Can bone loss in rheumatoid arthritis be prevented?

Transcription

1 Osteoporos Int (2013) 24: DOI /s REVIEW Can bone loss in rheumatoid arthritis be prevented? M. Vis & M. Güler-Yüksel & W. F. Lems Received: 17 December 2012 / Accepted: 20 February 2013 / Published online: 18 June 2013 # International Osteoporosis Foundation and National Osteoporosis Foundation 2013 Abstract Rheumatoid arthritis (RA) is a systemic inflammatory disease that can lead to local joint deformations (bone erosions and joint space narrowing) and to extraarticular phenomena, including generalized osteoporosis. In addition, in patients with RA, the risk of vertebral and nonvertebral fractures is doubled. High disease activity (inflammation), immobility, and glucocorticoid use are common factors that substantially increase fracture risk in these patients, on top of the background fracture risk based on classical risk factors such as high age, low body mass, and female gender. New insights on the links between the immune system and the bone system, the field of osteoimmunology, have shown that local and generalized bone loss share common pathways. The receptor activator of nuclear factor κb ligand/osteoprotegerin pathway (RANKl/OPG) is one of the most important pathways, as it is (strongly) upregulated by inflammation. In modern treatment of RA with biologics, for example, TNFαblocking agents and combination therapy of conventional disease-modifying antirheumatic drugs (DMARDs), clinical remission is a realistic treatment goal. As a consequence, in recent studies, it has been documented that both local and generalized bone loss is absent or minimal in those patients who are in clinical remission. M. Vis (*) Department of Rheumatology, Erasmus MC, Dr. Molewaterplein 50, 3015 GE Rotterdam, the Netherlands marijn.vis@erasmusmc.nl M. Güler-Yüksel Department of Rheumatology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands W. F. Lems Department of Rheumatology, Leiden and VU Medical Center, De Beoelelaan 1117, 1081 HV Amsterdam, the Netherlands Keywords Biologics. DMARD. Erosions. Osteoimmunology. Osteoporosis. Rheumatoid arthritis Introduction Rheumatoid arthritis (RA) is a systemic auto-immune inflammatory disease characterized by arthritis of particularly the small joints of the hands and feet, but extra-articular manifestations may also occur. Extra-articular signs and symptoms vary widely between patients: in some patients, they never occur, while in other patients nodules, vasculitis, pulmonary, and ocular manifestations can be found [1]. Generalized bone loss, which may lead to an elevated fracture risk, is one of the most serious extra-articular manifestation of RA. Active inflammation and bone and cartilage destruction lead to significant functional impairment and a substantial raise of the burden of disease leading to a reduced physical, emotional, and social quality of life [2, 3]. There is also a reduced life expectancy in RA, which is particularly due to a high prevalence of cardiovascular diseases. These factors also increase the burden to society by increasing health care costs and unemployment [2, 3]. The pathogenesis of RA is incompletely understood, but is thought to be multifactorial, involving multiple genes, environmental triggers, and chance [4]. The disease is currently classified on the basis of the clinical phenotype; in the near future, it may be possible to define different disease subgroups with different prognosis and with differences in local and generalized bone involvement [4]. Three types of bone involvement occur in RA: periarticular bone loss, joint erosions, and generalized bone loss (osteoporosis). Peri-articular bone loss is one of the first manifestations of local bone involvement in early RA; bone erosions and joint space narrowing usually occur later. In daily practice, conventional X-rays of the hand and feet are often performed regularly to detect radiological progression, which is regarded as a consequence of suboptimal suppression of

2 2542 Osteoporos Int (2013) 24: inflammation. For clinical trials, these X-rays are scored according to the Larsen or the Sharp-van der Heijde method, with a higher score indicating more joint damage [5, 6]. Osteoporosis and related fragility fractures represent one of the most important extra-articular complications that may occur in patients with rheumatoid arthritis; obviously these fractures contribute to an important decrease in quality of life. Disease activity (inflammation), immobility, and treatment with glucocorticoids (GC), especially a cumulative high dose, are the main factors that increase the risk of osteoporotic fractures, on top of the background fracture risk based on, amongst others, high age, low body mass, and female gender [7]. Recent data in the field of osteoimmunology, the crosstalk between cytokines and bone, have elucidated that activated inflammatory cells at sites of inflammation produce a wide spectrum of cytokines which stimulate local and generalised bone resorption, and which suppress bone formation in patients with active RA [8 10]. We will discuss the complex pathogenesis of local and generalized bone loss in RA, followed by describing the effects of modern treatment of RA with combination of conventional disease-modifying antirheumatic drugs (DMARDs) and biologics on local and generalized bone loss in RA. Pathogenesis The natural course of RA may result in chronic joint inflammation with longstanding synovial hyperplasia leading to articular bone damage, consisting of subchondral cysts, sclerosis, erosive bone damage, cartilage loss, and extraarticular loss of bone mineral density (BMD), with a subsequent increased fracture rate. Inflammation seems to have an uncoupling effect on bone resorption and bone formation [10]. For instance, in an elegant study by Seriolo et al., [11] it was shown that in patients with active RA compared to those with inactive RA, bone resorption (urinary crosslinks) was increased, whereas bone formation (osteocalcin) was decreased. The concept of osteoimmunology is based on growing insights on the links between the immune system and bone [9, 12]. A major breakthrough was the finding in the year 1998 of multinucleated cells in the inflamed synovial tissue at the site of joint erosions, the pannus-bone area, in which specific markers of osteoclasts such as cathepsin K and tartrate-resistant alkaline phosphatase could be demonstrated [8]. The same investigators some years later also found the receptor activator of nuclear factor κb ligand (RANKl) expression at these sites [13]. This finding was a breakthrough, particularly when it was documented in animal models that counteracting RANKl blocked the occurrence of new erosions [14]. RANKl is involved in the regulation of bone resorption in RA by stimulating the activation, differentiation, and proliferation of osteoclasts, while this effect is counteracted by osteoprotegerin (OPG), which acts as a decoy receptor. RANKl is expressed by osteoblasts but also by activated T cells and B cells and seems to be a critical factor for joint destruction in RA [15, 16]. Several inflammatory cytokines, such as TNFα, IL-1, IL- 6, and IL-17, and the macrophage colony stimulating factor (M-CSF) upregulated RANKl expression and thereby stimulate the differentiation, activation, and increasing the life span of osteoclasts, leading to elevated bone resorption [3, 8]. Antibodies against citrullinated proteins (ACPA) are an important prognostic factor in RA: ACPA-positive patients generally have higher disease activity and disability, but also more radiological damage [17, 18]. It is intriguing that in a recent observation ACPA had a direct and independent stimulating effect on osteoclasts and induced elevated bone resorption. In vitro human autoantibodies against mutated citrullinated vimentin bound to osteoclasts and led to induction of osteoclastogenesis and bone-resorptive activity [19]. The concept of bone destruction in RA is that the upregulated osteoclasts in the synovium destroy the cortex around the joint, particularly at mechanically vulnerable sites, leading to deep resorption pits, filled with inflammatory cells, and also to bone marrow involvement[12]. This theory is supported by the evidence that trabecular bone density, measured by high-resolution peripheral quantitative CT system, is decreased in metacarpal heads, before erosions are detectable in early RA patients [20]. However, another theory is that RA is primary a bone marrow disease, with secondary invasion of the joint via erosions created by intramedullary activated osteoclasts [12]. This is at least partly based on the finding that with high-resolution CT, small erosions (<1.9 mm) were found in the MCP joints of 37 % of healthy subjects without any signs and symptoms of active inflammation [21]. Another intriguing point is the healing of erosions, which has only scarcely been documented in some case reports in RA [22]. The underlying mechanism was recently investigated in an animal model in which a transient arthritis was induced: in the healing phase, bone resorption was depressed and bone formation upregulated, leading to repair of bone erosions. In this study, it was suggested that changes in the Wnt-signaling pathway play an important role in the healing process of erosions, particularly, the downregulation of the Wnt antagonists secreted frizzled-related protein 1 (sfrp1) and sfrp2 [23]. The Wnt pathway is a regulatory pathway of osteoblast activity: at the molecular level, the activation of the Wnt/β catenin pathway is crucial for osteoblastic differentiation [24].

3 Osteoporos Int (2013) 24: Two blockers of the Wnt-signaling pathway that seem to play an important role in local (erosion repair) and generalized bone loss in RA are dickkopf-1 (Dkk-1) and sclerostin [25 27]. Certain cytokines, for instance TNFα, can induce both sclerostin and dickkopf-1 (Dkk-1) and thereby suppress bone formation. Garnero et al.[27] found in a study in early RA that patients with Dkk-1 levels in the highest quartile had more than five times higher relative risk for radiological joint damage than patients in the lowest quartile. In another study in RA patients, the RANKL/OPG was higher than in controls, while Dkk-1 and sclerostin were also increased, indicating a state of high bone resportion and low bone formation. After treatment with anti-il-6, an effective biologic for the treatment of RA, RANKl/OPG increased and Dkk-1 decreased, while unexpectedly sclerostin levels further increased [28]. These data illustrate the elevated bone resorption and reduced bone formation in RA patients and that this is at least partly caused by changes in RANKl/OPG and the Wnt pathway. Osteocytes are the most prevalent bone cells: 90 % of all the bone cells are osteocytes. Osteocytes are the pivotal orchestrators of biomechanical regulation of bone mass and structure. Osteocytes are embedded in lacunae in the bone matrix and send their signals through the lacuno canicular system. Loading and unloading of bone activates the osteocytes, which then produce signals to regulate the osteoclasts and osteoblasts, i.e., RANKl and sclerostin (Fig. 1) [29 31]. Imaging Although it is possible to detect radiological joint damage with conventional X-rays, with MRI, it is possible to detect bone involvement much earlier than with conventional radiographs; particularly, bone marrow involvement can be found very early in the disease, and it is estimated that bone marrow edema (indicating active inflammation, sometimes called osteitis ) and bone erosions can be found 1 2 years earlier on MRI than on conventional radiographs. In addition, the finding of early bone marrow edema at baseline predicts erosions on conventional X-rays after 1 year, suggesting that this is an important predictor for radiological joint damage [32]. However, the use of MRI is limited by its costs and by the lack of data showing the additional predictive value above other important predictors of radiological progression, such as disease activity score (DAS) and ACPA antibodies. Other critical points are the worries about the specificity of the MRI bone lesions and the complexity of the scoring system. Generalized bone loss can be detected easily and relatively cheap with DXA of the lumbar spine and hip. The main limitation is that it only measures the amount of bone and not the bone quality [33]. Very recently, data have been published that suggest that the trabecular bone score of the lumbar spine may have some additional value above traditional DXA of the lumbar spine in the detection of vertebral fractures, suggesting that this technique shows some Fig. 1 Osteocytes as the orchestrator of osteoclasts by expressing RANKl, sclerostin, and Dkk-1 when bone is unloaded

4 2544 Osteoporos Int (2013) 24: superiority, probably because it measures, at least partly, the quality of bone [34]. Another relatively new technique is the LVA, the lateral vertebral assessment: with this technique, it is easy to measure the vertebral heights (vertebral fractures) of the spine directly following DXA. Vertebral fractures are often asymptomatic, but it is well known that vertebral fractures have an impact on quality of life, and they are an important risk factor for future vertebral and nonvertebral fractures [35, 36]. Since vertebral fracture risk is doubled in patients with RA, the finding of asymptomatic vertebral fractures in RA can be clinically relevant [37]. We suggest that in patients with clinical risk factors for fractures, e.g., patients 50 years and over with a recent fracture and a BMD measurement in the osteopenic range, the diagnosis of a vertebral fracture may necessitate antiosteoporotic therapy [38]. The peri-articular bone loss around the joint can be measured easily and reliable using Digital X-ray Radiogrammatry (DXR). DXR uses conventional X-rays of the hands and gives an estimate of cortical hand BMD in the metacarpals two to four [39]. In rheumatoid arthritis patients, a low-hand BMD measured by DXR is associated with an increased erosions score [40]. Also, changes in this BMD in patients with early RA predict the occurrence of joint erosions [41, 42]. Interestingly, loss of hand BMD is associated with measures of generalized bone loss like vertebral fractures and BMD at the hip [43]. RA and generalized bone loss In a cross-sectional study, the prevalence of osteoporosis defined as a T-score < 2.5 was increased two times in 394 female RA patients compared with an age and gender matched reference population [44]. Not only demographic factors such as age and low body weight were determinants of osteoporosis, but also disease related factors: disability (M-HAQ score), rheumatoid factor, and the use of GC. The same doubling of the risk was found in a smaller study in 94 male RA patients, in which osteoporosis was defined as a Z-score < 1 [45]. Before the introduction of biologicals, high bone loss was observed in a longitudinal study during 2 years in early RA: 2.4 % at the spine and 4.3 % at the hip [46]. In a subgroup analysis, bone loss in both the spine and the hips was much larger in those patients with high CRP levels (>20 mg/dl) than in those patients with low CRP levels (<20 mg/dl), e.g., in the lumbar spine, 2.1 % vs. 0.2 %, respectively. The same was found for patients with low functional capacity (HAQ-score >1) compared to patients with a better HAQ-score (<1): 1.9 % vs. 0.2 %, respectively. Xu et al.[29] investigated osteoimmunology in the pathogenesis of osteoporosis in 64 hospitalized DMARD naive RA patients and age- and sex-matched healthy controls. They found a higher prevalence of osteoporosis (T-score < 2.5) but also increased levels of RANKL and decreased OPG levels in RA patients compared to healthy controls. It is important to realize that not a low bone mass, but fractures are the clinically relevant outcome. Earlier studies have shown that patients with RA are also at an increased risk of both vertebral [47, 48] and nonvertebral fractures [49, 50]. In a large cross-sectional study in female RA patients, the number of vertebral deformities was roughly doubled versus a control group that was matched for age, gender, and social background [47]. In a large cohort study from the General Practice Research Database (GPRD) including RA patients, it was shown that the risk for osteoporotic fractures was increased compared with healthy controls: relative risk for hip fractures 2.0 (95 % CI, ), and for spine fractures: 2.4 (95 % CI, ) ) [49]. Disease duration, low BMI, and the use of GC were the main determinants of fractures in this study. In a recent study, we have shown that in a 5-year prospective follow-up study in female established RA patients 50 years and over, new nonvertebral fractures occurred in 16 % and a new radiological vertebral fracture occurred in 19 % of them [51]. Compared to historical controls, these frequencies are about 1.5 to 2 times higher than expected [52, 53]. In a retrospective cohort study in RA patients and matched healthy controls, it was found that the risk for osteoporotic fractures is particularly increased in younger RA patients: in the whole group of female RA patients, the odds ratio for an osteoporotic fracture was 1.7 (95 % CI, ), but in the subgroup of female patients under 50 years of age, an odds ratio of 4.3 (95 % CI, ) was found [54]. Thus, both generalized osteoporosis and an elevated fracture rate are documented in earlier studies in suboptimal-treated RA patients. The most frequently reported risk factors associated with osteoporosis and fractures in RA are particularly inflammation, but also immobility/disability, high-dose corticosteroid use, disease duration, and sarcopenia, but traditional risk factors for osteoporosis, i.e., low BMD and previous fractures, also contribute to fracture risk in RA (Fig. 2) [51]. The effect of pharmacological therapy on bone in RA Over the past two decades, the therapeutic approach to patients with RA has shifted from the conservative pyramid approach towards early and more aggressive use of biological agents and combinations of conventional DMARDs, aiming for clinical remission as well as structural joint protection preventing erosions, articular cartilage loss, and peri-articular bone loss/osteoporosis in and around the

5 Osteoporos Int (2013) 24: Fig. 2 Risk factors for generalized bone loss in RA Risk factors of generalized bone loss and fractures in RA General risk factors Disease related risk factors - Age - Gender - Family history - Low BMI - Fall risk - Lifestyle - Inflammation - Immobility - High-dose glucocorticoids - Sarcopenia Osteoporosis and Fractures in RA affected joints. These two therapeutic goals are closely linked to each other, since an effective anti-inflammatory approach will also prevent local structural damage. Furthermore, an increasing amount of evidence shows that inflammatory activity in RA induces also generalized bone loss/osteoporosis in the entire skeleton and that effectively suppression of inflammation halts generalized bone loss, thereby preventing increased fracture risk in RA patients. Unfortunately, it is nowadays not possible to fully suppress the inflammatory disease activity in all RA patients. Therefore, another option to prevent bone loss in active RA is to use bone active agents (as co-treatment), such as potent bisphosphonates (zoledronic acid) or the anti-rankl agent denosumab, that suppresses the elevated bone resorption, in those patients in which the inflammatory process cannot be fully blocked. The effects of several well-known, widely used DMARDs and biological agents on bone and in RA will be discussed below. DMARDs DMARDs are small-sized, orally available drugs that show anti-inflammatory and structure-modifying properties leading to better disease control in RA. Among DMARDs, the most widely used agent is methotrexate (MTX), which is considered as the cornerstone of RA treatment due to its favorable efficacy/toxicity ratio. Moreover, it is attractive that it can be used as co-treatment in patients treated with other conventional DMARDs or biological agents. Other frequently used DMARDs are leflunomide, sulfasalazine (SSZ), and hydroxychloroquine, and, to a lesser extent, cyclosporine A (CyA) and parenteral gold salts. GC, although having both anti-inflammatory and structure-modifying properties until recently not considered as DMARDs, are also frequently used as co-treatment to conventional DMARDs. Jones et al.[55] reviewed 38 randomized placebo-controlled trials to assess and rank the efficacy of pharmacological interventions in preventing radiographic joint damage progression in RA. According to this systematic review, the abovementioned conventional DMARDs were more effective in decreasing radiographic joint damage progression than placebo, but their effect, when used as monotherapy, is quite moderate when compared to biological agents. Methotrexate MTX suppresses the metabolism of folic acid mainly by inhibition of the enzyme dihydrofolate reductase and appears to have anti-inflammatory properties through induction of adenosine. In vitro, MTX has been shown to reduce the expression of RANKl in synovial fibroblast cultures, thereby inhibiting osteoclastogenesis, which indicates a specific, direct effect of MTX on the osteoclast [56]. However, this bone-sparing effect might be neutralized by a negative effect on bone formation; long-term treatment of rodents with MTX resulted in decreased bone volume due to inhibition of osteoblast proliferation [57]. Much clinical data exists on the effect of MTX on structural joint damage, since many clinical trials with biological agents have used MTX in the control arm. Treatment with monotherapy MTX results in retardation of radiographic joint damage progression, erosions as well as joint space narrowing, particularly when it is given in higher dosages, i.e., mg per week. With respect to the effect of MTX on bone density, a clinical, prospective, longitudinal study of 117 RA patients on long-term treatment with MTX showed no negative effects on bone turnover markers after MTX treatment; also, indices of bone formation in synovial biopsies taken before and after MTX treatment were not negatively influenced by MTX in four subjects [58]. The use of MTX was associated with a lower BMD at the femoral neck after 1 year; however, multivariate covariance analysis showed that the observed BMD reduction was due to disease severity and activity, and not due to a direct negative effect of MTX on bone. Furthermore, in a

6 2546 Osteoporos Int (2013) 24: large cross-sectional cohort involving 731 female RA patients, low-dose MTX was not a predictor of osteoporosis at the lumbar spine and femoral neck [59]. Thus, MTX seems to have some directs effects on bone metabolism, but its anti-inflammatory effects reduce the negative effect of RA on bone. Leflunomide Leflunomide is an isoxazole derivative inhibiting de novo pyrimidine biosynthesis by acting on dehydrogenase leading to suppression of T cell proliferation and activation. In vitro, leflunomide has a possible direct inhibitory effect on RANKl-mediated osteoclast formation and differentiation through its metabolite A771726; however, the exact mechanism is unclear [60]. Leflunomide use has resulted in a decrease of joint damage progression, both erosion and joint space narrowing scores, in RA, more or less comparable with treatment with MTX and SSZ [61, 62]. To date, however, there are no studies that investigated whether leflunomide has a sparing effect on bone mineral density or bone strength in RA. Sulfasalazine SSZ was initially designed as a drug that linked an antibiotic, sulfapyridine, with an anti-inflammatory agent, 5- aminosalicyclic acids. SSZ might in vitro, just like MTX, directly inhibit osteoclastogenesis by acting on osteoclast precursor cells and modulating the RANKl-RANK-OPG interaction primarily by decreasing expression of RANKl on synovial fibroblasts and increasing expression of OPG; however, its in vivo effect on bone is still poorly defined [56]. Until now, no clinical studies are performed to evaluate the effect of SSZ monotherapy on bone mineral density or bone turnover in RA. Hydroxychloroquine Both the working mechanism and the in vitro effect of HCQ on osteoclasts and osteoblast are not fully elucidated. Since HCQ is a less potent DMARD, it is not surprising that its use as monotherapy can be associated with radiological joint damage, both erosive damage and cartilage loss, and with generalized bone loss, at least partly due to suboptimal suppression of the inflammatory activity in RA. A direct effect of HCQ on bone density and strength has never been investigated. Nowadays, because of the possible synergistic effect and the favorable safety profile, HCQ is often used as combination therapy with for example MTX and SSZ, i.e., the O'Dell scheme, in RA patients [63]. Cyclosporine A CyA inhibits the activation of T lymphocytes, mainly via transcriptional suppression of the interleukin-2 gene. In undifferentiated marrow stromal cells, CyA decreases OPG mrna and increases RANKl mrna levels. In vivo, both osteoclast and osteoblast activity is stimulated; however, resorption rate exceeds the formation rate resulting in net bone loss [64, 65]. CyA reduces inflammation and slows radiographic progression in comparison with placebo [66]. Little is known about the effect of CyA on generalized bone loss.[67, 68] CyA is not often used in RA. Gold The anti-inflammatory effect of injectable or oral gold salts is largely unknown. In vitro, gold salts seem to dosedependently inhibit osteoclastic bone resorption [69]. Despite the reasonable efficacy of gold regarding averting structural joint damage, the use of gold has declined since the emergence of more rapidly active and less toxic DMARDs [70]. No in vivo data exists on the indirect or direct effect of gold salts on generalized bone strength and bone loss. Glucocorticoids It is well-known that GC have a strong anti-inflammatory effect. With regard to the direct effect of GC on bone, it is widely known that these induce bone loss directly by promoting osteoclastogenesis and osteoclast lifespan by increased expression of RANKl and decreased expression of OPG. On the other hand, the suppression of the development and functional activity of osteoblasts and osteocytes and the elevated induction of apoptosis of these cells are probably even more important [70, 71]. This results in cortical and trabecular bone density loss, microarchitectural destruction, and loss of bone strength, and therefore in increased fracture risk. Although high dose of GC, usually prescribed in patients with very high disease activity, is associated with bone loss and with fractures [72]. In patients with low dosages of GC or with quickly tapered high-to-moderate dose induction therapy, like in the COBRA scheme the direct negative effect of GC on bone is counteracted by the strong suppression of inflammation by GC [73]. This indicates that the bone-sparing effect due to quick and effective suppression of inflammation can outweigh the direct negative effect of GC on bone [74]. Furthermore, low-dose glucocorticoids reduce localized bone loss in the hands nearby the affected joints due to effective inflammation control [74, 75].

7 Osteoporos Int (2013) 24: A recent meta-analysis showed that glucocorticoid use has a consistent positive effect on structural joint damage in RA; however, this effect seems to be somewhat moderate, especially when compared to the effect of combination of MTX with biological agents, which is discussed below [72, 76]. Combination DMARD therapy Nowadays, different combinations of DMARDs and GC are frequently used in the treatment of RA to rapidly alleviate inflammation and prevent both bone loss and structural damage [73, 77]. In a meta-analysis, it is shown that the addition of low-dose prednisone to standard therapy with DMARDs substantially reduces the rate of erosion progression in RA, with a standardized mean difference in progression of erosions of 0.40 in favor of GC (95 % CI, 0.27, 0.54) [72]. This is in line with a recent study in which 10 mg prednisone per day was added to MTX in a randomized tight-control strategy: the combination had not only a superior effect on disease activity, but also on radiological progression[78]. Furthermore, the BeSt study, comparing four treatment strategies in early, active RA, showed that initial combination therapy with MTX, SSZ and quickly tapered prednisone, almost identical to the COBRA scheme, effectively retards joint damage progression, both erosions and cartilage loss, and localized bone loss in the hands compared to initial treatment with a single DMARD due to earlier and better disease control [79]. It is notable that initial combination therapy with MTX, SSZ, and quickly tapered high-dose prednisone and initial combination therapy with infliximab and MTX are equally effective in suppressing joint damage and localized bone loss. Moreover, a subanalysis in the BeSt study showed that patients in continuous clinical remission even gained in bone density in the hands, whereas this was rarely seen in patients with continuous inflammatory activity [80]. This emphasizes the importance of quick and effective suppression of inflammation in recent-onset RA to protect bone and cartilage in general, while the choice for specific agents is of less importance. Since the anti-inflammatory mode of action of conventional DMARDs is still difficult to pinpoint to a specific pathway, and since the bone-sparing effects of DMARDs (MTX excepted) are modest, it is difficult to evaluate and understand the specific effects of these agents on bone and cartilage turnover. Systemic effects on bone and cartilage of most of these drugs remain to be determined in appropriate animal models of inflammation and in clinical studies. The few available clinical observational studies are difficult to interpret, since both localized and generalized bone loss in RA patients could result from persisting high inflammatory activity despite the use of DMARDs and/or a direct negative effect of the DMARD on bone. The bone-sparing effect of DMARDs seems modest compared with that of biological agents. Biologicals Fifteen years ago, biological therapy was introduced in the treatment of RA; the treatment and prognosis of RA have dramatically improved. Biologicals are large antibodies produced by living organisms, targeting cytokines or cytokine receptors. They are administered intravenously or subcutaneously, and their costprice is high, roughly between and Euro per patient per year. The first biological to be used in RA was the tumor necrosis factor α (αα) blocking agent infliximab; a monoclonal antibody that binds to TNFα [81]. Nowadays, four other TNFα blockers are used (adalimumab, etanercept, certoluzimab, and golimumab), but also other biologics are available, counteracting B cell activity (rituximab), T cell activation (abatacept), and anti-il-6 (tociluzimab). TNFα blockers TNFα is a very important protein in inflammation induced bone loss: it stimulates osteoclastogenesis through upregulation of RANKl, but also has been shown to directly stimulate the activation of osteoclasts [82 84]. In animal models with a collagen-induced arthritis or TNFα transgenic mice, blocking of TNFα not only led to a large decrease in synovial inflammation, but also to a decrease in joint erosions and in generalized bone loss. In contrast, blocking of only RANKl in these animals has no effect on the synovial inflammation but did reduce joint erosions and generalized bone loss [15, 85, 86]. In RA patients, the effect of TNFα blockade on bone has been studied by Vis et al.,[87] who showed in a cohort of 102 RA patients (median age 53 years and median disease duration 8 years) that treatment with infliximab in combination with a stable dosage of MTX led to a statistically significant decrease (p<0.05) of 20 % in serum CTX levels (bone resorption), whereas PINP levels (bone formation) were increased slightly at 46 weeks. RANKl levels also significantly decreased by 33 % (p<0.001) in this study, while OPG more or less remained stable, leading to an improvement of the RANKl/OPG ratio. The changes in markers of bone resorption paralleled the decrease in disease activity. Seriolo et al.,[88] in a smaller study in RA patients treated with infliximab (n=10) and etanercept (n=11), found similar beneficial effects on markers of bone metabolism, while in a control group treated only with a stable dose of MTX and prednisone (n=9), no changes in markers

8 2548 Osteoporos Int (2013) 24: of bone metabolism were observed. The effects of 1 year infliximab in RA patients were also studied in a 1-year observational study in France: serum CTX-1 decreased by 19 % and 28 % at week 6 and week 22, and returned, remarkably, to pre-treatment levels at week 54, while serum 1CTP decreased around 25 % at all time points. Bone formation, measured by P1NP, remained stable over time, again showing a beneficial systemic effect of a TNFα blocking agent on bone markers in RA. All TNFα blockers have shown to reduce the progression and formation of joint erosions and joint space narrowing [89 92]. In a recently performed systematic review based on randomized, double-blind, controlled, comparative trials that radiological damage was inhibited versus MTX in six RCTs (all five TNFα blockers and abatacept) in early RA (mean difference in radiological damage 16.28; 95 % CI: 24.4 to 8.1), and in seven RCTs (all five TNFα blockers and abatacept and tocilizumab) in patients with longstanding RA: 39.3; 95 % CI, 53.8 to 24.7) [93]. The difference was statistically significant in 12 out of 13 studies, emphasizing the consistency of the strong inhibiting effect of biologicals on radiological joint damage. Since the majority of the investigations with these drugs are against placebo, and head-to-head trials are hardly available, we have no or little evidence about the superiority of one of these biologics versus another on endpoints such as radiological joint damage. Anti-TNFα also has a beneficial effect on generalized bone loss in RA patients. Vis et al.[87] showed that generalized bone loss was arrested in a cohort of patients treated with infliximab and MTX. Patients with a good response (low disease activity) had a slight gain in BMD of the lumbar spine and hips, whereas patients with a bad response (moderate to high disease activity) showed a loss of BMD (Fig. 3). In contrast, bone loss at the hands could not be arrested, both in responders and nonresponders. 0,8 0,6 0,4 0,2 0-0,2-0,4-0,6-0,8 * Spine * Total-hip EULAR respons Good response Non Fig. 3 Changes (%) in BMD between good and non-good responders to in RA patients treated with infliximab *p<0.05 Several other studies have shown the beneficial effects on generalized bone loss in RA [94 96]. Eekman et al.[94] showed that in RA patients treated with infliximab and MTX, this effect persisted during long-term treatment. In the BeSt study, it was demonstrated that in the combination therapy group with infliximab, the BMD change of the spine and hips was the same as in the other three treatment groups [97]. Remarkably, the bone loss after 2 years was small in all four groups ( 0.8 % to 1 %), indicating that intensive treatment of RA prevents generalized bone loss. An intriguing question is whether it is not only possible to prevent local joint damage and generalized bone loss with modern treatment in early RA, but whether fractures could also be prevented. Although this seems to be expectable, there are no randomized data prospectively observing fracture rates in biological-treated RA patients versus DMARDtreated patients. In a population-based cohort study in Canada consisting of 16,000 patients with RA, the fracture rate in anti-tnfα users was comparable to MTX-users and to RA patients using other non-biologic DMARDs. Since anti-tnfα is usuallyprescribedtopatientswithhighdiseaseactivity and a severe prognosis, these data suggest that adequate suppression of inflammation by TNFα blockers may reduce the elevated fracture rate in RA. When using DXR to measure localized BMD loss in the hands, it has been shown that in RA patients treated with adalimumab and MTX, combination therapy had significantly less bone loss in the hands measured by DXR than patient treated with MTX. Interestingly, this reduction in hand bone loss was independent of clinical response. In contrast, Guler-Yuksel et al.[97] found that in the alreadymentioned BeSt study, the hand bone loss was less in both initial combination therapy groups than in the other two groups, suggesting that the bone-sparing was resulting from adequate suppression of inflammation. It seems that anti-tnfα mainly prevents bone loss through inflammation control, but there also seems to be direct effects on bone metabolism by TNFα blockers that prevent bone loss independent of the clinical response [98, 99]. Rituximab Rituximab, an anti-cd20-directed B cell depletive therapy, is an effective treatment for RA patients, especially for those positive for rheumatoid factor and/or ACPA [100]. The effect of rituximab on radiological joint damage has been well established, since it significantly reduces the progression of joint erosion and joint space narrowing compared to RA patients treated with MTX [101]. RANKl is expressed in RA not only by osteoblasts, fibroblasts, and T cells, but also by B cells in the synovium of RA

9 Osteoporos Int (2013) 24: patients [17]. In RA patients treated with rituximab, there was a 37 % decrease of RANKl expression in the synovium and a 99 % decrease in RANK positive pre-osteoclasts. In addition, no TRAP positive osteoclasts could be detected in the synovium of these patients after 1-year treatment with rituximab [102]. Markers of bone resorption and bone formation measured in the serum of RA patients after treatment with RTX show a significant reduction mirroring the decrease in disease activity [103]. Only one small study (n=16) investigated changes in BMD in RA patients treated with rituximab, they found that at 18 months, it stabilized generalized bone loss, especially in responders [104]. Abatacept Abatacept is a recombinant fusion protein comprising the extracellular domain of human cytotoxic T lymphocyte antigen 4 (CTLA4) and a fragment of the Fc domain. CTLA4 (CD152) is a surface protein on T lymphocytes, which negatively regulates T cell activity [105]. From studies in rats, it seems that abatacept has a (indirect) bone-sparing effect through the reduction of inflammation. In rats with collagen-induced arthritis, abatacept treatment showed both reduction in synovitis but also a reduction of the number of osteoclasts in the synovium [106]. However, Schett et al. showed in vivo that CTLA4 can also directly inhibit the formation of osteoclast through binding to CD80/86 on monocytes and thereby preventing these cells to develop to osteoclasts [107]. There are no clinical data to support this direct effect of abatacept on osteoclastogenesis. Abatacept does effectively reduce the progression of erosions in RA patients compared to patients treated with placebo. Overall, 50 % of patients treated with abatacept did not progress from baseline to 2 years of treatment [108]. There are no data on changes in markers of bone formation and bone resorption and on generalized bone loss in RA patients treated with abatacept. Tocilizumab Tocilizumab (TCZ) is a humanized anti-il-6 receptor monoclonal antibody. IL-6 is involved in multiple immunologic processes such as T cell activation, B cell proliferation, and initiation of acute-phase protein [109]. IL-6 induces RANKl expression in fibroblast-like synoviocytes (FLS). In a coculture with FLS and osteoclast precursor cells, IL-6 induced TRAP5b expression in the osteoclast precursor cells [110]. In a co-culture using calvarian bones, IL-6 induced bone resorption, which was inhibited by RANKl blockers, suggesting that Il-6 induces osteoclastogenesis through upregulation of RANKl [111]. In RA patients, there is a decrease of bone resorption markers during treatment with TCZ to baseline values, and there also seems to be a small but non-significant increase of bone formation [112]. TCZ monotherapy for 52 weeks also showed significantly less radiological progression than with DMARD treatment [113]. Surprisingly, a study by Smolen et al.[114] revealed that in patients treated with tocilizumab, joint damage was even prevented in the group who had a poor clinical response, implying that TCZ may also have an effect on bone metabolism. Recently, Kumen et al.[115] showed that in a small group of RA patients, TCZ (n=12) also had a protective on BMD of the spine and hip as etanercept (n=13) and adalimumab (n=13) during 1-year treatment. There is no data on fractures and hand BMD in patients with RA treated with TCZ. Denosumab Denosumab is a fully human monoclonal antibody that binds to and inhibits RANKl, resulting in strongly suppressed bone resorption, by inhibiting the activation, proliferation, and survival of osteoclasts [116]. In a study in RA patients, twiceyearly subcutaneous injections of 60 and 180 mg of denosumab (or placebo) in RA patients all treated with methotrexate, does not have any effect on disease activity of RA. Nevertheless, there have been some worries about the immunologic side-effects of denosumab, since RANKl is a member of the TNF superfamily. In line with that, it can be doubted to prescribe denosumab in patients treated with TNFα blockers. Denosumab not only improved BMD of the lumbar spine and hip but also inhibited structural joint damage [117]. Both dosages prevented progression of erosions, already after 6 months on MRI and after 12 months on conventional X- rays. In addition, an increased BMD of the hand measured with DXA was observed, while no effect was observed on joint space narrowing [118]. Interestingly, it has also been documented that the intravenous use of 5 mg of the bisphosphonate zoledronic acid at baseline and after 3 months has shown to reduce erosions on MRI by 61 % after 6 months compared to RA patients treated with a placebo, while no effect on the disease activity has been observed [119]. These data suggest that the use of potent antiresorptive therapies specifically targeting osteoclasts without effecting inflammation in RA patients should be investigated further on, because it may prevent both local and generalized bone loss Summary Until recently, treatment of RA was not effective in the majority of patients, leading to a devastating effect on bone:

10 2550 Osteoporos Int (2013) 24: local bone loss, erosions, generalized bone loss, and fractures. This seems to be due to the uncoupling of bone metabolism in RA: active disease increases bone resorption and decreases bone formation. Fundamental studies have elucidated that the upregulated RANKl, with subsequent activated osteoclastogenesis, is an important determinant of bone loss in RA, while the inhibited bone formation in patients with active RA is modulated by an effects of the WnT signaling pathway. Nowadays, several biologics can be prescribed to patients with active RA: without any doubt, all these drugs are an enormous step forward in the treatment of early RA. Clinical remission is nowadays a realistic goal, particularly in patients treated with a biologic and high-dose MTX. Interestingly, recent data have shown that clinical remission is also possible in patients treated with combinations of conventional DMARDs, particularly when prednisone and MTX are used. 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