Review

Glucocorticoid-induced
osteoporosis: an update on
current pharmacotherapy and
1. Introduction
2. Epidemiology
future directions
3. Pathogenesis Irene EM Bultink†, Marijke Baden & Willem F Lems
†
4. Management of VU University Medical Center, Department of Rheumatology, Amsterdam, The Netherlands
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Notre Dame Australia on 07/09/13

glucocorticoid-induced
osteoporosis Introduction: Glucocorticoid-induced osteoporosis (GIOP) is one of the most
5. Conclusions devastating side-effects of glucocorticoid (GC) use, as it is associated with an
increased fracture risk. The importance of GIOP as a health problem is under-
6. Expert opinion
lined by the frequent use of GC treatment in patients with various chronic dis-
eases and by the high rates of osteoporosis found in these patient groups.
Areas covered: Recent studies on bone metabolism and the influence of GCs
have contributed to a better understanding of the pathogenesis of GIOP.
Furthermore, new intervention trials have reported beneficial effects of anti-
resorptive and anabolic agents on GIOP. This article reviews the epidemiology
and pathophysiology of osteoporosis and fractures in GC-treated patients and
discusses current pharmacotherapy and possible future treatment options.
Expert opinion: Several guidelines for the management of GIOP have been
For personal use only.

published, using different criteria for bone mineral density (BMD) thresholds
and for GC dosages above which anti-osteoporotic therapy should be started.
Although alendronate and risedronate are currently first choice, the anabolic
agent teriparatide seems to be superior and might be considered as a poten-
tial first-line therapy for patients with low BMD on long-term GC treatment.
Adherence to anti-osteoporotic drugs is limited, particularly in GIOP patients,
due to several factors.

Keywords: bone, fractures, glucocorticoids, osteoporosis

Expert Opin. Pharmacother. (2013) 14(2):185-197

1. Introduction

Glucocorticoid-induced osteoporosis (GIOP) is the most common cause of second-

ary osteoporosis and is one of the most devastating side-effects of glucocorticoid
(GC) use and is associated with substantial morbidity [1,2]. Unfortunately, this
side-effect is not uncommon, since it is estimated that 30% of all patients treated
with GCs for 6 months or more will develop osteoporosis [3].
GCs are frequently used for the treatment of a variety of diseases, such as rheuma-
toid arthritis, systemic lupus erythematosus, polymyalgia rheumatica, inflammatory
bowel disease and chronic obstructive pulmonary disease. They are widely used
because of their anti-inflammatory and immunosuppressive effects. Besides osteo-
porosis, multiple side-effects of GCs have been described, e.g., insulin resistance,
hypertension, increased risk of infections, myopathy, edema, cushingoid appear-
ance, skin thinning and glaucoma [4,5]. A questionnaire from the European League
Against Rheumatism (EULAR) among 140 patients and 110 rheumatologists
revealed that both groups have great concerns about GIOP [6].
An important problem of GIOP is the associated elevated fracture incidence, which
causes significant morbidity. It is estimated that fractures occur in 30 -- 50% of

10.1517/14656566.2013.761975 © 2013 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 185
All rights reserved: reproduction in whole or in part not permitted
 I. E. M. Bultink et al.
Article highlights.
. Glucocorticoid-induced osteoporosis (GIOP) is the most
common cause of secondary osteoporosis and is
associated with an increased risk of fractures.
. Despite the frequent use of glucocorticoid (GC) therapy
for a wide range of chronic diseases, GIOP remains
underdiagnosed and undertreated.
. Studies on the molecular pathways underlying bone
metabolism and the pathogenesis of GIOP have revealed
potential new therapeutic options that will be available
for the prevention and treatment of GIOP in the
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near future.
. Several guidelines for the management of GIOP from
different countries have been developed, which
demonstrate different criteria regarding the thresholds
of daily GC dosage and of bone mineral density values
which are regarded as cutoff values for initiating
anti-osteoporotic drugs.
. In clinical practice, bisphosphonates are used as
first-line drugs for the prevention and treatment of
GIOP, but the anabolic agent teriparatide has been
demonstrated more effective for the prevention of GIOP
than alendronate.
.
The low adherence to anti-osteoporotic drugs is an
important issue in clinical practice, particularly in
patients with GIOP, due to several factors.
For personal use only.
This box summarizes key points contained in the article.
patients receiving long-term GC therapy, which may have a
substantial negative impact on the quality of life [2,7].
Despite greater awareness among physicians, GIOP remains
underdiagnosed and undertreated, which is illustrated by the
fact that fractures are often the presenting manifestation of
GIOP in patients receiving long-term GC therapy [2].
This article reviews the current epidemiology and patho-
physiology of bone loss and fractures in GC-treated patients
and discusses current pharmacotherapy and future directions
in the management of GIOP. Furthermore, clinical relevant
issues such as adherence to anti-osteoporosis medication, dis-
crepancy between guidelines for management of GIOP, and
the question which anti-osteoporotic drugs are first choice in
GC-treated patients are addressed.
2. Epidemiology
It has been estimated that 3% of the population 50 years of
age or older has ever used GCs, and this percentage increases
to 5.2% among those 80 years of age and older [8]. Up to
4.6% of postmenopausal women are currently taking oral
GCs [1]. GC treatment results in bone loss and an increased
risk for vertebral and nonvertebral fractures [9]. The bone
loss starts within months after initiation of therapy and is
more pronounced in the trabecular bone, which is predomi-
nantly found in the spine and ribs [9,10]. Earlier studies have
demonstrated that the bone loss is biphasic, with a rapid ini-
tial phase of 3 -- 5% in the first year of GC therapy, followed
186 Expert Opin. Pharmacother. (2013) 14(2)
by a slower phase of 0.5 -- 1% bone loss annually during con-
tinued GC use [11-13]. Besides the adverse effects of GCs on
bone mass, the underlying disease for which GCs were pre-
scribed may also contribute to the bone loss. For example,
in patients with inflammatory rheumatic diseases elevated
bone resorption as well as reduced bone formation have
been described [14]. Even a small rise in the level of systemic
inflammation can precipitate bone loss and may increase frac-
ture risk [15]. In addition, many underlying diseases for which
GC therapy is initiated are characterized by an unfavorable
nutritional status and by reduced mobility, which may both
aggravate bone loss. For example, Haugeberg et al. demon-
strated a twofold increased prevalence of osteoporosis in
female patients with rheumatoid arthritis compared with
healthy controls [16].
The increased risk for fractures during GC treatment
appears to be dose-dependent [17-19]. Van Staa et al. demon-
strated that hip fracture risk in patients taking a standardized
daily dose of less than 2.5 mg prednisolone was
0.99 (0.82 -- 1.20), rising to 1.77 (1.55 -- 2.02) at daily doses
of 2.5 -- 7.5 mg, and 2.27 (1.94 -- 2.66) at doses of 7.5 mg or
greater [18]. The relative risk of vertebral fractures is particu-
larly elevated during GC treatment and ranges from
1.55 (1.20 -- 2.01) in patients using less than 2.5 mg prednis-
olone daily up to 5.18 (4.25 -- 6.31) in the highest dose
group [18]. The increase in the risk of fractures after the start
of GC therapy is the greatest for vertebral fractures (relative
rate (RR) 2.60; 95% confidence interval (CI) 2.31 -- 2.92),
but the relative rates for hip fractures (RR 1.61; CI
1.47 -- 1.76), forearm fractures (RR 1.09; CI 1.01 -- 1.17)
and nonvertebral fractures (RR 1.33; CI 1.29 -- 1.38) are
increased as well in GC users [18]. After discontinuation of
GC treatment, the fracture risk gradually returns to baseline
and is therefore supposed to be partially reversible [20]. How-
ever, in patients treated with high doses (daily dose ‡ 15 mg
and cumulative exposure > 1 g) oral GC therapy for a short
period of time, fracture risk returned to baseline not before
more than 15 months since discontinuation of therapy [20].
Besides GC dose, age, female gender, falls history, previous
fractures, low body mass index, smoking, immobility, and
the activity of the underlying disease also influence fracture
risk [21].
Despite the apparent effect of GC use on bone density and
fracture risk, GC-induced changes in BMD does not fully
account for the increased fracture risk in GC-treated patients.
An adverse effect of GCs on bone quality is supposed to fur-
ther increase the risk of fractures [22]. Earlier studies revealed a
so-called “reduced bone density threshold for vertebral
fractures” [23,24]. Two randomized controlled trials (RCTs)
demonstrated a significantly increased incidence of vertebral
fractures after a follow-up of 1 year in patients treated with
GCs compared to nonusers, despite higher BMD values
in the GC-treated patients. This phenomenon might be
explained by an increased risk of falling due to steroid-
induced muscle weakness and frailty, and by changes in
 Glucocorticoid-induced osteoporosis: an update on current pharmacotherapy and future directions
the bone architecture which were not captured by BMD
measurements [8,25].
3. Pathogenesis
3.1 Genomic and nongenomic effects of GCs
In recent years, more insight has been gained in the general
mechanisms of GC action. GCs exert their effect via genomic
and nongenomic pathways. The majority of the therapeutic
effects of GCs are exerted via genomic mechanisms by bind-
ing of GCs to cytosolic GC receptors (cGCRs). After binding
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of GCs to cGCRs, the GC/GCR complex translocates to the
nucleus, where binding to specific transcription factors leads
to induction or inhibition of specific genes, so-called transac-
tivation and transrepression genes, respectively. The GC/
GCR complex acts directly with the two transcription factors
activator protein 1 (AP-1) and nuclear factor-kB, which play
an important role in the regulation of several inflammatory
genes [26,27]. The most therapeutic effects of GCs are induced
by transrepression. However, transactivation is supposed to be
responsible for some of the well-known metabolic side-effects
of GCs.
The nongenomic effects of GCs are mediated by
membrane-bound receptors and/or are initiated by physico-
For personal use only.
chemical interactions with cellular membranes and can exert
rapid clinical effects, which can be induced by three distinct
mechanisms [28]. First, binding of GCs to the cGCR promotes
the release of signaling molecules, which cause rapid nuclear
effects. Second, GCs exert effects mediated by the recently
discovered membrane-bound GC receptor. Binding of GCs
with membrane-bound GC receptors has been demonstrated
to change transduction pathways within minutes, which
results in apoptosis of the cell. In the third place, at very
high doses of GCs, physico-chemical interactions between
GCs and the cellular membrane induce unspecific effects.
Direct contact with the cell membrane influences ion trans-
port and direct contact with the mitochondrial membrane
causes proton leakage.
3.2 Effects of GCs on bone
Earlier studies on the pathogenesis of GIOP were performed
in patients treated with high-dose GCs with anti-osteoporotic
drugs. These histomorphometric studies revealed reduced bone
formation, characterized by a low mineral apposition rate
(which is related to a reduction in the number of osteoblasts),
while bone resorption was unchanged or even elevated [29].
During the past few years, several studies have provided
more insight in the molecular mechanisms involved in the
pathogenesis of GIOP. These mechanisms include the
increased apoptosis of mature osteoblasts and osteocytes,
impaired differentiation of osteoblasts, and an increase in
the lifespan of osteoclasts (Figure 1).
GCs induce apoptosis of mature osteoblasts and osteo-
cytes, which results in reduced bone formation. In addition,
the loss of osteocytes is supposed to induce a disrupted
Expert Opin. Pharmacother. (2013) 14(2)
osteocyte-canalicular network and failure to respond to bone
damage [30], which may lead to reduced bone strength. Fur-
ther studies revealed that GCs induce apoptosis of osteoblasts
and osteocytes by activating caspase-3 [31]. Yun et al. recently
found that apoptosis of osteoblasts is related to the activation
of glycogen synthase kinase 3b (GSK 3b), which plays a
role in the Wnt signaling pathway [32]. The Wnt signaling
pathway has an important role in controlling osteoblast differ-
entiation and, subsequently, in bone formation. In the normal
situation, binding of Wnt to the low-density lipoprotein
receptor-related protein 5 and 6 and its co-receptor, frizzled,
stabilizes b-catenin, which induces transcription of target genes
and subsequently induces bone formation. GCs have been
demonstrated to suppress this pathway by stimulating the
production of Wnt pathway inhibitors, such as dickkopf-1
(Dkk-1) [33,34]. Interestingly, it was recently demonstrated
that silencing Dkk-1 reduces the GC-induced suppression of
osteoblast differentiation [35].
Besides inhibiting osteoblast differentiation by suppressing
the Wnt signaling pathway, GCs impair osteoblast function
via several other pathways. GCs were shown to interfere
with the bone morphogenetic protein pathway, which also
results in inhibition of osteoblast differentiation [36].
In addition, an influence of GCs on the differentiation of
bone marrow stromal cells, the precursor cells of osteoblasts,
has been demonstrated. GCs stimulate bone marrow stromal
cells to differentiate toward adipocytes instead of osteoblasts
and this effect is mediated by an increased expression of the
peroxisome proliferator-activated receptor-g2 and repression
of the osteogenic transcription factor runt-related protein
2 [37]. A recent study demonstrated that high doses of GCs
induce a shift toward adipogenesis mediated by repression of
AP-1. Therefore, repression of AP-1 not only influences
anti-inflammatory activity but also affects bone strength
negatively [38].
Another mechanism by which GCs induce bone loss is
the reduced apoptosis of osteoclasts during GC treatment.
GCs induce an increased lifespan of osteoclasts as a conse-
quence of an upregulation of receptor activator for nuclear
factor-kB ligand (RANKL) and suppression of osteoprote-
gerin (OPG) [39]. The GC-induced suppression of OPG
may be mediated by the Wnt signaling pathway [40]. How-
ever, the reduced apoptosis and subsequently increased
lifespan of osteoclasts might also be associated with an
impaired function of osteoclasts. An in vitro study demon-
strated that direct effects of GCs on osteoclasts induce a
reduced bone resorption capacity. Interference with the for-
mation of ruffled border and disruption of the cytoskeleton
are supposed to be two of those direct effects of GCs on
osteoclasts [41].
3.3 Indirect effects of GCs
Apart from the direct effects on osteoblasts, osteocytes and
osteoclasts, GCs have indirect effects on muscles, calcium
metabolism and bone mass. An adverse effect of GC use on
187
 I. E. M. Bultink et al.
Glucocorticoids
↑ Caspase-3 ↑ GSK3β ↑ Dkk-1
↓ Wnt signaling
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↑ Osteocyte ↑ Osteoblast
apoptosis apoptosis
↓ Bone strength ↓ Bone mass
↑ Fractures
Figure 1. Effects of glucocorticoids on bone cells.
BMP: Bone morphogenetic protein; Dkk-1: Dickkopf-1; GSK3b: Glycogen synthase kinase 3b; OPG: Osteoprotegerin; PPAR: Peroxisome proliferator-
For personal use only.
activated receptor; RANKL: Receptor activator for nuclear factor-kB ligand; Runx2: Runt-related protein 2.
muscle mass and muscle strength has been demonstrated [10]
and this so-called steroid myopathy may indirectly increase
fracture risk by enhancing the risk of falls. In addition, it is
well known that GCs impair bone metabolism by inhibition
of the intestinal calcium absorption and by inhibiting the
renal tubular calcium reabsorption, which might induce
hypocalcemia and subsequently hyperthyroidism. Further-
more, GCs were demonstrated to impair bone mineralization
by transrepression of two important matrix proteins,
osteocalcin and collagen I [7].
4.Management of glucocorticoid-induced
osteoporosis
4.1 General measures
First, general lifestyle measures are important, which include
to avoid smoking, to refrain from excessive alcohol use, to
maintain a normal body weight, to perform daily weight bear-
ing physical exercise, and to avoid falling. Since patients on
GC treatment might be at an increased risk of falling due to
steroid myopathy, an assessment of fall risk is recommended
in these patients. In recent years, various strategies for the
assessment of fall risk have been developed [42].
Second, efforts should be made to prescribe GCs in the
lowest possible dose and for a short period of time when pos-
sible. In addition, use of “steroid sparing” immunosuppressive
drugs may reduce cumulative GC dose in several conditions,
e.g., in patients with inflammatory rheumatic diseases.
188 Expert Opin. Pharmacother. (2013) 14(2)
↑ PPARγ 2 ↓ BMP ↑ RANKL
Runx2 ↓ OPG
↓ Osteoclast
↑ Adipocytes
apoptosis
↓ Osteoblast ↓ Osteoclast
differentiation life-span
Third, calcium and vitamin D supplementation have been
proven to be essential in the management of GIOP. Two
randomized trials [43,44] and a meta-analysis [45] demon-
strated that combined calcium and vitamin D supplementa-
tion was more effective in preserving BMD than either
calcium alone or no therapy in GC-treated individuals.
However, no effect on fracture incidence has been demon-
strated. In addition, it must be mentioned that the most
important reason for prescribing calcium and vitamin D
supplementation is that all Phase III intervention studies
have been performed in patients treated with bisphospho-
nates, or other anti-osteoporotic drugs, in combination
with calcium and vitamin D.
It has been suggested that the daily calcium intake should
be above 1000 to 1500 mg per day in GC-treated patients;
somewhat higher than in postmenopausal women not using
GCs, which is related to the lower intestinal calcium absorp-
tion and elevated urinary calcium excretion in GC-treated
patients. An adequate 25-hydroxyvitamin D3 serum level of
at least 50 nmol/L is advised during the whole year [46]. To
achieve these therapeutic levels vitamin D supplementation
in doses of at least 800 IU per day are recommended.
However, in some patient groups higher doses of vitamin D
supplementation may be necessary, probably because some
patients on GC therapy do not go outside often as a conse-
quence of the underlying disease for which GCs were
prescribed. Furthermore, it has been suggested that GCs neg-
atively influence vitamin D absorption. In a meta-analysis, it
 Glucocorticoid-induced osteoporosis: an update on current pharmacotherapy and future directions
was demonstrated that the use of calcium and vitamin D sup-
plementation results in stabilization of BMD in patients on
chronic GC therapy [47].
4.2 Fracture risk assessment
The etiology of osteoporotic fractures in patients on GC treat-
ment is multifactorial, including both bone-related and
fall-related factors, and is also strongly related to baseline
risk. Thus, the absolute fracture risk is particularly high in
GC-treated patients with a high background fracture risk,
e.g., postmenopausal women with an inflammatory rheumatic
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disease. BMD assessment once a year or every other year may
be indicated, with a review of medication in those patients
with a decrease in BMD. The occurrence of more than one
fracture during anti-osteoporotic therapy is regarded as
another indication for treatment review [25].
The identification of patients with increased fracture risk
solely using BMD measurements has several disadvantages,
such as its inaccuracy in measuring bone quality and its age
dependency [5]. Therefore, it has been recommended to assess
fracture risk using models that calculate the absolute fracture
risk for the individual patient. However, the disadvantage of
using the absolute fracture risk is the lack of consensus regarding
at which cutoff point treatment should be started. Therefore,
For personal use only.
any cutoff point will be arbitrary.
In the last decade, several algorithms for calculating the
absolute fracture risk for the individual patient have been
developed, most based on the T-score of BMD measurement
of the spine and hip and on the daily dosage of prednisone.
First, the Fracture in GIOP Score (FIGS) has been developed,
which calculates the 5- and 10-year risk of an osteoporotic
fracture of the hip, vertebrae, and wrist [19]. Although the
use of this model is somewhat complicated, this algorithm
has the advantage that the underlying disease, the fall risk,
and the GC dosage are taken into account. Second, a fre-
quently used model is the Fracture Risk Assessment (FRAX)
tool as proposed by the World Health Organization [48].
The FRAX tool takes BMD and family history into account,
but excludes the evaluation of risk factors for falls and the
presence or absence of prevalent vertebral deformities.
Another disadvantage is that GC use but not GC dosage is
recorded in this model. In addition, the FRAX tool is not
designed to calculate fracture risk in patients who are treated
with bone active drugs. Furthermore, the FRAX tool lacks
the possibility to calculate risk of vertebral fractures, which
is another important disadvantage of this model.
Unfortunately, research performed on risk factors for falls
and quality of life, and the influence of anti-osteoporotic
therapy on fall risk and quality of life in patients with
GIOP, is very limited. More attention should be paid to these
clinically relevant items in future studies.
Besides algorithms for calculating the absolute fracture risk
for the individual patient, several guidelines for the manage-
ment of GIOP have been developed which are discussed in
Section 4.5.
Expert Opin. Pharmacother. (2013) 14(2)
4.3 Medication
Unfortunately, the majority of studies performed in GC-treated
individuals included primarily postmenopausal women, while
men and premenopausal women were a minority of the study
population. In addition, the results of BMD measurements
were used as an endpoint in the most studies. Furthermore,
the majority of intervention studies performed in GC-treated
individuals have included heterogeneous groups of patients
with different underlying conditions (although the majority
suffers from an inflammatory rheumatic disorder), which
might differently affect bone strength. Preferably, the occur-
rence of fractures should be used as an endpoint and study
populations should consist of homogeneous groups of patients,
and studies should also be performed in other subgroups of
patients treated with GCs (e.g., men and premenopausal
women). In addition, not all available anti-osteoporotic drugs
are equally well investigated, and treatment duration is limited
in most studies.
Alendronate, etidronate, risedronate, zoledronic acid, and
teriparatide are approved for treatment of GIOP. Bisphosph-
onates have been demonstrated to be effective in preventing
GC-induced bone loss in several RCTs [11,12,49-53]. In patients
on long-term GC therapy, alendronate was shown to improve
lumbar spine BMD after 1 year, while the BMD decreased in
patients on placebo treatment [51]. After 2 years, the difference
was sustained [11]. Remarkably, the greatest increase in bone
density occurred within the first year of treatment. The effi-
cacy of risedronate to prevent GC-induced bone loss was
demonstrated in two studies [12,50]. In patients starting GC
treatment, risedronate prevented bone loss [12], while in
patients on long-term GC therapy an increase in BMD was
demonstrated [50]. Bisphosphonates are the most effective
drugs in the management of GIOP (effect size 1.03; 95%
CI 0.85 -- 1.17); the efficacy was even higher when adding
vitamin D (effect size 1.31; 95% CI 1.07 -- 1.50) [49].
For both alendronate and risedronate, a reduction in
vertebral fractures has been observed in RCTs in patients on
GC therapy [11,53]. The incidence of vertebral fractures in
patients treated with alendronate was 0.7% after 2 years of
follow-up, compared with 6.8% in placebo-treated patients
(p = 0.026) [11]. In line with these findings, for risedronate a
70% reduction in vertebral fracture incidence as compared
with placebo was found [53]. These results have to be treated
with caution, because the incidence rate of vertebral fractures
was low and treatment duration was limited (maximum 2 years)
in both studies. However, in both studies the reduction in verte-
bral fracture incidence was statistically significant. No reduction
in nonvertebral fractures was observed in both studies.
A very recently published 12-month, double-blind,
placebo-controlled trial demonstrated that oral ibandronate
once-monthly provides a significant increase in lumbar spine
and hip BMD in postmenopausal women treated with low-
dose GCs for inflammatory rheumatic diseases compared
with placebo [54]. The effect of ibandronate was also recently
studied in men on GC therapy after cardiac transplantation [55].
189
 I. E. M. Bultink et al.
After 1 year, spine BMD remained unchanged in ibandronate-
treated patients, while a 25% decline in spine BMD was
observed in placebo-treated patients. In addition, a significant
reduction in morphometric vertebral fractures was demon-
strated (13% in ibandronate-treated group vs 52% in
placebo-treated group).
Recently, an RCT demonstrated that zoledronic acid,
administered intravenously once a year, was more effective
than oral risedronate in both prevention and treatment of
GIOP after 12 months of therapy [13]. In this study, no statis-
tical significant difference in fracture incidence was observed
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between both treatment groups. This finding might be
explained by the fact that zoledronic acid was not compared
with placebo but with another anti-osteoporotic drug in this
trial. As a consequence of the intravenous way of administra-
tion, treatment with zoledronic acid has some practical impli-
cations. Depending on the health care system in a specific
country, this treatment may have an impact on hospital budg-
ets. In addition, the risk of renal damage is increased in
patients with impaired kidney function, e.g., in older patients
with moderately reduced kidney function.
Physicians should be aware that osteonecrosis of the jaw [56]
and atypical femoral shaft fractures [57,58] are rare but
important potential complications of bisphosphonate therapy,
For personal use only.
especially in patients with concomitant GC treatment.
Furthermore, bisphosphonates should not be prescribed to
premenopausal women planning a pregnancy, since these drugs
are associated with fetal abnormalities in animal studies [59].
The effect of GCs on bone is characterized by their inhib-
iting effect on bone formation. Therefore, theoretically, ana-
bolic agents should be the drugs of first choice in patients
on GC therapy. However, in clinical practice, bisphospho-
nates (which are antiresorptive drugs) are used as first-line
drugs for the prevention and treatment of GIOP and the ana-
bolic agent teriparatide is reserved as a second-line option
because of its higher cost price and the inconvenience of
parenteral administration by daily subcutaneous injections
during 2 years.
Clinical studies have demonstrated that PTH 1-34
(teriparatide) is more effective in preventing bone loss and
in reducing vertebral fracture risk than alendronate in a
high-risk population with pre-existing osteoporosis [60,61]. In
a randomized controlled trial in men and women with osteo-
porosis on GC treatment (> 5 mg daily) for at least 3 months,
teriparatide treatment was superior to alendronate with a
significantly higher increase in BMD in the lumbar spine
(7.2% vs 3.4%) after 18 months of treatment [60]. Moreover,
the frequency of new vertebral fractures was significantly
lower in patients treated with teriparatide compared to
patients receiving alendronate: 0.6% vs 6.1%, respectively
(p = 0.004). No difference in the occurrence of nonvertebral
fractures was observed. The long-term extension of this study
confirmed the superiority of teriparatide to alendronate in
preventing bone loss and in reducing fracture rate after in
total 36 months [61].
190 Expert Opin. Pharmacother. (2013) 14(2)
Interestingly, the results of a recent study demonstrated
that teriparatide not only reduces fracture rate, but also
reduces back pain and improves health-related quality of
life [62]. In postmenopausal women with severe osteoporosis
receiving GCs, who were treated with teriparatide for up to
18 months, a reduced incidence of clinical fractures during
the third period of 6 months vs during the first 6 months,
together with a significant and probably clinically relevant
reduction in back pain and improved health-related quality
of life were demonstrated. Despite the relatively high costs
and the inconvenience of daily subcutaneous administration,
teriparatide may be attractive to use as a first-line drug in
GC-treated patients with a very high risk of fractures for
two reasons. First, teriparatide is an anabolic agent, which
counteracts the adverse effects of GCs. Second, it has been
proven superior to oral bisphosphonates with respect to
prevention of bone loss and reduction of fracture rate in
GC-treated patients. Currently, however, no guidelines exist
regarding which GC-treated individuals should be offered ter-
iparatide treatment as a first-line therapy. Potential side-
effects of teriparatide include mild hypercalcemia, headache,
nausea, dizziness, and leg cramps. In addition, caution must
be taken in patients with preexisting nephrolithiasis.
No data are available on the effects of parathyroid hormone
(PTH 1-84) and strontium ranelate with respect to the
prevention and treatment of GIOP.
Denosumab, a monoclonal antibody against RANKL,
might be an attractive new therapeutic agent for GC-treated
patients with renal failure and for GC-treated patients with
rheumatoid arthritis. In a 12-month, placebo-controlled trial
in patients with rheumatoid arthritis concurrently receiving
treatment with GCs or bisphosphonates, denosumab therapy
was shown to increase BMD and reduce bone turnover
(determined by measurement of levels of serum type I
C-telopeptide and serum procollagen 1N-terminal peptide)
compared with placebo [63]. Further studies are needed to assess
the effect of denosumab on the risk of fractures. In addition,
physicians should be aware that hypocalcemia and vitamin D
deficiency must be treated before initiating denosumab
therapy, as with other agents that block bone resorption.
The different treatment options for GIOP and their effects
on BMD and fractures are summarized in Table 1.
Studies on the molecular pathways underlying bone metab-
olism and the pathogenesis of GIOP have revealed potential
new therapeutic targets for the prevention and treatment of
osteoporosis. We are eagerly awaiting studies on the effects of
cathepsin K inhibitors, and monoclonal antibodies against scle-
rostin in GC-treated patients. For ethical reasons, these new
drugs should preferably be tested against an active comparator.
4.4 Cost-effectiveness of the treatment of GIOP
In contrast to the large number of studies on the cost-
effectiveness of treatments for osteoporosis performed, only
a few studies specifically focused on cost-effectiveness of
anti-osteoporotic therapy in GC-treated patients [64-67].
 Glucocorticoid-induced osteoporosis: an update on current pharmacotherapy and future directions

Table 1. Grading of evidence for pharmacological the prevention and treatment of GIOP was published, which
interventions used for the management of includes renewed recommendations for counseling and
glucocorticoid-induced osteoporosis. monitoring GIOP and provides updated advices for pharma-
cotherapeutic interventions [68]. These recommendations pro-
Intervention Spine Hip Vertebral Nonvertebral vide for the management of two subgroups of patients:
BMD BMD fractures fractures postmenopausal women and men ages > 50 years, and pre-
menopausal women and men younger than 50 years initiating
Alendronate A A Bz nae
Risedronate A A Az nae or currently using GC therapy. Furthermore, patients are sub-
Zoledronic acid A* A nae nae categorized into fracture risk categories [low risk (< 10%),
Ibandronate A* A A nae medium risk (10 -- 20%), and high risk (> 20%)]. The frac-
Strontium ranelate nae nae nae nae ture risk categories were defined using the FRAX tool and,
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Notre Dame Australia on 07/09/13

Teriparatide A* A* A*,z nae

as mentioned earlier, this tool has some disadvantages since
PTH (1-84) nae nae nae nae
Denosumab A§ A§ nae nae it does not include risk factors for falling, the daily GC
dosage, and the presence or absence of prevalent vertebral
Grading of evidence was derived as follows: A: Meta-analysis or at least one fractures. In addition, the definition of risk categories was
randomized controlled trial; B: At least one controlled study but without defined by an expert panel and is not evidence-based.
randomization or a non-experimental descriptive study; C: Expert committee
The Dachverband Osteologie (DVO) Guideline 2009 has
reports, opinions and/or experience of respected authorities.
*Comparator study.
been developed in Germany, Austria and Switzerland and
z
Not a primary endpoint. provides a comprehensive guideline for the prevention, diag-
§
Only 40% of patients on chronic glucocorticoid therapy. nosis and treatment of osteoporosis [69]. In addition to the
BMD: Bone mineral density; nae: Not adequately evaluated; risk factors for fractures as assessed with the FRAX tool, the
PTH: Parathyroid hormone.
fracture prediction algorithm as proposed by the DVO
Guideline also takes into account additional risk factors which
Buckley and Hillner [65] used a decision analysis model and have been proven important predictors of future fractures,
For personal use only.

demonstrated that calcium and vitamin D supplementation
and low-cost bisphosphonate regimens decrease life-time ver-
tebral fracture risk at acceptable costs. Van Staa et al. [67]
developed an individual patient-based pharmaco-economic
model using data from the UK General Practice Research
Database which showed that cost-effectiveness of bisphospho-
nates varied substantially, depending on several factors.
Therapy with bisphosphonates was found cost-effective in
GC-treated patients with higher fracture risks, such as
elderly patients, younger patients with a previous fracture,
low body mass index, rheumatoid arthritis, or using high GC
doses. Of course, cost-effectiveness of therapy has dramatically
improved by the introduction of low-cost bisphosphonate
regimens.
In a systematic review and cost-utility analysis, Kanis et al.
described that cost-effectiveness of therapy with bisphospho-
nates is influenced by age, fracture history, and T-score [64].
In addition, the cost-effectiveness of different therapeutic agents
will vary between countries as a consequence of differences in
drug costs, fracture risk, costs associated with the treatment of
fractures, utility estimates and willingness to pay [1].
4.5 Guidelines for the management of GIOP
In the last decades, several guidelines for the management of
GC-induced osteoporosis from different countries have been
developed. Unfortunately, these guidelines demonstrate
relatively large differences regarding the thresholds of daily
GC dosage and of BMD values which are regarded as cutoff
values for initiating anti-osteoporotic drugs in subgroups of
GC-treated patients (Table 2). Recently, an update of the
American College of Rheumatology recommendations for
e.g., assessment of past or current GC use, GC dosage, mor-
phometric vertebral fractures, risk factors for falls, and BMD
of the lumbar spine.
Clearly, the currently available different country-specific
guidelines are still in development. Hopefully, further
validation studies and international collaboration will result
in a generally accepted international recommendation for
the management of GIOP.
Recently, a joint guideline working group from the
International Osteoporosis Foundation and the European
Calcified Tissue Society proposed a framework for the devel-
opment of guidelines for management of GIOP in men and
women in whom oral GC therapy is considered for 3 months
or longer, from which country-specific guidelines may be
derived [1]. This framework further categorizes patients
based on age (< 70 years or ‡ 70 years), prednisone dosage
(< 7.5 mg or ‡ 7.5 mg daily), and the presence or absence
of a previous fracture. Again, the FRAX tool was used
to determine intervention thresholds, based on a 10-year
fracture probability-based approach.
4.6 Adherence to therapy
It is well-known that compliance and persistence with anti-
osteoporotic drugs is poor, particularly with oral bisphospho-
nates [70]. This low adherence to anti-osteoporotic medication
is an important problem since in primary osteoporosis
patients low compliance is associated with a 17% increase in
the incidence of fractures and a 37% increase in risk of all-
cause hospitalizations [70]. A recent, large, retrospective study
demonstrated that less than 40% of patients were adherent
to treatment after 1 year follow-up [71]. Another retrospective

Expert Opin. Pharmacother. (2013) 14(2) 191

 I. E. M. Bultink et al.

Table 2. Guidelines for management of glucocorticoid-induced osteoporosis.

Guideline GC dose threshold BMD threshold

American College of GC dose ‡ 7.5 mg/day for at least 3 months, Based on the FRAX algorithm in addition
Rheumatology [68] but treatment with any dose and duration to “declining BMD, higher daily and
in patients at increased risk cumulative dose, and intravenous use”
National Osteoporosis GC dose ‡ 5 mg/day for at least 3 months T score -2.5, unless patient is at high risk
Foundation [80] on the basis of a modified FRAX model
Royal College of Physicians Any oral dose for at least 3 months in T score -1.5
of London [81] patients ‡ 65 years of age
and those with a prior fragility fracture
Belgian Bone Club [82] GC dose ‡ 9.3 mg/day for at least 3 months T score -1.0 to -1.5
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Notre Dame Australia on 07/09/13

Dutch CBO Guideline [83] GC dose > 15 mg/day and/or those

Finnish National Guideline [84]
DVO Guideline (Germany,
Austria, Switzerland) [69]
with a prior fracture
GC dose 7.5 -- 15 mg/day in
postmenopausal women and men > 70 years
of age; in premenopausal women
and men < 70 years of age
depending on BMD value
GC dose ‡ 5 mg/day for at least 3 months Osteopenic BMD (not further described)
GC dose ‡ 7.5 mg/day for at least 3 months T score £ -1.5

BMD: Bone mineral density; GC: Glucocorticoid; FRAX: Fracture risk assessment.

study on persistence and compliance to different anti- monitoring of high fracture risk patients was demonstrated
For personal use only.

osteoporotic drugs in more than 1 million patients in Ger-
many revealed that after 12 months the proportion of patients
that remained on treatment was 65.6% for zoledronic acid
intravenously, 56.6% for ibandronate intravenously, 54.7%
for teriparatide and 1-84 PTH, 51.0% for oral ibandronate,
44.8% for alendronate, 35.8% for risedronate, and 31.4%
for strontium ranelate [72]. Thus, intravenous and subcutane-
ous administration route are associated with the highest
adherence rates, but persistence is still suboptimal. In addi-
tion, extending dose interval of oral anti-osteoporotic drugs
has increased adherence only moderately. In recent years,
more insight has been gained in the causes of nonadherence.
Forgetfulness was found to be a reason for nonadherence to
oral bisphosphonates only in a small proportion of osteoporo-
sis patients, whereas deliberate choice was recognized as the
most frequent cause [73]. In addition, gender differences and
style of healthcare management play a role.
A better understanding of the reasons for poor compliance
is necessary to develop effective intervention strategies to
improve adherence. In recent years, several methods to
improve adherence in GIOP have been proposed, such as
the model of “shared decision making” [74] and the use of a
specialized “GIOP outpatient clinic” [75]. In the model of
shared decision making, the patient and the physician discuss
the pros and cons of anti-osteoporotic therapy. Calculating
the absolute fracture risk may be very useful in this model
since it gives the individual patient better insight into her or
his future fracture risk and the degree of risk reduction that
may be achieved when therapy with anti-osteoporotic drugs
is started. Another approach is the use of a specialized
GIOP care program, in which education and intensively
to significantly improve the patients’ knowledge and lifestyle
and to a 91% adherence to therapy after 1 year [75]. The
next challenge will be the development of implementation
strategies to translate these specialized care programs to
routine daily care.
5. Conclusions
GIOP has been recognized as the most common cause of
secondary osteoporosis and is associated with an increased
fracture risk and, subsequently, with substantial morbidity.
GC therapy induces increased apoptosis of osteoblasts and
osteocytes and an increased lifespan of osteoclasts, which leads
to a reduction in both bone density and bone strength. In
recent years, more insight has been gained in the molecular
pathways of bone metabolism and the RANKL/OPG path-
way and Wnt signaling pathway have been suggested to play
an important role in the pathogenesis of GIOP. New guide-
lines for the management of GIOP and new tools to assess
absolute fracture risk in the individual patient have been
developed, which may improve the identification of patients
with an increased fracture risk and improve treatment of
GIOP. Oral bisphosphonates and zoledronic acid adminis-
tered intravenously have been demonstrated to reduce the
development of GIOP and the occurrence of vertebral frac-
tures. However, adherence to oral bisphosphonates is low
and zoledronic acid has the disadvantage of an intravenous
administration route. Therapy with teriparatide is superior
to oral bisphosphonates, but is relatively expensive. Denosumab
might be an attractive new therapeutic agent for
GC-treated patients, but no data on reduction of fracture

192 Expert Opin. Pharmacother. (2013) 14(2)

 Glucocorticoid-induced osteoporosis: an update on current pharmacotherapy and future directions
risk are currently available. Studies on the molecular pathways
underlying bone metabolism and the pathogenesis of GIOP
have revealed potential new therapeutic options that will be
available in the near future for the prevention and treatment
of osteoporosis in GC-treated patients.
6. Expert opinion
Why is optimal fracture prevention in all
6.1
GC-treated patients so difficult?
In fact, there are two key issues in GC-treated patients:
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Notre Dame Australia on 07/09/13
1) What is the optimal treatment?
2) Why is implementation of treatment suboptimal in
GC-treated patients?
In addition to general measures, as described in section 4.1,
anti-osteoporotic drugs are necessary in patients at high
fracture risk. Unfortunately, several guidelines have been
published, with different criteria for a BMD threshold for
treatment and for the dosage of GCs above which treatment
should be considered. Should preferably patients be treated
with a high FRAX score (American College of Rheumatol-
ogy), or with a low T-score? T-score below -2.5 (National
For personal use only.
Osteoporosis Foundation), -1.5 (United Kingdom) or
-1.0 (Belgium)? And what is the threshold for GC dosage
above which anti-osteoporotic drugs should be prescribed? A
prednisone dosage above 7.5 mg/day (American College of
Rheumatology), above 5 mg/day (National Osteoporosis
Foundation), 9.3 mg/day (Belgium), or any dosage for at least
3 months in the elderly (United Kingdom)?
Thus, unfortunately, there is no detailed consensus in
which GC-treated patients anti-osteoporotic therapy should
be started. For the clinician it might be helpful to realize
that the common sense is that particularly those patients at
high fracture risk preferably be treated: those with high back-
ground risk (high age, and also low body mass index, family
history of osteoporosis, and immobility), and those with
high disease activity and the use of high doses of GCs [76].
6.2 Which drugs are first choice?
Since in GC-treated patients the effect of GCs on bone
is dominated by its inhibiting effect on bone formation,
anabolic agents and not bisphosphonates are first choice in
GC-treated patients [22].
Nowadays, only PTH 1-34 (teriparatide) has been investi-
gated in GC-treated patients; no data are available from
PTH 1-84. PTH 1-34 (20 µg/day) was compared with
the active comparator alendronate (10 mg/day) for treating
GC-induced osteoporosis in a 36-month, randomized, dou-
ble-blind, controlled trial in 428 patients who had received
prednisone 5 mg/day for 3 months or more [77]. A reduction
in vertebral fractures in the PTH 1-34 group vs the alendro-
nate group was observed: 3 (1.7%) vs 13 (7.7%); p = 0.007,
but no significant difference in the incidence of nonvertebral
Expert Opin. Pharmacother. (2013) 14(2)
fractures. In an editorial by Sambrook it was concluded that
for patients with low BMD who are receiving long-term GC
therapy, teriparatide should be considered as a potential
first-line therapy [78].
For both alendronate and risedronate an increase in BMD
and reduction of vertebral fractures have been observed in
RCTs in patients with (high-dose) GCs [11,53]. However, in
both the alendronate and the risedronate studies, the
reduction in new vertebral fractures was not accompanied
by a reduction in nonvertebral fractures, which might be a
type II error.
No data in GC-treated patients are available for strontium
ranelate, which is remarkable, since strontium ranelate indu-
ces an increase in bone formation and a reduction in bone
resorption, thus counteracting the effect of GCs on bone.
The effect of ibandronate has been studied in a placebo-
controlled RCT in men after cardiac transplantation, showing
a significant reduction in the number of morphometric
vertebral fractures [55]. An RCT in GC-treated patients com-
paring the effect of zoledronic acid with that of risedronate
showed that the increase in BMD was larger in the zoledronic
acid-treated patients than in the risedronate-treated
patients [13]. However, the clinical relevance of this difference
can be questioned, since increases in BMD do not necessarily
indicate increases in bone strength. Nevertheless, the trial
underlines that new anti-osteoporotic drugs that are potentially
attractive for the treatment of GIOP (such as denosumab,
cathepsin K inhibitors, and monoclonal antibody against
sclerostin) should be tested against an active comparator, for
ethical reasons.
6.3How long should anti-osteoporotic drugs be
prescribed?
The duration of treatment with anti-osteoporotic drugs is
another important issue, since the majority of the GIOP trials
studied changes in BMD during 1 year of follow-up. This
question has been discussed in a recent editorial, in which it
was stated that in the early phase of GC treatment bone for-
mation is depressed and bone resorption is increased, while
in the chronic phase the coupling between bone formation
and bone resorption leads to low bone turnover, which pro-
vides an argument to prescribe anabolic agents [79]. Thus, we
need more data on the effects of long-term therapy with
anti-osteoporotic drugs in GC-treated patients.
6.4Adherence to therapy
As mentioned before, one of the big issues in GIOP is
adherence to therapy.
The low adherence to therapy could be related to:
. Anti-osteoporotic drugs are prescribed for prevention of
future fractures. In comparable circumstances, e.g., hyper-
tension, low adherence to therapy is also a well-known and
important issue, while in patients with arthritis, adherence
193
 I. E. M. Bultink et al.

is usually higher, because anti-inflammatory drugs induce
relief of pain and inflammation.
. Monitoring the effect of anti-osteoporotic drugs is not
optimal. The changes in BMD can only be measured
after 2 or 3 years of therapy. Changes in bone markers
occur already after 2 -- 3 months of therapy, but the
use of measurements of bone markers is limited because
of a relatively high analytical variation, their circadian
rhythm, and the costs.
. Patients starting with GC treatment are usually ill, and
are getting informed about their underlying disease
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Notre Dame Australia on 07/09/13
. General factors, not directly related to bisphosphonates,
may play a role:
a) When the number of prescribed drugs increases, the
risk of non-adherence is rising.
b) Anti-osteoporotic drugs are usually prescribed in
older adults, in whom adherence may be limited
due to (early) dementia.
c) Some patients have a general negative opinion
against drugs.
Thus, there are several reasons why adherence to anti-

and about the possible side-effects of GCs (e.g., hyper-
tension, diabetes, glaucoma, increased infection risk,
osteoporosis). Thus, osteoporosis is just one item on
the long list of the possible side-effects of GCs, for
which nevertheless it might be necessary to take two or
three types of additional drugs.
. Side-effects. However, in clinical practice, side-effects of
bisphosphonates are usually not very serious: the most
important are (mild) gastrointestinal side-effects, which
may occur in 20 -- 30% of the patients, and 2 -- 3 days
of fever and flu-like symptoms occurring in nearly all
patients treated with high-dose bisphosphonates.
For personal use only.
osteoporotic drugs might be limited, particularly in GIOP
patients. On the other hand, the majority of all patients using
GCs are closely monitored for their underlying disease, which
opens up the possibility to check adherence to anti-osteoporotic
drugs in the same session.
Declaration of interest
WF Lems has received consultant and/or speaker fees from
MSD, Eli Lilly Co., Amgen and Servier Laboratories. IEM
Bultink has received consultant fees from Servier Laboratories
and speaker fees from MSD.

Bibliography
Papers of special note have been highlighted as
either of interest () or of considerable interest
() to readers.
1. Lekamwasam S, Adachi JD, Agnusdei D,
et al. A framework for the development
of guidelines for the management of
glucocorticoid-induced osteoporosis.
Osteoporos Int 2012;23:2257-76
2. Weinstein RS. Clinical practice.
Glucocorticoid-induced bone
disease. N Engl J Med
2011;365:62-70
3. Gudbjornsson B, Juliusson UI,
Gudjonsson FV. Prevalence of long
terrm steroid treatment and the
frequency of decision making to prevent
steroid induced osteoporosis in daily
clinical practice. Ann Rheum Dis
2002;61:32-6
4. Buttgereit F, Burmester GR,
Lipworth BJ. Optimised glucocorticoid
therapy: the sharpening of an old spear.
Lancet 2005;365:801-3
5. den Uyl D, Bultink IEM, Lems WF.
Advances in glucocorticoid-induced
osteoporosis. Curr Rheumatol Rep
2011;13:233-40
6. van der Goes MC, Jacobs JW, Boers M,
et al. Monitoring adverse events of
low-dose glucocorticoid therapy: EULAR
recommendations for clinical trials and
daily practice. Ann Rheum Dis
2010;69:1913-19
7. Canalis E, Mazziotti G, Giustina A, et al.
Glucocorticoid-induced osteoporosis:
pathophysiology and therapy.
Osteoporos Int 2007;18:1319-28
8. Kanis JA, Johansson H, Oden A, et al.
A meta-analysis of prior corticosteroid
use and fracture risk. J Bone Miner Res
2004;19:893-9
9. van Staa TP, Leufkens HG, Cooper C.
The epidemiology of
corticosteroid-induced osteoporosis:
a meta-analysis. Osteoporos Int
2002;13:777-87
10. Natsui K, Tanaka K, Suda M, et al.
High-dose glucocorticoid treatment
induces rapid loss of trabecular
bone mineral density and lean
body mass. Osteoporos Int
2006;17:105-8
11. Adachi JD, Saag KG, Delmas PD, et al.
Two-year effects of alendronate on bone
mineral density and vertebral fracture in
patients receiving glucocorticoids:
a randomized, double-blind,
placebo-controlled extension trial.
Arthritis Rheum 2001;44:202-11
12. Cohen S, Levy RM, Keller M, et al.
Risedronate therapy prevents
corticosteroid-induced bone loss: a twelve
month, multicenter, randomized,
double-blind, placebo-controlled,
parallel-group study. Arthritis Rheum
1999;42:2309-18
13. Reid DM, Devogelaer JP, Saag K, et al.
Zoledronic acid and risedronate in the
prevention and treatment of
glucocorticoid-induced osteoporosis
(HORIZON): a multicentre,
double-blind, double-dummy,
randomised controlled trial. Lancet
2009;373:1253-63
.. This article describes the results of a
double-blind study comparing
zoledronic acid with oral risedronate
in the prevention of GIOP in men and
women receiving treatment with GCs.
Zoledronic acid showed a greater
increase in BMD of the spine and a
faster inhibitory effect on markers of
bone loss than risedronate. Therefore,
this article showed that zoledronic acid
is an important additional treatment
option for GIOP.
14. Schett G, Stach C, Zwerina J, et al.
How antirheumatic drugs protect
joints from damage in rheumatoid
arthritis. Arthritis Rheum
2008;58:2936-48
15. Schett G, Saag KG, Bijlsma JW. From
bone biology to clinical outcome: state of

194 Expert Opin. Pharmacother. (2013) 14(2)

 Glucocorticoid-induced osteoporosis: an update on current pharmacotherapy and future directions
the art and future perspectives.
Ann Rheum Dis 2010;69:1415-19
16. Haugeberg G, Uhlig T, Falch JA, et al.
Bone mineral density and frequency of
osteoporosis in female patients with
rheumatoid arthritis: results from
394 patients in the Oslo County
Rheumatoid Arthritis register.
Arthritis Rheum 2000;43:522-30
17. Cooper C, Coupland C, Mitchell M.
Rheumatoid arthritis, corticosteroid
therapy and hip fracture.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Notre Dame Australia on 07/09/13
Ann Rheum Dis 1995;54:49-52
18. van Staa TP, Leufkens HG, Abenhaim L,
et al. Use of oral corticosteroids and risk
of fractures. J Bone Miner Res
2000;15:993-1000
19. van Staa TP, Geuzens P, Pols HA, et al.
A simple score for estimating the
long-term risk of fracture in patients
using oral glucocorticoids. QJM
2005;98:191-8
20. de Vries F, Bracke M, Leufkens HG,
et al. Fracture risk with intermittent
high-dose oral glucocorticoid therapy.
For personal use only.
Arthritis Rheum 2007;56:208-14
21. Kanis JA, Borgstrom F, de Laet C, et al.
Assessment of fracture risk.
Osteoporosis Int 2005;16:581-9
22. Lems WF. Bisphosphonates and
glucocorticoids: effects on bone quality.
Arthritis Rheum 2007;56:3518-22
23. van Staa TP, Leufkens HG, Abenhaim L,
et al. Use of oral corticosteroids in the
United Kingdom. QJM 2000;93:105-11
24. van Staa TP, Laan RF, Barton IP, et al.
Bone density threshold and other
predictors of vertebral fracture in patients
receiving oral glucocorticoid therapy.
Arthritis Rheum 2003;48:3224-9
25. Compston J. Clinical question: what is
the best approach to managing
glucocorticoid-induced osteoporosis?
Clin Endocrinol (Oxf) 2011;74:547-50
26. McKay LI, Cidlowski JA. Cross-talk
between nuclear factor-kappa B and the
steroid hormone receptors: mechanisms
of mutual antagonism. Mol Endocrinol
1998;12:45-56
27. Vayssaire BM, Dupont S, Choquart A,
et al. Synthetic glucocorticoids that
dissociate transactivation and
AP-1 transrepression exhibit
antiiflammatory activity in vivo.
Mol Endocrinol 1997;11:1245-55
28. Buttgereit F, Straub RH, Wehling M,
et al. Glucocorticoids in the treatment of
rheumatic diseases: an update on the
mechanisms of action. Arthritis Rheum
2004;50:3408-17
29. Weinstein RS, Jilka RL, Parfitt AM,
et al. Inhibition of osteoblastogenesis and
promotion of apoptosis of osteoblasts
and osteocytes by glucocorticoids.
Potential mechanisms of their deleterious
effects on bone. J Clin Invest
1998;102:274-82
30. O’Brien CA, Jia D, Plotkin LI, et al.
Glucocorticoids act directly on
osteoblasts and osteocytes to induce their
apoptosis and reduce bone formation and
strength. Endocrinology
2004;145:1835-41
31. Liu Y, Porta A, Peng X, et al. Prevention
of glucocorticoid-induced apoptosis in
osteocytes and osteoblasts by
calbindin-D28k. J Bone Miner Res
2004;19:479-90
32. Yun SI, Yoon HY, Jeong SY, et al.
Glucocorticoid induces apoptosis of
osteoblast cells through the activation of
glycogen synthase kinase 3beta. J Bone
Miner Metab 2009;27:140-8
33. Ohnaka K, Tanabe M, Kawate H, et al.
Glucocorticoid suppresses the canonical
Wnt signal in cultured human
osteoblasts. Biochem Biophys
Res Commun 2005;329:177-81
34. Wang FS, Ko JY, Yeh DW, et al.
Modulation of Dickkopf-1 attenuates
glucocorticoid induction of osteoblast
apoptosis, adipocytic differentiation, and
bone mass loss. Endocrinology
2008;149:1793-801
35. Butler JS, Queally JM, Devitt BM, et al.
Silencing Dkk1 expression rescues
dexamethasone-induced suppression of
primary human osteoblast differentiation.
BMC Musculoskelet Disord 2010;11:210
36. Pereira RC, Delany AM, Canalis E.
Effects of cortisol and bone
morphogenetic protein-2 on stromal cell
differentiation: correlation with
CCAAT-enhancer binding protein
expression. Bone 2002;30:685-91
37. Shi XM, Blair HC, Yang X, et al.
Tandem repeat of C/EBP binding sites
mediates PPARgamma2 gene
transcription in glucocorticoid-induced
adipocyte differentiation. J Cell Biochem
2000;76:518-27
Expert Opin. Pharmacother. (2013) 14(2)
38. Caramo-Orive I, Gaztelumendi A,
Delgado J, et al. Regulation of human
bone marrow stromal cell proliferation
and differentiation capacity by
glucocorticoid receptor and
AP-1 crosstalk. J Bone Miner Res
2010;25:2115-25
39. Hofbauer LC, Gori F, Riggs BL, et al.
Stimulation of osteoprotegerin ligand and
inhibition of osteoprotegerin production
by glucocorticoids in human osteoblastic
lineage cells: potential paracrine
mechanisms of glucocorticoid-induced
osteoporosis. Endocrinology
1999;140:4382-9
40. Kondo T, Kitazawa R, Yamaguchi A,
et al. Dexamethasone promotes
osteoclastogenesis by inhibiting
osteoprotegerin through multiple levels.
J Cell Biochem 2008;103:335-45
41. Kim HJ, Zhao H, Kitaura H, et al.
Glucocorticoids suppress bone formation
via the osteoclast. J Clin Invest
2006;116:2152-60
42. Gillespie LD, Robertson MC,
Gillespie WJ, et al. Interventions for
preventing falls in older people living in
the community. Cochrane Database
Syst Rev 2009(2):CD007146
43. Reginster JY, Kuntz D, Verdickt W,
et al. Prophylactic use of alfacalcidol in
corticosteroid-induced osteoporosis.
Osteoporosis Int 1999;9:75-81
44. Amin S, LaValley MP, Simms RW, et al.
The role of vitamin D in
corticosteroid-induced osteoporosis:
a meta-analytic approach.
Arthritis Rheum 1999;42:1740-51
45. Homik J, Suarez-Almazor ME, Shea B,
et al. Calcium and vitamin D for
corticosteroid- induced osteoporosis.
Cochrane Database Syst Rev
2000(2):CD000952
46. Lips P. Relative value of 25(OH)D and
1,25(OH)2D measurements. J Bone
Miner Res 2007;22:1668-71
47. Tang BM, Eslick GD, Nowson C, et al.
Use of calcium or calcium in
combination with vitamin D
supplementation to prevent fractures and
bone loss in people aged 50 years and
older: a meta-analysis. Lancet
2007;370:657-66
48. Kanis JA, Burlet N, Cooper C, et al.
European guidance for the diagnosis and
management of osteoporosis in
195
 I. E. M. Bultink et al.
postmenopausal women. Osteoporos Int
2008;19:399-428
49. Amin S, Lavalley MP, Simms RW, et al.
The comparative efficacy of drug
therapies used for the management of
corticosteroid-induced osteoporosis:
a meta-regression. J Bone Miner Res
2002;17:1512-26
50. Reid DM, Hughes RA, Laan RF, et al.
Efficacy and safety of daily risedronate in
the treatment of corticosteroid-induced
osteoporosis in men and women:
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Notre Dame Australia on 07/09/13
a randomized trial. European
Corticosteroid-Induced Osteoporosis
Treatment Study. J Bone Miner Res
2000;15:1006-13
51. Saag KG, Emkey R, Schnitzer TJ, et al.
Alendronate for the prevention and
treatment of glucocorticoid-induced
osteoporosis. Glucocorticoid-Induced
Osteoporosis Intervention Study Group.
N Engl J Med 1998;339:292-9
52. Stoch SA, Saag KG, Greenwald M, et al.
Once-weekly oral alendronate 70 mg in
patients with glucocorticoid-induced
bone loss: a 12-month randomized,
For personal use only.
placebo-controlled clinical trial.
J Rheumatol 2009;36:1705-14
53. Wallach S, Cohen S, Reid DM, et al.
Effects of risedronate treatment on bone
density and vertebral fracture in patients
on corticosteroid therapy.
Calcif Tissue Int 2000;67:277-85
54. Hakala M, Kroger H, Valleala H, et al.
Once-monthly oral ibandronate provides
significant improvement in bone mineral
density in postmenopausal women
treated with glucocorticoids for
inflammatory rheumatic diseases:
a 12-month, randomized, double- blind,
placebo-controlled trial.
Scand J Rheumatol 2012;41:260-6
55. Fahrleitner-Pammer A,
Piswanger-Soelkner JC, Pieber TR, et al.
Ibandronate prevents bone loss and
reduces vertebral fracture risk in male
cardiac transplant patients: a randomized
double-blind, placebo-controlled trial.
J Bone Miner Res 2009;24:1335-44
56. Khosla S, Burr D, Cauley J, et al.
Bisphosphonate-associated
osteonecrosis of the jaw: report of
a task force of the American Society
for Bone and Mineral Research.
J Bone Miner Res
2007;22:1479-91
57. Shane E, Burr D, Ebeling PR, et al.
Atypical subtrochanteric and diaphyseal
196
femoral fractures: report of a task force
of the American Society for Bone and
Mineral Research. J Bone Miner Res
2010;25:2267-94
58. Dell RM, Adams AL, Greene DF, et al.
Incidence of atypical nontraumatic
diaphyseal fractures of the femur. J Bone
Miner Res 2012;27:2544-50
59. Patlas N, Golomb G, Yaffe P, et al.
Transplacental effects of bisphosphonates
on fetal skeletal ossification and
mineralization in rats. Teratology
1999;60:68-73
60. Saag KG, Shane E, Boonen S, et al.
Teriparatide or alendronate in
glucocorticoid-induced osteoporosis.
N Engl J Med 2007;357:2028-39
61. Saag KG, Zanchetta JR, Devogelaer JP,
et al. Effects of teriparatide versus
alendronate for treating
glucocorticoid-induced osteoporosis:
thirty-six-month results of a randomized,
double-blind, controlled trial.
Arthritis Rheum 2009;60:3346-55
.. This article describes the results of the
extended randomized controlled trial
comparing the anabolic agent
teriparatide with the antiresorptive
agent alendronate, including data on
fracture risk. After 36 months,
teriparatide was demonstrated to be
superior to alendronate in preventing
bone loss and in reducing fracture risk
in individuals with GIOP.
62. Karras D, Stoykov I, Lems WF, et al.
Effectiveness of teriparatide in
postmenopausal women with
osteoporosis and glucocorticoid use:
3-year results from the EFOS study.
J Rheumatol 2012;39:600-9
63. Dore RK, Cohen SB, Lane NE, et al.
Effects of denosumab on bone mineral
density and bone turnover in patients
with rheumatoid arthritis receiving
concurrent glucocorticoids or
bisphosphonates. Ann Rheum Dis
2010;69:872-5
64. Kanis JA, Stevenson M, McCloskey EV,
et al. Glucocorticoid-induced
osteoporosis: a systematic review and
cost-utility analysis.
Health Technol Assess 2007;11:1-256
65. Buckley LM, Hillner BE. A cost
effectiveness analysis of calcium and
vitamin D supplementation, etidronate,
and alendronate in the prevention of
vertebral fractures in women treated with
Expert Opin. Pharmacother. (2013) 14(2)
glucocorticoids. J Rheumatol
2003;30:132-8
66. Beukelman T, Saag KG, Curtis JR, et al.
Cost-effectiveness of multifaceted
evidence implementation programs for
the prevention of glucocorticoid-induced
osteoporosis. Osteoporosis Int
2010;21:1573-84
67. Van Staa TP, Geusens P, Zhang B, et al.
Individual fracture risk and the
cost-effectiveness of bisphosphonates in
patients using oral glucocorticoids.
Rheumatology 2007;46:460-6
68. Grossman JM, Gordon R,
Ranganath VK, et al. American college of
rheumatology 2010 recommendations for
the prevention and treatment of
glucocorticoid-induced osteoporosis.
Arthritis Care Res (Hoboken)
2010;62:1515-26
.. This article describes the new
American College of Rheumatology
recommendations, which offer an
up-to-date guideline for the prevention
and treatment of GIOP.
69. DVO Guideline 2009 for prevention,
diagnosis and therapy of osteoporosis in
adults. Available from: www.dv-
osteologie.org/dvo_leitlinien/dvo-leitlinie-
2009
70. Silverman S, Gold DT. Compliance and
persistence with osteoporosis medications:
a critical review of the literature.
Rev Endocr Metab Disord
2010;11:275-80
71. Netelenbos JC, Geusens PP, Ypma G,
et al. Adherence and profile of
non-persistence in patients treated for
osteoporosis -- a large scale, long-term
retrospective study in The Netherlands.
Osteoporos Int 2011;22:1537-46
. Despite the increasing knowledge on
the prevention and treatment of GIOP,
this article demonstrates that
persistence to anti-osteoporotic
medication is still an important
problem in daily clinical practice.
72. Ziller V, Kostev K, Kyvernitakis I, et al.
Persistence and compliance of
medications used in the treatment
ofosteoporosis- -analysis using a large
scale, representative, longitudinal German
database. Int J Clin Pharmacol Ther
2012;50:315-22
73. Silverman SL, Schousboe JT, Gold DT.
Oral bisphosphonate compliance and
persistence: a matter of choice?
Osteoporos Int 2011;22:21-6
 Glucocorticoid-induced osteoporosis: an update on current pharmacotherapy and future directions
74. de Bekker-Grob EW, Essink-Bot ML,
Meerding WJ, et al. Preferences of GPs
and patients for peventive osteoporosis
drug treatment: a discrete-choice
experiment. Pharmacoeconomics
2009;27:211-19
75. Newman ED, Matzko CK,
Olenginski TP, et al.
Glucocorticoid-Induced Osteoporosis
Program (GIOP): a novel,
comprehensive, and highly successful care
program with improved outcomes at
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by University of Notre Dame Australia on 07/09/13
1 year. Osteoporos Int 2006;17:1428-34
76. Bultink IE, Vis M, van der
Horst-bruinsma IE, et al. Inflammatory
rheumatic disorders and bone.
Curr Rheumatol Rep 2012;14:224-30
77. Neer RM, Arnaud CD, Zanchetta JR,
et al. Effect of parathyroid hormone
(1-34) on fractures and bone mineral
density in postmenopausal women with
osteoporosis. N Engl J Med
2001;344:1434-41
78. Sambrook PN. Anabolic therapy in
glucocortcoid-induced osteoporosis.
N Engl J Med 2007;357:2084-6
For personal use only.
79. Teitelbaum SL, Seton MP, Saag KG.
Should bisphosphonates be used for
long-term treatment of
glucocorticoid-induced osteoporosis?
Arthritis Rheum 2011;63:325-8
80. National osteoporosis foundation’s
clinician’s guide to the prevention and
treatment of osteoporosis. National
Osteoporosis Foundation, Washington,
DC; 2009
81. Bone and tooth society of Great Britain.
Guidelines on the prevention and
treatment of glucocorticoid-induced
osteoporosis. Royal College of Physicians,
London; 2003
82. Devogelaer JP, Goemaere S, Boonen S,
et al. Evidence-based guidelines for the
prevention and treatment of
glucocorticoid-induced osteoporosis:
a consensus document of the Belgian
Bone Club. Osteoporos Int 2006;17:8-19
83. Dutch CBO guideline osteoporosis and
fracture prevention.
2011.Available from: www.cbo.nl/en/
Guidelines
Expert Opin. Pharmacother. (2013) 14(2)
84. Finnish national guidelines for treatment
of osteoporosis.
2006.Available from: www.kaypahoito.fi/
web/english/guidelines
Affiliation
Irene EM Bultink†1 MD PhD,
Marijke Baden2 MD &
Willem F Lems3 MD PhD
†
Author for correspondence
1
Rheumatologist,
VU University Medical Center,
Department of Rheumatology,
Room 3A51, De Boelelaan 1117,
1081 HV Amsterdam, The Netherlands
Tel: +31 20 4443432; Fax: +31 20-4442138;
E-mail: iem.bultink@vumc.nl
2
Department of Geriatrics, Kennemer Gasthuis,
Boerhaavelaan 22, 2035 RC Haarlem,
The Netherlands
3
Professor of Rheumatology,
VU University Medical Center,
Department of Rheumatology,
Room 3A57, De Boelelaan 1117,
1081 HV Amsterdam, The Netherlands
197