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* From the Asthma Center (Dr. Goldstein), Philadelphia, PA; the Pavilions of Voorhees (Dr. Fallon), Voorhees, NJ; and Merck Research Laboratories (Dr. Harning), Rahway, NJ.
Correspondence to: Ronald Harning, PhD, Merck Research Laboratories, PO Box 2000, RY 32–541, Rahway, NJ 07065-0900; e-mail: ronald_harning{at}merck.com
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Abstract |
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 TOP Abstract IntroductionPathophysiology of GC-Induced...Measurement of Bone Metabolism...Bone Loss and Fracture...Investigational Therapies for...DiscussionSummaryReferences |
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Key Words: asthma • bone metabolism • COPD • glucocorticoid • osteopenia • osteoporosis
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Introduction |
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TOPAbstractIntroductionPathophysiology of GC-Induced...Measurement of Bone Metabolism...Bone Loss and Fracture...Investigational Therapies for...DiscussionSummaryReferences |
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1 year, 86% demonstrated a decrease in bone mineral
density (BMD) at either the hip or lumbar spine. Furthermore, decreases
in BMD were dose related and observed in 80% of high-dose, 71% of
medium-dose, and 33% of low-dose patients. The incidence of GC-induced
bone loss in COPD has also been reported to be quite high. Shane et
al13
measured BMD at the femoral neck in a cohort of 28
COPD patients. The mean BMD T score of this population was in the range
associated with established osteoporosis (-2.7 ± 0.3 SD), while the
incidence of vertebral fractures was 29%. It is probable that the
incidence and prevalence of GC-induced bone loss will increase as the
use of chronic oral and high-dose inhaled GC therapy continues to rise
in parallel with the aging of the population at risk.
Many physicians are aware of the incidence of GC-induced bone loss, and
some physicians initiate therapy when osteoporosis is diagnosed.
However, in a recent study, > 50% of patients receiving chronic
high-dose oral GCs were not evaluated for osteoporosis.14
The concern regarding underdiagnosing and undertreating secondary
osteoporosis has been raised by others,15
and evidenced in
a recent study16
reporting that only 14% of patients
receiving high-dose chronic GC treatment also received treatment for
osteoporosis. The rising prevalence of GC-induced bone loss
precipitated a statement from the National Osteoporosis
Foundation17
recommending that all patients receiving
chronic GC treatment (> 1 month) with 7.5 mg/d prednisone or
equivalent should undergo screening for osteoporosis. Indeed, new
evidence suggests that oral dosages as low as 6.0 mg/d prednisone for 6
months may cause significant bone loss18
in nonasthma
patients, and may significantly increase the rate of osteoporotic
fracture in < 1 year.19
While other chronic drug
therapies (antiseizure drugs,20
luteinizing
hormone–releasing hormone agonists,21
and chemotherapy
for neoplasia22
) induce bone loss, it is generally held
that chronic GC therapy is the most common cause of drug-induced
osteoporosis.23
24
25
Asthma/COPD specialists who prescribe
inhaled and oral steroids for chronic use are very likely to encounter
osteopenia/osteoporosis in a percentage of patients (33 to
86%12
), and these numbers are likely to increase. Despite
the known risk factors and the availability of reliable diagnostic
tools, generalists and specialists alike often fail to recognize
asymptomatic bone loss and miss the opportunity to prevent, slow, or
reverse its progression.
This report provides a background regarding the pathophysiology behind GC-induced bone loss, and it reviews the recent literature (MEDLINE advanced and current contents search of references from 1990 and later) regarding evidence of GC-induced bone loss in adult asthma and COPD patients receiving long-term/short-term oral and/or inhaled GCs. This report also describes the results of recent investigational studies (limited to those studies conducted with asthma and COPD patients) designed to assess various treatments for GC-induced bone loss. Finally, diagnostic and treatment guidelines for the clinician are suggested. Although GC-induced bone loss is uncommon in children,26 children with asthma may ultimately face long-term bone effects from the cumulative use of inhaled and/or oral steroids. Therapeutic intervention to prevent osteoporosis in pediatric populations has not been adequately addressed in the literature and will not be discussed here.
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Pathophysiology of GC-Induced Bone Loss |
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TOPAbstractIntroductionPathophysiology of GC-Induced...Measurement of Bone Metabolism...Bone Loss and Fracture...Investigational Therapies for...DiscussionSummaryReferences |
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7.5 mg/d) has profound detrimental effects
on bone. Inhaled GCs have been associated with a lower risk of bone
loss as compared with oral GCs. However, some studies (described below)
suggest that the higher doses of inhaled GC therapy may also be
associated with an increased risk of bone loss.
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Measurement of Bone Metabolism and Bone Density |
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TOPAbstractIntroductionPathophysiology of GC-Induced...Measurement of Bone Metabolism...Bone Loss and Fracture...Investigational Therapies for...DiscussionSummaryReferences |
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The accuracy, reliability, and increasing availability of BMD measurement has allowed clinicians to measure bone density in patients and the rate of bone loss over time. Qualitative CT or dual energy x-ray absorptiometry (DXA) scans of the lumbar spine, hip, or wrist provide reliable assessment of BMD and predict the risk of future fracture49 50 51 52 53 (Fig 2 ). DXA is generally considered the preferred technique for the measurement of both cortical and trabecular BMD in the spine, hip, forearm, and total body,54 and radiation exposure is minimal. Therefore, because bone mass is inversely proportional to the risk of fracture—ie, lower bone mass correlates with increased risk of fracture (Fig 2) —BMD can be used to predict current and future osteoporotic fracture risk. Recently, Medicare reimbursement for the use of densitometry for the early diagnosis of bone loss in GC-treated patients has been approved.55 Guidelines for the use of DXA for diagnosing osteopenia and osteoporosis have been recently developed.56 DXA analysis of lumbar spine or hip BMD is generally measured as a comparative T score to peak bone mass in a young adult of the same race and sex, or, alternatively, as a comparative Z score to healthy age-, race-, and sex-matched control subjects.57 58 59 T scores below -1 SD or -2.5 SD (ie, BMD values > 1 or 2.5 SDs below the mean of a young adult) indicate osteopenia and osteoporosis, respectively (Figs 3 , 4 ), and are well correlated with the risk of fracture (Fig 2) . The correlation of BMD with fracture risk is greater than the correlation between serum cholesterol and risk of heart attack,52 and roughly equal to the correlation between resting systolic BP and risk of stroke.60 DXA analyses require ionizing radiation, but nonionizing radiation (ultrasound) densitometry is evolving as a diagnostic modality,61 and some technology has received Federal approval in the United States. Ultrasound densitometry may be widely available within the next 5 years to predict the risk of osteoporotic fracture.
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Bone Loss and Fracture Rates in Patients With Pulmonary Disease Receiving Chronic GC Treatment |
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TOPAbstractIntroductionPathophysiology of GC-Induced...Measurement of Bone Metabolism...Bone Loss and Fracture...Investigational Therapies for...DiscussionSummaryReferences |
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1 year with a
minimum prednisone dosage of 15 mg/d developed new vertebral or rib
fractures during the course of therapy, compared with no fractures in
age-matched untreated asthma patients. In the prospective cohort, 42%
of asthma patients receiving chronic GC therapy ( 1 year with a
minimum prednisone dosage of 15 mg/d) developed new vertebral or rib
fractures during the course of therapy, while no fractures were seen in
untreated asthma patients matched for age, sex, and disease intensity.
Furthermore, asthma patients receiving long-term GC therapy had
significantly lower BMD (85% of control value; p < 0.001) in the
distal and proximal radius. The observations of Adinoff and
Hollister62
have been recently confirmed by McEvoy et
al63
in a cross-sectional study of 312 men with COPD.
Patients were classified into three groups based on current GC use:
never-users, inhaled GC users (mean beclomethasone dipropionate or
triamcinolone acetonide usage, 11.8 puffs/d for 3.5 years), and oral GC
users (mean prednisone dosage, 18.5 mg/d for 5.2 years). The prevalence
of one or more vertebral fractures was dose-related: 48.7% in
never-users (n = 117), 57.1% in inhaled GC users (n = 70; odds
ratio = 1.38 compared with never-users), and 63.3% in oral GC users
(n = 125; odds ratio = 2.16 compared with never-users).
Interestingly, vertebral fractures in the oral GC users were more
likely to be multiple and more severe (p < 0.05) when compared with
fractures in both inhaled GC users and never-users. In a retrospective
study, the incidence of bone loss was examined in male asthma patients
receiving cumulative doses of 4 to 41 g equivalent prednisone over
1 to 15 years.64
Osteopenia was observed in 50% of all
patients and was most commonly seen in the spine (38%) and femoral
neck (19%). Regression analysis suggested that the highest cumulative
GC dose associated with no loss of bone was 5.6 g prednisone.
Bone Loss Studies and Inhaled GCs
In the United States, five inhaled GCs are approved for the
treatment of asthma: budesonide, beclomethasone dipropionate,
fluticasone propionate, flunisolide, and triamcinolone acetonide. With
regard to effects on bone metabolism, there are extensive clinical
trial data regarding budesonide and beclomethasone, but limited data
with regard to the short- or long-term effects of treatment with
fluticasone, flunisolide, or triamcinolone. As described above, the use
of inhaled GCs for the treatment of asthma has been strongly emphasized
in recent national and international guidelines. Recent evidence
suggests that although inhaled GCs are widely prescribed for the
long-term treatment of COPD, their long-term efficacy may be in
question.9
The safety of inhaled GCs has been examined by
observing changes in biochemical markers of bone metabolism (generally
over the short term) and BMD (generally longer-term studies).
Bone Metabolism Marker Studies and Inhaled GCs
In general, adverse effects observed during treatment with inhaled
GCs (as demonstrated by changes in bone metabolism markers and skeletal
effects [BMD]) are less severe than those caused by therapeutically
equivalent doses of oral GCs. Data supporting this observation are seen
in a number of studies. In healthy subjects, Hodsman et
al65
were one of the first groups to issue a safety
profile on differences between inhaled and oral GCs. Subjects were
randomly assigned to receive 40 mg/d oral prednisolone, 20 mg/d oral
prednisolone, 3.2 mg/d inhaled budesonide, 0.8 mg/d inhaled budesonide,
or placebo. High-dose prednisolone was associated with significantly
increased serum 1,25-dihydroxyvitamin D3
(p = 0.02), increased urinary calcium excretion (p = 0.07), and
significantly increased urinary hydroxyproline (p < 0.01). None of
these changes was associated with either high- or low-dose inhaled
budesonide treatment. The effect of inhaled GCs on other serum markers
of bone metabolism has also been well studied. In one of the first
double-blind, randomized studies to examine short-term differences
between inhaled GC regimens, Leech et al66
compared the
effects of 800 µg/d budesonide, 1,600 µg/d budesonide, 1,000 µg/d
beclomethasone, 2,000 µg/d beclomethasone, and placebo on serum
osteocalcin in 21 healthy premenopausal women. Serum osteocalcin was
lower (p value not stated) in subjects receiving 2,000 µg/d
beclomethasone, when compared with either 1,600 µg/d budesonide or
placebo. No difference in serum osteocalcin levels were seen when 800
µg/d budesonide, 1,000 µg/d beclomethasone, or placebo were
compared. Kerstjens et al67
also demonstrated no effect on
a bone formation serum marker (PICP) when patients were treated with
either 800 µg/d beclomethasone plus bronchodilator or placebo plus
bronchodilator for a more extended time period (2.5 years). Grove et
al68
treated nine healthy subjects with 800 µg/d
budesonide during week 1 and 1,600 µg/d budesonide during week 2, or
750 µg/d fluticasone during week 1 and 1,500 µg/d fluticasone
during week 2, in a crossover study (1-week washout between
treatments). Paradoxically, serum levels of carboxy terminal
telopeptide of type I collagen (ICTP, a bone resorption marker), but
not PICP, were significantly reduced (compared with baseline) during
budesonide treatment, but not during fluticasone treatment. Bootsma et
al69
also examined the effect of inhaled GC treatment on
bone metabolism in patients treated with 750 µg/d fluticasone or
1,500 µg/d beclomethasone for 6 weeks in a double-blind, randomized
study. While fluticasone did not alter serum markers of bone formation,
beclomethasone significantly decreased both osteocalcin and PICP.
Neither treatment regimen altered bone resorption as measured by ICTP
or deoxypyridinoline. In a double-blind study in 671 patients with
severe asthma, Ayres et al70
randomly assigned patients to
1.0 or 2.0 mg/d fluticasone propionate or 1.6 mg/d budesonide for 6
weeks. No significant differences between treatment groups at 6 weeks
(compared with baseline values) were seen for the following biochemical
markers of bone metabolism: serum calcium, osteocalcin, PICP, ICTP, or
urinary hydroxyproline. A disruption of collagen synthesis during
treatment with beclomethasone was also reported by Puolijoki et
al.71
In a 9-week study in postmenopausal asthmatic women
treated with 200, 1,000, or 2,000 µg/d beclomethasone, serum
propeptide of collagen type I was significantly decreased at dosages of
1,000 µg/d and 2,000 µg/d (p = 0.001).
BMD Studies With Inhaled GCs
Studies to determine the effects of inhaled GCs on bone mass have
also been reported for several of the inhaled GCs approved by the US
Food and Drug Administration.
Ip et al72
studied change in BMD in premenopausal female
and male asthma patients treated with inhaled GCs (mean beclomethasone
dosage, 1,100 µg/d for 40 months). Hip (femoral neck, -7.9%,
p = 0.007; Ward’s triangle, -13.1%, p = 0.016; and trochanter,
-6.6%, p = 0.034) and lumbar spine BMD (-6.6%, p = 0.041) were
significantly reduced in asthma patients receiving inhaled GCs when
compared with normal untreated control subjects. In female patients,
lumbar spine and trochanter BMD values were negatively correlated with
daily inhaled steroid dose (r = -0.47; p = 0.047). Herrala et
al73
also studied the effect of treatment with 1,000
µg/d beclomethasone on BMD. In contrast, after 1 year of inhaled GC
treatment, no differences were seen in BMD of either the lumbar spine
or proximal femur when asthma patients were compared with healthy,
age-matched subjects. Recently, Gagnon et al74
compared
the skeletal effects of high-dose (> 1,000 µg/d) vs low-dose
(< 500 µg/d) beclomethasone treatment in asthma patients. Although
serum osteocalcin levels were lower in patients receiving high-dose
treatment (p < 0.05), no differences between groups in BMD values
were observed. Lower serum osteocalcin levels in patients treated with
high-dose inhaled GCs were also confirmed by Boulet et
al.75
In a prospective study, 37 asthma patients receiving
high-dose beclomethasone or budesonide (mean dosage, 1,140 µg/d) for
> 18 months were compared with 37 asthma patients receiving low-dose
(mean dosage, 89 µg/d) beclomethasone or budesonide for the same time
period. Serum osteocalcin (p = 0.029) and urinary phosphorus
(p = 0.034) were significantly reduced in the high-dose treatment
group. No differences in BMD were observed, however. Bone loss
associated with inhaled GC treatment was measured by Wisniewski et
al76
in a study of 81 asthma patients (40% without
steroid exposure, 60% taking daily inhaled steroids [620 µg/d
beclomethasone] for an average of 7.8 years). Using multivariate
analysis, cumulative inhaled GC dose was associated with a reduction in
spine BMD equal to a 0.11 SD reduction per 1,000 µg
beclomethasone/d/yr. Similarly, Hanania et al77
confirmed
a dose-dependent reduction in BMD in patients treated with high-dose
beclomethasone. In an open, nonrandomized trial, 18 patients receiving
a mean dosage of 1,323 µg/d beclomethasone for 2 years were compared
with 18 nonsteroid-treated asthma patient control subjects. Mean serum
osteocalcin (p = 0.003) and femoral neck BMD (p = 0.0025) were
significantly reduced after 24 months of GC treatment, and these
reductions were positively correlated with increasing dose of
beclomethasone. Confirmation of bone loss was also suggested, but not
conclusively demonstrated, in a later trial conducted by Packe et
al.78
In a cross-sectional study, BMD was measured in
asthma patients treated with 800 µg/d budesonide for 1 year, 1,000
µg/d beclomethasone (mean = 3.0 years), or no GC treatment.
Unfortunately, most of the patients in the inhaled GC treatment groups
had previous exposure to oral GCs. Spine BMD values in both of the
inhaled GC treatment groups were similar, and were significantly lower
than in the non-GC control group (percent decrease not stated;
p < 0.01). In contrast, in a recent study, Luengo et
al79
measured BMD (at baseline and 2 years) in 48 asthma
patients treated with inhaled GCs (662 µg/d beclomethasone or
budesonide for a mean of 10.6 years), compared with 48 sex- and
age-matched control subjects. No correlation between either total daily
dose or cumulative dose and BMD was found. Although BMD significantly
decreased in both groups at the end of 2 years, no difference in bone
loss between groups was observed. Struijs and Mulder80
demonstrated treatment-related differences in bone metabolism and BMD
in a small 1-year study comparing beclomethasone 800 µg/d, budesonide
800 µg/d, and no inhaled GCs. Serum osteocalcin and PICP decreased
significantly in both inhaled GC groups, but serum ICTP significantly
increased in the beclomethasone group only. Further, BMD was
significantly decreased only in the beclomethasone treatment group
(1.1% spine, 1.7% hip; p < 0.05). Ebeling et al81
also studied BMD changes in patients receiving inhaled GCs
(beclomethasone or budesonide 1,500 µg/d) with or without a
previous history of treatment with oral GCs. Significant reductions in
lumbar spine and femoral neck BMD were observed in male and female
patients with a history of oral GC therapy (p < 0.01). A significant
reduction in lumbar spine BMD was seen in male patients without a
previous history of oral GC treatment (p < 0.01). Differences
between inhaled GCs were further demonstrated by Pauwels et
al.82
In a large, double-blind, randomized trial, they
compared the efficacy and safety of fluticasone propionate 250 µg/d
with beclomethasone dipropionate 500 µg/d in 306 asthma patients. No
significant between-group differences in serum cortisol, calcium and
hydroxyproline excretion, FEV1, and peak
expiratory flow rate were observed at any point in the study.
Serum osteocalcin levels increased over baseline in the fluticasone
treatment group (p < 0.001). BMD was significantly increased when
fluticasone treatment was compared with beclomethasone treatment
(spine, p = 0.05; femoral neck, p < 0.01; Ward’s triangle,
p = 0.01), and BMD of the spine and Ward’s triangle was
significantly improved over baseline in fluticasone-treated patients
(p < 0.0001 and p < 0.001, respectively). The safety of
flunisolide has been examined in a single, brief interim report by
Kaye.83
In a small, open-label study, safety was assessed
in 32 asthma patients who received 1,000 µg/d flunisolide for 1 year
compared with 22 untreated patients. After 1 year of follow-up, no
significant differences were seen between treatment groups in lumbar
spine or femoral neck BMD.
In summary, studies examining the long-term treatment of asthmatics
with inhaled GCs have yielded somewhat conflicting results because of
confounding variables such as prior or current use of oral GC therapy,
study design and population size, and vast differences in doses. The
threshold dose for adverse effects on bone metabolism may be distinct
for each inhaled GC. The long-term studies cited in this section
suggest dosages of 
800 to 1,200 µg/d beclomethasone, 800 to
1,000 µg/d budesonide, 750 µg/d fluticasone, and 1,000
µg/d flunisolide may have limited or no effect on bone metabolism
during chronic treatment. Long-term data for triamcinolone are not
available.
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Investigational Therapies for the Treatment of GC-Induced Osteoporosis |
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TOPAbstractIntroductionPathophysiology of GC-Induced...Measurement of Bone Metabolism...Bone Loss and Fracture...Investigational Therapies for...DiscussionSummaryReferences |
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1 year. Eight women were
concomitantly treated with HRT (0.625 mg conjugated estrogens for 25
days, 5 mg/d progesterone on days 15 to 25), while seven women did not
receive HRT. Seventeen age-matched women were randomly selected as
control subjects. BMD at the lumbar spine (measured using either dual
photon absorptiometry or DXA) increased significantly (4.1%) from
baseline at the end of 1 year in the HRT group, and decreased
significantly (-3.4%; p = 0.02) in the non-HRT group. The decrease
in BMD was highly correlated with the total cumulative dose of
prednisone (r = 0.759). Unfortunately, HRT has important side
effects, and patient withdrawal from therapy, primarily related to
concerns regarding the development of breast cancer or the resumption
of vaginal bleeding, may be as high as 81% within 3
years.89
Furthermore, recent data90
have
suggested that new users of HRT do not appear to have the
cardiovascular disease protection that has been formerly associated
with HRT therapy, while a significant increase in thromboembolic events
was still associated with HRT treatment (p = 0.004). Recently,
raloxifene, the first member of a new class of drugs (selective
estrogen receptor modulators, or SERMs) was approved in the United
States for the prevention of postmenopausal
osteoporosis.91
92
Raloxifene has been shown to produce
increases of 2.0% in lumbar spine BMD at 24 months (p < 0.01);
therapy with raloxifene has been associated with an increased incidence
of leg cramps, hot flushes, and a two- to threefold increase in the
risk of venous thromboembolic events.91
92
No data are
available on the use of raloxifene for GC-induced bone loss. Osteoporosis is also seen in men receiving chronic high-dose GC therapy. While the mechanism of GC-induced bone loss is presumably similar to that seen in women, a high percentage (up to 88%) of men in recent studies demonstrate GC-induced reductions in serum testosterone, which may contribute to the pathology of GC-induced bone loss.93 94 95 In a small study (n = 15), Reid et al96 assessed the effect of treatment with testosterone (250 mg/mo in a single depot injection for 12 months) to increase or maintain BMD in GC-treated asthmatic men in a random-drug-assignment, unblinded, 1-year trial. Testosterone therapy increased lumbar spine BMD by 5.0% (p = 0.005), and significantly decreased hydroxyproline and alkaline phosphatase serum levels (p < 0.02). Guidelines regarding the use of testosterone therapy in males for indications other than GC-induced bone loss have been published.97
Calcitonin
Intranasal (200 IU/d) and subcutaneous (100 IU/d) formulations of
calcitonin (an osteoclast-inhibiting polypeptide) have been approved in
the United States for the treatment of postmenopausal osteoporosis, but
their efficacy in reducing osteoporotic fractures has not been clearly
proven in large, prospective trials. Moreover, effects on BMD in
postmenopausal women are generally small (up to 2.0% during the first
year) and usually not significant at the hip and other
sites.98
The efficacy of nasal calcitonin for the
treatment of GC-induced bone loss was investigated in a small
population of severe persistent asthma patients treated concomitantly
with long-term GCs.99
In this study, 44 patients received
calcium 1 g/d and were randomly allocated to receive either nasal
calcitonin (200 IU, alternate days) or placebo for 2 years. At 2 years,
a small but significant gain in lumbar spine BMD was noted in the
calcitonin group (2.8%; p < 0.004), while the calcium-only group
showed a significant loss (-7.8%; p < 0.007) when compared with
baseline. Thirty-five percent of the calcitonin-treated patients
withdrew from therapy because of side effects (most commonly nausea and
allergic sensitivity), lack of compliance, and/or uncontrolled
asthma.99
The changes in BMD observed in this small study
are not consistent, however, with results obtained in other calcitonin
comparison studies,100
101
102
in which more modest changes
in lumbar spine BMD have been reported. A recent long-term study
completed in postmenopausal women with osteoporosis has confirmed very
modest gains in BMD (in the lumbar spine, 1.6% increase over 5 years)
with a significant reduction in vertebral fractures at the middle (200
IU/d) but not the highest dosage (400 IU/d).103
No
information regarding the effect of treatment with nasal calcitonin on
the rate of fractures in GC-treated patients is available.
Bisphosphonates
Bisphosphonates inhibit bone resorption by suppressing
osteoclast-mediated bone resorption. All bisphosphonates decrease bone
resorption, but they differ in their respective potencies. Etidronate,
the first bisphosphonate to be introduced for clinical use, is approved
in the United States for the treatment of Paget’s disease but not
osteoporosis. Alendronate, a more potent bisphosphonate, is approved
for the treatment and prevention of postmenopausal osteoporosis, the
treatment of Paget’s disease, and, very recently, the treatment of
GC-induced bone loss.
Etidronate:
Treatment with cyclic etidronate has been widely studied over
many years in relatively small GC-treated patient populations.
Thirty-nine patients with GC-induced bone loss (56% with obstructive
pulmonary disease) were enrolled in a prospective, 1-year, open-label,
unblinded study.104
Patients received either 500 mg/d
calcium or 4 cycles of intermittent (cyclic) etidronate therapy
followed by calcium 500 mg/d for 76 days. Because continuous, high-dose
etidronate is associated with bone mineralization defects such as
osteomalacia,105
cyclic treatment is utilized. When
compared with unusually large and significant losses in BMD in the
placebo-treated group, etidronate treatment significantly increased
spine BMD by 5.7% and total hip BMD by 6.8% (p < 0.001). Calcium
alone did not prevent significant losses of 3.4% and 4.1%,
respectively, at these sites. In an early study that was somewhat
larger but retrospective, Adachi et al106
examined 68
patients with GC-induced bone loss (25% with asthma). Thirty-five
patients received cyclic etidronate and 33 patients received no
treatment for osteoporosis. Etidronate treatment significantly
increased lumbar spine BMD 3.82% when compared with the 2-year value
of the control group (p < 0.001), but not when compared with
baseline. In a recent report, Pitt et al107
demonstrated
the efficacy of etidronate (400 mg, cyclic treatment) in a randomized,
2-year, placebo-controlled study of 49 GC-treated patients (taking 5 to
20 mg/d prednisone for > 6 months) with asthma (43% of total),
lupus, or polymyalgia rheumatica. Baseline BMD values showed that 61%
and 48% of all patients in this study met the World Health
Organization definition for osteoporosis ( 2.5 SD below the mean for
normal young adults) when measured at the hip and spine, respectively.
At the 2-year time point, the etidronate treatment group demonstrated a
significant increase (5.1%) in lumbar spine BMD when compared with
baseline (p < 0.05), while the placebo-treated group showed a
nonsignificant increase of 1.0%. The incidence of adverse events was
comparable in both groups. In a recent small study, Skingle et
al108
randomly assigned 55 GC-treated patients (16%
asthma patients) to either calcium alone or calcium plus cyclic
etidronate for 2 years. After 2 years, a significant difference
between groups (2.8% decrease in the calcium group, 4.7% increase in
calcium-plus-etidronate group; p = 0.04) was observed for lumbar
spine BMD, but not for femoral neck BMD. However, larger etidronate
studies conducted in more diverse patient populations report very
modest increases in BMD (approximately 3.0% at 12
months).109
110
In a recent, prospective, 1.5-year
study,111
GC-treated asthmatics ( 1.5 g/d
beclomethasone or budesonide) were randomly assigned to no supplemental
therapy, 1,000 mg/d calcium, or 1,000 mg/d calcium and cyclic
etidronate. At 18 months, the no-supplement group had a significant
loss in lumbar spine BMD (1.0%) when compared with baseline. Calcium
alone or calcium plus etidronate treatment significantly increased
lumbar spine BMD above baseline by 2.2% and 2.8%, respectively
(p < 0.05); the difference between these groups was not significant.
In the etidronate studies described in this section, etidronate was
generally judged to be safe and well tolerated.
Alendronate:
Recently, a large study (n = 477)
examining the use of alendronate for the treatment of GC-induced bone
loss was reported.112
In this study, significant increases
in lumbar spine BMD were seen in both 5- and 10-mg/d treatment groups
after 1 year of treatment (2.1 and 2.9%, respectively; p < 0.001
when compared with placebo). A subset of patients from these trials
(obstructive pulmonary disease with chronic GC treatment, n = 49) was
analyzed by McClung et al.113
In this analysis, percent
change from baseline in lumbar spine BMD was increased 1.9% and 3.7%
at 1 year in patients receiving alendronate 5% and 10 mg/d
(p < 0.001), respectively. These results compared favorably with
those described in the overall study population.112
In
these studies, alendronate was generally well tolerated. No serious
side effects were attributed to any treatment group; only a small
increase in nonserious upper GI mg/d side effects was seen in the
alendronate 10 mg/d group. Interestingly, placebo-treated women lost
bone mass (-0.6 ± 0.9%) in spite of concomitant estrogen
therapy.112
Among the postmenopausal women subgroup, 6 of
135 women (4.4%) receiving alendronate 5 mg/d or 10 mg/d reported at
least one vertebral fracture, compared with 7 of 54 women in the
placebo treatment group (13%; p = 0.026). This reduction was
consistent with similar statistically significant decreases seen in the
incidence of vertebral fractures in previous phase III
studies114
and in a large fracture intervention
trial.115
Alendronate is generally well tolerated, and
evidence from 6,457 patients in the combined studies of the Fracture
Intervention Trial116
indicates that the safety profile of
alendronate is comparable to that of placebo treatment. Recently, data
regarding the addition of alendronate therapy to HRT in women with
postmenopausal osteoporosis were presented. Lindsey et
al117
randomly assigned 428 postmenopausal women currently
receiving HRT (for a minimum of 1 year) to receive either alendronate
10 mg/d or placebo for a duration of 1 year. After 12 months of
treatment, the addition of alendronate to HRT significantly increased
lumbar spine BMD 2.6% above the mean for placebo/HRT treatment
(p < 0.001). No negative drug interactions were observed, and
combination therapy was well tolerated. Alendronate has very recently
been approved for the treatment of GC-induced bone loss.
Clodronate:
Clodronate is not approved for the
treatment of primary or secondary osteoporosis in the United States;
data describing the tolerability and efficacy of clodronate for the
treatment of GC-induced bone loss were recently obtained in a
randomized, placebo-controlled, 1-year trial118
examining
the effects of oral clodronate 800, 1600, or 2,400 mg/d in 74 asthma
patients with a history of long-term oral and inhaled GC use (mean
dosage, 8.3 mg/d prednisone). At 1 year, the clodronate 2,400-mg/d
treatment group demonstrated the largest gains in lumbar spine (3.0%;
p < 0.01), femoral neck (4.3%; p < 0.0001), and trochanter BMD
(2.8%; p < 0.02), while no changes were observed in the placebo
treatment group at any site. A trend test suggested a dose-response
relationship between clodronate treatment and increased lumbar spine
BMD (p < 0.02). The most common side effects reported were GI
disorders (35 to 42% in clodronate groups, 26% in placebo group).
Vitamin D and Calcium Supplementation
Recently, a panel of nutrition experts suggested a change in the
recommended intake of calcium for specific age
groups.119
This report suggested that adults 20 to
50 years of age take 1,000 mg/d calcium, while adults > 50 years old
should receive 1,200 mg/d calcium. The utility of vitamin D
(usually dosed at 400 to 800 IU) or its metabolites and/or calcium
supplementation for the treatment of GC-induced bone loss has been
recently reviewed.120
121
122
Although calcium and/or vitamin
D supplementation alone have been shown to attenuate bone loss, these
supplements do not increase bone mass in patients with
osteoporosis.96
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
Fluoride
Although sodium fluoride stimulates bone formation, thus
increasing trabecular mass and increasing BMD, the long-term safety of
fluoride is currently under debate,123
and fluoride
compounds are not approved for the treatment of either postmenopausal
or GC-induced osteoporosis in the United States. However, data on the
use of fluoride compounds for the prevention and/or treatment of
GC-induced bone loss have been reported. Guaydier-Souquieres et
al122
recently reported a small, randomized, double-
blind study in which 35 patients with severe persistent asthma
taking chronic GC treatment received either monofluorophosphate (MFP)
200 mg/d and calcium 1 g/d or calcium alone for 2 years. MFP-treated
patients demonstrated a significant increase in lumbar spine BMD
compared with the calcium-only treatment group (11 vs 1.0%;
p = 0.05). No statistical differences between the groups in fracture
rate or incidence of adverse experiences were seen. The most commonly
reported adverse effects were GI disorders and lower leg pain. Rizzoli
et al124
reported the results of a recently completed
18-month study in which 48 patients (44% pulmonary disease) were
treated with either MFP 26 mg/d and calcium 1 g/d or calcium alone.
Thirty-three patients were randomly assigned to double-blind therapy,
and the remaining 15 patients were followed in an open-label protocol.
At 18 months, a significant difference in lumbar spine BMD was observed
for MFP treatment (7.8%) vs calcium alone (3.6%; p < 0.02). In
this study, side effects were more commonly seen in the MFP-treated
group than in the control group. At 6, 12, and 18 months, GI discomfort
was recorded in 14, 8, and 15% of the control subjects and 62, 38, and
42% of the MFP-treated patients. No patients discontinued treatment
because of GI discomfort, however.
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Although a variety of agents for the treatment of GC-induced bone loss have been studied, only alendronate has received regulatory approval in the United States for the treatment of this disease. Treatment of secondary osteopenia or osteoporosis has largely been studied in cohorts of rheumatoid arthritis patients, and these trials have been thoroughly reviewed.23 24 25 In this article, we have purposely limited our review to those studies involving the treatment of GC-induced bone loss in patients with asthma and COPD. Although these trials are generally small in size and often retrospective or poorly controlled in design, the studies reviewed here involving primarily asthma patients are consistent with the results of previous larger studies in other patient populations receiving chronic GC therapy. In general, the specific safety and efficacy profile of each drug examined for the treatment of osteoporosis in asthma/COPD patients and reviewed here are consistent with larger clinical trials in nonasthma/COPD patients.
The following recommendations are relevant to the accurate and timely diagnosis of bone loss in GC-treated asthma and COPD patients. Attention to early diagnosis in patients at risk is of utmost importance because GC-induced bone loss may be prevented.
Evaluation of the Patient’s Current Steroid Therapy
Chronic use of GC therapy for the treatment of persistent asthma
and COPD (and other chronic inflammatory diseases) is an important risk
factor for the development of osteopenia and subsequent osteoporosis.
The minimal cumulative or daily dosage producing significant bone loss
has not been clearly established, but it has been suggested to be as
low as 6.0 mg/d oral prednisone or 1,000 µg/d inhaled
beclomethasone/budesonide for as few as 9 weeks. Alternate-day therapy
is not safer than daily therapy from the standpoint of bone loss.
Patient’s Osteoporosis Risk Factor Analysis
A detailed patient history and physical examination assessing
fractures, kyphosis, back pain, height loss, motor coordination (to
determine the risk of falls), and cumulative exposure to GC therapy
will determine the major risk factors for the presence of both primary
and secondary osteopenia/osteoporosis. Additional risk factors include
menopausal status, age, female gender, Asian ancestry, bilateral
oophorectomy, slight body build, tobacco and alcohol use, decreased
dietary calcium and vitamin D intake, irregular menstrual history
(< 4 menstrual cycles/yr or extreme physical activity resulting in
hypoestrogenemia, for example), history of infertility or impotence in
men, and family history of osteoporosis. Furthermore, a history of
chronic exposure to the following drugs may also predispose patients to
bone loss: anticonvulsants, thyroxin, lithium, heparin, methotrexate,
warfarin, and cyclosporin.
BMD
BMD (preferably in the lumbar spine or femoral neck) should be
determined in all patients currently receiving or expected to receive
long-term GC therapy. Patients who have received 7.5 mg/d oral
prednisone or 1.0 mg/d inhaled steroids (particularly
beclomethasone or budesonide) for > 6 months are clearly at risk for
bone loss,23
and DXA for the assessment of BMD is advised.
BMD analysis may also be prudent in patients who have important risk
factors (height loss, back pain, kyphosis, recent fracture) and are
receiving shorter courses of oral or inhaled GC treatment. Preferably,
BMD should be measured before or shortly after the
initiation of chronic GC therapy. BMD is accurately and precisely
measured using DXA, and this procedure is now reimbursed by
Medicare.55
To reduce variation between scans and to
ensure the highest accuracy and precision for BMD measurement, bone
scans should be repeated using the same instrument and technician, if
possible.
Laboratory Tests
Routine laboratory tests should be utilized along with additional
tests to assess bone metabolism and calcium excretion to rule out other
causes of osteoporosis. These tests should include the following: CBC
count, erythrocyte sedimentation rate, serum electrolytes, calcium,
phosphorus, alkaline phosphatase, 25-hydroxyvitamin D,
1,25-dihydroxyvitamin D, creatinine, 24-h total urine calcium, and free
serum testosterone in male patients. Specialized assays such as serum
and urine markers of bone metabolism (bone-specific alkaline
phosphatase, osteocalcin, and urinary N-telopeptide crosslinks
excretion) may also be required to rule out bone diseases other than
osteoporosis or to estimate the rate of bone turnover. For example,
serum protein electrophoreses may be required to rule out the
possibility of multiple myeloma, which may cause significant bone loss.
Treatment
Attempts to reduce the risk of bone loss through the use of the
lowest effective oral/inhaled GC dose and the optimal use of
alternative non-GC anti-inflammatory drugs are important. Guidelines
for the treatment of GC-induced bone loss in rheumatoid arthritis
patients have been published.23
Lifestyle modifications
that should be instituted to reduce other risk factors include smoking
cessation, reduced alcohol intake, weight-bearing exercise for 30 to 60
qd, calcium and vitamin D intake, and education for the prevention of
falls. Pharmacologic intervention depends on current BMD values, the
presence or absence of an osteoporotic fracture, the rate of bone loss,
age, sex, and current and future steroid requirements. Treatment
recommendations are briefly summarized below.
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Footnotes |
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Drs. Goldstein and Fallon received no funding from Merck & Co. Inc. for the production of this manuscript; Dr. Harning is a current employee of Merck & Co. Inc.
Received for publication March 11, 1999. Accepted for publication July 15, 1999.
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