Bone mineral density in women with asthma on long-term inhaled corticosteroid therapy

Bone mineral density in women with asthma on long-term inhaled corticosteroid therapy Savithri B Bonala, MD*; Byra M Reddy, MD*; Bernard A Silverman, MD*; Clifford W Bassett, MD*; Yalamanchili A K Rao, MD*; Sreenivasrao Amara, MD*; and Arlene T Schneider, MD*

Background: Inhaled corticosteroids (ICS) have become first line agents in the management of moderate-to-severe asthma. Long-term use of ICS is associated with decreased bone mineral density (BMD). Objective: To investigate the prevalence of BMD loss and its severity in women with asthma on long-term ICS. Methods: Fifty-six women with asthma on long-term ICS, attending an inner-city allergy clinic were selected to undergo bone densitometry in order to evaluate the association between BMD and the long-term use of ICS at different dose ranges. Results: Women (60.7%) had decreased BMD either at the lumbar spine or hip region. Among postmenopausal women, 17.1% of those ⬍65 years and 42.9% of those ⱖ65 years had osteoporosis compared with 5.7% (95% CI–3.9% to 8.5%) of those ⬍65 and 29.3% (95% CI–25.7%–33.5%) of those ⱖ65 years reported in the NHANES III survey.1 The prevalence of low BMD increased as ICS dose increased from 5% in the low dose group to 50% in the high dose group (P ⬍ .002). There were significant linear trends of decline by dose in mean BMD for the hip (P ⬍ .001) and the lumbar spine (P ⬍ .002). Women who received medium or high doses of ICS had significantly greater bone loss than those receiving low doses. Conclusion: The findings of increasing BMD loss with increasing ICS dose reinforce the necessity to monitor BMD periodically in women on ICS, particularly in the high risk postmenopausal group and those on medium to high doses. There should be a concurrent continual attempt to lower the dose by supplemental nonsteroidal controller medications and providing nutritional and pharmacologic treatment of identified BMD loss in these patients. Ann Allergy Asthma Immunol 2000;85:495–500.

INTRODUCTION Inhaled corticosteroids (ICS) are the mainstay in the treatment of chronic asthma.2–9 They offer an advantage over systemic corticosteroids due to their relatively minimal side effects. Osteoporosis is a known side effect of chronic corticosteroid use, but the effect of long-term use of ICS on BMD is largely uncertain. Inhaled corticosteroids have been shown to exert dosedependent adverse effects on a number of metabolic indices that signify increased bone resorption or decreased

* The Department of Allergy and Immunology, The Long Island College Hospital, Brooklyn, New York. Received for publication December 29, 1999. Accepted for publication in revised form May 1, 2000.

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bone formation,10 –14 and several crosssectional surveys of asthmatic adults receiving ICS therapy have observed a reduction in BMD in comparison to untreated subjects.15,16 These observations have led to concern among clinicians. To date, however, these crosssectional surveys have shown conflicting results.15–18 Where a significant reduction in BMD has been observed, the causal role of the ICS therapy remains unclear because of uncertainties about the documentation of the potentially confounding effects of past or current systemic corticosteroid use. It remains to be established whether low-dose ICS is associated with a lower prevalence and severity of BMD loss than high or medium dose. We examined these relationships in a survey of BMD in a group of women

with asthma attending an allergy clinic. The primary aim of the study was to determine whether the dose of ICS has a discernible relationship to the prevalence of decreased BMD. The secondary aims were to determine the severity of BMD loss across various dose ranges and to define whether post-menopausal women are particularly at risk. MATERIAL AND METHODS Fifty-six women with an established diagnosis of asthma by history, physical examination, and spirometry were selected from an allergy clinic of an academic inner-city hospital, based upon use of ICS continuously for a minimum of 3 or more years. Subjects who received more than three short (ⱕ2 weeks) courses of systemic corticosteroids per year over the last 3 years were excluded from the study. All subjects had bone densitometry done at the lumbar spine and hip regions by means of dual energy X-ray absorptiometry, using the Hologic QDR 4500 A densitometer. The definitions of osteoporosis and osteopenia are based on comparisons of any given patient’s measured bone density to the mean peak bone density of young healthy adults, usually expressed as the T-score.19 A T-score of less than ⫺2.5 indicates osteoporosis, ⫺1 to ⫺2.5 denotes osteopenia and more than ⫺1 signifies normal BMD. Data on duration, usage, and dose of ICS was collected by reviewing medical records. Inhaled corticosteroids dose was classified into high, medium, and low dose categories based on the 1997 National Heart, Lung, and Blood Institute guidelines as shown in Table 1. Cumulative doses were not calculated due to lack of bioequivalence on a microgram per microgram basis of

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Table 1. Estimated Comparative Dosages for Inhaled Corticosteroids2 Inhaled Corticosteroids (␮g) Beclomethasone propionate Triamcinolone acetonide Flunisolide Fluticasone propionate

High Dose

Medium Dose

Low Dose

⬎840 ⬎2000 ⬎2000 ⬎660

504–840 1000–2000 1000–2000 264–660

168–504 400–1000 500–1000 88–264

the various inhaled corticosteroids used. Since all patients were adherent to regular clinic attendance and reported adherence to medications, we can assume a minimal 3-year exposure to the dose ranges reported for each individual. All women had used nasal steroids at one time or another in the past, but not on a regular basis. Women with cessation of menstruation for more than 1 year were included in the postmenopausal group and the rest were grouped under premenopausal. None of the patients in the study group had history of a bone fracture. STATISTICAL ANALYSIS Differences in discrete variables were evaluated by using an exact trend test, which accounted for the ranking in categories of dose from low to high. Differences in age were assessed by oneway analysis of variance. Actual bone loss was compared for the hip and spine simultaneously using multivariate analysis of variance. In the models, bone loss was the outcome, dose of ICS the predictor, and age, hormone

replacement therapy, bursts of systemic steroids, calcium supplementation, and race, or ethnicity, the covariates. Several models were examined using different combinations of covariates and using both absolute and standardized measures of bone loss as outcome measures. Models were tested for homogeneity of variances and for outliers by examining residuals. We also analyzed, separately, the group of postmenopausal women with 2 or fewer bursts. The adjusted mean BMD are least square estimates and equal the value that would be expected for a balanced design including the independent variables in the model with continuous variables evaluated at their mean levels. Differences were considered statistically significant when P ⬍ .05. RESULTS Relevant demographic characteristics are summarized in Table 2. None of these were significantly different among the three dosage groups. As expected women with higher doses had more bursts of systemic steroids (P ⬍

Table 2. Demographic Characteristics of Study Population Dose Range of Inhaled Corticosteroids Characteristic

Mean age (⫾SD) in years Menopausal status Post Pre Race: Hispanic Blacks Others Ca⫹⫹ Supplement HRT* Systemic steroids bursts/year: 0–2 ⬎2

Medium n ⴝ 25

Low n ⴝ 19

54.8 (⫾11.0)

52.2 (⫾10.2)

53.8 (⫾10.3)

.76

10 2

(83.3%) (16.7%)

18 7

(72.0%) (28.0%)

14 5

(73.7%) (26.3%)

.68

8 4 0 6 3

(66.7%) (33.3%) (50.0%) (25.0%)

14 9 2 9 4

(56.0%) (36.0%) (8.0%) (36.0%) (16.0%)

15 3 1 9 4

(78.9%) (15.8%) (5.3%) (47.4%) (21.1%)

5 7

(41.7%) (58.3%)

20 5

(80.0%) (20.0%)

17 2

(89.5%) (10.5%)

* HRT ⫽ hormone replacement therapy.

496

P Value

High n ⴝ 12

.64 .99 .99 .01

.01). Women (60.7%) had decreased BMD either at the lumbar spine or hip region. Among postmenopausal women, 17.1% of those ⬍65 years had osteoporosis as opposed to 42.9% of those ⱖ65 years. This compares to 5.7% (95% CI–3.9% to 8.5%) in a national sample of estrogen deficient women under 65 years and 29.3% (95% CI–25.7%–33.5%) in such women 65 years and over reported in the NHANES III survey. Among our postmenopausal women on ICS, these findings are even more striking, in that our population is primarily Hispanic, a group that had a lower prevalence of decreased BMD as compared with non-Hispanics in the NHANES III survey. Table 3 shows the prevalence of loss of BMD by drug dose level. The prevalence of BMD loss increased as drug dose increased from 5% in the low dose group to 50% in the high dose group (P ⬍ .0002). Table 4 shows mean BMD by ICS dose for several demographic subgroups. Mean BMD was consistently lower among patients receiving high doses of ICS in almost every group; however, differences for African Americans and premenopausal women did not reach statistical significance. Table 5 shows estimated mean BMD by dosage level adjusted for age and race. There were significant linear trends of decline in mean BMD for the hip (P ⬍ .001) and the lumbar spine (P ⬍ .002). The mean BMD was higher at both lumbar spine and hip regions in low-dose group women compared to medium or high-dose groups after adjustment for age and race. Similar results were found in models that adjusted for hormone replacement therapy, calcium supplementation and menopausal status (data not shown). A significant linear decline in mean BMD was still found when the models were limited to the 36 postmenopausal women with 2 or fewer bursts of oral steroids. In every model, women who received medium or high doses of ICS had significantly greater bone loss than those receiving low doses.

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Table 3. Prevalence of Decrease in BMD by ICS Dose Level Dose Range

Osteoporosis %

Osteopenia %

Normal %

Low n ⫽ 19 Medium n ⫽ 25 High n ⫽ 12 Total n ⫽ 56

5.3 8.0 50.0 16.1

36.8 56.0 33.3 44.6

57.9 36.0 16.7 39.3

P Value* .002

* P value refers to all groups simultaneously and indicates a significant increasing trend in the prevalence of low BMD by level of ICS dose. Table 4. Mean Bone Mineral Density with Demographic Characteristics Mean Bone Mineral Density (g/cm2) Characteristic ICS Dose* Race Hispanic/white (n ⫽ 39) Blacks Age ⬍65 Years (n ⫽ 49) ⱖ65 Years (n ⫽ 7) Menopausal status Pre (n ⫽ 14) Post (n ⫽ 42) HRT No (n ⫽ 45) Yes (n ⫽ 11) Ca⫹⫹ supplement Yes (n ⫽ 32) No (n ⫽ 24)

Spine

Hip

L

M

H

P Value

L

M

H

P Value

1.03 1.10

0.91 0.99

0.82 0.98

0.01 0.31

1.02 1.16

0.84 0.96

0.80 0.88

.01 .12

1.02 1.21

0.96 0.81

0.89 0.75

0.05 0.01

1.04 1.10

0.91 0.73

0.87 0.63

.01 .04

1.00 1.05

0.99 0.92

1.04 0.84

0.66 0.01

1.05 1.04

0.94 0.87

0.93 0.80

.22 .01

1.05 1.00

0.94 0.96

0.91 0.76

0.02 0.02

1.06 0.98

0.89 0.92

0.85 0.77

.01 .08

1.09 0.97

0.95 0.93

0.91 0.82

0.03 0.03

1.08 1.00

0.90 0.88

0.85 0.80

.02 .01

* ICS dose: L ⫽ low, M ⫽ medium, H ⫽ high, and HRT ⫽ hormone replacement therapy. Table 5. Estimated Mean BMD by dosage level adjusted for Age and Race Mean Bone Mineral Density ICS Dose Low (n ⫽ 19) Medium (n ⫽ 25) High (n ⫽ 12)

Hip P < .001

Spine P < .002

1.08 0.94 0.85

1.05 0.96 0.90

DISCUSSION Corticosteroids influence both bone formation and bone resorption.20,21 The enhanced resorption is likely explained by both the development of secondary hyperparathyroidism and a direct effect on bone.20 The development of secondary hyperparathyroidism may be the result of reduced intestinal absorption and increased renal loss of calcium. Corticosteroids inhibit secretion of sex hormones including estrogen and testosterone contributing to further bone loss.22 The main bone ef-

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SE 0.04 0.05 0.04

fect of corticosteroids is a diminished amount of new bone formed. This reduced bone formation is attributed to a direct effect on osteoblast function and has been well documented in both biochemical and histomorphometric studies.20,23,24 A variety of factors are potential confounders to the accurate assessment of long-term ICS effects on bone. These factors include sex, age, menopausal status, gonadal status, smoking history, alcohol and calcium intake, exercise status, body mass index, concurrent

medications (corticosteroid rescue therapy, thiazide diuretics, anticonvulsants, estrogens), adherence to medications, and concurrent diseases.25 Severe asthma itself may affect BMD because of patient’s life style changes, such as decreased exercise tolerance and possible dietary restrictions. The bone effects of corticosteroids can be evaluated by measurement of biochemical markers of metabolism (both bone formation and degradation), BMD, or frequency of fractures. Bone turnover markers have varying degrees of sensitivity and specificity that differ among different assays. No single marker has been validated as a reliable and predictable guide to the extent of bone formation or resorption; the significance of some markers is also unclear.26,27 Bone mineral density measurement provides direct measures of skeletal health, which have been shown to correlate with fracture risk.28 The most commonly used and best validated technique for BMD measurement of cortical or trabecular bone in central sites is dual energy X-ray absorptiometry. Dual X-ray absorptiometry has been used both in population screening and individual fracture risk assessment. Bone mineral density likely predicts fracture with approximately the same power that blood pressure predicts stroke; a decrease in BMD of 1 SD below the population norm is associated with a 1.4 to 3.5 fold increase in fracture.29 Corticosteroid-induced BMD loss is expected to be more pronounced in trabecular bone rich sites like ribs and vertebrae.16,30 One study suggests that measurement of BMD at the hip may be preferable to that at the lumbar spine, which might be falsely increased by osteophyte and aortic calcification.16 We, therefore, considered BMD at both hip and the lumbar spine. Our data suggest an increased prevalence of BMD loss by drug dose level, as well as a declining linear trend in BMD loss by absolute dose. Mean BMD was consistently lower among patients receiving high doses of ICS in almost every demographic subgroup. Previously, there had been only

497

a suggestion that a linear trend in bone mineral loss exists in postmenopausal women.14,15,31 In our study none of the women were treated with multiple or prolonged courses of oral steroids. It is an unlikely possibility that one or two sporadic doses of oral corticosteroid played a major role in reduction of BMD. The role of nasal corticosteroid contributing to the reduction of BMD could not be accurately assessed, but it is probably minimal, because none of our patients used nasal corticosteroid on a regular basis. Because of the small sample size and lack of a comparable control group in the present study, we are not able to rule out the role of other confounding factors in BMD loss (see above) beyond chance. It is also possible that women with greater BMD loss have more severe asthma and are more likely to be placed on high dose ICS. If this were the case, the higher dosage could in part be the effect rather than the cause of greater bone loss. Longitudinal cohort studies and randomized trials will be needed to clarify these issues. It is not known whether the apparent decrease in BMD is self limited or progressive, because serial measurements of BMD have not been undertaken in this study. Several other investigators have demonstrated significant reduction in BMD with long-term use of ICS.32–37 Marystone et al38 in their large longitudinal controlled trial showed that both men and women who used low dose inhaled corticosteroids had BMD intermediate between those of the never users and those of the oral corticosteroid users. Hanania et al32 in their controlled trial showed that the regular use of conventional doses of inhaled corticosteroids by patients with asthma could suppress adrenal function and decrease BMD in a dose related fashion. Ip et al39 studied BMD by dual energy X-ray absorptiometry in controls and 30 asthmatics who received ICS and showed a significant decrease in BMD at the hip and lumbar spine mainly in asthmatic women. Some recent prospective comparative or placebo controlled studies did

498

not show significant reduction of BMD with the use of ICS.40 – 46 Martinati et al40 studied 64 prepubertal children with mild-to-moderate asthma treated with either beclomethasone dipropionate 150 to 600 ␮g/day or cromolyn sodium 30 mg/day (control group) for 6.7 ⫾ 1.3 months. They found no significant difference in bone mineral areal density and volume bone density in both groups. Agertoft et al41 conducted a cross-sectional study of 157 asthmatic children aged 5 to 16 years treated with budesonide for ⱖ3 years and 111 matched controls. Both groups were observed for 3 to 6 years. No statistically significant differences were found between the groups in BMD, bone mineral capacity, total bone calcium, or body composition. In another cross sectional study of 81 asthmatics aged 20 to 40 years, Wisniewski et al42 compared those who had never taken ICS or systemic corticosteroids with subjects who had taken ICS ⱖ5 years with limited exposure to systemic corticosteroids in the past. They found no significant difference in mean BMD values between those who were and those who were not taking ICS, in men or women. Luengo et al43 studied 48 asthmatic adults with mean age of 56 years taking a mean daily dose of 662 ⫾ 278 ␮cg of ICS for ⬎1 year and followed them for a 2-year period with a spacer attached to their inhalers. The group was compared with subjects who had never taken ICS. They concluded that BMD was reduced at 2 years in both ICStreated asthmatics and patients in control group. No correlation was found between BMD values and ICS doses or the duration of ICS treatment. Most of these studies included either children or mixed groups of patients of different sexes and ages, and many excluded individuals older than 50 years or postmenopausal women to avoid confounding influence of age and menopause status on bone loss. In summary, our data indicate that long-term use of inhaled corticosteroids by postmenopausal women with asthma results in an increased prevalence of BMD loss and a linear declin-

ing trend in mean BMD by drug dose level. We did not compare our patients to an age and ethnicity matched control population, and no significant age or ethnicity differences were observed in the various dosage groups examined. Adjustment was made for age and ethnicity in our analysis of mean BMD data; therefore, the observed trend of increased BMD loss with increased dose of ICS appears to be a real phenomenon within our population. A similar trend in premenopausal women, though not statistically significant, needs further evaluation. It must be emphasized that ICS are potent anti-inflammatory agents available to treat asthma2 and our findings should not deter clinicians from prescribing them when indicated. The use of ICS in asthma has brought great advancement in the overall control of the disease and has allowed a dramatic decrease in need for systemic corticosteroids, which have many more serious adverse effects, including severe osteoporosis. It stands to reason that the benefits of ICS outweigh the potential risk in the vast majority of patients. The recognition of this potential risk of ICS in high-risk group patients is important so that proper monitoring and therapeutic intervention may be instituted. Identification and management of osteoporosis is essential in any patients receiving long-term, highdose inhaled or systemic corticosteroid therapy. The dose of ICS should be titrated individually to the lowest necessary for disease control by utilizing appropriate adjunctive medications such as leukotriene modifiers, long acting beta2-agonists, theophyllines, nedocromil, and cromolyn.47–52 These patients should be offered vitamin D and calcium with or without inhibitors of bone resorption53–56 and encouraged to exercise and modify their life style. ACKNOWLEDGEMENT We would like to thank Dr Joseph Feldman, SUNY Brooklyn, for statistical assistance.

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Request for reprints should be addressed to: Bernard A Silverman, MD Department of Allergy and Immunology 339 Hicks Street, Brooklyn, NY 11201 email: [email protected]

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