Mechanisms and therapeutic targets for bone damage in rheumatoid arthritis, in particular the RANK-RANKL system

Available online at www.sciencedirect.com

ScienceDirect Mechanisms and therapeutic targets for bone damage in rheumatoid arthritis, in particular the RANK-RANKL system Yoshiya Tanaka1 and Takeshi Ohira2 Rheumatoid arthritis (RA), a chronic inflammatory disorder, causes swelling, bone erosion, and joint deformity. Bone erosion in RA-affected joints arises from activation of osteoclasts by inflammatory processes. RA patients may also have primary, disease-related, or glucocorticoid-induced osteoporosis, caused by a disrupted balance between osteoclasts and osteoblasts. Disease-modifying antirheumatic drugs (DMARDs) interfere with the processes causing inflammation in the joint but do not sufficiently treat bone erosion and osteoporosis. Denosumab, an inhibitor of receptor activator of nuclear factor k-B ligand (RANKL), protects bones in osteoporosis patients. Clinical studies have demonstrated that denosumab can also prevent bone erosion in RA patients. Because joint destruction progresses in some patients treated with DMARDs alone, denosumab will likely become standard treatment for some RA patients.

Addresses 1 The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahata-nishi, Kitakyushu 807-8555, Japan 2 Clinical Development Department, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan Corresponding author: Tanaka, Yoshiya ([email protected])

Current Opinion in Pharmacology 2018, 40:110–119

osteoporosis caused by the underlying disease, along with other risk factors, including use of glucocorticoids, postmenopausal status, age, sarcopenia, low body mass index, organ abnormalities (such as kidney), vitamin D deficiency, presence of anti-citrullinated protein antibodies, and smoking [1]. The incidence of osteoporosis is doubled in postmenopausal women with RA compared with age-matched women without RA [2]. In recent years, biologic disease-modifying antirheumatic drugs (bDMARDs) have become a valuable treatment option for RA. These drugs directly target inflammatory cytokines such as tumor necrosis factor (TNF)-a, which plays a major role in the pathogenesis of RA. Recent evidence suggests that bDMARDs can reduce joint destruction in RA-affected joints [3]. However, bDMARDs do not prevent the progression of osteoporosis caused by either RA or glucocorticoid therapy. Only about 20% of patients with RA in Japan are being treated with bDMARDs because of the cost of the drugs and concerns about safety [4]. The remaining 80% of patients are treated with conventional drugs, but progression of joint destruction is not fully controlled [5]. In particular, conventional synthetic DMARDs (csDMARDs) do not effectively prevent bone erosion. A drug effective for both preventing joint destruction and treating systemic osteoporosis has not yet been developed.

This review comes from a themed issue on Musculoskeletal Edited by S Jeffrey Dixon and Peter Chidiac For a complete overview see the Issue and the Editorial Available online 24th April 2018 https://doi.org/10.1016/j.coph.2018.03.006 1471-4892/ã 2018 Elsevier Ltd. All rights reserved.

Because activation of osteoclasts via receptor activator of NF-kB ligand (RANKL) is a necessary step in the development of both localized bone erosion and systemic osteoporosis, the therapeutic effect of the anti-RANKL antibody denosumab has been assessed in RA patients [6,7]. Based on these studies, ‘the suppression of progression of bone erosion associated with RA’ has been added to the indications for denosumab in Japan as of 2017. This review explains the mechanism of bone damage in RA patients and reviews RANKL and its clinical significance as a therapeutic target in RA.

Introduction The underlying pathology of rheumatoid arthritis (RA) involves progressive or chronic synovial inflammation arising from both the accumulation of self-reactive T-cells in the synovial membrane and increased production of inflammatory cytokines. Inflammatory cytokines produced by self-reactive T-cells eventually damage the articular cartilage and cause periarticular bone erosion in the affected joint, which often results in periarticular osteoporosis. Many patients with RA also have systemic Current Opinion in Pharmacology 2018, 40:110–119

Mechanism of bone damage in RA patients and the role of RANK/RANKL Bone metabolism in health and disease is based on a selfregulating cellular event. The two major processes of bone remodeling, bone formation and resorption, are closely regulated by multiple soluble factors and hormones. The initial event in bone remodeling is an increase in osteoclastic bone resorption, which is tightly www.sciencedirect.com

RANK-RANKL for bone damage in RA, mechanism and therapeutic insight Tanaka and Ohira 111

Figure 1

Lining osteoblast

Bone matrix

Resting phase

Osteoclast precursor

TNF-α, IL-1, IL-17, IL-6

Osteoblast

Formation phase Bone formation and mineralization

Activation phase Osteoclast maturation

Activated osteoclast

Resorption phase Bone resorption (TNF-α independent) [primary osteoporosis and glucocorticoid-induced osteoporosis]

Activated osteoclast

RA-related bone damage (osteoblast independent, TNF-α dependent)

Current Opinion in Pharmacology

Bone remodeling cycle and deviation (imbalance) induced by inflammatory cytokines. Bone remodeling involves a balanced cycle of bone formation and resorption. Osteoporosis results from reduced differentiation of osteoblasts and increased osteoclast differentiation. Inflammatory cytokines such as TNF-a increase the number of activated osteoclasts and cause RA-related bone damage in a manner independent of osteoblasts and osteocytes. IL = interleukin; TNF = tumor necrosis factor.

regulated by osteoblasts. That is, RANKL expressed on osteoblasts and osteocytes provides essential signals to osteoclast progenitors to promote maturation. However, in systemic osteoporosis, dysregulation of bone remodeling leads to excessive maturation and activation of osteoclasts, resulting in disproportionate bone resorption (Figure 1). The mechanism of bone erosion in the joints of RA patients differs from the mechanisms of systemic osteoporosis [8–10]. Multinuclear osteoclasts, present at the interface of the synovial membrane and bone, resorb bone tissue and cause bone erosion. Osteoblasts and osteocytes are not present near these osteoclasts, but synovial fibroblasts and T cells expressing RANKL accumulate around osteoclasts in the RA-affected synovium [11,12]. Proinflammatory cytokines, such as TNF, interleukin-1, interleukin-6, and interleukin-17, are produced in large amounts in the RA synovium and induce RANKL through the activation of NF-kB on synovial cells and T cells. RANKL can then efficiently induce maturation of osteoclasts, even in the absence of osteoblasts and www.sciencedirect.com

osteocytes. The progression of bone erosion in RA patients causes the subsequent destruction of calcified tissues, including cartilage and cortical bone. Furthermore, transgenic mice expressing human TNF-a manifest RA-like findings, such as synovial proliferation, increased numbers of osteoclasts at the site of contact of the synovial membrane and the bone, and bone erosion, implying that TNF induces bone erosion through osteoclast maturation [13]. Thus, during the pathological processes of RA, inflammatory cytokines such as TNF induce RANKL on synovial cells and activate osteoclasts, dysregulate the bone remodeling cycle, and cause joint destruction (Figures 1 and 2) [7,14,15]. Furthermore, various cells, including T cells, B cells, and osteoblasts, release RANKL in RA-affected tissues [16,17]. In fact, an increase in RANKL concentration in serum and tissues has been observed in RA patients [18]. In summary, the bone-related consequences of RA include both joint destruction and systemic osteoporosis, which are brought about by different mechanisms. Current Opinion in Pharmacology 2018, 40:110–119

112 Musculoskeletal

Figure 2

Hematopoietic stem cell

M-CSF IL-6, IL-17, TNF, PGE2

Activated osteoclast

Osteoclast precursor Maturation Activation

RANK

Anti-RANKL antibody

RANKL

IL-1, 6, 7, 17 TNF PGE2

Mesenchymal TNF, DKK-1, stem cell

Osteoblast/osteocyte/ fibroblast / T-cell

sclerostin

Anti-TNF, IL-6 antibody Current Opinion in Pharmacology

Induction of osteoclast maturation by inflammation. Prolongation of inflammation induces osteoclast differentiation and suppression of osteoblast differentiation through the production of cytokines and prostaglandins, resulting in osteoporosis due to imbalance in bone turnover. Disease-modifying antirheumatic drugs (including anti-TNF antibodies) and the anti-RANK ligand antibody denosumab interfere with various steps in this pathway. IL = interleukin; M-CSF = macrophage colony stimulating factor; PGE2 = prostaglandin E2; RANK = receptor activator of nuclear factor k-B; TNF = tumor necrosis factor.

Inflammatory cytokines such as TNF activate osteoclasts and dysregulate the bone remodeling cycle, resulting in joint destruction. The effects of these inflammatory cytokines are mediated by RANKL [14,19,20]. Thus, the antiRANKL antibody denosumab could potentially inhibit joint destruction as well as systemic and glucocorticoidmediated osteoporosis [21].

Management of bone damage in RA patients Bone erosion and periarticular osteoporosis are irreversible, so prevention and early intervention are critical for the long-term health of RA patients. Treatment guidelines recommend the initiation of methotrexate (MTX) or bDMARDs when bone erosion is detected even at one site [22–24]. This section reviews the evidence for the efficacy of conventional DMARDs and anti-osteoporotic drugs for prevention of bone damage in patients with RA. csDMARDs such as MTX are the first-line treatment in the European League Against Rheumatism, American College of Rheumatology, and Japanese guidelines [22– 24]. However, csDMARDs often fail to sufficiently prevent joint destruction in patients with RA [25]. Therefore, the timely introduction of bDMARDs targeting TNF, interleukin-6, and other inflammation-related factors is recommended. Furthermore, csDMARDs are not effective for treating the systemic osteoporosis commonly caused by RA or steroid treatment for RA. Shortterm use of glucocorticoids is recommended for their Current Opinion in Pharmacology 2018, 40:110–119

anti-inflammatory analgesic effect, but long-term use can cause or worsen osteoporosis [26,27] and increase the risk of fracture [28,29]. A higher proportion of RA patients achieve disease remission with bDMARDs or Janus kinase (JAK) inhibitors than with csDMARDs [30]. As a result, prevention of joint destruction has become possible. The ability of bDMARDs to prevent bone and cartilage damage has been confirmed using the modified total Sharp score (mTSS), which rates the extent of both joint space narrowing and bone erosion [31]. However, the impact of bDMARDs on bone mineral density (BMD) was assessed as only ‘stabilized’ in many patients, and there are reports that BMD can either increase or decrease with bDMARD treatment [3]. The aforementioned epidemiological survey conducted by Ochi et al. reported that the frequency of fractures remained unchanged after treatment with bDMARDs [5]. This result was confirmed in a Japanese cohort study (IORRA Cohort), which found that the fracture rate remained unchanged in patients treated with bDMARDs, although RA disease activity was greatly improved [32]. In other words, bDMARDs have no effect on systemic osteoporosis despite effectively preventing local bone and cartilage damage and periarticular osteoporosis. Bisphosphonates, drugs that suppress bone resorption by inducing apoptosis of osteoclasts, do not effectively www.sciencedirect.com

RANK-RANKL for bone damage in RA, mechanism and therapeutic insight Tanaka and Ohira 113

reduce joint destruction in RA patients. No significant difference in the development of new erosions was observed in a study comparing the combination of MTX and the strongest bisphosphonate, zoledronate, with MTX and placebo [33]. Another study compared bisphosphonate-treated and bisphosphonate-naı¨ve postmenopausal RA patients. Although there were differences in the cortical and muscle cross-sectional area between the groups depending on the age and duration of menopause, the study suggested a possibility that bisphosphonate use does not affect volumetric BMD in this patient group [34]. In summary, csDMARDs, bDMARDs, and bisphosphonates cannot adequately prevent both bone erosion and loss of BMD in RA patients simultaneously. New approaches to fill this clinical gap and improve outcomes for patients are required.

Management of bone damage by denosumab in RA patients When RANK expressed on the surface of osteoclast precursors is stimulated by RANKL, osteoclastogenesis ensues with the osteoclasts undergoing a specific process of differentiation to become multinucleated, bone resorbing cells. Denosumab, a fully humanized monoclonal IgG2 anti-RANKL antibody, was developed for treatment of osteoporosis and prevention of skeletal-related events in patients with bone metastases from solid tumors [35–40]. Binding of denosumab to RANKL effectively blocks the RANK-RANKL interaction and prevents bone erosion by suppressing osteoclast differentiation, maturation, and survival (Figure 1), thereby suppressing joint damage. Denosumab has high affinity and specificity for human RANKL and does not bind TNF-a, TNF-b, TNF superfamily member 10 (TRAIL: TNF-related apoptosis-inducing ligand), or CD40 ligand. Neutralizing antibodies for denosumab have not been detected in clinical studies [41]. In one clinical trial, patients with osteoporosis treated with denosumab had improved volumetric BMD of the cortical bone in the distal end of the radius and the femoral neck. Denosumab had a stronger effect on cortical bone than bisphosphonates [42]. Denosumab, which circulates in the peripheral blood throughout the bone, reaches osteoclasts in the cortical bone uniformly, without being affected by the bone microstructure, and efficiently suppresses bone resorption [21,43,44]. A study investigating the effect of denosumab and alendronate on remodeling of the trabecular and cortical bones in postmenopausal women demonstrated that denosumab significantly decreased the porosity of three cortical regions (compact-appearing cortex and the outer and inner transitional zones of the cortex) and suppressed remodeling compared with alendronate [44]. Denosumab has a more rapid and complete effect than alendronate, as assessed www.sciencedirect.com

by collagen biomarkers, because denosumab circulates freely to the bone remodeling compartments of the trabecular and cortical bones. Denosumab has other advantageous clinical properties — it is an injectable formulation with high treatment compliance, and adverse events and other incidents can be managed with dialysis. In contrast, bisphosphonates are deposited on the bone and may become incorporated into the bone for years. The invasion of synovial fluid into the bone causing bone erosion in RA patients mainly occurs on the outside of the cortical bone. Several studies have explored the potential therapeutic benefits of denosumab for RA patients. Two phase II studies, one phase III study, and several cohort and observational studies have demonstrated that denosumab is effective for preventing bone erosion in RA patients (Table 1) [45]. In a phase II study conducted in the US and Canada, patients with active RA treated with a combination of subcutaneous denosumab (60 or 180 mg every 6 months) and MTX had a significant decrease in mTSS and a significant decrease in bone metabolism markers compared with placebo-treated patients after 12 months [46]. A subsequent analysis found a significant reduction in metacarpal bone loss and a significant increase in hand BMD in the denosumab group [47,48]. These effects were consistent irrespective of baseline BMD and the use of bisphosphonates or glucocorticoids. Other prospective clinical studies have focused on Japanese patients. In the phase II DRIVE study conducted in 350 Japanese patients with RA being treated with MTX, the patients were randomized to either placebo or to 60 mg denosumab every two, three, or six months. The patients in all the denosumab dose groups had significant improvements in modified Sharp erosion scores, the primary efficacy endpoint [6]. The phase III DESIRABLE study randomized 667 Japanese patients with RA to denosumab (60 mg) every six months, denosumab every three months, or placebo. The mean modified Sharp erosion scores were significantly decreased in both denosumab groups compared with the placebo group [49]. There was no significant difference between the denosumab groups, although there was a trend toward improved mTSS in the group dosed every three months compared with the group dosed every six months [45]. In summary, denosumab-treated patients had significant decreases in mTSS and significant increases in periarticular BMD compared with placebotreated patients. However, an effect on joint space narrowing has not been observed. The ability of denosumab to safely increase long-term BMD and reduce the incidence of fractures is well established in patients with osteoporosis [50]. Bisphosphonates are effective in cancellous bone, whereas denosumab is effective in both cancellous and cortical bone. About 70% of bone loss in osteoporosis occurs in cortical bone [44]. In patients with RA, denosumab can increase Current Opinion in Pharmacology 2018, 40:110–119

114 Musculoskeletal

Table 1 Randomized controlled trials of denosumab in RA Study design

Phase II (Denosumab Rheumatoid Arthritis Study Group) NCT00095498

bDMARDs previous/ current 21%

Treatment

Denosumab 60 mg or 180 mg every six months versus placebo

Concomitant medications MTX, supplemental calcium, vitamin D

Follow up period (months)

n

Key results

12

218

Modified Sharp erosion score: decreased in both denosumab groups versus placebo. JSN score: no significant change Bone turnover markers: decreased in denosumab group Metacarpal bone loss: significantly less decrease in both denosumab groups BMD: increased in lumbar spine and hip in denosumab groups Reduced sCTx-1 and P1NP levels in denosumab groups BMD: increased in hand in denosumab group

[46]

218

218

56

Study

[47]

[52]

[48]

Phase II (DRIVE study, Japan)

NA

Denosumab 60 mg every two, three, or six months versus placebo

MTX, supplemental calcium, vitamin D

12

350

Modified Sharp erosion score: decreased in all denosumab groups versus placebo Modified Sharp JSN score: no significant change mTSS: decreased in all denosumab groups versus placebo. BMD: increased in lumbar spine and hip

[6]

Phase III (DESIRABLE study, Japan) NCT01973569

NA

Denosumab 60 mg every three or six months versus placebo

csDMARDs, supplemental calcium, vitamin D

12

667

Modified Sharp erosion score: decreased in all denosumab groups versus placebo Modified Sharp JSN score: no significant change mTSS: decreased in both treatment groups versus placebo BMD: increased in lumbar spine

[49]

Post hoc analysis (The Prince of Wales Hospital, Hong-Kong) NCT01770106

5–10%

Denosumab 60 mg once versus alendronate (70 mg) weekly

MTX (80–85%)

6

40

Erosion size: decreased in the denosumab group and significantly lower than alendronate group BMD of the margin around the erosion: increased in the denosumab group and significantly lower than alendronate group

[51]

bDMARD = biological disease-modifying antirheumatic drug; BMD = bone mineral density; JSN = joint space narrowing; mTSS = modified total Sharp score; MTX = methotrexate; NA = not available; P1NP = procollagen 1N-terminal peptide; RA = rheumatoid arthritis; sCTx-1 = serum type I Ctelopeptide.

BMD and repair bone damage [51]. The increase in BMD has also been confirmed in patients with RA complicated with osteoporosis. A subgroup analysis of a phase II study found a significant increase in the spine and hip BMDs of patients treated with denosumab (Table 1) [52]. In addition, the results of the phase II DRIVE study and the phase III DESIRABLE study conducted in Japanese patients with RA showed significant increases in BMD in the lumbar spine and hip (not measured in the phase III study) [6,49]. Current Opinion in Pharmacology 2018, 40:110–119

Although the long-term safety of denosumab has been established for patients with osteoporosis and cancer bone metastases [50,53], it is currently under evaluation for RA patients. Two phase II studies and a phase III study did not find a marked increase in the frequency of adverse events in patients with RA treated with denosumab [6,46,49]. Similarly, a cohort study also did not show any significant increase in the frequency of adverse events including infections [54]. In a study of patients with RA being treated with bDMARDs and initiating treatment www.sciencedirect.com

RANK-RANKL for bone damage in RA, mechanism and therapeutic insight Tanaka and Ohira 115

with denosumab or zoledronic acid, the frequency of infections was not significantly higher in the denosumab group than in the zoledronic acid group [55]. In a clinical trial in patients with osteoporosis, withdrawal from denosumab induced a bone marker rebound (i.e. a sudden increase or an overshoot) and a marked decrease in bone mass [56,57]. Therefore, doctors are advised to recommend long-term treatment with denosumab for patients with osteoporosis [58,59]. While the possible occurrence of a similar bone marker rebound in patients with RA has not been investigated, patients with RA discontinuing treatment should be monitored. Long-term treatment with denosumab is recommended for patients with RA with a high risk of fracture, such as those with concurrent osteoporosis or those receiving glucocorticoids. Because hypocalcemia may occur with administration of denosumab, periodic monitoring and calcium/vitamin D supplementation should be conducted. Caution should be exercised in patients with severe renal impairment. Denosumab may cause osteonecrosis or osteomyelitis of the jaw, especially after long-term treatment. Patients should maintain dental and oral hygiene with periodic dental checkups [60]. Occurrences of atypical fractures, such as a non-traumatic subtrochanteric fracture and a

femoral proximal diaphysis fracture, were reported in some patients [61,62]. Some of these reports indicated premonitory pain in the femur and groin for several weeks to several months before the occurrence of the complete fracture [63]. Therefore, when such symptoms are observed after starting denosumab treatment, an x-ray and other necessary tests should be performed, and appropriate intervention should be instituted.

Expert opinion Osteoporosis and bone damage associated with RA

The bone manifestations of RA include joint destruction and systemic osteoporosis, which are brought about by different mechanisms. Unlike osteoporosis, bone erosion in RA is independent of osteoblasts and osteocytes. bDMARDs targeting TNF and interleukin-6 suppress bone damage by inhibiting expression of RANKL on synovial cells and subsequent osteoclast maturation, although TNF-inhibitors do not affect bone metabolism and the pathological processes of osteoporosis (Figure 1). Denosumab was developed to treat systemic osteoporosis caused by menopause, aging, and various drugs such as glucocorticoids. Moreover, denosumab can prevent periarticular bone erosion by inhibiting expression of RANKL on synovial cells and subsequent osteoclast maturation through RANKL on synovial cells (Figure 3).

Figure 3

Autoimmune joint synovitis

Joint (synovial) inflammation, Joint swelling, pain

Joint structural damage Periarticular bone damage (cortical bone erosion) Periarticular bone inflammation (Cancellous bone disease) Articular cartilage destruction

Systemic osteoporosis and glucocorticoid-induced osteoporosis

Structural damage of bone (fracture)

MTX

Denosumab*

Bisphosphonate

TNF inhibitor IL-6 inhibitor

TNF inhibitor IL-6 inhibitor

Denosumab

Anti-inflammatory and structural damage suppression effects

Structural damage suppression effect

Worsening QOL / ADL Current Opinion in Pharmacology

Osteoporosis, bone damage associated with rheumatoid arthritis, and treatment target. Rheumatoid arthritis (RA) is characterized by joint inflammation and structural damage. Glucocorticoid therapy can cause systemic osteoporosis and bone damage in patients with RA. Different RA treatments can prevent different components of the joint damage associated with the disease and improve patient outcomes. ADL = activities of daily living; IL = interleukin; MTX = methotrexate; QOL = quality of life; TNF = tumor necrosis factor. * Efficacy of denosumab on cartilage destruction has not been reported. www.sciencedirect.com

Current Opinion in Pharmacology 2018, 40:110–119

116 Musculoskeletal

Thus, denosumab can inhibit joint destruction as well as systemic and glucocorticoid-mediated osteoporosis. Some patients with RA may benefit from treatment with denosumab

The accumulated evidence on the efficacy of denosumab in patients with osteoporosis and RA suggests that denosumab will be most beneficial to RA patients with low disease activity or remission during treatment with csDMARDs and any of the following: first, concomitant use of glucocorticoid therapy, second, progression of bone erosion, third, post-menopausal status, or fourth, systemic osteoporosis. However, the following RA patients may also benefit from concomitant denosumab therapy: a) Patients who respond poorly to a csDMARD who cannot use a higher dose and cannot switch to a bDMARD because of safety or cost concerns. b) Patients who respond poorly to bDMARDs or JAKinhibitors with progression of bone damage. c) Patients who achieve therapeutic targets with a DMARD or a JAK inhibitor but with progressive bone erosion. Bone erosion is an irreversible change that occurs frequently in RA patients. Conventional therapy sometimes cannot sufficiently prevent progression of bone erosion in these patients. Therefore, the clinical efficacy of denosumab for prevention of bone erosion must be confirmed to address this unmet clinical need. Furthermore, concomitant denosumab treatment might be an option during initial treatment with bDMARDs, particularly in RA patients with low bone mass or similar conditions, because an observation period of at least three months is required to confirm the effect of the initial treatment with bDMARDs, and joint destruction may progress during this time. Cost-effectiveness

The cost-effectiveness of denosumab has not been established for any group of patients with RA. In patients with postmenopausal osteoporosis, denosumab was more cost effective than oral anti-osteoporotic drugs such as bisphosphonate agents, particularly in patients with a high risk for fracture and low adherence to oral treatment [64]. An analysis of male patients with osteoporosis also showed that denosumab was more cost-effective [65,66]. Given that the price of denosumab is comparable to that of oral bisphosphonates in Japan, administration of denosumab to patients with RA who cannot tolerate bDMARDs may have economic advantages. Mori et al. conducted a cost-effectiveness analysis using a Markov microsimulation model to compare five-year treatment with denosumab every six months to weekly Current Opinion in Pharmacology 2018, 40:110–119

alendronate in Japanese female patients with osteoporosis. The results showed superior cost reduction or costeffectiveness for denosumab in all age groups investigated [67]. Because the risk factors for fractures in patients with RA differ from those in osteoporosis patients, the results cannot be directly applied to patients with RA. Nevertheless, the studies of cost-effectiveness in osteoporosis patients can provide some information relevant to RA and can help inform the study design for similar trials in RA.

Conclusion Two phase II studies and one phase III study have shown that denosumab inhibits local and systemic decreases in bone density in patients with RA [6,46,49]. Denosumab does not effectively treat synovitis in patients with RA but does reduce progression of bone erosion and periarticular osteoporosis. Because joint destruction progresses during treatment with glucocorticoids and DMARDs, concomitant denosumab treatment in patients with RA may become the standard of care for some patients in the future. After obtaining regulatory approval, clinical results with denosumab in Japan will be accumulated to establish more appropriate management methods and optimize denosumab treatment.

Conflict of interest statement YT has received speaking fees and/or honoraria from Daiichi Sankyo, Astellas, Pfizer, Mitsubishi-Tanabe, Bristol-Myers, Chugai, YL Biologics, Eli Lilly, Sanofi, Janssen, UCB and has received research grants from Mitsubishi-Tanabe, Takeda, Bristol-Myers, Chugai, Astellas, AbbVie, MSD, Daiichi Sankyo, Pfizer, Kyowa-Kirin, Eisai, and Ono. TO is an employee of Daiichi Sankyo Co., Ltd. In 2007, Daiichi Sankyo licensed the rights from Amgen to develop and commercialize denosumab in Japan.

Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-forprofit sectors.

Acknowledgements The authors would like to thank Susan Cottrell, PhD, of Edanz Medical Writing for providing medical writing services.

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