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S14 • JAOA • Vol 100 • No 7 • Supplement to July 2000 Singh and Muskelly • Inhaled corticosteroid–induced bone loss and preventive strategies Inhaled corticosteroids are the main-stay in the treatment of asthma, allow-ing effective control of symptoms with-out the serious side effects associated with systemic corticosteroids. The effi-cacy of inhaled corticosteroids in asthma treatment is dose-dependent, allowing greater anti-inflammatory effect with higher doses. Patients with severe asthma are often taking very high doses of inhaled corticosteroid.1 There is concern that high-dose inhaled corticosteroids may have adverse effects on bone metabolism. This concern arises from the frequency with which osteoporosis is known to occur with long-term use of oral steroids.2 Nearly 50% of patients may have osteoporotic fractures develop as a result of oral cor-ticosteroid therapy if adequate prevention and treatment of this complication are not initiated immediately.3 Other factors to consider are differ-ences between various types of inhaled corticosteroids (Table). Corticosteroids differ between each other in potencies, suppression of the hypothalamus-pitu-itary- adrenal axis, and degree of sys-temic absorption. The dose of each of the inhaled corticosteroids that is systemi-cally absorbed needs to be established. Whether all inhaled corticosteroids at equivalent doses are associated with the same risk is unknown. Mechanisms of corticosteroid-induced bone changes The mechanism of corticosteroid-induced bone loss is complex. Adult bone matrix reflects a constant balance of activity between bone-forming osteoblasts and bone-breakdown cells (osteoclasts).4 A change in this equilibrium may result in reduction of bone mass, resulting in osteoporosis and risk of fracture. Corti-costeroids affect both bone formation and resorption. Corticosteroids decrease osteoblast activity, which results in decreased matrix synthesis and a decreased active life span of osteoblasts. This results in a decrease in the bone mass of mainly the axial skeleton (that is, vertebrae), as the vertebrae contain more metabolically active trabecular bone than cortical bone. This effect with corticoste-roids has been observed using biochem-ical markers of bone turnover, particu-larly serum osteocalcin, which decreases in a dose-dependent way within 4 days of starting corticosteroid therapy.5 Other markers of bone formation include serum levels of alkaline phos-phatase, osteocalcin, procollagen type 1 carboxyterminal and aminoterminal propeptide, and procollagen type 3 aminoterminal propeptide.4 Corticoste-roids also effect osteoclast activity, lead-ing to an increase in bone resorption. Markers for the increase in osteoclast activity include urinary levels of hydrox-yproline, urinary or serum pyridinium cross-links, urinary collagen type 1 cross-linked N-telopeptide, urinary collagen type 1 cross-linked C-telopeptide, and serum carboxyterminal telopeptide of type 1 collagen.4 Bone formation mark-ers are considered to be more sensitive than bone resorption markers in assess-ing the effects of corticosteroids, with osteocalcin being the most sensitive, spe-cific, and reproducible.4 Review of clinical studies Pediatric Prolonged use of systemic corticoste-roids are known to suppress linear growth in children.4 Asthma itself seems to have a negative effect in delaying puberty and reducing growth height, and it should also be considered when evaluating the effect of corticosteroids on bone.4 In addition, there have been a number of studies evaluating the effects of inhaled corticosteroids on growth rate and biochemical markers, as well as bone mineral density (BMD) in chil-dren. Agertoft and Pedersen6 evaluated short-term knemometry (a measurement of velocity of lower leg growth) and 24- hour urine cortisol excretion in 48 chil-dren aged 6 to 12 years. One group of children received treatment with either fluticasone propionate, 200 g/d; budes-onide, 200 g/d; or placebo in a ran-domized, crossover manner. A second group of children received either fluti-casone propionate, 400 g/d; budes-onide, 400 g/d; or placebo in a similar manner. Each treatment period was 15 Systemic corticosteroids are known to cause adverse effects on bone loss and, with long-term use, may result in osteoporosis. There is evidence that inhaled cortico-steroids at moderate to high doses may also induce bone loss. This article discusses the effects of inhaled corticosteroids on bone formation and resorption. It also offers preventive strategies to minimize bone loss associated with long-term use of inhaled corticosteroids. (Key words: asthma, inhaled corticosteroids, osteoporosis, bone loss) Dr Singh is an assistant professor in the Depart-ment of Pharmacy Practice, College of Phar-macy and Allied Health, Wayne State University, Detroit, Mich. Dr Muskelly is a pharmacy prac-tice resident, Department of Pharmacy, Harper Hospital, Detroit. Correspondence to R. F. Singh, PharmD, Department of Pharmacy Practice, College of Pharmacy and Allied Health, Wayne State Uni-versity, 335 Shapero Hall, Detroit, MI 48201. E-mail: rfsingh@med.wayne.edu Inhaled corticosteroid–induced bone loss and preventive strategies RENU F. SINGH, PHARMD CHRIS C. MUSKELLY, PHARMD to 18 days. Knemometry was used to measure the lower leg length twice a week, and 24-hour cortisol excretion was measured at the end of each treat-ment period. No difference was seen in rate of lower leg growth within each group between budesonide or fluticas-one; however, growth rate was signifi-cantly lower in the group receiving budesonide at a dosage of 400 g/d than in the group receiving the place-bo. At this dose—fluticasone propionate, 400 g/d, and budesonide, 400 g/d— there resulted a significant reduction in urinary cortisol excretion compared with that with placebo. Konig and associates7 evaluated bone metabolism in 18 asthmatic children (aged 4 to 17 years) who were treated with inhaled beclomethasone dipropi-onate (400 g/d to 800 g/d) for at least 6 months. Each child was controlled with an age- and sex-matched patient with asthma who was not receiving corticoste-roid therapy. Serum levels of calcium, total alkaline phosphatase, bone-specific alkaline phosphatase, parathyroid hor-mone, 25-hydroxyvitamin D, and 1,25- dihydroxyvitamin D were measured, as was BMD. The study found no signifi-cant differences in the measured serum markers between the treated groups and their age-matched cohort. Further, no significant difference was seen on bone densitometry. The study concluded that inhaled beclomethasone does not reduce bone mineralization or increase bone resorption in children with asthma. These results were confirmed in a later study by Martinati and coworkers,8 who studied the effects of inhaled corticoste-roids on cortical and trabecular bone mass in 64 asthmatic prepubertal subjects (aged between 5 and 10 years) who were treat-ed with beclomethasone dipropionate, 150 g/d to 600 g/d, or cromolyn sodi-um, 30 mg/d for 6.7 months. Lumbar spine bone mass was measured by dual-energy x-ray absorptiometry (DEXA). The DEXA measurements showed no difference in trabecular bone mass in chil-dren who received beclomethasone versus children who received cromolyn sodium. Thus, it appears that inhaled corticoste-roids at low doses do not induce osteo-porosis in children. Adults A number of short- and medium-term studies have evaluated the effects of inhaled corticosteroids on biochemical bone markers in both healthy volunteers and asthmatic patients.9-12 During study periods of 2 to 4 weeks, most studies showed that levels of various markers significantly changed on inhaled corti-costeroid therapy, with the magnitude of effect being dose-related. Kerstjens and colleagues13 conducted two studies on the short-term and long-term effects of inhaled corticosteroids on bone metabolism of patients with asthma or chronic obstructive pulmonary disease. In the first pilot study, 15 patients (mean age, 41.1 years) received at least 800 g/d of beclomethasone dipropionate ( 20 puffs per day). Serum levels of alkaline phosphatase, osteocal-cin, procollagen type 1 carboxy terminal propeptide (PICP), and type 1 collagen carboxy terminal telopeptide (ICTP), and urine level of hydroxyproline were measured at baseline and after 4 weeks of inhaled beclomethasone therapy. In the second long-term, double-blind study, 70 patients (mean age, 40 years) received beclomethasone diproprionate, 800 g/d, while serum PICP and ICTP were mea-sured at baseline and after 2.5 years of treatment. Although the 4-week pilot study revealed a decrease in serum osteo-calcin levels and an increase in serum PICP levels, the long-term study showed no significant changes in serum levels of PICP and ICTP of patients treated with inhaled corticosteroids compared with patients treated without inhaled corti-costeroids. This finding suggests that the clinical significance of short-term changes in metabolic markers with inhaled corti-costeroids is not clear, because long-term studies result in no changes in these markers. Hence, these markers cannot be used as surrogate indicators for bone density to predict risk of developing osteoporosis. Luengo and colleagues14 conducted a case-control study on 48 asthmatic adults (mean age, 56 years) treated with inhaled corticosteroids—beclomethasone or budesonide (300 g to 1000 g) for Singh and Muskelly • Inhaled corticosteroid–induced bone loss and preventive strategies JAOA • Vol 100 • No 7 • Supplement to July 2000 • S15 Table Inhaled Corticosteroids No. of puffs Drug* Low dose Medium dose High dose Beclomethasone dipropionate 4 to 12 12 to 20 20 (Vanceril, Beclovent) 42 g per puff Budesonide 1 to 2 2 to 3 3 (Pulmicort Turbuhaler) 200 g per puff Flunisolide 2 to 4 4 to 8 8 (AeroBid) 250 g per puff Fluticasone propionate (Flovent) 44 g per puff 2 to 6 6 to 15 15 110 g per puff 2 2 to 6 6 220 g per puff 3 Triamcinolone acetonide 4 to 10 10 to 20 20 (Azmacort) 100 g per puff *Drugs are listed by generic names, with trade names in parentheses. more than 1 year (mean duration of treatment, 10.6 years). Twenty-four patients had received one to six short courses of oral corticosteroids while 7 patients had received oral corticosteroids (mean daily dose of 6.2 mg of pred-nisone) for 2 to 15 years more than 4 years before the bone densitometry mea-surements of this study. Vertebral BMD measured by DEXA was obtained at baseline and at 2 years in the asthmatic patients and their age-matched controls. The findings indicated no significant dif-ferences in BMD loss between the group using inhaled corticosteroid and the con-trol group; both groups showed a decrease in BMD over 2 years. These data suggested that inhaled corticoste-roids at mean doses up to 662 g/d do not further increase bone mass loss beyond that expected from natural bone mass loss. Prevention of inhaled corticosteroid–induced bone loss To date, there are no documented treat-ment guidelines for prevention of inhaled corticosteroid–induced bone loss. All recommendations have been geared toward oral corticosteroids.15 Therefore, we opt to suggest that the general rec-ommendations for prevention and treat-ment of glucocorticoid-induced osteo-porosis be considered in patients taking medium to high doses of inhaled cortico-steroids. 15 Calcium and vitamin D The American Rheumatologists Associ-ation recommends that all patients on glucocorticoid therapy have an adequate intake of calcium and vitamin D.15 A daily calcium intake of 1500 mg is rec-ommended, either obtained through dietary intake or calcium supplementa-tion. In addition, vitamin D (either 800 IU/d or 50,000 IU three times a week) or calcitriol (0.5 g/d) should be added. Hormone replacement therapy Postmenopausal women receiving medi-um to high doses of inhaled corticoste-roids should receive estrogen therapy. Estrogens increase bone mass and reduce the risk of fractures related to osteo-porosis. Women with a uterus should also receive a progesterone for 12 to 14 days per month to reduce the risk of endometrial hyperplasia. Women at high risk for breast cancer or having a histo-ry of breast cancer should consider ralox-ifene hydrochloride, an estrogen-receptor antagonist. In a multicenter, random-ized, placebo-controlled study of ralox-ifene in early postmenopausal women with osteoporosis, bone density increased by 2.1% to 2.4% in the femoral neck and 2.6% to 2.7% in the spine com-pared with those taking placebo.16 How-ever, the efficacy of raloxifene in patients receiving inhaled corticosteroids has not been published. Bisphosphonates The actual mechanism of action of bis-phosphonates is poorly understood; however, they are inhibitors of bone resorption (reduction of number of osteo-clasts) that are used in treatment of Paget’s disease, hypercalcemia, and osteo-porosis. 17 Many bisphosphonates (such as alendronate sodium, cyclic etidronate disodium, and pamidronate disodium) have been evaluated in corticosteroid-induced bone loss. Intermittent cyclical etidronate sodium (400 mg daily for 2 weeks) and calcium (500 mg/d for 11 weeks) was studied and resulted in an increase in BMD of lumbar spine by 1.8% (P .001) at both 6 months and 12 months.18 Intermittent etidronate dis-odium (400 mg/d for 14 days) and cal-cium (500 mg/d for 76 days) prevented loss of vertebral and trochanteric bone in 141 patients aged 19 to 87 years treated with high-dose oral prednisone ( 7.5 mg/d).19 The mean BMD of the lumbar spine and trochanter in the group receiv-ing etidronate increased by 0.61% and 1.46%, respectively, as compared with a decrease of 3.23% and 2.74%, respec-tively, in the group receiving the placebo. In a randomized, placebo-controlled study of adults receiving long-term glu-cocorticoid therapy, patients were treat-ed with alendronate, 5 mg/d to 10 mg/d for 48 weeks.20 The mean BMD of the lumbar spine in these patients increased by 2.1% and 2.9% (P .001); the femoral neck BMD increased by 1.2% and 1% (P .01) in the alendronate-treated group as compared with the placebo group. In an early postmenopausal interven-tion cohort study of 1202 women, aged 45 to 59 years, treated with alendronate, 2.5 mg/d and 5 mg/d for 2 years, there was an increased response in spine and hip BMD of 2% to 4% over 2 years.21 Comment Patients taking moderate to high doses of inhaled corticosteroids may be at increased risk for long-term bone loss, especially if used for a prolonged time. It remains to be established whether inhaled corticosteroid–induced bone changes are clinically important. Although no specif-ic guidelines are available, it would seem prudent to consider preventive measures such as calcium and vitamin D supple-mentation in patients taking moderate to high doses of inhaled corticosteroids (Table). Patients with additional risk fac-tors, such as a postmenopausal state, should consider estrogen replacement therapy. If high doses of inhaled corti-costeroids are used, a screening bone DEXA scan may be indicated to see if more aggressive therapy is needed. References 1. Packe GE, Douglas JG, McDonald AF, Robins SP, Reid DM. Bone density in asthmatic patients taking high dose inhaled beclomethasone dipropionate and intermittent systemic corticosteroids. Thorax 1992;47:414-417. 2. Toogood JH, Baskerville JC, Markov AE, Hodsman AB, Fraher LJ, Jennings B, et al: Bone mineral densi-ty and the risk of fracture in patients receiving long-term inhaled steroid therapy for asthma. J Allergy Clin Immunol 1995;96:157-166. 3. Libinati CR, Baylink DJ. Prevention and treat-ment of glucorticoid-induced osteoporosis. Chest 1992;102:1426-1435. 4. Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med 1999;159:941-955. 5. Eastell R, Reid DM, Compston J, Cooper C, Fogel-man I, Francis RM, et al. A UK Consensus Group on management of glucocorticoid-induced osteoporosis: an update. J Intern Med 1998;244:271-292. 6. Agertoft L, Pedersen S. Short-term knemometry and urine cortisol excretion in children treated with fluticas-one propionate and budesonide: a dose response study. Eur Respir J 1997;10:1507-1512. S16 • JAOA • Vol 100 • No 7 • Supplement to July 2000 Singh and Muskelly • Inhaled corticosteroid–induced bone loss and preventive strategies 7. Konig P, Hillman L, Cervantes C, Levine C, Mal-oney C, Douglass B, et al. Bone metabolism in children with asthma treated with inhaled beclomethasone dipro-pionate. J Pediatr 1993;122:219-226. 8. Martinati LC, Bertoldo F, Gasperi E, Micelli S, Boner AL. Effect on cortical and trabecular bone mass of dif-ferent anti-inflammatory treatments in preadolescent children with chronic asthma. Am J Respir Crit Care Med 1996;153:232-236. 9. Hodsman AB, Toogood JH, Jennings B, Fraher LJ, Baskerville JC. Differential effects of inhaled budes-onide and oral prednisolone on serum osteocalcin. J Clin Endocrinol Metab 1991;72:530-540. 10. Pouw EM, Prummel MF, Oosting H, Roos CM, Endert E. Beclomethasone inhalation decreases serum osteocalcin concentrations. BMJ 1991;302:627-628. 11. Teelucksingh S, Padfield PL, Tibi L, Gough KJ, Holt PR. Inhaled corticosteroids, bone formation, and osteocalcin. Lancet 1991;338:60-61. 12. Ali NJ, Capewell S, Ward MJ. Bone turnover during high dose inhaled corticosteroid treatment. Thorax 1991;46:160-164. 13. Kerstjens HA, Postma DS, van Doormaal JJ, van Zanten AK, Brand PL, Dekhuijzen PN, et al. Effects of short-term and long-term treatment with inhaled cortico-steroids on bone metabolism in patients with airways obstruction. Dutch CNSLD Study Group. Thorax 1994;49:652-656. 14. Luengo M, del Rio L, Pons F, Picado C. Bone min-eral density in asthmatic patients treated with inhaled corticosteroids: a case-control study. Eur Respir J 1997;10:2110-2113. 15. Recommendations for the prevention and treat-ment of glucocorticoid-induced osteoporosis. Ameri-can College of Rheumatology Task Force on Osteo-porosis Guidelines. Arthritis Rheum 1996;39:1791-1801. 16. MacReady N. Raloxifene reduces spinal fractures postmenopausally. Lancet 1999;354:653. 17. Saag KG, Emkey R, Schnitzer TJ, Brown JP, Hawkins F, Goemaere S, et al. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group. N Engl J Med 1998;339:292- 299. 18. Jenkins EA, Walker-Bone KE, Wood A, McCrae FC, Cooper C, Cawley MI. The prevention of corticoste-roid- induced bone loss with intermittent cyclic etidronate; Scand J Rheumatol 1999;28:152-6. 19. Adachi JD, Bensen WG, Brown J, Hanley D, Hods-man A, Josse R, et al. Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med 1997;337:382-387. 20. Ravn P, Hosking D, Thompson D, Cizza G, Was-nich RD, McClung M, et al. Monitoring of alendronate treatment and prediction of effect on bone mass by biochemical markers in the early postmenopausal inter-vention cohort study. J Clin Endocrinol Metab 1999;84:2363-2368. Singh and Muskelly • Inhaled corticosteroid–induced bone loss and preventive strategies JAOA • Vol 100 • No 7 • Supplement to July 2000 • S17
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Transcript | S14 • JAOA • Vol 100 • No 7 • Supplement to July 2000 Singh and Muskelly • Inhaled corticosteroid–induced bone loss and preventive strategies Inhaled corticosteroids are the main-stay in the treatment of asthma, allow-ing effective control of symptoms with-out the serious side effects associated with systemic corticosteroids. The effi-cacy of inhaled corticosteroids in asthma treatment is dose-dependent, allowing greater anti-inflammatory effect with higher doses. Patients with severe asthma are often taking very high doses of inhaled corticosteroid.1 There is concern that high-dose inhaled corticosteroids may have adverse effects on bone metabolism. This concern arises from the frequency with which osteoporosis is known to occur with long-term use of oral steroids.2 Nearly 50% of patients may have osteoporotic fractures develop as a result of oral cor-ticosteroid therapy if adequate prevention and treatment of this complication are not initiated immediately.3 Other factors to consider are differ-ences between various types of inhaled corticosteroids (Table). Corticosteroids differ between each other in potencies, suppression of the hypothalamus-pitu-itary- adrenal axis, and degree of sys-temic absorption. The dose of each of the inhaled corticosteroids that is systemi-cally absorbed needs to be established. Whether all inhaled corticosteroids at equivalent doses are associated with the same risk is unknown. Mechanisms of corticosteroid-induced bone changes The mechanism of corticosteroid-induced bone loss is complex. Adult bone matrix reflects a constant balance of activity between bone-forming osteoblasts and bone-breakdown cells (osteoclasts).4 A change in this equilibrium may result in reduction of bone mass, resulting in osteoporosis and risk of fracture. Corti-costeroids affect both bone formation and resorption. Corticosteroids decrease osteoblast activity, which results in decreased matrix synthesis and a decreased active life span of osteoblasts. This results in a decrease in the bone mass of mainly the axial skeleton (that is, vertebrae), as the vertebrae contain more metabolically active trabecular bone than cortical bone. This effect with corticoste-roids has been observed using biochem-ical markers of bone turnover, particu-larly serum osteocalcin, which decreases in a dose-dependent way within 4 days of starting corticosteroid therapy.5 Other markers of bone formation include serum levels of alkaline phos-phatase, osteocalcin, procollagen type 1 carboxyterminal and aminoterminal propeptide, and procollagen type 3 aminoterminal propeptide.4 Corticoste-roids also effect osteoclast activity, lead-ing to an increase in bone resorption. Markers for the increase in osteoclast activity include urinary levels of hydrox-yproline, urinary or serum pyridinium cross-links, urinary collagen type 1 cross-linked N-telopeptide, urinary collagen type 1 cross-linked C-telopeptide, and serum carboxyterminal telopeptide of type 1 collagen.4 Bone formation mark-ers are considered to be more sensitive than bone resorption markers in assess-ing the effects of corticosteroids, with osteocalcin being the most sensitive, spe-cific, and reproducible.4 Review of clinical studies Pediatric Prolonged use of systemic corticoste-roids are known to suppress linear growth in children.4 Asthma itself seems to have a negative effect in delaying puberty and reducing growth height, and it should also be considered when evaluating the effect of corticosteroids on bone.4 In addition, there have been a number of studies evaluating the effects of inhaled corticosteroids on growth rate and biochemical markers, as well as bone mineral density (BMD) in chil-dren. Agertoft and Pedersen6 evaluated short-term knemometry (a measurement of velocity of lower leg growth) and 24- hour urine cortisol excretion in 48 chil-dren aged 6 to 12 years. One group of children received treatment with either fluticasone propionate, 200 g/d; budes-onide, 200 g/d; or placebo in a ran-domized, crossover manner. A second group of children received either fluti-casone propionate, 400 g/d; budes-onide, 400 g/d; or placebo in a similar manner. Each treatment period was 15 Systemic corticosteroids are known to cause adverse effects on bone loss and, with long-term use, may result in osteoporosis. There is evidence that inhaled cortico-steroids at moderate to high doses may also induce bone loss. This article discusses the effects of inhaled corticosteroids on bone formation and resorption. It also offers preventive strategies to minimize bone loss associated with long-term use of inhaled corticosteroids. (Key words: asthma, inhaled corticosteroids, osteoporosis, bone loss) Dr Singh is an assistant professor in the Depart-ment of Pharmacy Practice, College of Phar-macy and Allied Health, Wayne State University, Detroit, Mich. Dr Muskelly is a pharmacy prac-tice resident, Department of Pharmacy, Harper Hospital, Detroit. Correspondence to R. F. Singh, PharmD, Department of Pharmacy Practice, College of Pharmacy and Allied Health, Wayne State Uni-versity, 335 Shapero Hall, Detroit, MI 48201. E-mail: rfsingh@med.wayne.edu Inhaled corticosteroid–induced bone loss and preventive strategies RENU F. SINGH, PHARMD CHRIS C. MUSKELLY, PHARMD to 18 days. Knemometry was used to measure the lower leg length twice a week, and 24-hour cortisol excretion was measured at the end of each treat-ment period. No difference was seen in rate of lower leg growth within each group between budesonide or fluticas-one; however, growth rate was signifi-cantly lower in the group receiving budesonide at a dosage of 400 g/d than in the group receiving the place-bo. At this dose—fluticasone propionate, 400 g/d, and budesonide, 400 g/d— there resulted a significant reduction in urinary cortisol excretion compared with that with placebo. Konig and associates7 evaluated bone metabolism in 18 asthmatic children (aged 4 to 17 years) who were treated with inhaled beclomethasone dipropi-onate (400 g/d to 800 g/d) for at least 6 months. Each child was controlled with an age- and sex-matched patient with asthma who was not receiving corticoste-roid therapy. Serum levels of calcium, total alkaline phosphatase, bone-specific alkaline phosphatase, parathyroid hor-mone, 25-hydroxyvitamin D, and 1,25- dihydroxyvitamin D were measured, as was BMD. The study found no signifi-cant differences in the measured serum markers between the treated groups and their age-matched cohort. Further, no significant difference was seen on bone densitometry. The study concluded that inhaled beclomethasone does not reduce bone mineralization or increase bone resorption in children with asthma. These results were confirmed in a later study by Martinati and coworkers,8 who studied the effects of inhaled corticoste-roids on cortical and trabecular bone mass in 64 asthmatic prepubertal subjects (aged between 5 and 10 years) who were treat-ed with beclomethasone dipropionate, 150 g/d to 600 g/d, or cromolyn sodi-um, 30 mg/d for 6.7 months. Lumbar spine bone mass was measured by dual-energy x-ray absorptiometry (DEXA). The DEXA measurements showed no difference in trabecular bone mass in chil-dren who received beclomethasone versus children who received cromolyn sodium. Thus, it appears that inhaled corticoste-roids at low doses do not induce osteo-porosis in children. Adults A number of short- and medium-term studies have evaluated the effects of inhaled corticosteroids on biochemical bone markers in both healthy volunteers and asthmatic patients.9-12 During study periods of 2 to 4 weeks, most studies showed that levels of various markers significantly changed on inhaled corti-costeroid therapy, with the magnitude of effect being dose-related. Kerstjens and colleagues13 conducted two studies on the short-term and long-term effects of inhaled corticosteroids on bone metabolism of patients with asthma or chronic obstructive pulmonary disease. In the first pilot study, 15 patients (mean age, 41.1 years) received at least 800 g/d of beclomethasone dipropionate ( 20 puffs per day). Serum levels of alkaline phosphatase, osteocal-cin, procollagen type 1 carboxy terminal propeptide (PICP), and type 1 collagen carboxy terminal telopeptide (ICTP), and urine level of hydroxyproline were measured at baseline and after 4 weeks of inhaled beclomethasone therapy. In the second long-term, double-blind study, 70 patients (mean age, 40 years) received beclomethasone diproprionate, 800 g/d, while serum PICP and ICTP were mea-sured at baseline and after 2.5 years of treatment. Although the 4-week pilot study revealed a decrease in serum osteo-calcin levels and an increase in serum PICP levels, the long-term study showed no significant changes in serum levels of PICP and ICTP of patients treated with inhaled corticosteroids compared with patients treated without inhaled corti-costeroids. This finding suggests that the clinical significance of short-term changes in metabolic markers with inhaled corti-costeroids is not clear, because long-term studies result in no changes in these markers. Hence, these markers cannot be used as surrogate indicators for bone density to predict risk of developing osteoporosis. Luengo and colleagues14 conducted a case-control study on 48 asthmatic adults (mean age, 56 years) treated with inhaled corticosteroids—beclomethasone or budesonide (300 g to 1000 g) for Singh and Muskelly • Inhaled corticosteroid–induced bone loss and preventive strategies JAOA • Vol 100 • No 7 • Supplement to July 2000 • S15 Table Inhaled Corticosteroids No. of puffs Drug* Low dose Medium dose High dose Beclomethasone dipropionate 4 to 12 12 to 20 20 (Vanceril, Beclovent) 42 g per puff Budesonide 1 to 2 2 to 3 3 (Pulmicort Turbuhaler) 200 g per puff Flunisolide 2 to 4 4 to 8 8 (AeroBid) 250 g per puff Fluticasone propionate (Flovent) 44 g per puff 2 to 6 6 to 15 15 110 g per puff 2 2 to 6 6 220 g per puff 3 Triamcinolone acetonide 4 to 10 10 to 20 20 (Azmacort) 100 g per puff *Drugs are listed by generic names, with trade names in parentheses. more than 1 year (mean duration of treatment, 10.6 years). Twenty-four patients had received one to six short courses of oral corticosteroids while 7 patients had received oral corticosteroids (mean daily dose of 6.2 mg of pred-nisone) for 2 to 15 years more than 4 years before the bone densitometry mea-surements of this study. Vertebral BMD measured by DEXA was obtained at baseline and at 2 years in the asthmatic patients and their age-matched controls. The findings indicated no significant dif-ferences in BMD loss between the group using inhaled corticosteroid and the con-trol group; both groups showed a decrease in BMD over 2 years. These data suggested that inhaled corticoste-roids at mean doses up to 662 g/d do not further increase bone mass loss beyond that expected from natural bone mass loss. Prevention of inhaled corticosteroid–induced bone loss To date, there are no documented treat-ment guidelines for prevention of inhaled corticosteroid–induced bone loss. All recommendations have been geared toward oral corticosteroids.15 Therefore, we opt to suggest that the general rec-ommendations for prevention and treat-ment of glucocorticoid-induced osteo-porosis be considered in patients taking medium to high doses of inhaled cortico-steroids. 15 Calcium and vitamin D The American Rheumatologists Associ-ation recommends that all patients on glucocorticoid therapy have an adequate intake of calcium and vitamin D.15 A daily calcium intake of 1500 mg is rec-ommended, either obtained through dietary intake or calcium supplementa-tion. In addition, vitamin D (either 800 IU/d or 50,000 IU three times a week) or calcitriol (0.5 g/d) should be added. Hormone replacement therapy Postmenopausal women receiving medi-um to high doses of inhaled corticoste-roids should receive estrogen therapy. Estrogens increase bone mass and reduce the risk of fractures related to osteo-porosis. Women with a uterus should also receive a progesterone for 12 to 14 days per month to reduce the risk of endometrial hyperplasia. Women at high risk for breast cancer or having a histo-ry of breast cancer should consider ralox-ifene hydrochloride, an estrogen-receptor antagonist. In a multicenter, random-ized, placebo-controlled study of ralox-ifene in early postmenopausal women with osteoporosis, bone density increased by 2.1% to 2.4% in the femoral neck and 2.6% to 2.7% in the spine com-pared with those taking placebo.16 How-ever, the efficacy of raloxifene in patients receiving inhaled corticosteroids has not been published. Bisphosphonates The actual mechanism of action of bis-phosphonates is poorly understood; however, they are inhibitors of bone resorption (reduction of number of osteo-clasts) that are used in treatment of Paget’s disease, hypercalcemia, and osteo-porosis. 17 Many bisphosphonates (such as alendronate sodium, cyclic etidronate disodium, and pamidronate disodium) have been evaluated in corticosteroid-induced bone loss. Intermittent cyclical etidronate sodium (400 mg daily for 2 weeks) and calcium (500 mg/d for 11 weeks) was studied and resulted in an increase in BMD of lumbar spine by 1.8% (P .001) at both 6 months and 12 months.18 Intermittent etidronate dis-odium (400 mg/d for 14 days) and cal-cium (500 mg/d for 76 days) prevented loss of vertebral and trochanteric bone in 141 patients aged 19 to 87 years treated with high-dose oral prednisone ( 7.5 mg/d).19 The mean BMD of the lumbar spine and trochanter in the group receiv-ing etidronate increased by 0.61% and 1.46%, respectively, as compared with a decrease of 3.23% and 2.74%, respec-tively, in the group receiving the placebo. In a randomized, placebo-controlled study of adults receiving long-term glu-cocorticoid therapy, patients were treat-ed with alendronate, 5 mg/d to 10 mg/d for 48 weeks.20 The mean BMD of the lumbar spine in these patients increased by 2.1% and 2.9% (P .001); the femoral neck BMD increased by 1.2% and 1% (P .01) in the alendronate-treated group as compared with the placebo group. In an early postmenopausal interven-tion cohort study of 1202 women, aged 45 to 59 years, treated with alendronate, 2.5 mg/d and 5 mg/d for 2 years, there was an increased response in spine and hip BMD of 2% to 4% over 2 years.21 Comment Patients taking moderate to high doses of inhaled corticosteroids may be at increased risk for long-term bone loss, especially if used for a prolonged time. It remains to be established whether inhaled corticosteroid–induced bone changes are clinically important. Although no specif-ic guidelines are available, it would seem prudent to consider preventive measures such as calcium and vitamin D supple-mentation in patients taking moderate to high doses of inhaled corticosteroids (Table). Patients with additional risk fac-tors, such as a postmenopausal state, should consider estrogen replacement therapy. If high doses of inhaled corti-costeroids are used, a screening bone DEXA scan may be indicated to see if more aggressive therapy is needed. References 1. Packe GE, Douglas JG, McDonald AF, Robins SP, Reid DM. Bone density in asthmatic patients taking high dose inhaled beclomethasone dipropionate and intermittent systemic corticosteroids. Thorax 1992;47:414-417. 2. Toogood JH, Baskerville JC, Markov AE, Hodsman AB, Fraher LJ, Jennings B, et al: Bone mineral densi-ty and the risk of fracture in patients receiving long-term inhaled steroid therapy for asthma. J Allergy Clin Immunol 1995;96:157-166. 3. Libinati CR, Baylink DJ. Prevention and treat-ment of glucorticoid-induced osteoporosis. Chest 1992;102:1426-1435. 4. Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med 1999;159:941-955. 5. Eastell R, Reid DM, Compston J, Cooper C, Fogel-man I, Francis RM, et al. A UK Consensus Group on management of glucocorticoid-induced osteoporosis: an update. J Intern Med 1998;244:271-292. 6. Agertoft L, Pedersen S. Short-term knemometry and urine cortisol excretion in children treated with fluticas-one propionate and budesonide: a dose response study. Eur Respir J 1997;10:1507-1512. S16 • JAOA • Vol 100 • No 7 • Supplement to July 2000 Singh and Muskelly • Inhaled corticosteroid–induced bone loss and preventive strategies 7. Konig P, Hillman L, Cervantes C, Levine C, Mal-oney C, Douglass B, et al. Bone metabolism in children with asthma treated with inhaled beclomethasone dipro-pionate. J Pediatr 1993;122:219-226. 8. Martinati LC, Bertoldo F, Gasperi E, Micelli S, Boner AL. Effect on cortical and trabecular bone mass of dif-ferent anti-inflammatory treatments in preadolescent children with chronic asthma. Am J Respir Crit Care Med 1996;153:232-236. 9. Hodsman AB, Toogood JH, Jennings B, Fraher LJ, Baskerville JC. Differential effects of inhaled budes-onide and oral prednisolone on serum osteocalcin. J Clin Endocrinol Metab 1991;72:530-540. 10. Pouw EM, Prummel MF, Oosting H, Roos CM, Endert E. Beclomethasone inhalation decreases serum osteocalcin concentrations. BMJ 1991;302:627-628. 11. Teelucksingh S, Padfield PL, Tibi L, Gough KJ, Holt PR. Inhaled corticosteroids, bone formation, and osteocalcin. Lancet 1991;338:60-61. 12. Ali NJ, Capewell S, Ward MJ. Bone turnover during high dose inhaled corticosteroid treatment. Thorax 1991;46:160-164. 13. Kerstjens HA, Postma DS, van Doormaal JJ, van Zanten AK, Brand PL, Dekhuijzen PN, et al. Effects of short-term and long-term treatment with inhaled cortico-steroids on bone metabolism in patients with airways obstruction. Dutch CNSLD Study Group. Thorax 1994;49:652-656. 14. Luengo M, del Rio L, Pons F, Picado C. Bone min-eral density in asthmatic patients treated with inhaled corticosteroids: a case-control study. Eur Respir J 1997;10:2110-2113. 15. Recommendations for the prevention and treat-ment of glucocorticoid-induced osteoporosis. Ameri-can College of Rheumatology Task Force on Osteo-porosis Guidelines. Arthritis Rheum 1996;39:1791-1801. 16. MacReady N. Raloxifene reduces spinal fractures postmenopausally. Lancet 1999;354:653. 17. Saag KG, Emkey R, Schnitzer TJ, Brown JP, Hawkins F, Goemaere S, et al. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group. N Engl J Med 1998;339:292- 299. 18. Jenkins EA, Walker-Bone KE, Wood A, McCrae FC, Cooper C, Cawley MI. The prevention of corticoste-roid- induced bone loss with intermittent cyclic etidronate; Scand J Rheumatol 1999;28:152-6. 19. Adachi JD, Bensen WG, Brown J, Hanley D, Hods-man A, Josse R, et al. Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med 1997;337:382-387. 20. Ravn P, Hosking D, Thompson D, Cizza G, Was-nich RD, McClung M, et al. Monitoring of alendronate treatment and prediction of effect on bone mass by biochemical markers in the early postmenopausal inter-vention cohort study. J Clin Endocrinol Metab 1999;84:2363-2368. Singh and Muskelly • Inhaled corticosteroid–induced bone loss and preventive strategies JAOA • Vol 100 • No 7 • Supplement to July 2000 • S17 |
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