- Email: [email protected]
High-dose corticosteroid exposure and osteoporosis intervention in adults
High-dose corticosteroid exposure and osteoporosis intervention in adults Maggie Che, MD*; Bruce Ettinger, MD†; Myngoc T. Nguyen, MD‡; Alice R. Pressman, MS§; and Jennifer Johnston, MPH¶
Background: High-dose corticosteroid exposure is associated with increased risk of bone loss and osteoporotic fractures. Objective: To examine high-dose corticosteroid use and osteoporosis screening and treatment trends in patients receiving high-dose oral or inhaled corticosteroids in a large managed care organization. Methods: We reviewed electronic records of inhaled and oral corticosteroid use and osteoporosis intervention in 2002 among patients 20 years or older and developed algorithms to quantitate high cumulative exposure to corticosteroids. Results: High-dose exposure to corticosteroids was found in 18,737 health plan members (0.8%) (7,757 men [41%] and 10,980 women [59%]). Prevalence increased with age, from 0.4% (age range, 20 – 49 years) to 1% (age range, 50 – 64 years) and 2% (age range, ⱖ75 years). Of high-dose users, 72% used only oral, 15% used only inhaled, and 13% used combined oral and inhaled corticosteroids. Bone densitometry was performed in 9% of men and 27% of women exposed to oral corticosteroids and in 4% of men and 23% of women exposed to inhaled corticosteroids. Prescriptions for osteoporosis drugs were filled by 6% of men and 11% of women receiving oral corticosteroids and by 1% of men and 5% of women receiving inhaled corticosteroids. Conclusion: Approximately 1 in 125 people 20 years or older were exposed to high doses of corticosteroids; oral exposure was 3 times more common than inhaled exposure. Most exposed patients do not receive bone density testing or osteoporosis drug prophylaxis. Use of prescription databases to identify high-dose oral and inhaled corticosteroid users can enable focused intervention to reduce bone loss and potentially reduce the risk of osteoporotic fractures. Ann Allergy Asthma Immunol. 2006;97:497–501.
INTRODUCTION Oral and inhaled corticosteroids are highly effective antiinflammatory medications prescribed for treating many chronic diseases. Increased risk of osteoporotic fracture, a well-recognized adverse effect of high-dose corticosteroid exposure, has focused attention on exposure to orally administered corticosteroid drugs.1–7 Evidence shows that inhaled corticosteroids cause a dose-related reduction in bone mineral density (BMD) and that this reduction could increase the risk of osteoporotic fracture, especially if corticosteroids are taken in high doses over a prolonged period.8 –13 In 2002, we eval* Department of Medicine, Kaiser Permanente Medical Center, Vacaville, California. † Division of Research, Kaiser Permanente Medical Care Program, Oakland, California. ‡ Department of Allergy, Kaiser Permanente Medical Center, Oakland, California. § Division of Research, Kaiser Permanente Medical Care Program, Oakland, California. ¶ The Permanente Federation, Oakland, California. Dr Johnston is currently with Kaiser Permanente Northwest, Portland, Oregon. This research was supported by funding from Merck Health Management Services and Procter and Gamble Pharmaceuticals. This study was presented at the 2005 Annual Meeting of the American Academy of Allergy, Asthma, and Immunology; March 18 –22, 2005; San Antonio, TX; and published in abstract form as Che M, Ettinger B, Nguyen M. High dose corticosteroid exposure in adult members of a large health maintenance organization. J Allergy Clin Immunol. 2005;115(2 suppl):835. Received for publication December 1, 2005. Accepted for publication in revised form April 11, 2006.
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uated the prevalence of high-dose oral and inhaled corticosteroid use and examined the prevalence of osteoporosis intervention among these users. We studied the management of potential osteoporosis by examining the number of BMD tests and osteoporosis medication prescriptions given to patients receiving high-dose oral or inhaled corticosteroids in a large managed care organization. The current study used a computerized prescription database for 3 purposes: to develop algorithms for quantitating patients’ cumulative exposure to corticosteroid drugs, to define exposure to high-dose corticosteroid drugs, and to determine the percentage of patients with this exposure who received BMD testing, drug therapy, or both to limit their risk of osteoporotic fracture. METHODS Study Participants Study participants were drawn from the Kaiser Permanente Medical Care Program in Northern California (KPNC), an integrated, group-model, not-for-profit managed care organization that serves approximately 3.1 million members throughout Northern California. The study was determined exempt from institutional review board review. The study cohort included both men and women; the women were divided into 3 age groups based on osteoporosis risk as defined in women. Groups thus consisted of patients aged 20 through 49 years (corresponding to premenopausal or perimenopausal women), patients aged 50 to 64 years (corresponding to postmenopausal women), and patients 65 years and older (corresponding to elderly women).
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Corticosteroid Prescription Data Using the Kaiser Permanente computerized pharmacy database (Pharmacy Information Monitoring Service [PIMS]) for the year 2002, we identified prescriptions issued to all members 20 years and older for drugs classified within the oral and inhaled glucocorticoid therapeutic classes. Annual cumulative exposure to oral glucocorticoid drugs was determined from the sum of all dispensed pills and was expressed as prednisone equivalents using the following published algorithm.14 We converted all glucocorticoid values to prednisone equivalents, because prednisone was the glucocorticoid most commonly prescribed. We used standard weighing factors based on these glucocorticoid drugs’ anti-inflammatory effects (Table 1).15 Patients 20 years or older who received more than 2 g of glucocorticoid drug in the 12-month period were defined as having high exposure to glucocorticoid drugs. Annual cumulative amount of inhaled corticosteroid drugs was determined from the sum of all dispensed inhalers and was expressed as hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP) equivalents. For this determination, we used the National Asthma Education and Prevention Program (NAEPP) guidelines16 to calculate a ratio whose numerator was the high-dose cut point value (expressed as micrograms per day) for each formulation of inhaled corticosteroid drugs and whose denominator was the high-dose cut point (expressed as micrograms per day) for HFA-BDP. Table 2 summarizes the high daily dosages for inhaled corticosteroid drugs suggested by these guidelines, which define high dose as the dose above which the annual cumulative effect of the inhaled corticosteroid may increase the risk of bone loss. Bone Densitometry Data Dual-energy x-ray absorptiometry was the standard method used for measuring bone density throughout KPNC and was available at 16 KPNC medical centers. Visits for dual-energy x-ray absorptiometry among patients using high-dose corticosteroid drug therapy were identified from the Kaiser Permanente radiology transcription database for the 41⁄2-year period of January 1999 through June 2003 in patients receiving high-dose corticosteroid therapy. We also examined Table 1. Prescriptions for Adult Members With High Exposure to Glucocorticoid Drugs, 1998 –1999* Drug class Cortisone Hydrocortisone Prednisone Prednisolone Methylprednisolone Triamcinolone Dexamethasone Total
Potency factor 0.20 0.25 1.00 1.00 1.25 1.25 6.25
No. (%) of prescriptions 68 (⬍0.1) 3,805 (2.2) 148,568 (87.7) 1,600 (0.9) 2,737 (1.6) 56 (⬍0.1) 12,611 (7.4) 169,445 (100.0)
* Excerpted and reprinted with permission of the publisher and author from Ettinger et al.15
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Table 2. High Daily Dosages of Inhaled Corticosteroids Among KPNC Health Plan Members Studied Drug name (trade name) Beclomethasone CFC (Beclovent) Beclomethasone HFA (Q-Var) Fluticasone (Flovent) Budesonide (Pulmicort) Flunisolide (AeroBid) Triamcinolone (Azmacort)
Dose, g/puff
No. of puffs
Dose, g/d
84 80 220 200 250 100
⬎10 ⬎6 ⬎3 ⬎6 ⬎8 ⬎20
⬎840 ⬎480 ⬎660 ⬎1,200 ⬎2,000 ⬎2,000
Abbreviations: CFC, chlorofluorocarbon; HFA, hydrofluoroalkane134a; KPNC, Kaiser Permanente Medical Care Program in Northern California.
BMD testing during the same period among health plan members throughout KPNC in general. We looked for BMD tests performed 3 years before exposure to high-dose steroids, during the exposure year, and 6 months after the year of exposure. Osteoporosis Drug Prescription Data For all patients with high exposure to corticosteroid drugs, we searched the PIMS database for the period January 2002 through June 2003 to identify filled prescriptions for the following osteoporosis medications: alendronate, risedronate, etidronate, calcitonin, and raloxifene. We also examined the use of these osteoporosis drugs in the same period among health plan members throughout KPNC. Provider responsibility for prescribing and refilling prescriptions for high-dose corticosteroid medication was assigned to the clinician who prescribed the last medication dispensed in 2002. Comparative Prevalence of High-Dose Oral Corticosteroid Use For health plan members aged 20 years and older, we used the 1998 PIMS database to compare prevalence of exposure to high-dose oral corticosteroid drugs in 1998 vs prevalence of this exposure during 2002. We applied the same algorithm to determine exposure to high-dose corticosteroid medication. Statistical Analysis High annual exposure to corticosteroid drugs was classified as follows: oral use of more than 2 g of prednisone equivalent (5.5 mg/d of prednisone equivalent); inhaled use of more than 175 mg of HFA-BDP equivalent (480 g/d of HFA-BDP equivalent); combination use of oral and inhaled medication, expressed as the sum of percentages for each route of ⬎100% (eg, 1 g orally [50%] and ⬎87.5 mg [⬎50%] inhaled). Osteoporosis intervention was defined either as bone densitometry performed during the period January 1999 through June 2003 or as an osteoporosis drug prescribed during the period January 2002 through June 2003. We used t tests to compare prevalence of BMD tests performed and prevalence of osteoporosis drugs prescribed. For both items, prevalence was grouped by patient sex and age.
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RESULTS Exposure to high-dose corticosteroid drugs was identified in 18,737 KPNC health plan members, including 7,757 men (41%) and 10,980 women (59%) (approximately 0.8% of adult KPNC health plan members 20 years and older). Highdose corticosteroid drug use ranged from 0.2% of members in the youngest decade to 2.2% in the oldest decade. Of members who used high-dose corticosteroid drugs, 72% used the drugs orally only (the oral group), 15% used the drugs in inhaled form only (the inhaled group), 2% used high amounts of the drugs by both routes (the both group), and 11% reached the high-exposure cut point only by combining the oral and inhaled routes (the hybrid group). Because outcomes for the hybrid group were similar to those of the inhaled group and because outcomes for the both group were similar to those of the oral group, we combined each group with its respective major group in subsequent analysis. Prevalence of exposure to high-dose corticosteroid drugs increased with increasing age and was similar for patients exposed to oral or inhaled forms of the drugs (Fig 1). Prevalence of exposure to high-dose corticosteroid drugs was greater in women than in men. Most patients (80%) exposed to high-dose inhaled corticosteroid drugs received the prescription for these drugs from a primary care practitioner, whereas patients who received high-dose oral corticosteroid drugs were equally likely to receive the prescription from a specialist (51%) or from a primary care practitioner (49%) (P ⬍ .001 for the oral group compared with the inhaled group). The caseload of patients receiving high-dose oral corticosteroid drugs per practitioner ranged widely among specialists and primary care practitioners and was different for the oral group vs the inhaled group. The volume of prescriptions for high-dose oral corticosteroid drugs was highest among oncologists and rheumatologists,
Figure 1. Percentage and number of health plan members receiving high-dose corticosteroid drugs prescribed by patient age, sex, and type of corticosteroid drug received.
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whereas allergists and pulmonologists prescribed the most high-dose inhaled corticosteroid drugs (data not shown). Compared with men, women taking high-dose oral and inhaled corticosteroids were approximately 4.5 times more likely to have received BMD testing (Table 3) (P ⬍ .001 for men vs women in the oral and inhaled groups). Compared with patients aged 20 through 49 years, patients older than 50 years were more likely to receive BMD testing, but no statistically significant increase in BMD testing was seen with increasing age after 50 years. In contrast, prevalence of exposure to osteoporosis drugs increased markedly in older patients. Compared with women and men aged 20 through 64 years, women and men aged 65 years or older were twice as likely to have filled a prescription for an osteoporosis medication (P ⬍ .001), and osteoporosis drugs were prescribed approximately 2 to 3 times more often among the oral group than in the inhaled group (P ⬍ .001) (Table 3). Compared with men, women in the oral or inhaled groups were 2 to 4 times more likely to receive osteoporosis drug treatment (P ⬍ .001 for women vs men comparisons). Among patients exposed to high-dose corticosteroid drugs, 3 times as many women (31%) as men (11%) received osteoporosis intervention (in the form of either densitometry or drug prophylaxis) (P ⬍ .001), and osteoporosis intervention was received by approximately twice as many patients 50 years or older as by patients aged 20 through 49 years (P ⬍ .001 for age comparisons), regardless of sex. Among health plan members in KPNC, BMD testing in women was approximately twice as likely in steroid users as in health plan members in general (age 50 – 64 years, 36% vs 18%; age ⱖ65 years, 29% vs 16%). Drug prescription was 2 to 3 times more likely among steroid users (age 50 – 64 years, 5% vs 1.5%; age ⱖ65 years, 15% vs 6%). Compared with the general health plan population, men older than 50 years who received high-dose corticosteroid drugs had approximately 10 times more osteoporosis attention (in the form of BMD testing, osteoporosis drug prescription, or both), but a lower percentage of men than women in this age group received care. In the oral high-dose corticosteroid group, prevalence of exposure to these drugs changed little between 1998 (0.54% of KPNC health plan members) and 2002 (0.61% of KPNC health plan members). Furthermore, the percentage of the oral high-dose corticosteroid group receiving osteoporosis drug therapy in 2002 (8.6%) was similar to the percentage receiving this therapy in 1998 (9.2%). DISCUSSION This study of corticosteroid drug therapy in adults showed that 1 in 125 KPNC health plan members were exposed to corticosteroid doses considered high by national experts. Exposure of patients to high-dose oral corticosteroid drugs was approximately 3 times more common than exposure to highdose inhaled corticosteroid drugs, and the proportion exposed to such doses increased substantially with increasing age. Of
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Table 3. Number (Percentage) of High-Dose Corticosteroid Users Receiving Osteoporosis Management Grouped by Age and Type of Steroid Drug Prescribed* Inhaled
Oral
Age, y Bone density Women 20–49 50–64 ⱖ65 Total Men 20–49 50–64 ⱖ65 Total
44 (6) 311 (30) 301 (26) 656 (23) 8 (2) 21 (3) 47 (5) 76 (4)
Osteoporosis drug 5 (1) 34 (3) 92 (8) 131 (5) 2 (⬍1) 4 (1) 23 (2) 29 (1)
Bone density
Osteoporosis drug
344 (15) 889 (36) 963 (29) 2,196 (27)
131 (6) 210 (5) 519 (15) 860 (11)
76 (5) 202 (11) 243 (10) 521 (9)
56 (4) 91 (5) 185 (7) 332 (6)
* Bone mineral density testing done from 1999 through mid-2003; osteoporosis drug prescribed from 2002 through mid-2003.
patients aged 65 years or older who were at highest risk for fracture, a few received osteoporosis intervention; men and patients who use inhaled corticosteroid drugs were least likely to receive osteoporosis intervention. Examining rates of BMD testing and osteoporosis drug prescription in health plan members aged 50 years or older and comparing these rates with osteoporosis attention given to our high-dose steroid cohort showed that the prevalence of bone density testing in our cohort increased after the age of 50 years. We were not surprised by this finding because this is the age at which many women seek initial evaluation of their bone health. In addition, the KPNC region clinical guidelines encourage use of osteoporosis medication for patients 65 years or older who are at risk of osteoporotic fracture; therefore, the increase in osteoporosis prescriptions in this age group was expected. Use of Oral Corticosteroid Drugs The choice of 2 g or more of prednisone as a cutoff for defining high annual exposure to oral corticosteroid drugs was based on several findings: (1) if taken throughout a 5-year period, this dose causes adrenal suppression17; (2) the dose is equivalent to a year’s exposure at 5.5 mg/d, a mean daily dosage that has been associated with a statistically significant increase in risk of hip and spine fracture18; and (3) the American College of Rheumatology19 has suggested a similar dose as the cutoff at which active intervention is required. Use of Inhaled Corticosteroid Drugs Evidence shows that inhaled corticosteroid drugs cause a doserelated reduction in BMD and that this reduction could increase the risk of osteoporotic fracture, especially if the drugs are taken in high doses for a prolonged period.20 Inhaled corticosteroid drugs exhibit dose-related adrenal suppression,11 a recognized risk factor for bone loss.21 On the basis of the NAEPP 2002 criteria16 and KPNC region clinical guidelines for treating asthma in adults,21 the present study used 480 g/d of HFABDP as a prime reference and as a cutoff point for defining high-dose use of inhaled corticosteroid drugs.20 During the present study, HFA-BDP was the main inhaled corticosteroid drug used in KPNC region members with asthma.
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Our high-dose cut points and ratios of high dosage were not intended for use in determining relative molecular potencies of inhaled corticosteroid drugs. Clinical experience accumulated by asthma specialists regarding the relative potency of various inhaled corticosteroid drugs shows that fluticasone is twice as potent as budesonide or beclomethasone dipropionate, either of which is 4 times as potent as flunisolide or triamcinolone acetonide. We are not aware of any comparative clinical trials that have used HFA-BDP (Qvar, IVAX Laboratories, Miami, FL). Specialist- vs Nonspecialist-Prescribed Refills of HighDose Corticosteroid Drugs Within the KPNC region, prescriptions for inhaled corticosteroid drugs are more often refilled by a patient’s primary care practitioner than by a specialist, whereas oral corticosteroid drugs are prescribed almost equally by specialists and primary care practitioners. A 2-part hypothesis for this finding is that (1) primary care practitioners feel more comfortable prescribing and refilling the inhaled form of corticosteroid drugs, believing that the inhaled form is less likely than the oral form to cause systemic adverse effects; and (2) primary care practitioners are usually responsible for refilling prescriptions initially ordered by a specialist. Depending on the status of the patient’s underlying disease, the specialist who prescribes a high dose of oral corticosteroid drugs might wish to decrease the dose over time and therefore may monitor the patient over time and refill the patient’s prescription for oral corticosteroid drugs. Comparison of Our Current and Earlier Findings Our previous study of patients receiving high-dose oral corticosteroid drugs14 examined use patterns for 1998 through 1999. Use of high-dose oral corticosteroid drugs changed little between 1998 and 2002. Since 2002, the American College of Rheumatology guidelines19 have changed, and marketing of alendronate and risedronate for osteoporosis has become more aggressive. However, although clinical guidelines have changed, we were surprised that the same proportion of patients following a regimen of high-dose corticoste-
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roid drugs received osteoporosis intervention (ie, new prescriptions of osteoporosis drugs) in 2002 as in 1998. A major strength of our report is its large size. We studied a patient population identified from the membership of a large managed care organization in Northern California. However, our study has several limitations. We included only patients who were continuously enrolled in the health plan during 2002; thus, high-dose corticosteroid drugs may be used more widely than we report. We did not determine whether patients were using a high-dose inhaled corticosteroid drug on their own initiative or as instructed by their clinicians. Our analysis excludes KPNC members who filled prescriptions or received BMD testing outside the KPNC system. However, a few KPNC members have coverage that allows them to obtain drugs outside our health plan. In this study, we did not categorize patients by diagnosis (eg, chronic obstructive pulmonary disease, which can independently increase risk of osteoporosis). Our review of the medical literature and the results of this study show a currently unmet need to protect a large number of adults from the potentially adverse skeletal effects of high-dose oral and inhaled corticosteroid drugs. Such patients can be identified by using administrative databases and algorithms; this identification could be the first step toward evaluating patients for potential bone loss and increased fracture risk, followed by implementation of clinical practice guidelines to reduce morbidity from osteoporosis-related fractures. ACKNOWLEDGMENTS Editorial assistance was provided by the Medical Editing Service of The Permanente Medical Group Physician Education and Development Department.
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REFERENCES 1. Adinoff AD, Hollister JR. Steroid-induced fractures and bone loss in patients with asthma. N Engl J Med. 1983;309:265–268. 2. Lane NE, Lukert B. The science and therapy of glucocorticoidinduced bone loss. Endocrinol Metab Clin North Am. 1998;27: 465– 483. 3. Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis: pathogenesis and management. Ann Intern Med. 1990;112: 352–364. 4. Saag KG. Glucocorticoid-induced osteoporosis. Endocrinol Metab Clin North Am. 2003;32:135–157. 5. Cooper C, Coupland C, Mitchell M. Rheumatoid arthritis, corticosteroid therapy and hip fracture. Ann Rheum Dis. 1995;54: 49 –52. 6. van Staa TP, Leufkens HG, Cooper C. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporosis Int. 2002;13:777–787. 7. Walsh LJ, Wong CA, Pringle M, Tattersfield AE. Use of oral corticosteroids in the community and the prevention of secondary osteoporosis: a cross sectional study. BMJ. 1996;313: 344 –346. 8. Israel E, Banerjee TR, Fitzmaurice GM, Kotlov TV, LaHive K, LeBoff MS. Effects of inhaled glucocorticoids on bone density in premenopausal women. N Engl J Med. 2001;345:941–947. 9. Ip M, Lam K, Yam L, Kung A, Ng M. Decreased bone mineral
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density in premenopausal asthma patients receiving long-term inhaled steroids. Chest. 1994;105:1722–1727. Wong CA, Walsh LJ, Smith CJ, et al. Inhaled corticosteroid use and bone-mineral density in patients with asthma. Lancet. 2000; 355:1399 –1403. Fujita K, Kasayama S, Hashimoto J, et al. Inhaled corticosteroids reduce bone mineral density in early postmenopausal but not premenopausal asthmatic women. J Bone Miner Res. 2001; 16:782–787. Kelly HW. Potential adverse effects of the inhaled corticosteroids. J Allergy Clin Immunol. 2003;112:469 – 478; quiz 479. Allen DB, Bielory L, Derendorf H, Dluhy R, Colice GL, Szefler SJ. Inhaled corticosteroids: past lessons and future issues. J Allergy Clin Immunol. 2003;112(3 suppl):S1–S40. Ettinger B, Chidambaran P, Pressman A. Prevalence and determinants of osteoporosis drug prescription among patients with high exposure to glucocorticoid drugs. Am J Manag Care. 2001;7:597– 605. Ettinger B, Pressman A, Shah HA. Who bears responsibility for glucocorticoid-exposed patients in a large health maintenance organization? J Manag Care Pharm. 2001;7:228 –232. National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program. Expert Panel Report: guidelines for the diagnosis and management of asthma: update on selected topics 2002 [monograph on the Internet]. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute; 2003 [cited December 1, 2004]. (NIH publication 02-5074) Available at: http://www.nhlbi.nih.gov/ guidelines/asthma/asthmafullrpt.pdf. Jasani MK, Boyle JA, Greig WR, et al. Corticosteroid-induced suppression of the hypothalamo-pituitary-adrenal axis: observations on patients given oral corticosteroids for rheumatoid arthritis. Q J Med. 1967;36:261–276. Richy F, Bousquet J, Ehrlich GE, et al. Inhaled corticosteroids effects on bone in asthmatic and COPD patients: a quantitative systematic review. Osteoporosis Int. 2003;14:179 –190. Epub 2003 Apr 23. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis. Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. Arthritis Rheum. 2001;44: 1496 –1503. Mortimer KJ, Harrison TW, Tattersfield AE. Effects of inhaled corticosteroids on bone. Ann Allergy Asthma Immunol. 2005; 94:15–21; quiz 22–3, 79. Kaiser Permanente. Care Management Institute. Evidence based guidelines and technical review for adult asthma in primary care [monograph on the Internet]. Oakland, CA: Kaiser Permanente Medical Program; 2003 [cited December 1, 2004]. Available at: http://cl.kp.org/pkc/national/cmi/programs/asthma/guideline/ files/adult_asthma_guidelines.pdf.
Requests for reprints should be addressed to: Maggie Che, MD Department of Medicine Kaiser Permanente Medical Center 3700 Vaca Valley Pkwy Vacaville, CA 95688-9430 E-mail: [email protected]
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Background: High-dose corticosteroid exposure is associated with increased risk of bone loss and osteoporotic fractures. Objective: To examine high-dose corticosteroid use and osteoporosis screening and treatment trends in patients receiving high-dose oral or inhaled corticosteroids in a large managed care organization. Methods: We reviewed electronic records of inhaled and oral corticosteroid use and osteoporosis intervention in 2002 among patients 20 years or older and developed algorithms to quantitate high cumulative exposure to corticosteroids. Results: High-dose exposure to corticosteroids was found in 18,737 health plan members (0.8%) (7,757 men [41%] and 10,980 women [59%]). Prevalence increased with age, from 0.4% (age range, 20 – 49 years) to 1% (age range, 50 – 64 years) and 2% (age range, ⱖ75 years). Of high-dose users, 72% used only oral, 15% used only inhaled, and 13% used combined oral and inhaled corticosteroids. Bone densitometry was performed in 9% of men and 27% of women exposed to oral corticosteroids and in 4% of men and 23% of women exposed to inhaled corticosteroids. Prescriptions for osteoporosis drugs were filled by 6% of men and 11% of women receiving oral corticosteroids and by 1% of men and 5% of women receiving inhaled corticosteroids. Conclusion: Approximately 1 in 125 people 20 years or older were exposed to high doses of corticosteroids; oral exposure was 3 times more common than inhaled exposure. Most exposed patients do not receive bone density testing or osteoporosis drug prophylaxis. Use of prescription databases to identify high-dose oral and inhaled corticosteroid users can enable focused intervention to reduce bone loss and potentially reduce the risk of osteoporotic fractures. Ann Allergy Asthma Immunol. 2006;97:497–501.
INTRODUCTION Oral and inhaled corticosteroids are highly effective antiinflammatory medications prescribed for treating many chronic diseases. Increased risk of osteoporotic fracture, a well-recognized adverse effect of high-dose corticosteroid exposure, has focused attention on exposure to orally administered corticosteroid drugs.1–7 Evidence shows that inhaled corticosteroids cause a dose-related reduction in bone mineral density (BMD) and that this reduction could increase the risk of osteoporotic fracture, especially if corticosteroids are taken in high doses over a prolonged period.8 –13 In 2002, we eval* Department of Medicine, Kaiser Permanente Medical Center, Vacaville, California. † Division of Research, Kaiser Permanente Medical Care Program, Oakland, California. ‡ Department of Allergy, Kaiser Permanente Medical Center, Oakland, California. § Division of Research, Kaiser Permanente Medical Care Program, Oakland, California. ¶ The Permanente Federation, Oakland, California. Dr Johnston is currently with Kaiser Permanente Northwest, Portland, Oregon. This research was supported by funding from Merck Health Management Services and Procter and Gamble Pharmaceuticals. This study was presented at the 2005 Annual Meeting of the American Academy of Allergy, Asthma, and Immunology; March 18 –22, 2005; San Antonio, TX; and published in abstract form as Che M, Ettinger B, Nguyen M. High dose corticosteroid exposure in adult members of a large health maintenance organization. J Allergy Clin Immunol. 2005;115(2 suppl):835. Received for publication December 1, 2005. Accepted for publication in revised form April 11, 2006.
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uated the prevalence of high-dose oral and inhaled corticosteroid use and examined the prevalence of osteoporosis intervention among these users. We studied the management of potential osteoporosis by examining the number of BMD tests and osteoporosis medication prescriptions given to patients receiving high-dose oral or inhaled corticosteroids in a large managed care organization. The current study used a computerized prescription database for 3 purposes: to develop algorithms for quantitating patients’ cumulative exposure to corticosteroid drugs, to define exposure to high-dose corticosteroid drugs, and to determine the percentage of patients with this exposure who received BMD testing, drug therapy, or both to limit their risk of osteoporotic fracture. METHODS Study Participants Study participants were drawn from the Kaiser Permanente Medical Care Program in Northern California (KPNC), an integrated, group-model, not-for-profit managed care organization that serves approximately 3.1 million members throughout Northern California. The study was determined exempt from institutional review board review. The study cohort included both men and women; the women were divided into 3 age groups based on osteoporosis risk as defined in women. Groups thus consisted of patients aged 20 through 49 years (corresponding to premenopausal or perimenopausal women), patients aged 50 to 64 years (corresponding to postmenopausal women), and patients 65 years and older (corresponding to elderly women).
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Corticosteroid Prescription Data Using the Kaiser Permanente computerized pharmacy database (Pharmacy Information Monitoring Service [PIMS]) for the year 2002, we identified prescriptions issued to all members 20 years and older for drugs classified within the oral and inhaled glucocorticoid therapeutic classes. Annual cumulative exposure to oral glucocorticoid drugs was determined from the sum of all dispensed pills and was expressed as prednisone equivalents using the following published algorithm.14 We converted all glucocorticoid values to prednisone equivalents, because prednisone was the glucocorticoid most commonly prescribed. We used standard weighing factors based on these glucocorticoid drugs’ anti-inflammatory effects (Table 1).15 Patients 20 years or older who received more than 2 g of glucocorticoid drug in the 12-month period were defined as having high exposure to glucocorticoid drugs. Annual cumulative amount of inhaled corticosteroid drugs was determined from the sum of all dispensed inhalers and was expressed as hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP) equivalents. For this determination, we used the National Asthma Education and Prevention Program (NAEPP) guidelines16 to calculate a ratio whose numerator was the high-dose cut point value (expressed as micrograms per day) for each formulation of inhaled corticosteroid drugs and whose denominator was the high-dose cut point (expressed as micrograms per day) for HFA-BDP. Table 2 summarizes the high daily dosages for inhaled corticosteroid drugs suggested by these guidelines, which define high dose as the dose above which the annual cumulative effect of the inhaled corticosteroid may increase the risk of bone loss. Bone Densitometry Data Dual-energy x-ray absorptiometry was the standard method used for measuring bone density throughout KPNC and was available at 16 KPNC medical centers. Visits for dual-energy x-ray absorptiometry among patients using high-dose corticosteroid drug therapy were identified from the Kaiser Permanente radiology transcription database for the 41⁄2-year period of January 1999 through June 2003 in patients receiving high-dose corticosteroid therapy. We also examined Table 1. Prescriptions for Adult Members With High Exposure to Glucocorticoid Drugs, 1998 –1999* Drug class Cortisone Hydrocortisone Prednisone Prednisolone Methylprednisolone Triamcinolone Dexamethasone Total
Potency factor 0.20 0.25 1.00 1.00 1.25 1.25 6.25
No. (%) of prescriptions 68 (⬍0.1) 3,805 (2.2) 148,568 (87.7) 1,600 (0.9) 2,737 (1.6) 56 (⬍0.1) 12,611 (7.4) 169,445 (100.0)
* Excerpted and reprinted with permission of the publisher and author from Ettinger et al.15
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Table 2. High Daily Dosages of Inhaled Corticosteroids Among KPNC Health Plan Members Studied Drug name (trade name) Beclomethasone CFC (Beclovent) Beclomethasone HFA (Q-Var) Fluticasone (Flovent) Budesonide (Pulmicort) Flunisolide (AeroBid) Triamcinolone (Azmacort)
Dose, g/puff
No. of puffs
Dose, g/d
84 80 220 200 250 100
⬎10 ⬎6 ⬎3 ⬎6 ⬎8 ⬎20
⬎840 ⬎480 ⬎660 ⬎1,200 ⬎2,000 ⬎2,000
Abbreviations: CFC, chlorofluorocarbon; HFA, hydrofluoroalkane134a; KPNC, Kaiser Permanente Medical Care Program in Northern California.
BMD testing during the same period among health plan members throughout KPNC in general. We looked for BMD tests performed 3 years before exposure to high-dose steroids, during the exposure year, and 6 months after the year of exposure. Osteoporosis Drug Prescription Data For all patients with high exposure to corticosteroid drugs, we searched the PIMS database for the period January 2002 through June 2003 to identify filled prescriptions for the following osteoporosis medications: alendronate, risedronate, etidronate, calcitonin, and raloxifene. We also examined the use of these osteoporosis drugs in the same period among health plan members throughout KPNC. Provider responsibility for prescribing and refilling prescriptions for high-dose corticosteroid medication was assigned to the clinician who prescribed the last medication dispensed in 2002. Comparative Prevalence of High-Dose Oral Corticosteroid Use For health plan members aged 20 years and older, we used the 1998 PIMS database to compare prevalence of exposure to high-dose oral corticosteroid drugs in 1998 vs prevalence of this exposure during 2002. We applied the same algorithm to determine exposure to high-dose corticosteroid medication. Statistical Analysis High annual exposure to corticosteroid drugs was classified as follows: oral use of more than 2 g of prednisone equivalent (5.5 mg/d of prednisone equivalent); inhaled use of more than 175 mg of HFA-BDP equivalent (480 g/d of HFA-BDP equivalent); combination use of oral and inhaled medication, expressed as the sum of percentages for each route of ⬎100% (eg, 1 g orally [50%] and ⬎87.5 mg [⬎50%] inhaled). Osteoporosis intervention was defined either as bone densitometry performed during the period January 1999 through June 2003 or as an osteoporosis drug prescribed during the period January 2002 through June 2003. We used t tests to compare prevalence of BMD tests performed and prevalence of osteoporosis drugs prescribed. For both items, prevalence was grouped by patient sex and age.
ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
RESULTS Exposure to high-dose corticosteroid drugs was identified in 18,737 KPNC health plan members, including 7,757 men (41%) and 10,980 women (59%) (approximately 0.8% of adult KPNC health plan members 20 years and older). Highdose corticosteroid drug use ranged from 0.2% of members in the youngest decade to 2.2% in the oldest decade. Of members who used high-dose corticosteroid drugs, 72% used the drugs orally only (the oral group), 15% used the drugs in inhaled form only (the inhaled group), 2% used high amounts of the drugs by both routes (the both group), and 11% reached the high-exposure cut point only by combining the oral and inhaled routes (the hybrid group). Because outcomes for the hybrid group were similar to those of the inhaled group and because outcomes for the both group were similar to those of the oral group, we combined each group with its respective major group in subsequent analysis. Prevalence of exposure to high-dose corticosteroid drugs increased with increasing age and was similar for patients exposed to oral or inhaled forms of the drugs (Fig 1). Prevalence of exposure to high-dose corticosteroid drugs was greater in women than in men. Most patients (80%) exposed to high-dose inhaled corticosteroid drugs received the prescription for these drugs from a primary care practitioner, whereas patients who received high-dose oral corticosteroid drugs were equally likely to receive the prescription from a specialist (51%) or from a primary care practitioner (49%) (P ⬍ .001 for the oral group compared with the inhaled group). The caseload of patients receiving high-dose oral corticosteroid drugs per practitioner ranged widely among specialists and primary care practitioners and was different for the oral group vs the inhaled group. The volume of prescriptions for high-dose oral corticosteroid drugs was highest among oncologists and rheumatologists,
Figure 1. Percentage and number of health plan members receiving high-dose corticosteroid drugs prescribed by patient age, sex, and type of corticosteroid drug received.
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whereas allergists and pulmonologists prescribed the most high-dose inhaled corticosteroid drugs (data not shown). Compared with men, women taking high-dose oral and inhaled corticosteroids were approximately 4.5 times more likely to have received BMD testing (Table 3) (P ⬍ .001 for men vs women in the oral and inhaled groups). Compared with patients aged 20 through 49 years, patients older than 50 years were more likely to receive BMD testing, but no statistically significant increase in BMD testing was seen with increasing age after 50 years. In contrast, prevalence of exposure to osteoporosis drugs increased markedly in older patients. Compared with women and men aged 20 through 64 years, women and men aged 65 years or older were twice as likely to have filled a prescription for an osteoporosis medication (P ⬍ .001), and osteoporosis drugs were prescribed approximately 2 to 3 times more often among the oral group than in the inhaled group (P ⬍ .001) (Table 3). Compared with men, women in the oral or inhaled groups were 2 to 4 times more likely to receive osteoporosis drug treatment (P ⬍ .001 for women vs men comparisons). Among patients exposed to high-dose corticosteroid drugs, 3 times as many women (31%) as men (11%) received osteoporosis intervention (in the form of either densitometry or drug prophylaxis) (P ⬍ .001), and osteoporosis intervention was received by approximately twice as many patients 50 years or older as by patients aged 20 through 49 years (P ⬍ .001 for age comparisons), regardless of sex. Among health plan members in KPNC, BMD testing in women was approximately twice as likely in steroid users as in health plan members in general (age 50 – 64 years, 36% vs 18%; age ⱖ65 years, 29% vs 16%). Drug prescription was 2 to 3 times more likely among steroid users (age 50 – 64 years, 5% vs 1.5%; age ⱖ65 years, 15% vs 6%). Compared with the general health plan population, men older than 50 years who received high-dose corticosteroid drugs had approximately 10 times more osteoporosis attention (in the form of BMD testing, osteoporosis drug prescription, or both), but a lower percentage of men than women in this age group received care. In the oral high-dose corticosteroid group, prevalence of exposure to these drugs changed little between 1998 (0.54% of KPNC health plan members) and 2002 (0.61% of KPNC health plan members). Furthermore, the percentage of the oral high-dose corticosteroid group receiving osteoporosis drug therapy in 2002 (8.6%) was similar to the percentage receiving this therapy in 1998 (9.2%). DISCUSSION This study of corticosteroid drug therapy in adults showed that 1 in 125 KPNC health plan members were exposed to corticosteroid doses considered high by national experts. Exposure of patients to high-dose oral corticosteroid drugs was approximately 3 times more common than exposure to highdose inhaled corticosteroid drugs, and the proportion exposed to such doses increased substantially with increasing age. Of
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Table 3. Number (Percentage) of High-Dose Corticosteroid Users Receiving Osteoporosis Management Grouped by Age and Type of Steroid Drug Prescribed* Inhaled
Oral
Age, y Bone density Women 20–49 50–64 ⱖ65 Total Men 20–49 50–64 ⱖ65 Total
44 (6) 311 (30) 301 (26) 656 (23) 8 (2) 21 (3) 47 (5) 76 (4)
Osteoporosis drug 5 (1) 34 (3) 92 (8) 131 (5) 2 (⬍1) 4 (1) 23 (2) 29 (1)
Bone density
Osteoporosis drug
344 (15) 889 (36) 963 (29) 2,196 (27)
131 (6) 210 (5) 519 (15) 860 (11)
76 (5) 202 (11) 243 (10) 521 (9)
56 (4) 91 (5) 185 (7) 332 (6)
* Bone mineral density testing done from 1999 through mid-2003; osteoporosis drug prescribed from 2002 through mid-2003.
patients aged 65 years or older who were at highest risk for fracture, a few received osteoporosis intervention; men and patients who use inhaled corticosteroid drugs were least likely to receive osteoporosis intervention. Examining rates of BMD testing and osteoporosis drug prescription in health plan members aged 50 years or older and comparing these rates with osteoporosis attention given to our high-dose steroid cohort showed that the prevalence of bone density testing in our cohort increased after the age of 50 years. We were not surprised by this finding because this is the age at which many women seek initial evaluation of their bone health. In addition, the KPNC region clinical guidelines encourage use of osteoporosis medication for patients 65 years or older who are at risk of osteoporotic fracture; therefore, the increase in osteoporosis prescriptions in this age group was expected. Use of Oral Corticosteroid Drugs The choice of 2 g or more of prednisone as a cutoff for defining high annual exposure to oral corticosteroid drugs was based on several findings: (1) if taken throughout a 5-year period, this dose causes adrenal suppression17; (2) the dose is equivalent to a year’s exposure at 5.5 mg/d, a mean daily dosage that has been associated with a statistically significant increase in risk of hip and spine fracture18; and (3) the American College of Rheumatology19 has suggested a similar dose as the cutoff at which active intervention is required. Use of Inhaled Corticosteroid Drugs Evidence shows that inhaled corticosteroid drugs cause a doserelated reduction in BMD and that this reduction could increase the risk of osteoporotic fracture, especially if the drugs are taken in high doses for a prolonged period.20 Inhaled corticosteroid drugs exhibit dose-related adrenal suppression,11 a recognized risk factor for bone loss.21 On the basis of the NAEPP 2002 criteria16 and KPNC region clinical guidelines for treating asthma in adults,21 the present study used 480 g/d of HFABDP as a prime reference and as a cutoff point for defining high-dose use of inhaled corticosteroid drugs.20 During the present study, HFA-BDP was the main inhaled corticosteroid drug used in KPNC region members with asthma.
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Our high-dose cut points and ratios of high dosage were not intended for use in determining relative molecular potencies of inhaled corticosteroid drugs. Clinical experience accumulated by asthma specialists regarding the relative potency of various inhaled corticosteroid drugs shows that fluticasone is twice as potent as budesonide or beclomethasone dipropionate, either of which is 4 times as potent as flunisolide or triamcinolone acetonide. We are not aware of any comparative clinical trials that have used HFA-BDP (Qvar, IVAX Laboratories, Miami, FL). Specialist- vs Nonspecialist-Prescribed Refills of HighDose Corticosteroid Drugs Within the KPNC region, prescriptions for inhaled corticosteroid drugs are more often refilled by a patient’s primary care practitioner than by a specialist, whereas oral corticosteroid drugs are prescribed almost equally by specialists and primary care practitioners. A 2-part hypothesis for this finding is that (1) primary care practitioners feel more comfortable prescribing and refilling the inhaled form of corticosteroid drugs, believing that the inhaled form is less likely than the oral form to cause systemic adverse effects; and (2) primary care practitioners are usually responsible for refilling prescriptions initially ordered by a specialist. Depending on the status of the patient’s underlying disease, the specialist who prescribes a high dose of oral corticosteroid drugs might wish to decrease the dose over time and therefore may monitor the patient over time and refill the patient’s prescription for oral corticosteroid drugs. Comparison of Our Current and Earlier Findings Our previous study of patients receiving high-dose oral corticosteroid drugs14 examined use patterns for 1998 through 1999. Use of high-dose oral corticosteroid drugs changed little between 1998 and 2002. Since 2002, the American College of Rheumatology guidelines19 have changed, and marketing of alendronate and risedronate for osteoporosis has become more aggressive. However, although clinical guidelines have changed, we were surprised that the same proportion of patients following a regimen of high-dose corticoste-
ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
roid drugs received osteoporosis intervention (ie, new prescriptions of osteoporosis drugs) in 2002 as in 1998. A major strength of our report is its large size. We studied a patient population identified from the membership of a large managed care organization in Northern California. However, our study has several limitations. We included only patients who were continuously enrolled in the health plan during 2002; thus, high-dose corticosteroid drugs may be used more widely than we report. We did not determine whether patients were using a high-dose inhaled corticosteroid drug on their own initiative or as instructed by their clinicians. Our analysis excludes KPNC members who filled prescriptions or received BMD testing outside the KPNC system. However, a few KPNC members have coverage that allows them to obtain drugs outside our health plan. In this study, we did not categorize patients by diagnosis (eg, chronic obstructive pulmonary disease, which can independently increase risk of osteoporosis). Our review of the medical literature and the results of this study show a currently unmet need to protect a large number of adults from the potentially adverse skeletal effects of high-dose oral and inhaled corticosteroid drugs. Such patients can be identified by using administrative databases and algorithms; this identification could be the first step toward evaluating patients for potential bone loss and increased fracture risk, followed by implementation of clinical practice guidelines to reduce morbidity from osteoporosis-related fractures. ACKNOWLEDGMENTS Editorial assistance was provided by the Medical Editing Service of The Permanente Medical Group Physician Education and Development Department.
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Requests for reprints should be addressed to: Maggie Che, MD Department of Medicine Kaiser Permanente Medical Center 3700 Vaca Valley Pkwy Vacaville, CA 95688-9430 E-mail: [email protected]
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