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Rheum Dis Clin North Am. Author manuscript; available in PMC May 1, 2011.
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PMCID: PMC2905601

Bone Damage in Rheumatoid Arthritis – Mechanistic Insights and Approaches to Prevention


In rheumatoid arthritis, cells within the inflamed synovium and pannus elaborate a variety of cytokines, including TNFα, IL-1, IL-6 and IL-17, that contribute to inflammation, and may directly impact bone. The RANKL/RANK/OPG pathway plays a critical role in regulating osteoclastogenesis in articular bone erosions in RA. Pro-inflammatory cytokines can modulate this pathway, and may also affect the ability of the osteoblast to repair bone at sites of articular erosion. In this review, we discuss the current understanding of pathogenic mechanisms of bone erosion in RA and examine current therapeutic approaches to prevent this damage.

Keywords: rheumatoid arthritis, therapy, osteoclasts, osteoblasts, Wnt, cytokines


Rheumatoid arthritis (RA) is a systemic disease process that is characterized by inflammation of the synovial tissues lining the joints. Proliferation of synovial lining cells and infiltration of inflammatory cells, including monocytes and activated leukocytes, into the joint tissues results in formation of “pannus” tissue that covers the surfaces of articular cartilage and bone (1) and produces proinflammatory factors that lead to destruction of both cartilage and bone matrix.

A common and characteristic feature of RA is focal articular bone loss, or erosion, that becomes evident early on in the disease process (2). In RA, inflamed joints are also often associated with periarticular bone loss, which precedes focal bone erosion. Erosions occur at sites where pannus invades cortical and subchondral bone and the adjacent marrow spaces. Ultimately, trabecular bone is lost as well. Systemic bone loss also commonly affects both the appendicular and axial skeleton in RA and, over time, results in increased fracture risk (3, 4). When RA is not detected and treated early, focal bone erosions progress rapidly and result in joint deformity and functional disability (2, 5). Thus, early treatment to prevent focal bone erosions is a critical objective in caring for patients with RA. In this review, we summarize the mechanisms, cell types and pro-inflammatory factors implicated in the pathogenesis of focal articular bone loss and review recent advances in targeted biologic therapies to prevent progression of structural damage in RA.

Role of osteoclasts in focal articular bone loss in RA

Osteoclasts are specialized multinucleated cells that arise from cells of monocyte-macrophage lineage. After attaching to bone matrix proteins, osteoclasts secrete proteinases and create a local acidic environment that mediates bone destruction. During physiologic bone remodeling, bone loss mediated by osteoclasts is balanced by bone formation mediated by osteoblasts. Focal bone loss in RA is mediated by osteoclasts located at the pannus-bone interface and in subchondral locations (6, 7). These cells express typical markers of the osteoclast lineage, including cathepsin K and tartrate-resistant acid phosphatase (TRAP), as well as the calcitonin receptor, a marker of terminal osteoclast differentiation (7, 8).

The receptor activator of NF-κB (RANK) ligand (RANKL) pathway regulates osteoclast differentiation and function during normal physiological bone remodeling. RANKL promotes osteoclastogenesis by binding to its cognate receptor RANK on osteoclast precursor cells. Osteoprotegerin (OPG) is a soluble decoy receptor for RANKL that blocks the pro-osteoclastogenic activity of RANKL. In inflammatory arthritis, the RANK/RANKL pathway is activated, resulting in dysregulated bone remodeling. RA synovial tissues exhibit an increased ratio of RANKL:OPG mRNA expression, indicating that pro-osteoclastogenic conditions dominate within the microenvironment of the RA joint (9).

Support for the critical role of osteoclasts in the process of bone erosion in RA is provided by studies using mice deficient in RANKL, an essential factor for osteoclast differentiation. These mice are devoid of osteoclasts and thus have an osteopetrotic bone phenotype (10). Induction of serum transfer arthritis in RANKL-deficient mice resulted in full-blown arthritis, but these osteoclast-deficient mice were protected from focal articular bone loss (11). This finding was confirmed in transgenic mice expressing human TNF (hTNF.tg) that develop a spontaneous, severe and destructive polyarthritis that results in extensive focal articular bone erosion (12). When crossed with osteopetrotic c-fos-deficient mice that have no osteoclasts, the resulting mutant mice developed TNF-dependent arthritis without focal articular bone loss, despite developing inflammation comparable to that of littermate controls expressing c-fos (13). In a T-cell-dependent model of rat adjuvant arthritis characterized by severe joint inflammation accompanied by bone and cartilage destruction, administration of OPG prevented bone and cartilage destruction but not inflammation, indicating the ability of OPG to block RANK signaling and focal bone erosion (14). Further support for a critical role of osteoclasts in mediating focal bone erosion in RA has arisen from murine studies that used bisphosphosphonates to block osteoclast-mediated bone resorption. hTNF.Tg mice treated with pamidronate or zolendronic acid demonstrated inhibition of focal articular bone loss without any significant change in inflammation (15, 16). This was also demonstrated with zolendronic acid treatment of mice with collagen-induced arthritis (17), a model of RA that is T cell and antibody-driven.

In addition to RANKL, macrophage-colony stimulating factor (M-CSF) is also required for osteoclastogenesis and serves to amplify the pool of osteoclast cellular precursors (18). Both RANKL and M-CSF are synthesized mainly by cells of the osteoblast lineage in the setting of physiologic bone remodeling (19). In both human disease and animal models of RA, activated CD4+T cells and synovial fibroblasts are alternative sources of RANKL that can drive osteoclastogenesis (8, 14).

Osteoprotegerin (OPG), a decoy receptor for RANKL that is synthesized by osteoblast-lineage cells, acts as a key negative regulator of osteoclastogenesis by binding soluble RANKL and preventing its binding to its receptor RANK, thereby inhibiting osteoclast differentiation (10, 20). In RA, the balance between RANKL and OPG expression levels is a fundamental regulator of osteoclast differentiation and function (21, 22). Thus, targeting the RANKL/RANK/OPG pathway to inhibit osteoclast differentiation represents an important potential therapeutic strategy to prevent bone erosion in inflammatory arthritis. However, even with aggressive treatment of RA to stop the progression of articular bone destruction, erosive lesions are not typically “repaired”; only a limited amount of new bone forms at sites of erosion. This suggests that osteoblast-mediated bone formation also may be compromised at sites where both inflammation and erosion occur, thereby contributing to the net loss of bone.

Role of osteoblasts in focal articular bone loss in RA

The role of osteoblasts in focal articular bone loss in RA has received less attention than that of osteoclasts. Osteoblasts are important regulators of bone remodeling. These cells both produce and mineralize bone matrix and also modulate osteoclast differentiation and function by producing RANKL and OPG (23). Osteoblasts arise from mesenchymal stem cells and undergo maturation and differentiation towards cells with the capacity to produce and mineralize bone matrix (24). As osteoblasts mature towards functional bone-forming cells, they diminish their expression of RANKL and increase their expression of OPG, thereby creating a microenvironment that favors bone formation over bone loss (25).

Interestingly, although RA patients receiving disease modifying anti-rheumatic drug (DMARD) therapy demonstrate slowing or inhibition of progression of articular bone erosions on plain radiographs in clinical trials and long-term observational studies (26), healing of erosions has been considered to occur only infrequently. However, in recent years, repair of bone erosions with formation of new bone has been documented in RA patients treated with DMARDs (2730). Based on results of two studies conducted by the OMERACT Subcommittee on Healing of Erosions, Sharp and colleagues confirmed that repair of erosions does occur in RA (31). Additional studies demonstrate a strong association between clinical remission of disease and radiographic evidence of repair of erosions (32, 33), suggesting that joint inflammation may play an important role in suppressing the functional capacity of osteoblasts to produce bone and thereby repair erosions.

These observations are supported by a recent study from our laboratory in a murine model of arthritis which demonstrated that mineralized bone formation was compromised at sites of erosion in areas of bone where there was local inflammation (34). It would be expected that bone formation rates would be increased at sites of erosion, where bone has been lost. However, using dynamic bone histomorphometry, no differences were observed in the rate of mineralized bone formation at bone surfaces in inflamed areas, as compared to similar areas without arthritis. In addition, there was a notable paucity of osteoblast-lineage cells expressing markers of cell maturity at bone surfaces adjacent to inflammation, but there were abundant immature osteoblast-lineage cells expressing Runx2, a marker of early osteoblast-lineage cells. Furthermore, cellular expression of alkaline phosphatase, a marker of the mineralization phase of bone formation, was minimal at sites of bone erosion. Taken together, these observations support the hypothesis that inflammation may inhibit the functional capacity of osteoblasts to repair erosions in RA.

Wnt signaling pathway in RA

To elucidate the effect of inflammation on osteoblasts and bone formation, investigators have focused on the Wingless (Wnt) family of proteins. The Wnt signaling pathway plays an important regulatory role in embryonic development, tissue homeostasis and cancer (35). Wnt proteins are secreted glycoproteins that bind and activate the receptor complex of a 7-transmembrane domain-spanning frizzled receptor and the low-density lipoprotein receptor-related protein 5 and 6 (LRP5/6) co-receptors present on mesenchymal cells. Binding of Wnt proteins to the receptor complex induces the differentiation of osteoblast-lineage cells into mature osteoblasts, leading to bone formation (36). The importance of the Wnt signaling pathway in bone homeostasis is demonstrated by the abnormal bone phenotypes that result from receptor mutations. Mutations inducing loss-of-function in the Lrp5 gene, which encodes the LRP5 receptor, decrease bone formation in both humans and mice (37). In contrast, gain-of-function mutations in the Lrp5 gene result in increased bone mass (38).

β-catenin plays a critical role in bone remodeling. Modulation of Wnt signaling alters β-catenin expression and activity, thereby impacting both bone formation and osteoclast-mediated bone resorption. Mice that do not express β-catenin on differentiated osteoblasts develop severe osteopenia associated with increased numbers of activated osteoclasts resulting from an increased RANKL:OPG ratio (39, 40). In contrast, mice expressing constitutively active β-catenin-mediated Wnt signaling in differentiated osteoblasts have increased OPG expression and exhibit a decrease in bone resorption and an osteopetrotic phenotype (39, 40). Interestingly, the functional dysregulation of osteoblasts seen in mice deficient in β-catenin signaling resembles the osteoblast phenotype found at sites of focal bone loss in inflammatory arthritis, suggesting that inhibition of Wnt signaling may be a mechanism whereby bone formation is compromised in inflammatory states.

Several families of endogenous inhibitors of the Wnt signaling pathway have been identified; these function by limiting the effects of Wnt signaling. The Dickkopf (DKK) and secreted frizzled-related protein (sFRP) family members are the best characterized. Diarra and colleagues (41) showed that DKK1, a member of the DKK family of Wnt antagonists, plays a central role in regulating bone remodeling in RA. Administration of a neutralizing antibody specific to DKK1 protected against focal bone erosion in the hTNF.Tg RA mouse model. In fact, in the setting of DKK1 blockade, new bone formation was observed at sites where erosion would typically occur. However, these effects were due, at least in part, to upregulation of OPG expression, which would result in inhibition of bone resorption; the effect of inhibition of Wnt signaling on osteoblast function at sites of erosion was not directly assessed in this study.

The possible role of DKK1 in promoting bone loss is supported by the finding of elevated serum levels of DKK1 in patients with RA (42) and in postmenopausal women with established osteoporosis (43). Recently, Uderhardt and colleagues (44) showed that blocking TNFα in hTNF.Tg mice did not promote ankylosis of sacroiliac joints. In contrast, blocking DKK1 promoted cartilage formation and ankylosis of sacroiliac joints but had no effect on inflammation, indicating a potential role of DKK1 in the anabolic pattern of axial skeletal remodeling that is observed in ankylosing spondylitis. These results indicate that DKK1 may be one of many factors regulating bone remodeling in the rheumatic diseases. In a recent study from our laboratory, we found that several members of the DKK and sFRP families of Wnt signaling inhibitors were expressed at sites of inflammation-induced bone erosion in arthritic mice (34), indicating their putative roles in regulating bone erosion at arthritic sites.

Proinflammatory cytokines in RA, and their effects on bone

Synovial tissue in inflamed joints, infiltrated with activated macrophages and leukocytes, is a rich source of pro-inflammatory cytokines, including TNFα, IL-1, IL-6 and IL-17, and of growth factors, such as M-CSF, that impact bone remodeling within the RA bone microenvironment (23). The pro-inflammatory cytokines expressed in the microenvironment of the arthritic joint exert their influence both on osteoclast differentiation and activation and on osteoblasts, thereby contributing to progressive joint destruction in RA. Several key cytokines that both mediate inflammation in RA and likely play a role in bone remodeling will be discussed in the following section.

Tumor necrosis factor-alpha (TNFα)

Within the inflamed bone microenvironment in RA, TNFα is a dominant pro-inflammatory cytokine with pleiotropic effects. Among its diverse pathologic effects, TNFα induces the production of other proinflammatory cytokines (IL-1, IL-6, IL-8) (45), stimulates synovial fibroblast cells to express adhesion molecules that attract leukocytes into affected joints (46), increases the rate of synthesis of metalloproteinases by synovial macrophages and fibroblasts (47), and inhibits the synthesis of proteoglycans in cartilage (48). TNFα is synthesized mainly by macrophages and synovial lining cells, as well as by activated T cells, within the microenvironment of the RA joint (49, 50). TNFα also exerts important effects on bone remodeling: it regulates the abundance of osteoclast precursors in the bone marrow directly by upregulating c-Fms expression (51) and activates osteoclasts by enhancing RANK signaling mechanisms (52).

TNFα also indirectly influences osteoclastogenesis by inducing expression of RANKL and M-CSF by bone marrow stromal cells of the osteoblast lineage (53). TNFα is considered to be an “upstream,” dominant pro-inflammatory cytokine, based on the observation that anti-TNFα antibodies significantly reduce IL-1 production in cultures of synovial cells from patients with RA (54). TNFα also impacts osteoblasts by inhibiting osteoblast differentiation (55) and maturation (56, 57), with an associated decrease in alkaline phosphatase and osteocalcin expression. Addition of TNFα to fetal calvarial precursor cells or MC3T3-E1 pre-osteoblastic cell cultures led to a dose-dependent suppression of mRNA for the critical osteoblast transcription factor Runx2 (58). TNFα also induced apoptosis of MC3T3-E1 cells when added to cell cultures (59).

The role of TNFα in inflammatory arthritis and bone erosion has been studied in detail, using the hTNF.tg mouse model. Both hTNF.tg mice and wild type mice treated with exogenous TNFα have increased numbers of CD11b+ osteoclast precursor cells (60, 61), an effect of TNFα that is independent of RANKL. Interestingly, differentiation of CD11b+ osteoclast precursors into activated osteoclasts requires the presence of functional RANKL/RANK signaling (60). Blocking either TNFα (using anti-TNFα antibodies) or RANKL (using OPG.Fc) signaling in the hTNF.tg murine model results in reduced osteoclastogenesis and reduced bone erosion (62). Interestingly however, blocking both cytokines together (using both anti-TNFα antibodies and OPG.Fc) did not result in a synergistic reduction of osteoclastogenesis (63). In human disease, data from clinical trials confirm that inhibiting TNFα activity in RA effectively protects against bone erosion (64). Although this is due in large part to the anti-inflammatory effects of TNF inhibition, direct reduction of osteoclast-mediated bone loss and augmentation of osteoblast-mediated bone formation are potential mechanisms by which TNF inhibition reduces structural damage in RA.

Interleukin-1 (IL-1)

The pro-inflammatory cytokine IL-1 belongs to a family of cytokines that includes IL-1α, IL-1β, the soluble antagonist IL-1Ra, and IL-18. Activated macrophages and synovial fibroblasts present within the inflamed joint are the main sources of IL-1 in RA (49). IL-1 signals through its cognate receptor, IL-1R1. IL-1Ra competes with IL-1 for binding to the IL-1R1 receptor. More than 95% occupancy of the IL-1R1 receptor by IL-1Ra is required to effectively block IL-1 signaling; however, this may be difficult to achieve in patients with RA (65).

Data from various animal models suggest an important role for IL-1 in the pathogenesis of inflammatory arthritis. Overexpression of IL-1α or IL-1β or deficiency of the soluble IL-1 receptor antagonist (IL-1Ra) in murine RA models resulted in the development of arthritis with associated bone and cartilage destruction (6668). Blocking IL-1 in the hTNF.tg mouse model of RA using recombinant IL-1Ra was not as effective in reducing numbers of osteoclasts or bone erosions as was blocking TNFα, although IL-1Ra effectively reduced inflammation (63). Blocking both IL-1 and TNFα resulted in almost complete suppression of osteoclast differentiation, inflammation, and bone destruction, indicating that the biological effects of these two pro-inflammatory cytokines are additive in vivo (63). In vitro studies have shown that addition of IL-1Ra inhibited TNFα-mediated induction of RANKL expression in bone marrow stromal cells (53). Furthermore, the addition of TNFα to these stromal cells induced the expression of IL-1 whereas the addition of both IL-1 and TNFα resulted in upregulation of IL-1R1 expression on these cells, indicating a positive feedback loop. Similarly, treating osteoclast precursor cells with TNFα induced the expression of IL-1 and IL-1R1 in these cells and, in turn, IL-1 augmented RANKL-mediated osteoclast differentiation. Also, treating mice deficient in IL-1R1 expression with TNFα resulted in almost 50% reduction in osteoclastogenesis, indicating the existence of IL-1-independent signaling pathways (53). Taken together, these studies provide evidence that IL-1 may be downstream of TNFα in RA.

Addition of IL-1 decreased the apoptotic rate of osteoclast-like cells in vitro (69). In addition, IL-1 has been shown to impact osteoblasts/osteoblast lineage cells in vitro. Addition of IL-1α to rat osteoblast cultures decreased formation of mineralized nodules (70). Fetal rat calvarial cell cultures treated with IL-1β resulted in potent inhibition of mineralized nodule formation (71). These in-vitro effects may also be relevant in inflammatory arthritis, though this has not been shown directly.

Interleukin-6 (IL-6)

Interleukin-6 (IL-6) belongs to the family of cytokines that signal via a gp130-dependent mechanism which also includes IL-11, leukemia inhibitory factor (LIF) and oncostatin M (OSM). These cytokines share common receptor subunits and signaling pathways. IL-6 is a pleiotropic proinflammatory cytokine produced by a variety of cell types in the inflamed RA bone microenvironment including macrophages, fibroblast-like synoviocytes, and chondrocytes (72). Synovial fluid levels of IL-6 are elevated in patients with RA and circulating levels of IL-6 correlate with progressive joint damage in RA (73, 74), indicating an important role for IL-6 in the pathogenesis of RA. Furthermore, in RA patients, levels of IL-6 and its soluble receptor (sIL-6R) have been correlated with the degree of bone loss evident on plain radiographs (75).

IL-6 modulates osteoclast differentiation by modulating its interaction with the sIL-6R complex that is present on osteoblast lineage cells, resulting in upregulation of cyclooxygenase (COX)-2-dependent PGE2 synthesis. This, in turn, upregulates RANKL expression while downregulating OPG expression, leading to enhanced osteoclastogenesis (76). In a recent study, in vitro blocking of IL-6R reduced osteoclast formation in mouse monocyte cells stimulated with either RANKL or RANKL plus TNF (77). Addition of IL-6 also stimulated osteoclast-like multinucleated cell formation in long term human bone marrow cultures by inducing synthesis of IL-1β (78). Furthermore, administration of blocking antibodies directed against IL-6R in hTNF.tg mice significantly reduced osteoclast formation and bone erosion, while not reducing joint inflammation, indicating that IL-6 exerts a specific and direct inhibitory effect on osteoclastogenesis both in vitro and in vivo. That IL-6 is an important effector of inflammation-induced joint destruction in arthritis is supported by the observation that mice deficient in IL-6 were protected against bone destruction in an antigen-induced arthritis model (79, 80). Blocking the IL-6 receptor in a murine collagen-induced arthritis (CIA) model delayed the onset of inflammation and reduced joint destruction. In addition, administration of IL-6R-neutralizing antibody at the time of CIA induction completely abolished the inflammatory response (81), indicating that IL-6 plays an important role in the initiation of arthritis. Accordingly, blockade of the interaction between IL-6 and its cognate receptor has been developed as a treatment for RA.

Interleukin-17 (IL-17)

The IL-17 cytokine family, which has at least six members, plays an important role in the pathogenesis of RA (82). IL-17 is synthesized by Th17 cells, a novel population of T helper cells that is distinct from the previously described Th1 and Th2 cell populations and that has a unique pattern of cytokine expression (83). High levels of IL-17 have been detected in synovial fluid specimens obtained from RA patients (84). In RA synovium, IL-17 is expressed in areas that are rich in T-cells (85). The addition of IL-17 to osteoblast-lineage cells induces the expression of RANKL and downregulates OPG expression (84). Furthermore, in cultured RA synoviocytes, the addition of exogenous IL-17 synergized with IL-1 and TNFα to induce the expression of IL-1, IL-6 and TNFα in vitro (86). IL-17 promoted bone erosion in a murine CIA model by upregulating the expression of RANKL and RANK, thereby enhancing osteoclastogenesis (87). In mice, blocking IL-17 after the onset of CIA reduced joint inflammation and bone erosion (88), whereas blocking IL-17 during reactivation of antigen-induced arthritis reduced both joint inflammation and bone erosion by suppressing RANKL, IL-1 and TNFα production (89). Interestingly, the development of spontaneous arthritis was completely suppressed in the progeny of IL-1Ra-deficient mice crossed with IL-17 deficient mice, indicating that both IL-17 and IL-1 are necessary for this spontaneous development of arthritis (90). IL-17 has also been shown to impact osteoblast lineage cells. Addition of IL-17 enhanced TNFα-stimulated IL-6 synthesis in osteoblast-like cells via activation of the p38 mitogen-activated protein (91) and also induced the expression of RANKL mRNA in mouse osteoblasts (84). Because blocking IL-17 attenuates both inflammation and bone erosion in murine models of inflammatory arthritis, IL-17 inhibition has emerged as an approach to treat RA. Table 1 lists the reported effects of pro-inflammatory cytokines on osteoclasts and osteoblasts.

Table 1
Reported effects of pro-inflammatory cytokines on cells within bone


Over the past decade, the introduction of targeted biologic therapy has resulted in significantly improved clinical and structural outcomes for patients with RA. These therapeutic agents have specific mechanisms of action, including inhibiting the action of individual cytokines, blocking cell-cell interactions, and depleting certain cell types. Observations of the effect of each targeted therapy on bone loss in patients with RA has provided further information about the role of each of these pathways in the pathophysiology of bone destruction in this disease.

RANKL blockade

The therapeutic potential of blocking of the biologic actions of RANKL was initially demonstrated in postmenopausal women (92). A single injection of OPG.Fc resulted in a rapid and sustained reduction in urinary NTX, an indicator of bone resorption. In a subsequent phase I study conducted in patients with multiple myeloma (MM) or breast cancer-related bone metastases, administration of a recombinant OPG.Fc construct also resulted in a rapid, sustained, dose-dependent reduction in urinary NTX (93). These results suggested the therapeutic potential of blocking RANKL to prevent further bone loss in patients with osteoporosis and bone malignancies. However, because OPG.Fc is a large, complex protein that requires frequent dosing in patients, further development of OPG.Fc as a therapeutic agent was curtailed in favor of the development of antibodies that directly target RANKL. Denosumab (formerly known as AMG 162), is a fully humanized IgG2 monoclonal antibody that inhibits the biologic activity of RANKL and has been studied in clinical trials in patients with RA and focal bone loss as well as in patients with osteoporosis.

In a study of 412 postmenopausal women with low bone mineral density, denosumab administration increased bone mineral density and decreased bone resorption (94). This finding was confirmed in the recently concluded Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) study, which enrolled 7868 women between the ages of 60 and 90. Blockade of RANKL with denosumab reduced the risk of spinal and hip fractures by 68% and 40%, respectively, in postmenopausal women with osteoporosis as compared to placebo-treated subjects (95). In a phase II clinical trial, administration of denosumab to patients with RA inhibited the development of structural damage evident on MRI, produced a sustained decrease in markers of bone turnover, and resulted in increased bone mineral density (96). Radiographic progression of structural damage over a period of 12 months was also significantly decreased among RA patients who received denosumab, as compared to those who received placebo. These studies suggest the promise of osteoclast inhibition as a therapeutic modality to protect against both focal and systemic bone loss in RA, osteoporosis, and other diseases in which bone is destroyed.

Targeting pro-inflammatory cytokines

Anti-TNF biologic agents

TNFα is a dominant pro-inflammatory cytokine in the pathophysiology of RA and is the target of five biologic agents now used to treat RA: adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab. The efficacy of these TNFα antagonists has been demonstrated primarily in two different populations of patients with RA: individuals with active early RA who had not yet been treated with methotrexate and those with RA of longer disease duration who were inadequately responsive to methotrexate. The administration of adalimumab (97), etanercept (98, 99), golimumab (100), and infliximab (101) to patients with active early RA significantly reduced clinical signs of disease activity and effected clinical remission in some patients. Among these patients, adalimumab (97), etanercept (102, 103), and infliximab (64) each also slowed progression of structural damage, more so when administered in combination with methotrexate than when used as monotherapy (97, 103). Among patients with active RA of longer duration, adalimumab (104), etanercept (105), and infliximab (106, 107), each administered in combination with methotrexate, have provided long-term sustained improvement in clinical signs and symptoms of RA and slowed progression of structural damage. Both of the newer TNF antagonists, certolizumab pegol (108110) and golimumab (100, 111), when administered either alone or in combination with methotrexate, have also significantly reduced clinical evidence of disease activity and effected clinical remission in some patients.

The goal of RA treatment is to achieve complete remission of disease activity and halt progression of structural damage. Despite “tight control” of clinical disease activity, treating to the target of a “low” disease activity state, progressive joint destruction becomes evident on radiographs of patients not receiving TNF antagonist therapy (112, 113). The addition of a TNF antagonist to the therapeutic regimen decreases the rate at which structural damage progresses among patients with active RA (97, 103, 113). The combination of methotrexate and TNF antagonist therapy slows this radiographic progression more than treatment with methotrexate alone, at any level of clinical response (97, 103, 114). In a study comparing methotrexate and etanercept monotherapy with the combination of etanercept plus methotrexate in patients with active RA, erosions did not progress over two years in 86% of patients treated with combination therapy, as compared to 75% of patients receiving etanercept alone and 66% of those receiving methotrexate alone. The combination of etanercept plus methotrexate resulted in a negative mean change in the total Sharp score over two years, suggesting that structural damage improves when a TNF antagonist is used in combination with methotrexate therapy (103). In another study that compared the combination of infliximab plus methotrexate to methotrexate monotherapy, structural damage progressed less among RA patients treated with infliximab plus methotrexate than among those treated with methotrexate alone, regardless of disease activity. Among those patients treated with methotrexate alone, progression of structural damage was associated with elevated levels of acute phase reactants or persistent disease activity (64). In fact, RA patients may demonstrate slowing of radiographic progression with etanercept or infliximab therapy, despite experiencing a suboptimal clinical response (106, 115). Thus, the effect of TNF antagonist therapy on reducing the progression of structural damage may be dissociated from the effect of these agents on decreasing signs and symptoms of RA. This is likely due to the independent effects of TNFα on osteoclast differentiaion and function.

Inhibition of IL-1

Interleukin-1 (IL-1) plays an important role in the progression of structural damage in RA by contributing to destruction of cartilage, bone, and periarticular tissues. Recombinant human IL-1Ra (anakinra) reduces the rate of radiographic progression of RA, as compared to treatment with placebo. (116). However, anakinra provides only modest benefit in improving signs and symptoms of active RA as monotherapy (117) or in combination with methotrexate (118). Treatment with anakinra in combination with etanercept was no more effective in controlling signs and symptoms of RA than treatment with etanercept alone. Because the incidence of serious infections, injection site reactions, and neutropenia was higher among patients treated with combination therapy, the use of anakinra together with other biologic therapies is not recommended (119).

Anti-IL-6 receptor biologic agent

Tocilizumab is a humanized anti-IL-6 receptor monoclonal antibody that binds to both the membrane-bound and soluble forms of the IL-6 receptor and blocks binding of IL-6 to its receptor, thereby preventing signaling. The combination of tocilizumab and methotrexate (120, 121) or of tocilizumab and DMARD therapy (122) was superior to methotrexate or DMARD monotherapy in controlling signs and symptoms of active RA among patients inadequately responsive to either methotrexate or DMARDs, respectively. The combination of tocilizumab and methotrexate also was more effective than methotrexate monotherapy in controlling signs and symptoms of RA among patients who previously had been exposed to a TNF antagonist (123). Both among patients with active RA who were naïve to methotrexate or had discontinued methotrexate for reasons other than lack of efficacy or toxicity (124) and among patients with active RA who were inadequately responsive to methotrexate monotherapy (120), tocilizumab monotherapy was superior to methotrexate monotherapy in improving signs and symptoms of disease. Based upon the results of these clinical trials, tocilizumab has been approved for the treatment of patients with active RA.

In a study of Japanese RA patients inadequately responsive to DMARDs, including low-dose weekly methotrexate, tocilizumab monotherapy improved signs and symptoms of disease and reduced progression of bone erosion and joint cartilage space narrowing on plain radiographs significantly more than did continuation of DMARD therapy alone (125). Similarly, in a multi-national clinical trial that enrolled patients with active RA who were inadequately responsive to methotrexate monotherapy, tocilizumab in combination with methotrexate was superior to methotrexate alone both in improving signs and symptoms of RA and in slowing the progression of radiographic evidence of structural damage (126). These findings support a significant role for IL-6 in the pathogenesis of joint destruction in RA.

Anti-IL-17 biologic agents

Initial results of phase II clinical trials of two monoclonal antibodies that neutralize IL-17 suggest that treatment with anti-IL-17 antibodies reduces the signs and symptoms of RA without notable adverse effects. In a randomized, placebo-controlled study of 77 RA patients treated with the monoclonal anti-IL-17 antibody LY2439821, clinical improvement was evident within a week of beginning drug therapy and persisted for 8 weeks (127). In another randomized, placebo-controlled study of 52 RA patients treated with the monoclonal anti-IL-17 antibody AIN457 for 6 weeks, signs and symptoms of RA also improved (128). However, both of these studies were of inadequate duration to assess progression of structural damage. Larger and longer multicenter, placebo-controlled clinical trials of these antibodies are needed to confirm these promising initial results.

Targeting B and T cells

B-cell-depleting monoclonal antibody

Rituximab is a chimeric monoclonal anti-CD20 monoclonal antibody that depletes B cells. Rituximab improved the signs and symptoms of RA significantly better than placebo, 24 weeks after two intravenous infusions of 1000 mg administered 14 days apart in combination with background methotrexate therapy, both in patients who had responded inadequately to treatment with a TNF antagonist (129) and in those who had responded inadequately to methotrexate therapy (130). Among patients inadequately responsive to TNF antagonist therapy, treatment with rituximab and methotrexate was superior to methotrexate alone in slowing the progression of both bone erosion and joint cartilage space narrowing on plain radiographs (131). This finding supports a significant role for B cells in the pathogenesis of bone and joint destruction in RA. However, the occurrence of the rare, usually fatal, central nervous system demyelinating disease progressive multifocal leukoencephalopathy in some patients with RA who were treated with rituximab may limit its widespread use, especially in patients with early disease who have not yet failed treatment with other medications (132).

Inhibition of T-cell co-stimulation

Abatacept is a fusion protein of recombinant, dimerized cytotoxic T-lymphocyte antigen 4 (CTLA-4), a natural inhibitor of T-cell activation, and the hinge, CH2, and CH3 domains of IgG1. By blocking the interaction of CD28 on a T-cell with B7 on an antigen presenting cell, abatacept interferes with T-cell co-stimulation. In patients with active RA inadequately responsive to a TNF antagonist, abatacept in combination with background DMARD therapy was more effective than background DMARD therapy alone in reducing the signs and symptoms of RA and improving physical function (133). The combination of abatacept and methotrexate also was more effective than methotrexate monotherapy in controlling signs and symptoms of RA and in improving physical function among patients with RA active despite methotrexate therapy (134). In combination with background methotrexate therapy, abatacept slowed the progression of both bone erosion and joint cartilage space narrowing significantly on plain radiographs (134, 135). These findings support a role for activated T cells in the pathogenesis of joint destruction in RA.


We have reviewed the current understanding of pathogenic mechanisms of focal articular bone damage in RA and discussed current therapeutic approaches to prevent this damage. In RA, cells within the inflamed synovium and pannus elaborate a variety of cytokines and factors that impact both osteoclast-mediated bone erosion and osteoblast-mediated bone repair. The RANKL/RANK/OPG pathway plays a critical role in regulating osteoclastogenesis in RA. Pro-inflammatory cytokines, including TNF-α, IL-1, IL-6 and IL-17, are expressed by various cell types in the inflamed synovium and exert effects on osteoclastogenesis as well as on osteoclast function and survival. Taken together, the results of clinical trials of targeted biologic therapies for RA indicate that multiple cytokines and cell types contribute to the pathogenesis of inflammation, and suggest possible direct effects on destruction of bone. Further study of these and additional novel targeted therapies, both in animal models and in human subjects, will clarify the molecular mechanisms of this important pathological process.


Dr. Karmakar’s work was funded by the Arthritis National Research Foundation and The Sontag Foundation. Dr. Gravallese’s work was funded by the American College of Rheumatology Research and Education Foundation Within Our Reach grant.


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