Journal of Orthopaedic Science 23 (2018) 717e721

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Journal of Orthopaedic Science

journal homepage: http://www.elsevier.com/locate/jos

Review Article

Emerging anti-osteoclast therapy for rheumatoid arthritis*

Sakae Tanaka 1
Department of Orthopedic Surgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Rheumatoid arthritis (RA) is an autoimmune inflammatory disorder characterized by progressive
Received 18 January 2018 destruction of affected synovial joints. Recently, it was demonstrated that osteoclasts play critical roles in
Received in revised form bone destruction in RA. Receptor activator of NF-kB ligand (RANKL), which belongs to the tumor necrosis
24 March 2018
factor superfamily, is indispensable for osteoclast differentiation and bone destruction in RA. Denosu-
Accepted 2 June 2018
Available online 30 June 2018
mab, a monoclonal antibody against human RANKL, not only increased bone mineral density, but also
efficiently suppressed the progression of bone erosion in RA patients in a randomized controlled study.
However, denosumab did not reduce the cartilage destruction or disease activity in RA, and further
Keywords:
Osteoclast
investigation is required to establish the appropriate positioning of denosumab in the treatment strategy
RANKL of RA.
Rheumatoid arthritis © 2018 The Japanese Orthopaedic Association. Published by Elsevier B.V. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction 1.1. Involvement of osteoclasts in bone destruction in RA

Progressive and massive joint destruction in rheumatoid
arthritis (RA) is caused by persistent synovitis, which deteriorates
the activity of daily living and the quality of life of RA patients [1].
Therefore, suppressing joint destruction is one of the most impor-
tant issues in the treatment of RA. Disease-modifying anti-rheu-
matic drugs (DMARDs), such as methotrexate, reduce inflammatory
synovitis in RA, and suppress joint destruction [2]. In addition,
recent clinical studies have demonstrated that biological DMARDs
such as cytokine inhibitors both suppress disease activity and
ameliorate joint destruction in RA [3]. In accordance with an
improvement in disease status, a trend of decreased incidence of
orthopaedic surgeries in RA patients has been reported in recent
years by many studies from different countries including Japan
[4,5]. Current RA treatment has thus been considerably improved,
but it is far from perfect because these drugs are not effective in all
patients, and their usage is sometimes associated with serious
adverse effects such as infection [6,7]. In addition, the high medical
costs of these drugs burden both patients and society.
The present review proposes that osteoclasts are involved in the
bone destruction in RA, and that a novel treatment strategy tar-
geting osteoclasts is an effective and safe treatment option.
* [11,12]. Multinucleated cells that differentiated from synovial
This Review Article was presented at the 32nd Annual Research Meeting of the
Japanese Orthopaedic Association, Okinawa, Oct. 27, 2017.
E-mail address: TANAKAS-ORT@h.u-tokyo.ac.jp.
1
Fax: þ81 3 5800 8858.
Radiographic studies have shown that bone erosion in RA
begins at the early stage of disease, and gradually (and some-
times rapidly) exacerbates. Proliferating synovium produces an
elevated amount of proinflammatory cytokines such as inter-
leukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-a, and matrix-
degrading enzymes matrix metalloproteinases and cathepsins,
which are involved in bone and cartilage destruction [8]. Bone
erosion usually begins at the interface of the cartilage and the
proliferating synovium (bare area), and numerous bone-
resorbing osteoclasts are present at the erosive synovium/bone
interface. Histochemical and ultrastructural studies by Bromley
and Woolley reported the presence of acid phosphatase-positive
multinucleated cells along the surface of mineralized sub-
chondral bone and mineralized cartilage [9]. These multinucle-
ated cells exhibited the morphological features of osteoclasts,
indicating osteoclasts are implicated in bone erosion in RA. More
recently, Gravallese et al. demonstrated that multinucleated cells
observed in the erosive surface expressed osteoclast-specific
genes, such as tartrate-resistant acid phosphatase and calci-
tonin receptors using in situ hybridization [10]. To further un-
derstand the mechanism of osteoclast development in RA joints,
Fujikawa et al. and Takayanagi et al. developed in vitro osteoclast
formation systems using synovial cells obtained from RA patients
macrophages exhibited bone-resorbing activity when cultured
on bone slices. These results suggest that RA synovial tissues

https://doi.org/10.1016/j.jos.2018.06.001
0949-2658/© 2018 The Japanese Orthopaedic Association. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.
org/licenses/by-nc-nd/4.0/).
718 S. Tanaka / Journal of Orthopaedic Science 23 (2018) 717e721
provide a favorable microenvironment for monocyte-
macrophage lineage cells to differentiate into osteoclasts.
The importance of osteoclasts in RA bone destruction was
further evidenced by studies of various arthritis model animals.
In mice generated by mating c-fos-deficient osteopetrosis mice,
in which osteoclastogenesis is impaired, with human TNF-a-
transgenic mice that spontaneously develop RA-like arthritis,
bone destruction does not occur despite synovial inflammation
and cartilage destruction [13]. In addition, we reported a case of
RA associated with osteopetrosis [14], an inherited disorder
characterized by increased bone mass caused by reduced bone
resorption. The most frequent form of osteopetrosis has auto-
somal dominant (ADO) inheritance (incidence 5:100,000), which
€ nberg disease or ADO type II. ADO type
is also called Albers-Scho
II results from mutations in the CLCN7 gene encoding type 7
chloride channels, and osteoclast activity is markedly reduced.
We reported a very rare case of RA associated with ADO type II.
Although the patient exhibited severe inflammation and rapid
progression of cartilage destruction, bone destruction was only
developed slowly because of reduced osteoclast activity [14].
These results indicate the essential role of osteoclasts in bone
destruction in RA.
1.2. Regulation of osteoclast development by the RANKLeRANK
pathway
Receptor activator of nuclear factor kappa B ligand (RANKL) is
a transmembrane protein belonging to the TNF superfamily
[15,16]. RANKL binds to its specific receptor RANK, a member of
the TNF receptor superfamily, expressed in monocyte-
macrophage lineage osteoclast precursor cells, mature osteo-
clasts, and dendritic cells. Osteoprotegerin (OPG) is a soluble
decoy RANKL receptor that suppresses RANKL function by
competitively inhibiting RANKL-RANK binding [15,16]. Although
RANKL was originally identified as a dendritic cell survival factor
produced by activated T cells, subsequent in vitro and in vivo
studies have shown that RANKL is indispensable for the differ-
entiation and activation of osteoclasts. Targeted disruption of the
Rankl or Rank gene induced osteopetrosis in mice because of the
lack of osteoclasts, while knock-out of the Opg gene induced
severe osteoporosis via a marked increase in osteoclasts, indi-
cating the essential role of the RANKL-RANK pathway in the
differentiation of osteoclasts from precursor cells [15]. Numerous
studies have shown that the RANKL-RANK system is implicated
in physiological bone resorption, and also plays an important role
in pathological bone destruction [16].
The important role of the RANKL/RANK/OPG system in the
development of bone destruction in RA has been recently
established [17] (Fig. 1). Several groups simultaneously reported
that RANKL is highly expressed in the synovial tissues of RA
patients [17e19]. The cells expressing RANKL are considered to
be activated T lymphocytes and/or synovial fibroblastic cells.
Kong et al. reported that when murine bone marrow precursors
were cocultured with activated CD4þ T cells fixed with para-
formaldehyde, osteoclasts were differentiated in vitro [20]. We
found that in a coculture system containing synovial fibroblasts
and peripheral monocytes, 1a,25-dihydroxyvitamin D3 treatment
induced RANKL expression in synovial fibroblasts and induced
osteoclast differentiation from monocytes [19]. Kong et al. also
reported that blocking RANKL by OPG treatment prevented joint
destruction but not inflammation in adjuvant arthritis rats. In
addition, Pettit et al. reported that RANKL knockout mice were
protected from bone erosion in a serum transfer model of
arthritis [21]. Several clinical studies have shown that the RAN-
KL:OPG ratio in serum or synovial fluid may predict the
progression of joint destruction in RA patients. A recent cohort
study demonstrated that the RANKL:OPG ratio independently
predicted annual radiological damage over 11 years [22]. These
results strongly suggest that RANKL-induced osteoclast forma-
tion critically regulates bone destruction in RA, and that anti-
RANKL therapy may be useful for the prevention of bone
destruction.
2. Clinical benefits of denosumab for osteoporosis and RA
Denosumab is a fully human monoclonal anti-RANKL antibody
that specifically inhibits the interaction between RANKL and RANK,
and strongly suppresses osteoclast differentiation and bone
resorption. In the pivotal Fracture Reduction Evaluation of Deno-
sumab in Osteoporosis Every 6 Months (FREEDOM) study, deno-
sumab significantly reduced osteoporotic fractures in
postmenopausal women with osteoporosis. Denosumab signifi-
cantly increased BMD and reduced the risks of vertebral, hip, and
non-vertebral fractures [23]. There was no increase in the risk of
cancer, infection, cardiovascular disease, delayed fracture healing,
hypocalcemia, or osteonecrosis of the jaw. In a phase III clinical trial
conducted to evaluate the effect of denosumab on Japanese oste-
oporosis patients, denosumab significantly reduced the risk of new
or worsening vertebral fracture by 65.7% at 24 months. No apparent
difference in adverse events was found between denosumab and
placebo groups [24].
Recently, it was demonstrated that denosumab was also effec-
tive in ameliorating bone destruction in RA. Cohen et al. investi-
gated joint destruction in RA patients who received placebo,
denosumab 60 mg, or denosumab 180 mg by subcutaneous injec-
tion Q6M for 12 months. The progression in erosion score analyzed
by MRI at 6 months was lower in the 60 mg denosumab group and
significantly lower in the 180 mg denosumab group compared with
the placebo group. The modified Sharp erosion scores in both
denosumab groups were significantly lower than those in the
placebo group at 12 months, while the progression of joint-space
narrowing or RA disease activity was unchanged [25].
A phase II clinical trial was conducted to analyze the effect of
denosumab in Japanese RA patients with a disease duration of 6
months to less than 5 years [26]. Patients were randomly assigned
to receive one of four treatments: placebo, denosumab 60 mg Q6M,
Q3M or every Q2M. While denosumab significantly inhibited the
progression of bone erosion at 12 months at all doses compared
with placebo, it had no protective effect on joint-space narrowing,
which was consistent with the results reported by Cohen et al.
(Fig. 2). There was no apparent difference in the safety profiles of
denosumab and placebo, including infection. All denosumab
groups significantly increased lumbar spine and total hip BMD
compared with the placebo group at 6 and 12 months. These results
provide strong evidence to suggest denosumab prevents the pro-
gression of bone erosion in the early stage of RA, but has little or no
effect on cartilage deterioration or disease activity. A subsequent
phase III clinical trial showed that denosumab 60 mg Q6M and Q3M
significantly suppressed bone erosion at 12 months in Japanese RA
patients [27]. Based on these results, denosumab was approved for
“inhibition of the progression of bone erosion associated with RA”
in Japan.
Denosumab has additional benefits in RA patients by preventing
osteoporosis and osteoporotic fractures. RA patients are at
increased risk of osteoporotic fractures. Although the proportion of
RA patients who achieve remission has greatly increased, recent
studies reported the number of fractures in RA patients was not
reduced [28,29]. This discrepancy is at least partly accounted for by
the multifactorial nature of osteoporosis in RA patients, with
contributory factors other than inflammation, such as immobility,
 S. Tanaka / Journal of Orthopaedic Science 23 (2018) 717e721 719

Fig. 1. Regulation of osteoclast differentiation and bone erosion in rheumatoid arthritis by RANKL. M-CSF: macrophage colony-stimulating factor.

Fig. 2. Denosumab significantly suppresses bone erosion score (a) but has no effect on joint-space narrowing score (b) Modified from a Figure in the article by Takeuchi et al. [26].
CI: confidence interval.
720 S. Tanaka / Journal of Orthopaedic Science 23 (2018) 717e721
Fig. 3. Schematic representation of the possible mechanisms of joint destruction in RA. Modified from a Figure in the article by Tanaka et al. [30].
steroid usage, and aging. Clinical studies to analyze the effect of
denosumab on RA patients also demonstrated an increase in BMD
[25,26]. Although it remains unknown whether denosumab treat-
ment can reduce fragility fractures in RA patients, anti-osteoporosis
treatment is absolutely required for these patients, and denosumab
may play a useful role. Fig. 3 summarizes the possible role of
denosumab in the treatment of RA.
In conclusion, recent studies demonstrated that denosumab is
effective in ameliorating bone destruction in RA. However, it
should be noted that denosumab has no effect on joint inflam-
mation or cartilage destruction in RA, and should therefore be
used in combination with other therapeutics. The optimal posi-
tioning of denosumab in the treatment strategy of RA remains
elusive, and many clinical questions remain unanswered. Further
investigation is necessary to answer these questions and to
establish the appropriate position of denosumab in the treatment
strategy of RA.
Conflict of interest
None.
Acknowledgements
The work of S. Tanaka is supported by The Japan Agency for
Medical Research and Development (AMED) (924887), Japan So-
ciety for the Promotion of Science (JSPS)/Grant-in-Aid for Scientific
Research (A) (406501), and Japan Society for the Promotion of
Science (JSPS)/Grant-in-Aid for Exploratory Research (934289).
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