Preventing steroid-induced osteoporosis

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Preventing glucocorticoid-induced osteoporosisSep 15, 2002Patient Care Bone loss from glucocorticoid therapy is immediate and occurs at thehighest rate during the first 6 months. Judicious use of calcium, vitamin D,hormone replacement therapy, and bisphosphonates at the onset of long-termtreatment can improve bone density. Exogenous glucocorticoids are the treatment of choice for many medicalconditions, and their beneficial effects can be quite dramatic. Yet thisclass of drugs is potentially one of the most toxic, with side effectsranging from less serious medical conditions such as truncal obesity,striae, and cataracts, to more serious ones such as hypertension, diabetesmellitus, osteonecrosis, and osteoporosis. Glucocorticoids have been a knownrisk factor for osteoporosis since the 1930s, when their association withskeletal changes and endocrine tumors was first reported.1 By the 1950s, exogenous glucocorticoid therapy became widespread, andthe severity of glucocorticoid-induced osteoporosis (GIO) was more fullyappreciated. Recent data suggest that osteoporosis will develop inapproximately 50% of patients who undergo long-term glucocorticoid therapy,thereby increasing their risk of sustaining spontaneous fractures.2Long-term therapy with 7.5 mg/d of prednisone is associated with an averageof 3% bone loss annually. Despite its prevalence and significant morbidity,this common iatrogenic disease is often underrecognized and inadequatelytreated. This article will review the problem and suggest solutions. HOW GLUCOCORTICOIDS CAUSE BONE LOSS Bone is actively remodeled throughout adult life. Even in the absenceof glucocorticoid exposure, 25% of trabecular bone and 3% of cortical boneare remodeled annually. Osteoblasts and osteoclasts are the cell types largely responsible forbone turnover. Osteoblasts are cuboidal cells found in clusters at the bonesurface. They produce a layer of osteoid, which matures over a period of 10days by a process of calcification that, over the course of several months,results in new bone. Osteoclasts are multinucleated giant cells responsiblefor bone resorption. They attach to bone matrix via integrin receptors,which help to create pockets of extracellular space bordered by folds ofruffled osteoclast membrane. This process creates secondary lysosomescharacterized by a low pH and an enzyme-rich environment in which bonematrix degradation occurs. When glucocorticoids cause bone resorption tooccur at a faster rate than bone formation, osteoporosis results. Corticosteroid receptors are partitioned into two types:mineralocorticoid (found in CNS and renal tissue) and glucocorticoid(present in virtually all cells of the body). Glucocorticoid receptorsmediate both the anti-inflammatory and metabolic effects of corticosteroids.When glucocorticoids bind to the cellular receptors, the resulting complexmigrates to the nucleus where gene expression is induced. Consequently, alllevels of the inflammatory cascade are inhibited. Glucocorticoids are mosteffective at suppressing T lymphocytes and natural killer cells, but theytend to be less effective at inhibiting mature B cells. Corticosteroids alsosuppress proinflammatory cytokines such as tumor necrosis factor-alpha andinterleukin-1. They have inhibitory effects on inflammatory mediators suchas gamma interferon, prostaglandin E2, and leukotrienes. The overall resultappears to be preferential suppression of cellular immunity rather thanhumoral immunity. GIO occurs as a consequence of multiple direct and indirect effects ofglucocorticoids on bone formation and resorption, the metabolism of calciumand vitamin D, and the modulation of sex hormones. Glucocorticoids directlyinhibit osteoblast proliferation and matrix synthesis and cause a decline incirculating levels of osteocalcin. They have also been implicated inosteoblast apoptosis. Since bone formation is linked to body mass and musclestrength, the catabolic effects of corticosteroids on muscle may indirectlyreduce bone formation. Hence, glucocorticoids weaken bone formation by wayof a glucocorticoid-induced myopathy with its associated loss of the trophiceffect of muscle stress on bone. Corticosteroids also reduce sex hormone levels. They specificallysuppress estrogen, luteinizing hormone, and follicle-stimulating hormone inwomen, which normally act to inhibit bone resorption. Moreover, a loss ofestrogen is associated with a net increase in numbers of osteoclasts. Theresultant hypogonadism favors osteoclastic over osteoblastic activity. In addition, glucocorticoids may indirectly accelerate bone resorptionby causing excessive calciuria. The reduced availability of substrate forbone formation that results is worsened by impaired renal tubularreabsorption of calcium caused by glucocorticoids as well as reduced serumlevels of 1,25-dihydroxyvitamin D. This net loss in calcium causes asecondary hyperparathyroidism, leading to further resorption of bone.3Furthermore, glucocorticoids also decrease trabecular bone mass byinterfering with bone-active cytokines such as insulinlike growth factors. GIO becomes detectable by sensitive radiologic methods as early as 1month into systemic glucocorticoid therapy. Dual-energy x-ray absorptiometry(DXA) and quantitative CT are radiologic methods available for detecting lowbone mass. Of these techniques, DXA is less expensive and more widelyavailable. T-scores, which are used in clinical decision-making, representthe number of standard deviations below or above the peak bone mass in ayoung adult reference population of the same sex. According to the WorldHealth Organization, a T-score above -1 reflects normal bone density,between -1 and -2.5 is osteopenia, and below -2.5 signifies osteoporosis.3 AT-score below -2.5 in addition to a personal history of fractures indicatessevere osteoporosis. Individuals at greatest risk for GIO are those experiencing high boneturnover or those with a preexisting imbalance between resorption andformation, including children aged 15 and younger, adults older than 50,postmenopausal women, and immobilized patients. Bone loss occurs mostly inareas of high turnover, such as trabecular bone of the vertebra, andresulting spontaneous fractures commonly involve the vertebrae or ribs.4,5In one study, current corticosteroid users were 2.7 times more likely tosustain a hip fracture compared with nonusers.6 Significant metabolic bone disease due to glucocorticoid therapyoccurs in a short amount of time. Even low-dose, 6-week corticosteroidtreatment is associated with adverse effects on bone metabolism.7 In onestudy, 10 mg/d of prednisone over a 2-month period adversely affectedcalcium and bone metabolism by uncoupling bone formation and resorption.7Another study found that 20 weeks of treatment with low-dose prednisoneinduced a mean trabecular bone mineral density decline of 8.2% in patientswith rheumatoid arthritis.8 Susceptibility to fracture is dependent ondosage, and the overall risk of fracture is increased during oralcorticosteroid therapy, becoming apparent within the first 3 months oftreatment.9 Therefore, preventive therapy for osteoporosis should commencewhen glucocorticoids are first prescribed.2 PROPHYLAXIS AGAINST GIO Early strategies for the prevention and treatment of GIO blunted theadverse impact of steroids on bone but did not consistently improve bonestrength, as has been seen with the more recently released class of agentsknown as bisphosphonates. Among those strategies were sodium restrictionwith concurrent thiazide diuretic therapy and treatment with sodium fluorideor calcitonin. In particular, the use of thiazide diuretics with saltrestriction remains of unproved benefit, while treatment with vitamin Dcarries a risk of hypercalciuria and urinary stone formation. Sodiumfluoride stimulates bone formation but remains controversial because of theresultant abnormal bone quality noted during such therapy.10 Over the past decade, however, some notable inroads toward thereduction of corticosteroid-induced bone mineral loss were made.11-15 Mostnotably, these include gonadal hormone supplementation and bisphosphonates,both of which have antiresorptive properties and may maintain or increasebone density in some persons taking corticosteroids. Calcitonin can beeffective in some cases and may be considered when bisphosphonates are not aviable option. In addition to using those therapies, the American College ofRheumatology (ACR) recommends treating confounding comorbid conditions suchas hyperthyroidism.2 Lifestyle alterations that may improve bone healthinclude exercise, reduction of alcohol use, and avoidance of cigarettes.Although the best preventive measure is to discontinue use ofglucocorticoids, in many situations this course of action is not feasible.Glucocorticoids should be prescribed at the minimum effective dose. Topicalor inhaled agents are preferred over systemic corticosteroids, if practical.Because bone loss is most rapid during the first 6 months of glucocorticoidtherapy, the ACR advises physicians to start all patients on calcium plusvitamin D at the onset of treatment. Calcitonin and vitamin D metabolites Providing adequate substrate for bone formation includessupplementation with calcium in addition to vitamin D. A daily intake of1500 mg of elemental calcium, either through diet or supplements, reducesbone turnover. In most patients, cholecalciferol, 400 to 800 IU/d, issufficient to maintain serum levels in a proper range. If high-dosecholecalciferol is used, carefully check both serum and urine calcium levelsperiodically. Intranasal salmon calcitonin administered in dosages up to 400 IU/dwas shown in several studies to blunt the loss of bone mineral content.10One study comparing prophylactic use of calcium, calcitriol, and calcitoninfound that only treatment with calcium and calcitriol (with or withoutcalcitonin) prevented or reduced bone loss from the lumbar spine.15 Asignificant side effect of treatment was hypercalcemia. Variable dosing ofcorticosteroid therapy and the lack of a placebo control group, however, maylimit interpretation of results of this particular study. Expertconsultation should be obtained before prescribing calcitriol. Hormone replacement therapy Corticosteroids reduce levels of sex hormones, thereby indirectlyfacilitating osteoclastic bone resorption. Therefore, patients takingglucocorticoids may benefit from hormone replacement therapy (HRT), astrategy that is still being investigated. One study using gonadal hormonereplacement for patients receiving chronic glucocorticoid therapydemonstrated either stability or improvement of bone mineral density in bothmen and women.16 Bisphosphonates Synthetic pyrophosphates that resist chemicaldegradation-bisphosphonates-have recently become key players in treating andpreventing GIO. A study assessing the benefit of alendronate for patients onlong-term corticosteroid therapy found that those taking alendronate showedincreased bone mineral density in the lumbar spine, hips, and overallcompared to patients taking placebo.12 In addition, fewer new vertebralfractures were observed in the alendronate group. The evidence suggests thatprophylaxis with alendronate, 5 mg/d, may be warranted in patients receivinglong-term glucocorticoids. More recently, a third-generation oralbisphosphonate was shown to prevent bone loss in patients initiatingcorticosteroid treatment. Risedronate, 5 mg/d, resulted in significantpositive treatment effects in both men and women after 12 months ofintervention.13 Other bisphosphonates that may help treat or prevent GIOinclude IV pamidronate and the cyclical administration of etidronate. Anabolic therapy Recently, anabolic therapy, with parathyroid hormone in particular,has shown promise in the treatment of GIO.17 Early studies, however, do notreveal consistent improvement throughout the skeleton, and primaryprevention studies are yet to be completed. EVIDENCE OF UNDERTREATMENT Despite recent guidelines published by the ACR and numerous studiesestablishing the efficacy of preventive therapy against GIO, growingevidence suggests widespread underutilization of these measures. A telephonesurvey of patients on long-term glucocorticoids reported that 29% weretaking calcium supplements and 45% were receiving vitamin D. Of thepostmenopausal women surveyed, 40% were receiving HRT, 14% were receivingbisphosphonates, and 29% had undergone a DXA scan.18 In another study,charts of 215 clinic patients on glucocorticoid therapy for more than 1month were reviewed. Prophylaxis against GIO was prescribed for 58% of thepatients.10 The rheumatology staff at The Washington University MedicalCenter, Washington, DC, performed a similar retrospective chart review. Inthis unpublished study, only 29% of the patients surveyed were givenpreventive therapy, and only 16% were assessed via DXA scan. All of thepatients evaluated and given prophylaxis were women, most of whom were intheir 40s. Preventive therapy was typically initiated after the patient hadtaken glucocorticoids for more than 2 years and at dosages equivalent tomore than 10 mg/d of prednisone. The results showed that evenuniversity-based rheumatologists who commonly confront the adverse effectsof excess exogenous glucocorticoids infrequently evaluate for, or provideprophylaxis against, GIO. A history of a DXA scan correlated with a higher rate of preventivetherapy by increasing the likelihood of diagnosing GIO. Therefore,increasing physician awareness concerning issues surrounding GIO may be ofsignificant importance in detecting and treating patients with metabolicbone disease. These studies show the need to initiate a better approach toeducate patients and physicians regarding the importance of GIO prevention. A checklist addressing issues pertinent to patients takingglucocorticoids, such as adverse effects of corticosteroids, risk factorsfor osteoporosis, previous DXA scan results, and preventive therapyselected, may be a useful tool for physicians (see "Monitoring patients onglucocorticoids"). This type of document can be placed in the charts of allpatients when initiating glucocorticoid therapy to serve as a reminder ofthe increased risk of osteoporosis and the need for prophylaxis. EDITED BY STACY DILORETO REFERENCES 1. Cushing H. Basophile adenomas of the pituitary body. J Nerv MentDis. 1932;76:50-56. 2. American College of Rheumatology Task Force on OsteoporosisGuidelines. Recommendations for the prevention and treatment ofglucocorticoid-induced osteoporosis. Arthritis Rheum. 1996;39:1791-1801. 3. NOF Physician's Guide: Diagnosis. National Osteoporosis FoundationWeb site. Available at: http://www.nof.org/physguide/diagnosis.htm .Accessed October 9, 2000. 4. Seeman E, Wahner HW, Offord KP, et al. Differential effects ofendocrine dysfunction on the axial and the appendicular skeleton. J ClinInvest. 1982;69:1302-1309. 5. Lane NE, Mroczkowski PJ, Hochberg MC. Prevention and management ofglucocorticoid-induced osteoporosis. Bull Rheum Dis. 1995;44:1-4. 6. C, Coupland C, M. Rheumatoid arthritis,corticosteroid therapy and hip fracture. Ann Rheum Dis. 1995;54:49-52. 7. Lems WF, s JW, Van Rijn HJ, et al. Changes in calcium and bonemetabolism during treatment with low dose prednisone in young, healthy, malevolunteers. Clin Rheumatol. 1995;14:420-424. 8. Laan RF, van Riel PL, van de Putte LB, et al. Low-dose prednisoneinduces rapid reversible axial bone loss in patients with rheumatoidarthritis. Ann Intern Med. 1993;119:963-968. 9. Van Staa TP, Leufkens HG, Abenhaim L, et al. Use of oralcorticosteroids and risk of fractures. J Bone Miner Res. 2000;15:993-1000. 10. Eastell R, Reid DM, Compston J, et al. A UK Consensus Group onmanagement of glucocorticoid-induced osteoporosis: an update. J Intern Med.1998;244:271-292. 11. Boutsen Y, Jamart J, Esselinckx W, et al. Primary prevention ofglucocorticoid-induced osteoporosis with intermittent intravenouspamidronate: a randomized trial. Calcif Tissue Int. 1997;61:266-271. 12. Saag KG, Emkey R, Schnitzer TJ, et al. Alendronate for theprevention and treatment of glucocorticoid-induced osteoporosis.Glucocorticoid-Induced Osteoporosis Study Group. N Engl J Med.1998;339:292-299. 13. Cohen S, Levy RM, Keller M, et al. Risedronate therapy preventscorticosteroid-induced bone loss: a twelve-month, multicenter, randomized,double-blind, placebo-controlled, parallel-group study. Arthritis Rheum.1999;42:2309-2318. 14. Buckley LM, Leib ES, Cartularo KS, et al. Calcium and vitamin D3supplementation prevents bone loss in the spine secondary to low-dosecorticosteroids in patients with rheumatoid arthritis: a randomized,double-blind, placebo-controlled trial. Ann Intern Med. 1996;125:961-968. 15. Sambrook P, Birmingham J, P, et al. Prevention ofcorticosteroid osteoporosis: a comparison of calcium, calcitrol, andcalcitonin. N Engl J Med. 1993;328:1747-1752. 16. Lukert BP, BE, RG. Estrogen and progesteronereplacement therapy reduces glucocorticoid-induced bone loss. J Bone MinerRes. 1992;7:1063-1069. 17. Lane NE, S, Genant HK, et al. Short-term increases in boneturnover markers predict parathyroid hormone-induced spinal bone mineraldensity gains in postmenopausal women with glucocorticoid-inducedosteoporosis. Osteoporos Int. 2000;11:434-442. 18. Aagaard EM, Lin P, Modin GW, et al. Prevention ofglucocorticoid-induced osteoporosis: provider practice at an urban countyhospital. Am J Med. 1999;107:456-460. ARTICLE CONTRIBUTORS DEBORAH T. ZAREK, MD, Internal Medicine Resident, Christiana CareHealth System-Christiana Hospital, Newark, Del. JAMES D. KATZ, MD, Assistant Professor of Medicine, Division ofRheumatology, The Washington University Medical Center, Washington,DC.http://www.patientcareonline.com/patcare/article/articleDetail.jsp?id=117083