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Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: Steroids in Neuroendocrine Immunology and Therapy of Rheumatic Diseases II Are glucocorticoids harmful to bone in early rheumatoid arthritis? Willem F. Lems Department of Rheumatology, VU University Medical Center, Amsterdam, the Netherlands Address for correspondence: Professor Dr. Willem F. Lems, Department of Rheumatology, 3A64, VU University Medical Center, Post box 7057, 1007 MB Amsterdam, the Netherlands. [email protected] In the past, patients with rheumatoid arthritis (RA) were treated with monotherapy with conventional drugs, such as sulfasalazine, methotrexate, and intramuscular gold, which often leads to persistent arthritis, loss of functional capacity, and decreased quality of life. Both active RA and the use of high-dose glucocorticoids (GCs) are associated with generalized bone loss and fractures, but it is well known that GCs have a strong immunosuppressive effect. With the introduction of tumor necrosis factor (TNF- )-blockers and other biologics, clinical remission is a realistic target in approximately half of the early RA patients; the same seems to be true for the use of methotrexate with chronic low-dose or initially high-dose GCs. With the use of a treat-to-target strategy focusing on clinical remission or low disease activity in early RA patients, the negative effects of systemic inflammation on bone can be arrested, and both local bone loss (in the joints) and generalized bone loss at the spine and hips can be prevented. Keywords: early rheumatoid arthritis; glucocorticoids; bone mineral density Active rheumatoid arthritis and bone loss Until recently, all rheumatoid arthritis (RA) patients were treated with conventional disease-modifying antirheumatic drug (DMARD) monotherapy, re- sulting in joint erosions and cartilage loss in many patients and, as a consequence, loss of functional capacity and quality of life. 1 Apart from local bone loss around the joints, generalized bone loss was also observed: a twofold increase in the prevalence of osteoporosis, defined as a T score of <2.5, was found in a large, cross-sectional study in Norway in female RA patients versus healthy controls. 2 In an observational study of early RA in 1994, before the introduction of biologics and combination therapy of conventional DMARDs, high bone loss was observed after 2 years: 2.4% at the spine and 4.3% at the hip. 3 In a subgroup analysis, bone loss in both the spine and hips was, after 1 year, much larger in those patients with high C-reactive protein (CRP) levels (>20 mg/dL) than in those patients with low CRP levels (<20 mg/dL), for example, in the spine: 2.1% versus 0.2%, respectively. The same was found in the lumbar spine for patients with low functional capacity (Health Assessment Questionnaire (HAQ) score > 1) compared to patients with a better HAQ score (<1): 1.9% versus 0.2%, respectively. In a cross-sectional study in three European countries, it was shown that chronic joint inflammation in chronic RA patients, estimated by the Larsen radiological joint damage score, is associated with both low bone mineral density (BMD) and with vertebral deformities. 4 However, generalized bone loss is usually asymp- tomatic; the clinical relevance of elevated bone loss is that it is associated with a higher fracture risk. In line with this, the risk of a having a vertebral fracture was doubled in chronic RA patients versus healthy controls, matched for age, gender, and social background. 5 In addition, the risk of the so-called peripheral or nonvertebral fracture risk was also elevated (roughly doubled) in chronic RA patients. 6 Thus, chronic, suboptimally treated RA is associated with both local and generalized bone loss, leading to joint deformations and fractures. Osteoporosis-related fragility fractures are one of the most important extra-articular complications that may occur in RA patients; obviously, these frac- tures may contribute to an important decrease in quality of life. High disease activity (inflammation), doi: 10.1111/nyas.12430 50 Ann. N.Y. Acad. Sci. 1318 (2014) 50–54 C 2014 New York Academy of Sciences.

Are glucocorticoids harmful to bone in early rheumatoid arthritis?

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Page 1: Are glucocorticoids harmful to bone in early rheumatoid arthritis?

Ann. N.Y. Acad. Sci. ISSN 0077-8923

ANNALS OF THE NEW YORK ACADEMY OF SCIENCESIssue: Steroids in Neuroendocrine Immunology and Therapy of Rheumatic Diseases II

Are glucocorticoids harmful to bone in earlyrheumatoid arthritis?

Willem F. LemsDepartment of Rheumatology, VU University Medical Center, Amsterdam, the Netherlands

Address for correspondence: Professor Dr. Willem F. Lems, Department of Rheumatology, 3A64, VU University MedicalCenter, Post box 7057, 1007 MB Amsterdam, the Netherlands. [email protected]

In the past, patients with rheumatoid arthritis (RA) were treated with monotherapy with conventional drugs, suchas sulfasalazine, methotrexate, and intramuscular gold, which often leads to persistent arthritis, loss of functionalcapacity, and decreased quality of life. Both active RA and the use of high-dose glucocorticoids (GCs) are associatedwith generalized bone loss and fractures, but it is well known that GCs have a strong immunosuppressive effect. Withthe introduction of tumor necrosis factor (TNF-�)-blockers and other biologics, clinical remission is a realistic targetin approximately half of the early RA patients; the same seems to be true for the use of methotrexate with chroniclow-dose or initially high-dose GCs. With the use of a treat-to-target strategy focusing on clinical remission or lowdisease activity in early RA patients, the negative effects of systemic inflammation on bone can be arrested, and bothlocal bone loss (in the joints) and generalized bone loss at the spine and hips can be prevented.

Keywords: early rheumatoid arthritis; glucocorticoids; bone mineral density

Active rheumatoid arthritis and bone loss

Until recently, all rheumatoid arthritis (RA) patientswere treated with conventional disease-modifyingantirheumatic drug (DMARD) monotherapy, re-sulting in joint erosions and cartilage loss in manypatients and, as a consequence, loss of functionalcapacity and quality of life.1 Apart from local boneloss around the joints, generalized bone loss wasalso observed: a twofold increase in the prevalenceof osteoporosis, defined as a T score of <−2.5, wasfound in a large, cross-sectional study in Norwayin female RA patients versus healthy controls.2 Inan observational study of early RA in 1994, beforethe introduction of biologics and combinationtherapy of conventional DMARDs, high bone losswas observed after 2 years: −2.4% at the spine and−4.3% at the hip.3 In a subgroup analysis, bone lossin both the spine and hips was, after 1 year, muchlarger in those patients with high C-reactive protein(CRP) levels (>20 mg/dL) than in those patientswith low CRP levels (<20 mg/dL), for example,in the spine: −2.1% versus 0.2%, respectively. Thesame was found in the lumbar spine for patientswith low functional capacity (Health Assessment

Questionnaire (HAQ) score > 1) compared topatients with a better HAQ score (<1): −1.9%versus −0.2%, respectively. In a cross-sectionalstudy in three European countries, it was shown thatchronic joint inflammation in chronic RA patients,estimated by the Larsen radiological joint damagescore, is associated with both low bone mineraldensity (BMD) and with vertebral deformities.4

However, generalized bone loss is usually asymp-tomatic; the clinical relevance of elevated bone lossis that it is associated with a higher fracture risk.In line with this, the risk of a having a vertebralfracture was doubled in chronic RA patients versushealthy controls, matched for age, gender, and socialbackground.5 In addition, the risk of the so-calledperipheral or nonvertebral fracture risk was alsoelevated (roughly doubled) in chronic RA patients.6

Thus, chronic, suboptimally treated RA isassociated with both local and generalized boneloss, leading to joint deformations and fractures.Osteoporosis-related fragility fractures are one ofthe most important extra-articular complicationsthat may occur in RA patients; obviously, these frac-tures may contribute to an important decrease inquality of life. High disease activity (inflammation),

doi: 10.1111/nyas.12430

50 Ann. N.Y. Acad. Sci. 1318 (2014) 50–54 C© 2014 New York Academy of Sciences.

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Lems DAS-steered treatment prevents bone loss in early RA

immobility, and treatment with glucocorticoids(GCs) are the main factors that increase the risk ofosteoporotic fractures, on top of the backgroundfracture risk based on, for example, advanced age,low body mass, and female gender.

Recent data in the field of osteoimmunology,the crosstalk between cytokines and bone, haveelucidated that activated inflammatory cells atsites of inflammation produce a wide spectrumof cytokines that stimulate local and generalizedbone resorption, modulated by changes in receptoractivator for nuclear factor-�B ligand (RANKL)and osteoprotegerin (OPG), and also interfere withthe Wnt signaling pathway, resulting in inhibitedbone formation in RA patients;7–9 the combinationof upregulated bone resorption with depressedbone formation might be hazardous to bonestrength.

GCs and bone

Early studies on the pathogenesis of GC-inducedosteoporosis (GIOP) were performed in patientstreated with high-dose GCs. In these histomorpho-metric studies, reduced bone formation character-ized by a low mineral apposition rate (which is re-lated to a reduction in the number of osteoblasts)was found, while bone resorption was unchanged oreven elevated.10 During the past few years, severalstudies have provided more insight into the molec-ular mechanisms involved in the pathogenesis ofGIOP. These mechanisms include a GC-inducedincrease in apoptosis of mature osteoblasts andosteocytes, impaired differentiation of osteoblasts,which results in reduced bone formation, and anincrease in the life span of osteoclasts. In addi-tion, the loss of osteocytes is supposed to inducea disrupted osteocyte–canalicular network and fail-ure to respond to bone damage,11 which may leadto reduced bone strength. GCs have been demon-strated to suppress the Wnt pathway by stimulatingthe production of Wnt pathway inhibitors, such asdickkopf-1 (Dkk-1) and sclerostin.12,13 In addition,GCs stimulate bone marrow stromal cells to dif-ferentiate toward adipocytes instead of osteoblasts.GCs induce an increased life span of osteoclasts asa consequence of upregulated RANKL and suppres-sion of OPG.14

The increased risk for fractures during GC treat-ment appears to be dose-dependent.15–17 van Staaet al. demonstrated that hip fracture risk in patients

taking a standardized daily dose of less than 2.5 mgprednisolone was 0.99 (0.82–1.20), rising to 1.77(1.55–2.02) at daily doses of 2.5–7.5 mg, and 2.27(1.94–2.66) at doses of 7.5 mg or greater.16 The rela-tive risk of vertebral fractures is particularly elevatedduring GC treatment and ranges from 1.55 (1.20–2.01) in patients using less than 2.5 mg prednisolonedaily, up to 5.18 (4.25–6.31) in the highest dosegroup.16 After discontinuation of GC treatment, thefracture risk gradually returns to baseline and is,therefore, supposed to be partially reversible.18 Be-sides GC dose, age, female gender, falls history, pre-vious fractures, low body mass index, smoking, im-mobility, and the activity of the underlying disease,also influence fracture risk.19

Despite the apparent effect of GC use on bonedensity, GC-induced changes in BMD do not fullyaccount for the increased fracture risk in GC-treatedpatients. An adverse effect of GCs on bone qualityis supposed to further increase the risk of fractures,which leads to “reduced bone density threshold forvertebral fractures.”20 Data from two randomizedcontrolled trials demonstrated a significantlyincreased incidence of vertebral fractures after afollow-up of 1 year in patients treated with GCscompared to nonusers, despite higher BMD valuesin the GC-treated patients.21 This phenomenonmight be explained by an increased risk of fallingdue to steroid-induced muscle weakness andfrailty, and by changes in the bone architecture,which were not captured by (two-dimensional)BMD measurements with dual-energy X-rayabsorptiometry.22

Modern treatment of RA

The pathogenesis of RA is still incompletelyunderstood, but thought to be multifactorial,involving multiple genes, environmental triggers,and chance.23 The disease is currently classified onthe basis of the clinical phenotype; maybe it willbe possible in the near future to define differentdisease subgroups with different prognoses.23

With the use of biologics, preferably in com-bination with methotrexate (MTX), it is possibleto induce clinical remission in around 50% ofearly RA patients. The number of biologics isgradually increasing over the years, and consistsof tumor necrosis factor (TNF-�)-blocking agents,rituximab (a B cell blocker), T cell interaction block-ade (abatacept), and interleukin (IL)-6 blockade

51Ann. N.Y. Acad. Sci. 1318 (2014) 50–54 C© 2014 New York Academy of Sciences.

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DAS-steered treatment prevents bone loss in early RA Lems

(tocilizumab). Without any doubt, the introductionof these biologics has brought an enormous step for-ward in the treatment of RA.24–26 However, the costof these drugs is high, and infection risk is elevated.One of the possibilities to obtain more insight intothe complex pathogenesis of local and generalizedbone loss in RA referred to as osteoimmunology,27

is to investigate the powerful effects of moderntreatment of RA with TNF-blocking agents andother biologics on local and generalized bone lossin RA.

Although bone loss was substantial in earlierstudies in patients with RA, we have recently shownthat treatment with anti-TNF arrests BMD loss atthe hip and spine. In an open cohort study of 102RA patients from Norway and the Netherlands, alltreated with infliximab and MTX, there was no boneloss at the spine and hip after 1 year, while BMD inpatients with a European League Against Rheuma-tism (EULAR) good response showed a favorablechange in BMD compared to patients not achiev-ing such a response, indicating that adequately sup-pressing systemic inflammation in RA is benefi-cial for the prevention of generalized bone loss.28

Prevention of bone loss was also observed during1-year treatment with adalimumab,29,30 and duringchronic (on average 3 years) treatment with inflix-imab and MTX.31 In RA patients treated with rit-uximab, bone resorption markers decreased, whilebone formation markers increased.32

During treatment with tocilizumab, more orless the same pattern was observed: no significantchanges in BMD at the lumbar spine and hips, adecrease in serum DKK-1, and an increase in serumP1NP.33 However, no changes in serum CTX-1,a marker of collagen degradation, were observed,which is somewhat more difficult to interpret.33

GCs in RA: effects on bone

One of the most intriguing questions within thefield of rheumatology relates to the effect of GCuse in RA patients on bone. As described, both GCuse and active RA might have a devastating effect onbone, but it is well known that GCs have strong anti-inflammatory effects. In other words, Is it possible tocounteract the negative effects on bone by adequatesuppression of systemic inflammation?34,35

This has been investigated in the BeSt study, anovel study design comparing four different treat-ment strategies in which treatment adjustments

were made continuously when low disease activity,defined as a disease activity score (DAS) of �2.4, wasnot reached in patients with recent-onset RA.36 Thetreatment strategies were: (1) group 1: sequentialmonotherapy starting with MTX; (2) group 2: step-up combination therapy starting also with MTX;(3) group 3: initial combination therapy with MTX,sulphasalazine, and a quickly tapered high dose ofprednisone (more or less the same as the conven-tional COBRA scheme);37 and (4) group 4: initialcombination therapy with MTX and the TNF-�inhibitor infliximab. After 2 years of DAS-steeredtreat-to-target therapy, BMD decreased at the hipsby −1.1% (group 1), −0.2% (group 2), −0.2%(group 3), and −0.6% (group 4). At the lumbarspine, the bone loss was −0.4%, −1.6%, −0.5%,and −1.0%, respectively.38 We concluded that gen-eralized bone loss was limited in all four groups ofpatients and that the generalized bone loss was nothigher in patients initially treated with high-doseprednisone. In addition, radiological joint damagewas low in all four groups. This clearly suggests thatthe negative effect of GCs on bone in early RA shouldbe outweighed against the strong anti-inflammatoryeffects of GCs on bone.8

The BeSt study was among the first modern treat-to-target studies that showed that the use of GCsmight not be harmful to bone in early RA. It isimportant to realize that the BeSt study was a DAS-steered treat-to-target study, in which several prede-fined treatment options were prescribed to patientswho do not have low disease activity: it was not arandomized controlled trial comparing the effectsof prednisone versus placebo. Another issue is thatno treat-to-target studies in chronic RA are availablethat demonstrated the arrest of local and generalizedbone loss. Earlier, it had been demonstrated that theuse of 7.5 mg prednisone per day versus placeboin addition to conventional DMARD therapy, usu-ally monotherapy at that time, prevents hand boneloss.39 However, it has recently been demonstratedthat prednisone 10 mg/day versus placebo in earlyRA patients treated with MTX has a positive effectnot only on disease activity but also on radiolog-ical joint damage.40 Additionally, it has been thecase that generalized bone loss both at the spineand hips could be prevented in these patients, forwhom calcium and vitamin D was prescribed, andwith bisphosphonates in patients at high risk forfractures.41

52 Ann. N.Y. Acad. Sci. 1318 (2014) 50–54 C© 2014 New York Academy of Sciences.

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Summary

Although both active RA and the use of high-doseGCs are associated with bone loss and fractures,with the use of low-dose GCs or initial high-doseGCs and MTX, it is possible to arrest both the localand generalized bone loss in early RA. Since more orless the same has also been demonstrated with thecombined use of (some of the) biologics and MTX,it seems plausible that with adequate suppression ofsystemic inflammation using a treat-to-target strat-egy, the negative effects of early RA on bone can beprevented.

Conflicts of interest

The author declares no conflicts of interest.

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