined
by currently available non-invasive imaging modalities.
Newer technologies, such as high resolution peripheral
quantitative computed tomography or micro magnetic
resonance imaging may be helpful in identifying individual
fracture risk of patients on glucocorticoids [88].


Although biochemical markers of bone turnover can be

useful measures of bone remodeling activity and can
predict fracture risk, their value in GIO has not been
established and their levels vary with the stage of the
disease [89]. Following the initial exposure to glucocorticoids, there is an increase in biochemical markers of bone
resorption, which is followed by a suppression of markers
of bone formation and bone resorption [89].
In addition to the direct effects of glucocorticoids on
bone cells, the catabolic effects of glucocorticoids on
muscle may contribute to fracture risk since these steroids
cause muscular weakness, which can increase the incidence
of falls. Glucocorticoid-induced myopathy may occur
following early exposure to glucocorticoids [90]. Chronic
glucocorticoid-induced myopathy is generally manifested
by weakness particularly of the pelvic girdle musculature
and may affect up to 60% of patients treated with
glucocorticoids [60]. The myopathy involves muscle loss
due to glucocorticoid induced proteolysis of myofibrils
[91]. This is mediated by activation of lysosomal and
ubiquitin-proteasome enzymes. Recent studies have demonstrated that glucocorticoids induce myostatin, a negative
regulator of muscle mass. Deletion of the myostatin gene
prevents glucocorticoid induced myofibril proteolysis and
muscle loss in murine models [91]. This would suggest that
myostatin plays a role in the mechanism of muscular
atrophy in GIO.

Osteoporos Int (2007) 18:13191328

Table 1 Guidelines for prevention and treatment of glucocorticoidinduced osteoporosis

and vitamin D
for primary
in secondary
Sex hormones

American College
of Rheumatology

Royal College
of Physicians


In vitamin D
If older than
65 yrs and/
or with history
of fragility fracture
BMD T-score
<1.5 or with
a reduction in BMD
of > 4% after 1 year

If glucocorticoids
( 5 mg) are
planned for >
3 months*
BMD T-score
< 1.0


*with caution in premenopusal women

daily), including lifestyle changes, such as tobacco cessation and reduction of alcohol consumption, an exercise
program, restriction of sodium intake in the presence of
hypercalciuria, sufficient calcium intake and adequate
vitamin D supplementation. ACR guidelines recommend
that treatment with bisphosphonates should be started in
these subjects if their T-score is 1.0, as assessed by
vertebral densitometry [84, 92]. Table 1 shows similarities
and differences between ACR and UK guidelines [84].
Specific therapeutic approaches

Management of GIO
ACR and the Royal College of Physicians have proposed
primary prevention and treatment guidelines. Primary
prevention is intervention with a bone-sparing agent at the
initiation of (or very soon after) commencement of
glucocorticoid therapy. Secondary prevention is initiation
of bone protective medication in patients already established on glucocorticoid therapy (Table 1). The guidelines
advocate the following measures for the prevention and
treatment of GIO: general health awareness, administration
of sufficient calcium and vitamin D, reduction of the dose
of glucocorticoids to a minimum and, when indicated,
therapeutic intervention with bisphosphonates and possibly
other agents [92]. UK guidelines recommend primary
prevention in all men and women over the age of 65 years,
in individuals with a history of previous fractures and in
younger people with BMD T scores of 1.5, who are
committed to at least 3 months of oral glucocorticoid
therapy at any dose (Table 1). ACR recommends preventive
measures in patients exposed to glucocorticoids for longer
than 3 months (5 mg prednisone equivalent, or higher,

Vitamin D plays an important adjuvant role in the

management of GIO [9397]. Vitamin D increases the
intestinal absorption of calcium and reabsorption of
calcium in the distal renal tubules. In addition to its role
in calcium homeostasis, vitamin D plays a function in the
maintenance of muscular strength and balance. A practical
consideration regarding vitamin D therapy in subjects
receiving glucocorticoids, relates to vitamin D resistance
that occurs in this setting. Rather than maintaining 25hydroxyvitamin D levels at an adequate level of 30 ng/ml
(82 nmoles/L), some experts recommend that the goal be
set at higher serum levels of 25 hydroxyvitamin D of
80 nmol/L. In order to maintain these levels, patients often
require amounts of 1,0002,000 International Units of
vitamin D daily [98].
Bisphosphonates are considered to be the pharmacologic
gold standard for the prevention and treatment of GIO [84,
99]. The benefits of bisphosphonates in GIO have been
ascribed to their anti-resorptive effect. Bisphosphonates are
more effective than vitamin D in the prevention of bone
loss and fractures in GIO, but should be given with
supplemental calcium and vitamin D [100]. The primary
end-point of bisphosphonate trials has been the stabilization

Osteoporos Int (2007) 18:13191328

or the increase of BMD, with fracture outcomes as

secondary end points. In selected trials, bisphosphonates
were shown to decrease the incidence of vertebral fractures
in GIO [61, 62, 101103]. It is advisable to continue
bisphosphonates for the duration of glucocorticoid treatment. This recommendation is consistent with data demonstrating that fracture risk is highest during the time of
glucocorticoid exposure [104]. The use of bisphosphonates
in women of childbearing age has to be carefully
considered, since bisphosphonates have a prolonged half
life, and they can cross the placenta with potential
unwanted effects on fetal skeletal development.
In postmenopausal women, estrogens preserve bone mass
whether in the context, or not, of glucocorticoid exposure,
and they can be a treatment option [105]. However, the use
of estrogens has to be carefully considered because of
unwanted adverse effects.
An anabolic approach to the treatment of GIO might
have promise since the disorder is primarily one of reduced
bone formation. PTH is an attractive candidate because it
induces skeletal IGF I and inhibits osteoblast apoptosis,
increasing osteoblast cell number [36, 106108]. The use of
PTH in GIO has been examined in postmenopausal women
with rheumatoid arthritis treated with prednisone and
estrogen replacement [109, 110]. In this population, daily
treatment with hPTH (134) increased vertebral BMD.
Modest increases in bone mass were observed at the hip.
PTH administration induces an initial uncoupling of bone
remodeling with an early increase in bone formation
followed by a more gradual increase of bone resorption
[111]. According to the concept of the anabolic window,
PTH rapidly and powerfully stimulates osteoblast function
[112]. PTH is currently being tested in clinical trials to
determine its efficacy in GIO.

GIO is a serious skeletal disorder that is associated with
fractures. New knowledge of mechanisms of glucocorticoid
action has demonstrated detrimental effects on osteoblast
and osteocyte function, and prolonged osteoclast life span.
The extent and rate of bone loss determine the risk of
fractures. GIO can be prevented and treated with
bisphosphonates. Future therapies may include the use of
PTH and other anabolic agents.

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