Therapeutic Advances in Musculoskeletal Disease

Glucocorticoid-induced osteoporosis:
treatment update and review

Review

Ther Adv Musculoskel Dis

(2009) 1(2) 7185
DOI: 10.1177/
1759720X09343729
! The Author(s), 2009.
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Lisa-Ann Fraser and Jonathan D. Adachi

Abstract: Glucocorticoid-induced osteoporosis (GIO) is a serious consequence of glucocorticoid

therapy leading to fractures in 3050% of patients. A wide range of protective medications have
been studied in this condition including calcium, vitamin D, vitamin D analogs, oral and
intravenous bisphosphonates, sex hormones, anabolic agents and calcitonin. The mechanism
of action, and evidence for these therapies, are reviewed focusing on important trials and
new evidence. Recently published guidelines are also reviewed and compared.
Bisphosphonates are currently the recommended first-line therapy for the prevention and
treatment of GIO. They have been shown to increase bone mineral density (BMD) at the spine
and hip and to decrease the incidence of vertebral fractures (especially in postmenopausal
women). Testosterone therapy and female hormone replacement therapy (HRT) have been
found to increase lumbar spine BMD in hypogonadal patients on glucocorticoid therapy, but
effects on hip BMD have not been consistent and there is no fracture data in the GIO population.
Similarly, calcitonin increases lumbar spine BMD but has no proven fracture efficacy. The
effect of selective estrogen receptor modulators, the oral contraceptive pill and strontium on
GIO is relatively unknown. Parathyroid hormone (PTH 1-34) and zoledronic acid have emerged
as exciting new options for the treatment of GIO. Both therapies have been found to result in
gains in BMD at the spine and hip that are either noninferior or superior to those seen with oral
bisphosphonate therapy. PTH 1-34 has also been found to decrease the incidence of new
vertebral fractures and may be an option in high-risk patients established on long-term
glucocorticoid therapy.
Keywords: glucocorticoids, osteoporosis, parathyroid hormone, zoledronic acid, treatment

Introduction
Epidemiology
Glucocorticoids are important therapeutic agents
that have been used for their potent anti-inflammatory and immunosuppressive properties for
over 50 years. According to a study performed in
the UK, 0.9% of the general adult population is
taking oral steroids at any given time and this proportion increases with age to 2.5% by age 7079
years [van Staa et al. 2000a]. Glucocorticoidinduced osteoporosis (GIO) is the most prevalent
form of secondary osteoporosis [Mazziotti et al.
2006]. Of the multiple side effects that can
occur with glucocorticoid therapy, osteoporotic
fractures are one of the most devastating, affecting
3050% of patients [Angeli et al. 2006; Feldstein
et al. 2005; Shaker and Lukert, 2005].

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Despite the prevalence of glucocorticoid therapy

and GIO, many patients on chronic steroid therapy do not receive bone mineral density (BMD)
assessment or the recommended preventative
therapy for osteoporosis [Guzman-Clark et al.
2007; Feldstein et al. 2005]. In a recent study of
a large managed care population in the United
States, Saag and colleagues found low rates of preventative interventions in individuals on long-term
glucocorticoid therapy. Postmenopausal women
were the most likely to receive recommended
interventions, yet only approximately 50% were
treated with anti-osteoporotic medication.
1019% of postmenopausal women underwent
bone mass measurements. This number dropped
to <6% in women under 50 years of age and in
men. The study also found that rheumatologists
were three to four times more likely to initiate the

Correspondence to:
Dr Jonathan D. Adachi
Department of Medicine,
St. Josephs Hospital,
25 Charlton Avenue East,
Suite 501, Hamilton,
Ontario, Canada
jd.adachi@sympatico.ca
Dr Lisa-Ann Fraser
Division of Endocrinology
and Metabolism,
Department of Medicine,
University of Western
Ontario, London, Ontario,
Canada

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Therapeutic Advances in Musculoskeletal Disease 1 (2)

above interventions than internists or family
practitioners [Saag et al. 2006]. Interventions
aimed at improving physician management of
GIO have largely been unsuccessful. When physicians were randomized to receive a web-based
GIO intervention (including a personalized performance-audit and feedback) versus control intervention, there was no significant increase in BMD
testing (19 versus 21%) or prescription of antiosteoporotic medications (32 versus 29%) in the
year following the intervention [Curtis et al.
2007].
Pathophysiology
Glucocorticoids have a detrimental effect on
bone formation, turnover and integrity. The
primary action is on osteoblasts, decreasing
replication and impairing differentiation and
maturation, leading to decreased bone formation
[Canalis et al. 2007; Ito et al. 2007]. Osteocytes
are also affected, with decreased cell function and
increased apoptosis resulting in impairment of
their ability to detect and repair bone microdamage. Decreased numbers of viable osteocytes are
found in iliac crest biopsies of patients on glucocorticoid treatment [Sambrook et al. 2003]. GIO
also involves an element of increased bone
resorption. In the early phase of glucocorticoid
treatment, decreased bone formation coupled
with increased resorption leads to rapid loss of
bone integrity and significant fracture risk.
Later in the course of treatment, however,
resorption slows resulting in a state of chronic
decreased bone turnover [Canalis et al. 2004].
During the early phase of therapy, high-dose steroids increase osteoclast generation. Osteoblast
signaling is affected, causing reduced osteoprotegerin (OPG) release and increased receptor activator of NF-B ligand (RANKL), resulting in
osteoclastogenesis [Sivagurunathan et al. 2005].
Other actions of glucocorticoids that negatively
affect bone include decreased calcium absorption
by the gastrointestinal tract and renal calcium
loss. Steroid myopathy results in muscle weakness and therefore increased risk of falls and fractures [Canalis et al. 2007].

Fracture risk
Chronic glucocorticoid use therefore causes
decreased bone remodeling and a state of low
bone turnover. Trabecular bone loss, including
vertebrae and the femoral neck, are usually the
most significantly affected [Maricic and Gluck,
2004; van Staa et al. 2002]. There is a strong

72

association between glucocorticoid dose, both

daily and cumulative, and fracture risk; the greatest risk being during the first 36 months after
steroids are initiated [van Staa et al. 2002].
Patients on oral glucocorticoid therapy have a
relative rate of fracture, compared to matched
controls, of 1.61 for hip fracture, 1.09 for forearm fracture and 2.6 for vertebral fracture [van
Staa et al. 2000b]. Fracture risk at a specific
BMD is greater for patients on glucocorticoid
therapy than the same BMD in a non-glucocorticoid-treated patient [Kanis et al. 2004], making
it imperative that clinicians use different BMD
thresholds for initiating osteoporosis treatments
in these patients. The risk of fracture decreases
after stopping glucocorticoid therapy. Similar to
postmenopausal osteoporosis, vertebral fractures
in GIO can be asymptomatic. One study found
>37% of chronic glucocorticoid-treated patients
had asymptomatic vertebral fractures with >14%
having two or more [Angeli et al. 2006].
Although traditional risk factors for fracture
(age, fall risk, BMI, gonadal status, physical
activity, calcium intake and vitamin D levels
[Johnell et al. 1995]) must be taken into consideration when assessing an individual patient for
GIO, glucocorticoid use has been found to be an
independent risk factor for fracture [van Staa
et al. 2002].
Treatment studies
There are multiple challenges associated with
treatment studies in the area of GIO. Most studies have been short term, using BMD as the
primary endpoint. Fracture data and long-term
outcomes are often lacking. The majority of studies have been performed predominantly in postmenopausal women, leaving the implications of
treatments on men and premenopausal women
less clear [Compston et al. 2008]. Studies are
also complicated by the wide range of inflammatory conditions that lead to treatment with
chronic glucocorticoid therapy. Many of these
comorbid conditions themselves can lead to secondary osteoporosis, complicating the interpretation of study results further.
Despite these difficulties, treatment of this
common and serious problem is of utmost importance. In this review, we discuss the various treatment options, focusing on new evidence and
recent developments. We then discuss and compare selected recently published guidelines and
recommend a treatment algorithm.

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L-A Fraser and JD Adachi

Treatment options
Vitamin D and calcium
Calcium and vitamin D are two nutrients essential for bone health [Gennari, 2001]. Adequate
amounts of each nutrient are necessary to achieve
optimal peak bone-mass and to decrease the rate
of bone loss with age [Rodriguez-Martinez and
Garcia-Cohen, 2002]. Vitamin D increases calcium absorption in the gastrointestinal tract as
well as reabsorption in the distal renal tubules
[Canalis et al. 2007]. Although sufficient calcium
and vitamin D intake is a prerequisite for most
current trials of osteoporosis medication, there
have been multiple studies looking specifically
at these agents used alone in GIO. Generally
safe, patients receiving treatment with active vitamin D compounds should be monitored for
hypercalcemia and hypercalcuria.
Calcium. Studies of calcium supplementation
alone have had variable results. One study of 36
patients on steroids for chronic active hepatitis
reported a decrease in loss of metacarpal bone
with a microcrystalline hydroxyapatite compound given for 2 years versus placebo [Stellon
et al. 1985], whereas other, more robust studies
in premenopausal women with systemic lupus
erythematosus (SLE) on glucocorticoid therapy
have found that calcium (1200 mg/d and 500 mg
twice daily) over 2 years preserves spine BMD,
but does not increase it [Yeap et al. 2008;
Lambrinoudaki et al. 2000]. There was a small
decrease (0.93%, p < 0.001) in hip BMD over 2
years reported in one study [Yeap et al. 2008] but
other studies have shown no significant change in
hip BMD [Lambrinoudaki et al. 2000].
Vitamin D. Studies of calcium combined with
vitamin D have also been variable. Trials including vitamin D 50 000 IU given weekly with calcium 1000 mg/d [Adachi et al. 1996], and
vitamin D 4000 IU on alternative days with calcium 500 mg/d [Bijlsma et al. 1988] found no
significant effect on BMD. However, a
Cochrane database systematic review in 2000,
that included 5 trials with 274 patients, found
calcium combined with vitamin D improved vertebral and radial BMD in glucocorticoid patients
with no significant effects on femoral BMD or
fracture incidence [Homik et al. 2000b].
Vitamin D analogs. The literature suggests that
vitamin D analogs [alfacalcidol 1-alpha(OH)D
and calcitriol 1,25(OH)(2)D] may be more

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effective then native vitamin D in GIO [Richy

et al. 2005]. In a 2004 meta-analysis, alfacalcidol
and calcitriol were found to have the same efficacy in all outcomes. In five trials, when tested
for maintaining spinal bone mass, they were
found to have an effect size of 0.43 (p < 0.001).
There was no significant reduction in fractures
[Richy et al. 2004]. In a primary prevention
study, 145 steroid-nave patients about to start
high-dose long-term steroid therapy were randomized to either 1 mg/day alfacalcidol or placebo.
Alfacalcidol prevented bone loss at the lumbar
spine at 12 months (increase in BMD of
0.39%, a decrease of 5.67% in the placebo
group for a difference of 6.06% between
groups, p 0.02) [Reginster et al. 1999]. When
used for secondary prevention in patients with
established GIO alfacalcidol was found to be
beneficial over native vitamin D 1000 IU/d for
lumbar spine BMD (increase of 2.0%,
p < 0.0001) with no significant improvement in
hip BMD or fractures [Ringe et al. 1999].
Calcitriol has also been shown to preserve or
increase lumbar spine BMD when used as secondary prevention in premenopausal women
with GIO over 2 years [Yeap et al. 2008;
Lambrinoudaki et al. 2000]. As primary prevention, 0.51.0 mg/day of calcitriol plus calcium,
with or without calcitonin, has been found to
increase lumbar spine BMD by 4.3% versus calcium alone (p 0.0035) [Sambrook et al. 1993].
However, in male and female asthma patients
treated with regular inhaled and intermittent
courses of oral steroids calcitriol was not found
to be protective against bone loss [McDonald
et al. 2006]. In a 2007 systemic review, no difference in vertebral fracture outcome was found for
calcitriol versus other interventions or calcitriol
versus placebo. Similarly, no significant decrease
in nonvertebral fractures were found [Kanis et al.
2007].
Summary. Calcium and vitamin D have not
been shown to protect against glucocorticoidrelated fragility fractures. They are, however,
important players when used as primary prevention to help prevent the bone loss seen with glucocorticoid use. As secondary prevention, they
can maintain or increased lumbar spine and
radial BMD, but they do not improve hip BMD.
Bisphosphonates
Bisphosphonates are potent inhibitors of
bone resorption. The nitrogen-containing

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Therapeutic Advances in Musculoskeletal Disease 1 (2)

bisphosphonates (including alendronate, risedronate, ibandronate, and zoledronic acid) appear to
work by inhibiting the osteoclast enzyme farnesyl
pyrophosphate synthase (FPPS) which is important for osteoclast function [Russell et al. 2008].
A 2000 Cochrane database systemic review concluded that bisphosphonates are effective both
for preventing and treating GIO; resulting in
improved BMD at the lumbar spine and femoral
neck. Although the review found a 24% reduction in the odds ratio for vertebral fracture, this
result was not significant [Homik et al. 2000a]. A
common side effect associated with bisphosphonate treatment, is gastrointestinal complaints
although many studies find no increase in these
complaints compared to the placebo group. A
more serious (albeit very rare) complication is
the association with osteonecrosis of the jaw
[Ruggiero et al. 2009]. Bisphosphonates are
retained in human bones for long periods and
therefore their use in women of childbearing
age is somewhat controversial. Animal studies
have shown a negative effect on fetal skeleton,
whereas the effect on the human fetus is relatively
unknown. A recent literature review identified
51 cases of babies born to women using bisphosphonates either before or during pregnancy,
and found no reported fetal abnormalities
[Djokanovic et al. 2008].
Etidronate. In 1997, the first randomized controlled trial (RCT) of bisphosphonate therapy
in GIO was performed by Adachi and colleagues.
There were 141 male and female patients who
had recently begun high-dose glucocorticoid
therapy, randomized to treatment with etidronate
(400 mg daily for 14 days followed by 500 mg of
calcium daily for 76 days; repeated for 4 cycles)
versus placebo [Adachi et al. 1997]. Significant
benefit was found in the etidronate group with
a mean difference in BMD compared to the placebo group at 1 year of 3.72% at the lumbar
spine (p 0.02) and 4.14% at the trochanter
(p 0.02). No statistically significant differences
in BMD were noted at the femoral neck or
radius. Vertebral fracture benefit was evident in
the etidronate group, especially in the subgroup
of postmenopausal women in whom there was an
85% decrease in new vertebral fractures compared to the control group (p 0.05); this
group also had fewer vertebral fractures per
patient (p 0.04). A similar study in 1998 also
found an increase of approximately 3% in lumbar
spine BMD in etidronate-treated patients versus
those receiving placebo [Roux et al. 1998].

74

However this study did not find a significant

difference in hip BMD and was not adequately
powered to comment on fracture incidence.
A 2000 review of pooled data found that etidronate, when used for prevention, produced an
increased BMD at the spine of 3.7%, an increase
at the femoral neck of 1.7% and an increase at
the trochanter of 3.7%, compared with the BMD
of placebo patients [Adachi et al. 2000]. A fracture benefit was present in postmenopausal
women. When used as treatment, there was a
pooled mean difference in lumbar spine BMD
between etidronate-treated patients and placebo
of 4.8% at the spine after one year and 5.4% after
2 years of therapy. A more recent 2007 systematic
review identified 12 RCTs with reported fracture
outcome in GIO etidronate studies [Kanis et al.
2007]. None of these studies showed significant
vertebral or nonvertebral fracture outcomes;
however, the review comments that none of the
studies were adequately powered for fracture
endpoints. The review did not look specifically
at fracture outcomes in the subgroup of postmenopausal women in whom fracture benefit is
described above.
Alendronate. Alendronate was studied in a
48-week RCT of 477 patients on glucocorticoid
therapy for a variety of underlying conditions
randomized to alendronate 5 or 10 mg per day
versus placebo [Saag et al. 1998]. All patients
also received elemental calcium 8001000 mg/d
and vitamin D 250500 IU/d. At 48 weeks, there
were significant gains in spine BMD in the alendronate groups (increase of 2.1% in the 5 mg
group and 2.9% in the 10 mg group, p < 0.001)
compared with the placebo group (BMD
decrease 0.4%). Femoral neck BMD also
improved (1.2 and 1%, respectively, versus a
decrease of 1.2% in the placebo group,
p < 0.01). There was no statistical difference in
fracture rates but there was a trend toward
fewer vertebral fractures in the alendronate
groups. Gastrointestinal complaints, in particular
abdominal pain, were the most commonly
reported side effects. In a 12 month extension
study, 208 patients (66 men and 142 women)
from this trial were followed [Adachi et al.
2001]. Treatment advantages with alendronate
were sustained with 2-year lumbar spine BMD
increased by 2.8% (5 mg/d group) and 3.9%
(10 mg/d group) (p < 0.001) from baseline,
versus a decrease of 0.8% in the placebo group.
At 2 years, there was a significant increase in

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L-A Fraser and JD Adachi

BMD at the trochanter (p < 0.05) but not at the
femoral neck. Incidence of vertebral, but not
nonvertebral, fractures did reach significance
with vertebral fractures in 0.77% of the alendronate group versus 6.8% in placebo group
(p 0.026).
Alendronate (10 mg/d) was found to be superior
to alfacalcidol (1 mg/d) in a direct comparison
RCT of female patients with rheumatic conditions starting glucocorticoid therapy [de Nijs
et al. 2006]. At 18 months, there was a mean
difference of change in lumbar spine BMD of
4% between the groups. There was also a trend
towards fewer new vertebral deformities in the
alendronate group, but these results were not
statistically significant. Alendronate (10 mg/day)
was also studied versus alfacalcidol (1 mg/day) in a
RCT designed to assess changes in bone markers
and associated changes in BMD in rheumatic
patients recently initiated on glucocorticoid therapy [Jacobs et al. 2007]. After 18 months, markers of bone metabolism showed decreased bone
resorption [measured by N-terminal telopeptide
of type I collagen (NTx)] and decreased bone
formation (measured by procollagen type ICpropeptide and osteocalcin) in the alendronate
group. In contrast, the alfacalcidol group
showed a decrease in markers of resorption and
an increase in markers of formation. Despite the
favorable bone metabolism picture suggested by
these metabolic bone markers in the alfacalcidol
group, lumbar spine BMD actually decreased in
this group by 5.7% (p 0.001), whereas it
increased by 4.6% (p < 0.001) in the alendronate
group. Changes in biochemical markers of bone
turnover were not found to be correlated with
changes in BMD, except for a negative correlation of total hip BMD with NTx. The study concluded that serial measures of bone turnover
could not replace follow up with serial BMD as
these measures did not correlate. Changes in
serial BMD should be interpreted cautiously as
both BMD and bone turnover markers are used
as surrogates for fracture risk. Further study
directly comparing changes in bone turnover
markers with fracture outcomes in the setting of
GIO are needed before firm conclusions can be
made.
Alendronate has also been studied in patients
with rheumatoid arthritis receiving chronic
(3 months) low-dose (10 mg/d) prednisone.
In this RCT, patients were randomized to
receive placebo or alendronate (5 mg/day in

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premenopausal women and men or 10 mg/d in

postmenopausal women). At 12 months, BMD
increased at the lumbar spine by 3.7% in the
alendronate group, whereas the placebo group
had a decrease in BMD of 1.07% (p < 0.0001).
Bone turnover markers were also significantly
lower in the alendronate group. There was no
significant difference between the groups for
changes in hip BMD or fracture rates. [Lems
et al. 2006].
In premenopausal women with SLE, alendronate
(70 mg qweekly) created an increase in lumbar
spine BMD at 2 years of 2.69% (p < 0.001) and
total hip BMD of 1.41% (p < 0.001) compared to
similar patients on just calcium carbonate or calcium plus calcitriol [Yeap et al. 2008]. A recent
study comparing alendronate (70 mg weekly)
versus placebo in GIO found a difference in the
mean per cent change from baseline BMD
between the alendronate group and the placebo
group to be 2.92% at the lumbar spine
(p  0.001), 1.66% at the trochanter (p
0.007), and 1.19% for total hip (p 0.008)
[Stoch et al. 2009]. The study was not powered
to detect a difference in fragility fracture
incidence.
Risedronate. A multicenter RCT of 224 men
and women initiating long-term glucocorticoids
was performed where patients were randomized
to treatment with risedronate (2.5 or 5 mg) versus
placebo. In this primary prevention study, all participants received 500 mg of elemental calcium
per day. At 12 months the mean difference in
BMD at the lumbar spine was 3.8% higher in
the risedronate group versus placebo (p < 0.001)
and 4.1% higher in the femoral neck (p < 0.001).
Although there was no statistically significant
reduction in fractures, there was a trend towards
decreased vertebral fractures in the 5 mg risedronate group [Cohen et al. 1999]. In a study of
secondary prevention, 290 men and women
already on 6 months of high-dose steroid therapy were randomized to receive either risedronate
2.5 mg/d versus risedronate 5 mg/d versus placebo
[Reid et al. 2000]. Everyone in the trial also
received 1 g/day of calcium and 400 IU of vitamin
D. After 12 months of therapy, overall, risedronate treatment significantly improved BMD at
the spine (p < 0.001), femoral neck (p 0.004)
and trochanter (p 0.010). In the risedronate
5 mg/d group, BMD increased by 2.9% at the
lumbar spine, 1.8% at the femoral neck and
2.4% at the trochanter. The study found a 70%

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Therapeutic Advances in Musculoskeletal Disease 1 (2)

decreased risk of vertebral fractures in the combined risedronate group (p 0.042). Similar
results have been replicated in other studies
[Wallach et al. 2000].
When studied specifically in men, risedronate has
been found to be beneficial when used both as
preventative therapy and in men on established
glucocorticoid therapy of 6 months [Reid et al.
2001]. 5 mg/d of risedronate was shown to significantly prevent bone loss at all skeletal sights
versus a placebo of calcium alone. 2.5 mg/d also
had beneficial effects, but to a lesser degree than
5 mg/d. In men on established glucocorticoid
therapy, 5 mg/d of risedronate increased BMD
after 12 months in the spine (4.8%), femoral
neck (2.1%) and trochanter (2.6%). An 82.4%
decrease in vertebral fractures was found in
men treated with risedronate (either dose)
versus placebo.
Ibandronate. Intravenous (IV) ibandronate significantly decreased vertebral fractures compared
to alfacalcidol in a 3-year open label parallel
group study. In the study 115 patients with established GIO (BMD 2.5 at baseline) on longterm high-dose glucocorticoids were paired
(based on similar baseline characteristics) and
then assigned to receive 500 mg of calcium and
either IV ibandronate 2 mg every 3 months or
1 mg of alfacalcidol daily. After 3 years, lumbar
spine BMD increased 13.3% in the ibandronate
group versus 2.6% in the alfacalcidol group
(p < 0.001), and hip BMD increased 5.2 versus
1.9% (p < 0.001). There were 8.6% of patients
in the ibandronate group who experienced a
new vertebral fracture compared with 22.8% in
the alfacalcidol group (p 0.043). There were no
significant differences in side effects between
groups and the ibandronate group experienced
less back pain (p < 0.001) and height loss
(p 0.001) [Ringe et al. 2003].
Pamidronate. IV pamidronate has been shown
to be of benefit in glucocorticoid-treated patients
in a primary prevention RCT [Boutsen et al.
1997]. In this study, 27 patients were randomized
to an initial dose of 90 mg of IV pamidronate
followed by 30 mg every 3 months versus standard
therapy with 800 mg/d of elemental calcium. At
12 months, lumbar spine BMD increased by
3.6% and hip BMD by 2.2% in the pamidronate
group compared with a decreased BMD of 5.3%
in the spine and femoral neck in the placebo
group. When the above pamidronate regimen

76

was compared in a trial with a single IV dose of

90 mg, with no further treatments, there was no
significant difference in BMD benefit found
between the two modes of administration
[Boutsen et al. 2001]. A 2007 systematic review
identified four open-labeled RCTs that commented on fracture risk with pamidronate therapy in
GIO [Kanis et al. 2007]. Few fractures were present in the trials, and no statistically significant
fracture benefit was identified.
Zoledronic acid. Zoledronic acid, 5 mg IV given
once per year, has been shown to be an effective
treatment for postmenopausal osteoporosis significantly reducing the incidence of vertebral,
hip and nonvertebral fractures while preserving
bone structure and not causing problems with
adynamic bone [Recker et al. 2008].
A recent noninferiority, multicenter, doubleblind, double-dummy RCT including 833
patients examined a single zoledronic acid 5 mg
IV infusion versus oral risedronate 5 mg daily for
12 months in GIO. Prevention (patients on steroids less then 3 months) and treatment arms were
included in each group. After 12 months, zoledronic acid was found to be noninferior and
superior to risedronate for increase of lumbar
spine BMD in both the treatment (least-squares
mean 4.06% [standard error (SE) 0.28] versus
2.71% [SE 0.28], mean difference 1.36% [95%
confidence interval (CI) 0.672.05], p 0.0001)
and prevention (2.60% [0.45] versus 0.64%
[0.46], 1.96% [1.042.88], p < 0.0001) subgroups at 12 months. Zoledronic acid also significantly increased BMD at the femoral neck
compared with risedronate, in both the treatment
(1.45% [0.31] versus 0.39% [0.30], mean difference 1.06% [95% CI 0.321.79]) and prevention
(1.30% [0.45] versus 0.03% [0.46], mean difference 1.33% [95% CI 0.412.25]) subgroups.
This study was designed as a noninferiority trial
and therefore the magnitude of the effect of zoledronic acid versus placebo is unknown. There
was no significant difference in new fractures
between the zoledronic acid and risedronate
groups. Adverse events were greater in the zoledronic acid group consisting mostly of flu-like
symptoms experienced within the first 3 days of
treatment [Reid et al. 2009].
Summary. Bisphosphonates
are
therefore
effective agents to increase BMD at the spine
and hip when used as primary prevention or
as treatment in both men and women on

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L-A Fraser and JD Adachi

long-term glucocorticoids. They have proven
efficacy in reducing the incidence of vertebral
fractures (especially in postmenopausal women)
and are considered first-line therapy for the prevention and treatment of GIO.
Sex hormones
Prolonged glucocorticoid therapy may lead to
hypogonadism by altering hypothalamic gonadotropin-releasing-hormone release, inhibiting
pituitary release of gonadotropins, suppressing
adrenal androgen production, and directly affecting ovarian and testicular hormone production
[ACR, 2001; Eastell et al. 1998]. Both estrogens
and androgens prevent osteoblast apoptosis and
decrease osteoclastogenesis and are thought to be
important in maintaining bone health [Clark and
Khosla, 2008].
Hormone replacement therapy. In postmenopausal women, whether in the context of glucocorticoid use or not, hormone replacement
therapy (HRT) reduces bone resorption leading
to a protective effect on bones [Hall et al. 1995].
There are not many studies looking specifically at
HRT in the context of glucocorticoid-induced
bone loss. An RCT of postmenopausal women
with rheumatoid arthritis randomized to treatment with transdermal estradiol (50 mg daily) or
calcium (400 mg daily) for 2 years was performed. The study included 42 women on glucocorticoid therapy. The glucocorticoid-treated
patients receiving HRT had an increase in their
lumbar spine BMD by a mean of 3.75% (versus
0.85% in the calcium group). Changes in hip
BMD were not significant [Hall et al. 1994]. In
another study, 28 young (aged 376 years)
hypogonadal women with SLE and GIO were
randomized to HRT or calcitriol. After 2 years,
spine BMD increased by 2.0% in the HRT group
versus a decrease of 1.74% in the calcitriol group
(p < 0.05) [Kung et al. 1999]. In Lanes 1998
study comparing parathyroid hormone (PTH)
plus HRT versus HRT alone in postmenopausal
GIO, the HRT group showed no change in BMD
at the lumbar spine, femur, or distal radius [Lane
et al. 1998]. Since the Womens Health Initiative
study was stopped early in 2002 because of
increased risk of breast cancer and cardiovascular
disease associated with the use of HRT, it is no
longer routinely used as a first-line treatment
of osteoporosis in postmenopausal women
[Rossouw et al. 2002].

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Testosterone. In men, hypogonadism is an

important cause of secondary osteoporosis, and
treatment with testosterone may lead to decreased
bone resorption and an increase in bone mass
[Kamel et al. 2001]. Hypogonadal men who are
treated with testosterone to bring their serum testosterone level back into the normal range have
increased BMD at the spine and hip [Snyder et al.
2000]. In a RCT where men on long-term glucocorticoid therapy were randomized to either testosterone (200 mg) versus nandrolone (200 mg)
versus placebo given intramuscularly (IM) every
2 weeks for 12 months, the lumbar spine BMD
increased significantly in the testosterone group
(4.7%, p < 0.01). There was no significant
change in BMD in the nandrolone group or in
either group at the hip [Crawford et al. 2003].
In a smaller randomized crossover study, 15
men with low serum testosterone levels were
given testosterone replacement or placebo.
Lumbar spine BMD increased by 5%
(p 0.005) during the treatment phase [Reid
et al. 1996]. Prostate cancer is a contraindication
to testosterone use, and digital rectal exam as well
as prostate-specific antigen must be followed
regularly while on therapy.
Oral contraceptive pill. The effects of the oral
contraceptive pill (OCP) on bone mass are controversial. One study found OCP use to be protective of BMD, with the duration of exposure
being related to the degree of protection
[Kleerekoper et al. 1991]. However, other studies
have shown a negative relationship between a history of OCP use and BMD at both the spine and
hip [Prior et al. 2001; Teegarden et al. 1995]. The
effect of the OCP on GIO has not been studied.
Selective estrogen receptor modulators.
Raloxifene, the selective estrogen receptor modulator (SERM) which has been best studied in
postmenopausal osteoporosis, has been found,
in that population, to increase BMD and
decrease the rate of vertebral fractures while
there has been no definitively demonstrated
effect on nonvertebral fractures [Sambrook,
2005]. There have been no randomized trials to
our knowledge looking at raloxifene in GIO. In a
small study, 20 postmenopausal women with
operable breast cancer were treated with glucocorticoid therapy as well as tamoxifen. At 24
months, these patients had BMD scores no different than a control group of similar cancer
patients on tamoxifen with no steroid, indicating
that tamoxifen may be beneficial in preserving

77

Therapeutic Advances in Musculoskeletal Disease 1 (2)

BMD in the setting of glucocorticoids [Fentiman
et al. 1992].
Summary. HRT and testosterone therapy have
therefore been found to increase lumbar spine
BMD in hypogonadal patients on glucocorticoid
therapy. Effects on hip BMD have not been consistent and there is no fracture data in this population. The effect of SERMs or the OCP on GIO
is relatively unknown.
Anabolic agents
Parathyroid hormone. Parathyroid hormone
(PTH) works to increase bone mass and quality
by directly stimulating osteoblastogenesis and
prolonging osteoblast lifespan by inhibiting apoptosis [Jilka et al. 1999]. Glucocorticoid-treated
rats show improved bone mineralization, mass,
and increased bone formation when treated
with PTH [Yao et al. 2008]. Teriparatide [recombinant human PTH (1-34)] is the only anabolic
agent currently approved by the FDA in the
United States for treatment of osteoporosis in
postmenopausal women and men with osteoporosis at high risk of fracture [Girotra et al.
2006]. In this population, it decreases the risk
of both vertebral and nonvertebral fractures.
There have been fewer studies in the GIO population, and no studies looking at PTH 1-84 in this
population.
Teriparatide was studied in a 12-month RCT of
51 postmenopausal women on chronic steroid
therapy who were also on HRT [Lane et al.
1998]. The women were randomized to subcutaneous PTH (25 mg daily) plus estrogen versus
estrogen alone. At 12 months, spinal BMD
increased dramatically in the PTH group (11
versus 0% in the estrogen only group,
p < 0.001). There was no significant difference
in hip or forearm BMD changes between the
two groups at 12 months, and no fracture data.
In follow up, 12 months after PTH was discontinued, the BMD benefit at the spine on continued estrogen alone was maintained. In the group
who had received PTH, there was a mean change
in lumbar spine BMD, 24 months from baseline,
of 12.6%. There was also improvement in total
hip BMD (p < 0.01) compared to the estrogenonly group noted at 24 months [Lane et al.
2000].
In 2007, Saag and colleagues published the
first RCT directly comparing teriparatide to

78

alendronate [Saag et al. 2007]. The study consisted of 428 patients, 80% women (the majority
being postmenopausal) from 12 countries. After
18 months on either teriparatide 20 mg daily or
alendronate 10 mg daily, the teriparatide group
had a greater increase in lumbar spine BMD
(7.2 versus 3.4%, p < 0.001), and total hip
BMD (3.8 versus 2.4%, p 0.005). New vertebral fractures were less frequent in the teriparatide group (0.6 versus 6.1%, p 0.004) whereas
there was no significant difference in nonvertebral fracture rate. There were no significant differences in reported adverse events between the two
groups in this study, but side effects experienced
in the teriparatide group included injection site
reactions, gastrointestinal complaints, arthralgias, musculoskeletal complaints and high
serum measurements of urate and calcium. The
patients included in this study all had established
osteoporosis with lower BMD and higher fracture
rate than in many other trials looking at the GIO
population. The results therefore cannot be generalized to a primary prevention population.
However, this study shows, as secondary prevention in high-risk patients, teriparatide is more
effective then alendronate.
In the non-GIO population, PTH 1-34 is recommended for 18 months of therapy followed by
bisphosphonate therapy to maintain gains in
BMD [Cosman, 2006]. The optimal duration
of treatment with PTH 1-34 in GIO is unknown.
Fluoride. Fluoride increases BMD by increasing
bone mineral apposition with no creation of new
trabeculae [Balena et al. 1998; Zerwekh et al.
1994]. Bone volume is increased but trabecular
thickness is not, especially when fluoride is used
in higher doses. At high doses it has been shown
to impair osteoblast function [Balena et al. 1998].
Several small RCTs have been performed
demonstrating favorable BMD results in patients
with GIO. Increased BMD has been reported
when fluoride is used as primary prevention
alone versus placebo [Lems et al. 1997a], when
it is used together with calcium and 25-hydroxyvitamin D [Lippuner et al. 1996], and when it is
used in combination with etidronate in patients
with established GIO [Lems et al. 1997b].
Fluoride use is controversial and is not currently
an approved osteoporosis treatment. There is
concern that, despite increasing BMD, fluoride
does not recreate normal boney architecture
and quality and may result in increased skeletal

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L-A Fraser and JD Adachi

fragility and fracture risk [Riggs et al. 1990]. A
recent meta-analysis, not specifically looking at
GIO, showed a lack of effect of fluoride on vertebral and nonvertebral fractures; with a trend
towards increased fracture risk with increased
dose of fluoride [Vestergaard et al. 2008].
Interestingly, in subgroup analysis, it was found
that, at low doses (20 mg fluoride equivalents),
fluoride is associated with a reduction in fracture
risk [odds ratio (OR) 0.28, 95% CI 0.090.87
for vertebral fractures and OR 0.52, 95% CI
0.280.76 for nonvertebral fractures]. This association has not been looked at specifically in the
GIO population.
Strontium. Strontium ranelate (SR) has proven
efficacy in postmenopausal osteoporosis and is
approved for its treatment. SR increases the replication of pre-osteoblast cells stimulating bone
formation while decreasing osteoclast differentiation and activity [Tournis, 2007]. It has been
shown to cause an increase in BMD that is associated with reduced fracture risk in postmenopausal osteoporosis [Bruyere et al. 2007].
Currently, there are no published studies that
we know of examining SR specifically in the
GIO population.
Summary. PTH is an exciting emerging therapy
for GIO resulting in gains in BMD at the spine
and hip that are superior to those seen with
bisphosphonates. PTH also decreases the incidence of vertebral fractures in this population
but has not yet been shown to decrease the incidence of nonvertebral fractures. Fluoride is not
currently used because of concerns of increased
fracture risk and strontium has not yet been studied in the GIO population.
Calcitonin
Calcitonin targets the most active osteoclasts and
decreases their action, resulting in decreased
bone resorption [Karsdal et al. 2008]. Multiple
studies have assessed the effect of calcitonin,
both intranasal and subcutaneous preparations,
on GIO. A 2000 Cochrane database systemic
review using 9 trials found calcitonin to be
3.2% more effective than placebo at increasing
lumbar spine BMD during the first 12 months
of treatment; however, this benefit was lost by
24 months. The improvement seemed to be
most prominent when calcitonin was used in
patients with established glucocorticoid use,
rather than as primary prevention, and when
administered subcutaneously. There was no

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improvement in femoral neck BMD or in the relative risk of vertebral or nonvertebral fractures
[Cranney et al. 2000]. Another, more recent, systemic review found similar results with no effect
on fracture risk for both vertebral and nonvertebral fractures [Kanis et al. 2007]. Side effects
reported in trials include nausea and facial
flushing.
Guidelines
Six recent clinical guidelines and recommendation summaries are presented in Table 1. Most
of these recommendations were formulated
based on systematic review of the literature. All
of the guidelines, unless not specified, recommend BMD testing in patients on chronic glucocorticoid therapy. Most also recommend a
screening BMD measurement in patients initiating glucocorticoid therapy that is expected to be
long term. Whereas the Osteoporosis Society of
Canada recommends adequate age-specific calcium and vitamin D to all individuals (not just
those on glucocorticoid) for osteoporosis prevention, the American College of Rheumatology
(ACR)
and
European
League
against
Rheumatism make specific recommendations
based on dose and duration of long-term glucocorticoid treatment. The ACR and Japanese
Society for Bone and Mineral Research
(JSBMR) recommend active vitamin D compounds as an alternative to native vitamin D
(ACR) or as a second-line or adjunctive treatment for GIO (JSBMR). Bisphosphonates are
consistently considered the first-line treatment
for GIO, but the guidelines differ significantly
with respect to who should be treated. Four of
the six guidelines specifically recommend bisphosphonates as preventative therapy at the initiation
of glucocorticoid treatment in certain groups
including those with prior fragility fractures,
older age [>65 years (Royal College of
Physicians[RCP]) versus >75yrs (National
health Service, UK[NHS])], low BMD [<1.5
(RCP) versus <2.0 (NHS)] and treatment with
5 mg/d of prednisone-equivalent for 3 months
(ACR). Recommendations for sex hormone
replacement vary. The two guidelines that specifically address monitoring frequency in patients
not on treatment with a bisphosphonate, recommend follow up of BMD every 612 months
(JSBMR also recommends spinal X-rays).
It is recommended that patients started on
therapy have repeat BMD testing performed in
12 years.

79

80

As often as every
6 months to follow if
not on therapy.
Annually if on
therapy
Continue as long as
receiving GC

BMD, bone mineral density; GC, glucocorticoid.

Duration of
treatment

Monitoring
frequency

12 years after starting

treatment

No specific recommendation, may

see effects of
therapy in
12 years
Not specified

Not specified

Not specified

Offer to hypogonadal patients

Not specified

Not specified

Not specified

Not specified

Not specified

Not specified

Not specified

Sex hormones

Consider raloxifene
in postmenopausal women if
cannot tolerate
bisphosphonate
BMD and spinal
X-rays every
612 mo to follow
if not on therapy

Based on risk factors: low BMD,

female gender,
older age,
postmenopausal
Patients with prior
fragility fracture.
All patients >75
years. Patients
with BMD  2.0.
Less stringent
BMD cut-off if
on higher-thanaverage dose
of GC

All patients with

prior fragility
fracture. All
patients on
5 mg/d of
prednisoneequivalent for
3 months or
BMD <80% young
adult mean

Bisphosphonates:
-patients
warranting
treatment

At initiation of GC
therapy if >65
years, with prior
fragility fracture,
or BMD1.5

If on 7.5 mg/d
prednisone
equivalent for
>3 months

Not specified

Active vitamin D as
second-line
treatment agent.
Active vitamin D
with bisphosphonate in high-risk
patients

All patients initiating

therapy (5 mg/d
prednisone equivalent for 3 months).
All patients on longterm GC. Use
800 IU/d Vitamin D or
active vitamin D
All patients at initiation
of GC therapy
(5 mg/d prednisone
equivalent for 3
months), and
patients on longterm GC if T-score
<1.0. Alendronate
or risedronate as
first-line agents. Use
caution in
premepausal women
Replace if deficient or
clinically indicated

Vitamin D and
calcium

All patients: 400 IU/d

vitamin D if <50
years, 800 IU/d if >50
years. 1000 mg/d
calcium for women
<50 years or men,
1500 mg/d for
women >50 years
Patients on >7.5 mg/d
prednisone-equivalent for >3 months,
or 2.5 mg/d7.5 mg/d
for >3 months and
BMD 1.5.
Alendronate, risedronate or etidronate
for prevention or
treatment

Not specified

All patients
<75 years and
with no prior fragility fracture

All patients on >2.5

mg/d prednisone
for >3 months

If GC planned for >6

months. All patients
on long-term GC

BMD testing

Not required for

those starting on
bisphosphonate,
but everyone else
should be tested
Adequate dietary
calcium recommended. Use as
adjunct with
bisphosphonate
therapy

Systematic review
with evidence
grading and
expert consensus

Systematic review
and cost-effectiveness analysis

Based on two studies by the subcommittee and

evidence from the
literature
If GC planned for
3 months and no
prior fragility
fractures

Systematic review with

evidence grading

Systematic review
with evidence
grading

2007

Expert committee
review of the
literature

2002

2002

European League
Against Rheumatism
(EULAR) [Hoes et al.
2007]
2007

National Health
Service, UK (NHS)
[Kanis et al. 2007]

2001

Japanese Society for

Bone and Mineral
Research (JSBMR)
[Nawata et al. 2005]
2004

Publication
date
Evidence

Osteoporosis Society of
Canada [Brown and
Josse, 2002]

American College of
Rheumatology (ACR)
[ACR, 2001]

Organization

Royal College of
Physicians, UK
(RCP) [RCP, 2002]

Table 1. Guidelines for glucocorticoid-induced osteoporosis.

Therapeutic Advances in Musculoskeletal Disease 1 (2)

http://tab.sagepub.com

L-A Fraser and JD Adachi

Summary and recommendations
GIO and associated fractures remain an important consequence of glucocorticoid therapy.
Although specific treatment guidelines vary,
prevention should be considered and discussed
in all patients when glucocorticoid treatment is
initiated. For premenopausal women and men
under the age of 50 years, fracture risk should
be determined and treatment decisions based
on this assessment. In postmenopausal women
and older men, the risk of GIO and fractures is
greater and the evidence demonstrating the benefit of preventative therapy is clear. In our opinion, these patients should be initiated on
preventative therapy. Currently, guidelines
recommend oral bisphosphonate therapy as
first-line treatment, with adjuvant calcium and
vitamin D. New evidence suggests greater BMD
gains with zoledronic acid and PTH 1-34 and
these therapies may therefore provide important
options particularly in high-risk patients with
established GIO. The studies of PTH 1-34 and
zoledronic acid in GIO were not yet available
when current treatment guidelines were created;
therefore, future guidelines may recommend a
more prominent role of these therapies. Given
the potential for rapid bone loss with glucocorticoid therapy, frequent monitoring is warranted
while bearing in mind that BMD is a surrogate
marker for fracture risk and patients on glucocorticoids fracture at higher BMD than other
patients [Maricic and Gluck, 2004]. Once treatment is initiated, BMD should be monitored
annually (expert opinion) to ensure compliance
and efficacy. Further research is needed to
define in an evidence-based manner the
most efficient frequency of BMD monitoring
and the optimal duration of treatment with
bisphosphonates.
Acknowledgement
Dr. Fraser is supported by the UWO Resident
Research Career Development (RRCD) Program.
Conflict of interest statement
Dr. L-A Fraser: no conflict of interest.
Dr. J.D. Adachi: Consultant/Speaker: Amgen,
Astra Zeneca, Eli Lilly, GSK, Merck, Novartis,
Nycomed, Pfizer, Procter Gamble, Roche, Sanofi
Aventis, Servier, Wyeth, Bristol-Myers Squibb.
Clinical Trials: Amgen, Eli Lilly, GSK, Merck,
Novartis, Pfizer, Procter & Gamble, Sanofi
Aventis, Roche, Wyeth, Bristol-Myers Squibb.

http://tab.sagepub.com

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