Joint Bone Spine 73 (2006) 349354

http://france.elsevier.com/direct/BONSOI/

Review

Bisphosphonate therapy in rheumatoid arthritis

Vronique Breuil *, Liana Euller-Ziegler
Rheumatology Department, Hpital LArchet 1, 151, route Saint-Antoine-de-Ginestire, 06202 Nice cedex 3, France
Received 16 June 2005; accepted 4 October 2005
Available online 15 March 2006

Abstract
Focal bone damage and generalized bone loss are features of rheumatoid arthritis (RA). The introduction of TNF antagonists has radically
improved the management of RA by providing a means of slowing or preventing the occurrence of focal bone damage. However, some patients
with severe RA have contraindications to TNF antagonist therapy and others either fail to respond or fail to tolerate TNF antagonists. In
addition, whether TNF antagonists effectively combat generalized bone loss remains unknown. Bisphosphonates can prevent generalized bone
loss. Their main target is the osteoclast, which has been identified as the culprit in focal bone damage caused by inflammatory diseases. As a
result, the potential effects of bisphosphonates on focal bone damage related to RA are generating strong interest. Although results from the few
studies in humans have been disappointing, new insights into the mechanisms of action of amino-bisphosphonates and recent data obtained in
animals, most notably with new-generation bisphosphonates, have rekindled the hope that bisphosphonates may be beneficial in RA. We review
herein the main studies of the effects of bisphosphonate therapy on focal bone damage and generalized bone loss in patients with RA.
2006 Elsevier SAS. All rights reserved.
Keywords: Rheumatoid arthritis; Bisphosphonate; Bone loss; Focal bone damage; Osteoclast

1. Introduction

New insights into the pathophysiology of bone and joint

diseases and data on the mechanisms of action of medications
have propelled the field of rheumatology into an exciting era
that offers both new drug classes and new concepts. Biologics
are the most promising new drugs at present. Osteoimmunology, one of the leading new concepts, grew out of the finding
that the immune system and bone metabolism are regulated by
the same cytokines (i.e. TNF, IL-1, and RANKL).
In rheumatoid arthritis (RA), which is the most common
inflammatory disease, focal bone damage occurs in combination with generalized bone loss. Studies showing a central role
for TNF in the inflammation and focal bone damage seen in
RA led to the development of TNF antagonists. These new
* Corresponding

author. Tel.: +33 4 92 03 55 12; fax: +33 4 93 86 68 39.

E-mail address: breuil.v@chu-nice.fr (V. Breuil).

1297-319X/$ - see front matter 2006 Elsevier SAS. All rights reserved.
doi:10.1016/j.jbspin.2005.10.019

drugs constitute a therapeutic breakthrough, as they are the first

medications capable of slowing or preventing the occurrence of
focal bone damage, which is a major source of disability in
patients with RA. However, intolerance or contraindications
preclude TNF antagonist therapy in a number of patients with
severe RA. These limitations, together with the high cost of
TNF antagonists, are fueling an active search for treatment
alternatives.
Research into new treatments for RA is exploring not only
the development of additional biologic agents, but also the possible effectiveness of bisphosphonates in protecting against focal bone damage. Bisphosphonates are known to be effective
in osteoporosis, which is common in patients with RA. After a
period of controversy, there is now general agreement that the
osteoclast, the cell type responsible for bone resorption and the
main target of the potent antiresorptive effect of bisphosphonates, is responsible not only for the generalized bone loss, but
also for the focal bone damage seen in RA [1]. In the light of
recent findings on the pathophysiological role for osteoclasts in

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V. Breuil, L. Euller-Ziegler / Joint Bone Spine 73 (2006) 349354

RA and on the mechanisms of action of bisphosphonates, we

will review the main studies investigating the effects of bisphosphonates on generalized bone loss and focal bone damage in
RA.
2. Pathophysiology of generalized bone loss and focal bone
damage in RA: role for the osteoclast
2.1. Focal bone damage
We will be brief on this point, which has been the focus of
several reviews, one of which was published very recently in
this journal [26]. The osteoclast is the main culprit in focal
bone damage in RA. RANKL, a key differentiation and activation factor for osteoclasts, is released by activated T cells and
synovial cells in the rheumatoid pannus. IL-1 and TNF not
only play a pivotal role in the pathogenesis of rheumatoid synovitis, but also exert direct and indirect effects on osteoclastogenesis via enhanced RANKL release. Osteoclasts are found
at the pannus/bone interface and in the adjacent subchondral
bone. Animals devoid of functional osteoclasts can be obtained
experimentally by targeting the RANKL gene (a key factor in
osteoclast differentiation and activation) or the c-fos gene (a
transcription factor that is key to osteoclast maturation) or by
administering osteoprotegerin (a naturally occurring soluble receptor that blocks the effects of RANKL). In animals devoid of
functional osteoclasts, experimental arthritis does not cause
bone erosions, despite the development of severe local inflammation.
Interestingly, although TNF is the central cytokine in the
inflammatory process that leads to focal bone damage in RA,
other factors are involved also. Thus, arthritis with bony erosions can be induced in TNF-knockout mice. The finding that
some patients with RA fail to respond adequately to TNF antagonist therapy also supports a role for other factors.
Taken together, available data indicate that alternative treatment strategies should be developed to prevent focal bone damage in patients with RA via direct or indirect effects on osteoclast activation and/or formation.
2.2. Generalized bone loss
Many studies have established that osteoporosis is common
in both women and men with RA. The prevalence of osteoporosis in studies of RA has ranged from 20% to 30% [2,6].
The many factors that contribute to cause osteoporosis in patients with RA [69] include glucocorticoid therapy, which is
too often given without prophylactic bisphosphonate therapy,
and disability-related immobility [6]. A role for disease activity
has been demonstrated in animals. In humans, after a period of
controversy, many studies found evidence that greater disease
activity was associated with bone loss. Cytokines such as TNF
and IL-1, which are at the hub of the rheumatoid inflammatory
process, may enhance osteoclastic resorption, thereby causing

bone loss [26]. In contrast to postmenopausal osteoporosis,

bone loss in RA predominantly affects the peripheral cortical
bone and largely spares the axial skeleton. The onset of bone
loss occurs early in the course of RA, indicating a need for
prompt treatment [6]. Shibuya et al. [7] and other groups have
reported that bone loss correlates with disease duration and severity, independently from the use of glucocorticoids. In addition, radiological focal bone damage is correlated with overall
bone mineral density (BMD) as measured by absorptiometry
[8,10,11]. In the COBRA study, biochemical markers for bone
and joint destruction (CTX I and II) predicted radiological progression after 4 years, underscoring the link between bone loss
and joint erosions [12].
Few data are available for evaluating whether adequate disease control is associated with a reduction in generalized bone
loss. The administration of disease-modifying antirheumatic
drugs (DMARDs), notably salazopyrine, was associated with
stabilization of BMD values or decreases in biochemical
bone-turnover markers. Femoral neck BMD was significantly
increased 6 months after the initiation of glucocorticoid therapy, supporting a beneficial effect of disease control on overall
bone metabolism [6,13]. Recent preliminary studies in small
numbers of patients evaluated the two TNF antagonists that
were available at the time, infliximab and etanercept [1416].
Infliximab therapy was associated with early declines in bone
resorption markers in two independent studies of adults with
RA [14,15]. In patients with juvenile idiopathic arthritis who
responded to etanercept therapy, bone density increased; however, bone density in this study was assessed ultrasonographically [16].

3. Mechanisms of action of bisphosphonates

Bisphosphonates are powerful inhibitors of osteoclastic

bone resorption and are widely used to manage diseases that
are characterized by bone loss. Bisphosphonates fall into two
main categories, amino-bisphosphonates (alendronate, ibandronate, risedronate, pamidronate, zoledronate, and icandronate)
and non-amino-bisphosphonates (etidronate, tiludronate, and
clodronate). Drugs in both categories inhibit bone resorption
by inducing osteoclast apoptosis. However, the underlying molecular mechanisms differ.

3.1. Non-amino-bisphosphonates closely resemble

pyrophosphates

They take the place of phosphate groups in ATP molecules,

generating non-hydrolysable analogs that cause osteoclast
apoptosis in the absence of caspase-3 activation. Their metabolism by macrophages decreases the acute-phase inflammatory
response [17,18].

V. Breuil, L. Euller-Ziegler / Joint Bone Spine 73 (2006) 349354

3.2. Amino-bisphosphonates have a stronger antiresorptive

effect
They induce osteoclast apoptosis chiefly by inhibiting a mevalonate pathway enzyme, farnesyl diphosphate synthase,
which is essential for posttranslation changes in GTP-binding
proteins. The result is osteoclast apoptosis mediated by caspase-3 activation [18,19]. Zoledronate is the most potent amino-bisphosphonate both in vitro and in vivo [20]. Differences
in mechanisms of action may exist across amino-bisphosphonates. Although all the medications in this category inhibit farnesyl diphosphate synthase, alendronate seems to have no
other effect, whereas other amino-bisphosphonates (including
pamidronate, NBP NE-21650 (a risedronate analog), and zoledronate) may also induce osteoclast apoptosis directly, by generating pyrophosphate analogs according to the mechanism
seen with non-amino-bisphosphonates [19,21]. Amino-bisphosphonates, particularly when given intravenously, sensitize
macrophages to inflammatory stimuli and can induce an acute
inflammatory reaction with a fever and other flu-like symptoms
that resolve within 48 h [17]. Finally, a number of bisphosphonates, such as zoledronate, inhibit angiogenesis in tumor models. Angiogenesis is a key factor in the inflammatory response
[19].
3.3. Effects of bisphosphonates on markers for inflammation
In vitro and in vivo, non-amino-bisphosphonates inhibit the
release by activated macrophages of proinflammatory cytokines such as IL-6, TNF and IL-1. In vitro, zoledronate and
pamidronate increase the release of TNF and IL-6 by peripheral blood mononuclear cells [1,17]. Etidronate, alendronate,
and to a lesser degree clodronate are associated with dose-dependent inhibition of the ability of IL-1 and TNF to induce
IL-6 production by the osteoblastic cell line MG-63 [22]. Amino-bisphosphonates stimulate histidine decarboxylase, the enzyme responsible for histamine generation, and increase the
numbers of macrophages and granulocytes, thereby exacerbating the inflammatory response in animal models of collageninduced arthritis. In contrast, clodronate decreases this inflammatory response [23].
4. Effects of bisphosphonates on bone loss in RA
4.1. Effects on generalized bone loss
Compelling evidence indicates that bisphosphonates prevent
bone loss and fractures related to glucocorticoid-induced osteoporosis in humans. Bisphosphonates constitute the treatment of
reference for this condition [24]. Studies have sought to determine whether bisphosphonates can prevent bone loss due to the
disease process itself. In animal models of RA without glucocorticoid therapy, bisphosphonate therapy is associated with
bone mass preservation. For example, etidronate and alendro-

351

nate prevented the decrease in tibial BMD seen in control rats

[25]. Zoledronate significantly reduced biochemical markers
for bone remodeling, increased BMD values, and preserved
bone microarchitecture in transgenic mice with arthritis [26].
Clodronate and alendronate preserved bone mass and bone
strength in rats with collagen-induced arthritis [27].
The effects of bisphosphonate therapy on bone loss due to
RA itself are more difficult to evaluate in humans, because
most of the available studies were done in patients taking concomitant glucocorticoid treatment. With this caveat in mind,
the results indicate that bisphosphonates are effective in preventing bone loss in patients with RA treated with glucocorticoids [2835]. For instance, clodronate preserved BMD values
at the spine and femur and reduced the risk of vertebral fractures [28]. Alendronate therapy induced significant increases in
BMD values at the spine and femoral neck and decreased the
levels of bone resorption markers [30,31]; furthermore, these
effects were far more marked than those of nasally administered calcitonin [33]. Similar results have been obtained with
risedronate and pamidronate [32,34,35].
4.2. Effects on focal bone damage
As early as 1979, the powerful antiresorptive effect of bisphosphonates prompted studies into the possible effects of
these drugs on focal bone damage in patients with RA. The
results were disappointing initially. However, new studies of
last-generation bisphosphonates are far more promising [1].
4.2.1. In vitro and animal studies
The effects of several bisphosphonates on parameters reflecting the inflammatory response prompted many groups to
investigate clodronate in murine models of collagen-induced
arthritis. Clodronate therapy decreased the severity of inflammation and focal bone damage, in part via depletion of specific
macrophage subpopulations in the synovial membrane [36].
In rats with collagen-induced arthritis, Itoh et al. [27] compared the non-amino-bisphosphonate clodronate to the aminobisphosphonate alendronate. Both medications reduced generalized bone loss, but only clodronate protected against focal
bone damage in this model. However, the effects of bisphosphonates may vary across models. Thus, in a murine model
of arthritis induced by Mycobacterium butyricum, high-dose
alendronate or etidronate significantly decreased the inflammation and focal bone damage, and similar effects were obtained
with the amino-bisphosphonate icandronate [25,37]. In addition, as mentioned above, the mechanisms of action vary
across bisphosphonates. In a rabbit model of experimentally
induced arthritis, zoledronate afforded partial protection against
focal bone damage [38]. Very recently, two elegant studies
conducted independently from each other showed that zoledronate afforded greater protection against focal bone damage
compared to other bisphosphonates used in earlier studies
[26,39]. In the first study, rats received a single subcutaneous
zoledronate injection at the clinical onset of collagen-induced

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arthritis and were evaluated 2 weeks later [39]. A moderate but

typical increase in local inflammation was found, whereas focal bone damage as evaluated by radiographs, microcomputed
tomography, and histomorphometry (focal erosion scores) was
significantly reduced with zoledronate dosages greater than
10 g/kg. The histological results showed a greater than 80%
reduction in bone damage. Interestingly, lower zoledronate dosages were associated with an increase in subchondral bone
erosions at the proximal interphalangeal joints and with worsening of the Larsen score, suggesting that the proinflammatory effects of low-dose zoledronate may predominate over
the bone-protecting effects. In the second study, mice transgenic for human TNF, which spontaneously develop severe
destructive arthritis, were treated with single or repeated dosages of subcutaneous zoledronate [26]. Zoledronate therapy
induced both a significant increase in bone mass, which was
ascribable to increases in the number and connectivity of bone
trabeculae, and significant decreases in biochemical markers of
bone resorption. Although local inflammation was not affected,
the development of bone erosions was reduced by 60% after a
single zoledronate injection and by 95% after repeated injections.
In addition to bisphosphonates, a number of other agents are
being evaluated in animal models of RA. Osteoprotegerin and
selective NF-B inhibitors have yielded promising results that
now require confirmation [40,41].
4.2.2. Clinical studies
Clinical studies investigating the effects of bisphosphonates
on focal bone damage in RA are both few in number and small
in size. In addition, comparisons of their results are hindered
by differences in the agents used, modalities of administration,
evaluation time points, and disease duration. Effects on laboratory parameters of inflammation varied across studies. Significant decreases in the erythrocyte sedimentation rate and C-reactive protein level were noted 7 days after a single infusion of
the amino-bisphosphonate neridronate and 3 months into oral
treatment with alendronate. These parameters showed no significant changes after a single infusion of etidronate or clodronate, whereas they improved in one study of pamidronate but
showed no change in another [30,4246]. In an original study
of intraarticular liposomal clodronate given 2 weeks before
knee replacement surgery, histological examination of the synovial membrane removed during surgery showed significant
macrophage depletion and decreased expression of the adhesion molecules ICAM-1 and VCAM-1 [47].
In keeping with data from animal studies, most studies in
humans found no evidence that bisphosphonate therapy (etidronate, pamidronate, or alendronate) alleviated the clinical
manifestations of inflammation [29,30,4446,48]. However,
in a trial of 40 patients allocated at random to pamidronate
20 mg, pamidronate 40 mg, or a placebo, Eggelmeijer et al.
[43] noted significant decreases in clinical disease activity
scores after a single infusion of either pamidronate dosage.
Most studies showed that oral or parenteral bisphosphonate
therapy protected against generalized bone loss. In contrast,

there is no proof to date that bisphosphonates significantly decrease focal bone damage. Statistically significant decreases in
markers for cartilage destruction were found in several studies
[35,44,46,4850].
5. Conclusion
Both generalized bone loss and focal bone damage must
receive attention in patients with RA. Although newly introduced biological agents have been proven effective in reducing
focal bone damage, their effect on generalized bone loss remains to be evaluated. For patients who cannot be treated with
biological agents, effective prevention of focal bone damage
will require new treatment strategies, for instance the concomitant administration of DMARDs and of drugs with specific effects on bone metabolism. Among these, bisphosphonates can
prevent generalized bone loss. They primarily target the osteoclast, which is the culprit in focal bone damage. Therefore,
their potential for preventing focal bone damage in patients
with RA deserves to be assessed. Early clinical trials in humans
produced disappointing results. However, new data on the mechanisms of action of amino-bisphosphonates and recent results obtained in animals using new-generation bisphosphonates such as zoledronate suggest that bisphosphonate therapy
may yield both medical and economic benefits in patients with
RA.
Researchers must strive to confirm the effects of biologics
on generalized bone loss and to evaluate the ability of newgeneration bisphosphonates combined with conventional
DMARDs to slow or to prevent focal bone damage. Then,
the indications for bisphosphonate therapy in patients with
RA will have to be defined. Bisphosphonates might prove useful in patients who have severe RA and contraindications or
intolerance to TNF antagonist therapy. In patients who do
not meet the severity criteria required for TNF antagonist
therapy, studies are needed to determine whether routine bisphosphonate therapy starting at the diagnosis of RA decreases
the generalized bone loss and focal bone damage that occur
during the lag time needed for DMARD therapy to take effect.
The optimal treatment schedule will need to be determined
(oral or intravenous route, and treatment duration). To answer
these questions, researchers will have to conduct carefully designed studies in large populations of patients that are homogeneous in terms of RA features and other factors known to
affect bone metabolism. Until then, it should be borne in mind
that bisphosphonates have been proven effective in patients
with RA and osteoporosis with or without fractures, in the absence or presence of glucocorticoid therapy.
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