new and emerging treatments for osteoarthritis management: will the dream come true with...

1. Introduction

2. DMOADs targeting pathways

of cartilage catabolism and

anabolism

3. DMOADs targeting

subchondral bone remodeling

4. Targeting inflammatory

pathways

5. Gene therapy in OA

6. Perspectives: microRNAs and

small interfering

RNA-based therapeutic

approaches in OA

7. Conclusion

8. Expert opinion: toward

targeted personalized

medicine in OA

Review

New and emerging treatments forosteoarthritis management: willthe dream come true withpersonalized medicine?Camille Roubille, Jean-Pierre Pelletier & Johanne Martel-Pelletier†

†University of Montreal Hospital Research Centre (CRCHUM), Notre-Dame Hospital, Department

of Medicine, Osteoarthritis Research Unit, Montreal, Quebec, Canada

Introduction: Osteoarthritis (OA) is a dynamic process involving the main tis-

sues of the joint for which a global approach should be considered. No

disease-modifying OA drug (DMOAD) has yet been approved. New therapeu-

tic strategies are needed that would be cost effective by reducing the need for

pharmacological interventions and surgical management while targeting

specific pathways leading to OA. The treatment landscape of OA is about to

change based on new agents having shown some structural effects and

emerging therapies with DMOAD effects.

Areas covered: In this review based on a Medline (via PubMed) search, prom-

ising new and emerging therapies with a potential structural effect (DMOAD)

will be discussed including growth factors, platelet-rich plasma, autologous

stem cells, bone remodeling modulators, cytokine inhibition, gene therapy,

and RNA interference.

Expert opinion: DMOAD development should focus on targeting some phe-

notypes of OA patients evidenced with sensitive techniques such as magnetic

resonance imaging, as a single treatment will unlikely be appropriate for all

OA patients. This will allow the development of DMOADs based on persona-

lized medicine. An exciting new era in DMOAD development is within reach,

provided future clinical trials are sufficiently powered, systematically

designed, use the appropriate evaluation tools, and target the appropriate

categories of OA patients.

Keywords: disease-modifying osteoarthritis drug, gene therapy, knee osteoarthritis, MRI, stem

cells, strontium ranelate, subchondral bone

Expert Opin. Pharmacother. (2013) 14(15):2059-2077

1. Introduction

Osteoarthritis (OA) is a whole joint disease characterized by degradation and loss ofarticular cartilage, hypertrophic bone changes with osteophyte formation, subchon-dral bone remodeling, and inflammation of the synovial membrane. Importantadvances have been made in understanding its pathological processes, and promisingnew structure-modifying therapeutic agents that may slow or arrest the progression ofthe disease are being developed, aimed at improving current treatment.

OA is a multifactorial disease resulting in the failure of the joint ‘organ,’ leadingto the degeneration of articular tissues. This disease may result from genetic predis-position, aging, mechanical stress, or low-grade systemic inflammation associatedwith trauma and obesity [1]. Joint tissue cells are responsible for the maintenanceof a healthy extracellular matrix. Modification in their environment, such asmechanical factors, could activate these cells’ anabolic function to repair tissue dam-age. Under stimulation by growth factors at an early stage of OA, the cells produce

10.1517/14656566.2013.825606 © 2013 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 2059All rights reserved: reproduction in whole or in part not permitted

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http://informahealthcare.com/journal/EOP

inadequate molecules, as well as osteophytes. With time, thisattempt fails and leads to an imbalance favoring degradation.During OA, the cells in cartilage, synovial membrane, andsubchondral bone release proteinases (e.g., metalloproteinases[MMPs] and aggrecanases [ADAMTS]) and inflammatorycytokines including interleukin-1b (IL-1b) and tumor necrosisfactor-a (TNF-a), which enhance the synthesis of proteinasesand other factors to further degrade the joint tissues, over-whelming endogenous inhibitors for example. Cartilage extra-cellular matrix is degraded and replaced by a matrix that isunable to withstand normal mechanical factors. A number ofstudies have demonstrated the importance of the cross-talk between cartilage, synovial membrane, and subchondralbone in the pathophysiology of OA. Synovial inflammation,secondary to the release of cartilage fragments into the synovialfluid, and subchondral bone remodeling by its release of solublemediators affect the cartilage by sustaining its degradation.Even if the precise interaction between cartilage erosion,

chronic synovial inflammation, and remodeling of subchon-dral bone is not yet determined, magnetic resonance imaging(MRI) has contributed to improve our understanding of theOA process and different phenotypes, underlining the inter-connection of these three joint tissues.Data reported poor correlation between cartilage preserva-

tion and symptoms. This is probably due to the fact that artic-ular cartilage is avascular and aneural and that OA pain ismost likely multifactorial, involving synovitis and subchon-dral bone lesions. This could explain why a sole agent hasnot achieved both symptomatic and structural effects so far.However, in our opinion, the overall goal in OA managementremains cartilage preservation.

One of the most exciting challenges in the field of rheuma-tology is to find novel therapeutics that will modify the struc-tural changes that occur in the joint tissues during the disease.The development of new OA treatment needs an innovativeand global approach. New therapeutic strategies that wouldbe cost effective by reducing the need for pharmacologicalinterventions and surgical management, while targetingspecific pathways leading to OA, are needed. Targetingcartilage changes (catabolism and anabolism), subchondralbone remodeling, and synovial inflammation and/or low-grade inflammation are the main thrusts of research indisease-modifying OA drug (DMOAD) development.

The present review will focus on therapies with DMOADeffect, not only new agents having evidence of structuraleffects, but also promising emerging treatments with a poten-tial for structural impact.

2. DMOADs targeting pathways of cartilagecatabolism and anabolism

2.1 Growth factors: bone morphogenetic protein-7

and fibroblast growth factor-18Two growth factors involved in OA cartilage repair are cur-rently in clinical trials: bone morphogenetic protein-7(BMP-7), also known as osteogenic protein-1, and fibroblastgrowth factor-18 (FGF-18).

In vivo, in animal models, BMP-7 demonstrated reparativeeffects on articular cartilage degradation [2]. In vitro, humanchondrocytes also promote cartilage formation in response toBMP-7 treatment [3]. One completed Phase I trial using aweekly intra-articular injection of BMP-7 found no dose-limiting toxicity. By the 12th week of treatment, there was atrend toward a greater symptomatic improvement comparedto placebo in knee OA patients who received 0.1 and 0.3 mgof BMP-7 [4]. Another Phase I trial ([5]-NCT01133613) anda Phase II trial ([5]-NCT01111045) have been completed butresults are not yet available.

In a meniscal tear rat model of OA, biweekly intra-articular injections of FGF-18 for 3 weeks induced chondro-genesis and cartilage repair, with dose-dependent increasesin cartilage thickness of the tibial plateau [6]. Two Phase Istudies ([5]-NCT01033994 and 00911469) have been com-pleted. The first placebo-controlled Phase I study [7] evaluatedthe DMOAD effects of intra-articular administration ofFGF-18 after single or multiple escalating doses over a3-week period in primary knee OA patients (Kellgren-Law-rence [KL] grades 2 or 3) with no major knee surgery plannedfor at least 1 year after the FGF-18 injection. Outcomes weretibiofemoral cartilage volume change assessed by MRI, loss ofjoint space width (JSW) measured by X-rays, as well as theWestern Ontario and McMaster Universities OsteoarthritisIndex (WOMAC) pain and function scores after 1 year.A dose-dependent reduction in tibiofemoral cartilage volumeloss was found in patients treated with FGF-18 compared to

Article highlights.

. OA should be considered a dynamic process and may bea systemic disease with several pathways to target forDMOAD development.

. Promising emerging therapies include autologous MSCs,PRP, bone remodeling modulators, cytokine inhibitors,and gene therapy.

. With the advent of DMOADs, physicians should aim attreating a ‘patient’ rather than a ‘disease.’ Combiningtherapeutics at both local and systemic levels to impactboth symptoms and joint structural changes will likely bethe future strategy instead of a sole drug, at least at thebeginning of the treatment.

. Selectively targeting some phenotypes of OA patientsevidenced by sensitive tools, such as MRI, may allow thedevelopment of DMOADs based onpersonalized medicine.

. Clinical trials that would be sufficiently powered,systematically designed and, based on reliable evaluationtechniques, targeting the appropriate categories of OApatients should translate the concept of DMOAD fromdream to reality.

This box summarizes key points contained in the article.

C. Roubille et al.

2060 Expert Opin. Pharmacother. (2013) 14 (15)

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placebo, particularly in the lateral compartment. A reductionin the lateral JSW loss was also evidenced in the FGF-18group compared to placebo. However, no significant symp-tomatic difference between the FGF-18-treated group andplacebo group was observed with regard to the WOMACpain and function scores. Tolerance of the active treatmentwas good and no safety issue was observed. A proof-of-concept Phase II study in patients with acute cartilage injuriesof the knee is ongoing ([5]-NCT01066871).

2.2 Platelet-rich plasma: rationale, primary results in

knee OA, and current issuesAutologous platelet-rich plasma (PRP) is plasma from thepatient’s own blood, in which the platelet concentration isabove baseline values [8]. The rationale for using PRP is thatplatelets contain storage pools of growth factors, includingtransforming growth factor-b (TGF-b), platelet-derivedgrowth factor (PDGF), vascular endothelial growth factor,as well as cytokines, chemokines, and other mediators [9],which are currently thought to accelerate the natural healingprocess and promote cartilage repair after local injection.Moreover, as TGF-b and PDGF can stimulate the prolifera-tion of mesenchymal stem cells (MSCs), these factors maydirect the local mesenchymal and epithelial cells to migrate,divide, and increase collagen and matrix synthesis [10]. Never-theless, the exact mechanism of how PRP could improve car-tilage healing in OA remains to be determined. It is suggestedthat PRP may have an indirect effect by reducing synovialinflammation and modulating cytokinic local environmentor a direct effect by stimulating the chondral anabolism andslowing the catabolic activity [11]. Indeed, growth factors con-tained in PRP may increase expression of the chondrocytephenotype and stimulate the differentiation of MSCs aswell as reduce IL-1 synthesis. Moreover, platelet-releasedgrowth factors may regulate endogenous hyaluronic acid(HA) synthesis [10], which could contribute to its action.

First reports of PRP efficacy in musculoskeletal conditionsconcerned sports- and overuse-related injuries, such as tendi-nitis, acute rotator cuff tears, and knee cartilage lesions [12].Nowadays a growing literature portrays PRP as a simple,low-cost, minimally invasive and promising therapy for kneeOA because of its potential for articular cartilage repair. How-ever, high-quality studies sufficiently powered to support suchpostulate are lacking; indeed, the literature contains mostlyanecdotal reports and case series or studies of small samplesize or uncontrolled studies [13-16]. On the other hand, somestudies compared PRP to HA for ethical reasons, while othersused placebo. Explanation of the data is also complicated by alack of standardization of study protocols, especially PRPpreparation and subsequent variability in platelet concentra-tions, as well as platelet activation status. Some used freshPRP, avoiding cold storage which is thought to potentiallyalter platelet function [11], while others preferred to freezePRP and delay intra-articular injection to assess the sample

quality [17]. Moreover, the role of white blood cell (WBC) fil-tering during PRP preparation remains uncertain as WBCsare not only a source of cytokines and enzymes but can alsorelease proteases and reactive oxygen [17]. Additional issuesare the number and frequency of injections for optimalresults, and for which OA patients this therapy would be themost effective [11]. Future clinical trials are needed to addressthese issues.

A recent prospective study enrolling 150 patients withdegenerative knee cartilage lesions and OA compared50 patients treated with PRP to 50 patients each receivingeither low-molecular-weight HA (LWHA) or high-molecu-lar-weight HA (HWHA) [13]. At 2 months, the PRP groupshowed improvement similar to the LWHA group but moreimprovement than the HWHA group. However, at 6 months,a better benefit in the PRP group was found [13]. Furthermore,PRP in patients under 50 years old with only cartilage lesionsor early OA had better results than LWHA, arguing thatyounger patients with early disease could have a better chanceto benefit from PRP therapy [17]. Spakova et al. [18] also com-pared PRP to viscosupplementation, both injected weekly for3 weeks, in a cohort of 120 knee OA patients (KL grades1 -- 3). Data showed a significantly better improvement inWOMAC and pain intensity numeric rating scale at 3 and6 months in both groups with statistically superior results inthe PRP group. Three main randomized controlled trials(RCTs) in knee OA, two comparing PRP to HA and one com-paring PRP to placebo, have been published so far [11,17,19].Filardo et al. [17] evaluated with various clinical scores 109knee OA patients (KL grades up to 3), 55 treated with HAand 54 with PRP (both 3 weekly injections) at 2, 6, and12 months. PRPs were obtained through a double-spinningprocedure providing a high concentration of platelets but alsocontaining WBCs, and were frozen before injection. Bothgroups improved and no statistical differences were foundbetween HA and PRP patients for all scores. A trend favoringthe PRP group was noted only in patients with low-gradearticular degeneration (KL grade up to 2) at 6 and 12 months.Sanchez et al. [19] compared at short-term follow-up (24 weeks)plasma rich in growth factors (PRGF) (single spinning proce-dure providing WBC-free PRP with a low platelet concentra-tion) with HA, both administered 3 times on a weekly basis.The primary outcome measure was a 50% decrease in kneepain from baseline to week 24. Compared with the rate ofresponse to HA, the rate of response to PRGF was significantat 14.1% points higher. However, no significant differenceswere found between PRGF and HA groups with regard to allsecondary outcomes measured, including WOMAC. Recently,Patel et al. [11] evaluated 78 patients (156 knees) with bilateralknee OA divided into 3 groups, one receiving a single injectionof PRP (WBC filtered), one 2 injections of PRP 3 weeks apart,and one a single injection of saline as placebo control group.WOMAC and Visual Analog Scale (VAS) pain and overall sat-isfaction were measured at 6 weeks, and at 3 and 6 months.Both groups treated with PRP compared to the placebo group

New and emerging treatments for osteoarthritis management

Expert Opin. Pharmacother. (2013) 14(15) 2061

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Table

1.Trials

evaluatingplatelet-rich

plasm

ain

OA

ascu

rrentlylistedonwww.clinicaltrials.gov

[5],April2013.

Country

Intervention

Comparator

Condition

Outcomes

Phase

ClinicalTrials.gov

identifierandstatus

Spain

IAIofPRP

IAIof

corticosteroid

KneeOAdiagnosedbyX-ray

withVASpain

>40/100

n=64

I:VASpain

atM1

II:VASpain,KOOSandSF36

QOLatweek4,M3,M6.

Phase

IIIRandomizeddouble-blind

efficacy

study

NCT01381081

Recruiting

France

IAIofPRP

IAIofHA

Sym

ptomatickneeOA,

BMI20--30

n=80

I:changesin

WOMAC

betw

een

MO

andM3

II:evolutionofpain

atM12

Phase

IIrandomized

double-blind

safety/efficacy

study

NCT01697423

Notyetrecruiting

Israel

IAIofPRP

SubtalarjointOA

n=30

I:changesin

ankle-hindfootscore

for

function/activitylevel1--100atM12

II:VASpain

1--10atM12

Open-labelefficacy

study

NCT01422460

Notyetrecruiting

Israel

IAIofPRP

IAIofHA

KneeOAdiagnosed

for>1year

n=100

I:changesin

pain,function,

QOL,

activityatM12,M24

Phase

II/IIIrandomized

double-blind

safety/efficacy

study

NCT01270412

Notyetrecruiting

Mexico

IAIofPRP

(3injections--

1every

2weeks)

Acetaminophen

(500mg/8

h)

while

PRP

treatm

entlasts

KneeOAKLgrades1,2

n=60

I:changesin

WOMAC

at

M3,M6,M12

II:changesin

VASandSF-12v2

HealthSurveyatM3,M6,M12

Complementedwithin

vitro

experiments

ofhumanOA

cartilageexplantcultures

(treatedwithPRP)forhistological

andgeneexpressionassays

Randomizedopen-label

efficacy

study

NCT01782885

Active,notrecruiting

Korea

IAIofPRP

(2injections,

second4weeks

afterthe

firstone)

EarlykneeOA

(KL£2)+

degenerative

chondropathy

inpatients

whohave

previously

takenmedicationfor>6months

withoutphysicalim

provement

I:changesin

pain

andfunctionat

M2,M4,M6,afterthe2nd

injectionassessedwithVAS,

CKRS,andLK

S

Phase

I/IInonrandomized

open-labelsafety/efficacy

study

NCT01747018

Completed

Italy

IAIofPRP

(3injections

1weekapart

from

each

other)

n=96

IAIofHA

(3injections

1weekapart

from

each

other)

n=96

Kneearticulardegenerative

pathologywithhistory

ofchronic

(>4months)

pain

or

swelling--KLgrades1--3

n=192

I:IKDCsubjectivescore

variationatM12

II:IKDSsubjective(M

2,M6)and

objective(M

2,M6,M12)score

variation;VASGeneralHealthstatus,

KOOS,KneeROM,Tegnerscore,

PatientGlobalsatisfaction,Adverse

Events,kneetranspatellarand

distalquadricepscircumference

variationatM2,M6,M12,VASpain,

swellinglevel,pain

durationand

swellingduration7days

after

each

injection

Phase

IVrandomized

double-blind

safety/efficacy

study

NCT01670578

Ongoing

Althoughanexhaustivelistingofthetrialswasaim

edfor,somemayhave

beeninvoluntary

missed.

CKRS:CincinnatiKneeRatingSystem;HA:Hyaluronic

acid;I:Primary

outcomemeasures;

II:Secondary

outcomemeasures;

IAI:Intra-articularinjection;ICRS:InternationalCartilageRepairSociety

score;

IKDC:InternationalKneeDocumentationCommitteescore;IKS:InternationalKneeScore;KL:

Kellgren-Lawrence;KOOS:Kneeinjury

andOsteoarthritisOutcomeScore;KSS:KneeSociety

RatingSystem;LK

S:Lysholm

KneeScale;M:Month;n:numberofpatients;OA:osteoarthritis;

PBS:phosphate-bufferedsaline;PRP:plasm

a-richplatelets;QOL:

qualityoflife;ROM:rangeofmotion;VAS:VisualAnalogScale;WOMAC:Western

OntarioandMcM

asterUniversitiesOsteoarthritisIndex.

C. Roubille et al.


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http://www.clinicaltrials.gov


had statistically significantly better results within 2 -- 3 weeksand lasting until 6 months. It is noteworthy that all these stud-ies described improvement in pain scores but did not assess car-tilage damage. Several studies are currently ongoing (Table 1),but we found no study that aimed at evaluating the structuralDMOAD effect of PRP. However, given the rationale of usingPRP in OA, partly based on the fact that growth factors mayinfluence cartilage repair through their potential effects onstem cells, PRP may be a future DMOAD. For this reason,investigation of its structural effects in future trials is needed.

2.3 Blocking nitric oxideNitric oxide (NO) contributes to extracellular matrix damagein OA [20]. Inducible NO synthase (iNOS) is responsible forexcessive and sustained NO production by chondrocytes.Selective inhibition of iNOS reduced the progression ofexperimental OA in an animal model [21]. However, a recent2-year RCT (Phase II/III) of an oral iNOS inhibitor (cinduni-stat) showed no superiority of cindunistat over placebo forrate of change in joint space narrowing (JSN) and no effecton pain or function. Only a transient slowing of JSN wasnoted in KL grade 2 OA patients at 48 weeks, which wasnot sustained at 96 weeks of follow-up. No slowing in OAprogression was evidenced in KL grade 3 OA patients [22].

2.4 Regenerative medicine in cartilage repair:

potential for stem cellsThe capacity of adult cartilage to regenerate is limited becauseof its avascular nature. Regeneration of normal cartilage is agreat challenge. Regenerative therapy is based on stem cellsand other tissue-engineering strategies aimed at replacingOA tissue with native-like functional tissue with the sameproperties as normal cartilage. Even though limited clinicaltrial data on the therapeutic impact of stem cells in OA havebeen reported to date, regenerative medicine may be a prom-ising emerging therapy for future OA management. Severaltypes of stem cells may be used: embryonic stem cells(ESCs) and adult stem cells, which are progenitor cells locatedinside differentiated tissues, such as MSCs, induced pluripo-tent stem cells, and in situ chondrogenic progenitor cells(CPCs) [23]. ESCs are pluripotent and immortal stem cells,with the advantage of a potential sustained differentiationinto chondrogenic lineage when stimulated by the growthfactors of the TGF-b family and bone morphogenic protein(e.g., BMP-7), but also the possibility of inducing teratomas.

MSCs may be a promising therapy for OA because of theirmultilineage potential, immunosuppressive activities, andlimited immunogenicity. Bone marrow and adipose tissueare the two main sources of MSCs for cell therapy. MSCsare defined by their plastic adherence property, their pheno-type (positive for CD73, CD90, and CD105 and negativefor hematopoietic markers such as CD11b, CD19, CD34,CD45, and HLA-DR), although no specific marker hasbeen identified, and by their capacity to differentiate into

chondrocytes, osteoblasts, and adipocytes [24]. They are hypo-immunogenic as they express low levels of HLA class I anti-gens and no HLA class II antigens. Hence, an allogeneictransplantation of MSCs does not require HLA matching [25].MSCs can contribute to cartilage repair and protect it fromfurther degradation by two main characteristics relevant tothe therapeutic applications. First, they can differentiateinto chondrocytes in the presence of adequate environmentalfactors such as growth stimuli (TGF-b, FGF, and BMP),transcriptional factors (SOX9, RUNX-2), and physicalparameters. MSCs loaded on a three-dimensional scaffoldwith appropriate stimuli can induce cartilage repair [25]. Sec-ondly, MSCs may possess anti-inflammatory, anti-apoptotic,anti-fibrotic, pro-angiogenic, wound-healing, and immuno-suppressive properties. MSC-mediated immunomodulationis not a constitutive property and requires exposure to pro-inflammatory cytokines (TNF-a, interferon-gamma, IL-1).After activation, immunosuppressive properties are mainlymediated via the secretion of soluble paracrine mediatorssuch as growth factors and cytokines which can inhibit T-and B-cell proliferation and function. This paracrine activitymay prevent or delay the cartilage degradation, especially inearly stages of OA, by favoring a regenerative local environ-ment, regulating immune infiltration and inhibiting localinflammation, as well as stimulating the proliferation andthe differentiation of the remaining progenitors present inthe cartilage [25]. Indeed, it is suggested that MSCs may beused to stimulate the CPCs that are already present in therepair tissue of the OA joint and manipulate them towardcartilage regeneration via differentiation into chondrocytesproducing type II collagen, instead of transplanting cells tocreate cartilage de novo [23]. All these key properties makeMSCs attractive for being considered an innovative therapyfor OA.

Furthermore, Johnson et al. [26] recently demonstrated in amouse model that a small heterocyclic compound called kar-togenin can stimulate endogenous progenitor cells to differen-tiate and proliferate as cartilage-producing chondrocyteswithout any marker for hypertrophic chondrocytes or bonecells. This technique using endogenous stem cells seemsattractive, promoting a (perfect) genetic match and a targetedlocalization, and avoiding external stem-cell delivery.

Hence, whether by means of MSCs or of a chemical com-pound, stimulating the differentiation of one’s own CPCsmight also be a future therapeutic strategy for cartilage repairin OA.

2.4.1 Preclinical and clinical studies using stem cells

in cartilage regenerationThe proof of concept of therapeutic benefit of bone marrowand adipose tissue-derived MSCs (ASCs) has been demon-strated in vivo using experimental animal models of OA.Intra-articular injection of an autologous MSCs in goat jointssubjected to total meniscectomy and resection of the anteriorcruciate ligament resulted in regeneration of meniscal tissue



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and in a delay of cartilage degradation [27]. Similarly, otherencouraging results of transplantation of MSCs in experimen-tal animal models of OA were reported [28,29]. In a mousemodel with early-stage collagenase-induced OA, a singleintra-articular injection of ASCs inhibited synovial inflamma-tion and cartilage destruction [30]. Safety and biodistributionof human ASCs after intra-articular injection have recentlybeen evaluated in severe combined immunodeficiency mice.Interestingly, 15% of these MSCs were detectable in the jointfor the first month and 1.5% engrafted on the long term, atleast 6 months [31].In humans, several studies using autologous MSCs deliv-

ered intra-articularly have been conducted in patients witharticular cartilage defects and OA [25]. However, transitioningthese strategies from filling a small defect in an otherwisehealthy cartilage to resurfacing an entire degraded joint sur-face in late-stage OA may be a real challenge. Hence, resultsfrom studies on cartilage defects should not be extrapolatedto OA [32].Although of limited evidence, some clinical studies

explored the therapeutic impact of stem cells in OA. At first,case reports described transplantation of MSCs through aninvasive approach (surgery) [33,34]. Later, introduction ofautologous MSCs within the joint by intra-articular injection,which represents a less invasive strategy, was reported tobe feasible and safe. Indeed, after intra-articular injection,MSCs are directly implanted in the injured site, which hasbeen suggested to avoid systemic distribution and toxicity aswell as to promote longer survival [31]. Davatchi et al. [35]

recently reported a reduction in pain after an intra-articularknee injection of autologous bone-marrow-derived MSCs(BM-MSCs) in four patients with moderate to severe kneeOA. Emadedin et al. [36] described a case series of six patientswith late knee OA who received an intra-articular injection ofBM-MSCs. Koh et al. [37] evaluated 18 patients with kneeOA who received intra-articular injections of autologousMSCs derived from the adipose synovium of the infrapatellarfat pad combined with PRP. The WOMAC and the VASscores were both significantly decreased after the intervention.However, the latter authors previously reported [38] no signifi-cant difference in the improvement in pain scores betweenknee OA patients who received MSCs plus PRP and thosewho received PRP alone. However, the lack of control groupsin case reports or case series on a small number of patients ham-pers any conclusion from being drawn on clinical efficiency.Stem-cell-based therapies are considered a promising

approach to delay OA progression, administered by intra-articular injection of exogenous stem cells or by harnessingendogenous stem cells for cartilage regeneration. Nevertheless,these preliminary results need to be confirmed with furtherstudies investigating not only the therapeutic potential ofMSCs, which is currently being explored in 14 Phase I/IItrials (Table 2), but also the biodistribution and survival ofMSCs after intra-articular injection as well as the safety ofsuch strategy. Cell therapy meets several challenges related

to cartilage. First, no specific differentiation factors for MSCchondrogenesis are clearly evidenced so far and this can limitthe clinical application of cell therapy. Moreover, to replacethe cartilage defect with a tissue having the same mechanicaland biological properties as native cartilage and achieve carti-lage-to-cartilage integration within the joint surface remain tobe optimized. To address this latter issue, several strategies arebeing developed to improve scaffolds combining MSCs, ade-quate chondrogenic factors, and various biomaterials. Anotherchallenge is to provide an adequate microenvironment ensur-ing the delivery of appropriate signals to stem cells, similar totheir initial niche, to maintain and stabilize their chondro-genic phenotype following implantation. Significant clinicalissues also remain to be addressed such as what type of stemcells, growth factors, and scaffolds should be used, in whichOA patients, and at which stage of the disease. For instance,the optimal MSC source for cell therapy in OA is still notclearly determined. The chondrogenic potential of ASCscompared with BM-MSCs remains controversial, some hav-ing suggested that ASCs may have the greatest chondrogenicpotential [39], while others argued for a lower chondrogenicpotential [40-42]. Nevertheless, ASCs are easier to obtain thanBM-MSCs [43]. Moreover, the influence on the regenerativepotential of stem cells of age, gender, and body weight, as obe-sity has been suggested to reduce the potential of ASCs [44],also have to be taken into account. Finally, the long-term safety of cell therapy also has to be evaluated, with regardto not only general hypothetical risks such as tumorigenesis orinfections, but also local complications such as ossification [40].Several Phase I and II trials are currently investigating thetherapeutic effect of MSCs (Table 2), which should hopefullyanswer some of these questions. Notably, the DMOAD struc-tural effect of such strategy will be assessed by MRI in most ofthe studies. Some clinical challenges and still unaddressedissues may currently temper immediate prospects of usingcell therapy in the near future in OA. Nevertheless, in ouropinion, cell therapy remains a promising emerging and inno-vative therapeutic strategy for OA, provided future researchfocuses on optimizing specific protocols for cartilage regener-ation, and on evaluating benefit-risk ratio, both at preclinicaland clinical levels, based on well-designed RCTs.

3. DMOADs targeting subchondral boneremodeling

Subchondral bone is at the interface between articular carti-lage and trabecular bone. Loss of integrity of the osteochon-dral junction in OA removes the barrier between intra-articular and subchondral compartments, and is associatedwith the invasion of articular cartilage by vascular channelsoriginating from the subchondral bone. A cross-talk betweensubchondral bone and cartilage as well as an increasedsubchondral turn-over was shown to play a key role in thedevelopment of OA and interest in subchondral bone as atherapeutic target is growing [45,46]. At present, the potential

C. Roubille et al.


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Table

2.Trials

evaluatingstem

cellsin

OA

ascu

rrentlylistedonwww.clinicaltrials.gov

[5],April2013.

Country

Intervention

Comparator

Condition

Outcomes

Phase

ClinicalTrials.

govidentifier

andstatus

Iran

IAIofautologous

BM-M

SCs

Case

group:MSCs

injectedatM1,M4after

boneaspirationand

placeboatM6afterfirst

injection

Intra-articularinjectionof

placebo

Controlgroup:placebo

injectedatM1,M4after

boneaspirationand

MSCsatM6afterfirst

injection

KneeOA

diagnosedby

MRI

n=40

Follow-upatweeks2,

6,M3andM6afterfirst

injection

I:WOMAC

+VAS,physical

improvementat2weeks

II:jointsw

elling,jointerythema,

deteriorationofjointfunction,

allergic

reactionatM3

MRIbefore

andatM6

Phase

IIrandomized

double-blind

efficacy

studyvs

placebo

NCT01504464

Completed

Malaysia

IAIofautologous

BM-M

SCsin

HA

(third

injectionofHA

ina

3-w

eeklyinjection

regim

en)


HA

(3-w

eeklyinjection

regim

en)

Mild

tomoderate

knee

OA

n=50

I:cartilagethickness/M

RIat

12months

II:VAS,IKDC

atM1,M3,M6,

M9,M12;progressionofOA

assessedbyX-rays

atM12

Phase

IIopen-label

randomized

efficacy

study

NCT01459640

Recruiting

India

IAIofautologous

BM-M

SCs

KneeOA

KLgrades3,4

n=10

I:WOMAC

pain,atM3,M6,

M12;adverseevents

atM12

II:changesin

MRIwithcartilage

mapping+clinicalim

provement

atM6,M12

Phase

I/II

open-labelsafety/

efficacy

study

NCT01152125

Enrollingby

invitation

Spain

IAIofBM-M

SCs

expandedexvivo

KneeOA

KLgrades2,

3,4

n=12

I:feasibility,safety

atM0,M3,

M6,M12,M24

Clinicalreview,questionnaires

II:efficacy

atM0,M3,M6,

M12,M24

Clinicalexploration,

questionnaires

MRIatM6,M12,M24

Phase

I/II

nonrandomized

open-labelsafety/

efficacy

study

NCT01183728

Ongoing

Spain

IAIofallogenicBM-M

SCs

(healthydonor)

expandedin

vivo


HA

KneeOA

KLgrades2,

3,4

n=30

I:adverseevents

Clinicalreview

andpain,

disability,QOLatM3,M6,M12

II:WOMAC

pain,SF36,QOLat

M0,M3,M6,M12

MRIatM0,M6,M12for

cartilagedegeneration

Phase

I/II

randomized

double-blindsafety/

efficacy

controlled

study

NCT01586312

Recruiting

Mexico

IAIofautologous

BM-M

SCs

Acetaminophen(oral)

KneeOA

KLgrades2,3

n=30

I:safety,WOMAC,KSS,SF36,

VASat1week

II:efficacy,WOMAC,KSS,VAS

at4weeksandM6

Phase

Irandomized

open-labelstudy

NCT01485198

Recruiting


edfor,somemayhave

beeninvoluntarily

missed.

ACR:AmericanCollegeofRheumatology;

BM:bonemarrow;I:primary

outcomemeasures;

II:secondary

outcomemeasures;

IAI:intra-articularinjection;ICRS:InternationalCartilageRepairSociety

score;IKDC:

InternationalKneeDocumentationCommitteescore;IKS:InternationalKneeScore;HA:Hyaluronic

acid;HAQ:HealthAssessmentQuestionnaire;KL:


andOsteoarthritisOutcome

Score;KSS:KneeSociety

RatingSystem;M:month;MRI:Magneticresonance

imaging;MSC:Mesenchym

alstem

cells;n=:numberofpatients;OA:osteoarthritis;

PBS:phosphate-bufferedsaline;PRP:platelet-rich

plasm

a;QOL:

qualityoflife;ROM:rangeofmotion;SAS:Short

ArthritisassessmentScale;SF-36:short

form

(36)healthsurvey;

TKA:totalkneearthroplasty;

VAS:VisualAnalogScale;WOMAC:Western

Ontarioand

McM




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http://www.clinicaltrials.gov


Table

2.Trials

evaluatingstem

cellsin

OA

ascu

rrentlylistedonwww.clinicaltrials.gov[5],April2013(continued).

Country

Intervention

Comparator

Condition

Outcomes

Phase

ClinicalTrials.

govidentifier

andstatus

India

IAIofallogenicMSCs

exvivo

cultured+HA


placebo(plasm

alyte-A)+

HA

KneeOA

KLgrades2,3

n=60

I:adverseevents,safety

atM24

II:WOMAC,X-ray,

MRI

WORMS,VAS,intakeof

analgesics

atM24

Phase

IIrandomized

double-blindsafety/

efficacy

placebo-controlled

study

NCT01453738

Ongoing

Iran

IAIofautologousBM-

MSCs

Ankle

OA

n=6

I:safety

atM2,M6

II:pain

SF-36,function,MRI

defect

atM6

Phase

Iopen-label

study

NCT01436058

Completed

Malaysia

IAIofallogenicexvivo

culturedMSCs+HA


placebo

(plasm

alyte)+HA

KneeOA

KLgrades2,3

n=72

I:adverseeventatM12

II:WOMAC,X-ray,

VAS,MRI

WORMS,intakeofanalgesics

at

M12

Phase

IIrandomized

double-blind

placebo-controlled

study

NCT01448434

Ongoing

China

IAIofadipose-M

SCsat

M0,M1,M3


placebo(PBS)atM0,M1,

M3

KneeOA

diagnosed

withX-ray

n=120

Follow-upat6months

I:WOMAC

atM6

II:adverseevents,KSSatM6

Phase

I/II

open-labelstudy

NCT01809769

Ongoing

Korea

IAIofautologous

adipose-M

SCs

KneeOA

n=18

I:safety,WOMAC

atM24

II:MRI,VAS,KSS,X-ray,

histologicalevaluationsatM24,

arthroscopyatM6

Phase

I/II

nonrandomized

open-labelstudy

NCT01300598

Completed

USA

IAIofautologousadipose

MSCs+PRP

‘currentproven

diagnosisofkneeOA

withconsistent

symptomatology’;

n=500

I:VAS,QOL,

intakeof

analgesics,adverseevents

at

M3,M6

II:Xrays

atM6

Phase

I/II

open-labelstudy

NCT01739504

Recruiting

Spain

IAIautologousBM-

MSCsexpandedexvivo

KneeOA

KLgrades2,3

n=15

I:feasibility,safety

atM12

II:MRIatM6,M12,HAQ,

SF36atM3,M6,M12

Phase

I/II

open-labelstudy

NCT01227694

Ongoing

France

ADIPOA

IAIofautologous

adipose-M

SCs

KneeOA

ACRgrades3,

4(m

oderate

tosevere

medialand/orlateral

tibiofemoralkneeOA

withindicationofTKA)

n=18

I:adverseevents

atM12

II:WOMAC,ROM,MRI,SAS,

QOLatM12

Phase

Inonrandomized

open-labelstudy

NCT01585857

Recruiting


edfor,somemayhave

beeninvoluntarily

missed.

ACR:AmericanCollegeofRheumatology;

BM:bonemarrow;I:primary

outcomemeasures;

II:secondary

outcomemeasures;

IAI:intra-articularinjection;ICRS:InternationalCartilageRepairSociety

score;IKDC:

InternationalKneeDocumentationCommitteescore;IKS:InternationalKneeScore;HA:Hyaluronic

acid;HAQ:HealthAssessmentQuestionnaire;KL:


andOsteoarthritisOutcome

Score;KSS:KneeSociety

RatingSystem;M:month;MRI:Magneticresonance

imaging;MSC:Mesenchym

alstem

cells;n=:numberofpatients;OA:osteoarthritis;

PBS:phosphate-bufferedsaline;PRP:platelet-rich

plasm

a;QOL:

qualityoflife;ROM:rangeofmotion;SAS:Short

ArthritisassessmentScale;SF-36:short

form

(36)healthsurvey;

TKA:totalkneearthroplasty;

VAS:VisualAnalogScale;WOMAC:Western

Ontarioand

McM


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DMOAD effect of anti-osteoporotic agents is currently beingexplored in OA [47].

After promising preclinical findings in OA animal models,particularly in early OA [48,49], clinical trials with bisphospho-nates in human OA have provided mixed results. In a cross-sectional study in postmenopausal women with knee OA,alendronate and estrogen therapy decreased the frequency ofbone marrow lesions (BMLs) detected by MRI, and alendro-nate use alone was associated with less severity of kneepain [50]. In a double-blind 1-year RCT of 284 patients withmild to moderate knee OA, risedronate decreased theWOMAC index but the reduction in JSN was found to benonsignificant compared to placebo [51]. In contrast, a2-year RCT found no significant effect of risedronate onWOMAC index or radiographic progression [52].

While most commonly used osteoporosis treatmentsincluding bisphosphonates act by inhibiting bone resorp-tion, strontium ranelate (SrRan) not only decreases boneresorption but also increases bone formation, and is cur-rently portrayed as the first potential DMOAD. Our groupfound that in vitro SrRan inhibited the resorptive propertiesof human subchondral bone osteoblasts by reducing the syn-thesis of some MMPs and modulating osteoprotegerin(OPG) and receptor activator of nuclear factor-kB ligand(RANKL) levels [53]. SrRan was also reported to stimulatecartilage matrix formation by human chondrocytes in vitro[54]. In vivo, in an experimental dog OA model, therapeuticdosages of SrRan significantly reduced the progression ofOA structural changes and inhibited the expression ofIL-1b and key proteases involved in cartilage degradation [55].Together, these data suggest that SrRan could target thethree major tissues involved in OA, namely the cartilage,subchondral bone, and synovium. In clinical studies, thedrug was found to reduce the radiological progression of spi-nal OA and back pain in women with osteoporosis and OAafter a 3-year treatment [56]. A recent 3-year double-blind,randomized, placebo-controlled Phase III trial, the SrRanEfficacy in Knee Osteoarthritis Trial (registrationISRCTN41323372), demonstrated that treatment withSrRan was associated with a significant protective effect onjoint structure and clinically relevant improvement of symp-toms in patients with knee OA [57]. In brief, the groupstreated with SrRan at both 1 and 2 g/day had less JSN andfewer radiological progressors compared to placebo. In addi-tion, patients treated with SrRan 2 g/day had a greaterreduction in WOMAC total score, as well as pain and phys-ical function subscores, than the placebo. A subgroup ofpatients from that trial was included in a study exploringthe effect of SrRan on cartilage volume loss and BMLs usingMRI [58]. Data showed that SrRan has a beneficial impact onboth cartilage and subchondral bone. As in vitro and in vivodata [53-55] demonstrated that SrRan has combined anti-catabolic and pro-anabolic properties, although speculative,SrRan could have a direct impact on cartilage as well as apositive effect on the cross-talk between subchondral bone

and cartilage. The loss of osteochondral integrity may exposethe cartilage to mediators released from subchondral chan-nels stimulating chondrocytes combined with a possibledirect effect on the chondrocytes and may partly accountfor the impact of SrRan on cartilage loss, in addition to itspreponderant effect on BMLs.

In this line of thought, Roux and Richette [59] recentlyproposed using BMLs seen on MRI as a relevant inclusioncriterion for clinical trials to explore the potential DMOADeffect of bone-acting agents instead of JSN, since the effectseen using X-rays might be irreversible or due to other fac-tors including meniscal extrusion. In a recent MRI study inknee OA patients, the significant reduction in pain andBMLs at 6 months after a single infusion of a zoledronicacid compared to placebo supports this proposal [60]. Hence,selecting patients with early OA and BMLs might be neces-sary in future studies to allow personalized and targetedOA therapy.

The data on the DMOAD properties of SrRan open thedoor to other promising bone pathways to target OA.Hence, targeting the OPG/RANKL system, which is criticalfor bone turn-over [46,61,62] appears interesting. RANKL,localized on osteoblasts, enhances osteoclastogenesis viainteraction with the receptor RANK, localized on osteo-clasts. OPG, produced by osteoblasts, is a secreted decoyreceptor for RANKL that serves as a physiological inhibitorof RANKL-driven osteoclast activities. Data showed thatOPG, RANK, and RANKL are also expressed and producedby human chondrocytes [63], and on human OA chondro-cytes the OPG/RANKL ratio was reduced, whereas theRANK/RANKL ratio was increased [63]. An imbalance inthe OPG/RANKL system, both in synovial fluid and serum,has been associated with OA severity [64]. The pro-resorptive effect of RANKL on the osteoclastogenesis processcould therefore be targeted by the use of either OPG or ananti-RANKL antibody. A study carried out in an experimen-tal mouse model of OA revealed, upon OPG administration,reduced cartilage degradation through an effect on trabecu-lar bone [65]. The potential of RANKL inhibition as aDMOAD is therefore interesting. Denosumab is a fullyhuman IgG2 monoclonal antibody that binds humanRANKL with a high affinity and which has been approvedfor use in postmenopausal osteoporosis [66] and in oncology.By analogy, in rheumatoid arthritis (RA), a Phase II RCTevaluated the effects of denosumab in addition to methotrex-ate (MTX) on structural damage. At 6 months, the increasein the MRI erosion score from baseline was lower in patientsreceiving 60 mg of denosumab and significance reached with180 mg of denosumab compared to placebo [67]. Denosu-mab has not yet been evaluated as a DMOAD.

Cathepsin K inhibitors may also be prospective DMOADs.In preclinical models, cathepsin K inhibition showed benefi-cial effects on protection of subchondral bone loss and againstcartilage degradation, and suggested reduced osteophyteformation [68].



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The use of parathyroid hormone (PTH) as a DMOAD isalso conceivable but not yet evaluated. Recombinant humanPTH (1 -- 34), teriparatide, is a bone anabolic therapy usedfor osteoporosis. In a mouse meniscal/ligamentous injurymodel of knee OA, intermittent teriparatide systemic injec-tions decreased cartilage degeneration and induced matrixregeneration [69].Calcitonin also appears an option. In a Phase IIa RCT in

knee OA [70], oral calcitonin improved the Lequesne’s functionscore, whereas no difference was found in terms of pain reliefcompared to placebo. Moreover, the nasal form of calcitoninwas found to improve WOMAC total score and subscales(pain, stiffness, and function) [71]. This study was limited bythe absence of a control group. A 2-year Phase III trial inknee OA patients resulted in the symptom-modifying efficacyof oral calcitonin with a significant improvement in WOMACpain, function, and stiffness scores compared to placebo. Withregard to structural effects, oral calcitonin did not impact JSW,which was the primary endpoint, but significantly increasedcartilage volume compared to placebo, suggesting somestructure-modifying efficacy [72]. Another Phase III trial wasterminated early, probably due to an imbalance in prostate can-cer events in male subjects, as indicated on the Clinical Trialswebsite ([5]-NCT00704847). Of note, the European MedicinesAgency’s Committee for Medicinal Products for Human Userecommended in 2012 that calcitonin therapy should only beused for short-term periods because of an increased risk for can-cer of 0.7 -- 2.4% with long-term use, especially with intra-nasal calcitonin [73]. This could limit the potential use ofcalcitonin as a DMOAD.Vitamin D supplementation failed to reduce WOMAC

pain or cartilage volume loss as assessed by MRI comparedto placebo in a recent 2-year knee OA trial [74]. AnotherRCT evaluating whether vitamin D supplementation canslow knee cartilage loss assessed by MRI in OA patients isongoing [75].

4. Targeting inflammatory pathways

Several pro-inflammatory cytokines play a pivotal role in OApathogenesis. In particular, IL-1b and TNF-a are key cyto-kines favoring the degeneration of articular cartilage matrix,which makes them prime targets for OA treatment [76].IL-1b stimulates joint tissue to produce several proteasesinvolved in cartilage degradation and reduces the productionof matrix macromolecules such as aggrecan. It was recentlyreported that one IL-1 receptor antagonist (IL-1Ra) haplotypecould be associated with increased OA progression [77].Targeting IL-1b in OA seems a logical approach to slow thedisease progression, either directly with recombinant humanIL-1Ra, antibodies against the cytokine or its specific recep-tor, or through gene therapy as described further on. Intra-articular injection of recombinant human IL-1Ra was foundto be protective against the development of induced OA ina dog model and associated with a reduction in the expression

of some MMPs [78], providing evidence of a role of IL-1 incartilage degradation. However, after a promising pilot clini-cal study [79] reporting that intra-articular injection of ana-kinra (a recombinant non-glycosylated version of the humanIL-1Ra) was well tolerated in 13 OA patients and improvedpain as well as WOMAC total scores through 3 months,Chevalier et al. [80] performed a 12-week double-blind RCTassessing the efficacy of a single intra-articular injection of50 or 150 mg of anakinra versus placebo in 170 patientswith moderate-to-severe knee OA evaluated 4 weeks later.Anakinra was found to be safe and well tolerated. Patientstreated with anakinra showed no significant difference versusplacebo in score change from baseline to week 4 in theWOMAC index. However, significant short-term pain reliefwas evidenced at day 4 with the 150 mg anakinra injectioncompared to placebo. In this study, several factors couldhave negatively impacted the evaluation of treatment responsesuch as the inclusion of patients with low-level pain at base-line, the short half-life of the drug, suggesting that repeatedinjections are necessary to obtain a sustained symptomaticeffect, and a strong placebo effect. Of note, the structuraleffect of such strategy has not been investigated and theabsence of symptomatic effect does not mean absence of struc-tural effect. In contrast, 3 months of daily subcutaneous injec-tions of anakinra in three patients with erosive hand OAshowed improvement of pain and disability [81]. Additionally,a double-blind, placebo-controlled RCT using a systemicadministration of a monoclonal antibody (AMG 108)directed against the functional type 1 receptor of IL-1 demon-strated no significant difference in the level of pain at 6 weekswhen compared to the placebo [82]. However, a trend towardefficacy favoring AMG 108 was found in patients with high-baseline WOMAC pain [83]. Additionally, although no differ-ence in the incidence of serious infections related to thereduction of neutrophil count was seen compared to placebo,such biological therapy may expose patients to serious adverseevents [83].

Briefly, most of the studies so far have failed to show abeneficial symptomatic effect of IL-1b inhibition in OA.However, a Phase II proof-of-concept study assessing the effi-cacy and safety of subcutaneous injections of gevokizumab, apotent anti-IL-1b antibody, compared to placebo, in thetreatment of active erosive OA of the hand, is currently enroll-ing ([5]-NCT01683396). Another study on the safety andeffect on pain of a single intra-articular administration of can-akinumab, an anti-IL-1b monoclonal antibody, in patientswith knee OA is completed but not yet published ([5]-NCT01160822). Further studies evaluating the effect ofanti-IL-1b, especially of repeated intra-articular injectionsfor instance on a weekly basis, or of biologic agents with sus-tained half-life, are needed before burying the concept ofIL-1 inhibition in OA management [84]. Moreover, as men-tioned above, studies should also evaluate the effect not onlyon pain, but also on the joint structure, which is the targetbenefit that we are looking for.

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Another approach is the intra-articular injection of anautologous anti-proinflammatory cytokine product namedOrthokin, consisting of autologous conditioned serumobtained after incubation with glass beads to induce thesynthesis of various anti-inflammatory cytokines such asIL-1Ra, IL-4, IL-10, and IL-13. Two RCTs provided contro-versial results. On the one hand, the first reported study failedto show any difference between WOMAC and VAS painscore, and Knee injury and Osteoarthritis Outcome Score(KOOS) between Orthokin and saline over 12 months offollow-up [85]. On the other hand, the second demonstratedsignificantly better outcomes compared to saline andHA [86]. Further RCTs will be needed before consideringthis technique in routine practice.

Targeting TNF-a in OA with infliximab and adalimumabhas also been evaluated in a few trials providing conflictingresults. In an open-label pilot trial in 10 patients with erosiveOA of the hands, monthly intra-articular injections of inflix-imab reduced pain in all patients, without adverse reactionsafter 1 year of follow-up [87]. In contrast, another open-label study [88] in 12 patients with erosive hand OA whoreceived subcutaneous injections of adalimumab every2 weeks for 12 weeks showed no improvement in the num-ber of tender joints, grip strength, disability, pain, and globaldisease assessment. However, there was a statistically signifi-cant improvement in the number of swollen joints comparedto baseline. An RCT [89] including 60 patients with erosivehand OA treated with subcutaneous injections of adalimu-mab or placebo every 2 weeks for 12 months failed to dem-onstrate the control of structural damage on radiography assimilar percentages of patients in both groups had eitherdevelopment of new erosions or progression of existing ero-sions. There were also no significant differences betweengroups as regards pain and swelling on palpation, gripstrength, morning stiffness, pain severity score, and func-tion. However, palpable soft tissue swelling in interphalan-geal finger joints at baseline was identified as the strongestpredictor of erosive progression in these joints and adalimu-mab was found to halt the erosive progression compared toplacebo in these joints with destructive features on radiogra-phy and palpable effusion [89]. A Phase II study also showedthe lack of efficacy of adalimumab in hand OA [90]. A recentopen-label evaluation of adalimumab for 12 weeks in20 patients with knee OA and clinical effusion reportedthat 70% of the patients achieved an Osteoarthritis ResearchSociety International/Outcome Measures in RheumatologyClinical Trials response at week 12 [91]. In these studies, dif-ferences within results from erosive hand OA and knee OAcould reflect different disease phenotypes.

In conclusion, the current evidence does not support theuse of anti-cytokine therapy in all OA patients. Further trialsare needed, especially with respect to the selection of OApatients who may be speculated to benefit most from suchtherapy [92]. As for strategies targeting subchondral boneremodeling, selecting patients with early OA and synovitis

may be necessary in future studies for targeted and personal-ized OA management. However, the method for selectinginflammatory OA patients, whether only clinically basedwith synovial effusion of a swollen and painful joint, orMRI-based with radiological synovitis, remains to bedetermined.

Another pro-inflammatory cytokine, IL-6, could be oftherapeutic benefit to OA patients, but to our knowledge nostudy has yet assessed IL-6 inhibition in OA.

Emerging data suggest that activated macrophages mayplay a role in the maintenance and progression of OA [93].Once activated, macrophages express the functional form ofthe folate receptor-b (FR-b), and these FR-b macrophagesinfiltrate OA synovial tissues [94]. Therefore, molecules thatcould link the FR-b would specifically target the OA activatedmacrophages expressing FR-b. Thus, an attractive therapeutichypothesis would be to assess such a specifically designed mol-ecule able to modulate the function of the FR-b OA activatedmacrophages as a potential targeted DMOAD.

In OA, inflammation does not seem to affect only thejoints but may also be more systemic than previouslythought. In other words, a low-grade systemic inflammationmay play a critical role in OA pathogenesis. Indeed, recentstudies showing an increased risk of hand OA in obesepatients opened the door to a role of adipokines, inflamma-tory mediators released by adipose tissue. Associationsbetween adipokine concentration and OA severity [95] aswell as with local synovial tissue inflammation [96] havebeen reported. Moreover, OA affects aging patients with sig-nificant comorbidities such as atherosclerosis. It is thustempting to speculate that low-grade inflammation linksthese two diseases, as recently discussed for RA. Hence, atight control of inflammation is recommended to preventcardiovascular disease in RA. Whether immunomodulatoryagents would have beneficial effects on atherosclerosis inOA and RA is open to discussion. Furthermore, in non-arthritis patients, a randomized controlled CardiovascularInflammation Reduction Trial will investigate whetherlow-dose MTX (target dose 20 mg/week) compared to pla-cebo will reduce major vascular events among stable post-myocardial infarction patients with either type 2 diabetesor metabolic syndrome ([5]-NCT01594333). Additionally,another interesting study performed in mice genetically atrisk for Alzheimer’s disease showed that induced OA couldexacerbate and accelerate the development of neuroinflam-mation [97]. Based on these results, it was hypothesizedthat systemic low-grade inflammation during metabolicsyndrome (obesity, insulin resistance, lipid abnormalities,and hypertension) or aging could initiate and/or perpetuatethe OA process via inflammatory mediators such as adipo-kines and cytokines [98]. Once activated, OA joint cellsmight in turn release inflammatory mediators into thejoint and the blood stream, increasing the low-gradeinflammation, which can induce other conditions, such asAlzheimer’s and cardiovascular diseases. This systemic



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low-grade inflammatory concept needs to be considered forfurther studies in OA.

5. Gene therapy in OA

Gene therapy is a promising specific and selective technologythat aims at transferring anti-arthritic genes to tissues by intra-articular injection using various different vectors and based ondirect, in vivo, and indirect, ex vivo, strategies, or implant.The advantages of gene therapy are to allow local and sus-tained delivery of therapeutic gene products to a small num-ber of target joints, and to avoid exposing non-target organsto the drug and subsequent adverse events [99].The induction of expression of anti-inflammatory cyto-

kines and growth factors using gene transfer may providean attractive approach for the treatment of OA. The first tar-get to be investigated in ex vivo gene therapy for both OAand RA was human IL-1Ra. It was shown that the localincrease of IL-1Ra production by intra-articular injectionof either transduced synovial cells [100] or a plasmid vectorand lipids [101] reduces the progression of OA-inducedlesions. The efficacy of gene transfer of IL-1Ra was also dem-onstrated in several RA animal models [102,103]. The firstclinical study of IL-1Ra gene transfer was performed byEvans et al. [104] by injection of autologous synovial fibro-blasts into metacarpophalangeal joints of nine femalepatients with RA scheduled for joint replacement surgeryshortly after transplantation. This study confirmed the feasi-bility and safety of such gene transfer into human joints [105]

and paved the way for further studies, especially in OA. Asproposed by Evans et al. [99], OA seems to be a better targetthan RA for intra-articular gene therapy, as it affects a lim-ited number of joints, without any extra-articular involve-ment. Another ex vivo gene delivery therapy in OA, namedTissueGene-C, based on retrovirally transduced allogenichuman chondrocytes expressing TGF-b, was assessed in aPhase I study in OA patients prior to total knee arthro-plasty [106]. There was no serious adverse event reported.Phase II studies are currently ongoing ([5]-NCT01671072and NCT01825811), exploring its effects on symptoms aswell as on cartilage as assessed by MRI.In vivo gene delivery therapy using adenoassociated virus

(AAV) vectors is emerging, given the advantages of AAV,which are non-integrating viruses that do not generate anydisease, and have low immunogenicity [99]. AAV may providean effective and safe in vivo gene-delivery techniquein OA [107], especially with self-complementing viruses(scAAV) [108]. Recently, Watson et al. [109] demonstrated, ina horse model, a successful transduction of the synovial fibro-blasts and of chondrocytes using scAAV vector encoding forhuman IL-1Ra injected in larger joints similar in size tohuman joints. Evans et al. [99] are currently developing anin vivo gene therapy using recombinant scAAV to deliverIL-1Ra cDNA into OA joints.

6. Perspectives: microRNAs and smallinterfering RNA-based therapeuticapproaches in OA

RNA interference and microRNAs (miRNAs) are excitingapproaches for the future treatment of OA by targetingcartilage repair genes and are expected to be part of the nextgeneration of OA therapeutic agents. Small interferingRNAs (siRNAs) can silence gene activity and specifically tar-get intracellular pathways. They can be delivered into thecell cytoplasm by mechanical means or using lipid-based for-mulations or expression vectors encoding short hairpinRNA [110]. However, siRNA-based therapy is still at an exper-imental stage in rheumatic diseases, especially in OA. As forgene therapy, the challenge of siRNA-based therapy is tolocally deliver the selective product to the specific cell typesin sufficient concentrations and in a sustained fashion toensure efficiency while avoiding not only off-target effectsbut also potential systemic toxicity [110]. Using OA animalmodels, two studies demonstrated positive effects of such anapproach [111,112]. Also proposed is to target monocytesthrough delivery of a combination of an anti-inflammatorysiRNA with an anti-osteoclastogenic siRNA to reduce bothsynovitis and bone resorption in RA and possibly in OA [110].

An additional field of research in OA concerns miRNAs,which are small noncoding RNA molecules naturally pro-duced by cells, which regulate posttranscriptional gene expres-sion [113]. The recognition that some miRNAs may play acentral role in cartilage and its dysregulation in OA providesa potential therapeutic target. Recently shown was that thedownregulation of miR-194 stimulated chondrogenic differ-entiation of human ASCs by increasing the expression ofits direct target gene SOX5, a key transcription factor forcartilage differentiation. Also found was that miR-194 wasupregulated in IL-1b-induced OA and associated with adecrease in SOX5 expression, suggesting that miR-194 andSOX5 could be targets for OA therapy [114]. Additionally,miR-140 was found decreased in human OA cartilage in com-parison to normal cartilage [115] and this miR is a direct regu-lator of the insulin-like growth factor-binding protein-5(IGFBP-5) [115] and ADAMTS5 expression. Transgenicmice overexpressing miR-140 in cartilage were resistant toantigen-induced arthritis [116]. Data also showed that anothermiR, miR-27a, indirectly downregulates both MMP-13 andIGFBP-5 in human OA chondrocytes [115]. Furthermore, inIL-1b-stimulated OA chondrocytes, miR-146a was found tobe upregulated [117]. Hence, it is suggested that administrationof both miR-140 and miR-146 into the joint might be anovel therapeutic target in early OA [118]. Other miRNAshave been found to act on different targets involved in OApathophysiology; however, more data are needed.

The challenge of in vivo applications is the difficulty ofdelivering siRNAs and miRNAs into cells such as chon-drocytes [118]. Nevertheless, even if there is currently onlylimited information on miRNA expression and function in

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the musculoskeletal system, proof-of-concept studies inpreclinical models can be expected in the near future [119].

7. Conclusion

Recent advances in the field of OA pathogenesis have eluci-dated the key roles of several pathways which can be targeted.A relevant step toward identifying new targets is to considerthat OA is not only a dynamic process involving the mainarticular tissues (cartilage, subchondral bone, and synovialmembrane) but also a systemic disease with low-grade inflam-mation. Promising emerging therapies include biologicalagents such as autologous stem cells, PRP, interleukin-1 inhib-itors, as well as bone remodeling modulators such as SrRan,and gene therapy. Future trials on DMOADs might succeedin bridging the gap between symptomatic drugs and surgery.

8. Expert opinion: toward targetedpersonalized medicine in OA

No DMOAD has yet been approved, whereas OA representsa huge unmet medical need worldwide in an aging popula-tion. Moreover, one should keep in mind that OA can alsooccur at younger ages, for example, in patients with inflam-matory rheumatic disorders or as a result of sports injuries.Based on the promising studies on different drugs and innova-tive techniques (e.g., MRI) to evaluate the joints, we can hopeand speculate that the treatment landscape of OA is about tochange, as it has in the past decade for RA and osteoporosis.The key concept to manage DMOAD development will beto target patients selectively according to the drug propertiesbecause OA, like other pathologies, is a heterogeneous diseaseand not all OA patients will respond to a sole drug. Indeed,for maximal benefit, a next step in DMOAD research is likelyto evaluate a drug in patients in whom specific features as wellas disease stage have been identified. It is unlikely that therewill be a sole powerful DMOAD molecule that will benefitthe general OA population, being effective on symptomsand on structural damage, which would be evaluated onlyusing radiographic changes (reduction of JSN). It seemsmore conceivable that future RCTs will demonstrate that amolecule has preferential DMOAD effects in some pheno-types of OA patients evidenced with sensitive techniquessuch as MRI, at a particular stage of the disease. This impliesthat future RCTs will need to select candidates in whom itwould be relevant to evaluate a DMOAD, focusing on a pre-determined population of OA patients. For instance, focusingon patients at higher risk of progression would probably bemore relevant while improving the probability of demonstrat-ing a beneficial effect.

It is our belief that for DMOAD development, MRIappears to be the most sensitive and reliable technique toselect patients for enrollment, to investigate the effect on car-tilage volume changes, BMLs, and synovitis in a sole exam,and to help identify predictive factors of treatment

responsiveness. Solutions to evaluate knee MR images haveprogressed at a rapid rate during the last decade and fullyautomated systems for quantifying cartilage, BMLs, osteo-phytes, synovial fluid, and bone volume and their changesover time have already been developed [120-123].

The therapeutic concepts aiming at targeting specific fea-tures of OA such as BMLs or synovitis, using locally deliveredchemical or biological agents, might seem contradictory to theconcept of a global therapeutic approach supporting systemicstrategies. Targeted and systemic strategies are not necessarilyconflicting but may be complementary and perhaps com-bined. Indeed, it is now well established that OA is not onlycartilage driven but rather a whole joint disease involvingother articular tissues. On a larger scale, OA often affectsseveral joints at the same time and therefore needs a moresystemic approach. Moreover, the role of low-grade inflam-mation, if proven, would argue for a global systemic manage-ment of OA. Thus, with the advent of DMOADs, physicianswould not treat a ‘disease’ but rather a ‘patient’ in acomprehensive way.

Another challenge in DMOAD development is to bothrelieve pain and arrest joint structural progression. It seemsboth desirable and desired (notably by the regulatory authori-ties), but unlikely, that a sole DMOAD will have this abilityto reduce pain in the very short term. A combination of twotherapeutic strategies would seem more conceivable, at least atthe beginning of the treatment, as one would expect that if aDMOAD can stop the disease progression, pain relief willensue. Further research to understand the underlying pathwayslinking pain, joint function, and structural progression in OA ismandatory. Moreover, safety concerns of long-term OA man-agement with DMOADs need to be taken into account.

For some of the agents discussed in the present review,adverse events, theoretical risks, or concerns have beendescribed, either in OA or in osteoporosis management:potential increased risk of cancer (very rare) with long-term use of calcitonin, atypical femoral fractures withbisphosphonates, hypocalcemia and risk of infections withdenosumab, cardiovascular, venous thromboembolism, andcutaneous adverse reactions with SrRan [73], in addition tothe well-known risks of TNF inhibitors such as infections,and the theoretical risks of infections with all intra-articular injections. Regarding MSC-based therapy, very fewadverse events have been reported to date. In a recent system-atic literature review [124], the most serious adverse events wereone infection and one pulmonary embolism probably relatedto bone marrow aspiration, and two unrelated tumors. How-ever, caution should be exercised regarding the inherenttheoretical risks of tumor development with such strategy.Increased pain and swelling were the main other adverseevents. Long-term safety studies for PRP are also needed,even if minimal risks of immunogenicity or tumor areexpected given that PRP is prepared from autologous serum.

In our opinion, SrRan is currently the most promisingagent with some evidence of DMOAD structural effect.



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However, the European Medicines Agency recently recom-mended that the use of SrRan be restricted based on an anal-ysis of pooled data from randomized studies in around7500 postmenopausal women with osteoporosis, showing anincreased risk of myocardial infarction compared with placebo(relative risk 1.6; 95% CI 1.07 -- 2.38). No increased risk ofmortality was observed [125].DMOAD treatment is mostly aimed at an older population

than RA patients. A single future or emerging DMOAD willunlikely be appropriate for all OA patients, partly consideringthe influence of age, weight, disability, and other comorbid-ities such as cardiovascular diseases. Hence, it would seemmandatory to determine the long-term safety of new andemerging OA treatments and to evaluate benefit-risk ratio.With regard to SrRan, further RCTs specifically designedand sufficiently powered should assess not only the cardiovas-cular risk of OA patients treated with SrRan, but also the car-diovascular risk of OA patients in general, independent of thetreatments they receive, as there is less evidence in this condi-tion than in RA or psoriasis for example. In the meantime, thelegal restrictions and contraindications must be followed, butwe should not, however, definitively bury the concept ofSrRan as a DMOAD because of these concerns which needto be confirmed. More precisely, those adverse events shouldalso be counterbalanced with the wide and more frequentadverse events, including cardiovascular events, of currentlyused treatments in OA management such as nonsteroidalanti-inflammatory drugs, corticosteroids, and analgesics,especially in older patients.

Obviously, in the development of novel DMOADs, con-sideration should be given to the cost of such management,including the cost of a pre-therapeutic MRI to predictwhether the given DMOAD is likely to succeed, and thecost of the biologic agents, gene therapy, or stem cell therapydescribed above. OA is considerably more prevalent than RAand osteoporosis, and given the current lack of effective struc-tural treatment for OA, it is more than likely that physicianswill largely be tempted to use a newly available DMOADwhich will be demonstrated both effective and safe. Thisis likely to create a significant expense which cannot beneglected. On the other hand, the cost of the disease itself,both from a societal and individual patient perspective, isalso considerable including, in particular, indirect costsrelated to inactivity and reduced work efficacy as well as costsfrom surgical management. Therefore, developing adequate(targeted) DMOADs will be crucial to reduce the medicaland economic burden of such a major public health problem.

In conclusion, an exciting and promising new era inDMOAD development may be within reach, provided thatfuture clinical trials are sufficiently powered, systematicallydesigned, use the right evaluation techniques, and target theappropriate, more homogeneous, categories of OA patients.

Declaration of interest

The authors state no conflict of interest and have received nopayment in preparation of this manuscript.

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125. Available from: http://www.ema.europa.

eu/ema/index.jsp?curl=pages/

news_and_events/news/2013/04/

news_detail_001774.

jsp&mid=WC0b01ac058004d5c1

C. Roubille et al.


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http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/04/news_detail_001774.jsp&mid=WC0b01ac058004d5c1






AffiliationCamille Roubille1, Jean-Pierre Pelletier2 &

Johanne Martel-Pelletier†3

†Author for correspondence1Research Fellow,

University of Montreal Hospital Research Centre

(CRCHUM), Osteoarthritis Research Unit,

1560 Sherbrooke Street East, Montreal,

Quebec, Canada2Professor of Medicine,

University of Montreal; Director,

Rheumatic Diseases Unit,

Department of Medicine,

University of Montreal;

Head, Arthritis Division, University of Montreal

Hospital Centre (CHUM);

Head, Chair in Osteoarthritis of the University of

Montreal; Director, Osteoarthritis Research Unit,


(CRCHUM), 1560 Sherbrooke Street East,

Montreal, Quebec, Canada3Professor of Medicine,

University of Montreal; Head, Chair in

Osteoarthritis of the University of Montreal;

Director, Osteoarthritis Research Unit,


(CRCHUM), 1560 Sherbrooke St. East, Y-2616,

Montreal, Quebec, H2L 4M1,

Canada

Tel: +514 890 8000, ext. 26658;

Fax: +514 412 7583;

E-mail: [email protected]



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mailto:[email protected]


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