Arthritis Care & Research Vol. 67, No. 6, June 2015, pp 754–764 DOI 10.1002/acr.22519 C 2015, American College of Rheumatology V
Meta-Analysis of Tumor Necrosis Factor Inhibitors and Glucocorticoids on Bone Density in Rheumatoid Arthritis and Ankylosing Spondylitis Trials STEPHANIE SIU,1 BOULOS HARAOUI,2 ROBERT BISSONNETTE,3 LOUIS BESSETTE,4 CAMILLE ROUBILLE,5 VINCENT RICHER,6 TARA STARNINO,7 COLLETTE McCOURT,8 ALEXANDRA McFARLANE,9 PATRICK FLEMING,10 JOHN KRAFT,11 CHARLES LYNDE,11 WAYNE GULLIVER,12 STEPHANIE KEELING,9 JAN DUTZ,8 AND JANET E. POPE1
Objective. To examine the impact of antirheumatic drugs on bone mineral density (BMD) in rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), and psoriasis using a systematic review. Methods. Electronic databases were systematically searched for randomized controlled trials. Studies were grouped based on disease, treatment, and site of BMD measurement. Change in BMD (DBMD) from baseline to end of study was recorded. Standardized mean difference (SMD) of DBMD between treatment and controls was standardized for meta-analyses and 95% confidence intervals (95% CIs) were calculated. Results. Treatment effects on BMD were not the primary outcomes of the trials. Thirteen studies were eligible (11 RA, 2 AS, 0 PsA, and 0 psoriasis). For RA, significantly less hand bone loss was seen with tumor necrosis factor inhibitors (TNFi; SMD DBMD 0.33 [95% CI 0.13, 0.53], P 5 0.001, I2 5 0%) and glucocorticoids (SMD DBMD 0.51 [95% CI 0.20, 0.81], P 5 0.001, I2 5 0%). TNFi had no significant effect on lumbar spine and hip BMD. Glucocorticoids were associated with a negative effect on lumbar spine (SMD DBMD 20.30 [95% CI 20.55, 20.04], P 5 0.02, I2 5 52%), but not hip BMD. For AS, a significant increase in BMD was seen with TNFi at the lumbar spine (SMD DBMD 0.96 [95% CI 0.64, 1.27], P < 0.001, I2 5 16%) and hip (SMD DBMD 0.38 [95% CI 0.13, 0.62], P 5 0.003, I2 5 0%). Data were insufficient to perform meta-analyses in PsA and psoriasis or for other antirheumatic drugs. Conclusion. In RA, TNFi and glucocorticoids appeared to attenuate hand bone loss. TNFi did not impact lumbar spine and hip BMD and glucocorticoids had negative effects on lumbar spine and no effect on hip BMD. In AS, TNFi was associated with improved lumbar spine and hip BMD.
INTRODUCTION Chronic inflammation has been demonstrated to be a risk factor for osteoporosis in large observational studies (1,2). Many signaling pathways have been proposed to mediate
inflammatory bone loss by perturbing the balance of osteoclast and osteoblast activity (3). Tumor necrosis factor (TNF) is a proinflammatory cytokine that is upregulated in many chronic inflammatory diseases. TNF
Supported by AbbVie. Dr. Roubille’s work was supported by a grant from the Foundation of the University of Montreal Hospital Center. Dr. McCourt’s work was supported by a fellowship from the British Association of Dermatology. 1 Stephanie Siu, MD, Janet E. Pope, MD, MPH: Western University, London, Ontario, Canada; 2Boulos Haraoui, MD: Centre Hospitalier de l’Universite de Montreal and Institut de Rhumatologie de Montreal, Montreal, Quebec, Canada; 3 Robert Bissonnette, MD: Inovaderm Research, Montreal, Quebec, Canada; 4Louis Bessette, MD, MSc: Centre Hospitalier Universitaire de Quebec, Quebec City, Quebec, Canada; 5Camille Roubille, MD: University of Montreal Hospital Research Center and Notre-Dame Hospital, Montreal, Quebec, Canada; 6Vincent Richer, MD: Saint Luc
Hospital, Montreal, Quebec, Canada; 7Tara Starnino, MD: Sacre-Coeur Hospital of Montreal and The University of Montreal, Montreal, Quebec, Canada; 8Collette McCourt, MB, Bch, Jan Dutz, MD: University of British Columbia, Vancouver, British Columbia, Canada; 9Alexandra McFarlane, MD, Stephanie Keeling, MD: University of Alberta, Edmonton, Alberta, Canada; 10Patrick Fleming, MD, MSc: University of Toronto, Toronto, Ontario, Canada; 11John Kraft, MD, Charles Lynde, MD: Lynde Dermatology, Markham, Ontario, Canada; 12 Wayne Gulliver, MD: Memorial University, St. John’s, Newfoundland, Canada. Dr. Haraoui has received consulting fees (less than $10,000 each) from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Pfizer, Roche, and UCB. Dr. Bissonette
Effect of Steroids and TNF Inhibitors on BMD
Significance & Innovations Inflammation is a risk factor for osteoporosis. Treating inflammation with antirheumatic drugs may theoretically lead to improved bone mineral density (BMD) in inflammatory diseases such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis, or psoriasis. Use of tumor necrosis factor inhibitors (TNFi) in the treatment of RA was associated with improved hand BMD, but had no significant effect on lumbar spine and hip BMD. Use of TNFi in the treatment of AS was associated with improved BMD at the lumbar spine and hip, which is suggestive of an overall improvement in systemic BMD. Although use of glucocorticoids has been linked to osteoporosis in the general population, use of glucocorticoids in RA improved hand BMD, but worsened lumbar spine BMD.
inhibitors (TNFi) have been shown to attenuate periarticular bone loss in rheumatoid arthritis (RA) (4); however, there is inconsistent evidence concerning their effects on systemic bone density. Glucocorticoids are often used in has received consulting fees, speaking fees, and/or honoraria (less than $10,000 each) from AbbVie, Celgene, Eli Lilly, Galderma, Incyte, Janssen, Leo Pharma, Merck, Novartis, Pfizer, and Tribute, and (more than $10,000) from Amgen. Dr. Bessette has received consulting fees, speaking fees, and/or honoraria (less than $10,000 each) from AbbVie, Amgen, Janssen, and UCB. Dr. McCourt has received consulting fees, speaking fees, and/or honoraria (less than $10,000) from Janssen. Dr. McFarlane owns stock and/or holds stock options in Pfizer. Dr. Kraft has received consulting fees, speaking fees, and/or honoraria (less than $10,000 each) from AbbVie, Amgen, Galderma, Janssen, Leo Pharma, and Novartis. Dr. Lynde has received consulting fees, speaking fees, and/or honoraria (more than $10,000 each) from AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Leo Pharma, Merck, and Novartis. Dr. Gulliver has received consulting fees, speaking fees, and/or honoraria (less than $10,000 each) from Amgen, Astellas, Bio-K, Celgene, Galderma, Leo Pharma, Merck, Novartis, Pfizer, Roche, and Valeant, and (more than $10,000 each) from AbbVie and Janssen. Dr. Keeling has received consulting fees, speaking fees, and/or honoraria (less than $10,000 each) from AbbVie, Amgen, AstraZeneca, Janssen, Pfizer, Roche, and UCB. Dr. Dutz has received consulting fees, speaking fees, and/or honoraria (less than $10,000 each) from AbbVie, Amgen, Centecor, Janssen, Leo Pharma, Novartis, ONO Pharmaceuticals, and Roche. Dr. Pope has received consulting fees, speaking fees, and/or honoraria (less than $10,000 each) from Abbvie, Actelion, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Genentech, GlaxoSmithKline, Janssen, MedImmune, Mediquest, Novartis, Pfizer, Roche, and UCB. Address correspondence to Janet E. Pope, MD, MPH, St. Joseph’s Hospital, 268 Grosvenor Street, London, Ontario, Canada, N6A 4VA. E-mail: [email protected]
Submitted for publication May 30, 2014; accepted in revised form November 11, 2014.
755 treatment of inflammation to induce rapid disease remission and allow time for slower-acting immune modulators to take effect. While the negative impact of long-term steroid use on bone density has been established in the general population (5,6), it is unclear if glucocorticoids used specifically in the treatment of chronic inflammation have the same deleterious effect. Reviews of the effects of biologic agents and steroids on bone loss have been performed (7–9); however, these were narrative reviews or included data from observational studies as well as randomized controlled trials (RCTs), potentially introducing bias. The purpose of this systematic review was to examine the effects of antirheumatic drugs on bone loss at various sites (hand, lumbar spine, and hip) in RA, ankylosing spondylitis (AS), psoriatic arthritis (PsA), and psoriasis, based on evidence from RCTs.
MATERIALS AND METHODS The systematic review and meta-analysis were conducted as part of the Canadian Dermatology-Rheumatology (DR) Co-morbidity Initiative, which was designed to provide evidence-based recommendations on management of comorbidities in RA, PsA, and psoriasis. In this analysis, we also included patients with AS, another form of commonly seen inflammatory arthritis, to allow for more informative comparison. Study selection. We systematically searched Medline, Embase, and the Cochrane Library (CENTRAL) for RCTs that examined the effects of licensed antirheumatic drugs on bone loss in patients with RA, AS, PsA, or psoriasis. Search terms used were “rheumatoid arthritis,” “psoriatic arthritis,” “psoriasis,” “ankylosing spondylitis,” “osteoporosis,” “bone loss,” “bone density,” “bone mass,” “bone mineral content,” “osteoporotic fracture,” “bone turnover markers,” “dual energy x-ray absorptiometry,” “digital x-ray radiogrammetry,” and “quantitative computed tomography.” Studies were limited to those performed in humans and published in English between 1960 and May 2013. In addition, we hand searched abstracts that had been presented at the 2010–2012 annual meetings of the American College of Rheumatology, European League Against Rheumatism, American Academy of Dermatology, and European Academy of Dermatology and Venereology. Study titles were independently screened for inclusion by 2 authors (SS and JEP). Discrepancy was resolved by consensus of the 2 authors (SS and JEP) after reviewing the full text. Studies that passed the initial screening were further assessed for inclusion in the meta-analyses. Studies were required to evaluate a licensed treatment used in RA, AS, PsA, or psoriasis; provide a bone mineral density (BMD) measurement; have a valid control group (the control group could be patients receiving a disease-modifying antirheumatic drug [DMARD], provided that DMARD was also used in the experimental group); and have sufficient data for analysis. Exception was made for one study that measured metacarpal cortical index (MCI), which has been shown to correlate well with hand BMD (10). Studies that provided data on bone marker turnover without
Siu et al
assessment of BMD were excluded due to potential variability of measurements and potential lack of clinical relevance. Studies in which fractures were used as indicators of osteoporosis were initially included; however, these were later excluded from the meta-analyses due to insufficient numbers of events within the relatively short study duration. Most trials did not have BMD as the primary outcome, so findings could be underpowered. Studies with protocols that allowed changes in bone-protective agent regimens (such as bisphosphonates) during the study period were excluded; otherwise, we assumed background treatment for bone mass was stable. Data extraction. The following information was extracted from each study: first author, publication year, antirheumatic drugs used in treatment and control groups, sample size, disease duration, length of followup, use of bone-protective agents, skeletal sites evaluated for BMD, and change in BMD from baseline to end of study (DBMD). For hip DBMD, total hip or femoral neck measurement was used, whichever was provided, in order to combine the majority of studies, as some reported only one of the above. For DBMD that was neither specified as median nor mean, the assumption was that it represented the mean. SDs were recorded or calculated from the SEM and sample size per group; for studies with neither available, SDs were imputed from the interquartile range. The quality of individual studies was evaluated according to the Oxford Centre for Evidence-based Medicine Levels of Evidence (March 2009, available online at http://www.cebm.net/?o=1025) and the Cochrane risk of bias tool (July 2011, available at http://www.bmj.com/content/343/bmj.d5928.full). Statistical analysis. Studies were analyzed in groups, based on the disease type, treatment, and site where BMD was measured. The outcome of interest was between-group difference in DBMD. The within-group DBMD (i.e., end of study minus baseline for each control and experimental group) is reported as the mean in the figures. The between-group difference in DBMD was reported as the standardized mean difference (SMD) and graphed in the forest plots. Because DBMD was reported in different units across included studies, with some reported as percent change measured in gm/cm2 compared to baseline and others reported as change in T or Z scores, we standardized our outcome for the metaanalyses. Meta-analyses were performed using a randomeffects model. The I2 statistic was used to examine heterogeneity between studies. A value greater than 50% indicates notable heterogeneity. All statistical analyses were performed using RevMan, version 5 (Cochrane Collaboration). A change of 3% in BMD may be considered relevant from literature in osteoporosis trials (11).
RESULTS Electronic database and congress abstract searches identified 382 studies for the initial screening (Figure 1). Screening of titles excluded 333 studies. Full-text review
Figure 1. Flow diagram showing selection of studies for inclusion in the meta-analyses. ACR 5 American College of Rheumatology; EULAR 5 European League Against Rheumatism; AAD 5 American Academy of Dermatology; EAV 5 European Academy of Dermatology and Venereology; BMD 5 bone mineral density; RCT 5 randomized controlled trial.
was carried out for the remaining 49 studies, of which 36 were excluded due to the reasons specified in Figure 1. We identified 11 eligible studies in patients with RA: 5 studies involved use of TNFi (total of 345 patients exposed to TNFi and 302 controls) (4,12–15) (Table 1) and 7 studies involved use of glucocorticoids (total of 445 patients exposed to glucocorticoids and 347 controls) (12,16–21) (Table 2). One study investigated the use of both TNFi and glucocorticoids (12) and was therefore included in both meta-analyses. Two eligible studies in patients with AS were found, both using TNFi (total of 106 patients exposed to TNFi and 215 controls) (22,23) (Table 3). Our search did not yield any eligible studies evaluating the use of conventional DMARDs or other biologic agents in any of the disease types. Furthermore, no eligible studies in patients with PsA or psoriasis were identified. In general, study quality was good (Tables 1–3) and the risk of bias was low (see Supplementary Appendix A, available in the online version of this article at http://onlinelibrary.wiley.com/doi/10.1002/ acr.22519/abstract). Effect of TNFi on BMD in RA. Of the RCTs evaluating TNFi in patients with RA, 2 studies measured hand BMD or MCI and 4 studies measured BMD at the lumbar spine or hip. RA disease duration ranged from 1–3 years at the time of study enrollment. Duration of treatment ranged from 1–2 years, except for one study with treatment for 26 weeks (14). This study compared treatment target remission in patients with early RA with initial DMARD versus DMARD with glucocorticoids versus DMARD with infliximab. Patients were followed for 1–2 years with interval BMD measurements. Use of TNFi was associated with less hand bone loss compared with control treatment (SMD DBMD 0.33 [95% confidence
Effect of Steroids and TNF Inhibitors on BMD
Author, year (ref.) Guler-Yuksel et al, 2008 (12)
Haugeberg et al, 2009 (13)
Hoff et al, 2009 (4) Valleala et al, 2009 (14)
Engvall et al, 2010 (15)
Randomized controlled trials evaluating the effects of tumor necrosis factor inhibitors on BMD in patients with rheumatoid arthritis*
Treatment Infliximab 4.5 mg/kg IV at weeks 0, 2, 6, then every 8 weeks 1 MTX (n 5 88)‡ Infliximab 3 mg/kg IV at weeks 0, 2, 6, then every 8 weeks 1 MTX (n 5 10) Adalimumab 40 mg SC every 2 weeks 1 MTX (n 5 201) Infliximab 3 mg/kg IV at weeks 4, 6, 10, 18, 26 1 MTX, sulfasalazine, hydroxychloroquine, prednisolone (n 5 32) Infliximab 3 mg/kg IV at weeks 0, 2, 6, then every 8 weeks 1 MTX (n 5 14)
Disease duration, years
DMARD monotherapy (n 5 81)
MTX (n 5 10)
MTX (n 5 169)
MTX, sulfasalazine, ,1 year hydroxychloroquine, prednisolone (n 5 31) MTX, sulfasalazine, hydroxychloroquine (n 5 11)
Use of boneprotective agent
BMD: Calcium, lumbar spine, vitamin D, total hip bisphosphonate, as indicated§ BMD: hand, Not specified lumbar spine, total hip, femoral neck MCI: hand Not specified
BMD: Calcium lumbar spine, 1,000 mg/day, femoral neck vitamin D 800 IU/day
21 months BMD: Not specified lumbar spine, femoral neck
Oxford quality† 1b
* BMD 5 bone mineral density; IV 5 intravenous; MTX 5 methotrexate; DMARD 5 disease-modifying antirheumatic drug; SC 5 subcutaneous; MCI 5 metacarpal cortical index. † Studies were graded 1b according to Oxford quality rating because they were randomized controlled trials; however, this grade may be too high for the outcomes assessed given that BMD was not the primary outcome of the studies and not all patients enrolled in the studies had BMD measured. ‡ Average infliximab dose per infusion for study period. § Calcium 500–1,000 mg/day if daily intake ,1,000 mg, vitamin D 400 IU/day if serum vitamin D below local reference value, and bisphosphonate if T score less than 22.5 in non–steroid user or less than 21.0 in steroid user.
interval (95% CI) 0.13, 0.53], P 5 0.001, I2 5 0%) (Figure 2A). No significant differences in bone loss were seen between TNFi and control groups at the lumbar spine (SMD DBMD 20.12 [95% CI 20.36, 0.11], P 5 0.30, I2 5 0%) or hip (SMD DBMD 0.20 [95% CI 20.11, 0.51], P 5 0.21, I2 5 26%).
greater decreases in BMD at the lumbar spine, although there was significant heterogeneity across studies (SMD DBMD 20.30 [95% CI 20.55, 20.04], P 5 0.02, I2 5 52%). No significant difference in BMD at the hip was evident between groups treated with glucocorticoids and controls (SMD DBMD 0.07 [95% CI 20.11, 0.25], P 5 0.45, I2 5 0%).
Effects of TNFi on BMD in AS. Two RCTs were identified that examined the effects of TNFi on BMD in patients with AS: both presented data for BMD at the lumbar spine and hip. Disease duration at the time of study enrollment ranged widely from 0–41 years. Patients were followed for 24–30 weeks and given treatment for the duration of observation. Compared with controls, use of TNFi was associated with increased BMD at both the lumbar spine (SMD DBMD 0.96 [95% CI 0.64, 1.27], P , 0.001, I2 5 16%) and hip (SMD DBMD 0.38 [95% CI 0.13, 0.62], P 5 0.003, I2 5 0%) (Figure 2B).
Exploratory analysis of glucocorticoids in early RA and effects on BMD. In a separate exploratory analysis, we included only RCTs that enrolled patients with early RA (defined as disease duration ,2 years; 222 patients exposed to glucocorticoids and 226 controls). Meta-analysis showed that glucocorticoids have no statistically significant effect on both lumbar spine (SMD DBMD 20.20 [95% CI 20.44, 0.05], P 5 0.11, I2 5 40%) and hip BMD (SMD DBMD 0.11 [95% CI 20.08, 0.29], P 5 0.27, I2 5 0%) for treatment duration of up to 2 years (Figure 3B).
Effects of glucocorticoids on BMD in RA. Of the 7 RCTs identified that examined the effects of glucocorticoid use on BMD in patients with RA, 2 reported data on hand BMD, 5 on lumbar spine BMD, and 4 on hip BMD. Four of the 7 studies involved patients with early RA (diagnosed within 2 years prior to study enrollment). Length of followup ranged from 20 weeks to 2 years. Use of glucocorticoids was associated with less hand bone loss than control treatment (SMD DBMD 0.51 [95% CI 0.20, 0.81], P 5 0.001, I2 5 0%) (Figure 3A). Compared with controls, glucocorticoid use was associated with
DISCUSSION Bone metabolism is mediated by a balance of osteoblast and osteoclast function. During inflammation, this balance is shifted in favor of osteoclasts. Cells of the immune system release a number of cytokines, including TNF, interleukin-1 (IL-1), and IL-6, that promote function of osteoclasts and inhibit osteoblasts. Furthermore, activation of B cells and T cells induces expression of RANKL, which also plays a role in activation of osteoclasts (3). Indeed, chronic inflammation has been shown
Siu et al
Randomized controlled trials evaluating the effects of glucocorticoids on BMD in patients with rheumatoid arthritis*
Author, year (ref.) Laan et al, 1993 (16)
Van Schaardenburg et al, 1995 (17)
Hansen et al, 1999 (18)
Verhoeven et al, 2001 (19)
Haugeberg et al, 2005 (20)
Engvall et al, 2008 (21)
Guler-Yuksel et al, 2008 (12)
Use of bone-protective agent
Prednisone 7.5 mg/day oral 1 IM gold (n 5 20)‡ Prednisone oral 8 mg/day (n 5 26)‡
IM gold (n 5 19)
BMD: lumbar spine
Patients on boneprotective agents were excluded
Chloroquine (n 5 20)
BMD: femoral neck
Prednisolone 6 mg/day oral 1 DMARD (n 5 42)‡ Prednisolone 12 mg/day oral 1 MTX, sulfasalazine (lumbar spine: n 5 63, femoral neck: n 5 59)‡ Prednisolone 7.5 mg/day oral 1 routine treatment at discretion of physician (n 5 47) Prednisolone 7.5 mg/day oral 1 DMARD (n 5 70) Prednisone 9.3 mg/day oral 1 DMARD (n 5 89)‡
DMARD (n 5 34)
BMD: hand, distal forearm, lumbar spine
Calcium 500 mg/day; vitamin D 400 IU/day if serum vitamin D ,30 nmoles/liter Calcium and vitamin D given to 5 patients in prednisolone group
Sulfasalazine (lumbar spine: n 5 62, femoral neck: n 5 57)
BMD: lumbar spine, femoral neck
Calcium 1,000 mg/day if on prednisolone; vitamin D (dose unspecified) if vitamin D deficient
Routine treatment at discretion of physician (n 5 48)
DMARD (n 5 80)
BMD: lumbar spine, femoral neck
Calcium 1,000 mg/day
DMARD (n 5 84)
BMD: lumbar spine, total hip
Calcium, vitamin D, bisphosphonate, as indicated§
* BMD 5 bone mineral density; IM 5 intramuscular; DMARD 5 disease-modifying antirheumatic drug; MTX 5 methotrexate. † Studies were graded 1b according to Oxford quality rating because they were randomized controlled trials; however, this grade may be too high for the outcomes assessed given that BMD was not the primary outcome of the studies and not all patients enrolled in the studies had BMD measured.
‡ Average daily dose over study duration. § Calcium 500–1,000 mg/day if daily intake ,1,000 mg, vitamin D 400 IU/day if serum vitamin D below local reference value, and bisphosphonate if T score less than 22.5 in non–steroid user or less than 21.0 in steroid user.
in a number of studies to be a risk factor for osteoporosis (1,2). Following this logic, it is conceivable that use of a TNFi may attenuate inflammatory bone loss. The role of glucocorticoids in bone metabolism in chronic inflammatory disease has been controversial. A meta-analysis of 7 large prospective multinational cohorts showed that ever use of corticosteroids was associated with a 66% higher relative risk of osteoporotic fracture compared with never use of corticosteroids (5). The contribution of glucocorticoid use to osteoporosis has also been highlighted in several professional recommendations (24–27). Conversely, in the context of chronic inflammatory disease, it may be that controlling inflammation can lower the risk of inflammatory bone loss. A recent study reported observational data that, in patients with RA, the use of glucocorticoids was associated with an 83% lower chance of having vertebral fractures (28). The purpose of our study was to examine current evidence of the effect of antirheumatic drugs on bone
metabolism. Because we wanted to extract high-quality data, we limited our literature search to RCTs only. Studies were found that examined the effects of TNFi and glucocorticoids on bone metabolism in patients with RA and AS; however, no RCTs were identified that evaluated the effects of conventional DMARDs, including methotrexate or other licensed biologic agents, on BMD in these populations. Furthermore, no studies in patients with PsA or psoriasis were eligible for inclusion. In patients with RA, our analysis showed that both TNFi and glucocorticoids were associated with less hand BMD loss than control treatments. This is consistent with the notion that antirheumatic drugs reduce inflammation around active joints, thereby improving periarticular osteopenia. The hand BMD may not be relevant to overall fracture risk, since it is likely more correlated with less inflammation with effective treatment. Lumbar spine and hip BMD have traditionally been used to predict fracture risk. TNFi appeared to have no significant effect on systemic bone loss based on lumbar
24 0.3–41 Placebo for 24 weeks (then crossed over to infliximab) (n 5 201)‡ Infliximab 5 mg/kg IV at weeks 0, 2, 6, 12, 18, then every 6 weeks (n 5 78) Visvanathan et al, 2009 (23)
* BMD 5 bone mineral density; IV 5 intravenous; MTX 5 methotrexate. † Studies were graded 1b according to Oxford quality rating because they were randomized controlled trials; however, this grade may be too high for the outcomes assessed given that BMD was not the primary outcome of the studies and not all patients enrolled in the studies had BMD measured. ‡ Only data prior to crossover were used.
1b Not specified
1b Not specified
BMD: lumbar spine, total hip, femoral neck BMD: lumbar spine, hip 30 0–41 Infliximab 5 mg/kg IV at weeks 0, 2, 6, 12, 22 1 MTX (n 5 28) Marzo-Ortega et al, 2005 (22)
MTX (n 5 14)
Use of boneprotective agent Followup duration, weeks Disease duration, years Author, year (ref.)
Randomized controlled trials evaluating the effects of tumor necrosis factor inhibitors on BMD in patients with ankylosing spondylitis*
Effect of Steroids and TNF Inhibitors on BMD
759 spine and hip BMD. This is contrary to the positive effect on bone metabolism we expected to see with TNFi. It is important to note that none of the included trials on TNFi studied osteoporosis as the primary outcome, and the trials may have been too short to have sufficient power to demonstrate meaningful changes in BMD. The relatively short trials that included many patients who did not have low bone mass/osteoporosis would also be very underpowered to detect changes in fracture, and our study finding may not be generalizable to longer use with the treatments studied. Additionally, these TNFi trials were conducted in patients with RA of less than 3 years’ duration. It remains to be determined if TNFi given for a treatment period longer than 2 years or in established RA would lead to improvement in BMD. It is also unclear if biologic agents other than TNFi yield similar effects on BMD in RA. Our literature search found 2 RCTs that examined the effects of tocilizumab, an IL-6 receptor inhibitor, on bone turnover markers in RA (29,30). Both studies found that tocilizumab administered at 4 mg/kg and 8 mg/kg for 24 weeks was associated with significant reduction in bone resorption markers, C-terminal crosslinking telopeptide of type I collagen generated by matrix metalloproteinases, and C-terminal crosslinking telopeptide of type I collagen compared with placebo. Tocilizumab did not yield significant changes in bone formation markers, osteocalcin, and N-terminal propeptide of type I collagen. Further studies are needed to determine if tocilizumab affects BMD and/or leads to a reduction in fracture risk. In AS, TNFi were associated with increases in both lumbar spine and hip BMD. Lumbar spine BMD may be falsely elevated due to the presence of syndesmophytes, especially in patients with advanced AS. In addition, TNFi use can increase syndesmophytes in the short term (31). However, patients receiving TNFi also had BMD increases in the hip, which is unaffected by syndesmophytes. This suggests that TNFi use improves bone metabolism in AS. TNFi might exert its effect on bone by controlling inflammation, down-regulating osteoclasts, and/or mitigating the RANK/RANKL pathway. It is unclear as to whether these improvements in BMD are sustained over the long term or if they translate into reduction in fractures. Also, one study compared infliximab with methotrexate to placebo and the other had no methotrexate. It makes sense to pool the studies if one considers that axial AS is not improved with methotrexate and the use of this drug would potentially be to decrease infliximab antibodies over time, not for added efficacy. However, there could be heterogeneity in the comparisons that were made, including in RA, where some trials were steroids added to a specific DMARD protocol and others were steroids added to usual care (with DMARD[s]) assuming that within a trial, treatment was otherwise similar between treatment arms. In our analysis, the use of glucocorticoids in patients with RA appeared to have a negative effect on BMD at the lumbar spine, but no significant effect on hip BMD. This is consistent with a previously published metaanalysis (9); however, our study included more recent
Siu et al
Figure 2. Meta-analysis of randomized controlled trials investigating the effect of tumor necrosis factor inhibitors (TNFi) on bone mineral density (BMD) in the hand, lumbar spine, and hip in patients with rheumatoid arthritis (A) and ankylosing spondylitis (B). The outcome was between-group mean difference in change of BMD or standardized mean difference (SMD; since the unit chosen for measurement of BMD varies among studies, the outcome was standardized and reported as the SMD). The within-group change of BMD was reported as the mean. The measurement units for BMD used in included studies were: Haugeberg et al, 2009 (13), percent change in gm/cm2; Hoff et al, 2009 (4), percent change in metacarpal cortical index measured by digital x-ray radiogrammetry; Guler-Yuksel et al, 2008 (12), percent change in gm/cm2; Valleala et al, 2009 (14), actual change in T score; Engvall et al, 2010 (15), actual change in gm/cm2; Marzo-Ortega et al, 2005 (22), percent change in gm/cm2; and Visvanathan et al, 2009 (23), percent change in gm/cm2. Unless otherwise specified, BMD was measured by dual x-ray absorptiometry. The mean is the difference within each treatment arm from the end of the treatment minus the beginning; the SMD is the between-group difference comparing the difference of one treatment arm minus the other (i.e., active difference minus placebo difference, or between-group differences), standardizing for differences in measuring the outcome across trials. 95% CI 5 95% confidence interval.
Effect of Steroids and TNF Inhibitors on BMD
Figure 3. Meta-analysis of randomized controlled trials investigating the effect of glucocorticoids on bone mineral density (BMD) in the hand, lumbar spine, and hip in all rheumatoid arthritis (RA) trials (A) and early RA trials only (B). The outcome was betweengroup mean difference in change of BMD or standardized mean difference (SMD; since the unit chosen for measurement of BMD varies among studies, the outcome was standardized and reported as the SMD). The within-group change of BMD was reported as the mean. The measurement units for BMD used in included studies were: Haugeberg et al, 2005 (20), actual change in gm/cm2 measured by digital x-ray radiogrammetry; Hansen et al, 1999 (18), percent change in gm/cm2; Laan et al, 1993 (16), percent change in mg hydroxyapatite/ml measured by quantitative computed tomography; Verhoeven et al, 2001 (19), percent change in gm/cm2; Engvall et al, 2008 (21), percent change in gm/cm2; Guler-Yuksel et al, 2008 (12), percent change in gm/cm2; and van Schaardenburg et al, 1995 (17), percent change in Z score. Unless otherwise specified, BMD was measured by dual x-ray absorptiometry. The mean is the difference within each treatment arm from the end of the treatment minus the beginning; the SMD is the between-group difference comparing the difference of one treatment arm minus the other (i.e., active difference minus placebo difference, or between-group differences), standardizing for differences in measuring the outcome across trials. 95% CI 5 95% confidence interval.
762 trials. The finding of a negative effect on lumbar spine BMD was based on data from 5 trials with differences in duration of disease, where bone loss may be different. These differences in population are reflected in the heterogeneity score of the meta-analysis. We performed a subanalysis that included only the trials in patients with early RA, which found that glucocorticoids had no significant effect on lumbar spine BMD in this population. This finding had a moderate degree of heterogeneity. It may be that short-term use of glucocorticoids in active early RA is not a risk for worsening BMD. Nevertheless, clinicians should continue to adhere to the usual glucocorticoidinduced osteoporosis guidelines in managing patients with RA. Of note, glucocorticoids often cause bone loss early in treatment. Patients in the established RA trials could have been taking chronic glucocorticoids at a low dose in steady state (often in biologic trials in RA, background glucocorticoid use ranges from one-quarter to onehalf of the patients). The meta-analysis evaluating the effect of the use of glucocorticoids on BMD was based on RCTs in which glucocorticoids were given by oral route. We found several RCTs that examined the use of parenteral glucocorticoids in RA; however, these studies were deemed ineligible for the current meta-analysis because they lack sufficient data and a valid placebo group. In one study, monthly intramuscular glucocorticoids were associated with lower hip BMD compared with placebo (32). Another RCT found that patients who received monthly pulses of intravenous methylprednisolone required lower cumulative doses of glucocorticoids and had less bone loss compared with those who received daily oral methylprednisolone (33). However, it remains unclear if the attenuated bone loss was due to the lower cumulative glucocorticoid dose and/or the route of administration. Overall, there has not been sufficient evidence to suggest a preferred route of glucocorticoid administration to minimize bone loss. Only RCTs were included in the systematic review and meta-analysis, so selection bias should be limited. The studies were evaluated using the Cochrane risk of bias assessment tools. The majority of included trials had low risk of bias. A few trials had high risk of incomplete outcome data reporting, all of which were related to a disproportionately higher percentage of participants from the control group dropping out of the study (4,17,22). More than half of those who dropped out of the control group in each of these studies did so because of lack of treatment efficacy or death. This might have led to underestimation of our outcome, between-group difference in DBMD, if assuming that those who dropped out had worse bone damage, or BMD due to heightened disease activity. Background DMARD use varied between the trials. As expected, for the TNFi trials, subjects with RA were often methotrexate-inadequate responders, and subjects with AS were often nonsteroidal antiinflammatory drug failures. Most patients in the RA trials evaluating glucocorticoids had DMARDs as background therapy. While several TNFi were included in these studies, one cannot know for certain if the findings are generaliz-
Siu et al able to all TNFi. Additionally, long-term effects of treatment on BMD beyond the followup periods cannot be assessed. In some RCTs, we were unable to ascertain if the active and control groups were balanced in the use of bone-protective medications, such as calcium, vitamin D, or bisphosphonates. However, the randomization process should have minimized confounding of background medications used for bone health between treatment arms in each trial. The end point of DBMD is a surrogate for fracture risk and cannot be extrapolated to change in fractures due to the limitations already mentioned. However, the effects of TNFi at the lumbar spine and hip in AS may indeed be clinically relevant (greater than 3% BMD improvement over the study period versus 1% or less in the control group). Similarly, there was less loss with glucocorticoids for hand BMD in RA, which again could be considered a clinically relevant difference (approximately 3% less BMD loss versus the control group). For patients with RA, TNFi and glucocorticoids both appear to attenuate hand bone loss. TNFi in RA did not impact lumbar spine and hip BMD. However, in AS, TNFi use was associated with improved lumbar spine and hip BMD. Glucocorticoid use was associated with negative effects on lumbar spine and no effect on hip BMD in RA. Our conclusions are limited by the low number of trials evaluable for analysis. There is insufficient evidence to suggest that antirheumatic drugs can mitigate systemic inflammatory bone loss and replace usual bone-protective medications. Additionally, some of the patients in these studies used bone-protective agents, so the effects of the medications studied (steroids and TNFi) cannot be determined independently, and we assumed that bone-protective treatment was randomly distributed between treatment groups, which may or may not be true. Although we did not study specific guidelines for osteoporosis prevention and treatment, it is recommended that usual guidelines for osteoporosis prevention and management should be followed in this group of patients, such as scoring fracture risk in patients using a standardized tool (i.e., the Fracture Risk Assessment Tool [FRAX], which considers age, height, weight, glucocorticoid use, past fracture, parent hip fracture, smoking, alcohol, secondary osteoporosis, presence of RA, and femoral neck BMD) (34). AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Pope had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Siu, Haraoui, Bessette, McCourt, Kraft, Lynde, Gulliver, Keeling, Dutz, Pope. Acquisition of data. Siu, Haraoui, Starnino, Keeling, Pope. Analysis and interpretation of data. Siu, Haraoui, Bissonnette, Bessette, Roubille, Richer, Starnino, McCourt, McFarlane, Fleming, Kraft, Lynde, Keeling, Pope.
ROLE OF THE STUDY SPONSOR AbbVie had no role in the study design or in the collection, analysis, or interpretation of the data, or the decision to submit
Effect of Steroids and TNF Inhibitors on BMD the manuscript for publication. AbbVie reviewed the manuscript prior to submission and made minor suggestions. Publication of this article was not contingent upon approval by AbbVie.
REFERENCES 1. Haugeberg G, Uhlig T, Falch JA, Halse JI, Kvien TK. Bone mineral density and frequency of osteoporosis in female patients with rheumatoid arthritis: results from 394 patients in the Oslo county rheumatoid arthritis register. Arthritis Rheum 2000;43:522–30. 2. Weiss RJ, Wick MC, Ackermann PW, Montgomery SM. Increased fracture risk in patients with rheumatic disorders and other inflammatory diseases: a case-control study with 53,108 patients with fracture. J Rheumatol 2010;37: 2247–50. 3. Redlich K, Smolen JS. Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat Rev Drug Discov 2012;11: 234–50. 4. Hoff M, Kvien TK, Kalvesten J, Elden A, Haugeberg G. Adalimumab therapy reduces hand bone loss in early rheumatoid arthritis: explorative analyses from the PREMIER study. Ann Rheum Dis 2009;68:1171–6. 5. Kanis JA, Johnell O, De Laet C, Johansson H, Oden A, Delmas P, et al. A meta-analysis of previous fracture and subsequent fracture risk. Bone 2004;35:375–82. 6. Van Staa TP, Leufkens HG, Cooper C. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int 2002;13:777–87. 7. Dimitroulas T, Nikas SN, Trontzas P, Kitas GD. Biologic therapies and systemic bone loss in rheumatoid arthritis. Autoimmun Rev 2013;12:958–66. 8. Kawai VK, Stein CM, Perrien DS, Griffin MR. Effects of anti–tumor necrosis factor a agents on bone. Curr Opin Rheumatol 2012;24:576–85. 9. Lee YH, Woo JH, Choi SJ, Ji JD, Song GG. Effects of lowdose corticosteroids on the bone mineral density of patients with rheumatoid arthritis: a meta-analysis. J Investig Med 2008;56:1011–8. 10. Bottcher J, Malich A, Pfeil A, Petrovitch A, Lehmann G, Heyne JP, et al. Potential clinical relevance of digital radiogrammetry for quantification of periarticular bone demineralization in patients suffering from rheumatoid arthritis depending on severity and compared with DXA. Eur Radiol 2004;14:631–7. 11. National Osteoporosis Society. Precision and monitoring change in BMD. URL: http://www.nos.org.uk/document. doc?id=663. 12. Guler-Yuksel M, Bijsterbosch J, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Hulsmans HM, de Beus WM, et al. Changes in bone mineral density in patients with recent onset, active rheumatoid arthritis. Ann Rheum Dis 2008;67: 823–8. 13. Haugeberg G, Conaghan PG, Quinn M, Emery P. Bone loss in patients with active early rheumatoid arthritis: infliximab and methotrexate compared with methotrexate treatment alone. Explorative analysis from a 12-month randomised, double-blind, placebo-controlled study. Ann Rheum Dis 2009;68:1898–901. 14. Valleala H, Kautiainen H, Mottonen T, Hannonen PJ, Korpela M, Kaipiainen-Seppanen O, et al. Bone mineral density in patients with recent onset, active rheumatoid arthritis: two-year data of the NEO-RACo study [abstract]. Arthritis Rheum 2009;60(Suppl 10):1008. 15. Engvall IL, Tengstrand B, Brismar K, Hafstrom I. Infliximab therapy increases body fat mass in early rheumatoid arthritis independently of changes in disease activity and levels of leptin and adiponectin: a randomised study over 21 months. Arthritis Res Ther 2010;12:R197. 16. Laan RF, van Riel PL, van de Putte LB, van Erning LJ, van ’t Hof MA, Lemmens JA. Low-dose prednisone induces rapid reversible axial bone loss in patients with rheumatoid
arthritis: a randomized, controlled study. Ann Intern Med 1993;119:963–8. Van Schaardenburg D, Valkema R, Dijkmans BA, Papapoulos S, Zwinderman AH, Han KH, et al. Prednisone treatment of elderly-onset rheumatoid arthritis: disease activity and bone mass in comparison with chloroquine treatment. Arthritis Rheum 1995;38:334–42. Hansen M, Podenphant J, Florescu A, Stoltenberg M, Borch A, Kluger E, et al. A randomised trial of differentiated prednisolone treatment in active rheumatoid arthritis: clinical benefits and skeletal side effects. Ann Rheum Dis 1999;58: 713–8. Verhoeven AC, Boers M, te Koppele JM, van der Laan WH, Markusse HM, Geusens P, et al. Bone turnover, joint damage and bone mineral density in early rheumatoid arthritis treated with combination therapy including high-dose prednisolone. Rheumatology (Oxford) 2001;40:1231–7. Haugeberg G, Strand A, Kvien TK, Kirwan JR. Reduced loss of hand bone density with prednisolone in early rheumatoid arthritis: results from a randomized placebo-controlled trial. Arch Intern Med 2005;165:1293–7. Engvall IL, Svensson B, Tengstrand B, Brismar K, Hafstrom I, and the Better Anti-Rheumatic FarmacO Therapy Study Group. Impact of low-dose prednisolone on bone synthesis and resorption in early rheumatoid arthritis: experiences from a two-year randomized study. Arthritis Res Ther 2008; 10:R128. Marzo-Ortega H, McGonagle D, Jarrett S, Haugeberg G, Hensor E, O’Connor P, et al. Infliximab in combination with methotrexate in active ankylosing spondylitis: a clinical and imaging study. Ann Rheum Dis 2005;64:1568–75. Visvanathan S, van der Heijde D, Deodhar A, Wagner C, Baker DG, Han J, et al. Effects of infliximab on markers of inflammation and bone turnover and associations with bone mineral density in patients with ankylosing spondylitis. Ann Rheum Dis 2009;68:175–82. Grossman JM, Gordon R, Ranganath VK, Deal C, Caplan L, Chen W, et al. American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken) 2010;62:1515–26. Duru N, van der Goes MC, Jacobs JW, Andrews T, Boers M, Buttgereit F, et al. EULAR evidence-based and consensusbased recommendations on the management of medium- to high-dose glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis 2013;72:1905–13. Lekamwasam S, Adachi JD, Agnusdei D, Bilezikian J, Boonen S, Borgstrom F, et al. A framework for the development of guidelines for the management of glucocorticoidinduced osteoporosis. Osteoporos Int 2012;23:2257–76. Papaioannou A, Morin S, Cheung AM, Atkinson S, Brown JP, Feldman S, et al. 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary. CMAJ 2010;182:1864–73. Ghazi M, Kolta S, Briot K, Fechtenbaum J, Paternotte S, Roux C. Prevalence of vertebral fractures in patients with rheumatoid arthritis: revisiting the role of glucocorticoids. Osteoporos Int 2012;23:581–7. Karsdal MA, Schett G, Emery P, Harari O, Byrjalsen I, Kenwright A, et al. IL-6 receptor inhibition positively modulates bone balance in rheumatoid arthritis patients with an inadequate response to anti–tumor necrosis factor therapy: biochemical marker analysis of bone metabolism in the tocilizumab RADIATE study (NCT00106522). Semin Arthritis Rheum 2012;42:131–9. Garnero P, Thompson E, Woodworth T, Smolen JS. Rapid and sustained improvement in bone and cartilage turnover markers with the anti–interleukin-6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate: results from a substudy of the multicenter double-blind, placebo-controlled trial of tocilizumab in inadequate responders to methotrexate alone. Arthritis Rheum 2010;62: 33–43.
764 31. Pedersen SJ, Sorensen IJ, Lambert RG, Hermann KG, Garnero P, Johansen JS, et al. Radiographic progression is associated with resolution of systemic inflammation in patients with axial spondylarthritis treated with tumor necrosis factor a inhibitors: a study of radiographic progression, inflammation on magnetic resonance imaging, and circulating biomarkers of inflammation, angiogenesis, and cartilage and bone turnover. Arthritis Rheum 2011;63:3789–800. 32. Choy EH, Kingsley GH, Khoshaba B, Pipitone N, Scott DL, and the Intramuscular Methylprednisolone Study Group. A two year randomised controlled trial of intramuscular depot steroids in patients with established rheumatoid arthritis who have shown an incomplete response to disease
Siu et al modifying antirheumatic drugs. Ann Rheum Dis 2005;64: 1288–93. 33. Frediani B, Falsetti P, Bisogno S, Baldi F, Acciai C, Filippou G, et al. Effects of high dose methylprednisolone pulse therapy on bone mass and biochemical markers of bone metabolism in patients with active rheumatoid arthritis: a 12-month randomized prospective controlled study. J Rheumatol 2004;31:1083–7. 34. Kanis JA, for the World Health Organization Scientific Group. Assessment of osteoporosis at the primary health care level: technical report. Sheffield (UK): University of Sheffield; 2007. URL: http://www.shef.ac.uk/FRAX/pdfs/ WHO_Technical_Report.pdf.