Inhaled corticosteroid-induced bone loss and preventive strategies [review; review, tutorial]

              S14 • JAOA • Vol 100 • No 7 • Supplement to July 2000 Singh and Muskelly • Inhaled corticosteroid–induced bone loss and preventive strategies
Inhaled corticosteroids are the main-stay
in the treatment of asthma, allow-ing
effective control of symptoms with-out
the serious side effects associated
with systemic corticosteroids. The effi-cacy
of inhaled corticosteroids in asthma
treatment is dose-dependent, allowing
greater anti-inflammatory effect with
higher doses. Patients with severe asthma
are often taking very high doses of
inhaled corticosteroid.1
There is concern that high-dose
inhaled corticosteroids may have adverse
effects on bone metabolism. This concern
arises from the frequency with which
osteoporosis is known to occur with
long-term use of oral steroids.2 Nearly
50% of patients may have osteoporotic
fractures develop as a result of oral cor-ticosteroid
therapy if adequate prevention
and treatment of this complication are
not initiated immediately.3
Other factors to consider are differ-ences
between various types of inhaled
corticosteroids (Table). Corticosteroids
differ between each other in potencies,
suppression of the hypothalamus-pitu-itary-
adrenal axis, and degree of sys-temic
absorption. The dose of each of the
inhaled corticosteroids that is systemi-cally
absorbed needs to be established.
Whether all inhaled corticosteroids at
equivalent doses are associated with the
same risk is unknown.
Mechanisms of corticosteroid-induced
bone changes
The mechanism of corticosteroid-induced
bone loss is complex. Adult bone matrix
reflects a constant balance of activity
between bone-forming osteoblasts and
bone-breakdown cells (osteoclasts).4 A
change in this equilibrium may result in
reduction of bone mass, resulting in
osteoporosis and risk of fracture. Corti-costeroids
affect both bone formation
and resorption. Corticosteroids decrease
osteoblast activity, which results in
decreased matrix synthesis and a
decreased active life span of osteoblasts.
This results in a decrease in the bone
mass of mainly the axial skeleton (that is,
vertebrae), as the vertebrae contain more
metabolically active trabecular bone than
cortical bone. This effect with corticoste-roids
has been observed using biochem-ical
markers of bone turnover, particu-larly
serum osteocalcin, which decreases
in a dose-dependent way within 4 days
of starting corticosteroid therapy.5
Other markers of bone formation
include serum levels of alkaline phos-phatase,
osteocalcin, procollagen type 1
carboxyterminal and aminoterminal
propeptide, and procollagen type 3
aminoterminal propeptide.4 Corticoste-roids
also effect osteoclast activity, lead-ing
to an increase in bone resorption.
Markers for the increase in osteoclast
activity include urinary levels of hydrox-yproline,
urinary or serum pyridinium
cross-links, urinary collagen type 1 cross-linked
N-telopeptide, urinary collagen
type 1 cross-linked C-telopeptide, and
serum carboxyterminal telopeptide of
type 1 collagen.4 Bone formation mark-ers
are considered to be more sensitive
than bone resorption markers in assess-ing
the effects of corticosteroids, with
osteocalcin being the most sensitive, spe-cific,
and reproducible.4
Review of clinical studies
Pediatric
Prolonged use of systemic corticoste-roids
are known to suppress linear
growth in children.4 Asthma itself seems
to have a negative effect in delaying
puberty and reducing growth height,
and it should also be considered when
evaluating the effect of corticosteroids on
bone.4 In addition, there have been a
number of studies evaluating the effects
of inhaled corticosteroids on growth
rate and biochemical markers, as well as
bone mineral density (BMD) in chil-dren.
Agertoft and Pedersen6 evaluated
short-term knemometry (a measurement
of velocity of lower leg growth) and 24-
hour urine cortisol excretion in 48 chil-dren
aged 6 to 12 years. One group of
children received treatment with either
fluticasone propionate, 200  g/d; budes-onide,
200  g/d; or placebo in a ran-domized,
crossover manner. A second
group of children received either fluti-casone
propionate, 400  g/d; budes-onide,
400  g/d; or placebo in a similar
manner. Each treatment period was 15
Systemic corticosteroids are known to cause adverse effects on bone loss and, with
long-term use, may result in osteoporosis. There is evidence that inhaled cortico-steroids
at moderate to high doses may also induce bone loss. This article discusses
the effects of inhaled corticosteroids on bone formation and resorption. It also offers
preventive strategies to minimize bone loss associated with long-term use of
inhaled corticosteroids.
(Key words: asthma, inhaled corticosteroids, osteoporosis, bone loss)
Dr Singh is an assistant professor in the Depart-ment
of Pharmacy Practice, College of Phar-macy
and Allied Health, Wayne State University,
Detroit, Mich. Dr Muskelly is a pharmacy prac-tice
resident, Department of Pharmacy, Harper
Hospital, Detroit.
Correspondence to R. F. Singh, PharmD,
Department of Pharmacy Practice, College of
Pharmacy and Allied Health, Wayne State Uni-versity,
335 Shapero Hall, Detroit, MI 48201.
E-mail: rfsingh@med.wayne.edu
Inhaled corticosteroid–induced
bone loss and preventive
strategies
RENU F. SINGH, PHARMD
CHRIS C. MUSKELLY, PHARMD
to 18 days. Knemometry was used to
measure the lower leg length twice a
week, and 24-hour cortisol excretion
was measured at the end of each treat-ment
period. No difference was seen in
rate of lower leg growth within each
group between budesonide or fluticas-one;
however, growth rate was signifi-cantly
lower in the group receiving
budesonide at a dosage of 400  g/d
than in the group receiving the place-bo.
At this dose—fluticasone propionate,
400 g/d, and budesonide, 400  g/d—
there resulted a significant reduction in
urinary cortisol excretion compared with
that with placebo.
Konig and associates7 evaluated bone
metabolism in 18 asthmatic children
(aged 4 to 17 years) who were treated
with inhaled beclomethasone dipropi-onate
(400  g/d to 800  g/d) for at least
6 months. Each child was controlled with
an age- and sex-matched patient with
asthma who was not receiving corticoste-roid
therapy. Serum levels of calcium,
total alkaline phosphatase, bone-specific
alkaline phosphatase, parathyroid hor-mone,
25-hydroxyvitamin D, and 1,25-
dihydroxyvitamin D were measured, as
was BMD. The study found no signifi-cant
differences in the measured serum
markers between the treated groups and
their age-matched cohort. Further, no
significant difference was seen on bone
densitometry. The study concluded that
inhaled beclomethasone does not reduce
bone mineralization or increase bone
resorption in children with asthma.
These results were confirmed in a later
study by Martinati and coworkers,8 who
studied the effects of inhaled corticoste-roids
on cortical and trabecular bone mass
in 64 asthmatic prepubertal subjects (aged
between 5 and 10 years) who were treat-ed
with beclomethasone dipropionate,
150  g/d to 600  g/d, or cromolyn sodi-um,
30 mg/d for 6.7 months. Lumbar
spine bone mass was measured by dual-energy
x-ray absorptiometry (DEXA).
The DEXA measurements showed no
difference in trabecular bone mass in chil-dren
who received beclomethasone versus
children who received cromolyn sodium.
Thus, it appears that inhaled corticoste-roids
at low doses do not induce osteo-porosis
in children.
Adults
A number of short- and medium-term
studies have evaluated the effects of
inhaled corticosteroids on biochemical
bone markers in both healthy volunteers
and asthmatic patients.9-12 During study
periods of 2 to 4 weeks, most studies
showed that levels of various markers
significantly changed on inhaled corti-costeroid
therapy, with the magnitude
of effect being dose-related.
Kerstjens and colleagues13 conducted
two studies on the short-term and long-term
effects of inhaled corticosteroids
on bone metabolism of patients with
asthma or chronic obstructive pulmonary
disease. In the first pilot study, 15
patients (mean age, 41.1 years) received
at least 800  g/d of beclomethasone
dipropionate ( 20 puffs per day). Serum
levels of alkaline phosphatase, osteocal-cin,
procollagen type 1 carboxy terminal
propeptide (PICP), and type 1 collagen
carboxy terminal telopeptide (ICTP),
and urine level of hydroxyproline were
measured at baseline and after 4 weeks
of inhaled beclomethasone therapy. In
the second long-term, double-blind study,
70 patients (mean age, 40 years) received
beclomethasone diproprionate, 800  g/d,
while serum PICP and ICTP were mea-sured
at baseline and after 2.5 years of
treatment. Although the 4-week pilot
study revealed a decrease in serum osteo-calcin
levels and an increase in serum
PICP levels, the long-term study showed
no significant changes in serum levels of
PICP and ICTP of patients treated with
inhaled corticosteroids compared with
patients treated without inhaled corti-costeroids.
This finding suggests that the
clinical significance of short-term changes
in metabolic markers with inhaled corti-costeroids
is not clear, because long-term
studies result in no changes in these
markers. Hence, these markers cannot be
used as surrogate indicators for bone
density to predict risk of developing
osteoporosis.
Luengo and colleagues14 conducted a
case-control study on 48 asthmatic adults
(mean age, 56 years) treated with inhaled
corticosteroids—beclomethasone or
budesonide (300  g to 1000  g) for
Singh and Muskelly • Inhaled corticosteroid–induced bone loss and preventive strategies JAOA • Vol 100 • No 7 • Supplement to July 2000 • S15
Table
Inhaled Corticosteroids
No. of puffs
Drug* Low dose Medium dose High dose
  Beclomethasone dipropionate 4 to 12 12 to 20  20
(Vanceril, Beclovent)
42  g per puff
  Budesonide 1 to 2 2 to 3  3
(Pulmicort Turbuhaler)
200  g per puff
  Flunisolide 2 to 4 4 to 8  8
(AeroBid)
250  g per puff
  Fluticasone propionate
(Flovent)
44  g per puff 2 to 6 6 to 15  15
110  g per puff 2 2 to 6  6
220  g per puff  3
  Triamcinolone acetonide 4 to 10 10 to 20  20
(Azmacort)
100  g per puff
*Drugs are listed by generic names, with trade names in parentheses.
more than 1 year (mean duration of
treatment, 10.6 years). Twenty-four
patients had received one to six short
courses of oral corticosteroids while 7
patients had received oral corticosteroids
(mean daily dose of 6.2 mg of pred-nisone)
for 2 to 15 years more than 4
years before the bone densitometry mea-surements
of this study. Vertebral BMD
measured by DEXA was obtained at
baseline and at 2 years in the asthmatic
patients and their age-matched controls.
The findings indicated no significant dif-ferences
in BMD loss between the group
using inhaled corticosteroid and the con-trol
group; both groups showed a
decrease in BMD over 2 years. These
data suggested that inhaled corticoste-roids
at mean doses up to 662  g/d do
not further increase bone mass loss
beyond that expected from natural bone
mass loss.
Prevention of inhaled
corticosteroid–induced
bone loss
To date, there are no documented treat-ment
guidelines for prevention of inhaled
corticosteroid–induced bone loss. All
recommendations have been geared
toward oral corticosteroids.15 Therefore,
we opt to suggest that the general rec-ommendations
for prevention and treat-ment
of glucocorticoid-induced osteo-porosis
be considered in patients taking
medium to high doses of inhaled cortico-steroids.
15
Calcium and vitamin D
The American Rheumatologists Associ-ation
recommends that all patients on
glucocorticoid therapy have an adequate
intake of calcium and vitamin D.15 A
daily calcium intake of 1500 mg is rec-ommended,
either obtained through
dietary intake or calcium supplementa-tion.
In addition, vitamin D (either 800
IU/d or 50,000 IU three times a week) or
calcitriol (0.5  g/d) should be added.
Hormone replacement therapy
Postmenopausal women receiving medi-um
to high doses of inhaled corticoste-roids
should receive estrogen therapy.
Estrogens increase bone mass and reduce
the risk of fractures related to osteo-porosis.
Women with a uterus should
also receive a progesterone for 12 to 14
days per month to reduce the risk of
endometrial hyperplasia. Women at high
risk for breast cancer or having a histo-ry
of breast cancer should consider ralox-ifene
hydrochloride, an estrogen-receptor
antagonist. In a multicenter, random-ized,
placebo-controlled study of ralox-ifene
in early postmenopausal women
with osteoporosis, bone density increased
by 2.1% to 2.4% in the femoral neck
and 2.6% to 2.7% in the spine com-pared
with those taking placebo.16 How-ever,
the efficacy of raloxifene in patients
receiving inhaled corticosteroids has not
been published.
Bisphosphonates
The actual mechanism of action of bis-phosphonates
is poorly understood;
however, they are inhibitors of bone
resorption (reduction of number of osteo-clasts)
that are used in treatment of
Paget’s disease, hypercalcemia, and osteo-porosis.
17 Many bisphosphonates (such
as alendronate sodium, cyclic etidronate
disodium, and pamidronate disodium)
have been evaluated in corticosteroid-induced
bone loss. Intermittent cyclical
etidronate sodium (400 mg daily for 2
weeks) and calcium (500 mg/d for 11
weeks) was studied and resulted in an
increase in BMD of lumbar spine by
1.8% (P .001) at both 6 months and 12
months.18 Intermittent etidronate dis-odium
(400 mg/d for 14 days) and cal-cium
(500 mg/d for 76 days) prevented
loss of vertebral and trochanteric bone in
141 patients aged 19 to 87 years treated
with high-dose oral prednisone ( 7.5
mg/d).19 The mean BMD of the lumbar
spine and trochanter in the group receiv-ing
etidronate increased by 0.61% and
1.46%, respectively, as compared with a
decrease of 3.23% and 2.74%, respec-tively,
in the group receiving the placebo.
In a randomized, placebo-controlled
study of adults receiving long-term glu-cocorticoid
therapy, patients were treat-ed
with alendronate, 5 mg/d to 10 mg/d
for 48 weeks.20 The mean BMD of the
lumbar spine in these patients increased
by 2.1% and 2.9% (P .001); the
femoral neck BMD increased by 1.2%
and 1% (P .01) in the alendronate-treated
group as compared with the
placebo group.
In an early postmenopausal interven-tion
cohort study of 1202 women, aged
45 to 59 years, treated with alendronate,
2.5 mg/d and 5 mg/d for 2 years, there
was an increased response in spine and
hip BMD of 2% to 4% over 2 years.21
Comment
Patients taking moderate to high doses of
inhaled corticosteroids may be at
increased risk for long-term bone loss,
especially if used for a prolonged time. It
remains to be established whether inhaled
corticosteroid–induced bone changes are
clinically important. Although no specif-ic
guidelines are available, it would seem
prudent to consider preventive measures
such as calcium and vitamin D supple-mentation
in patients taking moderate
to high doses of inhaled corticosteroids
(Table). Patients with additional risk fac-tors,
such as a postmenopausal state,
should consider estrogen replacement
therapy. If high doses of inhaled corti-costeroids
are used, a screening bone
DEXA scan may be indicated to see if
more aggressive therapy is needed.
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Singh and Muskelly • Inhaled corticosteroid–induced bone loss and preventive strategies JAOA • Vol 100 • No 7 • Supplement to July 2000 • S17