Hong Kong Bull Rheum Dis 2008;8:12-18 Review Article

Recent Advances in the Management of Steroid Induced Osteoporosis

Lai-Wa Kwok and Lai-Shan Tam

Abstract: Glucocorticoid-induced osteoporosis is the most common cause of drug-induced osteoporosis, leading to fragility
fractures, decrease in mobility and quality of life. Patients who receive equivalent dose of prednisolone 5 mg for
more than six months are at risk of glucocorticoid-induced osteoporosis, but there is no conclusive evidence for a
safe cutoff for either dose or duration of steroid exposure and bone loss. The general view is 'dual action'. Both
increased bone resorption and decreased bone formation contribute to the pathogenesis of glucocorticoid-induced
osteoporosis. Glucocorticoids increase the expression of receptor activator of nuclear factor kB ligand (RANK-
L) and decrease the expression of its soluble receptor osteoprotegerin (OPG) in stromal and osteoblastic cells,
leading to increased differentiation of pre-osteoclast to osteoclast. Fracture risk is related not only to bone mineral
density, bone structural and mechanical properties, but also other clinical risk factors such as smoking, excessive
alcohol, lack of exercises. Treatment threshold in glucocorticoid-induced osteoporosis is much lower than that in
postmenopausal osteoporosis since fractures in glucocorticoid-induced osteoporosis occur at a higher bone mineral
density than in postmenopausal osteoporosis. Bisphosphonates, being the first line therapy, have been shown to be
effective in the prevention of vertebral fractures and they should be given together with adequate vitamin D and
calcium supplement. The anabolic therapy parathyroid hormone, which targets on bone formation, has shown to
be effective in increasing bone mineral density and reducing fractures and it may act as an alternative therapy.

Keywords: Bisphosphonates, Bone mineral density, Calcium, Fractures, Glucocorticoid-induced osteoporosis, Parathyroid
hormone

Introduction rheumatoid arthritis (RA) patients.1 Bone loss with risk of

Osteoporosis is a skeletal condition characterized by low bone
mass, which is associated with microarchictectural disruption
and increased bone fragility that leads to reduced bone strength
and an increased risk of fractures. Glucocorticoids are used
widely in the treatment of different kind of rheumatic diseases.
A recent analysis of the national databank for rheumatic
diseases in the USA found prednisolone use in 38% of
DEPARTMENT OF MEDICINE & THERAPEUTICS, THE PRINCE OF WALES
H OSPITAL , T HE C HINESE U NIVERSITY OF H ONG K ONG , S HATIN ,
N.T., HONG KONG SAR
Lai-Wa Kwok MBChB, MRCP (UK)
Lai-Shan Tam MBChB, MD (CUHK), FRCP(Glasg)
Correspondence to: Lai-Wa Kwok
fractures resulting from glucocorticoid therapy is a relatively
common issue and it is the most prevalent form of secondary
osteoporosis. 2-6 An estimated 50% of patients taking
glucocorticoids for longer than 6 months will develop
secondary osteoporosis. 7 Long-term glucocorticoid use
worldwide is estimated at between 1% to 3% of adults.8
Treatment was usually short term, with 22.1% taking oral
glucocorticoids for over 6 months and 4.3% for over 5 years.
Historically, glucocorticoids at a prednisolone-equivalent dose
of less than 7.5-10 mg/day are considered low dose. This is
based on a review of a number of studies which show
decreased rates of osteoporosis, myopathy, cardiovascular
disease, and glaucoma below this dose.9 Use of the lowest
corticosteroid dose is possible because fracture risk is dose
dependent. 10 Generally, in most patients, doses below
5 mg/day prednisone equivalent result in minimal bone loss,
whereas doses above 10 mg/day will result in significant bone
loss. The severity of bone loss also depends on the cumulative
Kwok and Tam
dose.11 Alternate-day glucocorticoid use may lead to as much
bone loss as daily regimens.12,13 Inhaled glucocorticoids are
also associated with some degree of bone loss.14-16 However;
there is no conclusive evidence for a safe cutoff for either
dose or duration of glucocorticoid exposure and bone loss.
This article focuses on the recent advances in the pathogenesis
and assessment of glucocorticoid-induced osteoporosis and
the updated evidence on various treatment modalities.
Loss of Bone Mineral Density and the
Relationship with Glucocorticoid
There is a substantial and accelerated decrease in bone mineral
density (BMD) with glucocorticoid therapy, most pronounced
in the first year, with trabecular bone more affected than
cortical bone. Markedly decreased BMD at the lumbar spine,
femoral neck and whole body has been reported 2 months
after initiating high-dose glucocorticoids (40 mg/day), with
the greatest loss occurring predominantly in the trabecular
lumbar vertebrae.17 In a meta-analysis of 66 studies reporting
bone density measurements in 2891 glucocorticoid users with
an average daily dose of 9.6 mg, lumbar spine and hip BMD
were lower than a group of age and sex-matched patients who
were non-steroid users (89.4% and 88.8%, respectively).18
Decreases in BMD in the hip and lumbar spine correlate with
cumulative glucocorticoid dose.19
A complicated relationship between chronic glucocorticoid
therapy and bone density may exist in subgroup of patients
having underlying chronic inflammatory diseases. For
example, accelerated bone loss occurs early in the course of
rheumatoid arthritis in association with persistent
inflammation and immobility.20 Although glucocorticoids
intrinsically causes a decline in bone density and increased
fracture risk, appropriate use of low-dose glucocorticoid
therapy to reduce inflammation might also suppresses
rheumatoid arthritis disease activity and thereby attenuate bone
loss.21,22
Patients with systemic lupus erythematosus (SLE) have a high
risk of symptomatic vertebral and nonvertebral fractures
(9-16.5%),22-26 or prevalent vertebral deformities as a result
of fractures.27-33 Risk factors for fractures in SLE patients
included the duration of use of glucocorticoids,24,34,35 ever use
of IV methylprednisolone24,25,36 and male sex.36 A recent local
study on 152 patients with SLE also reported that around 20%
of patients had asymptomatic vertebral fractures, in which
13
thoracic vertebrae fractures being the most common. 37
Fractures occurred in 30% of SLE patients with normal BMD,
similar to previous studies.36,38
A local study evaluating the effect of calcitriol on bone mineral
density in premenopausal Chinese women taking chronic
glucocorticoid therapy with a mean cumulative prednisolone
dose of 2816.2 g found that the baseline T score at the lumbar
spine of the study group was <-1 in 43.2% and <-2.5 in 3.7%
of the patients.39
Fracture Risk
Higher fracture rates in glucocorticoid users have been
reported in numerous studies. A cross-sectional study found
a 37% prevalence of asymptomatic vertebral fractures in
postmenopausal women on chronic glucocorticoid therapy,
increasing with age.40 This increased risk of fracture has been
confirmed in a large metaanalysis of studies which included
2891 glucocorticoid users,18 with a relative risk (RR) of any
fracture of 1.91, hip fracture 2.01, vertebral fracture 2.86 and
forearm fracture 1.13. A study of a UK primary care database,3
comprising 244 235 oral glucocorticoid users and a similar
number of controls, found a RR of any fracture of 1.33, hip
fracture 1.61, vertebral fracture 2.60 and forearm fracture 1.09.
Fracture risk has been related to dose and duration of
glucocorticoid treatment. Those exposed to intermittent high-
dose glucocorticoids (daily dose more than 15 mg/day) with
little prior exposure had a small increased risk of osteoporotic
fracture,41 but this risk increased substantially with increasing
cumulative exposure and in those patients who were receiving
at least 30 mg/day and whose cumulative dose was over 5 g,
the RR was 3.63 for osteoporotic fracture.
Pathogenesis of Glucocorticoid-induced
Osteoporosis
The initial bone loss occurring in patients exposed to
glucocorticoids might be secondary to increased bone
resorption. 2 Glucocorticoids increase the expression of
receptor activator of nuclear factor kB ligand (RANK-L) and
decrease the expression of its soluble receptor osteoprotegerin
(OPG) in stromal and osteoblastic cells,17 leading to increased
differentiation of pre-osteoclast to osteoclast. Glucocorticoids
also enhance the expression of macrophage colony-stimulating
14
factor (M-CSF), which in the presence of RANK-L induces
osteoclastogenesis. Moreover, glucocorticoids have been
demonstrated to upregulate receptor subunits for
osteoclastogenic cytokines of the glycoprotein 130 family.42
Glucocorticoids might have direct effects on osteoclasts also
by suppressing the expression of an autocrine cytokine, such
as interferon -beta, that normally exerts inhibitory effects on
osteoclastogenesis.43 All these mechanisms could contribute
towards increased in bone resorption.
Corticosteroid also plays a central role in the pathogenesis of
osteoporosis by suppression of bone formation. Corticosteroid
lead to a reduction in osteoblast number and function by
inhibition of replication and differentiation of cells of
osteoblastic lineage, and enhanced apoptosis of osteoblasts
and osteocytes. 44 Glucocorticoids induce apoptosis of
osteoblasts and osteocytes by activating caspase 3, 45
a common downstream effector of several apoptotic signaling
pathways.
Prevention and Treatment of Glucocorticoid-
induced Osteoporosis
Diagnosis of Steroid Induced Osteoporosis
Bone mineral density (BMD) assessment by Dual Energy
X-ray Absorptiometry (DEXA) is the gold standard to
diagnose osteoporosis. The World Health Organization
(WHO) established a classification of BMD according the
standard deviation (SD) difference between a patient's
BMD and that of a young-adult reference population
(T-score). 46 The Z-score is a comparison of the patient's
BMD to an age-matched population. A BMD T-score that
is 2.5 SD or more below the young-adult mean BMD is
defined as osteoporosis. Premenopausal osteoporosis is
defined as premenopausal women who have low bone
density (Z score less than -2.0) and/or fragility fractures.
The American College of Rheumatology (ACR) recommends
a BMD measurement before starting bisphosphonates in all
subjects taking glucocorticoids.47 It is recommended that the
treatment threshold in glucocorticoid-induced osteoporosis
is much lower than in postmenopausal osteoporosis since
fractures in glucocorticoid-induced osteoporosis occur at
higher BMDs than in postmenopausal osteoporosis.48 The
intervention threshold of the ACR recommendation is a
T-score of less than or equal to -1, which is much lower than
that for postmenopausal women (T-score < of -2.5).
Management of Steroid Induced Osteoporosis
Evaluation of the Changes in Bone Mineralization and
Architecture
Apart from bone density, fracture risk is also related to bone
strength, including structural and material properties of
bone.49 Deterioration of cancellous structure can have a major
impact on fracture risk independent of BMD. As in other forms
of secondary osteoporosis, in glucocorticoid-induced
osteoporosis vertebral fractures may be asymptomatic.
Therefore, the clinical history may not be reliable.
Consequently, a radiological approach with morphometric
analysis is useful for the identification of vertebral
deformities.50
Therapeutic Guidelines
Guidelines published by the American College of
Rheumatology (ACR) advocates the following measures for
the prevention and treatment of glucocorticoid-induced
osteoporosis: general health awareness, administration of
sufficient calcium and vitamin D, reduction of the dose of
corticosteroids to a minimum and, when indicated, therapeutic
intervention with bisphosphonates.47 The ultimate goal is to
prevent fractures. Appropriate preventive measures include
intake of calcium (1500 mg daily) and vitamin D (800 IU
daily). Depending on the individual patient BMD and risk
factors, the use of calcium and vitamin D could be considered
to be sufficient, particularly if the level of glucocorticoid
exposure is lower than 7.5 mg of prednisone equivalent daily
and for less than three months.48
Guidelines from the UK suggest that treatment in
glucocorticoid-induced osteoporosis is indicated in (i) patients
who are at high risk of osteoporosis, such as those taking
prednisone equivalent doses higher than 7.5 mg daily, those
with a personal history of fractures or those with lifestyle risk
factors for osteoporosis; (ii) patients with a low risk of
osteoporosis but with T-scores lower than -1.5 SD as assessed
by vertebral dual energy X-ray absorptiometry; and (iii)
patients with a low risk of osteoporosis and a T-score higher
than -1.5 SD but with a decline in vertebral BMD of at least
4.0% after one year of glucocorticoid treatment.51
Various pharmacological agents have been assessed for
prevention and treatment of glucocorticoid-induced
osteoporosis. Vitamin D and calcium are recommended by
both ACR and Royal College of Physicians guidelines,
although the latter restrict the administration to patients with
Kwok and Tam
vitamin D insufficiency and/or with inadequate calcium
intake.47,51,52 Vitamin D and its analogues prevent bone loss
during glucocorticoid therapy.53,54 Alfacalcidol, a vitamin
D analogue, is said to have dual effects on bone by
increasing bone formation and reducing bone resorption.
Alfacalcidol suppresses the synthesis and release of
parathyroid hormone and increases the intestinal
absorption of calcium and its reabsorption in the distal
renal tubule. In a 2-year randomized trial, subjects with
rheumatoid arthritis receiving prednisolone therapy (mean
dose 5.6 mg day) BMD fell at a rate of 2.0% and 0.9% per
year in the lumbar spine and trochanter, respectively. In
contrast, patients randomized to calcium (1000 mg/day)
and vitamin D (500 IU/day) gained BMD at an annual
rate of 0.72% at the spine and 0.85% in the trochanter.55
Bisphosphonates are considered to be the gold standard for
the prevention and treatment of glucocorticoid induced
osteoporosis.52 Both ACR and Royal College of Physicians
guidelines point out the efficacy of these drugs.47,51 Available
data are for risedronate and alendronate, although newer
bisphosphonates ibandronate have been recently tested with
encouraging results.56 The benefits of bisphosphonates in
glucocorticoid induced osteoporosis have been ascribed
primarily to their antiresorptive effect.57 Bisphosphonates are
more effective than vitamin D in the prevention of fractures
in glucocorticoid-induced osteoporosis, but should be given
with supplemental calcium and vitamin D.
Study comparing Alendronate 10 mg daily with Alfacalcidol
1 mcg daily in glucocorticoid-induced osteoporosis showed
that at 18 months, the bone mineral density of the lumbar
spine increased by 2.1% in alendronate group, and
decreased by 1.9% in alfacalcidol group. 58 An overall
reduction in risk of radiological vertebral deformities of
37% (relative rate 0.63, 95% confidence interval 0.49-
0.80) was reported.
Risedronate is shown to be as effective as alendronate.
A local 6-month randomized double-blind placebo controlled
trial comparing Risedronate 5 mg daily with placebo
showed a significant gain in spinal BMD in the risedronate
group (+0.70.3%; p=0.03) but a drop in the placebo group
(-0.70.4%; p=0.12). No new fractures developed in
risedronate or placebo group.59
Parenteral administration of more potent bisphosphonates has
the advantages of less esophageal side effects. Ibandronate
15
2 mg administered intravenously every 3 months over 3 years
reduced the frequency of new vertebral fractures compared
with 1 mg/day alfacalcidol (8.6% versus 22.8%, respectively)
in an open-label, parallel group study of 115 patients with
established glucocorticoid-induced osteoporosis.60 There was
also a significantly greater increase in mean BMD at the
lumbar spine (13.3% versus 2.6%) and femoral neck (5.2%
versus 1.9%) with intravenous ibandronate versus daily oral
alfacalcidol.
Anabolic therapy has become the novel therapy for
glucocorticoid induced osteoporosis. Once-daily
recombinant human parathyroid hormone (PTH 1-34)
(teriparatide) stimulates bone formation, increases bone
mass, and reduces the risk of vertebral and nonvertebral
fractures.61,62 Teriparatide may be a rational treatment for
glucocorticoid-induced osteoporosis because it directly
stimulates osteoblastogenesis and inhibits osteoblast
apoptosis, thereby counteracting two key mechanisms
through which glucocorticoid therapy promotes bone loss.63
Patients with large deficits in bone mineral density are at
high risk for fracture and might preferentially benefit from
such anabolic therapy.64
Promotion of bone formation with parathyroid hormone
was shown to dramatically increase vertebral bone density
in a small trial of 28 postmenopausal women on a stable
dose of prednisone who were receiving concurrent
estrogen therapy and given daily human PTH 1-34 (hPTH
(1-34)) for 12 months and then had 12 months without
treatment compared with 23 women receiving estrogen
alone.65 Lumbar spine BMD increased dramatically in the
first year and the mean percentage differences in BMD of
the lumbar spine by quantitative computed tomography at
12 and 24 months were 32% and 43%, respectively, and
by dual energy X-ray absorptiometry were 11.8% in the
first year and 11.9% at 2 years. There was a smaller
difference between the treatment groups in hip BMD of
2% at 12 months and 4.7% at 24 months, 12 months after
hPTH treatment was discontinued. Biochemical markers
of bone turnover increased to more than 150% during the
first 6 months of hPTH therapy, remained elevated
throughout the 12-month treatment period, and returned
to baseline values within 6 months of discontinuing the
PTH treatment.
Latest study which compared teriparatide 20 g daily with
alendronate 10 mg daily in 428 women and men with
16
osteoporosis who had received prednisone equivalent,
5 mg daily or more for at least 3 months showed increase
in the mean bone mineral density at the lumbar spine more
in teriparatide group than in the alendronate group
(7.20.7% vs. 3.40.7%, P<0.001). At 12 months, bone
mineral density at the total hip had increased more and
new vertebral fractures become less in the teriparatide
group.66
Other Drugs for Glucocorticoid-induced
Osteoporosis
Although Raloxifene, a selective oestrogen receptor
modulator, is not the mainstream treatment in glucocorticoid-
induced osteoporosis, study showed that it may play a role in
prevention. An open controlled trial studying the effects of
raloxifene on bone mineral density in postmenopausal women
with systemic lupus erythematosus, in which low dose
prednisolone, illustrated that after 12 months, femoral neck
BMD and lumbar spine BMD was preserved in the raloxifene
group.67
Strontium ranelate, which act by increasing bone formation
and decreasing bone resorption was proven to be effective in
post-menopausal osteoporosis. SOTI trial (Spinal
Osteoporosis Therapeutic Intervention Trial) evaluated
postmenopausal women with >=1 vertebral fractures
receiving strontium 2 g daily showed increase in lumbar spine
BMD by 8.1%, reduce in new vertebral fractures at 1 year by
49%, and decrease in overall fracture risk after 3 years by
41%.68 Studies for glucocorticoid-induced osteoporosis are
underway.
All patients receiving long-term glucocorticoid treatment
should be assessed for hypogonadism since patients
receiving prolonged glucocorticoid therapy may develop
hypogonadism due to inhibition of secretion of luteinizing
hormone and follicle-stimulating hormone from the
pituitary gland, as well as direct effects on hormone
production by the ovary and testes. When hypogonadism
is present, this should be corrected if possible. In a trial of
postmenopausal women with RA who were taking
prednisone and were randomized to receive either HRT or
placebo, those who received HRT had a significant (3-4%)
increase in their lumbar spine BMD compared with
controls, while there was no significant change in femoral
neck BMD in either group.69
Management of Steroid Induced Osteoporosis
Conclusions
Glucocorticoid induced osteoporosis is the most common form
of drug-induced osteoporosis. The clinical impact of this
disease is related to the high prevalence of osteoporotic
fractures with associated impairment of quality of life.
Osteoporosis with increased risk of fracture is a serious
complication of using glucocorticoids, particularly at high
doses for prolonged periods. Interventions have been shown
to be effective at preventing bone loss and reducing fracture
risk. Bisphosphonates remain the gold standard of therapy at
present. Parathyroid hormone is the novel therapy that was
shown to be even more effective in management of
glucocorticoid-induced osteoporosis and studies are awaited
for evidence of its long term use.
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