Published ahead of print on January 7, 2004, doi:10.1164/rccm.200307-926OC
© 2004 American Thoracic Society
Fracture Risk Associated with Inhaled Corticosteroid Use in Chronic Obstructive Pulmonary DiseaseMidwest Center for Health Services and Policy Research, Hines VA Hospital, Hines; Center for Healthcare Studies, Division of General Internal Medicine, and the Department of Medicine, Feinberg School of Medicine, Northwestern University; and Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois Correspondence and requests for reprints should be addressed to Todd A. Lee, Pharm.D., Ph.D., Midwest Center for Health Services and Policy Research, Hines VA Hospital, P.O. Box 5000 (151-H), Hines, IL 60141. E-mail: lee{at}research.hines.med.va.gov
Patients with chronic obstructive pulmonary disease (COPD) are frequently treated with inhaled corticosteroids (ICS). However, the impact of ICS use on fracture risk remains unclear in these patients. This nested case–control study examines the association between ICS use and nonvertebral fractures in Veterans Affairs patients with COPD. From a cohort of 40,157 patients with a COPD diagnosis between October 1, 1998 and September 30, 1999, and that used services in the preceding 12-month period but did not have a COPD diagnosis, 1,708 cases with nonvertebral fractures were identified and matched to 6,817 control patients. Patients were 94% male, and average age was 62.7 years. ICS exposure was identified through prescription records and converted to beclamethasone equivalents. In conditional logistic regression models, exposure to ICS at any time during follow-up was not associated with an increased fracture risk (adjusted odds ratio = 0.97; 95% confidence interval, 0.84–1.11). However, current high-dose ICS users (  700 µg per day) had an increased risk of fractures compared with patients with no exposure (adjusted odds ratio = 1.68; 95% confidence interval, 1.10–2.57). In patients with COPD, current use of high-dose ICS was associated with an increased risk of nonvertebral fractures.
Key Words: inhaled corticosteroids • pharmacoepidemiology • chronic obstructive pulmonary disease • nested case–control studies • fractures The role of inhaled corticosteroids (ICS) in the treatment of chronic obstructive pulmonary disease (COPD) continues to evolve. A large proportion of patients with COPD are being treated with ICS (1). Guidelines for the pharmacological management of COPD recommend ICS for patients with moderate to severe disease who have a symptomatic or physiologic response to a trial of the medications (2–7). Concomitant with the increased use of ICS in patients with COPD, there is concern that users may be at an increased risk for fractures due to the harmful effects of steroids on bone. Systemic corticosteroids have long been linked to decreases in bone mineral density, and a recent epidemiologic study showed an association between systemic corticosteroids and fractures (8). The inhaled form is intended to deliver medication directly to the site of action and limit the systemic effects of the drugs. However, studies have shown that ICS have negative effects on biochemical markers of bone turnover (9). Studies of the association between ICS and fractures have been less conclusive—showing both an increased risk (10, 11) and no risk (12, 13) associated with ICS use and fractures. These analyses did not focus solely on patients with COPD. Assessing the risk of fractures in ICS users with COPD is particularly important because these patients are at an increased risk of fractures independent of their use of ICS (14–16). Patients with COPD may have a number of risk factors, including a history of smoking, sedentary lifestyle, and systemic corticosteroid use, that contribute to the development of osteoporosis, thereby increasing their risk of fractures. Because patients with COPD are at an increased risk of fractures, it is important to determine if ICS use modifies the magnitude of the risk. The purpose of this study is to examine the association between nonvertebral fractures in patients with COPD and the use of ICS in the Veterans Affairs population. Some of the results of this study have been reported previously in the form of abstracts (17, 18).
(See the online supplement for further details on METHODS.) We conducted a nested case–control study in a cohort of Veterans Affairs patients with COPD. Veterans Affairs inpatient, outpatient, pharmacy, and beneficiary databases were used (see online supplement for details). The research was approved by the institutional review boards of the Hines VA Hospital and Northwestern University. Patients were included in the cohort if they had a new diagnosis of COPD (491.x, 492.x, 496) between October 1, 1998 and September 30, 1999, did not fill a respiratory-related medication (Table E1 in the online supplement) or had a fracture in the 90 days after October 1, 1998, and filled at least one prescription for a respiratory-related medication during their follow-up period (see online supplement for additional details on cohort eligibility). Cases were patients with diagnosis or procedure codes for nonvertebral fractures (Table E2 in the online supplement) occurring after their initial COPD diagnosis date and before September 30, 2002. Fractures occurring within 14 days of a diagnosis code for an injury related to a motor vehicle accident were not included. The index date for cases was the date of their first nonvertebral fracture. Control patients were selected from the eligible cohort of patients without a nonvertebral fracture. Control patients were individually matched to cases (4:1) on date of COPD diagnosis, age, and sex and were assigned the index date of their matched case.
ICS exposure was determined from prescriptions dispensed between COPD diagnosis date and index date. Doses were converted to beclomethasone equivalents (19), and cumulative exposure was calculated. The average daily dose was calculated for each patient and categorized into low (< 300 µg per day), medium (300–699 µg per day), and high doses ( Additional covariates measured were factors associated with fractures and/or ICS use. Exposure to both systemic and topical steroids was measured during the follow-up period. We determined if patients filled prescriptions for the following medications: anticonvulsants, methotrexate, thiazide diuretics, anxiolytics, antipsychotics, antidepressants, anti-Parkinson medications, hormone replacement therapy, bisphosphonates, and vitamin D. Patients were classified with the following comorbidities if they had at least two visits with a diagnosis code for the condition: osteoporosis, osteopenia, diabetes, anemia, depression, dementia, psychoses, rheumatoid arthritis, Cushing's syndrome, hyperparathyroidism, inflammatory bowel disease, congestive heart failure, stroke, back pain, seizures, and a history of falls. Conditional logistic regression was used to assess the association between ICS exposure and the risk of nonvertebral fracture in patients with COPD (STATA, version 8; College Station, TX) (20). Odds ratios (ORs) and 95% confidence intervals (CI) were used to quantify the risk of fractures in unadjusted and adjusted models. Adjusted models controlled for exposure to other medications (including oral corticosteroids), comorbidities, and the number of hospitalizations. Separate ORs were estimated for any exposure during follow-up, recency of exposure, dose of exposure, and the interaction between recency of exposure and dose. Sensitivty analyses were conducted related to impact of oral corticosteroids, duration of follow-up time, and dose category definitions.
A total of 40,157 patients were included in the COPD cohort (Figure E1 in the online supplement). From the cohort, a total of 1,708 cases were matched to 6,817 control patients. We were unable to match four control patients to nine cases, and these cases have either two or three matched control patients. The population was predominantly male (cases = 94.4%, control patients = 94.6%), and the average age was 62.7 years (SD = 12.4) in both cases and control patients (Table 1). The average follow-up time was nearly 1.75 years (637 days in cases and 635 days in control patients).
A total of 21.4% of cases were exposed to ICS during the follow-up period, whereas 22.1% of control patients were exposed (Table 2). Slightly more cases were exposed within 30 days (5.7% cases vs. 4.5% control patients) and 90 days (11.3% cases vs. 9.7% control patients) of their index date. When categorized by average daily dose (11), a higher proportion of cases were in the high-dose category (6.3 vs. 5.2%). The average daily dose was 156.7 µg in the cases and 137.9 µg in the control patients. In addition, a higher proportion of cases were exposed to oral corticosteroids during the follow-up period (21.3 vs. 16.8%), and the average cumulative exposure was also higher in the cases (314 vs. 192 mg).
The case patients had more annual COPD hospitalizations over the follow-up period than the control patients, whereas the COPD-related outpatient visits were similar between the groups (Table 3). A larger proportion of cases had more than one COPD-related hospitalization annually than the control patients (4.9 vs. 3.3%, p = 0.002). The higher number of annual hospitalizations in the case group led to more COPD-related hospital days in the cases. However, the annual COPD-related outpatient utilization was similar between the two groups, with 75.2% of the cases and 76.5% of the control patients averaging less than one visit per year (p = 0.24).
Exposure to ICS during the follow-up period was not associated with an increased risk of fractures in the unadjusted analysis (OR = 0.96; 95% CI, 0.84–1.09) (Table 4). Adjustment for potentially confounding variables did not impact the risk of fracture (OR = 0.97; 95% CI, 0.84–1.11). When the recency of exposure was considered (current users), the risk of nonvertebral fractures was increased in exposed patients. In those exposed to ICS within 30 days of their index date, the OR was 1.29 (95% CI, 1.02–1.64) in the unadjusted analysis and decreased to 1.20 with a 95% CI that includes one (95% CI, 0.94–1.54) when controlling for potential confounders.
In addition to increases in risk associated with the recency of exposure, the risk of nonvertebral fractures was also related to the dose of ICS. Patients receiving the highest average daily dose were at an increased fracture risk. The risk of fracture was not increased in patients in the two lowest-dose categories (Table 4). However, those exposed to an average of 700 µg per day or more had an increased risk of nonvertebral fractures (OR = 1.20; 95% CI, 0.95–1.52). Further analyses indicated an interaction between current use and average daily dose. Patients classified as current users with exposure to ICS at high daily doses were at the highest risk for nonvertebral fractures (Figure 1). The risk of nonvertebral fracture in this group was high in both the unadjusted (OR = 1.71; 95% CI, 1.14–2.56) and adjusted (OR = 1.68; 95% CI, 1.10–2.57) analyses. In the highest-dose category, the average daily dose was 1,616 µg per day (SD = 917) in the cases and 1,469 µg per day (SD = 944) in the control patients.
Several additional analyses were conducted to test the robustness of the primary findings. Details on the findings from these can be found in the online supplement. The risk of fracture associated with current, high-dose use of ICS was consistent regardless of how oral corticosteroid use was categorized (Table E3 in the online supplement). The recency or cumulative dose of oral corticosteroid exposure did not modify the risk of fractures associated with ICS exposure. In addition, the risk of fractures was similar in these patients when the analysis was restricted to patients not exposed to oral corticosteroids during the follow-up period (adjusted OR = 1.55). An analysis was performed that was restricted to patients with at least 2 years of follow-up time. Patients with current and recent exposure had increased risks of fractures (current user OR = 1.48 [95% CI, 1.03–2.14]; recent user OR = 1.50 [95% CI, 1.15–1.96]) (Table E4 in the online supplement). The OR in current users of high doses was 2.45 (95% CI, 1.42–4.22), whereas the ORs in the other categories were consistent with no marked increase in the risk of fractures. To test the impact of drug categorization, drug dosings were recategorized according to National Asthma Education and Prevention Program criteria. In this analysis, the OR in current users of high doses was 1.75 (95% CI, 1.09–2.82), whereas the ORs in the other categories were consistent with no increase in the risk of fractures.
The objective of this study was to determine if ICS are associated with an increased risk of fractures in patients with COPD. The results of the analysis indicate that when comparing patients ever exposed to ICS during the follow-up period with those not exposed, there is no increase in the risk of fractures associated with exposure. However, the risk of fractures does appear to be impacted by recent exposure and the average daily dose. Patients who were currently using ICS at average doses greater than 700 µg beclomethasone equivalents per day had a slight increase in the risk of fracture compared with patients with COPD who never used ICS. The relation between an increased risk of fractures associated with recent use of high average daily doses observed in this analysis is consistent with findings in oral corticosteroid studies (8, 21). An early increase in the risk of fractures was associated with patients using the highest daily doses of oral corticosteroids. However, a metaanalysis of the association between corticosteroid use and osteoporosis indicated that cumulative dose had a stronger relation to decreased bone mineral density than did average daily dose (22). As pointed out by van Staa and coworkers (22), a potential explanation of these findings is that the association between corticosteroids and osteoporosis and fractures may be working through two mechanisms. Changes in bone mineral density associated with chronic exposure to corticosteroids may be due to increased bone resorption at the cellular level, which is impacted by long-term exposure to corticosteroids (22, 23). The mechanism associated with short-term impact of corticosteroids on fractures may result from increased osteocyte apoptosis (24). Manolagas (24) speculated that osteocyte apoptosis could lead to an increase in the risk of fracture due to a short-term reduction in bone quality. Thus, the impact of corticosteroids on fractures could be related to both the short-term effect of high doses on osteocyte apoptosis and the long-term decrease in bone mineral density due to increased bone resorption. The results of the analysis restricted to patients with at least 2 years of follow-up indicate that patients may be experiencing decreased bone quality from both acute high-dose exposure as well as long-term exposure. Importantly, the evidence related to both acute as well as chronic effects of steroids is from studies of systemic corticosteroid exposure. However, studies of ICS have shown there are dose-related systemic effects on bone density (25–28). ICS have been shown to significantly decrease bone density in as little as a 1-year period of exposure (27). Also, with systemic corticosteroids, there has been evidence of a decline in the risk of fracture on cessation of therapy (8). Therefore, the results of this study are consistent with the evidence of a systemic effect on bone density from ICS, which is likely related to the dose of the ICS. That is, there is more of a systemic effect, the higher the dose, and in patients at relatively high risk, it may be enough to lead to a fracture. In addition, the risk is highest in those patients actively treated with ICS, who we defined as current users in this analysis, and the risk of fracture is attenuated and even returns to normal on cessation of therapy. Therefore, our observation that an increase in the risk of fractures in current users of the highest doses of ICS is likely due to the systemic effects of active treatment with ICS. The results from this analysis add to the evidence on the association between ICS use and the risk of fractures (10–13). The results are consistent with the findings from the van Staa and coworkers' (11) cohort study in the General Practice Research Database that assessed the risk of nonvertebral fracture associated with ICS use. They observed a dose–response association between ICS use and the risk of nonvertebral fractures. The risk of nonvertebral fracture in the high-dose group in that study (> 700 µg beclomethasone equivalents/day) was 1.28 (95% CI, 1.15–1.42), whereas the point estimate in the high-dose group in this analysis was 1.20 (95% CI, 0.95–1.52). However, van Staa and coworkers do not present an evaluation of the risk in current versus past users of ICS. Therefore, results from this analysis expand on the van Staa and coworkers' findings by assessing the impact of current use. Other observational studies of the risk of fracture associated with ICS use have shown mixed results. Hubbard and coworkers (10) in a case–control study using the General Practice Research Database found an increased risk of hip fracture associated with ICS exposure (adjusted OR = 1.19; 95% CI, 1.10–1.28) in patients with asthma or COPD. In a study of elderly women in Ontario, Canada, Lau and coworkers (12) found no increase in the risk of hip fractures in those exposed to ICS compared with those exposed to proton pump inhibitors (adjusted RR = 0.92; 95% CI, 0.75–1.12). However, the average duration of follow-up in the ICS group was less than 300 days. Finally, Suissa and coworkers (13) in a case–control study of patients from Quebec, Canada, reported no increase in the risk of nonvertebral fractures associated with ever exposure (adjusted OR = 0.96; 95% CI, 0.91–1.01). However, they report an increased risk of fracture of 1.06 (95% CI, 1.01–1.12) with every 1,000 µg increase in dose (13). All but the article by Lau and coworkers (12) examine the impact of current use and dose on fracture risk; however, none of the previous studies report the impact of the combination of dose and active use. Our analysis indicates that both factors play a role in understanding the risk of fractures associated with ICS exposure. Results from both this study and previous observational studies demonstrate a slight increase in the risk of nonvertebral fractures associated with high-dose ICS use. van Staa and coworkers conclude that the risk is more a result of the severity of disease rather than exposure to ICS. To attempt to control for differences in severity, we restricted the cohort to patients with a new diagnosis of COPD who were treated during the follow-up time period. In addition, the analysis was adjusted for the number of annual hospitalizations. Other measures were also assessed as proxies for disease severity. Neither the intensity of COPD-specific healthcare service utilization nor the number of classes of respiratory medications patients were taking—factors that have been used previously as markers for disease severity in analyses of patients with COPD—impacted the estimated risk of fractures associated with ICS exposure (29). In addition to disease severity, comorbidities related to ICS use or fractures were included as covariates in the analysis. Although the analysis accounts for the individual comorbidities, the potential interaction between comorbidities was not included in the analysis. Because many of these patients have multiple chronic diseases, it is possible that the combination of certain diseases puts patients at higher risks for fractures. That is, patients with certain combinations may be frailer than other patients, and it is these individuals who are most impacted by the effect of ICS. A measure of frailty may be an important covariate in future analyses assessing the risk of fractures associated with ICS use. Our results indicate that in Veterans Affairs patients with COPD, the current use of high-dose ICS is associated with a slight increase in the risk of nonvertebral fractures. The increase in the risk of fracture associated with ICS use found in this study does not by itself warrant the stopping of treatment in patients with COPD. However, evidence from this and other epidemiologic studies (10, 11) of ICS dose and the risk of fractures indicate that providers should consider prescribing the lowest effective dose of ICS in the management of COPD.
The authors thank Brian Bartle and Jianglin Xu for their assistance with this project, Ramon A. Durazo-Arvizu for his statistical input, and Kourtney J. Davis for her valuable comments.
Supported by a research grant from GlaxoSmithKline, Research Triangle Park, NC. The investigators worked independent of the study sponsor in the design and analysis of the study and reporting of the results. This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org Conflict of Interest Statement: T.A.L. has received research grants from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, and Pfizer; K.B.W. has received research grants from Pfizer, AstraZeneca, Boehringer Ingelheim, and GlaxoSmithKline and has participated as a member of the Merck Respiratory Advisory Board and has consulted to AstraZeneca on several projects. Received in original form July 9, 2003; accepted in final form January 5, 2004
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