Osteoporosis

REVIEW

Glucocorticoid-induced osteoporosis
Karine Briot, Christian Roux

ABSTRACT
Key messages
Corticosteroid-induced osteoporosis is the most common
form of secondary osteoporosis and the first cause in ▸ Glucocorticoid-induced osteoporosis (GIOP) is
To cite: Briot K, Roux C. young people. Bone loss and increased rate of fractures the most common cause of secondary osteopor-
Glucocorticoid-induced occur early after the initiation of corticosteroid therapy, osis, the most common cause before 50 years
osteoporosis. RMD Open and are then related to dosage and treatment duration. of age, and the most common iatrogenic cause
2015;1:e000014. The increase in fracture risk is not fully assessed by bone of the disease.
doi:10.1136/rmdopen-2014-
mineral density measurements, as it is also related to ▸ Previous and current exposure to glucocorti-
000014
alteration of bone quality and increased risk of falls. In coids (GCs) increases the risk of fracture and
patients with rheumatoid arthritis, a treat-to-target strategy bone loss.
▸ Prepublication history for focusing on low disease activity including through the use ▸ The increase in fracture risk is not fully assessed
this paper is available online. of low dose of prednisone, is a key determinant of bone by bone mineral density measurements, as it is
To view these files please
loss prevention. Bone loss magnitude is variable and also related to alteration in bone quality and
visit the journal online
there is no clearly identified predictor of the individual risk increased risk of falls.
(http://dx.doi.org/10.1136/
rmdopen-2014-000014). of fracture. Prevention or treatment of osteoporosis ▸ Prevention or treatment of osteoporosis should
should be considered in all patients who receive be considered in all patients who receive GCs.
Received 12 February 2015 prednisone. Bisphosphonates and the anabolic agent ▸ Recent international guidelines are available and
Revised 16 March 2015 parathyroid hormone (1–34) have shown their efficacy in should guide management of corticosteroid-
Accepted 17 March 2015 the treatment of corticosteroid-induced osteoporosis. induced osteoporosis, which remains under-
Recent international guidelines are available and should diagnosed and under-treated.
guide management of corticosteroid-induced
osteoporosis, which remains under-diagnosed and under-
treated. Duration of antiosteoporotic treatment should be inflammatory rheumatic disorders (rheuma-
discussed at the individual level, depending on the toid arthritis, polymyalgia rheumatic…) and
subject’s characteristics and on the underlying lung disorders (asthma and chronic obstructive
inflammation evolution. lung diseases). Apart from bone and ocular
side effects, lipodystrophy and neuropsychiatric
disorders are also common adverse events of
INTRODUCTION long-term GC therapy.4
Glucocorticoid-induced osteoporosis (GIOP) A number of guidelines for GIOP are now
is the most common cause of secondary available, but the proportion of GC-treated
osteoporosis, the first cause before 50 years patients receiving preventatives for bone com-
and the first iatrogenic cause of the disease.1 plications remains low. Paradoxically, the
Prior and current exposure to glucocorti- numbers of underlying comorbidities and con-
coids (GCs) increases the risk of fracture and comitant treatments are strong determinants
bone loss. A key point is that the underlying of the absence of prevention of GIOP, although
inflammation for which GCs are used also they are themselves added risk factors for osteo-
has a role in bone fragility, as there is a porosis.8–11 There has been greater awareness
strong relationship between inflammatory of this condition in recent years, with improve-
cells and bone cells.2 This is one of the ment in the number of patients receiving
Department of determinants of rapid bone loss occurring at bisphosphonates.12 However, even interven-
Rheumatology, Research the initiation of GCs. tions by pharmacist do not significantly
Center, Epidemiology and improve these numbers,13 and recent studies
Biostatistics Sorbonne Paris
The prevalence of use of oral GCs in the
Cité, Cochin Hospital, community population is between 0.5 and confirm the neglecting of osteoporosis prophy-
INSERM U1153, Paris 0.9% (65% women), rising to 2.7% in women laxis in patients exposed to GCs.
Descartes University, Paris, aged ≥50 years.3–5 In the Global Longitudinal
France Study of Osteoporosis in Women (GLOW),
Correspondence to
conducted in 10 countries, 4.6% of 60 393 post- PATHOGENESIS
Professor Christian Roux; menopausal women were receiving GCs at Bone fragility in GIOP is characterised by
christian.roux@cch.aphp.fr baseline visit.6 7 The main causes of GC use are rapidity of bone loss at the introduction of

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GCs, and the discrepancy between bone mineral density by a number of cytokines, the main pathway being
(BMD) and risk of fractures. These two points can be driven by Th 17 cells subpopulation (ie, interleukin (IL)
explained by the pathogenesis of GIOP. 6 and IL23).22–26 Tumour necrosis factor α (TNF-α)
transgenic mice are models of osteoporosis with dra-
Role of underlying inflammation matic decrease in bone mass and deterioration of bone
In the general population, even small elevations of C microarchitecture. Moreover, an over expression of scler-
reactive protein within the normal range increase non- ostin has been observed in these models, with a conse-
traumatic fracture risk.14 In some studies, variations quence of inflammation-related decrease in bone
within the low levels of inflammatory markers and cyto- formation.27 Finally autoimmunity has a role in bone
kines predict bone loss and elevated inflammatory remodelling, as antibodies against citrullinated proteins
markers are prognostic for fractures.15 16 (ACPAs) can increase osteoclast numbers and activity
Rheumatoid arthritis (RA) doubles the risk of hip and through citrullinated vimentin located at the surface of
vertebral fractures, regardless of the use of GCs,17 and precursors and cells (through a TNF-α local effect).28
disease activity is consistently associated with low BMD. All these clinical observations and biological studies
In a prospective study of patients with early RA con- show that inflammation has a deleterious effect on bone
ducted at a time when biotherapies were not available, remodelling, inducing an increase in resorption and a
high bone loss was observed, mainly in patients with per- decrease in formation, before any effect of GCs
sistent inflammation during follow-up (ie, persistent themselves.
high CRP).18 In ankylosing spondylitis, an inflammatory
disease in which GCs are not used, there is bone loss Bone effects of GCs
and an increased risk of vertebral fractures, driven by The predominant effect of GCs on bone is the impair-
inflammation.19 20 ment in bone formation (figure 1).29 The evidence that
There is a strong biological rationale for these clinical this is a direct effect, independent of the inflammation
observations. Osteoclastogenesis is under the control of effect, comes from studies conducted in healthy volun-
RANK-ligand, which is produced by osteocytes in normal teers: prednisone 5 mg daily is enough to rapidly and sig-
bone remodelling, but also by lymphocytes and fibro- nificantly decrease serum P1NP and osteocalcin, which
blasts in other situations, such as oestrogen deficiency21 are specific markers of bone formation; the changes are
and inflammation. Osteoclastogenesis can be enhanced reversed after discontinuation of the prednisone.30

Figure 1 Pathophysiology of glucocorticoid-induced osteoporosis (adapted from ref 29).

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 Osteoporosis

GCs at high concentrations dramatically decrease bone EPIDEMIOLOGY

formation rate, osteoblast numbers, and osteocyte The risk of fractures is increased by twofold in patients
numbers and activity.31–33 The decrease in osteoblast with GCs, and the risk of vertebral fractures is even
differentiation includes induction of adipogenetic tran- higher. In a study comparing 244 235 oral GC users and
scription factors (PPARγ) and suppression of Wnt 244 235 controls, the risk of hip fracture is 1.6, and that
protein signalling;34–37 the increase of osteoblast and of vertebral fracture is 2.6; these numbers have been
osteocyte apoptosis is associated with caspase 3 activa- reproduced in many studies.44–46 The global prevalence
tion.38 Moreover, the osteoblast function is decreased of fractures in patients receiving long-term GCs has
through the antianabolic effects of GCs, such as decrease been reported to be 30–50%. In 551 patients receiving
in GH, IGF1 and IGFBP3-4-5. In contrast, GCs increase long-term GCs, the prevalence of vertebral fractures was
IGFBP6 transcription thus decreasing IGF2, another local 37%, with 14% of patients having 2 or more asymptom-
regulator of osteoblast function. GCs are associated with a atic vertebral fractures; 48% of patients aged ≥70 years
decrease in osteocyte viability, including changes in and 30% of those aged <60 years had at least one VF.47
matrix properties surrounding the osteocyte lacunae.31 The prevalence increases with age, a key point for pre-
GCs increase the expression of RANK-ligand and ventive strategies.
decrease the expression of osteoprotegerin in stromal A number of observations from epidemiological
and osteoblastic cells.39 As a consequence, a prolonged studies are relevant for clinical practice, as they could
lifespan of osteoclasts is observed (contrasting with the help to identify a high-risk group of patients.
decrease in the lifespan of osteoblasts). Although this
increased resorption has been demonstrated, much of Time effect
the GC-related bone loss is caused by the reduced bone The increase in fracture risk is immediate, as early as
formation, which persists throughout GC administration. 3 months after the initiation of therapy and reverses
sharply after discontinuation of GCs.45 This cannot be
explained by BMD changes, but can be related to the
Indirect effects of GCs added effects of GCs on bone remodelling previously
Earlier, emphasis had been placed on the effects of uncoupled by the inflammation itself, and the dramatic
GCs on calcium metabolism, because of decrease of effect on bone strength through induced apoptosis of
gastrointestinal absorption of calcium and induction osteocytes. Data also suggest a rapid increase in rate of
of renal calcium loss. A secondary hyperparathyroid- falls after start of oral GCs.45 Thus primary prevention,
ism has been suggested as a determinant of bone after careful assessment of the fracture risk, is recom-
effects. Actually, there is no evidence for elevated mended in high-risk patients.
endogenous levels of PTH in these patients and histo-
logical features are not those related to an increased Dose effect
PTH secretion.40 In epidemiological studies, the increased risk of frac-
GCs reduce production of sex steroid hormones, and tures is observed even at low doses of prednisone, that
hypogonadism can by itself induce increased bone is, 2.5–5 mg per day. The appropriate care of patients
resorption.29 receiving such low doses is not well defined. There is a
Glucocorticoid-induced myopathy is related to a direct dose-dependent increase in fracture incidence.
effect on muscle mass and muscle force; muscle weak- Interestingly, the fracture risk is related to the current
ness is one of the determinants of the risk of falls and daily dose, more than to the cumulative dose;48 this may
fractures in these patients.29 be related to the difficulty of an accurate calculation of
this cumulative dose.

Differential sensitivity to GCs Prior versus current GCs use

There is great variability of side effects of GCs among Ever use of GCs is associated with an increased risk of
individuals, including bone loss, for largely unknown hip fracture, and this justifies the assessment of osteopor-
reasons. Attention has been paid to the 11β-hydroxysteroid osis and fracture risk in all patients. However, the risk is
dehydrogenase (11β-HSD) system, which is a prereceptor mainly associated with recent and prolonged GC use,
modulator of GC action. This system catalyses the intercon- more than to remote or short courses.49
version of active/inactive cortisone, and the 11β-HSD1
enzyme amplifies GC signalling in osteoblasts. BMD loss
Interestingly, β11-HSD, widely expressed in GC target BMD loss is an immediate consequence of the introduc-
tissues including bone, can be modulated and amplified tion of GCs and affects the trabecular bone (ie, spine)
by proinflammatory cytokines,41 42 age and GC administra- more than it does the cortical bone (ie, femur). According
tion itself, suggesting that the mechanism could be a key to a meta-analysis of 56 cross-sectional studies and 10 longi-
regulator of the effects of GCs on bone. Individual GC sen- tudinal studies, bone loss assessed by dual-energy X-ray
sitivity can also be regulated by polymorphisms in the GC absorptiometry, can be 5–15% during the first year of treat-
receptor gene.43 ment.44 The main determinant of BMD at any time is the

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cumulative dose. The increased rate of bone loss persists fractures, and 0.65 and 1.20 for hip fracture probability.53
in chronic GC users, but more slowly. For very high doses of glucocorticoids, greater upward
adjustment of fracture probability may be required.
FRAX assessment has already been included in some
ASSESSMENT OF FRACTURE RISK guidelines at different steps of the treatment decision.
Role of BMD American College of Rheumatology guidelines recom-
There is a mismatch between BMD data and fracture data mend treatment in postmenopausal women and
in patients receiving GCs because of the disparity related men aged 50 years or older starting oral glucocorticoids
to the alteration of bone quality. At similar levels of BMD, with a FRAX-derived 10-year probability of major osteo-
postmenopausal women taking GCs have considerably porotic fracture of over 10%, and in those with a prob-
higher risk of fracture than controls not using GCs. ability of less than 10% if the daily dose of prednisolone
There is a debate on the appropriate T score threshold to or its equivalent is ≥7.5 mg/day.54 According to the
be considered a risk and as an indication for treatment in International Osteoporosis Foundation (IOF)–European
patients with GCs: the same diagnostic criterion as in Calcified Tissue Society55 recommendations, a treatment
postmenopausal women has been suggested (T≤−2.5),50 decision for postmenopausal women and for men aged
but a higher threshold (ie, T≤−1.5) has been proposed ≥50 years exposed to oral glucocorticoids for ≥3 months
for intervention,46 because bone loss can be 10% or should be based on fracture risk assessment with FRAX
more in some individuals over the first year of GC use. adjusted for glucocorticoid use (with or without BMD
There is no means to provide an evidence-based thresh- testing). Treatment can be considered directly (without
old for treatment decisions. A practical approach is to rec- FRAX assessment) if patients are at high risk defined by
ommend a BMD measurement in GC users (optimally at one of the following criteria: prevalent fracture, age
the initiation of treatment) and to consider that patients ≥70 years, exposure to a glucocorticoid dose ≥7.5 mg
with T ≤−2.5 as those who should receive the highest pri- per day or low BMD (T≤−2.5).55
ority for treatment.51 However, beyond the BMD, a more
comprehensive approach of the risk and clinical judge- Role of underlying disease
ment is needed. Persistent inflammation is associated with bone loss as
shown in longitudinal studies in patients with active RA
Role of FRAX or ankylosing spondylitis (SpA). In contrast, prospective
The WHO fracture risk assessment tool (FRAX) algo- open studies show that complete control of inflamma-
rithm has been developed to estimate the 10-year risk of tion (in parallel with clinical improvement and thus
hip and other major fractures (clinical spine, humerus or increased mobility) is accompanied by the absence of
wrist fracture) based on clinical risk factors, with or bone loss.56 This is expected in SpA in the absence of
without BMD.52 The risk factors included in FRAX are: GCs, but is also observed in RA of the hand, spine and
age, sex, body mass index (BMI), personal history of frac- hip, in patients receiving low doses of GCs.56–58 In the
ture, parental history of hip fracture, current smoking, BeSt study, conducted in patients with recent-onset
alcohol intake, glucocorticoid use, rheumatoid arthritis, active RA, bone loss was limited in all treated groups,
other causes of secondary osteoporosis and femoral neck including in the group initially treated with high-dose
(not spine) BMD. These clinical risk factors are largely prednisone.59 Thus, the concept that a high level of
independent of BMD and can thus improve the fracture inflammation is more deleterious for bone than a low
risk assessment. FRAX cannot be used in premenopausal dose of GCs, controlling this inflammation is relevant as
women, men aged <40 years and in subjects previously far as surrogate markers (BMD, biological parameters)
treated with antiosteoporotic drugs. are concerned. However, there is no evidence for a
One of the limitations of FRAX is that use of oral GCs reduction in fracture risk with such a strategy,60 and new
is entered as a dichotomous risk factor and does not take epidemiological studies are mandatory in this matter.
into account the dose of GCs and the duration of use.
Moreover, FRAX does not take into account the differ- Role of patient characteristics
ence in risk between prior and current use.49 FRAX Age, female gender, low BMI, history of falls and previ-
assumes an average dose of prednisolone (2.5–7.5 mg/ ous fractures, duration of menopause and smoking are
day or its equivalent) and may underestimate fracture associated with fracture risk in patients with GCs, simi-
risk in patients taking higher doses and may overestimate larly to how they are in primary osteoporosis. We have
risk in those taking lower doses. Moreover the predictive shown that prevalence of non-vertebral fractures is a
value of FRAX has been mainly validated for non- strong determinant of the risk of having vertebral frac-
vertebral fractures although the principal risk in GCs tures in patients with RA,61 implying that the individual’s
users is for vertebral fractures. Adjustment of FRAX has skeleton is already of inadequate strength to withstand
been proposed for postmenopausal women and men the trauma of daily living. Beyond GC use, these risk
aged ≥50 years with lower or higher doses than 2.5– factors must be assessed in all patients, and all causes of
7.5 mg/day: a factor of 0.8 for low-dose exposure and secondary osteoporosis are added risk factors of fractures
1.15 for high-dose exposure for major osteoporotic in patients with GCs.

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 Osteoporosis

TREATMENT 35 mg one weekly) and zoledronate (intravenous infusion

General measures 5 mg once yearly) prevent bone loss at the spine and hip
At the initiation of GC treatment, the patient’s height in patients initiating GCs, and increase BMD in patients
must be measured, as height loss in the follow-up could on long-term GCs. Alendronate was assessed in a placebo
be related to asymptomatic vertebral fractures. Biological controlled study in 477 men and women over 48 weeks.
tests are performed to screen for other causes of bone There was a 2.1 and 2.9% increase at the lumbar spine in
diseases. There is no indication for assessment of bio- the 5 and 10 mg alendronate groups, respectively and a
chemical markers of bone remodelling either at baseline 0.4% decrease in the placebo group. At the femoral neck
or during follow-up, as bone turnover is consistently low the changes were +1, +1.2 and −1.2%, respectively.
in GC users. Interestingly the decrease of BMD in the placebo group
As the daily dose of GCs is a determinant of fracture (receiving calcium and vitamin D) was driven by the dur-
risk, it must be constantly reviewed by considering both ation of GCs: −2.9, −1.4, +0.8 in patients receiving GCs
the reduction of the dose to the minimally active and alter- for less than 4 months, 4–12 months and more than
native administration such as intra-articular injections. 12 months, respectively.64 In a follow-up study in a second
The risk of falling should be assessed in particular in year, performed in 208 out of the 477 patients, there were
elderly patients, patients with painful joints of the lower fewer patients with new vertebral fractures in the treated
limbs and patients with massive doses of GCs. Physical group (0.7%) than in the placebo group (6.8%).65 Two
activity or mobilisation should be considered, adapted to 1-year studies were performed with risedronate, one for
the underlying condition. prevention in patients beginning GCs, and one in treat-
Attention to nutrition must be paid to prevent protein ment of GIOP in patients chronically treated with GCs.
and calcium intake deficiencies. Calcium and vitamin D Data from pooling these two studies suggest a reduction
have been used for decades in GIOP, although there are of fractures in the first year of therapy: 16% of placebo
controversies about their effect on BMD. In 66 patients patients and 5% of those on risedronate 5 mg/day.66–68
with RA receiving prednisone, 1000 mg/day of calcium In a comparative double blind randomised study, zoledro-
carbonate and 500 IU/day of vitamin D3 induced a posi- nic acid (1 injection) induced a higher BMD increase
tive change of 0.63% per year at the lumbar spine, versus than risedronate (daily) in treatment (+4.06 vs +2.71%)
a decrease of 1.31% per year in the placebo group; there and prevention (+2.6 vs 0.6%) subgroups over 1 year at
was no effect at the femoral neck.62 No benefit was the lumbar spine.69
observed in another study with a 3-year follow-up.63 Attention has been paid recently to osteonecrosis of
However, it is reasonable to consider that any deficiency the jaw and atypical femoral fractures such as side effect
in calcium and vitamin D could be deleterious in patients of long-term administration of antiresorptive drugs in
beginning or receiving GCs. For calcium, the recommen- osteoporosis; these events are very rare,70 71 but GC use is
dation is to have an intake of 1000–1500 mg/day, and one of the identified risk factors. Buccal hygiene proce-
supplementation should be prescribed only to patients dures should be implemented to prevent any local
whose dietary intake does not provide this adequate increased risk of infection. Whether these rare events can
quantity. GC-treated patients may seldom be outdoors, change the duration of anti-resorptive treatments in long-
and thus exposed more than the general population to term GC users needs further studies. Bisphosphonates
vitamin D deficiency. Supplementation is adequate should be used cautiously in premenopausal women, as
between 800 and 2000 IU per day. There is no evidence they cross the placenta; appropriate contraception must
of an advantage using calcitriol or alcalcidol, as there is a be used if necessary and preference given to a short bone
large variability of outcomes with these vitamin D meta- half-life bisphosphonate.
bolites over plain vitamin D. The use of administrative databases offers the oppor-
tunity to assess a huge number of patients, taking into
Pharmacological treatment account the methodological issues related to these
Bisphosphonates and teriparatide have been assessed in studies (retrospective design, lack of details in patient
prevention and treatment of GIOP. There are a number characteristics, absence of confirmation of the diagnosis
of issues regarding their efficacy. Fracture incidence has of fractures, etc). Two well-designed studies with such an
not been a primary end point of any study (the end point approach, suggest the efficacy of bisphosphonates in
being BMD), the duration of the studies is low (1 year on reducing fractures and a better efficacy when the antios-
average) and the number of men and premenopausal teoporosis medication is initiating within 90 days of
women in these studies is low. Thus the efficacy on frac- chronic GC use, reaching a 48% reduction rate of frac-
tures is mainly based on bridging data between the short- ture.72 73 However, not all studies support these conclu-
term change in BMD in patients with GCs, and the long- sions, and there is still a disconnect between GIOP care
term change in BMD and reduction of fracture risk in and improvement of outcomes.74
patients with postmenopausal osteoporosis. There is so far no study of denosumab on GIOP. In a
Bisphosphonates are the more popular antiosteoporo- subgroup analysis of a 12-month study of patients with RA
tic drugs. Alendronate (oral 5 or 10 mg once daily, or (still active although they were receiving methotrexate)
70 mg once weekly), risedronate (oral 5 mg daily or treated with denosumab, BMD increases were similar in

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patients with and without GCs.75 Such data are relevant 2. Roux C. Osteoporosis in inflammatory joint diseases. Osteoporos Int
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