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Clinical Review: Focused
Adverse Effects of Corticosteroids on BoneMetabolism: A Review
Raj Mitra, MDAbstract: Glucocorticoid (GC) exposure is the most common etiology of drug-inducedsecondary) osteoporosis. Twenty percent of all cases of osteoporosis have been attributed toC exposure. Significant risk factors for the development of fractures after GC exposure
nclude age older than 65 years, prolonged GC exposure (�3 months), positive familyistory of osteoporosis, and low calcium intake. GCs are known to inhibit bone remodelingnd to increase fracture risk. GC exposure alters the fragile balance between osteoclast andsteoblast activity in bone metabolism. GC stimulates osteoclast-mediated bone resorptionnd reduces osteoblast-mediated bone formation, which results in increased overall netone resorption. Specifically, the 2 main effects of GCs on bone metabolism are (1) inducingpoptosis in osteoblasts and osteocytes, thereby decreasing bone formation, and (2) pro-onging the lifespan of osteoclasts and increasing bone resorption. The risk of fractureecreases 3 months after cessation of GC therapy; thus, a 3-month period may be idealetween GC exposures in patients at high risk for the development of osteoporosis. Patientsanaged with GCs who are at high risk for the development of secondary osteoporosis
hould have appropriate diagnostic testing; pre-GC exposure medication management (ie,se of bisphosphonates, human parathyroid hormone); and a limitation of GC therapy, withwait period of 3 months between GC exposures if possible.
PM R 2011;3:466-471
INTRODUCTION
Steroids were first described in 1901 in the management of sciatica and cancer pain [1,2]. In1932, Cushing [3] described the effects of glucocorticoid (GC) exposure on bone metabo-lism, and, in 1953, GCs subsequently were used neuroaxially for spinal pathology [4]. Sincethat time, GCs have become common in the palliative management of the spine (especiallyin cases of neurogenic claudication and radiculopathy attributed to a herniated disk),inflammatory arthropathies, and musculoskeletal pain disorders [5,6].
The mechanism by which GCs provide patients long-term relief for pain syndromes isnot totally clear. It has been postulated that, in addition to their anti-inflammatory effects,GC may induce neuronal reorganization [7]. GCs may also exert their analgesic effects bybinding cytosolic GC receptor located on primary and secondary immune cells [8].
Although GC-induced osteoporosis is the leading cause of secondary osteoporosis, manypatients do not undergo appropriate preprocedure risk assessment before GC exposure [9].Unlike primary osteoporosis, which is characterized by low bone mass in the absence of adisease process or exposure, secondary osteoporosis may result from a variety of chronicconditions and exposures, including exposure to GCs [10]. Other adverse effects associatedwith GC exposure include mania, hyperglycemia, hypertension, weight gain, insomnia, anddisorders of bone metabolism that lead to osteoporosis (Table 1) [11].
Roughly one-fifth of all osteoporosis cases have been attributed to GC exposure; despitethe high prevalence, however, no formal guidelines exist for steroid exposure in high-riskpopulations that undergo repeated GC therapy [12]. Although many physicians will limitthe number of GC therapies in a calendar year, there is no clear consensus on the number ofGC exposures and dosage. The intention of this article is, first, to summarize the literature
concerning the effects of GC on bone metabolism and, second, to formulate evidence-basedPM&R © 2011 by the American Academy of P1934-1482/11/$36.00
Printed in U.S.A.466
R.M. Stanford University School of Medicine,450 Broadway St, Mailcode 6342, RedwoodCity, CA 94063. Address correspondence to:R.M.; e-mail: [email protected]: nothing to disclose
Peer reviewers and all others who controlcontent have no relevant financial relation-ships to disclose.
Disclosure Key can be found on the Table ofContents and at www.pmrjournal.org
Submitted for publication March 24, 2010;accepted February 7, 2011.
hysical Medicine and RehabilitationVol. 3, 466-471, May 2011
DOI: 10.1016/j.pmrj.2011.02.017
w
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467PM&R Vol. 3, Iss. 5, 2011
recommendations for the use of GCs in patients at high riskfor the development of secondary osteoporosis and fractures.
METHODS
Search Strategy and Selection Criteria
A computer-aided search of several databases was performed:MEDLINE (US National Library of Medicine, Bethesda, MD),1966 to October 2010; EMBASE (Elsevier BV, Amsterdam,the Netherlands), 1982 to present; CINAHL (CumulativeIndex to Nursing and Allied Health Literature; EBSCO Indus-tries, Glendale, CA), 1982 to October 2010; and all EBM(Evidence-Based Medicine, US National Library of Medicine,Bethesda, MD) reviews, including Cochrane DSR (Databaseof Systematic Reviews, ACP Journal Club (American Collegeof Physicians, Philadelphia, PA); DARE (Database of Ab-stracts of Reviews of Effects; National Health Service Centerfor Reviews & Dissemination (NHS CRD), University ofYork, York, UK), and CCTR (Cochrane Controlled TrialsRegister, now known as Cochrane Database of SystematicReviews, The Cochrane Collaboration). The search termswere steroid, corticosteroid, bone, and metabolism. Caseseries and studies with low statistical power were omitted forthis focused review.
Epidemiology
Osteoporosis attributed to GC exposure is the most commonetiology of drug-induced (secondary) osteoporosis, with one-fifth of all cases of osteoporosis having been attributed to GCexposure [13]. Corticosteroid used in musculoskeletal andspinal pain syndromes accounts for almost half of all GCtreatments. GC therapy has become quite common, espe-cially in the elderly population. It has been reported that upto 2.5% of the general population in the United Kingdommay be receiving steroid therapy at any given time, whereasroughly 10% of Americans require long-term GC therapy forthe management of chronic illness [14,15]. Almost 50% ofpatients receiving chronic GC therapy will develop osteope-nia and fractures; 17% of these patients will develop fractureswithin the first year of GC therapy [16]. Significant riskfactors for the development of fractures after steroid exposure
Table 1. Major adverse sequelae of glucocorticoid exposure
HyperglycemiaWeight gainOsteoporosisDiabetes mellitusHypertensionMania or hypomaniaImmune suppressionCushing syndromeHypothalamic pituitary adrenal axis suppression
include age older than 65 years, prolonged steroid exposure
(�3 months), positive family history of osteoporosis, andlow calcium intake [17] (Table 2). Patients receiving long-term steroid medication have been found to have an elevatedrisk of developing new fractures after vertebroplasty [18].Furthermore, the incidence of vertebral fractures is higher inpatients with GC-induced osteoporosis when compared withprimary osteoporosis [19].
Pathophysiology
Oral GC has been shown to increase bone resorption in adose-response relationship [20]. Steroids are produced inthe adrenal cortex and modulated by the hypothalamic–pituitary–adrenal axis. Corticotropin-releasing hormone(CRH) produced by the hypothalamus stimulates the pi-tuitary gland to produce adrenocorticotropic hormone(ACTH); ACTH, in turn, stimulates the adrenal cortex toproduce glucocorticoids [21]. Sex steroids are importantin bone metabolism. Patients with lower free androgenand estradiol levels are more likely to have symptomaticvertebral body fractures [22].
GC exposure alters the fragile balance between osteoclastand osteoblast activity in bone metabolism (Figure 1) [23].GC receptors have been found in human osteoblasts andosteoclasts [24]. GC stimulates osteoclast-mediated boneresorption and reduces osteoblast-mediated bone formation,which results in increased overall net bone resorption. Spe-cifically, the 2 main effects of GCs on bone metabolism are(1) inducing apoptosis in osteoblasts and osteocytes, therebydecreasing bone formation; and (2) prolonging the lifespan ofosteoclasts and increasing bone resorption [25,26]. In con-trast, in postmenopausal osteoporosis, increased bone re-sorption seems to be the key factor [27].
Effects on Osteoblasts
The majority of normal osteoblasts will undergo apoptosis.The remainder will differentiate into an osteocyte, which iscapable of proliferation and secretion of osteoid matrix inte-gral for bone formation. In addition, osteoblasts secrete nu-clear factor–�B ligand (RANKL, an osteoclast activator) as
ell as osteoprotegrin (a RANKL inhibitor).GC affects osteoblasts throughout their lifespan and in-
ibits stem cell differentiation into osteoblasts [28]. These
Table 2. Patients at risk for the development of glucocortico-id-induced osteoporosis
Advanced age (�65 y)Prolonged exposureKnown history of osteoporosisFamily history of osteoporosisLow calcium intakeHistory of fractureFamily history of hip fracture
Rheumatoid arthritis
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468 Mitra ADVERSE EFFECTS OF CORTICOSTEROIDS ON BONE METABOLISM
stem cells instead proliferate into adipocytes and decrease theosteoblast pool [29]. GC also causes osteoblasts to decrease
roduction of insulin-like growth factor (IGF-I), which de-reases proliferation and anabolic activity [30]. The overall
effect of GC on osteoblasts, therefore, results in significantlydecreased anabolic activity, apoptosis, and decrease in stemcell differentiation into osteocytes; this, in turn, decreases thesecretion of osteoid matrix and new bone formation.
Effects on Osteoclasts
Osteoclasts are essentially members of the macrophage fam-ily and eventually differentiate into multinucleated giant cells[31]. Osteoclasts attach to the bone surface and digest bonematrix by creation of an acidic environment; these cellsnormally work in harmony with osteoblasts and eventuallyundergo apoptosis.
As mentioned above, the increase in osteoblast RANKligand production (induced by GC) leads to increased oste-oclastic activity. In addition, receptor activation of RANKligand secondary to GC exposure prolongs the lifespan ofosteoclasts [14]. Parathyroid hormone also leads to stimula-tion of the osteoclasts.
Systemic Effects of GC Exposure
GC exposure has been demonstrated to affect the hypotha-lamic–pituitary–adrenal axis; production of adrenal and go-nadal hormones are reduced (including estrogen and testos-terone) [32]. Osteoprotegrin and estrogen both inhibitosteoclast activity. Experiments have demonstrated that acti-
Figure 1. Glucocorticoid stimulates osteoclast-mediatedbone resorption and reduces osteoblast-mediated bone for-mation, which results in increased overall net bone resorption.Specifically, the 2 main effects of glucocorticoids on bonemetabolism are (A) inducing apoptosis in osteoblasts andosteocytes, thereby decreasing bone formation; and (B) pro-longing the lifespan of osteoclasts and increasing bone resorp-tion [13]. Reprinted with permission.
vation of the estrogen receptor � and androgen receptor
esult in a stimulatory effect on both the cortical and trabec-lar bone mass in males [33]. Reduction in estrogen recep-or activation secondary to GC exposure, therefore, mayurther increase bone resorption (by decreasing estrogen-elated osteoclast inhibition). Recently, much interest haseen placed on GC receptor antagonists; the steroid mife-ristone (RU-486) is primarily antiestrogenic, and re-earch on its efficacy in decreasing the incidence of bonereakdown is limited [34].
GCs are known to affect calcium metabolism by decreas-ng renal uptake and intestinal absorption in a dose-depen-ent manner [25]. GC exposure, which decreases renal cal-ium uptake, in turn, stimulates an increase in parathyroidormone (PTH), further increasing the number of osteoclastsnd stimulating bone resorption [35]. Interestingly, not allatients managed with GC develop low bone mineral den-ity. The current literature suggests that the phenomenonay be caused by multiple genes as opposed to polymor-hism in a single gene [36]. Vitamin D polymorphisms,owever, have not been consistently linked to low boneineral density in patients managed with GC, and the asso-
iation is still unclear [37,38].GC therapy also has been associated with the develop-
ment of avascular necrosis. It has been postulated that GCpotentiates fat accumulation in bone marrow, which subse-quently leads to intraosseous hypertension, decreased bloodflow, and eventually necrosis of bone [39]. The proximalfemur is most commonly involved, followed by distal femur-proximal tibial plateau, and shoulder [40].
GC Exposure and Fracture Risk
Fractures continue to be a common risk of prolonged steroidexposure and remain the most clinically relevant endpoint.The magnitude of the risk and relationship to duration ofexposure are not clear. Steroids are known to increase frac-ture risk by their inhibition of bone remodeling [41]. Patientsmanaged with long-term steroids have a significantly higherrisk of developing vertebral compression fractures [42]. Atudy by Cooper et al [43] reported a doubling of the risk of
hip fractures in patients with rheumatoid arthritis who hadbeen managed with long-term steroids, when compared withage- and gender-matched community controls.
There are numerous studies that have analyzed the rela-tionship between dosage of GC and fracture risk. Bone losssecondary to GC treatment has been shown to be dosedependent, with an increase in fracture risk being correlatedwith GC dosage [44]. Eighty percent of patients with asthmamanaged with high-dose GC therapy had a decrease in bonemineral density compared with 33% of patients managedwith a low dose of GCs [45]. Fractures may occur within3 months of GC therapy at dosages as low as 2.5 mg of pred-nisone daily [46]. De Vries et al [47] analyzed 191,752
patients who were receiving intermittent GCs over a 10-year
469PM&R Vol. 3, Iss. 5, 2011
period; those patients who received less than 7.5 mg ofprednisone daily had a roughly 60% increase in vertebralbody fracture. In the same study, a dose-dependent relation-ship was described with patients who received 30 mg of oralprednisone daily having substantially more risk of spinalfracture than those who received 7.5 mg of prednisone daily.
GC therapy has been shown to affect trabecular bone slightlymore than cortical bone, which affects the spine more than thehip [48]. Although the risk of fracture increases within the firstfew months of GC exposure, the likelihood of fracture rapidlydecreases after cessation of steroid therapy [49]. The highest rateof bone loss occurs in the first 6 months of treatment [50]. Therelationship between cessation of GC exposure and a decrease infracture risk has been well characterized by Van Staa et al [48],with the greatest decrease in relative risk occurring within thefirst 3 months of cessation (Figure 2).
Management
Appropriate management may help prevent or reduce boneloss and fracture development in patients chronically ex-posed to GC [51]. Bisphosphonates are the first-line agentsfor the prevention of GC-induced osteoporosis. Teriparatide,calcium supplements, active vitamin D, and hormonal re-placement are alternative agents [21]. Patients have beenshown to achieve optimal results when they have been pre-scribed calcium supplements and vitamin D before and dur-ing bisphosphonate use [52] (Table 3).
Alendronate has been shown to be beneficial in increasingbone mineral density and deceasing vertebral spinal frac-tures. At 1-year follow-up, patients exposed to GC who weretreated with alendronate were found to have 3% increase inlumbar spine bone mineral density and an overall 40%relative risk reduction [53]. Risedronate has been shown to
Figure 2. Adjusted relative rate of nonvertebral fractures aftercessation of oral glucocorticoids. Reprinted with permissionfrom reference [48].
reduce the relative vertebral body fracture risk by 70%; in
contrast to alendronate, risedronate has been approved toprevent and treat GC-induced osteoporosis [54].
Benucci et al [55] analyzed 69 patients with rheumatismwho were receiving low-dose GC therapy; 23 patients hadcontraindications to bisphosphonate therapy and were man-aged with oral calcium and vitamin D. The remaining 46patients received bisphosphonate therapy (intramuscularneridronate) in addition to oral calcium and vitamin D. At12-month follow-up, the group managed with bisphospho-nate had significantly increased lumbar and femoral bonemineral density. Results of studies have demonstrated thatintravenous bisphosphonate infusion presents an effectivealternative for patients who cannot tolerate oral medications[56]. Reid et al [57] compared intravenous single infusion ofzoledronate with daily risedronate in patents managed withGC in a double-blind, randomized, controlled trial; it wasfound that the single intravenous infusion was more effectiveat increasing lumbar spine bone mineral density at 12 months.
Teriparatide is a recombinant human parathyroid hor-mone. The medication induces preosteoblasts into osteo-blasts, thereby stimulating formation of new bone [58]. Inaddition, teriparatide decreases osteoblast apoptosis [59].
Devogelaer et al [60] conducted a double-blind random-ized control study on the efficacy of teriparatide 20 mg/d oralendronate 10 mg/d in 387 patients with GC-induced osteo-porosis on bone mineral density of the lumbar spine, femoralneck, and total hip. It was found that bone mineral densitywas increased in both groups, with teriparatide being signif-icantly more efficacious then alendronate. In a similar trial,Saag et al [61] compared the efficacy of teriparatide withalendronate in 428 patients with GC-induced osteoporosis.The patients were followed up for 36 months; it was foundthat the patients in the teriparatide group had significantlygreater increases in bone mineral density, higher serum cal-cium concentration, and fewer vertebral fractures than sub-jects in the alendronate group [61].
The American College of Rheumatology recommends thatpatients who are chronically managed with GC (eg, �5 mgprednisone daily for 3 months) start calcium daily, vitamin D,and bisphosphonates [62]. Bisphosphonate therapy also wasrecommended to be started in patients with T scores of �1on bone mineral density testing [63]. Calcitonin has beenshown to prevent GC-induced bone loss, but to ourknowledge no studies have documented decreased frac-ture risk [64].
Table 3. Recommendations for patients with osteoporosiswho are undergoing glucocorticoid injections
Increase daily calcium intake to �1000 mgBisphosphonate useBaseline bone mineral densitometryParathyroid hormone treatmentMinimize steroid dosage, especially in patient older than 65 y
Three-month waiting time between steroid injections
470 Mitra ADVERSE EFFECTS OF CORTICOSTEROIDS ON BONE METABOLISM
Dual-energy x-ray absorptiometry scans have been shownto be valuable in the monitoring of bone density in patientsexposed to GC [65]. Early detection of decreased bone den-sity may allow the physician to initiate medication treatments(ie, bisphosphonates) as well as to discontinue further expo-sure to GC (if this is an option); thus, early detection maysignificantly decrease skeletal morbidity [66].
CONCLUSION
Based on the current literature, essential facts have been estab-lished. GC exposure alters the fragile balance between osteoclastand osteoblast activity in bone metabolism, which favors overallbone loss. Osteoblasts exposed to GC have significantly de-creased anabolic activity, induction of early apoptosis, and adecrease in stem cell differentiation into osteocytes; this, in turn,decreases the secretion of osteoid matrix and new bone forma-tion. GC exposure also induces receptor activation of RANKligand secretion exposure, which, in turn, increases activity andprolongs the lifespan of osteoclasts.
The metabolic effects of GC increases the relative risk offracture development in a dose-dependent manner. Further-more, the cessation of GC decreases the relative risk offractures over the first year; this decrease is most profoundwithin the first 3 months of cessation of GC therapy. Becausethe risk for fracture decreases after cessation of GC exposureafter 3 months, a 3-month period may be ideal between GCexposures in patients at high risk for the development ofosteoporosis [24,59].
Patients managed with GCs who are at high risk for thedevelopment of secondary osteoporosis should have appropri-ate diagnostic testing, pre-GC exposure medication manage-ment (ie, use of bisphosphonates, human parathyroid hor-mone), and a limitation of GC therapy, with a wait period of 3months between GC exposures if possible.[67].
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CME QuestionThe effects of glucocorticoid administration on bone metabolism inc
a. induction of apoptosis in osteoblastsb. promotion of stem cell differentiation in osteocytesc. prolonging the life span of osteoclastsd. stimulation of osteoclast mediated bone resorption
Answer online at me.aapmr.org
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This CME activity is designated for 1.0 AMA PRA Category 1 Credit™ andcan be completed online at me.aapmr.org. Log on to www.me.aapmr.org,go to Lifelong Learning (CME) and select Journal-based CME from thedrop down menu. This activity is FREE to AAPM&R members and $25 fornon-members.
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