Medicographia115 PDF

Vol 35, No.
2, 2013
Medicographia
115
A Ser vier publication
Osteoarthritis: a story of
close relationship between
bone and cartilage
E DITORIAL
139 Osteoarthritis: new approaches
Arthrose : nouvelles approches
M. C. Hochberg, USA
T HEMED ARTICLES
145 Epidemiology of osteoarthritis
C. Cooper, E. Dennison, M. Edwards, A. Litwic, United Kingdom
152 Osteoarthritis and comorbidities

L. I. Alekseeva, E. L. Nasonov, Russia
158 Osteoarthritis pathophysiology: similarities and dissimilarities with other

rheumatological diseases and the role of subchondral bone
J. A. Roman-Blas, G. Herrero-Beaumont, Spain
164 Role of imaging in osteoarthritis: diagnosis, prognosis, and follow-up

A. Guermazi, F. W. Roemer, H. K. Genant, USA and Germany
172 Osteoarthritis treatments: where do we stand at the moment?

C. Roubille, J. Martel-Pelletier, J. P. Pelletier, Canada
181 Knee replacement for osteoarthritis: facts, hopes, and fears

L. S. Lohmander, Sweden and Denmark
189 Disease-modifying osteoarthritis drugs (DMOADs): what are they and

what can we expect from them?
A. J. Barr, P. G. Conaghan, United Kingdom
197 The economic weight of osteoarthritis in Europe

M. Hiligsmann, J. Y. Reginster, The Netherlands and Belgium
Contents continued on next page

Vol 35, No. 2, 2013
Medicographia
115
C ONTROVERSIAL QUESTION
203 Can normal age-related changes in cartilage be distinguished from early
osteoarthritic changes?
Kingdom - S. Blkba i, Turkey - O. P. Bortkevych, Ukraine - P. Hork,

L. A. Alekseeva, Russia - J. P. A. Arokoski, Finland - F. N. Birrell, United
Czech Republic - A. El Maghraoui, Morocco - A. Mahmoud Ali Elsayed,

Egypt - A. Migliore, Italy - T. Pap, Germany - J. del Pino-Montes, Spain -
C. A. F. Zerbini, Brazil
I NTERVIEW
216 Nonpharmacological treatments in osteoarthritis
E. Kon, Italy
F OCUS
221 Long overlooked: the role of subchondral bone in osteoarthritis
pathophysiology and pain
D. M. Findlay, Australia
U PDATE
228 Clinical research in osteoarthritis: whats new?
X. Chevalier, F. Eymard, France
A TOUCH OF F RANCE
237 Cinema, science, and medicine in France
C. Rgnier, France
246 Children of the Cinmathque

I. Spaak, France
EDITORIAL
In early phases of OA, there

are anabolic changes in both ar-
ticular cartilage and subchondral
bone. In the former, there is in-
creased synthesis of matrix mole-
cules while, in the latter, there is
activation of the bone remodel-
Osteoarthritis:
ing cycle. With progression of OA,
catabolic changes dominate in the
new approaches
articular cartilage with increased
synthesis of tissue-destructive en-
zymes including matrix metallopro-
teases (MMPs), and disintegrins
and MMPs with thrombospondin
motifs.
by M. C. Hochberg, USA
steoarthritis (OA) is a disease of the total joint, not just the articular car-
O tilage. The Osteoarthritis Research Society International Disease State

Working Group defined OA as a progressive disease representing the
failed repair of joint damage that, in the preponderance of cases, has
been triggered by abnormal intra-articular stress.1 They noted that all tissues of the
joint are involved, including not only the articular cartilage, but also the subchondral
bone, ligaments, periarticular structures, and menisci, when present. The results of
the OA process are cartilage degradation and bone remodeling; these features are
associated with the development of symptoms of pain, stiffness, and functional dis-
ability. In this current concept of OA, the structural changes represent the disease
Marc C. HOCHBERG, MD, MPH while the symptoms of aching, discomfort, pain, and stiffness represent the illness
Professor of Medicine and for which patients seek medical care. This concept has profound implications for
Epidemiology and Public Health
University of Maryland School treatment: while there are drugs currently approved for treating the illness of OA,
of Medicine, Baltimore there are none currently approved for slowing the structural progression of OA.
Maryland, USA
Osteoarthritis (OA) is the most common form of arthritis, and is a major cause of
morbidity, activity limitation, physical disability, excess health care utilization and re-
duced health-related quality of life, especially in people aged 45 and above in de-
veloped countries.2 The incidence (risk of developing the disease) and prevalence
(proportion of persons with the disease) of OA increase with advancing age in both
sexes. In general, women have a higher incidence and prevalence of symptomatic
radiographic OA, particularly in the hands and knees. There are ethnic and racial
differences in the occurrence of OA that may be due to genetic and/or lifestyle fac-
tors; these include the lower prevalence of hand and hip OA in Chinese and the
higher prevalence of hip and knee OA in African Americans compared with whites.3
It is now recognized that OA is not only a cause of pain and physical dysfunction,
but is also associated with excess mortality.4,5 Losina and colleagues reported that
the presence of knee OA, especially when combined with the presence of obesi-
Address for correspondence:
ty, was associated with the loss of 3 to 4 quality-adjusted years of life.4 Neusch
Professor Marc C. Hochberg, and colleagues, in analyzing data from a 15-year prospective cohort study in the
MD, MPH, c/o Division of United Kingdom, reported that persons with symptomatic hip and/or knee OA had
Rheumatology, University of Maryland
School of Medicine, 10 S. Pine St., a 50% increase in all-cause mortality compared with that expected based on their
MSTF 8-34, Baltimore, Maryland age and gender distribution.5 Risk factors for all-cause mortality included not only
21201, USA (e-mail: mhochber@
medicine.umaryland.edu)
the presence of comorbid conditions such as cardiovascular disease, cancer, and
diabetes, but also the presence of walking disability. This suggests that an approach
Medicographia. 2013;35:139-144.
to reducing walking disability in patients with symptomatic lower limb OA might not
www.medicographia.com only improve quality of life, but also prolong survival.
Osteoarthritis: new approaches Hochberg MEDICOGRAPHIA, Vol 35, No. 2, 2013 139
EDITORIAL
Much research has focused on the role of obesity, joint injury, of the spinal cord underlying both primary and secondary hy-
and genetic predisposition as risk factors for the development peralgesia. In addition, there is central sensitization, manifest-
of OA.6-8 Metabolic syndromethe phenotype characterized ed by lower pressure pain thresholds and higher pain sum-
by abdominal obesity, dyslipidemia, hypertension, and type 2 mation scores. The mechanisms of central sensitization in OA
diabetes mellitus due to insulin resistanceis associated with may be due to spinal hyperexcitability coupled with defective
OA; this association may be mediated by the production of descending inhibitory noxious control pathways. Functional
circulating adipokines and accumulation of age-related gly- MRI studies in patients with chronic OA pain have demon-
cation end products in articular cartilage.6 While the heritability strated atrophy in the thalamus and gray matter of pain-re-
of OA has been recognized for over 60 years, only in the past lated cortical areas, which is partially reversible after total joint
decade, with the development of commercially available geno- arthroplasty.
typing platforms, have scientists been able to perform genome-
wide association studies examining the association of sin- The management of patients with OA continues to evolve with
gle nucleotide polymorphisms (SNPs) with OA.8 The largest more evidence supporting the efficacy of nonpharmacologic
consortium to investigate the association of SNPs with radio- modalities as well as the approval and study of newer phar-
graphic and clinical OA is Translational Research in Europe macological modalities, including biologic agents.16 The Amer-
Applied Technologies for OsteoArthritis (TreatOA); indeed, the ican College of Rheumatology published new recommenda-
TreatOA website (http://www.treatoa.eu/publications.html) tions for the medical management of OA of the hand, hip, and
currently lists more than 50 peer-reviewed articles on the re- knee in 2012.17 Nonsteroidal anti-inflammatory drugs (NSAIDs)
sults of genetic studies in OA. remain the cornerstone of oral therapy for pain in patients with
OA, despite their association with potential serious adverse
The interplay between the articular cartilage and subchondral events including gastrointestinal bleeding from complicated
bone in the pathophysiology of OA has been increasingly rec- ulcers and small and large bowel lesions, and cardiovascular
ognized over the past decade and is a major focus for current thrombotic events, especially myocardial infarction. Patients
research into the development and progression of OA.9-11 In who have an inadequate response to or are unable to toler-
early phases of OA, there are anabolic changes in both artic- ate oral NSAIDs may be treated with intra-articular agents
ular cartilage and subchondral bone. In the former, there is in- such as glucocorticoids and hyaluronates and/or centrally act-
creased synthesis of matrix molecules while, in the latter, there ing analgesics such as tramadol, duloxetine, and opioids. The
is activation of the bone remodeling cycle. With progression efficacy of duloxetinea serotonin norepinephrine reuptake
of OA, catabolic changes dominate in the articular cartilage inhibitor that can be used either alone or as an adjunct to acet-
with increased synthesis of tissue-destructive enzymes in- aminophen or NSAIDssupports the observations summa-
cluding matrix metalloproteases (MMPs), and disintegrins and rized above that demonstrate the role of central sensitization
MMPs with thrombospondin motifs. Accompanying changes in chronic OA pain due to loss of diffuse inhibitory noxious
in the subchondral bone include trabecular thinning leading to control.
relative osteopenia below areas of sclerosis due to thickening
of the cortical plate. These changes are mediated, in part, by There remains an unmet need for both more efficacious treat-
the diffusion of small molecules between bone and cartilage, ments for pain and agents that are capable of modifying the
including cytokines, angiogenic growth factors, and MMPs. rate of structural progression in OA. Tanezumab, a monoclon-
al antibody directed against nerve growth factor, has demon-
Another component of the OA process that has received in- strated efficacy in patients with hip and knee OA with mod-
creasing recognition is the role of synovitis.12,13 Studies have erate-to-severe pain.18 However, the development of this agent,
demonstrated increased expression of genes that encode cy- and of other compounds in its class, has been placed under
tokines (such as interleukin-1 and 15), chemokines, and MMPs clinical hold by the US Food and Drug Administration (FDA)
in synovial fibroblasts. Synovitis, as measured on magnetic res- because of reports of osteonecrosis adverse events that were
onance imaging (MRI) and/or ultrasound, is associated with eventually adjudicated to be rapidly destructive OA involving
both pain and structural progression; it is not known, howev- not only index joints such as the hip and knee, but also non-
er, whether specific anti-inflammatory therapy is more effica- index joints such as the shoulder. Further studies of the mech-
cious in patients with synovitis than in those without it.
SELECTED ABBREVIATIONS AND ACRONYMS
Synovitis is but one feature of OA that is associated with pain;
others include the presence of moderate-to-large bone mar- MMP matrix metalloprotease
row lesions and joint effusions. Studies of the mechanisms of MRI magnetic resonance imaging
pain in OA have increasingly explored the nature of OA pain NSAID nonsteroidal anti-inflammatory drug
and the role of peripheral and central sensitization superim- OA osteoarthritis
posed on peripheral nociception.14,15 Peripheral sensitization SNP single nucleotide polymorphism
has a spinal component with signal amplification in neurons
140 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Osteoarthritis: new approaches Hochberg
EDITORIAL
anism underlying these joint-related serious adverse events width compared with placebo in subjects with knee OA fol-
are needed to assess the risk-benefit relationship of this prom- lowed for a mean of 30 months.19 Similar results were noted
ising treatment for pain in patients with OA. when subjects were classified as progressors based on a
decline in joint space width of at least 0.5 mm.20 Another ap-
There have been many studies involving potential disease- proach to disease modification is the application of principles
modifying OA drugs (DMOADs); however, there are no agents of regenerative medicine with endogenous stem cells.21 It is
that are approved at this time by either the FDA or European hoped that the results of basic biomedical, clinical, and trans-
Medicines Agency (EMA) for this indication. Recent data sug- lational research will provide new approaches to the manage-
gest that oral strontium ranelate, at doses of either 1 or 2 g ment of patients with OA during the remaining years of this
per day, significantly reduced the rate of decline in joint space and future decades. I
References
1. Lane N, Brandt K, Hawker G, et al. OARSI-FDA initiative: defining the disease symptoms of osteoarthritis. Nat Rev Rheumatol. 2010;6:625-635.
state of osteoarthritis. Osteoarthritis Cartilage. 2011;19:478-482. 13. Scanzello CR. Pathologic and pathogenic processes in osteoarthritis: the ef-
2. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of fects of synovitis. HSS J. 2012;8:20-22.
arthritis and other rheumatic conditions in the United States. Arthritis Rheum. 14. Mease PJ, Hanna S, Frakes EP, Altman RD. Pain mechanisms in osteoarthritis:
2008;58:26-35. understanding the role of central pain and current approaches to its treatment.
3. Jordan JM: Impact of race/ethnicity in OA treatment. HSS J. 2012;8:39-41. J Rheumatol. 2011;38:1546-1551.
4. Losina E, Walensky RP, Reichmann WM, et al. Impact of obesity and knee 15. Schaible HG. Mechanisms of chronic pain in osteoarthritis. Curr Rheumatol
osteoarthritis on morbidity and mortality in older Americans. Ann Intern Med. Rep. 2012; 14:549-556.
2011;154:217-226. 16. Hochberg MC. Osteoarthritis year 2012 in review: clinical. Osteoarthritis Carti-
5. Nuesch E, Dieppe P, Reichenbach S, Williams S, Iff S, Juni P. All cause and dis- lage. 2012. 20:1465-1469.
ease specific mortality in patients with knee osteoarthritis: population based 17. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology
cohort study. BMJ. 2011;342:d1165. 2012 recommendations for the use of nonpharmacologic and pharmacologic
6. Zhuo Q, Yang W, Chen J, Wang Y. Metabolic syndrome meets osteoarthritis. therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 2012;
Nat Rev Rheumatol. 2012;8:729-737. 64:455-474.
7. Muthuri SG, McWilliams DF, Doherty M, Zhang W. History of knee injuries and 18. Lane NE, Schnitzer TJ, Birbara CA, et al. Tanezumab for the treatment of pain
knee osteoarthritis: a meta-analysis of observational studies. Osteoarthritis from osteoarthritis of the knee. N Engl J Med. 2010;363:1521-1531.
Cartilage. 2011;19:1286-1293. 19. Reginster JY, Chapurlat R, Christiansen C, et al. Structure modifying effects of
8. Hochberg MC, Yerges-Armstrong L, Mitchell BM. Osteoarthritis susceptibility strontium ranelate in knee osteoarthritis. Osteoporos Int. 2012;23(suppl 2):
genes continue trickling in. Lancet. 2012;380:785-787. S58-S59.
9. Lories RJ, Luyten FP. The bone-cartilage unit in osteoarthritis. Nat Rev Rheu- 20. Reginster JY, Chapurlat R, Christiansen C, et al. Strontium ranelate reduces the
matol. 2011;7:43-49. number of radiological or radioclinical progressors in patients with primary knee
10. Goldring MB. Articular cartilage degradation in osteoarthritis. HSS J. 2012;8:7-9. osteoarthritis. Osteoporos Int. 2012;23(suppl 2):S366-S367.
11. Weinans H. Periarticular bone changes in osteoarthritis. HSS J. 2012;8:10-12. 21. Marini JC, Forlino A. Replenishing cartilage from endogenous stem cells. N Engl
12. Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical J Med. 2012;366:2522-2524.
Keywords: osteoarthritis, pathophysiology, risk factors, treatment
Osteoarthritis: new approaches Hochberg MEDICOGRAPHIA, Vol 35, No. 2, 2013 141
DITORIAL
Dans les phases prcoces de

larthrose, des changements ana-
boliques interviennent aussi bien
dans le cartilage articulaire que
dans los sous-chondral. Dans le
premier type de tissu se produit
une augmentation de la synthse
Arthrose :
des molcules de la matrice tandis
que dans le second se droule une
nouvelles approches
activation du cycle du remodelage
osseux. Au fur et mesure de la
progression de larthrose, les chan-
gements cataboliques dominent
dans le cartilage articulaire, avec
une augmentation de la synthse
denzymes destructrices des tis-
sus.
par M. C. Hochberg, tats-Unis
L
arthose est une maladie qui affecte la totalit de larticulation, et non pas
seulement le cartilage articulaire. Le Groupe de travail de lOARSI (Osteoar-
thritis Research Society International, la Socit internationale de recherche
sur larthrose) a dfini larthrose de la faon suivante : maladie progres-
sive correspondant une incapacit de rparation des lsions articulaires qui, dans
la majorit des cas, ont t dclenches par des stress intra-articulaires anormaux .1
Il a t observ que tous les tissus de larticulation sont touchs, non seulement le
cartilage articulaire, mais galement los sous-chondral, les ligaments, les structures
priarticulaires et les mnisques lorsquils sont prsents. Le processus arthrosique
conduit une dgradation du cartilage et un remodelage osseux ; ces caract-
ristiques sont associes au dveloppement de symptmes douloureux, de raideur
et dincapacit fonctionnelle. Dans ce concept actuel de larthrose, les altrations
structurelles reprsentent la maladie, tandis que les symptmes type de douleur
sourde, gne, douleur et raideur constituent la pathologie pour laquelle les patients
consultent un mdecin. Ce concept a dimportantes rpercussions sur le traitement :
alors que certains mdicaments sont actuellement autoriss pour le traitement de
la pathologie de larthrose, il nexiste actuellement aucun traitement approuv ra-
lentissant la progression structurelle de larthrose.
Larthrose, la forme la plus frquente darthropathie, est une cause importante de

morbidit, de limitation des activits, dincapacit physique, de surutilisation des soins
de sant et de rduction de la qualit de vie lie la sant, et ce plus particulire-
ment chez les personnes ges de 45 ans et plus dans les pays dvelopps.2 Lin-
cidence (le risque de dvelopper la maladie) et la prvalence (proportion de personnes
atteintes de la maladie) de larthrose augmentent avec lge dans les deux sexes.
Dune manire gnrale, les femmes prsentent une incidence et une prvalence
suprieures darthrose symptomatique radiographique, en particulier au niveau des
mains et des genoux. Il existe des diffrences ethniques et raciales dans la surve-
nue de larthrose, principalement lies des facteurs gntiques et/ou relatifs au
style de vie ; notamment une prvalence plus faible de larthrose des mains et de
la hanche chez les Chinois, et une prvalence suprieure de larthrose de la hanche
et du genou chez les Afro-Amricains par rapport aux blancs.3
Il est dsormais tabli que larthrose provoque non seulement une douleur et un dys-
fonctionnement physique, mais quelle est galement associe un excs de mor-
talit.4,5 Losina et coll. ont indiqu que la prsence dune arthrose du genou, en
particulier en cas dobsit concomitante, tait associe une perte de 3 4 an-
nes de vie ajustes sur la qualit de vie.4 Neusch et coll., qui ont analys les don-
142 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Arthrose : nouvelles approches Hochberg
DITORIAL
nes dune tude de cohorte prospective de 15 ans mene le premier type de tissu se produit une augmentation de la
au Royaume-Uni, ont montr que les personnes prsentant synthse des molcules de la matrice tandis que dans le se-
une arthrose symptomatique de la hanche et/ou du genou cond se droule une activation du cycle du remodelage os-
prsentaient une augmentation de 50 % de la mortalit de seux. Au fur et mesure de la progression de larthrose, les
toute cause par rapport celle prvue sur la base dune dis- changements cataboliques dominent dans le cartilage articu-
tribution par tranche dge et sexe.5 Les facteurs de risque laire, avec une augmentation de la synthse denzymes des-
de mortalit de toute cause comprennent la prsence de co- tructrices des tissus, notamment les mtalloprotinases de la
morbidits, notamment les maladies cardio-vasculaires, le can- matrice (MMP), ainsi que des dsintgrines et des MMP mu-
cer et le diabte, mais galement la prsence dune incapa- nies de motifs thrombospondines. Les changements conco-
cit la marche. Cela suggre quune approche permettant mitants dans los sous-chondral comprennent un amincisse-
de rduire lincapacit la marche chez les patients atteints ment trabculaire provoquant une ostopnie relative sous
darthrose symptomatique des membres infrieurs pourrait les zones de sclrose, lie lpaississement de la plaque cor-
non seulement amliorer leur qualit de vie, mais galement ticale. Ces changements sont assurs en partie par la diffu-
prolonger leur dure de vie. sion de petites molcules entre los et le cartilage, notamment
des cytokines, des facteurs de croissance angiogniques et
Un grand nombre de recherches ont port sur le rle de lob- des MMP.
sit, des lsions articulaires et de la prdisposition gntique
comme facteurs de risque du dveloppement de larthrose.6-8 Un autre composant du processus arthrosique de mieux en
Le syndrome mtabolique un phnotype caractris par une mieux identifi est le rle de la synovite.12,13 Des tudes ont
obsit abdominale, une dyslipidmie, une hypertension et un dmontr une augmentation de lexpression des gnes co-
diabte de type 2 d une insulinorsistance est associ dant pour les cytokines (notamment les interleukines 1 et 15),
larthrose ; cette association pourrait tre due la produc- les chimiokines et les MMP dans les fibroblastes synoviaux.
tion dadipokines circulantes et laccumulation de produits ter- La synovite, mesure par imagerie par rsonance magntique
minaux de glycation lis lge dans le cartilage articulaire.6 (IRM) et/ou chographie, est associe la fois la prsence
Si la transmission hrditaire de larthrose est reconnue de- de douleurs et une progression structurelle ; il na cepen-
puis plus de 60 ans, ce nest quau cours de la dernire d- dant pas t tabli si un traitement anti-inflammatoire sp-
cennie que les scientifiques, grce la disponibilit dans le cifique tait plus efficace chez les patients atteints de syno-
commerce de plates-formes de gnotypage, ont t en me- vite que chez ceux qui ne ltaient pas.
sure deffectuer de larges tudes dassociation sur lensemble
du gnome, en examinant lassociation des polymorphismes La synovite est lune des caractristiques de larthrose as-
nuclotidiques (single nucleotide polymorphisms, SNP) avec socie la douleur ; les autres comprennent la prsence de
larthrose.8 Le plus large consortium ayant explor lassocia- lsions modres importantes de la moelle osseuse et
tion des SNP avec les preuves radiographiques et cliniques dpanchements articulaires. Les tudes des mcanismes de
darthrose est TreatOA (Translational Research in Europe Ap- la douleur dans larthrose explorent de plus en plus souvent
plied Technologies for OsteoArthritis) ; en effet, le site Internet la nature de la douleur arthrosique et le rle de la sensibilisa-
de TreatOA (http://www.treatoa.eu/publications.html) com- tion priphrique et centrale associe la nociception pri-
porte actuellement une liste de plus de 50 articles valus par phrique.14,15 La sensibilisation priphrique a une compo-
des pairs sur les rsultats dtudes gntiques dans larthrose. sante rachidienne saccompagnant dune amplification des
signaux dans les neurones de la moelle pinire, qui sous-tend
Linterconnexion entre le cartilage articulaire et los sous-chon- une hyperalgie primitive et secondaire. En outre, il existe une
dral dans la physiopathologie de larthrose a t confirme au sensibilisation centrale, qui se manifeste par labaissement
cours de la dernire dcennie, et constitue lun des sujets ma- des seuils de douleur la pression et une augmentation des
jeurs des recherches actuelles sur le dveloppement et la pro- scores totaux de douleur. Les mcanismes de la sensibilisa-
gression de larthrose.9-11 Dans les phases prcoces de lar- tion centrale dans larthrose peuvent tre dus une hyperex-
throse, des changements anaboliques interviennent aussi bien citabilit rachidienne couple un dficit des voies de contrle
dans le cartilage articulaire que dans los sous-chondral. Dans descendantes inhibitrices des stimuli nociceptifs. Des tudes
dIRM fonctionnelle menes chez des patients prsentant une
douleur arthrosique chronique ont mis en vidence latrophie
ABRVIATIONS ET ACRONYMES
des zones corticales lies la douleur dans le thalamus et la
MMP matrix metalloprotease (mtalloprotinases de la matrice) substance grise, partiellement rversible aprs une arthroplas-
IRM Imagerie par rsonance magntique tie articulaire totale.
AINS Anti-inflammatoires non strodiens
SNP single nucleotide polymorphism (polymorphisme nuclo- La prise en charge des patients atteints darthrose ne cesse
tidique) dvoluer au fur et mesure que les preuves confirmant lef-
ficacit des modalits non pharmacopidmiologiques sac-
Arthrose : nouvelles approches Hochberg MEDICOGRAPHIA, Vol 35, No. 2, 2013 143
DITORIAL
cumulent, mais galement avec lautorisation de nouvelles mo- modre svre.18 Cependant, le dveloppement de cet
dalits pharmacologiques, notamment les agents biologiques, agent et des autres composs de sa classe a fait lobjet dune
et les tudes qui sont menes dessus.16 L Acadmie amri- suspension clinique de la part de la Food and Drug Adminis-
caine de rhumatologie (American College of Rheumatology) tration (FDA), cause dvnements indsirables type dos-
a publi en 2012 de nouvelles recommandations sur la prise toncrose finalement confirms comme constituant une ar-
en charge mdicale de larthrose de la main, de la hanche et throse rapidement destructrice affectant non seulement les
du genou.17 Les anti-inflammatoires non strodiens (AINS) articulations de rfrence comme la hanche et le genou, mais
restent la base du traitement oral de la douleur chez les pa- galement dautres articulations, notamment lpaule. Dau-
tients arthrosiques, malgr leur association des effets ind- tres tudes sur le mcanisme li ces vnements indsi-
sirables potentiellement graves, notamment des hmorragies rables articulaires graves sont ncessaires pour valuer le
gastro-intestinales provenant dulcres compliqus et de l- rapport bnfice-risque de ces traitements prometteurs de
sions de lintestin grle et du gros intestin, ainsi que des v- la douleur chez les patients atteints darthrose.
nements cardio-vasculaires thrombotiques, en particulier lin-
farctus du myocarde. Les patients prsentant une rponse De nombreuses tudes ont t menes sur les traitements de
inadquate ou ntant pas en mesure de tolrer les AINS fond de larthrose ; cependant, aucun mdicament na jusqu
oraux peuvent tre traits par des agents intra-articulaires, prsent t approuv par la FDA ou lAgence europenne
notamment les glucocorticodes et les hyaluronates et/ou des des mdicaments (EMA) dans cette indication. De rcentes
analgsiques centraux, par exemple le tramadol, la dulox- donnes suggrent que le ranlate de strontium par voie orale,
tine et les opiacs. Lefficacit de la duloxtine un inhibiteur des posologies de 1 ou 2 g par jour, rduit de manire signi-
de la recapture de la srotonine et de la noradrnaline pou- ficative le taux de dclin de lpaisseur de linterligne articu-
vant tre utilis seul ou en complment du paractamol ou laire par rapport un placebo chez des sujets prsentant une
des AINS confirme les observations rsumes ci-dessus, arthrose du genou suivis pendant une dure moyenne de 30
dmontrant le rle de la sensibilisation centrale dans la dou- mois.19 Des rsultats similaires ont t recueillis lorsque les su-
leur arthrosique chronique provoque par la perte du contrle jets ont t classs comme progresseurs sur la base dune
inhibiteur diffus induit par la nociception. diminution de linterligne articulaire dau moins 0,5 mm.20 Une
autre approche de lvolution de la maladie est lapplication
Il reste sur ce plan un besoin non satisfait de traitements plus des principes de la mdecine rgnrative avec des cellules
efficaces de la douleur et dagents capables de modifier la vi- souches endognes.21 Les rsultats de recherches biom-
tesse de progression structurelle de larthrose. Le tanzumab, dicales fondamentales, cliniques et translationnelles suscitent
un anticorps monoclonal dirig contre le facteur de croissance lespoir de fournir de nouvelles approches pour la prise en
nerveuse, a dmontr son efficacit chez les patients atteints charge des patients atteints darthrose vers la fin de cette d-
darthrose de la hanche et du genou prsentant une douleur cennie et dans les dcennies venir. I
144 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Arthrose : nouvelles approches Hochberg
OSTEOARTHRITIS: A STORY OF CLOSE R E L AT I O N S H I P
BETWEEN BONE AND CARTILAGE
A systematic review and

meta-analysis of the risk factors
for the onset of knee osteoarthri-
tis in older adults has shown that
there is a consistent strong asso-
ciation between increased bone
Epidemiology of
mineral density and the onset of
knee osteoarthritis Although a
definite molecular basis and com-
osteoarthritis
mon pathophysiology have not
been identified to explain the in-
verse relationship between osteo-
arthritis and osteoporosis, a shared
genetic component may explain
why they seldom coexist.
b y C . C o o p e r, E . D e n n i s o n , M . E d wa rd s ,
and A. Litwic, United Kingdom
O
steoarthritis is a global degenerative joint disease involving the car-
tilage and many of its surrounding tissues. Prevalence and incidence
estimates of osteoarthritis in different populations may vary consid-
erably due to different diagnostic classifications; in general, radiographic case
definition produces the highest estimates, with self-reported and symptomatic
osteoarthritis definitions producing similar estimates. The World Health Orga-
nizations Scientific Group on Rheumatic Diseases estimates that 10% of the
worlds population aged 60 years or older have significant clinical problems
that could be attributed to osteoarthritis. The highest osteoarthritis prevalence
estimates are found in the hand joints, with women more commonly affected
L
than men.
Cyrus COOPER,a,b MA, DM,
FRCP, FFPH, FMedSci Medicographia. 2013;35:145-151 (see French abstract on page 151)
Elaine DENNISON,b MB BChir,
MA, MSc, FRCP, PhD
Mark EDWARDS,b BSc, MBChB,
MRCP
Definition and classification
steoarthritis (OA) is a degenerative joint disease involving the cartilage and
O
Anna LITWICb
a
IHR Musculoskeletal Biomedical many of its surrounding tissues. In addition to damage and loss of articu-
Research Unit lar cartilage, there is remodeling of subarticular bone, osteophyte formation,
University of Oxford, UK
b
ligamentous laxity, weakening of periarticular muscles, and, in some cases, synovial
MRC Lifecourse Epidemiology
inflammation.1 These changes may occur as a result of an imbalance in the equilib-
Unit, (University of Southampton)
Southampton General Hospital rium between the breakdown and repair of joint tissue. Primary symptoms of OA in-
Southampton, UK clude joint pain, stiffness, and limitation of movement. Disease progression is usually
slow but can ultimately lead to joint failure with pain and disability.
There have been many attempts to accurately identify and grade radiographic dis-
ease in OA. Of these, the classification by Kellgren and Lawrence (K&L) is the most
widely accepted and used. Overall, grades of severity are determined from 0 to 4
and are related to the presumed sequential appearance of osteophytes, joint space
loss, sclerosis, and cysts.2 The World Health Organization (WHO) adopted these
criteria as the standard for epidemiological studies on OA. Cross-sectional imaging
methods, such as magnetic resonance imaging (MRI), can visualize joint structures
Address for correspondence: in more detail and continue to undergo evaluation to determine if they will provide
Professor Cyrus Cooper, Director
and Professor of Rheumatology, a means by which the definition of OA can be refined.
MRC Lifecourse Epidemiology Unit,
(University of Southampton),
Southampton General Hospital,
Many studies now report the prevalence of self-reported or symptomatic OA; these
Southampton SO16 6YD, UK differing approaches may go some way toward explaining part of the heterogeneity
(e-mail: [email protected]) in OA estimates.3 A recent systematic review3 attempted to understand the differ-
www.medicographia.com ences in prevalence and incidence of OA according to case definition in knee, hip,
Epidemiology of osteoarthritis Cooper and others MEDICOGRAPHIA, Vol 35, No. 2, 2013 145

Self-reported
OA BMI body mass index
COPCORD Community Oriented Program for the Control of
Rheumatic Disorders
DIP distal interphalangeal
Symptomatic
NHANES National Health And Nutrition Examination Survey
OA
OA osteoarthritis
WHO World Health Organization
Radiographic OA
age of 50 years. A leveling off or decline occurs at all joint sites
around the age of 80 years. For example, the age- and sex-
standardized incidence rate from the Fallon Community Health
Plan in Massachusetts (USA) was highest for knee OA (240/
100 000 person-years), with intermediate rates for hand OA
(100/100 000 person-years), and lowest observed rates for
hip OA (88/100 000 person-years) (Figure 3).6 The incidence
rates found by the Dutch Institute for Public Health (RIVM)
Figure 1. Relationships between osteoarthritis (OA) classifications.
After reference 3: Pereira et al. 2011;19:1270-1285. 2011, Elsevier Ltd.
in 2000 were similar. For hip OA, the reported prevalence was
0.9 and 1.6 per 1000 per year in men and women, respec-
and hand joints and concluded that radiographic case defi- tively, and for knee OA the corresponding figures were 1.18
nition afforded the highest estimates, while self-reported and and 2.8 per 1000 per year in men and women, respectively
symptomatic OA definitions presented similar estimates. The (Figure 4).7
interrelationship between the different classifications used is
shown in Figure 1. N Hand OA
The prevalence of radiographic hand OA varies greatly and
Epidemiology has been reported to range from 27% to over 80%.8,9 In a
OA may develop in any joint, but most commonly affects the study from the Netherlands, 75% of women aged between
knee, hip, hand, spine, and foot. In 2005, it was estimated that 60 and 70 years had evidence of OA in the distal interpha-
over 26 million people in the USA had some form of OA.4 langeal (DIP) joints, and 10% to 20% of subjects aged below
Self-reported physician-diagnosed OA data from the 2004- 40 years were reported to have OA radiological changes in
2005 Australian National Health Survey is shown in Figure 2.5 their hands or feet.7 In a rural sample from the former Soviet
The incidence of hand, hip, and knee OA increases with age, Republic of Turkmenia,10 all males over the age of 65 years had
and women have higher rates than men, especially after the at least one affected hand joint. Symptomatic hand OA, as
defined by the American College of Rheuma-
tology (ACR) criteria, is, however, far less com-
35% mon. Its prevalence was found to be 8% in
the US National Health and Nutrition Exam-
30% Males
Females ination Survey (NHANES III).11 Data from the
25% Framingham cohort demonstrated a preva-
lence of 13.2% in men and 26.2% in women
20%
aged 70 years, with at least one hand joint
15% with symptomatic OA.8 A study from Teheran
10% showed that the prevalence of hand OA in
people aged 40 to 50 years was 2.2%, ris-
5%
ing with age to 22.5% in people aged >70
0% years.12 As with many studies, including the
0-14 15-24 25-34 35-44 45-54 55-64 65-74 75+ Framingham cohort, differentiation by sex in
Age group (years) this population showed that women were
more frequently affected than men.12 Interest-
Figure 2. Age-specific prevalence of osteoarthritis in Australia in 2004-2005 (Aus- ingly, data from China based on thirteen sur-
tralian Institute of Health and Welfare analysis of the Australian Bureau of Statistics veys involving 29 621 adults demonstrated
2004-2005 National Health Survey).
After reference 5: Australian Institute of Health and Welfare. 2007. Arthritis series no 5. Cat no. PHE
that symptomatic OA of the hand was rarely
93. Canberra: AIHW. 2007, Australian Institute of Health and Welfare. observed, irrespective of age or sex.13
146 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Epidemiology of osteoarthritis Cooper and others
Men Women
1200 1200 Figure 3.
Incidence of
Incidence (per 10 5 patient-years)
1000 1000 clinical osteo-

Knee
arthritis of
800 800 the hand,
knee, and
600 600 Hip hip among
Knee participants
400 400
Hand
in the Fallon
Hip
Health Plan.
200 200 After reference
Hand 6: Oliveria SA
et al. Arthritis
0 0
Rheum. 1995;
20 30 40 50 60 70 80 20 30 40 50 60 70 80
38:1134-1141.
Age (years) Age (years) 1995, Ameri-
can College of
Rheumatology.
Men Women
80 80
DIP Figure 4.
Prevalence
Prevalence of osteoarthritis (%)
of clinical
60 60
osteoarthritis
of the hand,
DIP
knee, and hip
40 40
in a Dutch
Knee
Knee population.
Reproduced
20 20 with permission
Hip from reference
Hip
7: van Saase
0 0 JL et al. Ann
20 30 40 50 60 70 80 20 30 40 50 60 70 80 Rheum Dis.
1989;48:271-
Age (years) Age (years) 280. 1989,
BMJ Publishing
Group Ltd.
N Knee OA could not be fully explained by increasing obesity. According

Knee involvement occurs less frequently than hand OA, al- to data produced by the Dutch Institute for Public Health,
though, similarly, it is more common in women, with female- the prevalence of knee OA in those aged 55 and above was
to-male ratios varying between 1.5:1 and 4:1. Prevalence rates 15.6% in men and 30.5% in women.7
for knee OA, based on population studies in the USA, are com-
parable to those in Europe. These studies report that severe Geographical variation in OA epidemiology also exists. Stud-
radiographic changes affect 1% of people aged between 25 ies from China, which used similar methods and definitions
and 34 years and this figure increases to nearly 50% in those to those used in the Framingham Study, found that the preva-
75 years and above.14 Few studies have reported secular trends lence of bilateral knee OA and lateral compartment disease
in knee pain; a recent report from the Framingham Study were two to three times higher in Chinese cohorts compared
found that the age- and BMI-adjusted prevalence of knee with estimates from the Framingham OA Study.16 Data on clin-
pain and symptomatic knee OA approximately doubled in ically diagnosed knee OA in the Community Oriented Program
women and tripled in men over 20 years (Figure 5, page 148); for the Control of Rheumatic Disorders studies (COPCORD) in
no such trend was observed in the prevalence of radiographic Asia showed that the prevalence within this area ranged from
knee OA.15 Similarly, using questionnaire data enquiring about 1.4% in urban Filipinos to 19.3% in rural communities in Iran.17
pain in and around the knee, the same researchers found Part of the reason for this difference may be explained by the
that the age- and BMI-adjusted prevalence of knee pain in- physical and socioeconomic environment. The COPCORD
creased by about 65% in NHANES from 1974 to 1994 among studies conducted in India, Bangladesh, and Pakistan looked
non-Hispanic white and Mexican American men and women specifically into differences between rural and urban popula-
and among African American women.15 These secular trends tions. In India, it showed a significantly higher prevalence of
Figure 5. Varying prevalence of radiographic

and symptomatic knee osteoarthritis over
50
a 20-year period among participants in the
Framingham Osteoarthritis Study.
Radiographic knee OA
radiographic and symptomatic knee OA (%)
41.9 Abbreviations: BMI, body mass index; OA, osteoarthritis.

39.7 Reproduced with permission from reference 15:
Age- and BMI-adjusted prevalence of
40
Nguyen US et al. Ann Intern Med. 2011;155:725-732.
35.1 2011, American College of Physicians.
36.5 35.4
32.5
30
fect the forces applied to the joint. Risk
Women factors are discussed individually below;
Men the varying prevalence of some, such as
20 obesity and nutritional factors, may part-
16.7
ly explain the differing rates of OA seen
11.8 16.1 in different populations.
10.4
10
7.8 Symptomatic knee OA N Age
5.7
The prevalence and incidence of radi-
0 ographic and symptomatic OA consid-
1983-1985 1992-1995 2002-2005 erably increase with age. The relation-
Original Original Offspring and ship between age and the risk of OA is
community
Examination period likely multifactorial and is probably the
consequence of numerous individual fac-
tors that may include oxidative damage,
knee pain in rural (13.0%) than in urban (8.1%) communities.17 thinning of cartilage, muscle weakening, and a reduction in
Furthermore, in China, men aged 60 years and above from a proprioception. Furthermore, the basic cellular mechanisms
rural community had approximately double the prevalence of that maintain tissue homeostasis decline with age, leading to
symptomatic knee OA than their urban counterparts.16 an inadequate response to stress or joint injury and resultant
joint tissue destruction and loss.
N Hip OA
Hip OA is less common than either hand or knee OA. The N Sex
mean prevalence of primary radiographic hip OA in studies The incidence of knee, hip, and hand OA is higher in women
from Asia and Africa is 1.4% and 2.8%, respectively.17 These than men and in women it increases dramatically around the
levels are much lower than those seen in Europe and North time of menopause. The latter finding has led investigators to
America. In the Study of Osteoporotic Fractures, the preva- hypothesize that hormonal factors may play a role in the de-
lence of radiographic hip OA was analyzed in women over the velopment of OA, but the results of clinical and epidemiolog-
age of 65, using eleven different definitions. Excluding the def- ic studies have not universally corroborated this.20-22 A recent
inition of minimum joint space of less than 2.5 mm, the preva- systematic review of 17 studies found that there was no clear
lence ranged from 1.0% to 6.2%, depending on the defini- association between sex hormones and hand, knee, or hip
tion used.18 OA in women, although single analysis of the studies was not
possible due to study heterogeneity.23
Risk factors
OA is referred to as primary in the absence of an extrinsic N Ethnicity and race
cause. The proportion of individuals with primary OA within a The prevalence of OA and patterns of joint involvement vary
specific OA population varies greatly. As age increases, the among different racial and ethnic groups. Both hip and hand
likelihood of an individual having primary OA increases. There OA were much less frequent among Chinese in the Beijing
are also differences by sex; in the Queensland Aboriginal com- Osteoarthritis Study than in whites in the Framingham Study,
munities it was found that 88% of women had primary OA, but interestingly, Chinese women had a higher prevalence of
whereas 82% of men had secondary OA.19 knee OA, which may be explained by excessive knee loading
from squatting.24 Indeed, prolonged squatting and kneeling
The risk of developing OA is determined by both systemic and has been associated with an increased risk of moderate to se-
local factors. Several systemic factors have been identified; vere radiographic knee OA.24 Results from the Johnston Coun-
these may act by increasing the susceptibility of the joints to ty Osteoarthritis Project have shown that the prevalence of
injury, by direct damage to joint tissues, or by impairing the hip OA in African American women was similar to that in white
process of repair in damaged joint tissue. Local factors are women, but that the prevalence was slightly higher in African
most commonly biomechanical in nature and adversely af- American men (21%) than in white men (17%).25
N Genetics smoking may be associated with a greater risk of both car-

Strong evidence from family clustering and twin studies indi- tilage loss and knee pain in OA. A recent meta-analysis of
cates that the risk of OA has an inherited component. Classic observational studies concluded that the observed protective
twin studies have shown that the influence of genetic factors effect of smoking in OA is likely to be false.35 It may be caused
is between 39% and 65% in radiographic OA of the hand by selection bias, as many studies have been conducted in a
and knee in women, about 60% in OA of the hip, and about hospital setting where control subjects have smoking-relat-
70% in OA of the spine.26 Although specific genes have been ed conditions, and subjects were recruited as part of studies
identified, the individual effects are relatively small; for exam- that were not primarily designed to investigate smoking.36
ple, Kerkhof et al27 reported a genome-wide association study
showing that the C allele of rs3815148 on chromosome 7q22 N Obesity and metabolic disease
was associated with a 1.14-fold increased prevalence of knee Obesity is one of the strongest and best-established risk fac-
and/or hand OA and also with a 30% increased risk of knee tors of OA. The current literature suggests that, although both
OA progression. show significant associations, the relationship between obe-
sity and hip OA is weaker than with knee OA.37 Recent data
N Nutrition (including vitamin D) suggest that OA is associated with the metabolic syndrome,
Dietary factors are the subject of considerable interest in suggesting a possible common pathogenic mechanism in-
OA.28,29 Protection against knee OA progression has been re- volving metabolic abnormalities and systemic inflammation.38
ported in older men and women with high dietary vitamin D Studies have specifically suggested significant associations
intakes, and for those with high serum levels of vitamin D.28 between OA and cardiovascular risk factors, such as hyper-
The Rotterdam Study reported that low vitamin D intake in- tension and hypercholesterolemia. However, clinical evidence
creased the risk of progression of knee OA.30 The Osteoporot- of an association between diabetes and OA is inconsistent.
ic Fractures in Men study found that men with vitamin D de- Several studies did find an association between diabetes and
ficiency were twice as likely to have prevalent radiographic OA39 and fascinating hypotheses explaining this association
OA,31 but a recent longitudinal study of Finnish participants have been suggested, including that high glucose concentra-
failed to find associations between low vitamin D status and tions produce reactive oxygen species (ROS) and advanced
risk of incident hip or knee OA.32 Although the results are in- glycation end products, which induce cartilage degeneration
consistent, a biologically plausible mechanism for the effect of and degradation. Other studies have failed to confirm the as-
vitamin D on OA could be postulated, through its important sociation and further research is required.
role in bone metabolism, which may modulate periarticular
bone responses to excess loading and joint damage. The N Sarcopenia
results of further studies are awaited. Muscle weakness may be an important risk factor for knee OA.
Men and women with pre-existing radiographic evidence of
Low vitamin C dietary intake has also been associated with an knee OA have been identified as having weaker quadriceps
increased risk of OA progression among participants in the than those without OA, particularly when the joints are symp-
Framingham Study.33 A role for selenium has also been pos- tomatic.40 One consequence of quadriceps weakness is that
tulated.34 the knee becomes less stable during physical activity. Quadri-
ceps exercises may therefore offer some protective advan-
N Osteoporosis tage to patients involved in activities that are known to be as-
Osteoporosis is, like OA, a common age-related skeletal dis- sociated with a high risk of OA development. Greater muscle
order. While early results indicated that reduced bone miner- strength is not, however, always protective as it corresponds
al density might be protective against OA, further studies have to higher forces and thus increased joint loading during ac-
been inconsistent with this finding. A systematic review and tivity. It has been shown that higher grip strength in men is
meta-analysis of the risk factors for the onset of knee OA in associated with a greater risk of developing OA in the prox-
older adults has shown that there is a consistent strong as- imal interphalangeal, metacarpophalangeal, and first carpo-
sociation between increased bone mineral density and the metacarpal jointsthe joints subjected to the largest forces
onset of knee OA in the three studies that investigated this risk during grip.41
factor in women.35 Although a definite molecular basis and com-
mon pathophysiology have not been identified to explain the N Local mechanical risk factors
inverse relationship between OA and osteoporosis, a shared A traumatic knee injury is one of the strongest risk factors for
genetic component may explain why they seldom coexist. the development of knee OA. Acute injuries, including menis-
cal and cruciate tears, fractures, and dislocations, can result
N Smoking in an increased risk of OA development and musculoskeletal
There have been conflicting reports on the role of smoking in symptoms. In addition to the direct trauma-induced damage
OA. Some studies have reported a protective association be- to local tissues, disruption of normal biomechanics and altered
tween smoking and OA, but others in contrast, report that load distribution within the joint also contribute to the subse-
quent increased OA risk. This risk is greater still if the sub- load is transmitted through the medial compartment. Any shift
ject has OA in another joint. The repetitive and excessive joint in either a valgus or varus direction affects load distribution.
loading that accompanies specific physical activities increas- Abnormal increases in compartmental loading are thought
es the risk of developing OA in the involved joints. Workers to increase stress on the articular cartilageand other joint
whose jobs require repeated pincer grip have an increased structuressubsequently leading to degenerative change.
risk of hand OA, particularly in the DIP joint.42 Similarly, pro- A systematic review has confirmed that knee malalignment is
longed squatting and kneeling stresses the larger joints and an independent risk factor for the progression of knee OA.45
is consequently associated with increased risk of moderate
to severe radiographic knee OA. Conclusion
OA is the commonest joint disease worldwide and mainly
There have been conflicting results in studies examining the occurs in later life. It tends to be slowly progressive and can
relationship between sporting activities and subsequent OA. cause significant pain and disability. Symptoms and radio-
There is some evidence that elite long-distance runners are graphic changes are poorly correlated and thus defining OA
at high risk of developing knee and hip OA.43 Other studies for research purposes is challenging. Established risk factors
suggest that in the absence of joint injury, moderate recreation- include obesity, local trauma, and occupation. These, in ad-
al running and sports participation do not appear to increase dition to genetic factors, may partly explain geographic varia-
the risk of hip or knee OA.44 The mechanical alignment of the tions in OA prevalence. There is conflicting evidence regard-
knee influences load distribution across the articular surfaces. ing the roles of nutrition, smoking, and sarcopenia, with the
In a normally aligned knee, 60% to 70% of the weight-bearing results of further studies awaited. I
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Meta-analysis of observational studies Ann Rheum Dis. 2011;70:1231-1237. 44. Spector TD, Harris PA, Hart DJ, et al. Risk of osteoarthritis associated with long-
37. Grotle M, Hagen KB, Natvig B, et al. Obesity and osteoarthritis in knee, hip and/ term weight-bearing sports: a radiologic survey of the hips and knees in female
or hand: An epidemiological study in the general population with 10 years fol- ex-athletes and population controls. Arthritis Rheum. 1996;39:988-995.
low-up. BMC Musculoskelet Disord. 2008;9:132. 45. Tanamas S, Hanna FS, Cicuttini FM, Wluka AE, Berry P, Urquhart DM. Does
38. Puenpatom RA, Victor TW. Increased prevalence of metabolic syndrome in knee malalignment increase the risk of development and progression of knee
individuals with osteoarthritis: an analysis of NHANES III data. Postgrad Med. osteoarthritis? A systematic review. Arthritis Rheum. 2009;61:459-467.
Keywords: burden; epidemiology; osteoarthritis; risk factor
EPIDMIOLOGIE DE LARTHROSE
Larthrose est une maladie dgnrative articulaire mondiale touchant le cartilage et la plupart des tissus environ-
nants. Sa prvalence et son incidence varient considrablement dune population lautre selon les classifications
diagnostiques utilises pour les estimer; la dfinition radiologique de larthrose donne gnralement les estimations
les plus leves, tandis que les dfinitions symptomatiques et auto-rapportes donnent des estimations peu prs
quivalentes entre elles. Daprs le groupe scientifique des maladies rhumatologiques de lOMS, 10% des gens gs
de 60 ans ou plus ont des problmes cliniques significatifs pouvant tre attribus larthrose. Larthrose a une plus
forte prvalence au niveau des articulations de la main, et touche plus volontiers les femmes que les hommes.
Adipose tissue is an active

metabolic and endocrine organ
producing hormones and bioac-
tive substances, such as adipo-
kines (also known as adipocyto-
kines), that have various biological
Osteoarthritis
effects and underlie the associa-
tion of obesity with concomitant
diseases Adipokines, including
and comorbidities
leptin, are involved in the local
modulation of articular cartilage
metabolism. Patients with OA were
found to have elevated levels of
leptin in both synovial fluid and
subchondral bone.
b y L . I . A l e k s e e va
a n d E . L . N a s o n ov, R u s s i a
O
steoarthritis (OA) is the most common disorder of the musculoskele-
tal system and the leading cause of functional incapacity and disabil-
ity in adults. A significant number of studies have demonstrated that
patients with OA are at significantly higher risk of developing comorbid con-
ditions than people without the disease. OA is most commonly associated with
cardiovascular diseases, including arterial hypertension, as well as obesity,
diabetes mellitus, and pulmonary diseases. The combination of various chron-
ic diseases with diseases of the musculoskeletal system, especially with OA,
will be observed more and more frequently, and will affect not only health care
systems, but also the quality of life. The relation between OA and comorbid dis-
L
orders may be explained, to some extent, by common etiologic and patho-
Eugeny L. NASONOV, MD, PhD
Director, National Scientific genetic mechanisms, or may be related to the biological processes of aging,
Research Institute of Rheumatology which can lead not only to the development, but possibly also to the mainte-
(Russian Academy of Medical
nance of comorbidities. The data presented in this article suggest that OA is
Sciences), Moscow
RUSSIA a disease that is pathogenetically related to cardiovascular diseases, obesity,
Lyudmila I. ALEKSEEVA, and other metabolic conditions. As a consequence, the examination of OA
MD, FACPh patients should not be limited to the assessment of their articular disorder, but
Research Institute of Rheumatology
rather should be comprehensive, with particular attention paid to the state of
(Russian Academy of Medical
Sciences), Chief of Department their cardiovascular system. This article highlights the importance of using
Department of Metabolic Disorders an integrated approach when considering treatment options.
of the Musculoskeletal System and
Medicographia. 2013;35:152-157 (see French abstract on page 157)
Osteoarthritis and Osteoporosis
Laboratories, Moscow
RUSSIA
steoarthritis (OA) is the most common disorder of the musculoskeletal
O system: about 15% of the world population suffers from OA and 65% of
them are aged 60 years and over. Osteoarthritis is the leading cause of func-
tional incapacity and disability in adults1 and reduces the quality of life of patients.
Moreover, patients with OA were found to have higher all-cause mortality rates than
the general population.2 The analysis of 617 lethal outcomes in osteoarthritic pa-
tients, compared with a population of similar age and sex, has shown that almost
40% of deaths were caused by atherosclerotic coronary artery disease (CAD) and
gastrointestinal tract disorders.3
Professor Eugeny L. Nasonov,
Institute of Rheumatology, Russian In 1990, in a study of 2384 people aged 55 to 74 years, Lawrence et al showed that
Academy of Medical Sciences,
34 A Kashirskoye shosse,
patients with radiographic evidence of knee OA had higher mortality rates than sub-
115522 Moscow, Russia jects without radiographic abnormalities (38.9% vs 31.6% in men; 30% vs 17.7%
(e-mail: [email protected]) in women, respectively).4 Haara et al found an association between the presence
www.medicographia.com of OA in any finger joint and increased cardiovascular mortality, and in women the
152 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Osteoarthritis and comorbidities Alekseeva and Nasonov
risk of death was higher in the presence of radiographic evi- in the period from 1966 to July 2004 revealed that hyperten-
dence of OA of the distal interphalangeal joints of both hands.5 sion is present in 48% to 65% of patients with OA and in more
Although there is a discrepancy between the presence of pain than 65% of patients over 80 years of age with OA requiring
and the radiographic signs of OA, which are observed togeth- knee arthroplasty.11 Rosemann et al showed that osteoarthrit-
er in 15% to 76% of cases,6 higher mortality rates are found ic patients of both sexes have similar rates of hypertension
both in patients with symptomatic OA and in those with only (53%), high cholesterol (36%), heart failure (19%), diabetes
radiographic evidence of the disease.5 This suggests that OA mellitus (17%), and CAD (13%).12 Women with OA were found
is not only the most common disease of the joints, but also to have a lower quality of life and lower mood (P<0.01), a high-
the most urgent problem in general practice. Osteoarthritis er degree of disability (P<0.01), and to feel more pain (P<0.01).
along with cardiovascular diseases (CVD), degenerative dis-
eases of the nervous system, and osteoporosisis an age- In the large-scale AMICA study (Atrial Fibrillation Management
related disorder. Moreover, joint dysfunction and pain and the in Congestive Heart Failure With Ablation) in Italy, which in-
resulting reduction in physical activity are destabilizing factors volved 3080 physicians and 29132 patients with OA, hyper-
in the course of various somatic disorders. In patients with un- tension was found in 53% of study participants, type 2 dia-
derestimated concomitant somatic diseases, OA is associ- betes in 15%, and history of myocardial infarction or angina in
ated with a high rate of drug-related complications, especially 6%. The degree of hypertension correlated with pain inten-
when nonsteroidal anti-inflammatory drugs (NSAIDs) are used.7 sity, joint dysfunction, and worsening quality of life.9 Danish
researchers found CVD in 54% patients with hip OA aged be-
Many studies have demonstrated that patients with OA are tween 50 and 85 years.1 In Russia, a 1-year study of the rates
at significantly higher risk of developing comorbid conditions of concomitant diseases associated with knee OA in an out-
than people without the disease. In their 18-month follow-up patient clinic also revealed twice higher rates of CAD, AH, and
study of 1026 patients with OA, Kadam et al revealed a clear obesity, compared with patients without OA from the same
correlation between the number of concomitant conditions clinic.13
(morbidity count) and a patients physical function. Almost
half of the patients with OA (49%) were diagnosed with more The increase in life expectancy has resulted in an aging popu-
than 5 conditions other than OA (high morbidity count), 28% lation. Therefore, the combination of various chronic diseases
had 3 or 4 conditions (medium morbidity count), 25% had 1 with diseases of the musculoskeletal system, especially with
or 2 conditions (low morbidity count), and only 3.7% of the OA, will be observed more and more frequently, and will affect
patients had OA alone.8 In osteoarthritic patients, high mor- not only health care systems, but also the quality of life. The re-
bidity counts were associated with reduced physical function lation between OA and comorbid disorders may be explained,
(after adjusting for age, sex, and socioeconomic parameters). to some extent, by common etiologic and pathogenetic mech-
anisms, or may be related to the biological processes of ag-
Osteoarthritis and cardiovascular disease ing, which become more prevalent with age (such as cartilage
OA is most commonly associated with CVD, including arteri- degeneration, insulin resistance, weight gain, dyslipidemia, etc),
al hypertension (AH), as well as obesity, diabetes mellitus, and and lead not only to the development, but possibly also to the
pulmonary diseases.8-10 An analysis of publications in Medline maintenance of comorbidities.
OA and CVD are both considered to be age-related diseases.

With aging, various human tissues accumulate advanced gly-
AGE advanced glycation end-product cation end-products (AGEs), which play an important role in
AH arterial hypertension the pathogenesis of both atherosclerosis and OA.14-16 The for-
AMICA Atrial fibrillation Management In Congestive heart mation of AGEs on the basement membrane of vascular walls
failure with Ablation leads to wall thickening, a narrowing of the lumen of capillar-
BMI body mass index ies, and reduced vascular wall elasticity, which can accelerate
CAD coronary artery disease the development of the atherosclerotic process. AGEs also
CVD cardiovascular diseases accumulate in human cartilage tissue,16 where they bind with
ICAM-1 intracellular adhesion molecule-1 long-lived proteinsmainly collagenand subsequently dam-
IGF-1 insulin-like growth factor age and deteriorate their functional properties. AGEs are sup-
IL interleukin posed to adversely affect the metabolic activity of chondro-
MMP matrix metalloproteinase cytes and can stimulate the formation of proinflammatory
NSAID nonsteroidal anti-inflammatory drug cytokines.17,18
OA osteoarthritis
PAI plasminogen activator inhibitor Metabolic disturbances and nonspecific inflammation also play
TGF-1 transforming growth factor-1 an important role in the pathogenesis of atherosclerosis and
OA. Traditionally, OA has been considered to be a degenera-
Osteoarthritis and comorbidities Alekseeva and Nasonov MEDICOGRAPHIA, Vol 35, No. 2, 2013 153
tive disease of the joints, but accumulating evidence suggests capsule of atherosclerotic plaques, and elevated levels of
that nonspecific inflammation is also important in its patho- inhibitor of plasminogen activator-1 (PAI-1) are implicated in
genesis.19,20 In OA, there are no classical macroscopic signs the process of thrombogenesis.28
of inflammation and no severe infiltration by inflammatory cells
in joint tissues. However, elevated levels of proinflammatory Another aspect of the association of vascular disease with OA
cytokines, interleukins (IL)-1, and tumor necrosis factor relates to changes in the blood vessels of subchondral bone.
(TNF-) are observed in the synovial fluid of osteoarthritic pa- The occurrence of OA and its subsequent progression are
tients. IL-1 stimulates the chondrocytes, thereby increasing thought to be a consequence of atheromatous disease in
the production of matrix metalloproteinases (MMPs)prote- these vessels.29,30 Bone is a highly vascularized tissue, and its
olytic enzymes that degrade collagen and cartilage proteo- vasculature is involved in all aspects of the growth, recovery,
glycans. Increased levels of MMP-3 were found in the syn- and metabolism of bone tissue. It is possible that in the con-
ovial fluid and blood of patients with OA of the knee and hip text of vascular disease, episodic circulatory disorders take
joints. Moreover, serum levels of MMP-3 and MMP-9 were place in the subchondral bone, resulting in the development
significantly higher in patients with hip OA compared with of OA. Subchondral bone ischemia, on the one hand, may
those with less severe OA.21 Therefore, MMP-3 and MMP-9 lead to impaired nutrition and gas exchange in the articular
levels can serve as diagnostic markers of rapidly progressive cartilage, and thus trigger degenerative changes; on the other
OA. In addition, the chondrocytes of osteoarthritic individuals hand, it may promote osteocyte apoptosis in the subchon-
overexpress COX-2; this induces the synthesis of proinflam- dral bone, thereby inducing osteoclastic resorption.31,32
matory prostaglandins and the inducible form of nitric oxide
synthase (iNOS), an enzyme that regulates the formation of The association of OA with CVD is probably determined not
nitric oxide and exerts a toxic action on the cartilage. only by common pathogenetic mechanisms, but also by oth-
er external factors. Thus, the limitation of physical activity in
Epidemiological and immunopathological data suggest that patients with OA is a significant aggravating factor for car-
inflammation is the major manifestation of atherosclerosis and diovascular disease. By inducing a neuroendocrine response,
is associated with dyslipidemia and chronic immune dysreg- chronic pain is often the cause of complications in CVD pa-
ulation.22,23 Proinflammatory cytokines and cell adhesion mol- tients. Pincus and Sokka have found that reduction in life ex-
ecules expressed by vascular and blood cells play an impor- pectancy in older people is determined, to a great extent, by
tant role in the pathophysiology of atherosclerosis. Prospective the severity of pain.33 They assessed the survival rates of 1525
epidemiological studies have shown an association between patients, of which 24% (370 patients) had OA, 16% (246 pa-
the clinical manifestations of atherothrombotic disease and tients) had CVD, and 7.1% (109 patients) had OA and CVD.
systemic markers of inflammation, including white blood cell The results showed that the relative risk of death among pa-
count and various hemostatic proteins that reflect acute in- tients with OA and a pain intensity of more than 40 mm on the
flammation, such as fibrinogen, plasminogen activator inhibitor visual analog scale (VAS) was higher than in patients with a
(PAI), and von Willebrand factor.20,24 C-reactive protein is di- pain intensity of less than 40 mm, without any significant dif-
rectly involved in the pathogenesis of atherothrombosis and ferences according to age or sex.
stimulates the production of tissue factor by the macrophages.
Osteoarthritis and obesity
Tissue factor is the main inductor of coagulation in vivo and Obesity is among the most urgent health care and social
its local concentration in the arterial wall is associated with problems of contemporary society. It is a risk factor not only
the development of events resulting in coronary thrombosis.25 for OA, but also for many other diseases associated with meta-
In patients with a high risk of vascular complications, elevated bolic disturbances. OA, in turn, through the dysfunction and
levels of other markers of inflammation, such as IL-6, intracel- limitation of physical activity leads to an increase in body mass
lular adhesion molecule-1 (ICAM-1), macrophage inhibitory index (BMI) that can result in the development of CVD and
cytokine-1 (MIC-1), and soluble CD40 ligand are also ob- diabetes. The risk of developing these conditions increases
served. Experimental studies have shown that the vascular progressively with increasing BMI. In overweight patients with
endothelium and the smooth muscle cells of the arteries pro- a 40% excess in body mass, the risk of premature death is
duce IL-6. At the same time, the IL-6 gene is expressed in twice that of people of average weight. In Russia, a study of
areas of atherosclerotic lesions in man; therefore, IL-6 may 298 patients with overt OA of the knee and hip joints showed
also have procoagulant properties.25,26 Metalloproteinases a marked increase in the prevalence of CVD and diabetes
take part in the remodeling of blood vessels and increase the with increasing BMI.34
rigidity of the arteries with age.27 Matrix metalloproteinase-3
(MMP-3) has been associated with lipid structures in arte- Many studies have demonstrated an association between
riosclerotic plaques and MMP-3 genotype may be an impor- obesity (BMI >30) and OA of the knee, for both symptomatic
tant determinant of age-related vascular remodeling and ar- and radiographic OA.35,36 Moreover, the risk of OA of the knee
terial stiffness.27 MMP-9 is involved in the rupture of the fibrous increases progressively with increasing BMI. Prospective stud-
ies have revealed that excess body mass contributes to the of insulin-like growth factor (IGF-1) and transforming growth
progression of the radiographic manifestations of knee OA.37 factor-1 (TGF-1).46 Leptin, IGF-1, and TGF-1 can be found
In a prospective cohort study, Wang et al found that both in the cartilage of osteoarthritic patients (in osteophytes), but
central obesity and the amount of fat mass represent risk not in the cartilage of disease-free patients.47 Moreover, os-
factors for arthroplasty of the knee and hip joints.38 Interest- teophytes are associated with increased TGF1 expression.
ingly, not only is increased body weight associated with an TGF1 induces fibrotic changes in the synovial membrane,
increased risk of OA, but it was also shown that weight loss bone sclerosis, and the differentiation of stem cells from the
causes a decrease in the risk of OA. A 2-kg/m2 decrease in periosteal layer, resulting in the formation of osteophytes.48
BMI was shown to reduce the risk of OA development by more An experimental study showed that injections of leptin into
than 50% at 10 years.39 the joints of healthy rats caused symptoms of OA.45 In addi-
tion, Miller et al showed that a decrease in serum leptin levels
There is also some evidence of an association between obe- may be one of the mechanisms by which weight loss slows
sity and OA of the joints of the hand. A study in female twins down the progression of OA.49
has shown that obesity is an important risk factor for the
development of OA of the knee and carpometacarpal joints, Treatment of OA
with a significant 9% to 13% increase in the risk of OA per The data presented above suggest that we can consider OA
each additional kilogram of body weight.40 A recently pub- as a disease that is pathogenetically related to cardiovascular
lished systematic review confirms the existence of a posi- diseases, obesity, and other metabolic conditions. As a result,
tive association between body weight and OA development the examination of OA patients should not be limited to the
in the hands.41 assessment of their articular disorder, but rather should be
comprehensive, with particular attention paid to the state of
There is some controversy in the data published on the rela- their cardiovascular system. This highlights the importance of
tionship between obesity and OA of the hip. Some researchers having an integrated approach when choosing a treatment,
identified a clear correlation between BMI and the risk of hip which should ideally combine nonpharmacological and phar-
OA,42 while others did not find any correlation at all.43 macological therapy. Patients should be informed about their
condition, its main symptoms, and what may cause its pro-
However, a majority of studies have demonstrated an asso- gression. Patient education is, therefore, required in order to
ciation between OA and obesity. Excess weight increases the teach patients to follow an exercise regimen at work and at
load on the skeleton and causes lesions in bone and mus- home and to perform regular aerobic exercise. Physical ex-
cle tissue. Pressure-sensitive mechanoreceptors capable of ercise regimens should be individualized, taking into account
triggering a signaling cascade were found on the surface of the presence of comorbidities and their severity. Patients should
chondrocytes.17 Activation of these mechanoreceptors can clearly understand that overweight, especially of the viscer-
lead to the expression of cytokines, metalloproteinases, pros- al type, is a confounding factor for the disease and, there-
taglandins, and nitric oxide.19 Experimental data show that, fore, the target is not only to prevent weight gain, but also to
under certain conditions, overload can trigger the inhibition reduce it. In addition, information should be provided on the
of matrix synthesis and degradation of cartilage.44 Obesity can use of orthopedic devices that facilitate the reduction of the
potentially induce cartilage damage through activation of the load applied to the joints.
mechanoreceptors.
The main goals of pharmacological therapy in OA are effec-
Available data not only suggest an effect of overweight on tive pain relief, suppression of inflammation in the joint, im-
the development of OA in the knee joints, but also confirm provement in functional capacity, and prevention of disease
the existence of other mechanisms related to obesity that can progression. When treating the clinical manifestations of OA
change the metabolism of cartilage and bone tissue and lead in patients with obesity and other metabolic diseases (AH,
to the development of OA. Adipose tissue is an active meta- CAD, etc)or who are at high risk of their development
bolic and endocrine organ producing hormones and bioac- doctors should thoroughly think through their choice of ther-
tive substances, such as adipokines (also known as adipo- apy. In the presence of comorbidities, the excessive and un-
cytokines), that have various biological effects and underlie reasonable prescribing of drugs without first considering the
the association of obesity with concomitant diseases. Thus, particularities of their interactions can lead to a sharp increase
leptin and adiponectin can have an influence on cartilage, in the risk of adverse effects and a worsening of the disease.
bone tissue, and vascular walls. Adipokines, including lep-
tin, are involved in the local modulation of articular cartilage NSAIDs are commonly used to relieve pain in osteoarthritic
metabolism.45 Elevated levels of leptin were found in both the patients, in accordance with the European League Against
synovial fluid and subchondral bone of osteoarthritic patients. Rheumatism (EULAR), Osteoarthritis Research International
Mainard et al demonstrated the importance of leptin in the (OARSI), and American College of Rheumatology (ACR) treat-
pathogenesis of OA by showing its impact on the synthesis ment guidelines. However, despite their being the most com-
monly prescribed drugs for the treatment of OA, NSAIDs were nally, it should also be borne in mind that NSAIDs can reduce
shown to cause a significant proportion of side effects in phar- the efficacy of drugs used in the conventional therapy of CVD
maco-epidemiological studies, especially due to their improp- (-blockers, diuretics, angiotensin-converting enzyme inhib-
er use in elderly patients with comorbidities. Both selective itors, and, to a lesser extent, calcium channel blockers).
and nonselective NSAIDs have pronounced anti-inflammato-
ry and analgesic effects, but in patients with OA and metabol- Conclusion
ic diseases (obesity, AH, CAD, etc), or at high risk of develop- Current data suggest that OA is a disease that is pathogenet-
ing them, they may cause a number of side effects that can ically related to cardiovascular diseases and other metabol-
aggravate the course of cardiovascular conditions. An in- ic conditions. The problem of comorbidity in patients with OA
creased risk of cardiovascular accidents (myocardial infarc- has clear prognostic significance. Early recognition of the
tion, stroke, and sudden cardiac death) can be considered to comorbid conditions associated with OA and their compre-
be a class-specific side effect for all NSAIDs.50 NSAIDs can hensive treatment with well-evidenced therapies will substan-
cause the destabilization of AH and progression of heart fail- tially reduce cardiovascular risks and improve patient prog-
ure and it was found that NSAID treatment in patients with a nosis. I
history of heart disease increases the likelihood of hospitaliza- Acknowledgements. Professor Eugeny L. Nasonov is chief editor of
tion due to heart failure by 10 times (odds ratio=10.5), com- Scientific-Practical Rheumatology (Russia) and on the editorial board of
pared with patients not taking NSAIDs (odds ratio=1.6).51 Fi- Clinical Rheumatology (EULAR).
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meta-analysis. Ann Rheum Dis. 2007;66:4:433-439. teoarthritic patients show abnormal expression and production of leptin: Pos-
40. Cicuttini FM, Baker JR, Spector TD. The association of obesity with osteoarthri- sible role in cartilage degradation. J Bone Min Res. 2004;19(suppl 1):S149.
tis of the hand and knee in women: a twin study. J Rheumatol. 1996;23:1221- 48. Chevalier X, Tyler JA. Production of binding proteins and role of the insulin-
1226. like growth factor I binding protein 3 in human articular cartilage explants. Br J
41. Yusuf E, Nelissen RG, Ioan-Facsinay A, et al. Association between weight or Rheumatol. 1996;35:6:515-522.
body mass index and hand osteoarthritis: a systematic review. Ann Rheum Dis. 49. Miller GD, Nicklas BJ, Loeser RF. Inflammatory biomarkers and physical func-
2010;69:761-765 tion in older, obese adults with knee pain and self-reported osteoarthritis after
42. Liu B, Balkwil A, Cooper C, et al; Million Women Study Collaborators. Reproduc- intensive weight-loss therapy. J Am Geriatr Soc. 2008;56:644-651.
tive history, hormonal factors and the incidence of hip and knee replacement for 50. Antman EM, Bennett JS, Daugherty A, et al. Use of nonsteroidal antiinflamma-
osteoarthritis in middle-aged women. Ann Rheumat Dis. 2009;68:1165-1170. tory drugs: an update for clinicians: A scientific statement from the American
43. Tepper S, Hochberg MC. Factors associated with hip osteoarthritis: data from Heart Association. Circulation. 2007;115:1634-1642.
the First National Health and Nutrition Examination Survey (NHANES-I). Am J 51. Page J, Henry D. Consumption of NSAIDs and the development of congestive
Epidemiol. 1993;137:1081-1088. heart failure in elderly patient: an unrecognized public health problem. Arch Int
44. Pottie P, Presle N, Terlain B, et al. Obesity and osteoarthritis: more complex than Med. 2000;160:777-784.
Keywords: arterial hypertension; cardiovascular system; comorbidity; metabolic disorder; obesity; osteoarthritis; pathogen-
esis; treatment goal
ARTHROSE ET COMORBIDITS
Larthrose est la pathologie la plus courante du systme musculosquelettique et la cause principale de handicap et
dincapacit fonctionnelle chez ladulte. Daprs un nombre significatif dtudes, les patients arthrosiques ont un
risque nettement plus important de dvelopper des comorbidits que ceux qui nont pas darthrose. Larthrose se re-
trouve le plus souvent associe aux maladies cardiovasculaires, dont lhypertension artrielle, lobsit, au diabte
et aux maladies pulmonaires. Lassociation de diverses maladies chroniques avec des pathologies du systme mus-
culosquelettique, en particulier larthrose, va devenir de plus en plus frquente et cela aura des consquences non
seulement sur les systmes de soins de sant, mais aussi sur la qualit de vie. Les liens entre larthrose et les trou-
bles comorbides peuvent sexpliquer, en partie, par des mcanismes tiologiques et pathogntiques communs, ou
peuvent tre lis aux processus biologiques du vieillissement, qui peuvent conduire non seulement au dveloppe-
ment, mais peut-tre aussi au maintien des comorbidits. Les donnes prsentes dans cet article suggrent que
larthrose est lie pathogntiquement aux maladies cardiovasculaires, lobsit et dautres troubles mtabo-
liques. Ainsi, lexamen des patients arthrosiques ne devrait pas se limiter lvaluation de leur pathologie articulaire,
mais devrait tre plus complet, en faisant particulirement attention leur systme cardiovasculaire. Ceci souligne
limportance de lusage dune approche globale lors du choix des traitements dans larthrose.
A complex and paradoxical

relationship seems to exist be-
tween osteoarthritis and osteo-
porosis, although there is increas-
ing evidence to support a close
biomolecular and mechanical as-
Osteoarthritis pathophysiology:
sociation between subchondral
bone and cartilage. Indeed, micro- similarities and dissimilarities with
array profiles have identified a
number of genes differentially ex-
pressed in osteoarthritic bone that other rheumatological diseases
are key players in the structure and
function of both bone and carti-
lage.
and the role of subchondral bone
by J. A. Roman-Blas
a n d G . H e r re ro - B e a u m o n t , S p a i n
O
steoarthritis (OA) is a disease not only of the cartilage, but also of the
whole joint. In osteoarthritis and chronic inflammatory arthritides, the
intensity of the inflammatory response of the joint determines juxta-
articular bone loss. Thus, in rheumatoid arthritis, the intense synovial and car-
tilage inflammation, pannus formation, and systemic bone loss induce in-
creased subchondral bone turnover with subsequent juxta-articular bone loss.
By contrast, the mild and patchy synovitis seen in osteoarthritis results in low-
er subchondral bone turnover and less subsequent bone loss than in rheuma-
toid arthritislike conditions. Angiogenesis and sensory nerve growth also
contribute to joint damage to different extents in these arthropathies. How-
L
ever, the main underlying pathogenic mechanisms may be common among
Gabriel HERRERO-BEAUMONT, MD
these joint diseases. A better understanding of the biological events involved
Jorge A. ROMAN-BLAS, MD
in inflammation-induced bone loss in these diseases could lead to the iden-
Bone and Joint Research Unit
Rheumatology Service tification of novel therapeutic strategies for the prevention of bone loss and
IIS Fundacin Jimnez Daz also potentially progression of joint damage.
Universidad Autnoma
Madrid, SPAIN
steoarthritis (OA) is a multifactorial disease that affects not only articular
O cartilage, but also the whole joint. The involvement of subchondral bone in
OA is of great relevance and interest, as are changes that occur in the syn-
ovial membrane, tidemarks, and periarticular structures in the course of the dis-
ease.1,2 Thus, acquired or genetically conditioned biomechanical and biochemical
alterations affecting any joint tissue may cause anomalous intra-articular stresses
and subsequent tissue damage associated with a failure of repair.3 OA is charac-
terized by pain, stiffness, and functional impairment ultimately resulting in chronic
disability and significant economic burden, especially in the elderly.
Subchondral bone
The bone underlying joint cartilage is composed of several specific anatomical re-
gions, including the subchondral cortical plate, subchondral trabecular bone, and
subarticular bone.4 Each region is likely to contribute to cartilage pathology in a dis-
Professor Gabriel Herrero-Beaumont, tinct manner. Current imaging techniques show unclear anatomical boundaries be-
Bone and Joint Research Unit, tween these tissues, generating some confusion with regard to their study.5 Bone at
Fundacin Jimnez Daz,
Avenida Reyes Catlicos, 2,
the joint margins is markedly active and is frequently the site of osteophyte develop-
28040 Madrid, Spain ment in primary OA or bone erosion in inflammatory arthritis. The close relationship
(e-mail: [email protected]) between subchondral bone and joint cartilage, two tissues that are adjacent to one
www.medicographia.com another as well as mechanically and biologically intertwined, makes them a function-
158 MEDICOGRAPHIA, Vol 35, No. 2, 2013 OA pathophysiology vs other rheumatological diseases Roman-Blas and Herrero-Beaumont
al unit that contributes significantly to normal joint function. of estrogen deficiency.10 Lastly, in an ovariectomized mouse
Changes to either the mechanical or biological properties of model, use of either estrogen supplementation or bisphos-
subchondral bone may alter the corresponding state of artic- phonate treatment resulted in inhibition of tibial and patellar
ular cartilage, and vice versa.6 When both tissues are damaged, subchondral cortical thinning.11 Taken together, these studies
the relationship between them changes, thereby posing an as- demonstrate a relevant and negative effect of systemic OP on
yet-unanswered question that has valuable therapeutic impli- the structure and metabolism of subchondral bone.
cations in the setting of chronic joint diseases.
Influence of osteoporosis in the remodeling of
Effect of systemic osteoporosis on subchondral subchondral bone in osteoarthritis
bone structure and remodeling It is increasingly acknowledged that articular cartilage home-
Systemic osteoporosis (OP) alters the microstructural and bi- ostasis is dependent on the integrity of the underlying bone.12-15
ological properties of subchondral bone. Compared with nor- Several studies have identified specific changes that occur to
mal and osteoarthritic femoral heads, the femoral heads of the architecture and turnover of subchondral bone in OA.16,17
patients with OP show the least stiff and dense subchondral The study of the influence of OP on subchondral bone remod-
bone plates (OA femoral heads show values in between nor- eling could reveal relevant mechanisms involved in the devel-
mal and OP femoral heads). Although osteoporotic bone has opment of OA. Thus, our group developed a rabbit model of
been found to contain less mineral, its organic and water con- surgically-induced OA preceded by OP, and demonstrated
tents have been found to be proportionally higher, suggesting that microstructure impairment in subchondral bone asso-
no change in the relative amount of organic matrix.7 Studies in ciated with increased remodeling increases cartilage dam-
different animal models have reported that OP has a negative age.9 Indeed, compared with control and OA knees, OPOA
effect on subchondral bone integrity.8-10 In an experimental knees demonstrated diminished subchondral bone area/tissue
model of OP in rabbits, which was induced by glucocorticoid area, trabecular thickness, and polar moment of inertia, as
administration and ovariectomy, subchondral bone mineral well as a pronounced decline in subchondral plate thickness.
density was significantly lower compared with controls.8 This Compared with controls, the subchondral bone of OA, OP,
experimental model also showed a decrease in subchondral and OPOA knees showed a decrease in alkaline phosphatase
plate thickness and only a negative tendency in bone area expression and OPG/RANKL ratio as well as an increase in
fraction and trabecular thickness values, while the microar- the fractal dimension and MMP-9 expression. In addition, the
chitecture index fractal dimension was increased. The de- severity of cartilage damage was increased in OPOA knees
crease in subchondral plate thickness would indicate that versus controls. Remarkably, good correlations were observed
this experimental model of OP exhibits a much more profound between structural and remodeling parameters in subchon-
effect on subchondral cortical bone than subchondral tra- dral bone, and furthermore, between subchondral structural
becular bone. Increased remodeling in favor of subchondral parameters and cartilage Mankin score.
bone resorption has also been reported in osteoporotic rab-
bits, as determined by reduced alkaline phosphatase expres- In line with our results, a decrease in subchondral plate thick-
sion and increased matrix metalloproteinase (MMP)9 expres- ness was also reported in an ovariectomized murine model
sion, also supported by a decrease in the osteoprotegerin of intra-articular iodoacetate-induced knee OA,11 as well as
(OPG)/receptor activator of nuclear factor-B ligand (RANKL) in experimental models of OA evaluating the early disease
ratio compared with healthy controls.9 In ovariectomized sheep, stage.13,14,18-20 Thinning and porosity of the subchondral plate
bone volume fraction was found to be reduced in subchon- were only present in the medial compartment and were relat-
dral bone compared with controls. Trabeculae were also sig- ed to superjacent cartilage damage, while in the canine ante-
nificantly thinner in these animals, with reduced connectivity rior cruciate ligament transection (ACLT)medial meniscectomy
density, and significant alterations observed in the trabecu- model of OA,20 trabecular bone changes were mostly found in
lar architecture under the tibial plateau following 12 months the lateral compartment and were related to mechanical un-
loading. Thickening of the subchondral plate has, however,
been described in animal models of surgically-induced OA cor-
responding to late-stage disease.13,19,21 Remarkably, in some
ACLT anterior cruciate ligament transection of these studies, the early decrease in subchondral plate thick-
AIA antigen-induced arthritis ness was followed by late plate thickening.13,19 Furthermore,
BML bone marrow lesion in the rat ACLT and meniscectomy models of OA, increased
MMP matrix metalloproteinase mRNA levels of cathepsin K and tartrate-resistant acid phos-
OA osteoarthritis phatase were found in subchondral bone at week 2 postsur-
OP osteoporosis gery, as well as invasion of cathepsin K+ osteoclasts into the
OPG osteoprotegerin articular cartilage from the subchondral region. These events
RANKL receptor activator of nuclear factor-kB ligand thus confirm that bone resorption is an early event in the dis-
ease course of OA. Upregulation of the osteoanabolic mark-
OA pathophysiology vs other rheumatological diseases Roman-Blas and Herrero-Beaumont MEDICOGRAPHIA, Vol 35, No. 2, 2013 159
ers runx2 and osterix was observed from week 4 to 6 post- Effects of systemic osteoporosis in osteoarthritis
surgery, which is thought to constitute the pathophysiolog- A complex and paradoxical relationship seems to exist be-
ical basis for late events in the disease course of OA such as tween OA and OP, although there is increasing evidence to
subchondral sclerosis and osteophyte formation. Local and support a close biomolecular and mechanical association be-
temporal regulation of matrix degradation, differentiation, and tween subchondral bone and cartilage.15 Indeed, microarray
vascular invasion markers was seen in articular cartilage in a profiles have identified a number of genes differentially ex-
manner consistent with the aforementioned changes in sub- pressed in osteoarthritic bone that are key players in the struc-
chondral bone.22 ture and function of both bone and cartilage. These include
genes involved in the Wingless-type mouse mammary tumor
In human knee OA, cartilage damage is frequently associat- virus/-catenin (Wnt/-catenin) and transforming growth fac-
ed with thickening of the subchondral plate and osteophyte tor/mothers against decapentaplegic (TGF-/SMAD) sig-
development.16,23 Aside from this hypertrophic OA, some au- naling pathways and their targets.30 Furthermore, aggrecan
thors consider that there is another variant, the atrophic form, production, as well as SOX9, type II collagen, and parathyroid
which is characterized by a lack of osteophytes and loss of hormonerelated protein mRNA expression, were inhibited in
subchondral bone volume in OA patients with compromised sclerotic but not nonsclerotic osteoblasts, while expression
hip and knee.24 This atrophic form probably shares several of MMP-3, MMP-13, and osteoblast-specific factor 1 by hu-
etiopathogenic mechanisms and phenotypic features with OA man OA chondrocytes was augmented in a coculture system.
associated with OP (Table). Furthermore, the correlation ob- Thus, sclerotic osteoarthritic subchondral osteoblasts may
served in hypertrophic OA between serum levels of C-propep- contribute to cartilage degradation and chondrocyte hyper-
tide and type II collagenase has been found to be lost in atroph- trophy.31 In addition, in our animal model of OA preceded by
ic OA, the latter showing reduced type II collagen synthesis.25 OP, improvement in subchondral bone integrity was shown
This could contribute to the absence of osteophyte formation to reduce the progression of cartilage damage, suggesting a
as well as the increased subchondral bone turnover seen in direct relationship between these two conditions.32 On the oth-
rapidly progressive hip and knee OA. Of note, the presence er hand, several cross-sectional studies have demonstrated
Disease mechanism/phenotypic feature
Role of osteoporosis
Subchondral Systemic Cartilage in disease progression Table.
Disease type bone remodeling osteoporosis inflammation (cartilage degradation) Etiopathogenic
mechanisms
Atrophic OA* ++ (toward resorption) ++ ? ++ ++ (predominantly joint and phenotypic
space narrowing) features of
atrophic osteo-
Hypertrophic OA ++ (toward formation) +/
arthritis (OA),
Rheumatoid arthritis +++ ? +++ +++ ++ hypertrophic OA,
and rheumatoid
* Atrophic OA probably shares common development events with OA associated with osteoporosis. arthritis, and the
+/ presence or absence; + mild; ++ moderate; +++ severe. involvement of
osteoporosis.
of subchondral bone attrition in knee OA, defined as flatten- an inverse relationship between OP and OA,33,34 although oth-
ing or depression of the osseous articular surface, is strong- ers have produced opposite results.35 Confounding variables
ly associated with subchondral bone marrow lesions (BMLs) such as race, obesity, and physical activity could explain the
on magnetic resonance imaging. In turn, BMLs reflect the pres- mutually exclusive relationship between OA and OP, whereby
ence of active remodeling processes due to chronic overload.26 overweight individuals and/or those who undertake exces-
Cartilage loss occurs in the same knee subregions as sub- sive physical activity could have a higher risk of developing
chondral bone attrition.27 In addition, it is possible that in post- OA and having a higher bone mass.
traumatic OA, trabecular microarchitecture changes differ from
those in primary OA. Indeed it has been proposed that during Recently, we proposed that high as well as low bone mass
the early postoperative period in the canine ACL-deficient knee, conditions can result in OA induction and/or progression.5
disuse osteopenia can potentially occur due to decreased Thus, both bone mass phenotypes may be considered risk
loadbearing.28 Likewise, subchondral bone in animal models of factors for OA initiation. The presence of other risk factors such
OA with early stages of the disease has shown both decreased as skeletal shape abnormalities, joint overload, or obesity may
volume and stiffness and increased remodeling.29 The impact have a synergistic effect regarding OA initiation. In addition,
of these subchondral bone changes in OA is still a matter for inflammatory mediators released by the articular cartilage in
debate, in part due to the heterogeneity of the disease. OA may lead to subchondral bone loss through increased
bone remodeling. Accordingly, treatment goals for OA must growth,43 acting in a paracrine manner on the subchondral
consider improvement of subchondral bone integrity. This bone plate. We have also shown that RANKL synthesized by
therapeutic approach should be individualized according to prostaglandin E2stimulated mature articular chondrocytes
the patients bone mineral density status and OA pheno- is also biologically active and is responsible for the mononu-
type, and the use of drugs should also subsequently be in- clear cell differentiation into osteoclast in the absence of ex-
dividualized for each patient. Recent findings suggest that ogenous RANKL.41
the same drugs could be useful for treating both processes
simultaneously, at least in a subgroup of patients with OA and By contrast, in OA, mild synovial hyperplasia is predominant-
concomitant OP.32 ly present, with proliferation and activation of lining cells as-
sociated with fibrosis-related changes.44-46 Synovial inflamma-
Effect of chronic synovitis on subchondral tory infiltrates are composed of mononuclear cells that appear
bone remodeling in far less abundance than in the synovium in rheumatoid arthri-
Juxta-articular bone loss is related to the intensity of the in- tis, and they are distributed in a patchy pattern, mostly con-
flammatory response in the affected joint.36,37 This fact is ob- fined to areas adjacent to sites of damaged cartilage, there-
served not only in rheumatoid arthritis, but also in other arthri- by increasing OA severity throughout the disease course.47,48
tides associated with a high degree of inflammation.38,39 Juvenile The inflammatory synovial changes are associated with in-
idiopathic arthritis, seronegative spondyloarthropathies, sys- creased production of proinflammatory cytokines and medi-
temic lupus erythematosus, as well as septic arthritis, are all ators of OA joint damage.49 The Krenn synovitis score was
rheumatic diseases in which intense inflammation is associ- found to be well correlated with subchondral bone structural
ated with skeletal pathology. Although some of the mecha- parameters in an experimental model of OA preceded by OP.46
nisms of skeletal remodeling are shared among these dis- Furthermore, rabbits with surgery-induced knee OA showed
eases, each disease has a unique impact on articular bone or a lower synovial inflammatory response and less subchondral
the axial or appendicular skeleton.39 bone loss than rabbits with AIA.41 Remarkably, RANKL ex-
pression in OA cartilageparticularly in calcified cartilage
Various hormones, cytokines, and chemokines produced by was less than in AIA cartilage, suggesting that the relevant
the inflamed synovial membrane have been reported to be involvement of this osteoclastogenic molecule in subchondral
involved in juxta-articular osteoporosis in these diseases.36 bone loss in OA is smaller in degree than in chronic inflamma-
The inflammatory mediators modulate the expression of the tory arthritis.41
crucial factor RANKL, in whose presence macrophages dif-
ferentiate into bone-resorbing osteoclasts in zones of contact In addition, inflammation drives synovial angiogenesis through
between the inflamed synovium and subchondral bone, as macrophage activation, which in turn perpetuates inflamma-
described in rheumatoid arthritis.40 In addition to membrane- tion and synovial hyperplasia, inducing pannus formation to
bound RANKL in osteoblasts, RANKL secreted by synovial variable extents. This is a well-recognized pathogenic mech-
cells actively promotes bone destruction in chronic inflamma- anism in the rheumatoid arthritis joint. Novel studies, howev-
tory arthritis.37 Hence, high local RANKL concentrations lead er, have identified the presence of increased angiogenesis in
to increased osteoclastogenesis at the bone-pannus interface. the synovium, osteophytes, menisci, and osteochondral junc-
tion in OA patients.50 Channels extending from subchondral
We have recently described that RANKL expressed by chon- bone into noncalcified articular cartilage provide the anatom-
drocytes also contributes significantly to the pathogenesis of ical basis for angiogenesis and sensory nerve growth through
the juxta-articular bone loss associated with chronic arthritis the osteochondral junction. Thus, to different extents, angio-
in a rabbit model that develops a more intense and destruc- genesis also contributes to structural damage in chronic joint
tive version of the well-established antigen-induced arthritis diseases.50
(AIA).41 This experimental arthritis was found to be accom-
panied by severe juxta-articular bone loss, as estimated by In summary, the intensity of the inflammatory response of the
x-ray and bone mineral density measurement. The increase in joint determines the juxta-articular bone loss in OA and
RANKL expression in the cartilage of AIA rabbits was linked chronic inflammatory arthritides. In articular conditions such
to the particular presence of extracellular RANKL in the cal- as rheumatoid arthritis, the intense synovial and cartilage in-
cified cartilage. Previous results from our group have also flammation, pannus formation, and systemic bone loss will
shown that RANKL is localized in the extracellular matrix of lead to high production of key biological mediators such as
human OA cartilage and could reach the subchondral bone RANKL, which are involved in increased subchondral bone
through the calcified cartilage.42 These results indicate that turnover with subsequent juxta-articular bone loss. By con-
chondrocyte-synthesized RANKL acts on subchondral bone trast, during the OA disease process, mild and patchy synovi-
cells, stimulating juxta-articular bone loss. Other studies have tis will occur with less RANKL expression in cartilage, resulting
demonstrated that soluble RANKL produced by hypertrophic in lower subchondral bone turnover and subsequent bone
chondrocytes is a biologically active molecule during bone loss than in rheumatoid arthritislike conditions. In addition,
angiogenesis and sensory nerve growth also contribute to the biological events involved in inflammation-induced bone
joint damage to varying extents in these arthropathies. How- loss will potentially lead to the identification of novel thera-
ever, the main underlying pathogenic mechanisms may be peutic strategies for the prevention of bone loss, and poten-
common among these joint diseases. Further elucidation of tially joint damage progression, in these diseases. I
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sorption in the early phase of experimental dog osteoarthritis by licofelone is fects of inflammation on bone. Immunol Rev. 2005;208:228-251.
associated with a reduction in the synthesis of MMP-13 and cathepsin K. 40. Udagawa N, Kotake S, Kamatani N, Takahashi N, Suda T. The molecular mech-
Bone. 2004;34:527-538. anism of osteoclastogenesis in rheumatoid arthritis. Arthritis Research. 2002;4:
19. Dedrick DK, Goldstein SA, Brandt KD, OConnor BL, Goulet RW, Albrecht M. 281-289.
A longitudinal study of subchondral plate and trabecular bone in cruciate-defi- 41. Martnez-Calatrava MJ, Prieto-Potn I, Roman-Blas JA, Tardio L, Largo R, Her-
cient dogs with osteoarthritis followed up for 54 months. Arthritis Rheum. 1993; rero-Beaumont G. RANKL synthesized by articular chondrocytes contributes
36:1460-1467. to juxta-articular bone loss in chronic arthritis. Arthritis Res Ther. 2012;14:
20. Intema F, Hazewinkel HA, Gouwens D, et al. In early OA, thinning of the sub- R149.
chondral plate is directly related to cartilage damage: results from a canine ACLT- 42. Moreno-Rubio J, Herrero-Beaumont G, Tardio L, Alvarez-Soria MA, Largo R.
meniscectomy model. Osteoarthritis Cartilage. 2010;18:691-698. Nonsteroidal antiinflammatory drugs and prostaglandin E(2) modulate the syn-
21. Pastoureau P, Leduc S, Chomel A, De Ceuninck F. Quantitative assessment thesis of osteoprotegerin and RANKL in the cartilage of patients with severe
of articular cartilage and subchondral bone histology in the meniscectomized knee osteoarthritis. Arthritis Rheum. 2010;62:478-488.
guinea pig model of osteoarthritis. Osteoarthritis Cartilage. 2003;11:412-413. 43. Usui M, Drissi H, Zuscik M, OKeefe R, Chen D, Boyce BF. Murine and chicken
22. Pickarski M, Hayami T, Zhuo Y, Duong le T. Molecular changes in articular car- chondrocytes regulate osteoclastogenesis by producing RANKL in response
tilage and subchondral bone in the rat anterior cruciate ligament transection to BMP2. J Bone Miner Res. 2008;23:314-325.
and meniscectomized models of osteoarthritis. BMC Musculoskelet Disord. 44. Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical
2011;12:197. symptoms of osteoarthritis. Nat Rev Rheumatol. 2010;6:625-635.
45. Oehler S, Neureiter D, Meyer-Scholten C, Aigner T. Subtyping of osteoarthritic 48. Loeuille D, Chary-Valckenaere I, Champigneulle J, et al. Macroscopic and mi-
synoviopathy. Clin Exp Rheumatol. 2002;20:633-640. croscopic features of synovial membrane inflammation in the osteoarthritic knee:
46. Lugo L, Villalvilla A, Gmez R, et al. Effects of PTH[1-34] on synoviopathy in an correlating magnetic resonance imaging findings with disease severity. Arthri-
experimental model of osteoarthritis preceded by osteoporosis. Osteoarthri- tis Rheum. 2005;52:3492-3501.
tis Cartilage. 2012;20:1619-1630. 49. Benito MJ, Veale DJ, FitzGerald O, van den Berg WB, Bresnihan B. Synovial
47. Ayral X, Pickering EH, Woodworth TG, Mackillop N, Dougados M. Synovitis: tissue inflammation in early and late osteoarthritis. Ann Rheum Dis. 2005;64:
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knee osteoarthritisresults of a 1 year longitudinal arthroscopic study in 422 50. Mapp PI, Walsh DA. Mechanisms and targets of angiogenesis and nerve growth
patients. Osteoarthritis Cartilage. 2005;13:361-367. in osteoarthritis. Nat Rev Rheumatol. 2012;8:390-398.
Keywords: inflammatory arthritis; osteoarthritis; subchondral bone
PHYSIOPATHOLOGIE DE LARTHROSE : RESSEMBLANCES ET DIFFRENCES AVEC

D AUTRES PATHOLOGIES RHUMATOLOGIQUES ; LE RLE DE L OS SOUS - CHONDRAL
Larthrose est non seulement une pathologie du cartilage mais aussi de toute larticulation. Dans larthrose et les ar-
thrites inflammatoires chroniques, lintensit de la rponse inflammatoire de larticulation dtermine la perte osseuse
juxta-articulaire. Ainsi, dans la polyarthrite rhumatode, linflammation intense du cartilage et de la synovie, la forma-
tion de pannus et la perte osseuse gnralise provoquent une augmentation du renouvellement osseux sous-chon-
dral entranant une perte osseuse juxta-articulaire. linverse, la synovite modre et clairseme de type arthrosique
conduit un renouvellement osseux sous-chondral plus faible et une perte osseuse ultrieure moins importante
que dans la polyarthrite rhumatode. Langiogense et la croissance des nerfs sensoriels contribuent galement cau-
ser des lsions articulaires de svrit diffrente dans ces arthropathies. Toutefois, les principaux mcanismes pa-
thognes sous-jacents sont probablement communs ces maladies articulaires. De nouvelles stratgies thrapeu-
tiques pour prvenir la perte osseuse et, ventuellement, lvolution des lsions articulaires pourraient tre labores
si les phnomnes impliqus dans la perte osseuse provoque par linflammation au cours de ces maladies taient
mieux compris.
Radiography is the only EMA-

and FDA-recommended imaging
modality for defining the inclusion
criteria and efficacy end points of
a clinical trial. However, it has its
limitations and well-defined MRI-
Role of imaging in
based diagnostic criteria of OA are
needed. MRI plays a crucial role in
understanding the natural history
osteoarthritis: diagnosis,
of the disease and in guiding fu-
ture therapies due to its ability to
image the knee as a whole organ
prognosis, and follow-up
and to directly and three-dimen-
sionally assess cartilage morphol-
ogy and composition.
b y A . G u e r m a z i , F. W. R o e m e r,
and H. K. Genant, USA and Germany
O
steoarthritis is a highly prevalent joint disorder primarily affecting eld-
erly people worldwide. The importance of imaging for assessment
of all the structures of the joint such as cartilage, meniscus, subartic-
ular bone marrow, and synovium for diagnosis, prognostication, and follow-
up has been well recognized over the past decade. Conventional radiography
is still the most commonly used imaging technique for evaluation of a patient
with a known or suspected diagnosis of osteoarthritis. However, recent MRI-
based knee osteoarthritis studies have begun to reveal the limitations of ra-
diography. The ability of MRI to image the knee as a whole organ and to di-
L
Ali GUERMAZI,a MD, PhD rectly and three-dimensionally assess cartilage morphology and composition
Frank W. ROEMER,b MD plays a crucial role in understanding the natural history of the disease and in
a,b
Quantitative Imaging Center the search for new therapies. Use of the appropriate MRI pulse sequences is
Department of Radiology crucial to assess the various features of osteoarthritis, and support from ex-
Boston University School of
Medicine, Boston, USA perienced musculoskeletal radiologists is necessary for study design, image
b
Department of Radiology acquisition, and interpretation. This article describes the roles and limitations
Klinikum Augsburg of conventional radiography and MRI in osteoarthritis imaging, and also pro-
Augsburg, GERMANY vides some insight into the use of other modalities such as ultrasound, nuclear
medicine, computed tomography, and computed tomography arthrography
in clinical practice and research in osteoarthritis, with a particular emphasis
on the assessment of knee osteoarthritis in the tibiofemoral joint.
steoarthritis (OA) is a highly prevalent joint disorder and is becoming in-
O creasingly common, posing major health and economic challenges for ag-
ing industrialized societies. Despite various surgical and symptom-oriented
approaches, there is still no definitive disease-modifying therapy, other than total
Harry K. GENANT, MD joint replacement, for this complex and heterogeneous disease.
Department of Radiology
University of California
San Francisco, USA
Most research studies of knee OA involve acquisition of conventional radiographs
and magnetic resonance images, including the Osteoarthritis Initiative (OAI,
http://www.oai.ucsf.edu/datarelease/), one of the largest epidemiological OA stud-
Professor Ali Guermazi, Department ies.1 The OAI is an ongoing 4-year observational study of approximately 4800 par-
of Radiology, Boston University ticipants, sponsored by the National Institutes of Health, and targeted at identify-
School of Medicine, 820 Harrison
Avenue, FGH Building, 3rd Floor, ing the most reliable and sensitive biomarkers for evaluating the development and
Boston, MA 02118, USA progression of symptomatic knee OA. Data from baseline through the 48-month
(e-mail: [email protected]) follow-up visit for the entire cohort were made publically available in 2011. This ar-
www.medicographia.com ticle aims to describe the current role of radiography and magnetic resonance im-
164 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Imaging of osteoarthritis Guermazi and others
aging (MRI) in OA imaging, and also

to give some insight into the use of A B
other modalities: ultrasound, nuclear
medicine, and computed tomogra-
phy (CT). Current research tends to
focus on the knee due to the high
prevalence of knee OA and the rel-
ative ease of use of MRI compared
with other central appendicular joints.
This nonsystematic review article will
focus primarily on the assessment
C D
of OA in the tibiofemoral joint of the
knee.
Conventional radiography
Radiography is the simplest and least
expensive imaging technique. It can
detect OA-associated bony features
including marginal osteophytes, sub-
chondral sclerosis, and subchondral
cysts.2 Radiography can also deter- Figure 1. Multitissue contribution to joint space narrowing.
(A) Baseline anterior-posterior radiograph showing doubtful joint space narrowing in the medial tibiofemoral com-
mine joint space width (JSW), an in- partment (arrowheads). (B) Follow-up image at 24 months showing a definite increase in joint space loss medially
direct surrogate of cartilage thickness (arrows).(C) Corresponding baseline intermediate-weighted magnetic resonance imaging (MRI) showing normal
and meniscal integrity, but precise cartilaginous tibiofemoral surface and no relevant meniscal extrusion. (D) MRI at 24 months showing definite menis-
cal extrusion (arrows) likely to be responsible for the joint space narrowing on the radiograph.
measurement of each of these artic-
ular structures is not possible by x-ray.3 Despite this, slowing The severity of OA can be estimated using semiquantitative
of radiographically detected joint space narrowing (JSN) is the scoring systems. Published atlases provide images that repre-
only structural end point currently recommended by the reg- sent specific grades.2 The most widely used system, the Kell-
ulatory bodies in the United States (US Food and Drug Ad- gren and Lawrence (K&L) classification,5 has limitations, espe-
ministration [FDA]) and in Europe (European Medicines Agency cially as K&L grade 3 includes all degrees of JSN, regardless
[EMA]) to prove the efficacy of disease-modifying OA drugs of the actual extent. In contrast, the Osteoarthritis Research
in phase-3 clinical trials. OA is defined radiographically by the Society International (OARSI) atlas2 classification grades tibio-
presence of osteophytes.4 Progression of JSN is the most femoral JSW and osteophytes separately for each compart-
commonly used criterion for the assessment of OA progres- ment of the knee. Compartmental scoring appears to be more
sion and the complete loss of JSW characterized by bone- sensitive to longitudinal radiographic changes than K&L grading.
on-bone contact is one of the indicators for joint replacement.
Methods of JSW measurement can be manual or semiauto-
mated using computer software. However, previously held be-
liefs that JSN and its changes are the only visible evidence of
BML bone marrow lesion cartilage damage have been shown to be incorrect. Recent
CE-MRI contrast-enhanced MRI studies have demonstrated that alterations in the meniscus,
CT computed tomography such as meniscal extrusion or subluxation, also contribute to
DESS double-echo steady state JSN (Figure 1).3 The lack of sensitivity and specificity of radi-
dGEMRIC delayed gadolinium-enhanced MRI of cartilage ography for the detection of the pathologic features associ-
FLASH fast low-angle shot ated with OA, and the poor sensitivity to change at follow-up
GRE gradient-recalled echo imaging, are inherent limitations of radiography.
JSN joint space narrowing
JSW joint space width Interestingly, an older methoddigital tomosynthesishas
K&L Kellgren and Lawrence lately experienced a revival. Tomosynthesis generates an ar-
MRI magnetic resonance imaging bitrary number of section images from a single pass of the x-
OA osteoarthritis ray tube. Using 3T MRI as a reference, Hayashi et al found
OAI Osteoarthritis Initiative that tomosynthesis depicted more osteophytes and subchon-
PET positron emission tomography dral cysts than radiography.6 The clinical availability of these
SPGR spoiled gradient echo systems is currently limited, but the potential of this tech-
nique for OA research may be worth exploring.
Imaging of osteoarthritis Guermazi and others MEDICOGRAPHIA, Vol 35, No. 2, 2013 165
Magnetic resonance imaging

Figure 2. Osteoarthritis is a
MRI offers a number of advantages for OA imaging. whole-joint disease process that
First, MRI has a tomographic viewing perspective can only be completely visualized
and thus provides cross-sectional images of the by magnetic resonance imaging.
anatomy free of the projectional limitations of radi- This sagittal intermediate-weighted fat-
saturated image shows diffuse cartilage
ography. Second, MRI is uniquely able to directly de- loss in the medial tibio-femoral joint.
pict all the components of the joint and their patholo- A horizontal-oblique tear extending to
the superior surface is seen in the pos-
gies, including the articular cartilage, menisci, intra- terior horn of the medial meniscus
articular ligaments, synovium, effusion, bone attrition, (arrowhead) and a small subchondral
bone marrow lesions (BMLs), subchondral cysts, cyst appears in the medial weight bear-
ing part of the femoral condyle (arrow).
and intra- and periarticular cystic lesions (Figure 2). There is also joint effusion and a popliteal
The joint can be evaluated as a whole organ, pro- cyst (asterisk) and a small osteophyte
at the posterior medial femoral condyle
viding a much more detailed picture of the changes (no arrow).
associated with OA than is possible with other tech-
niques.7 Third, MRI can detect the pathology of preradiograph- The role of contrast-enhanced MRI (CE-MRI) in the clinical and
ic OA and possible complications of the disease at a much research environment remains to be fully established. Visu-
earlier stage than radiography.8 alization of synovitis in OA is superior on contrast-enhanced
scans using the intravenous paramagnetic agent gadolinium
N Technical considerations with histological correlation,11 and recent studies have shown
Several MRI systems are commercially available but 1.5T sys- that CE-MRI-detected synovitis is associated with knee pain
tems are the most widely used in clinical and research set- (Figure 4).12
tings. Examination times vary depending on the purpose of
the exam, but usually last between 20 and 40 minutes, in- Since different tissues are involved in OA and both morpho-
cluding patient positioning. High-field 3T MRI was introduced logic and quantitative analyses are needed, a variety of dif-
for clinical application several years ago. A higher signal-to- ferent sequences have been developed for whole-organ
noise ratio is a definitive advantage, but disadvantages include assessment of OA. Selecting the appropriate MR pulse se-
increased susceptibility artifacts, high costs, and the limited quences to study specific features of OA is essential for suc-
commercial availability of coils. Most OA studies that include cess. In general, fluid-sensitive fat-suppressed sequences
MRI use 1.5T MRI systems because of their wide availability (eg, T2-weighted, proton-density-weighted, or intermediate-
and reliable image quality. The OAI is one of the few large stud- weighted fast spin-echo sequences) are useful for evaluation
ies to have used a 3T system (Figure 3). of cartilage, bone marrow, ligaments, menisci, and tendons.13
It is particularly important to use these sequences to assess fo-
So far, 7T MRI in humans has only been applied in research.9 cal cartilage defects and BMLs. Gradient-recalled echo (GRE)-
In the future, 7T systems may be able to produce higher-res- type sequences (eg, 3D-spoiled gradient echo at steady state
olution images with a shorter scan time than 3T systems. So [SPGR], double-echo steady state [DESS], and fast low-an-
far, however, the available 7T protocols have not been any gle shot [FLASH]) are not suitable for marrow or focal defect
better than 3T for knee cartilage evaluation.10 assessment. They are prone to susceptibility artifacts, which
A B C
Figure 3. Development of a focal cartilage defect over two years as visualized with 3T magnetic resonance imaging (MRI).
(A) Coronal intermediate-weighted image showing a small superficial cartilage defect in the weight-bearing part of the medial femoral condyle (arrow). (B) Follow-up
MRI at 12 months reveals extension of defect to the subchondral bone, now representing a full-thickness focal lesion (arrow). (C) MRI image at 24 months showing
a slight increase in the size of the focal full thickness defect.
Figure 4. Visualiza- Knee Score (MOAKS).22 MOAKS is a recent effort to combine

tion of synovitis on the strengths of existing systems, but little information on its
contrast-enhanced
use has been published to date. In addition to these scoring
magnetic resonance
imaging (MRI). systems based on non-enhanced MRI, semiquantitative scor-
Sagittal T1-weighted fat- ing systems for synovitis using contrast-enhanced MRI have
saturated image showing been proposed.12,23 In particular, the system proposed by Guer-
severe synovitis in the
suprapatellar recess (ar- mazi et al enables comprehensive assessment of synovitis
rowheads), at the Hoffa fat in the whole knee joint,12 rather than being restricted to the
pad (small arrow) and es-
pecially posterior to the peripatellar regions.23 These contrast-enhanced MRIbased
posterior cruciate ligament, scoring systems will enable longitudinal assessment of syn-
the most common location
of synovitis in osteoarthrit-
ovitis in future clinical trials.12
ic knees (large arrow). Syn-
ovitis cannot be visualized Recently, MRI-based semiquantitative scoring systems for
with nonenhanced MRI.
hand OA (Oslo Hand OA MRI score [OHOA-MRI]) and hip
hinder accurate interpretation of images.14 GRE-type se- OA (Hip OA MRI Scoring system [HOAMS]) have been pro-
quences also usually require long imaging times, and motion posed.24,25 However, further validation, evaluation of respon-
artifacts can degrade image quality.15 A recent study demon- siveness, and iterative refinement of these new systems are
strated that focal cartilage lesions were more conspicuous needed to assess their utility in clinical trials and epidemiolog-
and larger on the intermediate-weighted fast spin-echo se- ical studies. To the authors knowledge, no semiquantitative
quence with fat suppression compared with the DESS se- scoring systems enabling evaluation of other joints, such as
quence.16 It was also shown that GRE-
type sequences have limited sensitivity A B
to BMLs compared with fast spin-echo
sequences (Figure 5).17 For synovitis,
CE-MRI is preferable to nonCE-MRI,
but if only nonCE-MRI is available, gra-
dient-echo type sequences should again
be avoided because they are prone to
chemical shift artifacts, making accu-
rate assessment difficult.18
On the other hand, GRE-type sequences

do provide high spatial resolution and
excellent contrast of cartilage to sub-
chondral bone, and are well suited for
quantitative measurement of volume Figure 5. Sequence selection for visualizing specific osteoarthritis features.
and thickness.15 MRI is a powerful tool (A) Coronal proton-density-weighted fat-saturated image showing a large bone marrow lesion (BML) in the
central part of the medial femur (ill-defined area of hyperintensity indicated by arrows). A large BML is also
for OA research, but it is also complex depicted in the medial tibial plateau (asterisk). (B) Fast low-angle shot (FLASH) image. Although commonly
and how it is used is largely determined used for cartilage segmentation due to the excellent contrast between cartilage and subchondral bone and
by the goal of the research. Clinicians high resolution acquisition, the FLASH image depicts the femoral BML poorly compared with the proton-
density-weighted image (arrow). The large tibial BML can barely be distinguished on the FLASH image.
planning clinical OA research using MRI-
derived data should seek expert advice from trained and ex- the shoulder, elbow, and ankle, as a whole joint have been
perienced musculoskeletal radiologists on which pulse se- published. A limited number of small studies have been pub-
quences are best suited to their purpose. lished recently involving cartilage repair techniques or novel
imaging methodologies for these joints.26
N Semiquantitative MRI whole-organ scoring
Semiquantitative whole-organ scoring has been applied to N Compositional imaging of cartilage
a multitude of OA studies.7,19 Analyses based on semiquan- Compositional MRI can assess the biochemical properties of
titative scoring have added greatly to our understanding of different joint tissues and is thus very sensitive to early pre-
the pathophysiology and natural history of OA as well as to morphologic changes. The vast majority of studies applying
the clinical implications of structural changes. A short list of compositional MRI have focused on cartilage, although the
semiquantitative scoring systems includes the Whole-ORgan technique can also be used to assess other tissues such as
Magnetic resonance imaging Score (WORMS),7 the Knee Os- the meniscus or ligaments.27 T2 mapping has been used to
teoarthritis Scoring System (KOSS),20 the Boston Leeds Os- describe the molecular composition of hyaline cartilage in the
teoarthritis Knee Score (BLOKS),21 and the MRI OsteoArthritis knee on the basis of collagen structure and hydration.
In healthy cartilage, T2 values increase from deep to super- index over 12 months in the medial but not in the lateral tibio-
ficial cartilage layers.28 It has been shown that T2 values are femoral compartment. This finding supports the notion that
related to age and activity levels and that they are associated body weight affects disease progression and emphasizes the
with OA severity.29,30 T2* relaxation measures have also been role of weight loss in clinical and structural improvement.38
tested for their ability to depict the collagen matrix. T2* map-
ping was shown to be a reproducible process that can differ- Novel compositional techniques have been reported. Raya et
entiate between OA and non-OA subjects.31 al studied the feasibility of in vivo diffusion tensor imaging at
7T MRI and demonstrated better discrimination of OA ver-
T1rho is also sensitive to the interactions of water with macro- sus non-OA knees than with T2 mapping.39 Although this tech-
molecules. It has been shown to correlate with the proteogly- nique shows promise, it will have to be more practical and
can concentration in cartilage,32 and is also sensitive to col- widely available for use with standard MRI systems before it
lagen.33 Although T1rho has been shown to have a larger can be applied in broader clinical research settings.
A B C
Figure 6. Biochemical magnetic resonance imaging.

(A) Sagittal intermediate-weighted fat-saturated image depicts a horizontal-oblique tear of the posterior horn of the medial meniscus (arrow). (B) Corresponding baseline
color-coded T1-weighted image showing normal delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) map of femoro-tibial cartilage. (C) At 24 months there is
a marked decrease in the dGEMRIC index in the medial femoral cartilage (coded in red - arrowheads). An incidental partial meniscal maceration is also seen (arrow).
dynamic range than T2,34 it is more complex to implement, N Quantitative cartilage morphometry
and is limited by radiofrequency power deposition. It has been Quantitative analysis of knee OA features has been applied
reported that T1rho and T2 values show different spatial dis- mainly to cartilage morphology, where the three-dimensional
tributions and may provide complementary information on car- nature of MRI data can be exploited to assess tissue param-
tilage degeneration.35 eters such as volume, thickness, or other continuous vari-
ables. The real strength of quantitative measurements is that
Sodium MRI and the delayed gadolinium-enhanced MRI of they are more objective and less observer-dependent than
cartilage technique (dGEMRIC) are designed to measure fixed semiquantitative scoring methods and that relatively small
charge densities in cartilage and, by implication, its proteo- changes in cartilage thickness or volume can be detected over
glycan content (Figure 6).36 These techniques are based on time.40 Correctly segmenting the cartilage requires well-trained
the premise that mobile ions will distribute themselves in car- users, working either manually or with segmentation software.
tilage in relation to the concentration of the charged proteo- Most investigations have focused on measuring cartilage vol-
glycan molecules; in MRI, the mobile ions are the naturally ume, but volume has its limitations. Discrimination of patients
abundant sodium, or the negatively charged MRI contrast with OA from healthy subjects is limited because men in
agent Gd(DTPA)2 (Magnevist, Berlex, NJ, USA). general, and anybody with large bones, will have larger joint
surfaces and more cartilage volume, so there is a wide over-
In the dGEMRIC technique, Gd(DTPA)2 is injected intravenous- lap between groups.41 While this problem can be mostly over-
ly, and images are acquired typically around 90 minutes af- come by adjusting the analysis for the bone surface area in
ter injection. The negative charge on the Gd(DTPA)2 molecule each subject, a new analytic strategy called extended ordered
causes it to disperse into the cartilage in inverse relation to values has been proposed.42 The extended ordered values
the negatively charged glycosaminoglycan molecular concen- approach sorts changes in subregional thickness in the me-
tration.37 A recent interventional study evaluating the effect dial and lateral tibial and femoral cartilage plates in ascending
of weight loss on articular cartilage showed an improvement order. This analytic method enables more efficient measure-
in cartilage quality reflected by an increase in the dGEMRIC ment of changes in cartilage thickness, independently of their
anatomical locations, and shows better sensitivity for de- tenuation difference between the cartilage and the contrast
tecting differences in longitudinal rates of cartilage loss than medium within the joint make focal morphologic changes con-
anatomical subregions and radiography.42 spicuous. Limitations of the technique are its insensitivity to
changes of the deep layers of cartilage without surface alter-
Ultrasound ations and its invasive nature.
Ultrasound is a technique that enables multiplanar and real-
time imaging at a relatively low cost, without radiation expo- Nuclear medicine
sure. It has the ability to image soft tissue and to detect syn- Scintigraphy uses radiopharmaceuticals to visualize skeletal
ovial pathology without the need for contrast administration. metabolism, to contribute to the localization of disease, and
Limitations of ultrasound are primarily that it is an operator-de- to assess the severity of pathologic changes in OA. 99mTC-hy-
pendent technique and that the physical properties of sound droxymethane diphosphate scintigraphy shows increased
hinder its application to deeper articular structures and the activity during the bone phase in the subchondral region in
subchondral bone. The ability to detect synovial pathology is nodal hand OA.49 This finding can be observed before the typ-
perhaps the major advantage of ultrasound over radiography. ical radiographic changes and reflects the osteoblastic activ-
Ultrasound-detected grey-scale synovitis has been validated ity of early cartilage loss. A study comparing MRI with scintig-
against arthroscopy, MRI, and histology in large-joint OA, and raphy in patients with chronic knee pain demonstrated good
ultrasound has been demonstrated to be more sensitive than agreement between MRI-detected subchondral BMLs and
clinical examination in detecting synovial hypertrophy and joint radionuclide uptake, but generally poor agreement between
effusion.43 Additionally, color-coded Doppler signal has been increased bone uptake and cartilage defects or osteophytes.50
validated as an indirect measure of histological synovial vas- A prospective study showed that a normal bone scan at base-
cularity in large-joint OA.44 Tissues other than synovium have line was highly predictive of a lack of progression of knee OA
also been studied using ultrasound. Saarakkala et al com- over a 5-year period.51 Two other recent studies showed that
pared knee ultrasonography to arthroscopic grading for de- scintigraphy may predict JSN, but no better than baseline ra-
tecting degenerative changes in articular cartilage.45,46 The au- diographic or pain status.52,53
thors concluded that positive findings on ultrasound are strong
indicators of degenerative changes in cartilage, but also stat- Positron emission tomography (PET) demonstrates metabol-
ed that negative findings do not rule out degenerative cartilage ic changes in target tissues and can detect foci of inflamma-
alterations. A study by Kawaguchi et al used ultrasound to tion, infection, and tumors. PET utilizes 2-18F-fluoro-2-deoxy
look at medial radial displacement of the meniscus in the D-glucose (FDG) and reflects glucose metabolism. A recent
supine and weight-bearing positions and showed that the pilot study in knees with medial OA showed increased uptake
medial meniscus was significantly displaced radially by weight in periarticular regions, the intercondylar notch, and also in
bearing in control knees and in knees with K&L grades 1-3.46 areas of subchondral bone marrow corresponding to MRI-de-
Its use with dynamic and weight-bearing conditions is one tected BMLs.54 A recent animal study showed increased up-
of the inherent strengths of ultrasound and warrants further take of FDG after experimentally induced knee OA in rats,
exploration. suggesting that PET could be useful for early detection of OA
changes.55 However, whether FDG-PET will have a role in the
Computed tomography assessment of OA in a clinical and research setting remains
CT is a valuable tool for the characterization of OA, particular- to be seen. Limitations of PET include its limited availability,
ly when imaging of osseous changes or detailed presurgical high radiation exposure, and costs.
planning is required. Helical multidetector (MD) CT systems
enable acquisition of isotropic voxels and multiplanar recon- Conclusion
structions in any given plane with quality equal to the original Conventional radiography is still the first and most widely used
plane. Cortical bone and soft tissue calcifications are better imaging technique for evaluation of a patient with a known or
depicted than on MRI. CT has an established clinical role in suspected diagnosis of OA. In research and clinical trials it is
assessing facet joint OA of the spine.47 Drawbacks are its low the only EMA- and FDA-recommended imaging modality for
soft-tissue contrast and the relatively high dose of radiation it defining the inclusion criteria and efficacy end points of a clin-
delivers. CT arthrography is an alternative method for indirect ical trial. However, radiography has its limitations and well-de-
visualization of cartilage and other intrinsic joint structures, fined MRI-based diagnostic criteria of OA are needed. MRI
especially in the knee joint. CT arthrography may be relevant plays a crucial role in understanding the natural history of the
especially where access to MRI facilities is limited or when disease and in guiding future therapies due to its ability to
MRI is contraindicated. Spiral CT arthrography of the knee image the knee as a whole organ and to directly and three-
and shoulder enables excellent imaging of the articular sur- dimensionally assess cartilage morphology and composition.
face.48 Penetration of contrast medium into the deeper layers Ultrasound and contrast-enhanced MRI play important sub-
of the cartilage surface indicates an articular-side defect of the sidiary roles in the diagnosis and follow-up of treatment of OA-
chondral surface. The high spatial resolution and the high at- related synovitis. I
References
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20. Kornaat PR, Ceulemans RY, Kroon HM, et al. MRI assessment of knee osteo- 44. Walther M, Harms H, Krenn V, Radke S, Faehndrich TP, Gohlke F. Correlation of
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21. Hunter DJ, Lo GH, Gale D, Grainger AJ, Guermazi A, Conaghan PG. The reli- 45. Saarakkala S, Waris P, Waris V, et al. Diagnostic performance of knee ultrasonog-
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22. Hunter DJ, Guermazi A, Lo GH, et al. Evolution of semi-quantitative whole joint medial radial displacement of the medial meniscus in knee osteoarthritis. Arthri-
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tis Cartilage. 2011;19:990-1002. 47. Hechelhammer L, Pfirmann CW, Zanetti M, Hodler J, Boos N, Schmid MR. Im-
23. Baker K, Grainger A, Niu J, et al. Relation of synovitis to knee pain using con- aging findings predicting the outcome of cervical facet joint blocks. Eur Radiol.
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24. Haugen IK, Lillegraven S, Slatkowsky-Christensen B, et al. Hand osteoarthritis 48. Vande Berg BC, Lecouvet FE, Poilvache P, et al. Assessment of knee cartilage
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25. Roemer FW, Hunter DJ, Winterstein A, et al. Hip Osteoarthritis MRI Scoring 49. Hutton CW, Higgs ER, Jackson PC, Watt I, Dieppe PA. 99mTc HMDP bone
scanning in generalised nodal osteoarthritis. II. The four hour bone scan image grade. J Rheumatol. 2004;31:329-332.
predicts radiographic change. Ann Rheum Dis. 1986;45:622-626. 53. Mazzuca SA, Brandt KD, Schauwecker DS, et al. Severity of joint pain and
50. Boegard T, Rudling O, Dhalstrom J, Dirksen H, Petersson IF, Jonsson K. Bone Kellgren-Lawrence grade at baseline are better predictors of joint space nar-
scintigraphy in chronic knee pain: comparison with magnetic resonance imag- rowing than bone scintigraphy in obese women with knee osteoarthritis. J Rheu-
ing. Ann Rheum Dis. 1999;58:20-26. matol. 2005;32:1540-1546.
51. Dieppe P, Cushnaghan J, Young P, Kirwan J. Prediction of the progression of 54. Nakamura H, Masuko K, Yudoh K, et al. Positron emission tomography with 18F-
joint space narrowing in osteoarthritis of the knee by bone scintigraphy. Ann FDG in osteoarthritic knee. Osteoarthritis Cartilage. 2007;15:673-681.
Rheum Dis. 1993;52:557-563. 55. Umemoto Y, Oka T, Inoue T, Saito T. Imaging of a rat osteoarthritis model us-
52. Mazzuca SA, Brandt KD, Schauwecker DS, et al. Bone scintigraphy is not a ing (18)F-fluoride positron emission tomography. Ann Nucl Med. 2010;24:663-
better predictor of progression of knee osteoarthritis than Kellgren and Lawrence 669.
Keywords: magnetic resonance imaging, osteoarthritis, radiography, ultrasound
RLE DE L IMAGERIE DANS LARTHROSE : DIAGNOSTIC , PRONOSTIC , ET SUIVI

Larthrose est une maladie articulaire la prvalence leve touchant essentiellement les sujets gs du monde en-
tier. Les dix dernires annes ont reconnu limportance de limagerie dans lvaluation des structures articulaires (car-
tilage, mnisque, moelle osseuse sous-chondrale, synovie) pour le diagnostic, le pronostic et le suivi. La radiographie
conventionnelle est toujours la technique la plus couramment utilise dans lvaluation dun patient pour lequel lar-
throse est connue ou suspecte. Ses limites ont nanmoins t mises en vidence par des tudes rcentes sur lar-
throse du genou utilisant lIRM. La capacit de lIRM reprsenter le genou comme un organe part entire et
valuer la morphologie et la composition du cartilage directement et en trois dimensions joue donc un rle essen-
tiel dans la comprhension de lhistoire naturelle de la maladie et dans la recherche de nouveaux traitements. Lva-
luation des diffrentes caractristiques de larthrose ncessite des squences IRM adquates et la comptence de
radiologues expriments dans la pathologie musculosquelettique est indispensable pour la conception des tudes,
ainsi que pour lacquisition et linterprtation des images. Cet article prsente les rles et limites de la radiographie
conventionnelle et de lIRM dans limagerie de larthrose et aborde galement lutilisation dautres techniques comme
lchographie, la mdecine nuclaire, la tomodensitomtrie et larthro-scanner en pratique clinique et dans la re-
cherche sur larthrose, en insistant plus particulirement sur lvaluation de larthrose du genou au niveau de larti-
culation tibio-fmorale.
Guidelines for the medical

management of osteoarthritis fo-
cus on controlling pain and im-
proving function and quality of
life while minimizing therapeutic
toxicity Clinicians managing os-
Osteoarthritis treatments:
teoarthritis are able to draw upon a
wide spectrum of therapeutic op-
tions, combining nonpharmaco-
where do we stand
logical approaches and pharma-
cological treatments both to relieve
pain and to attempt to delay dis-
at the moment?
ease progression The current
therapeutic options, however, are
neither exclusive nor sufficient.
b y C . R o u b i l l e , J . M a r t e l - Pe l l e t i e r,
a n d J . P. Pe l l e t i e r, C a n a d a
O
steoarthritis is the most common form of arthritis and results in pain
and reduced quality of life. Although a structure-modifying treatment
remains the greatest unmet need in osteoarthritis, several sympto-
matic treatments are available. This article will review the nonpharmacolog-
ical approaches and pharmacological treatments currently available for os-
teoarthritis management, as well as the surgical treatments available for the
condition. At present, a multimodal approach combining nonpharmacologi-
cal and pharmacological treatments is still the best option for the manage-
ment of osteoarthritis, as recommended in the guidelines of Osteoarthritis
Research Society International and the American College of Rheumatology.
Camille ROUBILLE, MD Nonpharmacological management mainly relies on patient education, exer-
cise, prevention of injuries, weight loss in overweight patients, and use of or-
thotic devices. Pharmacological symptomatic treatments include a number
of analgesic options such as acetaminophen, nonsteroidal anti-inflammatory
drugs (NSAIDs), opioids, duloxetine, topical NSAIDs, capsaicin, lidocaine patch-
es, intra-articular corticosteroids and hyaluronic acid injections, and slow-
acting drugs including glucosamine and chondroitin sulfate, diacerein, and
avocado soybean unsaponifiables. When the combination of nonpharmaco-
logical and pharmacological approaches becomes unsuccessful at managing
symptoms, surgical treatment may be considered.
L
Johanne MARTEL-PELLETIER, PhD
Jean-Pierre PELLETIER, MD
Nonpharmacological management
Osteoarthritis Research Unit
he combination of patient education, improved muscle strength, and reduced
University of Montreal Hospital
Research Centre
University of Montreal
Montreal, Quebec, CANADA
T body mass index has been reported to be joint protective. Recent guidelines
from the American College of Rheumatology (ACR) strongly recommend weight
loss for overweight patients with knee or hip osteoarthritis, as well as cardiovascu-
lar and/or resistance land-based exercises and aquatic exercise.1 No preference
is made regarding aquatic versus land-based exercise, as the choice will depend
Address for correspondence: on individual ability. As to date there have been very few high-quality randomized
Professor Jean-Pierre Pelletier, controlled trials reported in the literature, the ACR conditionally recommends self-
Osteoarthritis Research Unit,
University of Montreal Hospital management programs, manual therapy in combination with supervised exercise,
Research Centre (CRCHUM), psychosocial interventions, use of thermal agents, walking aids if needed, tai chi,
Notre-Dame Hospital,
1560 Sherbrooke Street East,
Chinese acupuncture, and transcutaneous electrical stimulation. For hand os-
Montreal, Quebec H2L 4M1, teoarthritis, assistive devices, joint protection techniques, thermal modalities, and
Canada (e-mail: [email protected]) trapeziometacarpal joint splints are also conditionally recommended by the ACR
www.medicographia.com guidelines.1
172 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Osteoarthritis treatments: where do we stand at the moment? Roubille and others
N Patient education of weight at a lower level seems to reduce osteoarthritis-re-

Patient education should form the cornerstone of nonphar- lated pain.12 Weight loss in obese people was reported to im-
macological management for osteoarthritis,2,3 and patients prove the content of the macromolecule proteoglycan in the
should be involved in the management of their condition as cartilage, as well as the cartilage thickness in the medial, but
much as possible.3 Indeed, as with other chronic diseases, pa- not lateral, compartment of the knee.13 Interestingly, obesity in-
tients should know about their conditions evolution over time creases the risk of progressive osteoarthritis in neutrally aligned
as well as its management and any associated investigations, knees or those in valgus alignment, but not in patients with
and this can be achieved through use of books, regular tele- varus alignment.14 Thus, overload alone across the joints does
phone calls, and education groups. It has been suggested not seem to be sufficient to induce the development of os-
that education contributes to pain reduction and optimization teoarthritis. As obese individuals also have a higher incidence
of health care resource usage.4 of osteoarthritis in nonweight-bearing areas, including finger
joints, it has been suggested that factors such as adipokines,
N Exercise programs one representative of this family being leptin, could promote
Physical activity involving aerobic and/or resistance land-based cartilage damage, thus inducing osteoarthritis.15,16 Therefore,
exercises and/or aquatic exercises, including local muscle although mechanical factors may be one element favoring the
strengthening and general fitness, is recommended for osteo- development of osteoarthritis in obese patients, inflammatory
arthritis patients.1 Strengthening exercises, especially for the mediators also appear to be important contributing factors.
quadriceps femoris muscle, may improve muscular balance, Thus, in addition to weight loss, additional treatments may
decrease impact loads, and support function, and they have eventually be required for optimal therapeutic intervention.
also been reported to reduce pain and disability in hip5 and
knee osteoarthritis.6 Water-based exercises have been shown N Orthotic devices
to have short-term effects on pain relief for patients with hip Orthotic devices such as special footwear, insoles, knee brac-
and/or knee osteoarthritis.7 In addition, contrary to popular being, and canes are recommended for patients with hip and/or
lief, runningeven long distancesas part of normal nonpro- knee osteoarthritis.2,17 The latest ACR guidelines recommend
fessional conditioning does not accelerate the development medially-directed patellar taping, as well as medially-wedged
of osteoarthritis of the knee.8 However, the risk of osteoarthri- insoles for patients with lateral compartment knee osteo-
tis development may be different for middle-intensity levels of arthritis, and laterally-wedged subtalar strapped insoles for
running compared with high or competitive levels: moderate those with medial compartment knee osteoarthritis.1 Canes
regular running may be safe, whereas professional runners held in the contralateral hand as a walking aid can reduce pain
may have an increased risk for osteoarthritis.9,10 in patients with hip and knee osteoarthritis. In knee osteo-
arthritis, use of braces1 and sleeves was shown to have ben-
N Prevention of injuries eficial effects compared with medical treatment alone (aceta-
Prevention of injuries is necessary in contact sports such as minophen, nonsteroidal anti-inflammatory drugs [NSAIDs]),
soccer.11 Increased joint traumatisms such as anterior cruci- as assessed by the Western Ontario and McMaster Universi-
ate ligament lesions or meniscal lesions increase the risk of ties Arthritis index (WOMAC) and function tests.18 Moreover,
developing osteoarthritis. Effective treatment such as postop- braces seem to be more effective than sleeves, and laterally-
erative rehabilitation should decrease this risk. wedged insoles may decrease NSAID intake compared with
neutral insoles.18
N Weight loss
Does weight loss reduce osteoarthritis symptoms and pre- N Alternative therapies
vent overall progression of structural damage? This is a most Acupuncture3 and transcutaneous electrical stimulation17 have
important and relevant question in the management of os- been reported to show some short-term pain relief efficacy,
teoarthritis. In obese patients, weight loss and maintenance and they are considered alternative strategies for the man-
agement of osteoarthritis. These strategies are conditionally
recommended by the ACR guidelines for those patients with
knee osteoarthritis who are candidates for total knee arthro-
ACR American College of Rheumatology plasty but are unwilling or unable to undergo surgery because
ASU avocado soybean unsaponifiables of comorbidities or concomitant medications contraindicating
COX cyclooxygenase such surgery.1
NSAID nonsteroidal anti-inflammatory drug
OARSI Osteoarthritis Research Society International
Pharmacological treatment
TKA total knee arthroplasty
The prescribing habits of physicians have changed over time.
UKA unicondylar knee arthroplasty
Because osteoarthritis is a chronic disease and is more com-
WOMAC Western Ontario and McMaster Universities Arthritis
index mon in people aged over 60 years, safety remains critical.
Guidelines for the medical management of osteoarthritis fo-
Osteoarthritis treatments: where do we stand at the moment? Roubille and others MEDICOGRAPHIA, Vol 35, No. 2, 2013 173
Treatment type Adverse effect/safety profile

Acetaminophen GI discomfort, bleeding; renal failure; hypertension; hepatotoxicity
NSAIDs; coxibs GI ulcer/bleeding; cardiovascular events; renal events
Oral Opioids Constipation; vomiting; somnolence; increased risk of fracture,
morbidity, and mortality in elderly
Duloxetine Constipation; nausea; hyperhidrosis
Symptomatic
drugs Topical NSAIDs Skin reactions; Gl events
Topical Capsaicin Skin burning sensation; long-term skin desensitization?
Lidocaine patches
Intra-articular corticosteroids Local infection, systemic effects
Injectable
Intra-articular hyaluronic acid Local reactions at the site of injection, swelling, flares of pain
or viscosupplementation
Glucosamine and chondroitin
sulfate
Slow-acting
symptomatic Oral Diacerein Lower GI effects
drugs
Avocado soybean
unsaponifiables
Table I. Adverse effects of different pharmacological options for the treatment of osteoarthritis.
Abbreviations: GI, gastrointestinal; NSAID, nonsteroidal anti-inflammatory drug.
cus on controlling pain and improving function and quality es, acetaminophen can cause asymptomatic elevation of liver
of life while minimizing therapeutic toxicity (see Table I for an enzymes in healthy people.24 The implications of this remain
overview of the adverse effects of the different pharmacolog- unclear, but it is recommended that acetaminophen should
ical treatments available).2,3,17 For hand osteoarthritis, the re- not be used in patients with existing liver dysfunction or re-
cent ACR guidelines recommend topical capsaicin, topical lated risk factors. On the basis of the aforementioned infor-
NSAIDs, oral NSAIDs including cyclooxygenase (COX)-2 in- mation, it is recommended that the lowest effective dose of
hibitors, and tramadol.1 They also advise against the use of acetaminophen be used for pain relief.
opioids or intra-articular treatments for this condition. For knee
and hip osteoarthritis, acetaminophen, oral NSAIDs, topical NSAIDs are generally recommended for patients who are un-
NSAIDs (except for hip osteoarthritis), tramadol, and intra-ar- responsive to appropriate dosages of acetaminophen. These
ticular steroid injections are recommended.1 should be prescribed at the lowest dose and for the shortest
possible duration,17 and preferentially for inflammatory flares.
N Symptomatic treatments According to the new ACR guidelines,1 NSAIDs should be
N Oral analgesics used for the initial management of hand, hip, and knee os-
Acetaminophen remains the first-line therapeutic agent for teoarthritis, as with acetaminophen and tramadol. Moreover,
mild-to-moderate pain2,3,17 because of its low cost and its ef- for patients aged over 75 years, rather than prescribing oral
ficacy and safety profile for doses not exceeding 4 g per day NSAIDs, guidelines recommend the use of topical NSAIDs,
(although a maximum of 3 g is more advisable, in line with US duloxetine, tramadol, or intra-articular hyaluronan injections.
Food and Drug Administration recommendations). If found to In patients suffering from upper gastrointestinal ulcers with-
be successful at alleviating pain, it is recommended that acet- out any gastrointestinal bleeding in the prior year, for cases
aminophen be the preferred long-term oral analgesic.2 It has where the physician chooses to prescribe an NSAID, the ACR
been reported that acetaminophen is less effective at reliev- and Osteoarthritis Research Society International (OARSI)
ing osteoarthritis pain than NSAIDs19 but more effective than guidelines recommend the use of either a COX-2 inhibitor
placebo.20 However, this result was not confirmed by a study rather than a nonselective NSAID, or a nonselective NSAID
using WOMAC and the Lequesne index to assess efficacy.20 combined with a proton-pump inhibitor.1,17 For patients with
The use of analgesics in osteoarthritis should take into account reports of gastrointestinal bleeding within the past year, the
the clinical context, however. Significant adverse effects have use of a COX-2 inhibitor in association with a proton-pump
been reported with acetaminophen, including gastric ulcera- inhibitor is recommended.1 Although NSAIDs are known to
tions and bleeding, increased risk of mild loss of renal function be superior to acetaminophen for pain relief,19 their use is lim-
with long-term consumption, and hypertension with doses of ited by a number of adverse effects, including gastrointestinal,
up to 3 g per day.21-23 Furthermore, even at therapeutic dos- renal, and cardiovascular adverse effects, which increase with
age.25-27 The risk level varies according to the drug and dosage. has been shown to involve centrally-mediated pain pathway
COX-2 inhibitors were shown to be as effective as convention- dysfunction, which has led to the study of drugs that have a
al NSAIDs for pain relief, with fewer gastrointestinal compli- centrally-mediated action. Duloxetine is a selective serotonin
cations,28 but with a potential cardiovascular risk27which is and norepinephrine reuptake inhibitor with central nervous sys-
also shared by conventional NSAIDs. Physicians should there- tem activity that is already used in three chronic pain condi-
fore take into account their patients comorbidities and as- tions: diabetic peripheral neuropathic pain, fibromyalgia, and
sess their individual global risk before prescribing NSAIDs. chronic low back pain. Recently, duloxetine was found to im-
prove pain as well as function in knee osteoarthritis, as eval-
In recent years, opioids have become a widely prescribed uated by clinically relevant outcomes in two 13-week trials.33
class of drugs, especially for osteoarthritic patients who either
have contraindications or an intolerance to NSAIDs or who The drugs effect is related to a direct analgesic effect, inde-
have failed to respond to both acetaminophen and NSAID pendent of improvement of depression and anxiety. The main
treatment.2,17 Opioids are recommended by the new ACR adverse events reported included nausea, constipation, and
guidelines for patients with symptomatic knee osteoarthritis hyperhidrosis. Duloxetine is recommended by the ACR guide-
who have not had an adequate response to nonpharmaco- lines as an alternative treatment for patients with symptomatic
logical or pharmacological modalities and are either unwilling knee osteoarthritis who have failed to respond to both phar-
to undergo or are not candidates for total joint arthroplasty.1 macological and nonpharmacological options.1 Controlled
However, opioids are not recommended for the management trials to compare duloxetine with other interventions in os-
of hand osteoarthritisrelated pain.1 It is common to start with teoarthritis and to evaluate its efficacy in combination with
a weak opioid such as codeine or tramadol, often in combi- other therapies may be useful to potentially enhance treat-
nation with acetaminophen, and if ineffective or not tolerated, ment options.
to use a stronger opioid like hydrocodone, oxycodone, mor-
phine, or transdermal fentanyl. However, adverse events are N Topical treatments
frequent and significant, and include sedation, constipation, Adjuvant topical therapies are interesting treatments that can
urinary retention, nausea and vomiting, respiratory depression, be used to decrease the consumption of analgesics. Topical
and confusion. Impaired coordination and judgment can lead NSAIDs, such as diclofenac and ketoprofen, seem to be as
to falls, particularly in older adults who are more susceptible effective as oral NSAIDs34,35 but with a lower risk of systemic
to opioid-related effects as a result of renal insufficiency and/or exposure and gastrointestinal complications. Their principal
lower lean body mass. In elderly people, opioids may cause reported adverse effect is local skin reactions. They are rec-
severe injuries from falls, such as hip fractures, or even death. ommended as alternative or adjuvant therapy,17 although ACR
Fracture risk appears to be greater with opioids than with guidelines recommend them for the initial management of knee
NSAIDs in older people, and the risk increases with higher opi- osteoarthritis and prefer them to oral NSAIDs for patients old-
oid dosage, especially during the first 2 weeks after initiating er than 75 years of age.1
short-term opioid therapy.29 Moreover, it seems that opioids
do not improve patient functioning30 or quality of life. Capsaicin, the active principle ingredient of hot chili peppers,
can cause depletion of substance P from sensory nerve end-
Patients with osteoarthritis have been shown to have higher ings and reduce or abolish the transmission of painful stimuli.
mortality than the general population, particularly because of However, its effectiveness and safety in pain relief remains con-
cardiovascular events. This appears to be strongly related to troversial.36 A burning sensation is the most common adverse
walking disability and reduced physical activity.31 Thus, im- effect, particularly during the first week of application.36 It is
mobility resulting from osteoarthritis may shorten lifespan. One still unclear if long-term capsaicin treatment can cause per-
may wonder if opioids, by reducing patient mobility, may re- sistent desensitization of the skin that may not be totally re-
duce life expectancy by increasing cardiovascular risk. How- versible. Capsaicin is recommended by guidelines for the
ever, this relationship has not yet been established.31 The use initial management of hand osteoarthritis, but not knee os-
of opioids in a chronic and painful disease such as osteoarthri- teoarthritis.1,2
tis is still controversial for many reasons. It is recommended
that opioid treatment be started at a low dose and gradually Lidocaine patches, which are approved for postherpetic neu-
adjusted upwards, taking into account renal function, age, and ralgia, have also been reported to reduce neuropathic pain as-
other relevant risk factors. Long-term opioid use should be sociated with moderate to severe osteoarthritis of the knee,
avoided or at least regularly reevaluated.32 The benefits of us- without any reported treatment-related adverse effects.37
ing opioids should be weighed as judiciously as possible.
For the past few years, antidepressants have been used in N Injectable therapies
chronic pain management because of their reported analgesic Intra-articular injection of a long-acting corticosteroid is rec-
action, which is independent of their antidepressive effect. In ommended for relief of pain from osteoarthritic flares, especial-
recent years, the chronic pain often observed in osteoarthritis ly if accompanied by effusion and when NSAIDs are ineffec-
tive.2,17 The ACR guidelines recommend intra-articular cortico- sible.43 This explains why in the latest ACR guidelines, these
steroid injections for the initial management of knee and hip agents were not recommended for treatment of osteoarthritis.1
osteoarthritis.1 Short-term pain reduction in knee osteoarthri- Glucosamine sulfate was found to be effective as an osteo-
tis occurs after 2 to 3 weeks, but has no significant effect on arthritic pain relief treatment and for improvement of func-
function. The Cochrane Database of Systematic Reviews re- tion.42 Recommendations using the Grading of Recommen-
ported that after 4 weeks, there was no effect on pain, phys- dations Assessment, Development and Evaluation (GRADE)
ical function, or stiffness.38 However, repeated injections of in- system concluded that glucosamine sulfate demonstrated
tra-articular corticosteroids every 3 months for 2 years showed pain reduction and improvement in physical function with very
pain relief efficacy after 1 year but not after 2 years.38 The long- low toxicity and with moderate-to-highquality evidence.44 The
term safety of repeated intra-articular steroid injections in latest OARSI guidelines recommend the use of glucosamine
symptomatic knee osteoarthritis has been demonstrated, with sulfate and chondroitin sulfate for osteoarthritis treatment, as
improvement of osteoarthritis symptoms for up to 2 years.39 they demonstrated pain relief with a moderate to large effect
Comparisons between corticosteroids have revealed that tri- size (0.58 and 0.75, respectively).3 When a purified preparation
amcinolone hexacetonide is superior to beta-methasone.38 of glucosamine sulfate is used, it appears to be safein partic-
ular, with no induction of glucose intolerance in healthy adults.46
Viscosupplementation could have a significant benefit for knee The protective effect of glucosamine sulfate on structural pro-
osteoarthritis, despite some reported local acute reactions gression of knee osteoarthritis was reported in two studies ex-
such as transient pain and swelling at the injection site.40 Vis- ploring the radiological progression of knee osteoarthritis af-
cosupplementation is recommended by guidelines for knee ter daily administration of glucosamine sulfate for 3 years.47-51
osteoarthritis,2 and compared with intra-articular corticos- Chondroitin sulfate has been shown to improve knee joint
teroids, it shows delayed but prolonged efficacy.40 The OARSI swelling and delay radiographic progression in patients with
guidelines consider that intra-articular hyaluronate injections knee osteoarthritis evaluated by x-rays,51,52 and more recent-
may be useful for the treatment of knee osteoarthritis and have ly a magnetic resonance imaging study reported that chon-
a beneficial symptomatic effect.17 Moreover, the ACR guide- droitin decreases cartilage loss and the progression of bone
lines conditionally recommend viscosupplementation for pa- marrow lesions.53 A recent post-hoc analysis of an osteoarthri-
tients who have had an inadequate response to initial ther- tis clinical trial reported a trend favoring chondroitin sulfate
apy.1 By contrast, a single injection of hyaluronic acid in hip versus placebo for delayed occurrence of total knee replace-
osteoarthritis seems to be no more effective than placebo.41 ment at 4 years.54 However, the structural effects of glucos-
More data are needed on the structural effect of viscosup- amine and chondroitin sulfate remain under debate, and these
plementation. treatments are not registered as structure-modifying agents.
N Symptomatic slow-acting drugs for osteoarthritis Diacerein, an inhibitor of interleukin-1, is a slow-acting agent
Disease-modifying agents that not only reduce joint pain but with pain-relieving symptomatic effects in patients with knee
also slow progression of the disease are of interest for allevia- osteoarthritis,55 and which also reduces the progression of
tion of the manifestations of osteoarthritis over the long term. hip osteoarthritis.56,57 Diacerein provides sustained pain relief
For the past 10 years, chondroitin sulfate and glucosamine for several weeks after discontinuation, suggesting a long car-
sulfate have been widely prescribed and used by osteoarthri- ry-over effect,55 and an analgesic-sparing effect. Moreover,
tis patients for symptom relief. They are safe, and have pos- the effect of diacerein has been found to be additive to that
sible structure-modifying effects.17 Glucosamine is a naturally of NSAIDs. Interestingly, it does not inhibit cyclooxygenase
occurring amino monosaccharide, and chondroitin sulfate be- or prostaglandin E2. Loose stools and diarrhea are the most
longs to the group of glycosaminoglycans and is a major com- frequent adverse events. It is safer for the upper gastrointesti-
ponent of the articular cartilage. nal system than NSAIDs55 and has a good overall safety pro-
file, and it is therefore an alternative option to NSAIDs for the
In osteoarthritis clinical trials, the symptomatic effect size of treatment of osteoarthritis.
glucosamine varies and is considered controversial. Howev-
er, the results of studies have greatly depended on the differ- Avocado soybean unsaponifiables (ASU) are fractions of un-
ent products used, the study population, and study design and saponifiable avocado and soybean oils. The symptomatic
quality.42-45 Formulations of glucosamine that result in lower efficacy of ASU has been assessed in patients with hip and
plasma concentrations and potential low bioavailability, as well knee osteoarthritis.58 ASU seems to be effective at pain reduc-
as study populations with a low baseline level of pain, may tion and has shown some beneficial effects on clinical symp-
have contributed to the controversy.45 Glucosamine sulfate toms of knee and hip osteoarthritis, with a carry-over effect
and chondroitin sulfate have been approved as drugs for the that persists after treatment discontinuation.59 A recent study
treatment of osteoarthritis in Europe, but not in North America, reported that in hip osteoarthritis, a 3-year treatment with ASU
where they are regulated not as drugs but as nutraceuticals. reduced the percentage of joint space width progressors, in-
As a consequence, substantial variation in their content is pos- dicating a potential structure-modifying effect.60
arthroplasty [UKA] and total joint replacement).61 Arthroscopy

is a minimally invasive surgical technique used for chondral
surface debridement, lavage of joints, removal of torn menis-
Non- Pharmacological
pharmacological treatment cal fragments, and repair of menisci and cruciate ligament in-
treatment juries. It remains controversial because it usually provides a
Oral
Education Acetaminophen
Exercises
short-term benefit and does not seem to delay progression
NSAIDs and COX-2
Prevention of injuries inhibitors to joint replacement.62 Arthroscopy should be of interest for
Weight loss SYSADOA selected patients such as those with symptomatic meniscal
Orthotic devices Duloxetine
Opioids
Topical
Surgery NSAIDs
Arthroscopic Capsaicin
lavage
Lidocain patches
Cartilage repair Surgery
Intra-articular
Osteotomy
Corticosteroids Intra-articular
Arthroplasty
Hyaluronic acid Corticosteroids,
hyaluronic acid
Oral
Acetaminophen, NSAIDs,
Figure 1. Multimodal management of osteoarthritis. SYSADOA, opioids, duloxetine
Abbreviations: COX, cyclooxygenase; NSAID, nonsteroidal anti-inflammatory
drug; SYSADOA, symptomatic slow-acting drugs for osteoarthritis.
Topical
NSAIDs, capsaicin, lidocaine patches
Surgical treatment
Initial treatment of osteoarthritis should be conservative. How-
Nonpharmacological
ever, when pain and loss of function persist after the use of Education, exercise, prevention of injuries,
appropriate nonpharmacological and pharmacological treat- weight loss, orthotic devices
ments, surgery should be considered to reduce disease mor-
bidity. Surgical options for knee osteoarthritis are arthroscopy,
including lavage and debridement (the efficacy of which is Figure 2. Multimodal management of osteoarthritis: initiate with non-
controversial), cartilage repair surgery (bone marrow stimulat- pharmacological approaches (blue), follow with pharmacological
treatments (pink), and if ineffective, culminate in surgery (green).
ing techniques, transplantation of osteochondral grafts), osteo- Abbreviations: NSAID, nonsteroidal anti-inflammatory drug;
tomy with axis correction, and arthroplasty (unicondylar knee SYSADOA, symptomatic slow-acting drugs for osteoarthritis.
Treatment type Component
Nonpharmacological Education; exercise; injury prevention; weight loss; orthotic devices
Acetaminophen Table II.

Multimodal
NSAIDs and COX-2 inhibitors approach to
Oral
Opioids osteoarthritis
management
Duloxetine involving
Pharmacological Symptomatic Topical NSAIDs nonpharma-
drugs cological,
Topical Capsaicin pharmaco-
logical, and
Lidocaine patches surgical
Intra-articular corticosteroids treatment
Injectable options.
Intra-articular hyaluronic acid or Abbreviations:
viscosupplementation COX, cyclooxy-
genase; NSAID,
Glucosamine and chondroitin sulfate nonsteroidal
Slow-acting
anti-inflammato-
symptomatic Oral Diacerein ry drug; THR,
drugs total hip replace-
Avocado soybean unsaponifiables
ment; TKR, total
knee replace-
Surgical Arthroscopic lavage and debridement; cartilage repair; osteotomy with axis
ment; UKA, uni-
correction; arthroplasty (UKA, TKR, THR) condylar knee
arthroplasty.
OARSI effect size*

Treatment type Intervention (95% CI)
Education 0.06 (0.03, 0.10)

Exercise
Strengthening for knee 0.32 (0.23, 0.42)
Aerobic for knee 0.52 (0.34, 0.70)
Nonpharmacological Exercises for hip 0.38 (0.08, 0.68)
In water for hip and knee 0.19 (0.04, 0.35)
Prevention of injuries
Weight loss 0.20 (0.00, 0.39)
Orthotic devices
Acetaminophen 0.14 (0.05, 0.22)

NSAIDs and COX-2 inhibitors 0.29 (0.22, 0.35)
Oral
Opioids 0.78 (0.59, 0.98)
Duloxetine
Topical NSAIDs 0.44 (0.27, 0.62)
Pharmacological Symptomatic
Topical Capsaicin
drugs
Lidocaine patches
Intra-articular corticosteroids 0.58 (0.34, 0.75)
Injectable Intra-articular hyaluronic acid or 0.60 (0.37, 0.83)
viscosupplementation
Glucosamine sulfate 0.58 (0.30, 0.87)
Symptomatic Glucosamine hydrochloride 0.02 (0.15, 0.11)
slow-acting
osteoarthritis Oral Chondroitin sulfate 0.75 (0.50, 1.01)
drugs Diacerein 0.24 (0.08, 0.39)
Avocado soybean unsaponifiables 0.38 (0.01, 0.76)
Arthroscopic lavage and debridement 0.21 (0.12, 0.54)

Surgical Osteotomy with axis correction
Arthroplasty (UKA, TKR, THR)
*An effect size of 0.2 is considered small, while 0.5 is considered moderate, and >0.8 is considered large.
Table III. Multimodal management of osteoarthritis and effect size of the different components of the 2010 guidelines from Osteoarthritis
Research Society International (OARSI).
Abbreviations: CI, confidence interval; COX, cyclooxygenase; NSAID, nonsteroidal anti-inflammatory drug; THR, total hip replacement; TKR, total knee replacement;
UKA, unicondylar knee arthroplasty.
Based on data from reference 3: Zhang et al. Osteoarthritis Cartilage. 2010;18:476-499. 2010, Osteoarthritis Research Society International.
tears, in whom it can be used to remove the degenerative when knee osteoarthritis is associated with valgus or varus
fragments and alleviate mechanical symptoms. Bone mar- deformation. It transfers load-bearing from the pathological
row stimulation through the use of a microfracture technique compartment of the knee to the normal compartment in or-
induces subchondral injury and bleeding that may promote der to reduce pain and delay joint replacement. Nevertheless,
chondrogenesis by mesenchymal stem cells in the defective its longevity is limited, and conversion to total knee replace-
area. Its efficacy is uncertain, however, because of variability ment often occurs within the following few years. UKA seems
in the volume of cartilage repair that has been achieved, as to be as safe and effective for pain relief and functional im-
well as possible functional deterioration.62 provement as TKA, as well as high tibial osteotomy in patients
with unicompartmental knee osteoarthritis.63 Long-term sur-
Patients with unicompartmental osteoarthritis of the knee can vival rates with UKA are variable but are reported to be around
be treated with a correction osteotomy17 or unicondylar or to- 90% at 10 years, which is less than for TKA (up to 98% at 15
tal knee arthroplasty (TKA). Osteotomy can be considered years), except in younger patients.61 TKA remains a success-
ful treatment for end-stage symptomatic knee osteoarthritis, Conclusion

especially in elderly patients. The main complications are per- Clinicians managing osteoarthritis are able to draw upon a
sistent postoperative pain (especially in the femoropatellar wide spectrum of therapeutic options, combining nonphar-
compartment), infections, and stiffness of the knee. In order macological approaches and pharmacological treatments
to improve outcomes with TKA, computer-assisted naviga- both to relieve pain and to attempt to delay disease progres-
tion and minimally invasive techniques are being developed. sion (Figures 1 and 2; Table II, page 177), as recommended
by the OARSI (Table III) and ACR guidelines. The trade-off be-
The choice of surgical treatment may be based on level of pain tween benefits and adverse effects should always be consid-
and physical function, disease stage, patient age, and comor- ered when choosing an appropriate treatment from among
bidities. No specific cut-off point defining the requirement for the available agents. The current therapeutic options, how-
joint replacement currently exists.64 However, the aim of a ever, are neither exclusive nor sufficient. Thus, the focus is
surgical intervention for osteoarthritis such as joint replace- moving toward developing disease-modifying osteoarthritis
ment should be to restore patient mobility and give the pa- drugs that can be taken in association with conventional
tient enough capacity to perform the level of activity required therapeutic strategies to provide more effective treatment of
to help prevent cardiovascular diseases. osteoarthritis. I
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Keywords: analgesic; chondroitin sulfate; exercise; glucosamine sulfate; guideline; intra-articular; osteoarthritis; weight loss;
surgery
TRAITEMENTS DE LARTHROSE : O EN SOMMES - NOUS ACTUELLEMENT ?

Larthrose, la forme la plus courante des pathologies articulaires, entrane douleur et diminution de la qualit de vie.
Actuellement, pour cette maladie, plusieurs mdicaments symptomatiques sont commercialiss. Cependant, il nexiste
ce jour aucun traitement prvenant la dtrioration articulaire. Dans cet article seront dcrits les traitements non phar-
macologiques et pharmacologiques disponibles dans la prise en charge de larthrose, ainsi que les traitements chi-
rurgicaux possibles. Les recommandations actuelles de lOsteoarthritis Research Society International et de lAmerican
College of Rheumatology suggrent une approche multidimensionnelle, associant des traitements non pharmaco-
logiques et pharmacologiques. La prise en charge non pharmacologique de larthrose repose essentiellement sur
lducation du patient, lexercice physique, la prvention des blessures, la perte de poids lorsquelle est ncessaire
et lutilisation dorthses. Les traitements pharmacologiques axs sur la rduction des symptmes comprennent les
analgsiques tels que lactaminophne, les anti-inflammatoires non strodiens (AINS), les opiodes, la duloxtine,
les AINS locaux, la capsacine, les patchs de lidocane, les injections intra-articulaires de corticodes et dacide hya-
luronique, et les mdicaments daction lente comme la glucosamine et la chondrotine sulfate, la diacerhine et les
insaponifiables davocat et de soja. Le traitement chirurgical est envisag lorsque les approches non pharmacolo-
giques et pharmacologiques visant rduire les symptmes ont chou.
Rates of total knee replace-

ment (TKR) are increasing world-
wide, and in 2010, more than
600 000 procedures were carried
out in the US alone, with rates
tripling over the last decade in
Knee replacement
those aged between 45 and 64.
At over $20 000 per procedure, the
annual cost of TKR in the US now
for osteoarthritis: facts,
exceeds $13 billion The reasons
for this increase are most certainly
multifactorial. Population growth,
hopes, and fears
the increasing number of elderly
people, and the increase in aver-
age body mass index (BMI) are, no
doubt, important factors.
b y L . S . Lo h m a n d e r,
Sweden and Denmark
O
steoarthritis (OA) affects hundreds of millions of people worldwide and
is responsible for a huge burden of pain, functional limitations, and
loss of quality-adjusted life expectancy. OA of the knee accounts for
more than 90% of total knee replacements (TKR). By 2030, the incidence of
TKR in the US is expected to increase by more than 6-fold. Pain and difficulty
walking limiting participation in daily activities are the primary reasons for un-
dergoing TKR. However, among patients with disabling OA, only a minority are
willing to consider TKR. Reduced willingness to undergo TKR is associated
with increasing age, being black (in the US), overestimation of the pain and
disability needed to warrant TKR, and rejection of the medicalization of OA.
L. Stefan LOHMANDER, MD, PhD The perception of the benefits of TKR is less positive among women and those
Department of Orthopedics of lower socioeconomic status. TKR is one of the most cost-effective medical
Clinical Sciences Lund
Lund University, SWEDEN interventions. Data from joint registries show that the 10-year reoperation rate
Research Unit for Musculoskeletal for TKR is less than 5%. However, between 10% and 30% of patients under-
Function and Physiotherapy going TKR report little or no improvement following surgery, or are not satis-
Department of Orthopedics fied. Patients expectations of joint replacement are relief of pain and improved
and Traumatology
University of Southern Denmark mobility. Following TKR, the expectations regarding pain relief, walking abil-
DENMARK ity, and the ability to perform daily activities are fulfilled to a greater extent
than the expectations of being able to perform more physically demanding ac-
tivities. To ensure optimal patient satisfaction, health professionals should
provide sufficient information so that patients have realistic expectations of
the results of TKR.
steoarthritis (OA) affects hundreds of millions of people worldwide and ac-
O counts for a huge burden of pain, functional limitations, loss of productiv-

ity, disability, and loss of quality-adjusted life expectancy.1,2 Any estimate of
the burden of OA is strongly dependent on the criteria used, and the population
and age group studied. The most recent estimates of the World Health Organization
(WHO) Global Burden of Disease Study 2010 reported that OA of the knee and hip
is now ranked as the 11th leading cause of years lived with disability (YLD [preva-
Address for correspondence: lence of a condition multiplied by the disability weight associated with that condition]),
Professor L. Stefan Lohmander, up from the 15th position in 1990. There was an estimated 64% increase in the glob-
Department of Orthopedics, Lund
University Hospital, 221 85 Lund,
al burden of OA-related YLD between the years 1990 and 2010. OA of the knee is
Sweden responsible for four-fifths of the OA-related YLDs of the lower extremities. In the US,
(e-mail: [email protected]) it is estimated that the direct and indirect costs of OA exceed US $100 billion per
www.medicographia.com year.3-5 Excess mortality is observed in patients with OA and this is related to increas-
Knee replacement for osteoarthritis: facts, hopes, and fears Lohmander MEDICOGRAPHIA, Vol 35, No. 2, 2013 181
ing functional impairment in those patients.6 OA most com-

monly affects the knees, hips, and hands, but may affect oth-
er joints as well, such as the shoulders, elbows, ankles, feet,
Few
and spine. The prevalence rises steeply between the ages of
50 and 60 for both women and men, so that the majority of Surgery
patients with symptomatic OA are aged between 60 and 80
years. However, OA also occurs in younger and middle-aged Some
patients. In fact, effective treatment of OA represents a partic- Drugs,

ularly difficult challenge in patients aged between 30 and 60 walking aids
years.
All
OA of the knee represents a major share of the OA disease

Information, exercise,
burden, and OA is by far the most common reason for total weight loss, self-management
knee replacement (TKR), usually accounting for more than
90% of knee replacement procedures. The incidence of TKR
for OA is rising steeply, and should continue to rise dramat-
ically, with a more than 6-fold increase expected by 2030 in
Figure 1. A stepwise approach to the management of osteoarthritic
the US.7 The following discussion will focus on knee replace- patients.
ments for OA, but will also, where appropriate, use evidence
gathered from the study of hip replacement for OA. justed years of life lost, and almost 1 million hospital admis-
sions per year.2,9,10 Although knee OA is usually perceived as
Risk factors for knee OA a disease of the elderly, the mean age at diagnosis is actually
OA of the knee shares the same general risk factors as OA 56 years.11 The prevalence of knee OA is rising due to the ag-
of the other joints in that each patient and each joint carries ing of the population and increasing rates of joint injury and,
its own mix of genetic and environmental factors responsible most importantly, obesity.
for the development of OA. For the knee, individual genetic
variability is thought to account for about 40% of the risk, with Management options for knee OA
environmental factors accounting for the remaining 60%. Ge- A wide range of treatments are used for knee OA, including
netic variability may, for example, be expressed as individual nonpharmacological, pharmacological, and surgical approach-
differences in the quality of the cartilage matrix, reactivity of es.12-14 OA management strategies are determined by disease
inflammation pathways, growth and repair pathways, and joint severity, patient preferences, local resources, and established
shape. Environmental risks are mostly biomechanical, affect- treatment modalities.
ing the dynamic loading of the joints and increasing stress on
joint tissues. This in turn will result in the activation of inflam- A stepwise approach to the management of osteoarthritis is
mation and tissue degradation. Leading examples of such en- widely recommended, starting with patient empowerment and
vironmental joint stressors are overweight and obesity, joint self-management, and, if these simple approaches are un-
injury, and occupational overload. Genetically determined vari- successful, the addition of specific medical or surgical inter-
ations in joint shape may also influence the risk of OA by inventions (Figure 1). With the exception of knee replacement,
creasing joint stress. the effect size for most therapeutic interventions in knee OA
is only small to moderate.
Epidemiology of knee OA
As already stated, the disease burden of OA is enormous. It Basic management of osteoarthritis includes education, ex-
is the most common form of progressive joint disease, and ercise, and weight loss (for overweight people), which can be
affects 50 million adults in the US and Europe,1,8 with OA of complemented as needed by simple analgesics, and, for hand
the knee representing a major share of this burden. In the and knee joints, topical nonsteroidal anti-inflammatory drugs
US, knee OA accounts for more than 10 million quality-ad- (NSAIDs). Additional studies are needed to tailor the different
programs to different patients. Common sense suggests that
a combination of treatments benefits most patients.
BMI body mass index Oral NSAIDs and paracetamol (acetaminophen) are often used
NSAID nonsteroidal anti-inflammatory drug by patients with OA. However, gastrointestinal, renal, and car-
OA osteoarthritis diovascular side effects are of particular concern with NSAIDs,
TKR total knee replacement since many patients with OA are elderly and have comorbidi-
YLD year lived with disability ties, and thus are at increased risk of some or all of these side
effects. These concerns add complexity to the task of pre-
182 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Knee replacement for osteoarthritis: facts, hopes, and fears Lohmander
scribing pain relievers for patients with OA. The utility of opi- Practice variations in the use of knee replacement
oids for OA is limited by their side effects. Corticosteroid in- and future projections for TKR use
jections are frequently used, but their benefit is short-lived (1 Joint replacement for OA of the knee may be the only inter-
to 4 weeks). In addition to these treatments, patients with knee vention with a large effect size, but it is only appropriate for
OA use a wide range of alternative therapies. patients with advanced disease or substantial symptoms that
do not respond to other treatments. This group is but a minor-
The surgical management of knee OA commonly includes ity of all those with knee OA, but still represents a very sub-
arthroscopic surgery of the knee upon suspicion of a menis- stantial number of patients. Rates of TKR are increasing world-
cus tear or cartilage derangement amenable to surgical treat- wide, and in 2010, more than 600 000 procedures were carried
14 000 A 180 B
OA 160 Females
12 000
RA Males
Posttraumatic 140
10 000
Yearly incidence of knee
arthroplasty/100 000
120
8000
Number
100
6000 80
60
4000
40
2000
20
0 0
1975 1980 1985 1990 1995 2000 2005 2010 1975 1980 1985 1990 1995 2000 2005 2010
Year of operation Year of operation
Figure 2. (A) Annual number of knee replacements in Sweden for osteoarthritis (OA), rheumatoid arthritis (RA), and posttraumatic os-
teoarthritis between the years 1975 and 2010. (B) Annual incidence of knee replacements (all replacements) for men and women.
Reproduced with permission from reference 24: Annual report 2011. www.knee.nko.se. 2011, Swedish Knee Arthroplasty Register.
ment. However, high-quality trials comparing arthroscopic sur- out in the US alone, with rates tripling over the last decade in
gical debridement (including meniscus resection) with sham those aged between 45 and 64.9,21 At over $20 000 per pro-
surgery, medical care as usual, or exercise programs found no cedure, the annual cost of TKR in the US now exceeds $13
difference between the groups compared,15-18 thereby show- billion.5,22,23
ing that arthroscopic surgery is of no added benefit for these
patients. Over the age of 35, meniscus lesions are often part National knee replacement registry data from the Scandina-
of the early stages of the osteoarthritic process, and the di- vian countries, UK, and Australia also confirm the continuous
agnosis of a meniscus tear by magnetic resonance imaging and rapid increase in the incidence of knee replacement for
(MRI) of the osteoarthritic knee does not correlate with the OA. For example, results from the Swedish Knee Arthroplas-
presence of symptoms.19 ty Register show that the annual rate of primary TKR for OA in
Sweden doubled between 2000 and 2010 (Figure 2), while
Valgus osteotomy of the tibia can provide long-lasting pain the annual rate of TKR in those younger than 55 increased
relief and functional improvement in physically active pa- 5-fold.24,25 The dramatic increase seen in younger patients may
tients of less than 60 years of age in whom OA is mainly lim- in part reflect a change in surgical practice from the use of os-
ited to the medial knee compartment. If and when needed, teotomy and unicompartmental knee replacement to TKR
the osteotomy can later be converted to a knee replacement. in younger patients.25
In a large national Swedish series of about 3000 patients who
had undergone tibial osteotomy for knee OA at a mean age of The mean age for TKR has changed over time, and in Swe-
52 years, the 10-year conversion rate to TKR was 30%.20 den it now shows a decreasing trend, being about 69 years
This suggests that osteotomy should remain a viable option for for both women and men (Figure 3, page 184).24 Reflecting
patients in this group, thereby delaying or obviating the need the current routine widespread use of TKR as a procedure to
for knee replacement by more than 10 years in most cases. treat severe knee OA, 1 in 14 elderly women in Sweden has
74 A 110 B
Females 100 Females 2010
72
Males 90 Males 2010
Females 2000
70 80 Males 2000
Prevalence /1000
70
Mean age
68
60
50
66
40
64 30
20
62
10
60 0
1975 1980 1985 1990 1995 2000 2005 2010 50 60 70 80 90 100+
Year of operation Age
Figure 3. (A) Temporal shifts in the mean age at primary total knee replacement surgery for women and men in Sweden between 1975
and 2010. (B) Comparison of the 2000 and 2010 prevalence rates of knee replacement according to age for women and men in Sweden.
Reproduced with permission from reference 24: Annual report 2011. www.knee.nko.se. 2011, Swedish Knee Arthroplasty Register.
now had a TKR.24 Similarly, nearly 1 in 20 Americans over 50 tifactorial. Population growth, the increasing number of elder-
years of age have had knee replacement surgery, which reply people, and the increase in average body mass index (BMI)
resents more than 4 million people.9,21 are, no doubt, important factors.
Direct comparisons of the rates of TKR for OA between dif- The increase in the age-standardized prevalence of knee OA
ferent countries are hindered by the limited availability of high- (for which there is limited evidence) may be driven by the
quality specific data for OA procedures, as well as by differ- now global epidemic of overweight and obesity (for which
ences in population structure. The 2007-2009 estimated rates there is strong evidence), and by an increase in joint injury
of primary TKR for all diagnoses per 100 000 people varied rates. These two environmental risk factors may together
between 9 for Romania and 213 for the USA.26 Even between be responsible for up to 50% of knee OA cases in some so-
countries with seemingly similar socioeconomic conditions, cieties.21 The importance of overweight and obesity in the risk
national health care systems, and population structures, the of severe knee OA leading to TKR was investigated in a pros-
TKR rates per 100 000 varied greatly, ranging from 188 for pective population-based cohort study (Figure 4); a mean BMI
Germany, 178 for Finland, 112 for Sweden, to 98 for France.26 of 30 was associated with an 8-fold increase in TKR risk when
The reasons for these wide variations in usage are not clear, compared with a normal BMI of about 22.28 Even an increase
but are likely to be due to differences on both the supply side in BMI from 21-22 to 24-25 (ie, within a BMI range that is con-
(health care services) and the demand side (patients). sidered normal) was associated with a 3-fold risk increase in
the rate of TKR for OA. In fact, in this large population-based
Time-related trends in TKR use study, very few TKR procedures were carried out on patients
The projections for future TKR rates have regularly been out- in the lowest BMI quartile (Figure 4). In the US, the major im-
done by reality. In the US, the demand for primary TKR was, pact of obesity on the risk of knee OA and TKR can also be
in 2005, expected to grow by more than 600%, to reach 3.48 illustrated by estimating the number of TKRs averted by re-
million procedures by 2030.27 The growth of total knee revi- versing the prevalence of obesity to the levels of 10 years ago.
sion surgeries was projected to be proportional, with the de- This would correspond to a mean BMI reduction of 0.6 or a
mand for revision procedures expected to double between reduction in body weight of less than 2 kg for a person of av-
2005 and 2015. If these predictions hold true, both health erage height. This means that more than 100 000 TKRs would
care infrastructures and the training of orthopedic surgeons be averted over the remaining life span of this population.2
will need to expand accordingly. The dramatic increase in TKR
rates inevitably leads to questions about financial feasibility in Population growth, aging, and an increase in BMI all seem
the future: who will pay? So what are the possible reasons to result in an increase in the demand for TKR, even if these
for the steeply increasing demand for TKR seen over the last factors do not fully explain the recent steep increase in de-
decade? The reasons for this increase are most certainly mul- mand.21 However, increased availability on the supply side
among women than men, and among those of lower socio-

economic status.36 Although blacks suffer from more severe
1.00 OA than whites in the US, they are less likely to consider sur-
gery as a solution to their problem, and this is associated
0.99 with less positive beliefs about the benefits of surgical pro-
cedures.37 A persons knowledge and beliefs regarding TKR
Fraction of the study population
appears to be largely shaped by his or her interactions with

0.98
family and friends. The differences summarized here may at
least in part explain the inequities observed in joint disease
0.97 care.38,39
0.96 Given the low proportion of patients with OA in whom TKR is

indicated who are actually willing to undergo the procedure,
changes in willingness to undergo TKR seem to be an impor-
0.95
tant contributing factor in driving the recent increase in the
incidence of TKR, and also in driving a future increase in the
0.94 demand for TKR. Increased expectations regarding the main-
0 2 4 6 8 10 12 14
tenance of an active lifestyle into older age may influence will-
Years of follow-up
ingness, as may direct-to-consumer advertising, which is now
common in many countries. Studies investigating temporal
Figure 4. Kaplan-Meier survival analysis of population fraction changes and changes in willingness to undergo TKR in differ-
without total knee replacement (TKR) or osteotomy for knee os-
teoarthritis.
ent settings would be of considerable interest.
The graph shows the fraction of the population studied who did not undergo
TKR or osteotomy for knee osteoarthritis. Individual survival plots show body Indications for TKR as perceived by health
mass index (BMI) quartiles (population, n=11026 [men] + 16934 [women]), with
a statistically significant difference between each of the four survival curves.
professionals and patients
Each BMI quartile consisted of 2756 men and 4233 women on average. The Several attempts have been made to develop consensus cri-
median BMI values of the population quartiles were 22.5/21.1 (men/women) teria for TKR indications. As in all such efforts, the composi-
(green), 25.0/23.6 (gray), 27.0/26.0 (blue), and 30.1/30.1 (red), respectively, for
BMI quartiles 1 to 4. tion of the group and the method used to form the consensus
Modified from reference 28 with permission: Lohmander et al. Ann Rheum determine the result. Well-known examples of such criteria are
Dis. 2009;68:490-496. 2008, BMJ Publishing Group Ltd & European League
Against Rheumatism.
those developed in New Zealand and Canada.40,41 Compo-
nents of these scores include pain, functional impairment,
is a further important and possible reason for the increase problems in care giving, and radiographic severity. However,
in the incidence of TKR surgery, as total joint replacements attempts to determine cut-off points leading to an appropri-
have changed from the early days of being boutique proce- ate indication for TKR by correlating preoperative patient-
dures to now being a generally available commodity in many reported symptoms with recommendations for placement on
settings.29,30 a TKR waiting list have not been successful.42 This suggests
that these more easily measured components explain only a
What determines patient demand for TKR? minor proportion of the decisions to place patients on waiting
Pain and difficulty walking limiting mobility and participation lists for surgery.
in normal daily activities are the primary reasons for undergo-
ing TKR for OA. However, several studies have indicated that Most TKR criteria have been dominated by the views of health
among patients with a marked need for joint replacement, ie, professionals, often orthopedic surgeons. The views of pa-
those with disabling OA, only a minority (around one-third) tients on the appropriateness of TKR have been explored to
were willing to consider joint replacement as a treatment op- some extent, and suggest that they do not always agree with
tion.31-33 Patients willingness to undergo total joint replace- the views of health professionals. The concept of the capac-
ment is, therefore, a critical predictor in determining the de- ity to benefit from TKR suggests that the benefits should out-
mand for this procedure.34,35 weigh any likely risks or unintended consequences by a con-
siderable margin for TKR to be indicated.43,44
Reduced willingness to consider joint replacement was shown
to be associated with increasing age, being black rather than Effectiveness of knee replacement: what
white (in the US), overestimation of the levels of pain and dis- determines outcome and patient satisfaction
ability needed to warrant joint replacement, and rejection of after TKR for OA?
the medicalization of OAie, considering OA as a natural It has been said that total joint replacement doesnt bring
and inevitable part of aging.34,35 The perception of the bene- years to life, but brings life to years. This is true in the sense
fits of joint replacement for OA was shown to be less positive that patient-reported outcomes of joint replacement are on
average good to excellent, and it is particularly pertinent in function following TKR may not be the same in all studies.51,54
comparison with most nonsurgical treatments for severe OA. The most important expectations of patients undergoing joint
The Scandinavian national joint registries have for many years replacement surgery are pain relief and improved mobility. It
reported on the continuous improvement of outcomes over appears that at 5 years following TKR, patients expectations
time as a result of improved surgical, anesthesiological, and of pain relief, walking ability, and ability to perform the activi-
care procedures and materials.45 In Sweden, the 10-year re- ties of daily living are fulfilled to a greater extent than their ex-
vision (reoperation) rate is now estimated to be less than 5% pectations of being able to perform more physically demand-
for patients operated with TKR for OA at the beginning of this ing activities.50 For example, 41% of patients expected to be
century.24 This means that for more than 95 out of 100 patients able to perform activities such as golfing and dancing follow-
undergoing TKR for OA, the patient will be survived by the im- ing TKR, while only 14% were in fact able to perform these
plant. Reoperation rates from other countries have general- activities 5 years after undergoing TKR. To ensure optimal pa-
ly been somewhat higher, perhaps because of the choice of tient satisfaction, it is important that health care profession-
implants, surgical techniques, and other factors.26 However, it als provide adequate information before surgery so that pa-
is well-known that the risk of reoperation is considerably high- tients have realistic expectations of the results of TKR.
er for younger patients operated with TKR, than for older pa-
tients.24 Higher revision rates for younger patients operated Conclusion
with TKR are expected in light of the changing demograph- The expectations, results, and patient satisfaction with TKR
ics of TKR surgery, with rapidly increasing numbers of younger surgery for OA summarized above reflect the current case
patients undergoing joint replacement.46 The Swedish nation- mix of patients with regard to disease severity, expectations
al registry reports no difference in revision rates between men of outcome, age, and active life expectancy. TKR stands out
and women operated with TKR for OA in the 2000s.24 as one of the most effective and cost-effective medical inter-
ventions. However, whether this outstanding record will be up-
When considering these excellent results, it should be noted held or not given the changing demographics of patients un-
that they represent reoperation rates, not patient-reported out- dergoing this type of procedure, with those aged between 45
comes. In fact, between 10% and 30% of patients undergo- and 64 years being the most rapidly increasing group, remains
ing joint replacement report little or no improvement follow- to be seen. Innovations and new implant designs have at times
ing surgery, or are not satisfied with the outcome.47-50 been introduced before evidence of their efficacy and safety
could be established. Improved regulatory and clinical process-
Factors associated with a less than optimal patient-reported es for the introduction of new devices are badly needed.
outcome of TKR at 6 months include worse preoperative
pain and function, increased anxiety/depression, and living Another pressing question is that of health economics. The
in poorer areas.51 Multiple joint involvement negatively influ- projected dramatic increase in TKR use, if it becomes a real-
ences the outcome after TKR,52 while severe obesity results ity, will demand increased orthopedic and hospital resources,
in slower recovery after surgery, but with no difference at 3 among others, and this will result in sharply increased costs
years.53 It should be noted that the determinants of pain or for patients and society. I
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Surg Am. 2012;94:201-207. 42. Gossec L, Paternotte S, Maillefert JF, et al; OARSI-OMERACT task force total
22. Medicare Fee Schedules. Centers for Medicare & Medicaid Services; 2010. articular replacement as outcome measure in OA. The role of pain and func-
http://www.cms.gov/home/medicare.asp. Accessed October 22, 2012. tional impairment in the decision to perform total joint replacement in hip and
23. Medicare Hospital Inpatient Prospective Payment System. Centers for Medicare knee osteoarthritis: an international cross-sectional study of 1909 patients.
& Medicaid Services; 2010. http://www.cms.gov/MedicareFeeforSvcPartsAB/ Report of the OARSI-OMERACT Task Force on total joint replacement. Osteo-
03_MEDPAR.asp. Accessed October 22, 2012. arthritis Cartilage. 2011;19:147-154.
24. Swedish Knee Arthroplasty Register. Annual report 2011. http://www.knee. 43. Petrou S, Wolstenholme J. A review of alternative approaches to healthcare re-
nko.se/english/online/thePages/publication.php. Accessed October 22, 2012. source allocation. Pharmacoeconomics. 2000;18:33-43.
25. W-Dahl A, Robertsson O, Lidgren L. Surgery for knee osteoarthritis in younger 44. Dieppe P, Lim K, Lohmander S. Who should have knee joint replacement sur-
patients. A Swedish Register Study. Acta Orthopaedica. 2010; 81:161-164. gery for osteoarthritis? Int J Rheum Dis. 2011;14:175-180.
26. Kurtz SM, Ong KL, Lau E, et al. International survey of primary and revision to- 45. Swedish Knee Arthoplasty Register. http://www.knee.nko.se/english/online/
tal knee replacement. Int Orthop. 2011;35:1783-1789. thePages/publication.php. Accessed October 22, 2012.
27. Kurtz S, Ong K, Lau E, Mowat F, Halpern M. Projections of primary and revision 46. Ravi B, Croxford R, Reichmann WM, Losina E, Katz JN, Hawker GA. The chang-
hip and knee arthroplasty in the United States from 2005 to 2030. J Bone Joint ing demographics of total joint arthroplasty recipients in the United States and
Surg Am. 2007;89:780-785. Ontario from 2001 to 2007. Best Pract Res Clin Rheumatol. 2012;26:637-647.
28. Lohmander LS, Gerhardsson M, Rollof J, Nilsson PM, Engstrm G. Incidence 47. Dickstein R, Heffes Y, Shabtai EI, Markowitz E. Total knee arthroplasty in the eld-
of severe knee and hip osteoarthritis in relation to different measures of body erly: patients self-appraisal 6 and 12 months postoperatively. Gerontology. 1998;
mass. A population-based prospective cohort study. Ann Rheum Dis. 2009; 44:204-210.
68:490-496. 48. Jones CA, Voaklander DC, Johnston DW, Suarez-Almazor ME. Health related
29. Katz JN, Martin TL. Clinical Pathways and the commodification of total joint quality of life outcomes after total hip and knee arthroplasties in a community
replacement. Osteoarthritis Cartilage. 2012;20:1057-1058. based population. J Rheumatol. 2000;27:1745-1752.
30. Gooch K, Marshall DA, Faris PD, et al. Comparative effectiveness of alternative 49. Nilsdotter AK, Petersson IF, Roos EM, Lohmander LS. Predictors of patient-rele-
clinical pathways for primary hip and knee joint replacement patients: a prag- vant outcome after total hip replacement for osteoarthritisa prospective study.
matic, randomized, controlled trial. Osteoarthritis Cartilage. 2012;20:1086- Ann Rheum Dis. 2003;62:923-930.
1094. 50. Nilsdotter AK, Toksvig-Larsen S, Roos EM. Knee arthroplasty: are patients ex-
31. Frankel S, Eachus J, Pearson N, et al. Population requirement for primary hip- pectations fulfilled? A prospective study of pain and function in 102 patients with
replacement surgery: a cross-sectional study. Lancet. 1999;353:1304-1309. 5-year follow-up. Acta Orthopaedica. 2009;80:55-61.
32. Hawker GA, Wright JG, Coyte PC, Williams JI, Harvey B, Glazier R, Wilkins A, 51. Judge A, Arden NK, Cooper C, et al. Predictors of outcomes of total knee re-
Badley EM. Determining the need for hip and knee arthroplasty: the role of clin- placement surgery. Rheumatology. 2012;51:1804-1813.
ical severity and patients preferences. Medical Care. 2001;39:206-216. 52. Perrucio AV, Power JD, Evans MK, et al. Multiple joint involvement in total knee
33. Hawker GA, Wright JG, Badley EM, Coyte PC, for the Toronto arthroplasty replacement for osteoarthritis: effects on patient-reported outcomes. Arthritis
health services research consortium. Perceptions of, and willingness to con- Care Res (Hoboken). 2012;64:838-846.
sider, total joint arthroplasty in a population-based cohort of individuals with 53. Jones CA, Cox V, Jhangri GS, Suarez-Almazor ME. Delineating the impact of
disabling hip and knee osteoarthritis. Arthritis Care Res. 2004;51:635-641. obesity and its relationship on recovery after total joint arthroplasties. Osteo-
34. Hawker GA, Guan J, Croxford R, Coyte PC, Glazier RH, Harvey BJ, Wright JG, arthritis Cartilage. 2012;20:511-518.
Williams JI, Badley EM. A prospective population-based study of the predictors 54. Dowsey MM, Nikpour M, Dieppe P, Choong PF. Associations between pre-
of undergoing total joint arthroplasty. Arthritis Rheum. 2006;54:3212-3220. operative radiographic changes and outcomes after total knee joint replace-
35. Frankel L, Sanmartin C, Conner-Spady B, et al. Osteoarthritis patients percep- ment for osteoarthritis. Osteoarthritis Cartilage. 2012;20:1095-1102.
Keywords: indication; osteoarthritis; total joint replacement; willingness
PROTHSES DE GENOU POUR LARTHROSE : RALIT , ESPOIRS ET CRAINTES

Larthrose touche des centaines de millions de personnes dans le monde. Elle est responsable de douleurs, de res-
trictions fonctionnelles et de perte desprance de vie ajuste sur la qualit. Larthrose du genou est la cause de plus
de 90% des prothses totales de genou (PTG). Dici 2030, lincidence des PTG aux tats-Unis devrait tre multi-
plie par 6. Les principales raisons pour la pose dune PTG sont la prsence de douleur et une difficult la marche
limitant les activits de la vie quotidienne. Toutefois, seule une minorit de patients ayant une arthrose invalidante
sont prts envisager la PTG. Ce faible engouement pour la pose dune PTG est li au vieillissement, au fait dtre
Noir (aux tats-Unis), la surestimation de la douleur et du handicap ncessaires pour justifier une PTG et un rejet
de la mdicalisation de larthrose. Les femmes et les personnes dont le statut socio-conomique est bas ont une per-
ception des bnfices dune PTG moins positive que les autres. Le rapport cot-efficacit de la chirurgie pour PTG
est lun des meilleurs. Les donnes issues des registres sur les articulations montrent que le taux de rintervention
10 ans pour PTG est infrieur 5%. Cependant, de 10% 30% des patients ayant eu une PTG ne sont pas satis-
faits de lintervention, ou nont peru, au mieux, quune amlioration modre. Ce quattendent les patients dune pro-
thse, cest le soulagement de leur douleur et une mobilit amliore. Aprs la pose dune PTG, les attentes concer-
nant le soulagement de la douleur, laptitude la marche et la capacit effectuer les activits de la vie quotidienne
sont satisfaites dans une plus grande mesure que celles concernant la possibilit de pratiquer des activits plus phy-
siques. Les professionnels de sant devraient informer les patients de faon ce que leurs attentes soient ralistes,
ce qui leur assurerait une meilleure satisfaction.
There may be some lessons

to be learned from the manage-
ment of rheumatoid arthritis, al-
though the disease-modifying os-
teoarthritis drugs (DMOADs) that
are used in the treatment of estab-
Disease-modifying osteo-
lished osteoarthritis (OA) are likely
to differ from disease-modifying
antirheumatic drugs (DMARDs) in
arthritis drugs (DMOADs):
some respects. DMARDs are typ-
ically used in a younger population
where toxicity may be better toler-
what are they and what can
ated and the absence of comor-
bidities and their concurrent ther- we expect from them?
apies permits the use of agents
with greater potential toxicity.
b y A . J . B a r r a n d P. G . C o n a g h a n ,
United Kingdom
O
steoarthritis (OA) is the most common form of arthritis and represents
a huge burden on individuals and health economies. The mainstay
of current therapy involves a combination of nonpharmacological and
pharmacological interventions aimed at reducing pain and improving func-
tion. Current treatments do not inhibit structural deterioration of the OA joint;
yet, the unmet need for this type of treatment is immense. The current defi-
nition of a disease-modifying OA drug (DMOAD) is that of a drug that inhibits
structural disease progression and ideally also improves symptoms and/or
function. There are currently no licensed DMOADs but there are many prospec-
tive agents under investigation. The challenges of DMOAD development in-
Andrew J. BARR, MBBS, MRCP clude the establishment of appropriate preclinical animal models that reflect
human OA, the limitations of the current radiographic standard for structural
assessment, and the lack of stratification of patients in trials by phenotype or
tissue involvement. Furthermore, DMOADs should probably be used in early
disease before irreversible molecular and biomechanical pathology is estab-
lished, as is commonly present at the time of diagnosis. DMOADs are likely
to be prescribed for long periods in this chronic illness of an aging popula-
tion, which demands excellent safety data in a target population with mul-
tiple comorbidities and the potential for drug interactions. Issues in DMOAD
development, potential DMOADs, magnetic resonance imaging biomarkers,
and lessons learned from the treatment of rheumatoid arthritis are briefly dis-
cussed in this review.
Philip G. CONAGHAN
MBBS, PhD, FRACP, FRCP Medicographia. 2013;35:189-196 (see French abstract on page 196)
Division of Rheumatic and
Musculoskeletal Disease
University of Leeds and NIHR
steoarthritis (OA) is the most common form of arthritis and represents a
Leeds Musculoskeletal
Biomedical Research Unit, UK
O huge burden on both individuals and health economies. It is character-
ized by changes involving all the joint tissues. Affected individuals suffer
pain, functional limitation, and poor quality of life. We can predict a dramatic in-
crease in the burden of OA in aging and increasingly obese Western populations.
OA represents whole joint failure and occurs when the homeostatic equilibrium of
Professor Philip G. Conaghan, joint tissue repair and breakdown becomes unbalanced. Risk factors for disease
Division of Rheumatic and initiation and progression vary according to anatomical site and include age, obe-
Musculoskeletal Disease, Chapel
Allerton Hospital, Chapeltown Road,
sity,1,2 anthropometric and anatomical characteristics, joint malalignment, and trau-
Leeds LS7 4SA, UK ma.3 A genetic predisposition also contributes to OA risk; OA is a polygenic disease
(e-mail: [email protected]) whose susceptibility results from the interaction of many genes.4,5 The mainstay of
www.medicographia.com current therapy involves a combination of nonpharmacological and pharmacologi-
DMOADs: what are they and what can we expect from them? Barr and Conaghan MEDICOGRAPHIA, Vol 35, No. 2, 2013 189
cal interventions aimed at reducing pain and improving func- order to adequately power a clinical study. Furthermore, the
tion. The pharmacological interventions include paracetamol, sensitivity of this measure to change may be reduced by knee
nonsteroidal anti-inflammatory drugs, and opiate analgesics. repositioning variability in serial radiographic measurement of
Their utility is limited byat bestmoderate effect size,6 or by JSW, so great care must be taken in repositioning methods.12
significant toxicities, especially as OA is most prevalent in the
elderly where comorbidities are more common. Current treat- Conventional radiography does not detect early (preradiograph-
ments do not appear to inhibit the structural deterioration of the ic) OA changes in the subchondral bone, cartilage, or menis-
OA joint; the unmet need for such a treatment is immense. ci.13 Typically, inclusion criteria for research trials have includ-
ed patients with radiographically detectable JSN (Kellgren and
What are disease-modifying osteoarthritis drugs? Lawrence grade 2). While this selects a group of patients
A disease-modifying osteoarthritis drug (DMOAD) is a drug who no doubt have OA, multiple large MRI studies suggest
that inhibits the structural disease progression of OA and that these patients have complex multiple tissue pathologies,
ideally also improves symptoms and/or function. There are with gait studies suggesting a high probability of abnormal
currently no licensed DMOADs. There are draft guidelines from biomechanical features, meaning that these may be patients
the US Food and Drug Administration (FDA) and the Euro- in whom pharmacological intervention alone and aimed at a
pean Medicines Agency (EMA) both requiring that a DMOAD single tissue would be unlikely to modify structural deterio-
should not only slow or halt radiographic structural disease ration. A preradiographic patient cohort with milder disease
progression, but also achieve patient-reported long-term clin- may be more likely to respond. Treatment of rheumatoid arthri-
ical benefit.7,8 Historically, attempts at developing DMOADs tis according to the concept of early disease has certainly rev-
have focused primarily on preventing hyaline cartilage loss, olutionized the management of rheumatoid arthritis.
thereby providing putative chondroprotective agents. How-
ever, and perhaps appropriately, as typical clinical OA involves N Magnetic resonance imaging as a potential end point
multiple tissues, more recent attempts have been made at tar- Conventional radiography cannot capture the extent of the
geting other tissues including the subchondral bone, which multi-tissue involvement in OA joints. Typically, patients with
plays an important role in OA pathogenesis. Kellgren-Lawrence grade 2 are recruited for DMOAD trials,
but these patients may lack uniformity in terms of joint tissue
There are a number of issues to consider in developing ther- involvement, and this is clinically indistinguishable. Stratifying
apies that modify structural disease progression. and monitoring these tissue changes among patients would
require MRI.
Challenges in DMOAD development
N The current standard for structural assessment: The advantages of MRI include the ability to examine the pres-
conventional radiography ence and extent of pathology in all of the individual joint tis-
Conventional radiography is widely available and radiograph- sues in OA.14 There is good evidence of the reliability and re-
ic joint space width (JSW) is the traditionally used surrogate sponsiveness of MRI cartilage morphometry in knee OA and
for assessing cartilage thickness. JSW can be used for both there is some evidence of its predictive and construct valid-
defining and measuring structural disease progression. Man- ity.15,16 This includes quantitative loss of cartilage volume be-
ual and semiautomated methods can be used to quantify JSW ing a potential predictor of total knee replacement. The assess-
from a conventional radiographic image, providing different ment of subchondral bone marrow lesions and synovitis in
measures such as minimum, mean, or location-specific JSW. knee OA has also demonstrated good responsiveness for
Joint space narrowing (JSN) is used as the primary end point
in DMOAD trials in OA. Although JSN is a predictor of total
joint replacement,9 the limitations of radiographic JSN should
be appreciated. Indeed, while JSN is used to define cartilage BMP-7 human bone morphogenetic protein 7
loss in knee OA, magnetic resonance imaging (MRI) studies DMOAD disease-modifying osteoarthritis drug
have shown that it measures a complex construct including DMARD disease-modifying anti-rheumatic drug
meniscal degeneration, meniscal extrusion, and hyaline car- iNOS inducible nitric oxide synthase
tilage loss.10 IL-1 interleukin 1
JSW joint space width
The annual rate and variability of JSN in the natural history of JSN joint space narrowing
OA is well described, which facilitates powering in clinical tri- MRI magnetic resonance imaging
als.11,12 However, the average annual change in JSN is approx- MMP matrix metalloproteinase
imately 0.1 to 0.2 mm per annum, with change occurring in a MSS musculoskeletal syndrome
small group of progressors. The relative insensitivity to change OA osteoarthritis
of this surrogate measure of hyaline cartilage loss means TIMP tissue inhibitor of metalloproteinases
that long trials with large numbers of patients are needed in
190 MEDICOGRAPHIA, Vol 35, No. 2, 2013 DMOADs: what are they and what can we expect from them? Barr and Conaghan
semiquantitative MRI assessment.16 Further work is required cacy of existing analgesics has often not been clearly demon-
to investigate the predictive validity and quantification of these strated. Such long-duration trials are often associated with
noncartilage MRI pathologies. While MRI acquisition is, of patient drop-out, especially in an elderly population, and ro-
course, more expensive and time-consuming than plain radi- bust statistical modeling will be required to cope with miss-
ography, there are trade-offs in that increased responsiveness ing data.
should result in fewer patients being required to demonstrate
a structure-modifying effect. N DMOAD safety profile
Prospective DMOADs for use in established OA are likely to
MRI-based joint tissue measures of OA have not been rou- require long-term administration in an aging population with
tinely used as clinical outcome measures in structure-mod- significant comorbidities, and will thus be prescribed along-
ification DMOAD trials. However, following the last decade side a variety of medications. For that reason, prospective
of MRI-OA cohort studies and trials, a recent Osteoarthritis Re- DMOADs will be required to demonstrate a good safety pro-
search Society International (OARSI) working group recom- file with respect to both patient tolerance and drug interac-
mended that MRI cartilage morphology assessment be used tions. Long-duration trials will therefore be needed to achieve
as a primary structural end point in clinical trials and noted this.
the rapid evolution of quantitative MRI assessments of sub-
chondral bone and synovium.17 N Preclinical models
Animal models can mimic certain aspects of human disease.
N Novel end points: joint arthroplasty and virtual joint However, there is no single model that reflects all of the phe-
arthroplasty notypes and components of human OA. The marked differ-
While pain and function outcomes are common outcomes ences between animal models and human disease may result
that may be adapted for DMOAD studies from symptom-mod- in dismissing drugs that may be viable DMOADs in humans
ifying trials, less frequently used measures such as quality of due to preclinical failure in animal models. Existing models
life and delay in time to joint replacement may also provide include primary idiopathic and secondary experimentally in-
important information about the value of a putative agent. Rate duced disease. Small animal models may provide us with a
of joint arthroplasty has been used as an end point reflecting clearer understanding of the molecular pathways involved in
the severity of symptoms and structural damage, but many the pathogenesis of OA and the effects of prospective
variables influence both the decision to perform and the tim- DMOADs on these pathways.23 Although large weight-bear-
ing of this outcome measure. These include the surgeons or ing models may be more relevant, they are less frequently
physicians opinion and the patients comorbidities and will- used. Animal models generally achieve adequate severity of
ingness to undergo surgery, in addition to local and national OA but some may exceed that seen in humans. There is a
health system variations in surgical waiting lists. In an attempt general consensus of opinion that animal models of less se-
to overcome these confounding factors influencing the time vere OA will be better placed to establish the efficacy of pros-
to total joint replacement end point, an alternative has been pective human DMOADs. Furthermore, establishing animal
proposed. This is time to fulfilling criteria for total joint replace- models with relevance to human OA will require standardiza-
ment or virtual total joint replacement, which could be used tion of experimental techniques, disease severity, and treat-
to evaluate treatment response to DMOADs in clinical trials.18 ment responses.24
The criteria consist of a composite index of three domains:
physical function, pain, and structure19; its validity is currently Are there candidate DMOADs?
being assessed in an international study although provision- A number of prospective DMOADs are under investigation
al reports indicate that large patient numbers would be re- and some of those more advanced in development are sum-
quired to detect differences between groups in DMOAD ran- marized in Table I (page 192). The degradation of cartilage
domized control trials.20 and that of subchondral bone are closely linked in OA. Ta-
ble I describes the mechanism of action of the prospective
N Symptomatic improvement DMOADs on cartilage, although they may also structurally
The current regulatory approval standard for DMOADs requires modify subchondral bone.
that structural disease modification be linked with some clin-
ical benefit. However, in observational studies in OA there is N Calcitonin
generally a weak relation between pain and/or function and Calcitonin is responsible for regulating calcium homeostasis
JSN and radiographic structural change.21 Furthermore, car- and promotes osteoblastic bone formation. It inhibits bone
tilage is not directly attributable as the cause of the typical OA resorption by binding to calcitonin receptors on osteoclasts.
symptoms, including pain and stiffness.22 Importantly, most Calcitonin is indicated for the prevention of osteoporosis in
trials of symptom-modifying drugs have been of short dura- postmenopausal women. It can be administered orally, intra-
tion, often only 3 months long. DMOAD trials need to monitor nasally, or subcutaneously. Its inhibition of subchondral bone
pain over long periods of time (1 to 2 years), where the effi- turnover may be chondroprotective and, therefore, it may in-
sponse.33 Some potentially beneficial effects have nonethe-

Mechanism of action less been observed. A reduction in biomarkers of cartilage
Prospective DMOAD Anticatabolic Anabolic degradation at 6 months of therapy was noted, along with
slower knee OA progression.34
Systemic therapy
Calcitonin Zoledronic acid is a long-acting bisphosphonate that is li-
Bisphosphonates censed for postmenopausal osteoporosis. Along with other
Strontium ranelate bisphosphonates, zoledronic acid has demonstrated chon-
iNOS inhibitors droprotective effects in animal models of OA35 in conjunction
MMP-13 inhibitors with its impact on subchondral bone. In a 1-year random-
Aggrecanase inhibitors ized placebo controlled trial of zoledronic acid in patients with
Anti-IL-1 knee OA, zoledronic acid demonstrated a reduction in bone
Doxycycline marrow edema (a marker associated with structural disease
Cathepsin K inhibitors progression) and knee pain.36 As it improves symptoms and a
marker of structural disease progression at the same time,
Local therapy
zoledronic acid represents an important prospective DMOAD.
BMP-7

N Strontium ranelate
MMP-13 inhibitors
TIMP-3
Strontium ranelate is a drug used in the treatment of osteo-
FGF-18
porosis with antiresorptive and anabolic effects on the sub-
Anti-IL-1
chondral bone. Strontium ranelate influences bone remod-
eling through calcium-sensing receptors on osteoclasts and
Table I. Prospective disease-modifying osteoarthritis drugs
osteoblasts in subchondral bone and by an antiresorptive ac-
(DMOADs) and their mechanisms of action on cartilage.
tion via inhibition of osteoclastogenesis.37 In vitro studies sug-
hibit the structural disease progression of OA.25 In a human gest that strontium ranelate has anabolic effects on cartilage
trial, bone resorption and cartilage degradation markers were by directly promoting the formation of human cartilage ma-
significantly lower in the oral salmon calcitonin group com- trix.38 In studies of human osteoporosis, strontium ranelate
pared with placebo.26 In a 2-year phase 3 trial of knee OA, reduces cartilage degradation markers and inhibits clinical
oral calcitonin modified symptoms and increased cartilage symptoms and radiographic features of spinal OA, indicating
volume but did not have an effect on JSW.27 its potential as a DMOAD.39 A double-blind, placebo-con-
trolled, randomized, international 3-year study of knee OA
N Bisphosphonates demonstrated a chondroprotective effect and symptomatic
Bisphosphonates are frequently used for treating conditions improvement in WOMAC (Western Ontario and McMaster
with osteoclastic bone resorption, especially osteoporosis. Universities) index scoring.40
Increased subchondral bone turnover in OA is integral to the
pathogenic process of OA,28 and may be associated with pro- N Bone morphogenetic protein
gressive cartilage loss.29 This disease-specific pathogenic Human bone morphogenetic protein-7 (BMP-7)also known
process can be targeted using antiresorptive agents such as as osteogenic protein-1 (OP-1)is a transforming growth fac-
bisphosphonates, which hinder the bone remodeling process tor with a broad range of effects on a variety of cells, including
and could be chondroprotective. Animal models identified a cartilage. It signals through transmembrane serine-threonine
beneficial effect of bisphosphonates in OA through their im- kinase receptors, and is involved in cartilage homeostasis and
pact on subchondral bone, which includes inhibition of re- repair via anticatabolic and anabolic properties.41 In animal
modeling and osteophyte formation along with decreased models, BMP-7 demonstrated reparative effects on cartilage
vascular invasion of calcified cartilage.30 lesions.42 Human chondrocytes also promote cartilage forma-
tion in response to BMP-7 treatment.43 Clinical trials inves-
Initially, a phase 2 study of risedronate31 reported promising tigating the efficacy of BMP-7 in human knee OA have com-
findings with a trend toward inhibition of JSN in knee OA. How- menced.
ever, a subsequent phase 3 study of risedronate in knee OA
reported no significant change in JSN or symptom severity.32 N Inducible nitric oxide synthase
As yet, no study has accounted for the heterogeneity of the Nitric oxide is considered to play a pathogenic role in carti-
OA population regarding subchondral bone abnormalities lage degradation and pain in OA.44 Nitric oxidealong with its
when selecting patients. The insensitivity to change of con- metabolitesinduces cartilage degradation and cytotoxic tis-
ventional radiography used as an outcome measure (vide sue damage via inhibition of proteoglycan and collagen syn-
supra) for structural change suggests that the above-men- thesis, apoptosis of chondrocytes, and activation of matrix
tioned studies were significantly underpowered to show a re- metalloproteinases (MMPs).
In animal models, selective inhibition of one isoform of nitric N Interleukin 1 inhibitors

oxide synthase (iNOS) significantly reduces articular cartilage Interleukin 1 (IL-1) has been proposed to be involved in the
degradation and the number of osteophytes.45 There is also degradation of articular hyaline cartilage based upon pre-
a significant reduction in the severity and incidence of OA in clinical studies. Inhibition of the enzyme that activates the
iNOS knock-out mice, indicating a potential role of iNOS in proinflammatory cytokine IL-1, interleukin-1 beta-convert-
human OA. However, in a recent 2-year randomized, dou- ing enzyme (ICE), has been achieved with a highly selective
ble-blind, placebo-controlled trial of an oral selective iNOS in- caspase-1 inhibitor called pralnacasan. In animal models, a
hibitor, cindunistat, there was only a transient slowing of JSN reduction in joint damage was demonstrated.54 However, in
in Kellgren-Lawrence grade 2 OA, which was not sustained human OA, monoclonal antibody IL-1 inhibitors have failed to
at 2 years, and no significant evidence of inhibition of struc- demonstrate an improvement in symptoms.55
tural progression was seen in OA of greater radiographic
severity.46 N Neutraceuticals and supplements
Glucosamine, an amino sugar, is a substrate for the forma-
N Matrix metalloproteinase inhibitors tion of glycosaminoglycans, and chondroitin sulfate is a sul-
MMPs are collagenases that cleave type II collagen and result fated glycosaminoglycan. Glycosaminoglycans are important
in loss of biomechanical integrity of normal human articular constituents of articular cartilage. The availability of these sub-
cartilage. This important pathogenic process in OA can be in- strates may limit the formation of cartilage and therefore glu-
hibited using MMP inhibitors. However, these MMP inhibitors cosamine and chondroitin were used in trials as prospective
have failed early clinical trials due to the frequent development DMOADs. A recent meta-analysis of glucosamine and chon-
of a painful musculoskeletal syndrome (MSS). This has been droitin concluded that there is no structural modifying effect
attributed to the broad spectrum of MMP inhibition. MMP-13 of these agents based upon trials using JSN as a clinical end
appears to be an important collagenase in human OA and point.56
specific inhibitors targeting it are in development.47 This more
targeted approach will, hopefully, avoid MSS. Collagen hydrolysate is another dietary supplement. It is formed
as a result of collagen hydrolysis and has only demonstrated
N Tissue inhibitors of metalloproteinases small clinical improvement in OA. Phase 2/3 trials with colla-
Aggrecan is an important protein found in articular cartilage gen hydrolysate are yet to be published.
that is degraded as part of the pathogenesis of OA. This
process occurs as a result of the action of a variety of differ- N Doxycycline
ent aggrecanases, including a disintegrin and metallopro- Although there is no evidence to support an infectious eti-
teinase with thrombospondin motifs (ADAMTS). Endogenous ology in OA, doxycycline has demonstrated potential as a
inhibitors of MMPs include the tissue inhibitor of metallopro- DMOAD based on preclinical data. Possible mechanisms of
teinase TIMP-3, which can inhibit the action of these aggre- action include inhibition of type XI cartilage degradation, in-
canases.48 Greater cartilage degradation was noted in TIMP-3 hibition of collagenase activity and a decrease in iNOS mRNA
knockout mice compared with wild-type mice.49 Therefore, tis- transcription. A randomized, placebo-controlled, double-blind
sue inhibitors of metalloproteinases represent a prospective trial of doxycycline of over 30 months that included 431 obese
DMOAD target. women with unilateral radiographic knee OA reported a small
reduction in the rate of JSN in knees with established OA.11
N Vitamin D Doxycycline is not currently recommended for the treatment
Vitamin D is required for normal cartilage and bone metab- of OA.
olism. It regulates the expression of MMPs by chondrocytes.50
Vitamin D insufficiency is common and is associated with re- N Cathepsin K
duced osteoblast activity and reduced bone quality, which Cathepsin K, a cysteine proteinase, appears to play a role in
may explain its association with structural progression of OA.51 the pathogenesis of OA.57 In preclinical models, cathepsin K
Several clinical trials are investigating the effect of vitamin D inhibition reduced evidence of cartilage degradation.58 It is,
on structural disease progression therefore, a prospective DMOAD.
N Fibroblast growth factor 18 Can we learn lessons from disease modification

Fibroblast growth factor 18 (FGF-18) is involved in cartilage in rheumatoid arthritis?
and bone development during skeletal maturation.52 In ani- There may be some lessons to be learned from the manage-
mal models, it has been shown to promote chondrogenesis, ment of rheumatoid arthritis, although the DMOADs that are
cartilage repair, and subchondral bone remodelling.53 It rep- used in the treatment of established OA are likely to differ from
resents an important potential DMOAD and is currently un- disease-modifying anti-rheumatic drugs (DMARDs) in some
dergoing phase 2 clinical trials examining changes in cartilage respects. DMARDs are typically used in a younger population
volume. where toxicity may be better tolerated and the absence of co-
morbidities and concurrent therapies to treat them permits the The cornerstone of DMARD therapy has been effective tar-
use of agents with greater potential toxicity. DMOADs for es- geting of synovitis. While the synovium is only one of the tis-
tablished OA will require excellent toxicity profiles in light of the sues involved in OA pathogenesis, synovitis may contribute to
greater prevalence of comorbidities and potential for drug disease progression.59 Therapies that modify synovitis could
interactions. However, DMOADs, like DMARDs, are likely to re- therefore potentially modify OA structural progression. Stud-
quire chronic administration. OA affects a significantly greater ies in this area are ongoing.
proportion of the population than rheumatoid arthritis and,
therefore, its treatment may represent a significant burden to Conclusion
health services. Ideally, DMOADs should be inexpensive, pa- OA is the most common form of arthritis and is a chronic and
tient-administered, and require little or no monitoring in com- progressive disease of the whole joint with only moderately
parison with DMARDs such as tocilizumab and infliximab. effective treatment options currently available. There are a
number of prospective targets for structural and symptomatic
DMARDs are often prescribed in combination to improve the disease modification in patients with established OA, early
efficacy of treatment in terms of symptoms and structural dis- OA, or at the time of acute joint injury, with a view to prevent-
ease progression. Similarly, DMOADs may also need to be ing structural progression, improving symptoms and function,
prescribed in combination, particularly if a single joint tissue and avoiding the need for total joint replacement. DMOADs
is targeted by the DMOAD. It is important to recognize that are the highest unmet need in the field of OA and prospective
OA is a whole joint disease involving pathophysiological in- DMOADs will need to demonstrate excellent safety profiles in
teractions between subchondral bone, cartilage, synovium, view of their target population. However, DMOAD trials will
and ligaments and it is likely that an individual DMOAD will require improved biomarkers and clinical end points to ap-
only target a single tissue, thereby increasing the need for propriately demonstrate the construct of OA structure mod-
combination therapy. ification. I
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Keywords: biomarker; cartilage; DMOAD; subchondral bone; structure
LES MDICAMENTS CONTRE LARTHROSE MODIFIANT LA MALADIE (DMOAD) :

QUE SONT- ILS ET QUE PEUT- ON EN ATTENDRE ?
Larthrose, forme la plus courante des arthropathies, reprsente un lourd fardeau pour les individus et les conomies
de la sant. Les traitements actuels reposent sur lassociation dinterventions pharmacologiques et non pharmaco-
logiques dans le but de rduire la douleur et damliorer la fonctionnalit. Ces traitements ne permettent pas dvi-
ter la dtrioration structurale de larticulation arthrosique ; les besoins pour ce type de traitement sont donc im-
menses. La dfinition actuelle dun mdicament contre larthrose modifiant la maladie (DMOAD) est celle dun pro-
duit qui inhibe la progression structurale de la maladie et qui, idalement, amliore aussi les symptmes et/ou la
fonctionnalit. ce jour, aucun DMOAD na obtenu lAMM, mais il existe de nombreux produits en cours de d-
veloppement. Le dveloppement des DMOAD est confront la mise en place de modles animaux prcliniques
adquats reproduisant larthrose humaine, aux limites du standard radiographique utilis actuellement pour lvalua-
tion structurale de la maladie et au manque de stratification des patients par atteinte tissulaire ou phnotypique dans
les tudes. De plus, il va probablement falloir utiliser les DMOAD dans les stades prcoces de la maladie, avant lta-
blissement dune pathologie irrversible, comme cest frquemment le cas au moment du diagnostic. Dans cette pa-
thologie chronique dune population vieillissante, les DMOAD vont vraisemblablement devoir tre prescrits sur de
longues priodes, ce qui exige dexcellentes donnes de scurit pour leur utilisation chez une population sujette
de multiples comorbidits et donc, potentiellement, de nombreuses interactions mdicamenteuses. Dans cet ar-
ticle, nous passons brivement en revue les questions relatives au dveloppement des DMOAD, les DMOAD poten-
tiels, les biomarqueurs utiliss en imagerie par rsonance magntique et les leons tires du traitement de la poly-
arthrite rhumatode.
OA has a substantial effect

not only on health care budgets
but also on patients, their employ-
ers, and their caregivers. For ex-
ample, in Belgium, the costs of OA
in active patients are distributed
The economic weight of
among the employers (45%), the
health care system (41%), and the
patients themselves (14%). There-
osteoarthritis in Europe
fore, in addition to pain and a
poorer quality of life, patients liv-
ing with OA may face significant
personal expenses due to OA.
b y M . H i l i g s m a n n a n d J . Y. R e g i n s t e r,
The Netherlands and Belgium
T
his article aims to describe the economic weight of osteoarthritis (OA)
in Europe based on published data and to underline the principal cost
headings and their respective weights for patients and governments.
This review suggests that OA has a significant economic effect not only on
health care budgets, but also on patients, their employers, and their caregiv-
ers. The average total annual cost of OA per patient in Europe ranges from
1330 to 10 452. When considering only direct medical costs, the annual
cost of OA ranged from 534 to 1788. In active patients, the indirect costs
were found to be much higher than the direct costs. European studies are,
however, not directly comparable with each other because of differences in
L
the approach taken, in patient characteristics, in health care systems, and in
Mickal HILIGSMANN,a,b PhD
the calculation of productivity losses. Our review confirms the immense bur-
Jean-Yves REGINSTER,b MD, PhD
a den of OA in Europe, which is expected to rise substantially further in the fu-
Department of Health Services
Research, School for Public Health ture with demographic changes and increasing obesity. Developing effective
and Primary Care (CAPHRI) and efficient treatment programs for OA is becoming increasingly important
Maastricht University
to reduce the clinical and economic consequences of this major public health
THE NETHERLANDS
b problem worldwide.
Department of Public Health
Epidemiology and Health Economics Medicographia. 2013;35:197-202 (see French abstract on page 202)
University of Lige, BELGIUM
steoarthritis (OA), the most common form of arthritis, is a serious disease
O affecting the joints.1,2 OA affects nearly 10% of the population worldwide.3

In the United Kingdom, the lifetime risk of developing symptomatic knee
and hip OA is estimated to be 44.7% and 25.3%, respectively.4,5 OA causes pain,
stiffness, and severe disability. In the United States, knee OA is one of the five lead-
ing causes of disability among noninstitutionalized people.6 Symptomatic hip and
knee OA are also associated with excess mortality7 and account for many hospi-
talizations, primarily related to knee and hip replacement surgery.8 Since OA is a
disease whose prevalence increases with age, its prevalence and burden are ex-
pected to increase substantially in the near future due to demographic changes.
In addition, obesity, which is rising worldwide, is a strong risk factor for knee and hip
replacement.9 An increased trend in the prevalence of symptomatic knee OA and
Dr Mickael Hiligsmann in the number of OA-related hospitalizations has already been observed recently.10
Department of Health Services
Research, Maastricht University
PO Box 616. 6200 MD, Maastricht,
The economic cost of OA is also particularly high, resulting from decreased quality
The Netherlands (e-mail: of life, hospitalizations, and loss of productivity. Cost-of-illness studies have be-
[email protected]) come increasingly important to identify how much society is spending on a partic-
www.medicographia.com ular disease and thus help decision makers establish research and treatment prior-
The economic weight of osteoarthritis in Europe Hiligsmann and Reginster MEDICOGRAPHIA, Vol 35, No. 2, 2013 197
ities. In the United States, the annual medical care expendi- es attributable to the disease resulting from absence from
tures for OA were estimated at $185.5 billion (in 2007 dol- work and reduced effectiveness at work. These costs may
lars), of which $149.4 billion were insurer expenditures and be related to the patients themselves or to their caregivers.
$36.1 billion were paid directly by the patients. In Europe,
some data has been published over the last few years on the Cost of osteoarthritis in Europe
economic impact of OA on individuals, including those in the A literature review was conducted using PubMed to find ar-
workplace. The goal of this article is to review these publica- ticles assessing the burden of OA in European countries be-
tions so as to clarify the economic weight of OA in Europe tween January 2000 and July 2012. The bibliographies of the
based on available published data. Specific attention will be papers included were also analyzed to search for additional
devoted to describing the principal cost headings (visits to references. Published studies on the economic cost of OA
health professionals, drugs, loss of productivity, etc.) and were found in Belgium, France, Germany, Italy, the Nether-
their respective weights for patients and governments. lands, and Spain. All of these studies, with the exception of the
French study, used a bottom-up approach.
Cost-of-illness evaluation
Burden-of-disease evaluation of OA aims to describe the im-
pact of OA on society, including its impact on health care sys- Informal care
Contact with
(2%)
tems, patients, their caregivers, and their employers. Meas- health care
uring the burden of disease can be very helpful in guiding the professionals
(22%)
setting of health research priorities.11
The burden of OA can be measured with epidemiological pa-

rameters (incidence, prevalence) or with the impact of the dis-
ease on mortality, morbidity, quality of life, or health care costs. Medical
Cost-of-illness studies evaluate the direct and indirect health examinations
(8%)
care costs of a particular disease over a period of time. This
can be done using two different approaches: a prevalence-
based approach and an incidence-based approach. While Hospital
the incidence-based approach estimates the costs of new stays
Work (6%)
cases of the disease during the period of time considered, disability
Drugs
the prevalence-based approach includes the costs of all the (58%)
(4%)
patients affected by the disease. Prevalence-based studies
are far more common and are more suitable for the estimation Figure 1. Direct and indirect costs of osteoarthritis in Belgium.
of the annual burden of a disease.12 Based on a sample of 1811 active subjects with a mean age of 51 years. Total
cost per year = 1330. Direct costs are represented in red and indirect costs
in blue.
The cost of a disease can be estimated using either a top- Data from reference 13: Rabenda et al. J Rheumatol. 2006;33:1152-1158.
down or a bottom-up approach. The top-down approach 2006, The Journal of Rheumatology.
examines the costs in an aggregated form (such as nation-
al indicators) while in the bottom-up approach, the overall N Belgium
cost is based on the costs for the individuals.11 Most cost- In Belgium, the cost of OA was assessed in 2004 in a sam-
of-illness studies of OA in Europe have used the bottom-up ple of 1811 active subjects employed by the Lige City Coun-
method to estimate the economic burden of OA (see below). cil (mean age, 51 years) who were followed prospectively for
6 months.13 The self-reported prevalence of OA was 34%. The
The cost of a disease can be categorized into direct and in- burden of OA was measured comprehensively, taking into
direct costs. Direct costs are those directly related to the dis- account the direct medical costs (consultations with health
ease, including, for example, visits to health care profession- professionals and with alternative medicine professionals, the
als, medical examinations, drug therapy, hospital admissions, number and type of medical examinations, the number of hos-
and nonmedical costs. Indirect costs include productivity loss- pital stays and emergency department consultations, and all
drugs taken) and the indirect costs (the number of sick leave
days, and the number of days off work taken by active sub-
jects helping relatives or friends with OA).
GNP gross national product
OA osteoarthritis The mean total direct and indirect costs were estimated at
WOMAC Western Ontario and McMaster Universities Osteo- 44.50 and 66.30 per OA patient-month, respectively,
arthritis index which, when extrapolated to 1 year, came to 1330 per OA
patient annually. The average distribution of costs is shown in
198 MEDICOGRAPHIA, Vol 35, No. 2, 2013 The economic weight of osteoarthritis in Europe Hiligsmann and Reginster
Figure 1. Consultations with health professionals, medical ex- 58% on physiotherapy. Nonmedical costs (which represent
aminations, drugs, and hospital stays accounted for 23.70, 37% of the total costs) were mainly driven by temporary care-
8.70, 6.70, and 4.90 per OA patient-month, respective- givers. In contrast with the study of Rabenda et al in Belgium,13
ly. Of all these direct costs, 29.10 (65%) was covered by the which only included active patients, the indirect costs were
Belgian health care system and 15.40 (35%) was paid out found to be mainly due to informal care provided by primary
of pocket by the patients. The average number of sick-leave caregivers, which accounted for around 60% of the total in-
days was 0.8 per OA patient-month, yieldingfrom the pay- direct costs. The remaining indirect costs were due to loss of
ers perspectivea cost of 64.50 per OA patient-month. The productivity (31%) and to other caregivers (9%). Sensitivity
Belgian health care system covered 25.9% of all sick-leave analyses revealed higher costs for patients with comorbidities
payments, with employers covering the remaining 74.1%. In- and for women. Age was also shown to be a predictor of costs.
formal care was estimated to cost employers 1.80 per ac-
tive subject-month, based on a mean of 0.02 days off work N Netherlands
per active subject-month. Multiple regression analyses showed In the Netherlands, the productivity and medical costs of work-
that age was a significant predictor of direct medical costs ing patients with knee OA were recently assessed by Her-
and that poorer quality of life was a major determinant of di- mans et al.15 Loss of productivity and health care consump-
rect and indirect costs. tion were assessed by questionnaires in a sample of 117 knee
OA patients participating in a randomized clinical trial inves-
N Italy tigating cost-effectiveness (mean age, 52 years). Interest-
In Italy, the direct and indirect costs of knee OA were assessed ingly, this study included the measurement of reduced work
retrospectively in a sample of 254 patients (mean age, 65 productivity while present at work in addition to loss of pro-
years) over a period of 12 months in 2000-2001.14 The cost ductivity resulting from absence from work.
per patient per year was estimated at 2170, of which 43%
were direct costsincluding medical (hospitalization, diag- The average total monthly knee OArelated costs were es-
nosis, and therapies) and nonmedical costs (transport, tem- timated at 871 per patient. The productivity costs account-
porary caregivers, and auxiliary devices)and 57% were in- ed for 83% (722) and the medical costs accounted for 17%
direct costs (productivity losses and informal care). (149) of these costs. As observed in Figure 3, the medical
costs were primarily driven by visits to primary (62) and sec-
The distribution of costs is shown in Figure 2. Hospitalization ondary care (33), and by imaging (40). Reduced produc-
represented the largest medical cost, absorbing 25% of the tivity while present at work accounted for the majority (62%)
direct resources (mean annual cost, 233). The annual cost of the productivity costs. The inclusion of loss of productivity
of therapy was 136, of which 42% was spent on drugs and while being present at work, which represented around 50%
Loss of productivity Aids

Hospitalization Imaging (1%)
other caregivers Loss of
(11%) Medication (4%)
Loss of (5%) productivity
productivity use (1%) present at work
primary Diagnosis (51%)
caregiver Visits
(10%) (11%)
(34%)
Compensation
for work
Therapy in the
(7%) household
(9%)
Transport
(2%)
Auxillary
devices
(2%)
Loss of
Temporary
productivity
caregivers
Loss of absent from work
(12%)
productivity (23%)
patient (17%)
Figure 3. Direct and indirect costs of osteoarthritis in the Nether-
Figure 2. Direct and indirect costs of osteoarthritis in Italy. lands.
Based on a sample of 254 patients with a mean age of 65 years. Total cost per Based on a sample of 117 active patients with a mean age of 51 years. Total cost
year = 2170. Direct costs are represented in red and indirect costs in blue. per year = 10 452. Direct costs are represented in red and indirect costs in blue.
Data from reference 14: Leonardi et al. Clin Exp Rheumatol. 2004;22:699-706. Data from reference 15: Hermans et al. Arthritis Care Res. 2012;64:853-861.
2004, Clinical and Experimental Rheumatology. 2012, American College of Rheumatology.
of the total costs (448 per patient-month), could explain the 4.7 billion, which represents 0.5% of the gross national prod-
relatively high cost of OA found in this study. Logistic regres- uct (GNP) of Spain. Using regression models, the authors also
sion analyses reported that increased pain during activity and found that higher costs were associated with comorbidity,
performing physically intensive work were significantly asso- poorer health status, and lower WOMAC score (Western On-
ciated with loss of productivity. tario and McMaster Universities Osteoarthritis index).
N Spain N France
The direct and indirect costs of osteoarthritis in Spain were In France, the direct and indirect costs of osteoarthritis were
estimated by Loza et al in 2007.16 Based on a sample of 1071 estimated by Le Pen et al using the top-down approach with
patients aged over 50 years (mean age, 71 years) with symp- nationwide data from 2001 to 2003.17 The direct costs of os-
tomatic and radiologic knee and/or hip OA who were seen teoarthritis were estimated at 1.6 billion Euros (2002), rep-
at primary care centers in all provinces of Spain, data related resenting approximately 1.7% of the expenses of the French
to OA health resources utilization, patient and caregiver ex- health insurance system. Hospitalization represented 50% of
penses, and time lost in the previous 6 months were collect- the direct expenses. The costs of medication and physicians
ed in two separate interviews. The costs were divided into were estimated at 574 million (34%) and 270 million (16%),
direct costs, including medical costs (professional time [all respectively. A 156% increase in direct medical costs was re-
consultations], image, laboratory, and other tests, medications, ported compared with 1993, which was related to an increase
and hospital admissions); and nonmedical costs (help at work in the number of OA patients (+54%). The authors mentioned
and home, and self-care adaptive aids, devices, and assis- that the cost per patient increased by only 2.5% per year.
tive household equipment purchased), and indirect costs
including compensation payments for lost productivity and N Germany
housekeeping help costs if the patient was a homemaker.16 In a recent article, Sabariego et al aimed to determine the di-
rect medical costs in patients with osteoporosis, osteoarthri-
tis, back pain, or fibromyalgia in Germany.18 The mean direct
Help for housewives cost of OA was estimated at 1511 in a sample of 97 OA pa-
Lost labor/ at home (8%) tients. Medication, outpatient physician visits, nonphysician
productivity
(6%) Professional services, and inpatient services accounted for 699, 357,
time 171, and 175, respectively.
Transport (21%)
(0%)
N Other European countries
Aid
devices For other European countries, no detailed estimations of the
(9%)
Image and cost of OA have been published in any of the journals includ-
laboratory ed in the database we searched. In the United Kingdom, how-
tests ever, the National Institute for Clinical Excellence (NICE) has
(10%)
reported that the burden of OA represents 1% of the GNP.19
Drugs
(5%) Discussion
This review suggests that OA represents a significant eco-
House/work/
Hospital nomic burden to patients and society in Europe. The annual
self-care help
admissions
(28%) cost of OA per patient ranges from 1330 to 10 452, de-
(13%)
pending on the country and the approach taken (Table). When
Figure 4. Direct and indirect costs of osteoarthritis in Spain. considering only the direct medical costs, the annual cost
Based on a sample of 1071 patients with a mean age of 71 years. Total cost of OA ranges from 534 to 1788. Drug therapies repre-
per year = 1502. Direct costs are represented in red and indirect costs in blue. sent between 5.3% and 24.8% of the total direct medical
Data from reference 16: Loza et al. Arthritis Rheum. 2009;61:158-165. 2009,
American College of Rheumatology. costs,13-16 while hospitalizations and visits to health care pro-
fessionals range from 15.2% to 39.6%,13,14,16 and from 35.5%
The average total annual cost of osteoarthritis was estimat- to 53.9%,13-16 respectively. Indirect costs range from 205 to
ed at 1502 per patient (2007). Direct costs accounted for 8664 per year, depending on patient characteristics and
86% of the total cost, mostly due to home, work, and self- the mode of calculation of productivity losses.13-16 The direct
care help (29%), professional medical time (21%), and hos- and indirect costs of OA were shown to increase with patient
pital admissions (13%) (Figure 4). Indirect costs represented age and with poorer quality of life in several studies.13,14,16
only 14% of the total cost, with the largest component relat-
ed to providing help for housewives at home. Assuming a Our review highlights the importance of indirect costs on the
prevalence of knee and hip OA of, respectively, 10% and 4% burden of OA. In particular, in studies assessing the burden of
in Spain, the authors estimated the national cost of OA at OA in active patients, indirect costs were found to be greater
costs of OA in active patients are distributed among the em-

Total Direct medical Indirect ployers (45%), the health care system (41%), and the patients
Country costs costs costs
themselves (14%). Therefore, in addition to pain and a poor-
Belgium13 1330 534 796 er quality of life, patients living with OA may face significant
Italy14 2170 588 1237 personal expenses due to OA.
Netherlands15 10 452 1788 8664
Our review confirms the great magnitude and economic
Spain16 1502 724 205
impact of OA worldwide. Non-European countries have also
Germany18 NR 1511 NR
reported a substantial burden of OA. For example, in the
United States, the average direct cost of OA is approxi-
Table. Annual total costs, direct medical costs, and indirect costs
of osteoarthritis per patient in Europe. NR, not reported. mately $2600 per year per person living with OA20, while in
Canada, the excess burden of OA was recently estimated
than direct costs.13,15 Indirect costs are especially high in OA at Can$-1200.21
as patients have to take days off work or early retirement, and/
or are less efficient at work.11 The analysis performed in the Cost-of-illness studies could be very useful in guiding health
Netherlands showed that the indirect costs related to reduced care priorities but there are limitations to their use for health
work efficiency were considerable, representing more than care decision-making and they do not necessarily lead to more
50% of the total cost of OA. 15 To adequately estimate the efficient health care systems. Cost-effectiveness analyses are
burden of OA, it is therefore important to estimate not only the potentially more interesting in order to assign health care re-
indirect costs due to time off from work but also to reduced sources more efficiently. By comparing the costs and effects
work efficiency at work. of health interventions, health economic evaluation is a pow-
erful tool for decision makers.22 However, current economic
Cost variations were observed across the European studies. analyses in OA are limited and mainly pragmatic studies.23
These studies are, however, not directly comparable because Providing high-quality economic evaluations in OA would be
of differences in the approach taken, in patient characteristics, of major importance to help decision makers make rational
and in health care systems. Moreover, there are methodolog- decisions and efficiently allocate health care resources ded-
ical differences in the calculation of productivity losses and icated to OA.
no time adjustment was made for the costs. Despite such po-
tential differences, the direct medical costs were very similar In summary, this review illustrates the immense burden of OA
in Belgium, Italy, and Spain.13,15,16 to patients and society in Europe. Developing adequate treat-
ment programs for OA is becoming increasingly important
The burden of OA is considerable, both from a societal and to reduce the clinical and economic consequences of this
individual patient perspective. OA has a substantial effect not major public health problem worldwide. Establishing the most
only on health care budgets but also on patients, their em- effective treatments and determining the best use of resources
ployers, and their caregivers. For example, in Belgium, the should also become a priority in this area. I
References
1. Felson DT, Lawrence RC, Dieppe PA, et al. Osteoarthritis: new insights. Part 1: 10. Nguyen US, Zhang Y, Zhu Y, Niu J, Zhang B, Felson DT. Increasing preva-
the disease and its risk factors. Ann Intern Med. 2000;133:635-646. lence of knee pain and symptomatic knee osteoarthritis: survey and cohort data.
2. Reginster JY. The prevalence and burden of arthritis. Rheumatology (Oxford). Ann Intern Med. 2011;155:725-732.
2002;41(suppl 1):3-6. 11. Hunsche E, Chancellor JV, Bruce N. The burden of arthritis and nonsteroidal
3. Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of anti-inflammatory treatment. A European literature review. Pharmacoeconomics.
arthritis and other rheumatic conditions in the United States. Part I. Arthritis 2001;19(suppl 1):1-15.
Rheum. 2008;58:15-25. 12. Segel J. Cost-of-Illness Studies - A primer. RTI-UNC Center of Excellence in
4. Murphy L, Schwartz TA, Helmick CG, et al. Lifetime risk of symptomatic knee Health Promotion Economics. 2006.
osteoarthritis. Arthritis Rheum. 2008;59:1207-1213. 13. Rabenda V, Manette C, Lemmens R, Mariani AM, Struvay N, Reginster JY. Di-
5. Murphy LB, Helmick CG, Schwartz TA, et al. One in four people may develop rect and indirect costs attributable to osteoarthritis in active subjects. J Rheu-
symptomatic hip osteoarthritis in his or her lifetime. Osteoarthritis Cartilage. matol. 2006;33:1152-1158.
2010;18:1372-1379. 14. Leardini G, Salaffi F, Caporali R, et al. Direct and indirect costs of osteoarthritis
6. Guccione AA, Felson DT, Anderson JJ, et al. The effects of specific medical con- of the knee. Clin Exp Rheumatol. 2004;22:699-706.
ditions on the functional limitations of elders in the Framingham Study. Am J 15. Hermans J, Koopmanschap MA, Bierma-Zeinstra SMA, et al. Productivity costs
Public Health. 1994;84:351-358. and medical costs among working patients with knee osteoarthritis. Arthritis
7. Nuesch E, Dieppe P, Reichenbach S, Williams S, Iff S, Juni P. All cause and Care Res. 2012;64:853-861.
disease specific mortality in patients with knee or hip osteoarthritis: population 16. Loza E, Lopez-Gomez JM, Abasolo L, et al. Economic burden of knee and hip
based cohort study. BMJ. 2011;342:d1165. osteoarthritis in Spain. Arthritis Rheum. 2009;61:158-165.
8. Arden N, Nevitt MC. Osteoarthritis: epidemiology. Best Pract Res Clin Rheu- 17. Le Pen C, Reygrobellet C, Grentes I. Financial cost of osteoarthritis in France.
matol. 2006;20:3-25. The COART France study. Joint Bone Spine. 2005;72:567-570.
9. Felson DT, Zhang Y, Anthony JM, Naimark A, Anderson JJ. Weight loss reduces 18. Sabariego C, Brach M, Stucki G. Determinants of major direct medical cost cat-
the risk for symptomatic knee osteoarthritis in women. The Framingham Study. egories among patients with osteoporosis, osteoarthritis, back pain or fibromyal-
Ann Intern Med. 1992;116:535-539. gia undergoing outpatient rehabilitation. J Rehabil Med. 2011;43:703-708.
19. National Institute for Health and Clinical Excellence. Osteoarthritis: the care and province of Ontario, Canada. Arthritis Rheum. 2012;64:1153-1161.
management of osteoarthritis in adults. Clinical Guideline 59. London, UK: NICE; 22. Drummond M, Sculpher M, OBrien B, Stoddart G, Torrance G. Methods for
2008. the economic evaluation of health care programmes. 3rd edition. New York, NY:
20. Gabriel SE, Crowson CS, Campion ME, OFallon WM. Direct medical costs Oxford University Press; 2007.
unique to people with arthritis. J Rheumatol. 1997;24:719-725. 23. Bruyre O, Reginster J. The need for economic evaluation in osteoarthritis. Aging
21. Tarride JE, Haq M, OReilly DJ, et al. The excess burden of osteoarthritis in the Health. 2009;5:591-594.
Keywords: burden, cost-of-illness, direct cost, economic, indirect cost, osteoarthritis
LE POIDS CONOMIQUE DE LARTHROSE EN EUROPE

Cet article dcrit, laide de donnes publies, le poids conomique de larthrose en Europe et souligne les prin-
cipaux cots et leur poids respectif pour les patients et les gouvernements. Il montre que larthrose entrane des
consquences conomiques significatives non seulement sur les budgets de soins de sant mais aussi sur les pa-
tients, leurs employeurs et leurs soignants. Le cot annuel total moyen de larthrose par patient en Europe varie de
1 330 10 452 . Si lon ne prend en compte que les cots mdicaux directs, le cot annuel de larthrose varie de
534 1 788 . Chez les patients actifs, les cots indirects sont beaucoup plus levs que les cots directs. Les
tudes europennes ne sont cependant pas directement comparables les unes avec les autres car les approches,
les caractristiques du patient, les systmes de soins et le calcul des pertes de productivit diffrent. Notre article
confirme limmense fardeau de larthrose en Europe, qui augmentera de faon importante dans le futur, avec les
changements dmographiques et laugmentation de lobsit. Il devient donc crucial de dvelopper des programmes
de traitement efficaces pour larthrose, afin de rduire les consquences cliniques et conomiques de ce problme
majeur de sant publique dans le monde entier.
THE QUESTION CONTROVERSIAL QUESTION
lthough the development
A of secondary osteoarthritis
can readily be pinpointed,
the boundary between age-asso-
ciated changes in articular carti-
lage and the pathogenetic changes
Can normal age-related
related to primary osteoarthritis is
not so easy to define. Changes in
cartilage with age are likely univer-
changes in cartilage
sal, but development of osteoarthri-
tis is not. This article will discuss
the way to differentiate these two
be distinguished from early
fates of the joint.
osteoarthritic changes?
1. L. A. Alekseeva, Russia
2. J. P. A. Arokoski, Finland
3. F. N. Birrell, United Kingdom
4. S. Blkbai,
s Turkey
5. O. P. Bortkevych, Ukraine
6. P. Hork, Czech Republic
7. A. El Maghraoui, Morocco
8. A. Mahmoud Ali Elsayed, Egypt
9. A. Migliore, Italy
10 . T. Pap, Germany
11. J. del Pino-Montes, Spain
12 . C. A. F. Zerbini, Brazil
Can age-related cartilage changes be distinguished from early OA changes? MEDICOGRAPHIA, Vol 35, No. 2, 2013 203
CONTROVERSIAL QUESTION
1. L. A. Alekseeva, Russia
On the other hand, articular cartilage has no innervation and
Lyudmila A. ALEKSEEVA, MD, PhD cannot be a direct cause of pain, but the reduction in its thick-
Department of Metabolic Disorders of ness and volume with OA results in a higher load on the sub-
Musculoskeletal System
Osteoarthritis and Osteoporosis Laboratories
chondral bone within the weight-bearing areas of the joint. Re-
Research Institute of Rheumatology modeling processes, which take place in these areas, lead to
(Russian Academy of Medical Sciences) the development of osteosclerosis, osteophytes, and micro-
34 A, Kashirskoye shosse
115522 Moscow, RUSSIA
fractures, and eventually to an increase in the stiffness of sub-
(e-mail: [email protected]) chondral bone that can cause significant syndromic pain. An-
other cause of pain is the formation of foci of bone marrow
edema and an increase in the intramedullary pressure.4
C
urrently, osteoarthritis (OA) is the most common of
all the musculoskeletal diseases, and this relates to
the general increase in life expectancy and the ac- In recent years, evidence has accumulated about the role of
cumulation of risk factors. The main symptom of OA and im- subchondral bone in the development of OA. Subchondral
mediate reason for seeking medical care is pain, and this re- bone has been found to be able to produce a large number
mains a permanent symptom over time. Despite traditional use of proinflammatory cytokines and growth factors. Changes in
of analgesic and anti-inflammatory drugs, most patients with its microarchitecture can influence the intensity of pain, and
OA continue to experience pain. the bone mineral density value in subchondral areas of the
tibia can be considered as a predictor of OA progression.
There are many reasons for the occurrence of pain in OA and All of this demonstrates the importance of investigating pain
many factors determining its severity. The proportion of pain OA, especially given the available information that pain can
tients with so-called painful or overtly symptomatic knee OA affect disease prognosis. As was described in the National
increases with age and reaches almost 80% in the oldest age Health and Nutrition Examination Survey (NHANES)1 and by
group.1 Moreover, the individual perception of pain by each pa- Mazzuca and colleagues,5,6 the initial level of pain in the knee
tient cannot be ignored, and may depend not only on changes joint in OA is a risk factor for the development of functional
in the joint, but also on the emotional and social status of the impairment and radiological progression in the future. I
patient.
References
The source of pain in OA can be almost any structure of the 1. McAlindon TE, Cooper C, Kirwan JR, Dieppe PA. Knee pain and disability in the
community. Br J Rheumatol. 1992;31:189-192.
joint: the synovial membrane, bone, or soft tissues.2 Mecha- 2. Creamer P, Hunt M, Dieppe P. Pain mechanisms in osteoarthritis of the knee: ef-
nisms of pain perception may include activation and local re- fect of intraarticular anesthetic. J Rheumatol. 1996;23:1031-1036.
lease of pro-inflammatory mediators, such as prostaglandins 3. Sofat N, Ejindu V, Kiely P. What makes osteoarthritis painful? The evidence for
local and central pain processing. Rheumatology. 2011;50:2157-2165.
and cytokines. Clinically, however, there is often a disparity be- 4. Sowers MF, Hayes C, Jamadar D, et al. Magnetic resonance-detected subchon-
tween the degree of pain perception and the extent of de- dral bone marrow and cartilage defect characteristics associated with pain and
structive changes in the joint. A study with functional magnet- X-ray-defined knee osteoarthritis. Osteoarthr Cartil. 2003;11:387-393.
5. Hassan BS, Doherty SA, Doherty M. Effect of pain reduction on postural sway,
ic resonance imaging revealed that numerous areas in the proprioception, and quadriceps strength in subjects with knee osteoarthritis. Ann
brain are involved in the occurrence of pain in OA. This study Rheum Dis. 2002;61:422-428.
demonstrated that perception of pain in OA is a complex 6. Mazzuca SA, Brandt KD, Schauwecker DS, et al. Severity of joint pain and Kell-
gren-Lawrence grade at baseline are better predictors of joint space narrowing
mechanism involving local factors and the activation of cen- than bone scintigraphy in obese woman with knee osteoarthritis. J Rheumatol.
tral pain pathways.3 2005;32:1540-1546.
204 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Can age-related cartilage changes be distinguished from early OA changes?
2. J. P. A. Arokoski, Finland
Cartilage in osteoarthritis
Jari P. A. AROKOSKI, MD, PhD OA is characterized by a deterioration and progressive loss
Clinical Lecturer and Adjunct Professor of articular cartilage, and it manifests clinically with pain that
(docent) of Physical and Rehabilitation
Medicine, Department of Physical
does not occur in normal aged cartilage.1 In experimental mod-
and Rehabilitation Medicine els of OA, some of the first detectable abnormalities that can
Kuopio University Hospital be observed even before there is any deterioration visible on
P. O. B. 1777, FI-70211 Kuopio
FINLAND
the cartilage surface include a decrease in the superficial pro-
(e-mail: [email protected]) teoglycan concentration, increased water content, and the
separation and disorganization of the superficial collagen fib-
rils.1 In early OA, the synthesis of both type II collagen and
T
he etiology of osteoarthritis (OA) is not fully understood,
but there are known to be several predisposing risk fac- proteoglycans is increased. Advanced OA with fibrillation is
tors for the condition.1 These include obesity, injuries to accompanied by a net loss and damage to type II collagen
the joints, andmost importantlyold age. The prevalence fibrils, as well as a loss of proteoglycans. The loss of proteo-
and incidence of OA increases with age.2 However, although glycans and collagen results in diminished cartilage stiffness.
epidemiological studies seem to indicate that primary OA and
aging are interrelated, aging does not directly cause OA.3 Age- At the molecular level, OA is viewed as being a metabolically
related changes in the musculoskeletal system may contribute active process, including both cartilage destruction and re-
to the development of OA by making the joints more suscep- pair.5 This equilibrium is regulated by the complex interplay
tible to the effects of other OA risk factors.3 Several novel ag- between anabolic growth factors (especially TGF and IGF-1)
ing theories such as progressive apoptotic cell loss, mitochon- and catabolic proinflammatory cytokines (especially IL-1 and
drial degeneration, and cell senescence have been proposed TNF ). In a normal joint, these mediators are present at low
to account for the cartilage degeneration in OA.4 levels to maintain the homeostasis of cartilage, but in OA,
these processes become imbalanced, with the increased pro-
The pathogenetic changes in primary, and especially early, OA teolytic degradation being mediated by matrix metalloprotein-
are difficult to distinguish clinically from normal aging, but there ases, ie, collagenases and stromelysins.
are some differences discernible between these two fates of
the joint. The current research in this area focuses on artic- Early diagnosis of osteoarthritis
ular cartilage. The traditional diagnostic techniques, plain X-ray imaging or
arthroscopic examination, can only detect late and major tis-
Age-related changes in cartilage sue changes in OA and are incapable of differentiating early
Articular cartilage undergoes significant structural and me- cartilage OA changes from age-associated changes. How-
chanical changes with age.2 Articular cartilage collagen and ever, early diagnosis would be highly advantageous as initial
proteoglycan metabolism are relatively active during growth OA changes may still be reversible.6 Recent developments in
and adolescence, but in adult individuals, the metabolism with- quantitative imaging techniques, including magnetic resonance
in cartilage is more sluggish.5 There is evidence of an increas- imaging and ultrasound methods, as well as more sensitive
ing prevalence of articular surface fibrillation with age,2 and car- biomarkers, mean that diagnostic evaluation of cartilage in ear-
tilage also thins with age, suggesting a loss of the cartilage ly OA may in the future become reality.6 I
matrix.3
References
This might be due to the fact that chondrocytes become less 1. Arokoski JPA, Jurvelin J, Vtinen U, Helminen HJ. Normal and pathological
adaptation of articular cartilage to joint loading. Scand J Med Sci Sports. 2000;
responsive to the proliferative and anabolic effects of growth 10:186-198.
factors with increasing age.3 Aggrecan, the major cartilage pro- 2. Martin JA, Buckwalter JA. Roles of articular cartilage aging and chondrocyte
teoglycan, decreases in molecular size and content,5 and this senescence in the pathogenesis of osteoarthritis. Iowa Orthop J. 2001;21:1-7.
3. Loeser RF. Age-related changes in the musculoskeletal system and the devel-
would be expected to reduce cartilage stiffness and hydra- opment of osteoarthritis. Clin Geriatr Med. 2010;26:371-386.
tion.3 There is no major change in the content of total collagen 4. Aigner T, Richter W. OA in 2011: age-related OAa concept emerging from in-
and pyridinoline during aging, but there is a marked increase fancy? Nat Rev Rheumatol. 2012;10:70-72.
5. Goldring MB, Goldring SR. Osteoarthritis. J Cell Physiol. 2007;213:626-634.
in the formation of advanced glycation end products, includ- 6. Chu CR, Williams AA, Coyle CH, Bowers ME. Early diagnosis to enable early treat-
ing pentosidine crosslinks, making the cartilage more brittle.3 ment of pre-osteoarthritis. Arthritis Res Ther. 2012;14:212.
3. F. N. Birrell, United Kingdom

joint in early OA include synovitis and ligament/enthesis and
subchondral bone abnormalities: the importance of these
changes relates to their association with pain, which in clinical
Fraser N. BIRRELL, MD, PhD, FRCP
Musculoskeletal Research Group
studies has been of stronger importance than early joint space
Institute of Cellular Medicine narrowing (although advanced disease has a very strong re-
4th Floor, Cookson lationship with radiographic change,3 in contrast to earlier as-
Framlington Place, Newcastle University
Newcastle NE2 4HH, UK
sertions). Specific enzymes, such as matriptase, are upregu-
(e-mail: [email protected]) lated in OA cartilage,4 which suggests potential relevance as
a target for treatment.
T
he short answer is yes. However, interest and a degree
of controversy derive from the techniques that are avail- However, probably the most definitive current technique for
able to discriminate between the two and considera- distinguishing OA from age-related change alone in cartilage
tion of whether osteoarthritis (OA) is a disease restricted to is gene expression profiling. A recent study by Loeser et al 5
cartilage alone or should more correctly be considered a dis- has shown that there are quite different profiles in young ver-
ease of the whole joint. sus aged mice, with 493 genes showing differential expres-
sion and an age-related decrease in matrix gene expression
The main techniques used to investigate cartilage include im- and increase in immune and defense response gene expres-
aging, histology, and gene expression profiling. Clinically, the sion. Thus, there is a characteristic aging gene profile signa-
most useful test would be one that is noninvasive and read- ture in mice. Replication in humans will provide us with an in-
ily available. Unfortunately, plain radiographs usually provide vasive tool for discriminating age-related change: arguably
no direct visualization of cartilage, unless chondrocalcinosis a controversial answer to the controversial question.
is present, and the indirect evidence is limited by difficulties
in interpreting joint space, which is affected by positioning, A growing appreciation of OA as a disease of the whole joint
and the variable interposition of other low-density tissues such suggests that a narrow focus on cartilage alone is, however,
as menisci. High-resolution musculoskeletal ultrasound and probably counterproductive. Ongoing longitudinal studies will
magnetic resonance imaging can directly visualize cartilage, but allow us to define which changes in and around the joint are
there is a lack of true population data on age-related changes, associated with progression and response to treatment. We
even with magnetic resonance imaging. Large studies, for ex- should increasingly use these predictors and regard cartilage
ample Osteoarthritis Initiative, sponsored by the National In- changes as just one of several key outcomes of OA. I
stitutes of Health in the United States,1 have focused on a sin-
gle joint (the knee) and used convenience sampling.
References
Histological techniques include macroscopic examination of 1. Osteoarthritis Initiative. Available at: http://oai.epi-ucsf.org/datarelease/. Accessed
cartilage sections for thinning and fibrillation and microscopic November 21, 2012.
2. McNulty MA, Loeser RF, Davey C, Callahan MF, Ferguson CM, Carlson CS.
examination with stains for proteoglycans (such as Safranin O). Histopathology of naturally occurring and surgically induced osteoarthritis in
While grading systems for cartilage are discriminating for ad- mice. Osteoarthritis Cartilage. 2012;20:949-956.
vanced disease, early OA changes may be difficult to discrim- 3. Neogi T, Felson D, Niu J, et al. Association between radiographic features of
knee osteoarthritis and pain: results from two cohort studies. BMJ. 2009;339:
inate from age-related change using grading systems for car- b2844.
tilage alone.2 Three other approaches to discriminate early 4. Milner JM, Patel A, Davidson RK, et al. Matriptase is a novel initiator of cartilage
OA changes are: microscopic examination of the whole joint, matrix degradation in osteoarthritis. Arthritis Rheum. 2010;62:1955-1966.
5. Loeser RF, Olex AL, McNulty MA, et al. Microarray analysis reveals age-related
measurement of specific enzymes upregulated in OA, and differences in gene expression during the development of osteoarthritis in mice.
gene expression profiling. Pathological changes around the Arthritis Rheum. 2012;64:705-717.
4. S. Blkbai, Turkey
arthritis is a multifactorial disease and age is the major (but not
only) risk factor, it is difficult to determine whether cartilage
degradation and cartilage aging are different processes.
Seluk BLKBAI, MD
Department of Orthopedics
and Traumatology In an experimental study, the accumulation of advanced gly-
Gazi University School of Medicine cation end products (AGEs) was investigated in relation to os-
06500 Besevler
Ankara, TURKEY
teoarthritis.3 AGEs adversely affect the formation of cartilage,
(e-mail: [email protected]) lead to the formation of osteoarthritis, and increase with aging.
In this study, the accumulation of AGEs was found to cause a
C
urrently, it is not possible to give an exact answer to tendency to develop osteoarthritis. The results showed that
this question. In order to begin to answer the ques- higher AGE levels in the cartilage increased the severity of os-
tion, one must first elucidate whether or not aging of teoarthritis, and they provided the first in vivo molecular ev-
the cartilage is the same process as cartilage degradation. idence to demonstrate the role of aging in the development of
osteoarthritis.3
As the role of mitochondria is known in degenerative diseases,
a study was conducted to investigate mitochondrial function With the development of microarray technology, studies have
in healthy chondrocytes and osteoarthritic chondrocytes, as emerged suggesting that gene expression analysis of sub-
well as age-related changes in mitochondria. The study showed chondral bone can be conducted in early experimental os-
that mitochondrial mass was increased in osteoarthritic chon- teoarthritis and can be used in its diagnosis and treatment.4
drocytes, but no correlation was found between mitochon- However, it is currently impossible to obtain suitable subchon-
drial function and age in normal and osteoarthritic chondro- dral bone and cartilage samples from humans and animals
cytes.1 This result suggests that cartilage aging and cartilage in order to study the beginning and early stages of osteo-
degradation are two separate processes.1 arthritis.4 Another study indicated that by measuring certain
biomarkers of bone, cartilage, and synovial metabolism (sC2C,
In another study, the matrix homeostasis of a healthy human uCTX-II, sCPII, uNTx, and sHA), changes in cartilage matrix
ankle was evaluated.2 Type I collagen synthesis and denatu- and early structural changes in cartilage could be identified.5
ration were found to be associated with the pericellular ma- This and many similar studies show that biomarkers may be
trix, and the type II collagen (CII) and proteoglycan content in important indicators of early-stage osteoarthritis. With such
the matrix were determined as remaining constant through- biomarkers, it could be possible to differentiate early osteo-
out life. Age had an important effect on the denaturation of CII, arthritis from cartilage aging.
which decreased as age increased, relative to collagenase-
mediated cleavage.2 These observations suggest that carti- To date, studies have not been able to clearly reveal the dis-
lage aging and the osteoarthritic process are two separate tinction between osteoarthritis and cartilage aging. It is there-
processes, since the aging of the ankle cartilage bore no re- fore difficult to distinguish primary osteoarthritis in its early
semblance to the molecular degenerative changes of osteo- stages from cartilage aging, hence the need for further stud-
arthritis.2 Thus, a clear difference emerges between aging and ies in this area. I
osteoarthritis.
References
On the basis of the two aforementioned studies, new inves- 1. Manerio E, Martin MA, Andres MC, et al. Mitochondrial respiratory activity is al-
tigative molecular studies could in the future be used routine- tered in osteoarthritic human articular chondrocytes. Arthritis Rheum. 2003;48:
700-708.
ly to help differentiate the early stage of osteoarthritis from car- 2. Aurich M, Poole R, Reiner A, et al. Matrix homeostasis in aging normal human
tilage aging. Currently, however, the results of studies such ankle cartilage. Arthritis Rheum. 2002;46:2903-2910.
as these are not completely clear and remain to be clarified. 3. De Groot J, Verzijl N, Wenting-van Wijk MJG, et al. Accumulation of advanced
glycation end products as a molecular mechanism for aging as a risk factor in
osteoarthritis. Arthritis Rheum. 2004;50:1207-1215.
Additionally, contrary to the aforementioned results, aging is 4. Zhang Y, Fang H, Chen Y, et al. Gene expression analyses of subchondral bone
one of the most important risk factors in the development of in early experimental osteoarthritis by microarray. PloS One. 2012;7:1-19.
5. Ishijima M, Watari T, Naito K, et al. Relationships between biomarkers of carti-
osteoarthritis, and more than 50% of the population over the lage, bone, synovial metabolism and knee pain provide insights into the origins
age of 60 years have osteoarthritic joints.3 Because osteo- of pain in early knee osteoarthritis. Arthritis Res Ther. 2011;13:R22.
5. O. P. Bortkevych, Ukraine
Normal aging involves a marked increase in the formation of
advanced glycation end products, including pentosidine cross-
links. The resultant increased crosslinking of collagen mole-
Oleg P. BORTKEVYCH, MD, PhD, DMedSc
Department of Clinical Rheumatology
cules can alter the biomechanical properties of cartilage, re-
National Scientific Centre M. D. Strazhesko sulting in increased stiffness and susceptibility to fatigue.
Institute of Cardiology
5, Narodnogo Opolcheniya St, 03151
UKRAINE
A highly prevalent change in aging cartilage is deposition of
(e-mail: [email protected]) calcium-containing crystals due to increased pyrophosphate
production by chondrocytes. Calcium crystals may stimulate
O
steoarthritis (OA) is a disease of the joint affecting all chondrocyte production of inflammatory mediators and extra-
joint tissues. Similarly, joint aging is systemic. Age is cellular matrixdegrading enzymes, contributing to the onset
the most prominent risk factor for OA, and although and progression of OA, and may play a role in erosive OA, a
the relationship between aging and OA is well known, its mech- more destructive form of OA most commonly seen in the dis-
anisms are not fully understood. tal interphalangeal joints in elderly women.
Joint changes that are both intrinsic and extrinsic (sarcope- Age-associated cellular changes in articular cartilage include
nia, altered bone remodeling, reduced proprioception) con- cell depletion and impaired responses to extracellular stimuli
tribute to OA development. The concept that aging contributes resulting in abnormal gene expression and cell differentiation.
to, but does not directly cause OA, is consistent with the mul- In full-thickness cartilage, cell density decreases with aging. In
tifactorial nature of the condition and the joints most com- OA-affected cartilage, chondrocyte proliferation in the form
monly affected. OA normally develops after long periods of of cell clusters or cloning has been observed in areas of
exposure to risk factors such as obesity, joint trauma, joint fibrillation. Cells in these clusters express progenitor cell mark-
malalignment, or abnormal shape and leg length inequality. ers and a wide spectrum of proteins associated with abnor-
Age-related changes occur in the joint tissues of all individu- mal chondrocyte activation and differentiation. This represents
als, most notably in articular cartilage. However, symptomatic, a tissue repair response of progenitor cells. The activation pat-
radiographic, macroscopic, or microscopic signs of OA do not tern of the cluster cells also underscores the notion that aging
manifest in all individuals, even at an advanced age. This sug- does not uniformly affect all cells in cartilage and that certain
gests that aging does not necessarily cause OA, rather age- cell subsets in aging and OA-affected cartilage are capable
related changes provide a basis upon which OA can develop. of proliferation and activation.
Individuals with OA risk factors may undergo an accelerated With increasing age, chondrocytes become less responsive
rate of change similar to that associated with aging, consis- to the proliferative and anabolic effects of growth factors,
tent with the concept that aging results from an imbalance be- which may contribute to an imbalance between anabolic and
tween stressors causing damage and mechanisms that re- catabolic activity. Altered cell signaling in response to growth
pair or protect against damage. factors may also account for the reduced anabolic response
with age.
In both aging and OA, changes occur in the total amount and
composition of articular cartilage extracellular matrix, which Conceptually, age-related pathologies originate from limitations
also undergoes proteolysis and other modifications. The su- in the maintenance and repair mechanisms of DNA, anom-
perficial zone is where the earliest age-related changes occur alies in the antioxidant mechanisms that contribute to the de-
in human articular cartilage. In OA, increased proteolytic ac- toxification of reactive oxygen species, or abnormalities in
tivity in cartilage and synovial fluid causes cartilage matrix mechanisms for removal of abnormal proteins and organelles.
changes and increased degradation of collagen molecules. A clear distinction between aging and OA has not always been
There is also a decrease in fixed charge density due to degra- provided, so that it can be difficult to differentiate primary age-
dation and loss of aggrecan. related changes from those that are part of the OA process. I
6. P. Hork, Czech Republic

over, and are among the oldest cells in the body. They ac-
Pavel HORK, MD, PhD cumulate age-related changes and are also unable to move
Department of Internal Medicine from damaged regions due to the constraint of the extracel-
Nephrology, Rheumatology, Endocrinology
Faculty of Medicine and Dentistry
lular matrix. Aside from aging, repeated injuries (joint insta-
Palack University of Olomouc bility) increase the requirements for replication and damage
I. P. Pavlova 6 repair and thus contribute to the exhaustion of mitotic po-
772 00 Olomouc
CZECH REPUBLIC
tential. As a result of the specific local environment, oxida-
(e-mail: [email protected]) tively damaged molecules can accumulate in chondrocytes,
leading to a decreased ability to maintain matrix synthesis and
O
steoarthritis (OA) is a slow-developing disease of the homeostasis. Chondrocyte senescence reduces the ability
diarthrodial joints associated with progressive car- to respond to growth factor stimulation, contributing to an
tilage damage, soft tissue and subchondral bone imbalance in cartilage formation and degradation, as well as
changes, bony osteophytes, and joint inflammation. OA is most decreased chondrocyte anabolic activity. Furthermore, senes-
common in the hands, causing significant pain and function- cence-associated secretory phenotype (SASP) may negative-
al loss, but involvement of the knees or hips is usually more ly affect the local environment. Cells exhibiting SASP pro-
disabling. Aging is the most important risk factor, followed duce proinflammatory cytokines and matrix metalloproteinases
by obesity, previous joint injury, female sex, and genetic dis- very similar to those in OA. Another cell senescence factor,
position. Two fundamental mechanisms lead to OA: normal high-mobility group box protein 2, regulates gene transcrip-
load on abnormal cartilage (primary OA) or abnormal load on tion and decline in the superficial zone of aging chondro-
normal cartilage (secondary OA). Although cartilage aging is cytes and is associated with increased chondrocyte death in
universal, OA is not found in all elderly people; a proportion of OA models.
them are free of symptomatic and radiographic OA, indicat-
ing the presence of additional risk and/or protective factors. Current findings support the view that cartilage aging usually
occurs before overt primary OA. In many cases, it is impossi-
There are several theories explaining the pathogenesis of pri- ble to distinguish the senescent chondrocyte from the osteo-
mary OA. The oldest theory, wear and tear of the cartilage ma- arthritic chondrocyte because cell senescence is the number
trix, emphasizes the effect of mechanical load over a lifetime. one precondition for OA. There is some evidence of increased
The extracellular matrix theory links OA to intrinsic changes chondrocyte proliferation during the development of OA, and
in proteoglycans, the collagen network, and chondrocyte bi- chondrocyte death has also been observed, with reduced
ology that are caused by advanced glycation end products numbers particularly in the superficial regions of cartilage.
and oxidative stress. The apoptotic theory views OA as the However, it is not clear if the cell damage and reactivity rep-
result of chondrocyte apoptosis or other types of cell death. resent changes associated with the aging process, early OA,
The mitochondrial theory emphasizes the role of mitochon- or a continuum from aging to OA.
drial DNA damage, which may be advanced by inflammato-
ry cytokines, contributing to chondrocyte energy failure and A better understanding of the role of senescence biology in OA
death. A recent theory on cell senescence describes OA as development may translate practically into the development
the increasing inability of the chondrocytes to keep up with of new strategies to delay the onset of chondrocyte senes-
mechanical or inflammatory attacks leading to failure in main- cence and prevent the development or progression of OA. I
taining cartilage integrity.
The causes of cell aging remain unclear, but it is increasingly Further reading
accepted that there are a limited number of cell replication 1. Aigner T, Richter W. Age related OAa concept emerging from infancy? Nat
Rev Rheumatol. 2012;8:70-72.
cycles, culminating in replicative senescence. Replication is 2. Horton Jr WE, Bennion P, Yang L. Cellular, molecular, and matrix changes in
limited by telomere exhaustion. Telomeres are eroded by each cartilage during aging and osteoarthritis. J Musculoskelet Neuronal Interact.
division cycle, eventually down to the minimum length for DNA 2006;6:379-381.
3. Loeser RF. Aging and osteoarthritis. Curr Opin Rheumatol. 2011;23:492-496.
replication, resulting in cycle arrest. 4. Anderson AS, Loeser RF. Why is osteoarthritis an age-related disease? Best
Pract Res Clin Rheumatol. 2010;24:15-26.
In adults, subchondral bone isolates cartilage from the vas- 5. Martin JA, Buckwalter JA. Aging, articular cartilage chondrocyte senescence
and osteoarthritis. Biogerontology. 2002;3:257-264.
cular system, resulting in no influx of progenitor cells into car- 6. Loeser RF. Age-related changes in the musculoskeletal system and the devel-
tilage. Chondrocytes are postmitotic, with little or no cell turn- opment of osteoarthritis. Clin Geriatr Med. 2010;26:371-386.
7. A. El Maghraoui, Morocco
mechanical stress on joint cartilage (arising from a number of
factors, including altered gait, muscle weakness, degenera-
tion of ligaments, changes in proprioception, and changes in
Abdellah El MAGHRAOUI, MD
Professor of Rheumatology
body weight), and changes within the joint (including cell and
Rheumatology Department matrix changes in joint tissues, thickening of the subchondral
Military Hospital Mohammed V bone, variable degrees of synovial inflammation, loss of menis-
Rabat
MOROCCO
cal tissue, and hypertrophy of the joint capsule contributing
(e-mail: [email protected]) to joint enlargement) contribute to the development of OA
when other OA risk factors are also present.3 The patholog-
O
steoarthritis (OA) is a common age-related disorder, ical changes noted in the other joint tissues also contribute
often described as a chronic degenerative disease to the loss of normal joint function, and because, unlike carti-
and thought by many to be an inevitable conse- lage, they contain pain fibers, these tissues are responsible
quence of growing old. Epidemiological studies show that age for the pain experienced by people with OA.
remains the most prominent risk factor for the initiation and
progression of primary OA in susceptible joints.1 The preva- Thus, it is very important to question how to distinguish nor-
lence of OA increases with age: radiographic surveys of mul- mal age-related changes in cartilage that do not progress to
tiple joints (hands, spine, hips, and knees) reveal the pres- OA from early changes that reliably do progress to OA. In this
ence of OA in at least one joint in over 80% of older adults.2 regard, magnetic resonance imaging (MRI) studies have shown
However, not all older adults with symptoms of joint pain have promising results. New methodological approaches for quan-
radiographic evidence of OA in the painful joint, and only about titative assessment have been introduced, and an MRI-based
half of people with radiographic OA experience significant definition of OA has been suggested.4 A recent study using
symptoms. Moreover, it is well-known that not all older adults MRI methods sensitive to cartilage matrix composition demon-
develop OA and not all joints in the body are affected to the strated that subjects at risk for OA have both higher and more
same degree. It is also well-known that radiographic OA heterogeneous cartilage T2 values than controls, and that T2
changes, particularly osteophytes, are common in the aged parameters are associated with morphologic degeneration.5
population, but symptoms of joint pain are frequently inde- One could speculate that the development of these kinds of
pendent of radiographic severity. Consequently, due to the dis- techniques could help to distinguish age-related changes in
crepancies between osteoarthritic pain and radiographic ev- cartilage that predispose patients to OA from those that do
idence of OA, most current epidemiological studies define OA not. More information is needed to better understand how
through a combination of clinical and radiographic criteria. aging changes in the bone, meniscus, and ligaments con-
tribute to the development of OA. I
The current concept is that OA is a disease of the whole joint,
which involves a complex series of molecular changes at the
cell, matrix, and tissue levels and complex interactions be- References
tween the tissues that make up the joint. Aging is the major 1. Aigner T, Richter W. OA in 2011: age-related OAa concept emerging from in-
risk factor, and it contributes to, but does not directly cause fancy? Nat Rev Rheumatol. 2012;8:70-72.
2. Loeser RF. Age-related changes in the musculoskeletal system and the develop-
OA. This is consistent with the multifactorial nature of the con- ment of osteoarthritis. Clin Geriatr Med. 2010;26:371-386.
dition and the differing joints most commonly affected. Be- 3. Heijink A, Gomoll AH, Madry H, et al. Biomechanical considerations in the patho-
sides age, the common risk factors for OA include obesity, genesis of osteoarthritis of the knee. Knee Surg Sports Traumatol Arthrosc. 2012;
20:423-435.
previous joint injury, genetics, and anatomical factors includ- 4. Hunter DJ, Arden N, Conaghan PG, et al. Definition of osteoarthritis on MRI: re-
ing joint alignment. These risk factors appear to interact with sults of a Delphi exercise. Osteoarthritis Cartilage. 2011;19:963-969.
age to determine which joints are affected by OA and how 5. Joseph GB, Baum T, Carballido-Gamio J, et al. Texture analysis of cartilage T2
maps: individuals with risk factors for OA have higher and more heterogeneous
severe the condition will be. Thus, there are important differ- knee cartilage MR T2 compared to normal controlsdata from the osteoarthri-
ences between an aged joint and one with OA. Age-related tis initiative. Arthritis Res Ther. 2011;13:R153.
8. A. Mahmoud Ali Elsayed, Egypt

morphology, cell proliferation rate, and patterns of protein se-
cretion (in particular stromelysin-1 and interstitial collagenase).3
Adel Mahmoud ALI ELSAYED, MD During aging, nonenzymatic glycation results in the accumu-
Professor of Internal Medicine
Head of Rheumatology Division
lation of advanced glycation end products (AGEs) in cartilage
Ain Shams University collagen. The highest AGE levels are found in tissues with
53 El Makrizy Street slow turnover, such as cartilage. AGEs exert their effects by ad-
Roxy, Cairo
EGYPT
versely affecting the biomechanical, biochemical, and cellu-
(e-mail: [email protected]) lar characteristics of the tissue, as well as by modulating tis-
sue turnover.
A
rticular cartilage is a unique tissue from the perspec-
tive of aging, in that chondrocytes and the majority This ultimately increases cartilage stiffness and brittleness, in-
of the extracellular matrix proteins experience little creases chondrocyte-mediated proteoglycan degradation,
turnover, thus resulting in a tissue that must withstand years reduces resistance to matrix metalloproteinasemediated de-
of use and can also accumulate years of aging-associated gradation, and decreases proteoglycan synthesis by chon-
changes. It has been known for a very long time that aging drocytes. Articular cartilage becomes more prone to damage
is the most prominent risk factor for the initiation and progres- and development of osteoarthritis.4
sion of osteoarthritis. This might be related to continuous me-
chanical wear and tear and/or time/age-related modifications In addition, an age-associated reduction in growth factor sig-
of cartilage matrix components. In addition, a mere loss of vi- naling and an increase in oxidative stress may also play an im-
able cells over time due to apoptosis or any other mechanism portant role in the age-osteoarthritis connection.5
might contribute. More recent evidence, however, supports
the notion that stressful conditions for the cells might pro- Although different studies have shown that age is inversely as-
mote chondrocyte senescence and be particularly important sociated with cartilage volume, cartilage turnover, and aggre-
in the progression of the osteoarthritic disease process.1 can expression in healthy individuals, the exact differentiation
between aged cartilage and early osteoarthritic cartilage seems
In animal models, aging predisposes articular cartilage to difficult, and age-related changes leading to failure of human
changes in viable cell density and to expression of specific pro- articular cartilage to resist damage are considered to be OA. I
apoptotic genes. Also, fetal and young (but still skeletally ma-
ture) bovine chondrocytes behave similarly, while aged chon-
drocytes display diminished proliferation, slightly reduced References
proteoglycan accumulation, and significantly less collagen ac- 1. Aigner T, Haag J, Martin J, Buckwalter J. Osteoarthritis: aging of matrix and
cumulation per cell compared with the younger cells. Histo- cellsgoing for a remedy. Curr Drug Targets. 2007;8:325-331.
2. Tran-Khanh N, Hoemann CD, McKee MD, Henderson JE, Buschmann MD.
logical observations and mechanical properties support these Aged bovine chondrocytes display a diminished capacity to produce a colla-
findings, and a particularly significant reduction in the tensile gen-rich, mechanically functional cartilage extracellular matrix. J Orthop Res.
stiffness produced by aged chondrocytes compared with 2005;23:1354-1362.
3. Dozin B, Malpeli M, Camardella L, Cancedda R, Pietrangelo A. Response of
younger cells has been observed.2 young, aged and osteoarthritic human articular chondrocytes to inflammatory
cytokines: molecular and cellular aspects. Matrix Biol. 2002;21:449-459.
In humans, chondrocytes from normal but aged subjects dis- 4. DeGroot J. The age of the matrix: chemistry, consequence and cure. Curr Opin
Pharmacol. 2004;4:301-305.
play biochemical properties closer to osteoarthritic-derived 5. Loeser RF Jr. Aging cartilage and osteoarthritiswhat's the link? Sci Aging
cartilage than to normal young cartilage, as indicated by cell Knowledge Environ. 2004;pe31.
9. A. Migliore, Italy
cretory phenotype has some features in common with the OA
chondrocyte phenotype, including increased production of
cytokines and matrix metalloproteinases.
Alberto MIGLIORE, MD The age-related increase in ROS levels could play an impor-
Director UOS of Rheumatology tant role in OA. The various inflammatory mediators that are
Hospital Villa S. Pietro
Rome, ITALY
increased in OA, including IL-1, IL-6, IL-8, TNF-, and other
(e-mail: [email protected]) cytokines, can all stimulate additional production of ROS. Ex-
cess ROS production can directly damage intracellular pro-
A
ging is the main risk factor for primary osteoarthritis teins and DNA, as well as the extracellular matrix, by stimu-
(OA) and OA is the disease most strongly correlated lating matrix metalloproteinase production and activity, thus
with aging. Both in humans and other animals, OA playing a significant role in stimulation of cartilage degrada-
development seems to be not rigorously time-dependent, but tion in OA.
to hold pace with the aging process. Despite older age being
the greatest risk factor for OA, OA is not an unavoidable con- The extracellular and cellular changes in aging compound each
sequence of growing old. Moreover, radiographic changes in- other, leading to biomechanical dysfunction and tissue de-
dicative of OAmainly osteophytesare frequent in the aged struction. Some of these changes differ from those seen in OA,
population, but symptoms of joint pain may not correlate with which is also characterized by cell activation with increased
the severity of radiographic findings in many older subjects. proliferation and gene expression. Disruption of the articu-
lar surface or superficial zone (SZ) seems to be a key trigger-
OA is a degenerative disease characterized by structural ing event for the chronic and progressive extracellular ma-
changes to joint tissues that include synovial inflammation, trix degradation process leading to OA. The SZ contains the
catabolic destruction of articular cartilage, alterations in sub- majority of mesenchymal stem cells in adult cartilage. The
chondral bone, and decreasing muscle strength. presence of stem cells endows the SZ with the capacity for
self-renewal, which may be required to respond to mechan-
This article will only address differences between cartilage ical stress. However, the SZ can be compromised by acute
changes caused by OA and those caused by aging. The ef- or chronic mechanical stress and by age-related cellular dys-
fects of aging involve the whole articular cartilage. Major ex- function. Once the SZ is disrupted, cartilage cells are acti-
tracellular matrix changes comprise reduced cartilage thick- vated, and through the production of matrix-degrading en-
ness, proteolysis, advanced glycation, and calcification. Cellular zymes, lesions enlarge causing joint inflammation, pain, and
changes consist of decreased cell density, cellular senes- dysfunction. Loss of cells (eg, via apoptosis) is among the ma-
cence with reduced chondrocyte survival, decreased mitotic jor changes that occur in the SZ due to aging and exposure
and anabolic activity, anomalous cytokine excretion, and im- to mechanical stress.
paired cellular resistance.
Cartilage degradation results in the production of fragments of
One of the most pronounced age-related changes in chon- extracellular matrix molecules. Some of these molecules may
drocytes is a senescent phenotype, which is caused mainly be detected in blood, serum, synovial fluid, and urine, and
by the accumulation of reactive oxygen species (ROS) and can act as useful biomarkers. The ability to detect biomarkers
advanced glycation end products. Senescent chondrocytes of cartilage degradation may enable clinicians to differentiate
display an impaired ability to respond to many mechanical the appearance of subclinical OA from natural joint aging. Bio-
and inflammatory insults. Protein secretion is also altered in markers indicating early phases of degeneration would be
aging chondrocytes, as demonstrated by a decrease in an- useful in detecting preradiographic OA changes. Proteomic
abolic activity and increased production of proinflammatory techniques have the potential to improve our understanding
cytokines and matrix-degrading enzymes. The senescent se- of OA pathophysiology. I
10. T. Pap, Germany

its concentration correlates with disease severity.4 Interest-
ingly, the loss of syndecan-4 in genetically modified mice, as
Thomas PAP, MD well as its inhibition by specific antibodies, was capable of
Institute of Experimental
Musculoskeletal Medicine
preventing the development of OA-like changes.4 These data
University Hospital Mnster are also of interest because according to recent data, in-
Domagkstrasse 3 creased expression of syndecan-2 can compensate for the
D-48149 Mnster
GERMANY
loss of syndecan-4 during embryogenesis but not during OA,
(e-mail: [email protected]) due to differential regulation of these two syndecans. While
the exact mechanisms are not fully understood, these data
O
steoarthritis (OA) is the most frequent joint disease suggest that while the program appears to be similar, the
and an important cause of disability in the Western triggers and mechanisms of cartilage remodeling during en-
world. It involves all parts of articular joints and is dochondral ossification and OA may be distinct.
characterized primarily by the progressive, irreversible loss of
articular cartilage. Given that the incidence of osteoarthritic Given that during endochondral ossification, deposition of ba-
changes increases with age, the question of whether OA is a sic calcium phosphate crystals is an important part of bone
mere aging phenomenon or as with cardiovascular disorders, formation, calcification of articular cartilage during OA is an-
cancer, or neurodegenerative diseases, becomes more fre- other indication of similarities between both conditions. Our
quent during aging because of the cumulative effects of path- group found that the calcification of hyaline cartilage is a reg-
ogenic factors (which in principle can affect individuals at any ular event in human OA and is strongly associated with the
age), is a controversial, yet important, one. hypertrophic differentiation of chondrocytes.5 The mechanisms
involved in pathological cartilage calcification during OA, and
One main reason for the difficulty in answering this question particularly the pathways that link chondrocyte differentiation
is that the processes that lead to and characterize normal to the calcification of the surrounding matrix, are not com-
cartilage aging remain largely unknown. While it is well accept- pletely understood. However, changes in the synthesis and
ed that the composition of the extracellular matrix changes transport of inorganic pyrophosphate, as well as in extracel-
with aging, aside from the loss of proteoglycans, disease-spe- lular pyrophosphate metabolism, have been found to be as-
cific alterations in osteoarthritic cartilage are poorly charac- sociated with this process.6
terized and understood. Also, OA most likely does not con-
stitute a uniform disease, but rather an initially complex yet Collectively, these data indicate that while mechanistically sim-
ultimately narrow path of how cartilage responds to different ilar and part of a rather uniform program, the developmental
types of stress. In this context, it has been suggested that in- processes that occur either during embryogenesis or during
flammation is a distinguishing factor between normal aging aging can be distinguished from the pathological changes
and OA.1 However, the role of inflammation as a trigger and seen in OA. Distinguishing factors appear to include the na-
accelerating force of osteoarthritic changes remains contro- ture, strength, and duration of underlying stimuli. I
versial, and while some recent data suggest a key role for
inflammatory signals, the most recent studies have failed to References
demonstrate a key role for IL-1mediated inflammation in 1. Furuzawa-Carballeda J, Macip-Rodriguez PM, Cabral AR. Osteoarthritis and
murine models of OA.2 Of interest, several lines of evidence rheumatoid arthritis pannus have similar qualitative metabolic characteristics and
pro-inflammatory cytokine response. Clin Exp Rheumatol. 2008;26:554-560.
indicate that osteoarthritic changes are linked to the reex- 2. Bougault C, Gosset M, Houard X, et al. Stress-induced cartilage degradation does
pression in chondrocytes of molecules and pathways that not depend on NLRP3 inflammasome in osteoarthritis. Arthritis Rheum. 2012;64:
are characteristic of different stages of endochondral ossi- 3972-3981
3. Saito T, Fukai A, Mabuchi A, et al. Transcriptional regulation of endochondral os-
fication during embryonic development.3 sification by HIF-2alpha during skeletal growth and osteoarthritis development.
Nat Med. 2010;16:678-686.
Members of the syndecan family of transmembrane heparin 4. Echtermeyer F, Bertrand J, Dreier R, et al. Syndecan-4 regulates ADAMTS-5 ac-
tivation and cartilage breakdown in osteoarthritis. Nat Med. 2009;15:1072-1076.
sulfate proteoglycans, particularly syndecan-4, are prominent 5. Fuerst M, Bertrand J, Lammers L, et al. Calcification of articular cartilage in hu-
examples in this respect.4 We were able to show that syn- man osteoarthritis. Arthritis Rheum. 2009;60:2694-2703.
decan-4, which is expressed prominently in hypertrophic chon- 6. Bertrand J, Nitschke Y, Fuerst M, et al. Decreased levels of nucleotide pyrophos-
phatase phosphodiesterase 1 are associated with cartilage calcification in osteo-
drocytes of developing joints in the embryo, is reexpressed arthritis and trigger osteoarthritic changes in mice. Ann Rheum Dis. 2012;71:
both in human OA and in animal models of the disease, and 1249-1253.
11. J. del Pino-Montes, Spain

Besides these mechanisms, the chondrocyte anabolic re-
Javier DEL PINO-MONTES, MD, PhD sponse to growth factors decreases with age. Under such cir-
Professor of Medicine cumstances, the chondrocyte is unable to maintain cartilage
University of Salamanca
Service of Rheumatology
homeostasis. Cell death has also been related to aging, and
University Hospital of Salamanca formation of advanced glycation end products (AGEs) in-
Paseo San Vicente, 54 creases with age.4 Modification of collagen by AGE formation
37007 Salamanca
SPAIN
results in increased crosslinking of collagen molecules affect-
(e-mail: [email protected]) ing the biochemical properties of cartilage and making it more
brittle. Moreover, there is an age-related increase in reactive
O
steoarthritis (OA) is probably the most common oxygen species, and this may contribute to cell death and
chronic joint disorder. It is defined by focal lesions matrix degeneration.5
of the articular cartilage, a hypertrophic reaction in
the subchondral bone, and new bone formation. OA is often There is no clear frontier between the features of articular car-
considered a chronic degenerative disease, with degradation tilage in aging and OA, and both share some common char-
of articular cartilage attributed to wear and tear. Although ag- acteristics. Senescent and osteoarthritic chondrocytes share
ing is a known risk factor for OA, the condition is not a con- a secretory phenotype. Cell death has been observed during
sequence of growing old, but involves a destructive chronic the development of OA as well as in aging cartilage. Age-re-
active inflammatory mechanism mediated by cells within the lated loss of autophagy, a protective mechanism for normal
articular cartilage.1 chondrocytes that protects cells during the stress response,
is associated with cell death and OA development.6 Age-re-
In OA, there is a change in the normal adult chondrocyte state lated changes in cartilage matrix could also be important in
characterized by cell proliferation, cluster formation, and in- contributing to the development of OA. The increased ac-
creased production of matrix proteins and matrix-degrading cumulation and expression of AGEs that occurs in aging
enzymes. Chondrocytes in OA cartilage express cytokine and chondrocytes is associated with enhanced sensitivity to cy-
chemokine receptors, matrix metalloproteinases (MMPs), and tokines and chemokines, which trigger expression of MMPs.
other proteins that enhance or modulate inflammatory and The increased production of reactive oxygen species could
catabolic responses. MMPs such as aggrecanases and col- also play an important role in OA.
lagenases are found in the osteoarthritic joint. In early OA,
MMP-3 and ADMTS-5 degrade aggrecan.2 Next, collagenas- The relationship between aging and OA is well known, but
es degrade type II collagen and the collagen network. As the the mechanisms by which aging predisposes the joint to OA
articular cartilage matrix proteins are degraded, fragments development are not fully understood. Age-related changes
of matrix proteins such as fibronectin and small leucine-rich observed in cell and cartilage matrix may increase the sus-
proteoglycans are produced, which can feed back and stim- ceptibility to OA, but they do not directly cause it in older
ulate further matrix destruction. This early stage may reflect an adults. More information is needed to better understand how
effort by the hypertrophic chondrocytes to repair cartilage dam- aging changes in the bone, meniscus, and ligaments con-
age. As OA progresses, the proteoglycan level eventually tribute to the development of OA. I
drops very low, causing cartilage to soften and lose elastic-
ity, thereby further compromising joint surface integrity.
References
1. Goldring MB, Marcu KB. Cartilage homeostasis in health and rheumatic diseases.
Aging produces a gradual loss of cartilage matrix as well as Arthritis Res Ther. 2009;11:224.
a decrease in cartilage hydration and cellularity. Aging carti- 2. Wang M, Shen J, Jin H, Im HJ, Sandy J, Chen D. Recent progress in under-
lage is characterized by an age-related loss in the ability of cells standing molecular mechanisms of cartilage degeneration during osteoarthritis.
Ann N Y Acad Sci. 2011;1240:61-69.
and tissues to maintain homeostasis. Normal aging chondro- 3. Leong DJ, Sun HB. Events in articular chondrocytes with aging. Curr Osteo-
cytes are reduced in number, rarely divide, and exhibit no poros Rep. 2011;9:196-201.
cellular proliferation or hypertrophic cells. They show short- 4. DeGroot J, Verzijl N, Wenting-van Wijk MJ, et al. Accumulation of advanced gly-
cation end products as a molecular mechanism for aging as a risk factor in os-
ened telomeres characteristic of cellular senescence. Howev- teoarthritis. Arthritis Rheum. 2004;50:1207-1215.
er, aging chondrocytes can exhibit a senescence secretory 5. Del Carlo M Jr, Loeser RF. Cell death in osteoarthritis. Curr Rheumatol Rep.
phenotype, characterized by increased production of cyto- 2008;10:37-42.
6. Goldring MB. Chondrogenesis, chondrocyte differentiation, and articular carti-
kines, MMPs, and several growth factors.3 As a result, in the lage metabolism in health and osteoarthritis. Ther Adv Musculoskelet Dis. 2012;
elderly, there is increased age-related cartilage catabolism. 4:269-285.
12. C. A. F. Zerbini, Brazil

mitochondrial and nuclear DNA damage. Mitochondrial DNA
damage can be observed in OA and is associated with in-
creased matrix degradation and decreased matrix synthesis.
Cristiano A. F. ZERBINI, MD
Rheumatology Department
ROS production may be induced by inflammatory cytokines
Hospital Helipolis such as IL-1 and TNF-, and is also associated with me-
Rua Conego Xavier #276 chanical injury to joints. An increase in ROS may contribute
04231-030, So Paulo, SP
BRAZIL
to chondrocyte death.4
(e-mail: [email protected])
Thus, ROS, mitochondrial dysfunction, and DNA damage may
O
steoarthritis (OA) is considered a characteristic age- be features of chondrocyte senescence associated with de-
related disease. Its prevalence increases with age, af- velopment of SASP and may lead to cartilage matrix impair-
fecting 30% to 50% of adults aged over 65 years.1 ment and development of OA.
Although it is the greatest risk factor for OA, older age alone
is not responsible for its development. Age, obesity, female Aged and osteoarthritic chondrocytes have a reduced ability
sex, previous trauma (knee injury), and hand OA were report- to respond to transforming growth factor- and insulin-like
ed as consistent risk factors for knee OA in people aged 50 growth factor-1 (IGF-1) stimulation. This leads to a reduced
years and older.2 Risk factors for OA such as obesity, genet- capacity for matrix repair, and consequently, a degeneration
ics, anatomical abnormalities, and joint injury are well known, of the articular cartilage. The decrease in chondrocyte respon-
but how they interact with age to initiate and develop OA is siveness to IGF-1 is associated with increased ROS levels.5
still unclear. Recent advances in molecular biology are start-
ing to clarify the connection between cellular aging changes Autophagy is a mechanism used by the cell to degrade and
and the propensity to develop OA. recycle dysfunctional proteins. It is an important mechanism
by which cells are protected against stress. Autophagy de-
Chondrocytes are the only cell type in articular cartilage, and clines with age, and its loss has been associated with in-
they particularly suffer during aging. They are responsible creased chondrocyte death. Recent studies in autophagy have
for the synthesis and breakdown of the cartilaginous matrix attempted to clarify the possible role of this process in senes-
and are driven by signals from growth factors, cytokines, and cence and OA.6
the matrix itself. The chondrocytes of older cartilage are the
same cells present in the cartilage during youth. Chondrocytes Thus, to answer the question, we must determine if and when
rarely divide or die in normal adult articular cartilage, with the the aging process results in the development of SASP. Senes-
same cells remaining active for many years. Chondrocytes cent chondrocytes developing this phenotype are very sim-
have a very long lifespan, but in older individuals they may ex- ilar to chondrocytes found in osteoarthritic joint tissues. In
press changes characteristic of cell senescence. Cell senes- my opinion, development of this phenotype with its associ-
cence found in chondrocytes is called stress-induced or ated inflammatory cytokines, or lack of it, will determine how
extrinsic senescence, as opposed to replicative or intrin- much we can distinguish between normal age-related changes
sic senescence. Stress-induced senescence can develop in cartilage and early osteoarthritic changes. I
from stimuli including activated oncogenes, ultraviolet radia-
tion, and chronic inflammation. Stress-induced senescence
is associated with oxidative DNA damage, which results in References
telomere shortening (as in replicative senescence). Many age- 1. Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthri-
tis and other rheumatic conditions in the United States: Part II. Arthritis Rheum.
related changes in chondrocytes, particularly oxidative DNA 2008;58:26-35.
damage, may induce development of the senescence-asso- 2. Blagojevic M, Jinks C, Jeffery A, et al. Risk factors for onset of osteoarthritis of
ciated secretory phenotype (SASP).3 This phenotype when the knee in older adults: a systematic review and meta-analysis. Osteoarthritis
Cartilage. 2010;18:24-33.
expressed in chondrocytes may link the articular aging process 3. Freund A, Orjalo AV, Desprez PY, et al. Inflammatory networks during cellular
with the development of OA. SASP is characterized by in- senescence: causes and consequences. Trends Mol Med. 2010;16:238-246.
creased production of inflammatory mediators such as cy- 4. Loeser RF. Aging and osteoarthritis. Curr Opin Rheumatol. 2011;23:492-496.
5. Yin W, Park JI, Loeser RF. Oxidative stress inhibits insulin-like growth factor-I
tokines and matrix metalloproteinases, which may induce car- induction of chondrocyte proteoglycan synthesis through differential regulation
tilaginous matrix degradation and joint impairment and may of phosphatidylinositol 3-Kinase-Akt and MEK-ERK MAPK signaling pathways.
also be found in osteoarthritic cartilage. SASP expression in J Biol Chem. 2009;284:3197231981.
6. Carames B, Taniguchi N, Otsuki S, et al. Autophagy is a protective mechanism in
chondrocytes may be linked to the production of reactive oxy- normal cartilage, and its aging-related loss is linked with cell death and osteoarthri-
gen species (ROS) by dysfunctional mitochondria, resulting in tis. Arthritis Rheum. 2010;62:791-801.
INTERVIEW
While noninvasive treatments

such as exercise and physical ther-
apy should be started in the earlier
phases, injective treatments should
be considered for the management
of patients after noninvasive pro-
cedures have failed. Prosthetic re-
Nonpharmacological
placement, which is an irreversible
procedure, should of course be re-
treatments in osteoarthritis
served as a last option during the
advanced and debilitating phas-
es of osteoarthritis refractory to
other treatments.
I n t e r v i e w w i t h E . Ko n , I t a l y
T
he goal of this interview is to better understand the role of nonpharma-
cological treatments in osteoarthritis. A wide spectrum of treatment op-
tions is available, ranging from adaptation of activity levels, exercise,
and physiotherapy, to intra-articular injections, surgical unloading of the de-
generated joint compartment, and knee replacement. While the aim of all treat-
ments is to improve symptoms, function, and therefore quality of life, each has
its own advantages and disadvantages and is more suitable for certain specif-
ic phases of joint osteoarthritis. There is currently no agreement on the most
effective management of osteoarthritis, and none of the available treatment
options have been proven to produce better results over all others or have been
Elizaveta KON, MD clearly shown to have disease-modifying properties. In general, the optimal
III Clinic, Biomechanics Laboratory conservative management of knee osteoarthritis requires a combination of
Rizzoli Orthopaedic Institute
Bologna, ITALY pharmacological and nonpharmacological treatment modalities. Among non-
pharmacological treatments, a combination of different approaches is also
recommended. Aside from considering the treatment to be applied, one must
also consider that osteoarthritis is a chronic condition and that long-term dis-
ease management can be cumbersome. Thus, therapeutic education of pa-
tients with osteoarthritis is of major importance. Finally, prostheses produce
a high percentage of good results but require adaptation to the activity level
of the patient and also carry some important risks related to the surgical im-
plant. Thus, when treating a patient affected by osteoarthritis, it is important
to consider all the available options for improving the clinical condition of the
patient and keep prosthetic replacement as a last option for when functional
limitations and symptoms prove to be refractory to less invasive procedures.
When should nonpharmacological management of osteoarthritis

be started?
he etiology of osteoarthritis (OA) is multifactorial. Age is the major independ-

Dr Elizaveta Kon, Biomechanics
Laboratory, Rizzoli Orthopaedic
T ent risk factor for OA; however, aging and OA are interrelated, not interde-
pendent. It is becoming apparent that age-related changes in the musculo-
skeletal system contribute to the development of OA by working in conjunction with
Institute, Via Di Barbiano, 1/10, other factors that are both intrinsic (eg, malalignment, overloading) and extrinsic (eg,
40136 Bologna, Italy genetics) to the joint. Regardless of the initial cause, once started, osteoarthritic
(e-mail: [email protected]) alterations lead to progressive loss of hyaline cartilage, leading eventually to end-
www.medicographia.com stage OA.1
216 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Nonpharmacological treatments in osteoarthritis Kon
INTERVIEW
Thus, nonpharmacological OA management should be start- International clinical guidelines recommend exercise as an ef-
ed even before the clinical onset of symptoms, with the aim fective approach in the management of knee OA. The aims of
of treating the predisposing factors. Early OA should be de- exercise in these patients are to reduce pain, improve physi-
tected. Clinical recurrence of pain and discomfort of the knee cal function and health status, and prevent progression of the
and/or short periods of stiffness, in between long periods with disease. While the optimal dosage (frequency, intensity, and
very few clinical manifestations, should set the stage for per- duration) has not yet been determined, good results have been
forming additional investigations such as radiographs, ultra- reported for different types of exercise.5 In general, physical
sound, magnetic resonance imaging (MRI), or arthroscopy.2 activity is beneficial, rather than detrimental, to joint health, and
an MRI study showed that moderate exercise may also im-
Malalignment, loss of meniscal tissue, cartilage defects, and prove the knee cartilage glycosaminoglycan content in pa-
joint instability or laxity should be evaluated, and treatment (in- tients at high risk of developing OA, but long-term effective-
cluding surgery if appropriate) should be discussed with the ness still needs to be clarified.6
patient, taking into consideration their activity level and expec-
tations as well as the risks of failure and complications asso- As mentioned, injective treatments also play an important role
ciated with every procedure. in the management of OA, ranging from corticosteroids to vis-
cosupplementation and also to more innovative biological
In addition to its preventative use in the early phase, nonphar- procedures such as the use of blood derivatives to aid the
macological management should also always be considered restoration of joint homeostasis and tissue regeneration.7
when OA is clearly established. Of course, when considering
treatment options, one should also always take into consid- Moreover, although the degenerative OA environment is an ob-
eration the disease phase and the invasiveness of the pro- stacle to tissue regeneration, progress made in bioengineer-
cedure. ing and the development of new scaffolds seems to represent
a promising solution that may help to avoid, or at least delay,
Nonpharmacological management is a broad definition, rang- the need for more sacrificing metal resurfacing procedures.8
ing from physiotherapy to knee replacement. While noninva-
sive treatments such as exercise and physical therapy should How should cost, availability, or practicality
be started in the earlier phases, injective treatments should of delivery be taken into account?
be considered for the management of patients after noninva-
sive procedures have failed. Prosthetic replacement, which ost, availability, and practicality of delivery should al-
is an irreversible procedure, should of course be reserved as
a last option during the advanced and debilitating phases of
OA refractory to other treatments.
C ways be taken into account in the management of OA
patients, especially when one considers that there is
currently no agreement on the most effective management of
these patients and none of the available treatment options
What is the cornerstone of nonpharmacological have been proven to produce better results over all others or
treatment? have been clearly shown to have disease-modifying properties.
here is no cornerstone of nonpharmacological treat- Luckily, one of the nonpharmacological treatments proven to
T ment. As previously underlined, this is a broad defini-

tion, ranging from adaptation of activity levels to ex-
ercise, from physiotherapy to intra-articular injections, from
be comparatively more effective for OA patients is exercise.
Hydrotherapy was found to produce a small-to-moderate im-
provement in function and quality of life and a small reduc-
surgical unloading of the degenerated joint compartment to tion in pain in osteoarthritic patients. Hydrotherapy is not al-
knee replacement, and so on.3,4 While all treatments are aimed ways available, however, but other exercise modalities have
at improving symptoms, function, and therefore quality of life, also proven to be useful: strength and aerobic training, range-
every treatment presents its own advantages and disadvan- of-motion exercises, and stretching have beneficial effects in
tages and is more appropriate for specific phases of joint OA. modulating pain, increasing range of motion, reducing or elim-
One nonpharmacological approach that is probably indicat- inating soft tissue inflammation, inducing relaxation, improv-
ed across different phases of articular degeneration with min- ing repair, extensibility, or stability of contractile and noncon-
imal contraindications is exercise. tractile tissues, facilitating movement, and improving function.
Tai-chi, a traditional Chinese exercise that enhances balance,
strength, and flexibility, has also been shown to be effective
in treating knee OA.
MRI magnetic resonance imaging
OA osteoarthritis A special comment should be made about the cost, availabil-
OARSI Osteoarthritis Research Society International ity, and practicality of delivery of the new injective procedures.
Among these, platelet-rich plasma therapy, a procedure based
Nonpharmacological treatments in osteoarthritis Kon MEDICOGRAPHIA, Vol 35, No. 2, 2013 217
INTERVIEW
on the injection of platelet concentrate to encourage tissue Therapeutic education is also of fundamental importance af-
regeneration through the release of growth factors contained ter surgery in order to limit the risk of complications such as
in the platelet alpha-granules, has been recently gaining pop- infection, or even fatal events, and to optimize treatment. For
ularity as a promising therapeutic option for early OA. How- example, biological implants for tissue regeneration require a
ever, despite some promising clinical results, the beneficial maturation phase during which the healing structure has to
effect of this procedure is limited over time.9 Thus, it is im- be protected, and even after metal resurfacing, therapeutic
portant to consider that the high costs, the contraindications education is mandatory to ensure adaptation of life activities
for several comorbidities, and the need for specialist centers and preservation of the prosthetic joint over time.
are major limitations that favor more classic injective proce-
dures. Among these, viscosupplementation seems to offer a How long can nonpharmacological management
clinical benefit, albeit limited over time, without side effects on put off surgical intervention?
the joint tissues. However, in patients where the joint has al-
ready degenerated, corticosteroid injections can be consid- onpharmacological management can put off the need
ered as a cheap option that is easily and widely accessible.
Other more invasive surgical procedures also present specific

N for surgical intervention, but in this regard every sin-
gle case must be considered individually. First, it has
to be stressed that sometimes it can be counterproductive to
limitations with regard to cost, availability, or practicality of de- put off surgical intervention. This is particularly true when there
livery. Patient comorbidities should also be taken into consid- are clearly recognized predisposing factors that could be ad-
eration when contemplating more invasive surgical procedures, dressed surgically. A previous total meniscectomy, joint in-
as comorbidities can complicate treatment, and logistical prob- stability due to ligament rupture, incongruity of the articular
lems and the need for assistance during the sometimes long surface due to previous intra-articular fractures, misalignment
postoperative rehabilitation phase also need to be considered. causing overload, and degeneration of an articular compart-
ment are just some examples of clinical conditions for which
How important is therapeutic education delaying surgical treatment would only result in a worsening
in osteoarthritis and why? of the joint condition with a worse final outcome.
herapeutic education in OA is of major importance. OA On the other hand, when there are no clear predisposing fac-
T is a chronic condition, and long-term management of

a disease can be cumbersome. Aside from occasional
injections or other medical procedures, patients affected by
tors or when patients present with comorbidities that contra-
indicate surgical treatments, nonpharmacological manage-
ment can be used to put off surgical intervention. Of course
OA are required to undergo much more difficult changes in every case is different, but it is possible to state that in the ma-
their life. In fact, correct management of OA often involves life- jority of cases, proper management of OA can delay the need
style adaptation with continuous exercise, frequent physical for prosthetic replacement for several years. Lifestyle adapta-
therapy, and diet modification. None of this is achievable with- tion with diet modification and exercise, together with other
out proper therapeutic education. Patients need to be aware medical treatments such as physical therapy or injections to
of their condition, of the factors affecting the disease, and of treat the acute inflammatory OA phases, can improve the clin-
their responsibility in following the correct lifestyle and pre- ical condition and delay the need for more invasive surgery.
scribed therapies. In terms of pharmacological therapy, pa-
tients must follow the treatment indications to obtain optimal It is important for the patient to have clear expectations about
results, and personal initiatives or treatment adaptations that all the treatment options. Surgery can sometimes be consid-
do not follow the physicians indications can only lead to less- ered by the patient as an easy way to improve their clinical
er benefits. A recent review of the role of exercise in OA man- condition, but knowledge of the limitations and risks of sur-
agement focused on the different methods of treatment de- gery can give them the correct perspective in understanding
livery, which can entail individual treatment, treatment within the importance of properly applying nonsurgical manage-
a supervised group, or exercise performed at home. No dif- ment for major beneficial effects and the longest delay be-
ference was found in terms of the beneficial effects of exer- fore surgical intervention.
cise when patients had received proper therapeutic education
and performed the prescribed exercise. However, regular su- Is there any randomized controlled study available
pervision may improve adherence to exercise, which is required on the nonpharmacological approach?
to maintain the benefits over time, and a recent study report-
ed that the effects of exercise were better when conducted ome randomized controlled studies are available on the
over more than 12 supervised sessions.5 Supervised sessions
allowed for more therapeutic education and more control over
patients, who as a consequence followed their therapies bet-
S nonpharmacological approach, but results are still far
from conclusive. Controversial findings, as well as the
incredibly high number of variables differing between each
ter and thus achieved better results. study, make comparison of the available studies difficult.
INTERVIEW
Surprisingly, the definition of OA has not changed since 1986. A further 8 recommendations cover pharmacological treat-
The diagnosis of knee OA can usually be made from the pa- ment modalities, and finally, 5 recommendations cover sur-
tient history and physical examination, and includes signs/ gical modalities: total joint replacements, unicompartmental
symptoms of knee pain with stiffness, joint crepitus and func- knee replacement, osteotomy and joint-preserving surgical
tional limitations, and typically an age above 50 years. Diagno- procedures, joint lavage and arthroscopic debridement in
sis is confirmed by radiograph demonstrating changes such knee OA, and joint fusion as a salvage procedure when joint
as osteophytes and joint space narrowing, subchondral bone replacement has failed.
sclerosis, and cysts, and is graded according to the classifi-
cation of Kellgren and Lawrence (Kellgren & Laurence grades These strategies can be combined according to the specific
II-IV). It appears clear that this definition of OA cannot distin- requirements of the patient with the aim of producing tailored
guish between the pathological changes in different tissues. treatment and thus more satisfactory clinical results.
Thus, study populations can be heterogeneous and can re-
spond differently to different treatments, even though they ap- What can you tell us about life after knee
parently present in the same disease phase. replacement surgery?
There is no agreement in the literature on the best treatment any options are currently available for knee replace-
option for OA, and this is reflected in clinical practice where
treatment is mainly empirical and based on the personal ex-
perience of the individual physician. Moreover, leaving aside
M ment, from focal metal resurfacing to total prosthet-
ic replacement of the affected joint.10 Of course,
functional improvement and limitations will depend strictly
the contradictory findings of the different studies, it is also dif- on the implant type as well as the specific characteristics of
ficult to translate the study results into clinical practice be- the patient, and also eventually on the presence of any sur-
cause the selected study populations are often a specific cat- gical complications.
egory of patients that is rare in the normal population. Patients
in clinical practice typically present with more complex clinical In general, this procedure offers a dramatic improvement in
situations and with comorbidities and combined treatments. the clinical condition. Most patients have minimal pain by 3
months (or sooner) after surgery and return to their normal
New imaging techniques are required to better assess the daily activities. It is not unusual to have occasional muscle
disease phase and to properly classify study populations, aches and persistent (but usually slight) swelling of the knee
and more randomized controlled trials are needed to prove and extremity for several months, and some patients require
which treatment approach is more suitable for each of the a longer time to achieve good and stable results. Depending
different phases of OA degeneration. on numerous factors, a persistent limp is usually expected,
but results tend to improve over time.
Can nonpharmacological treatment be combined
with pharmacological treatment? Unfortunately, 5% of patients will be unsatisfied because of
the persistence of pain or the onset of complications. More-
hile it is true that properly applied nonpharmaco- over, it has to be remembered that despite the technological
W logical treatment can sometimes limit the need for

pharmacological treatment, it is also well accepted
that combined treatment can often offer a better clinical out-
improvements of the last decades, implants still have limited
longevity and may require revision surgery. Age is one of the
major factors in determining reduced longevity. Younger pa-
come. In general, the optimal conservative management of tients wear out their replacements more quickly than older
knee OA requires a combination of pharmacological and non- patients, and this has to be taken into consideration in the
pharmacological treatment modalities, and among the non- management of a patient affected by OA.
pharmacological treatments, a combination of different ap-
proaches is recommended. In general, prostheses give good results, but they also require
adaptation to the activity level of the patient and there are some
Osteoarthritis Research Society International (OARSI) pro- important risks related to the surgical implant. Thus, when treat-
duced a list of 25 recommendations regarding the treatment ing a patient affected by OA, it is important to consider all
of OA. These cover the use of 12 nonpharmacological modal- the available options to improve their clinical condition and to
ities: education and self-management, regular telephone con- keep prosthetic replacement as a last option when function-
tact, referral to a physical therapist, aerobic, muscle strength- al limitations and symptoms prove to be refractory to less in-
ening and water-based exercises, weight reduction, walking vasive procedures. I
aids, knee braces, footwear and insoles, thermal modalities,
transcutaneous electrical nerve stimulation, and acupuncture. The author declares that she has no conflict of interest.
Nonpharmacological treatments in osteoarthritis Kon MEDICOGRAPHIA, Vol 35, No. 2, 2013 219
INTERVIEW
References
1. Heijink A, Gomoll AH, Madry H, et al. Biomechanical considerations in the patho- glycan content in knee cartilage: a four-month, randomized, controlled trial in
genesis of osteoarthritis of the knee. Knee Surg Sports Traumatol Arthrosc. patients at risk of osteoarthritis. Arthritis Rheum. 2005;52:3507-3514.
2012;20:423-435. 7. Kon E, Filardo G, Di Martino A, Marcacci M. Platelet-rich plasma (PRP) to treat
2. Luyten FP, Denti M, Filardo G, Kon E, Engebretsen L. Definition and classifica- sports injuries: evidence to support its use. Knee Surg Sports Traumatol Ar-
tion of early osteoarthritis of the knee. Knee Surg Sports Traumatol Arthrosc. throsc. 2011;19:516-527.
2012;20:401-406. 8. Kon E, Delcogliano M, Filardo G, Altadonna G, Marcacci M. Novel nano-com-
3. Gomoll AH, Filardo G, de Girolamo L, et al. Surgical treatment for early osteo- posite multi-layered biomaterial for the treatment of multifocal degenerative car-
arthritis. Part I: cartilage repair procedures. Knee Surg Sports Traumatol Ar- tilage lesions. Knee Surg Sports Traumatol Arthrosc. 2009;17:1312-1315.
throsc. 2012;20:450-466. 9. Kon E, Mandelbaum B, Buda R, et al. Platelet-rich plasma intra-articular injec-
4. Gomoll AH, Filardo G, Almqvist FK, et al. Surgical treatment for early osteo- tion versus hyaluronic acid viscosupplementation as treatments for cartilage
arthritis. Part II: allografts and concurrent procedures. Knee Surg Sports Trau- pathology: from early degeneration to osteoarthritis. Arthroscopy. 2011;27:1490-
matol Arthrosc. 2012;20:468-486. 1501.
5. Kon E, Filardo G, Drobnic M, et al. Non-surgical management of early knee os- 10. Marcacci M, Bruni D, Zaffagnini S, et al. Arthroscopic-assisted focal resurfac-
teoarthritis. Knee Surg Sports Traumatol Arthrosc. 2012;20:436-449. ing of the knee: surgical technique and preliminary results of 13 patients at 2
6. Roos EM, Dahlberg L. Positive effects of moderate exercise on glycosamino- years follow-up. Knee Surg Sports Traumatol Arthrosc. 2011;19:740-746.
Keywords: injective treatment; nonpharmacological management; osteoarthritis; replacement surgery
TRAITEMENTS NON PHARMACOLOGIQUES DE LARTHROSE

Le but de cette interview est de mieux comprendre le rle des traitements non pharmacologiques de larthrose. Lven-
tail de traitements est large : adaptation des niveaux dactivit, exercice physique, physiothrapie, injections intra-
articulaires, dchargement chirurgical du compartiment articulaire abm et prothse de genou. Tous les traitements
visent amliorer les symptmes, le fonctionnement et donc la qualit de vie ; toutefois, chacun dentre eux prsente
ses propres avantages et inconvnients et convient mieux certaines phases spcifiques de larthrose articulaire. Il
ny a actuellement aucun consensus sur la prise en charge la plus efficace de larthrose, et aucun des traitements
disponibles na montr de meilleurs rsultats que les autres ou na clairement manifest des proprits modifiant la
maladie. En gnral, la prise en charge conservatrice optimale de larthrose du genou ncessite une association de
traitements pharmacologiques et non pharmacologiques. Parmi les traitements non pharmacologiques, lassociation
des diffrentes approches est galement recommande. Hormis les considrations sur le choix traitement, il faut
aussi tenir compte du fait que larthrose est une pathologie chronique et que sa prise en charge long terme peut
tre pesante. Lducation thrapeutique des patients arthrosiques est donc dune extrme importance. Enfin, les pro-
thses ont un fort pourcentage de bons rsultats mais ncessitent dtre adaptes au niveau dactivit du patient et
prsentent aussi des risques importants lis la prothse implante. Lorsque lon traite un patient atteint darthrose,
il est important de prendre en compte toutes les options disponibles pour amliorer son tat clinique et garder la
pose dune prothse comme dernire solution, lorsque les symptmes et les limitations fonctionnelles ne rpondent
pas des procdures moins invasives.
FOCUS
It is clear that changes in sub-

chondral bone parallel the progres-
sion of osteoarthritis and may even
be causally involved. The subchon-
dral compartment may therefore
be a treatment target to delay or
prevent progression of the disease.
Long overlooked:
Since this compartment is richly
innervated, and cartilage is devoid
the role of subchondral
of nerves, bone is also a legitimate
treatment target for joint pain. How- bone in osteoarthritis
ever, treatments designed to nor-
malize the bone changes in osteo-
arthritis are controversial pathophysiology and pain
b y D . M . F i n d l a y, A u s t ra l i a
O
steoarthritis was previously considered to be solely a disease of car-
tilage degeneration. However, it is now recognized that all structures
in the joint are affected by the disease, notably subchondral bone, in
which characteristic changes occur throughout disease progression. These
changes in the bone seem to parallel disease progression and are associat-
ed with joint pain. This article focuses on the role played by subchondral bone
remodeling in the pathogenesis of osteoarthritis and in the expression of pain
in this condition. It examines the evidence for altered osteoblast and osteoclast
function and the possible involvement of osteocytes in establishing changes
in the subchondral bone environment in osteoarthritis. It also explores the bio-
David M. FINDLAY, PhD mechanical and genetic influences that may lead to an altered interaction be-
Discipline of Orthopaedics tween bone and cartilage. A large number of genes have been found to be
and Trauma
University of Adelaide differentially expressed in subchondral bone in osteoarthritis compared with
Adelaide, South Australia osteoporotic or normal bone, and many of these changes persist in osteoblasts
AUSTRALIA derived from osteoarthritic bone. Relevant questions include how the cellular
and molecular changes give rise to structural changes in subchondral bone,
including bone marrow lesions; what the evidence is that bone marrow le-
sions are predictive or even causal of disease progression; and whether treat-
ments targeting the subchondral bone could have efficacy in delaying or re-
versing degeneration of the overlying articular cartilage.
steoarthritis (OA) is characterized by progressive degenerative damage to
O articular cartilage, although it is also associated with weakened muscles,

synovial inflammation, joint stiffness, altered bone alignment, loss of joint
congruency, and structural changes in the subchondral bone.1,2 There are well-de-
scribed changes observed in the subchondral bone in OA,1-4 which include scle-
rotic but less mineralized bone, the formation of osteophytes, and subchondral cysts.
In addition, the development of bone marrow lesions (BMLs) that can be visualized
by magnetic resonance imaging (MRI) is frequently seen in OA, and these lesions
Address for correspondence: seem to be predictive of degeneration in the overlying cartilage compartment.5 The
Professor David M. Findlay, Discipline
of Orthopaedics and Trauma, changes in bone structure and remodeling are due ultimately to changes in the ac-
University of Adelaide, Level 4 Bice tivity of bone cells, osteoclasts, osteoblasts, and osteocytes, driven in turn by altered
Building, Royal Adelaide Hospital,
Adelaide, South Australia, 5000,
expression of key regulatory genes. These changes are likely in response to altered
Australia (e-mail: loading of the joint and/or systemic changes, and the way that these influences are
[email protected]) transduced to gene expression and cell activity needs to be understood in order to
www.medicographia.com find effective treatments for OA. Since there is evidence of important communica-
The role of subchondral bone in osteoarthritis pathophysiology and pain Findlay MEDICOGRAPHIA, Vol 35, No. 2, 2013 221
FOCUS
tion between articular cartilage and its underlying bone, al- sporting activity, being more prevalent in elite young basket-
tered events in the subchondral bone may have significant ball players than in age-matched controls.13 Similarly, the preva-
implications for cartilage health, which validates attempts to lence of flattening of the femoral head-neck junction was sig-
treat OA by directing treatment to the subchondral bone. nificantly increased in young male soccer players compared
with controls, and the presence of a convex prominence (cam
Bone shape and osteoarthritis deformity) was found only in the soccer players.14 These stud-
It is clear that shape deformities in bone are associated with ies highlight the responsiveness of bone to influences such as
OA and may either predispose to the disease, or result from loading, which has already been well described as a mech-
it.6,7 Malalignment of the knee, with varus or valgus alignment, anism by which bone strengthens in response to increased
has been thought to predispose individuals to knee OA. How- demand.15,16 They are also a reminder that bone is a dynamic
ever, as reviewed by Hunter et al,8 it is unclear whether mal- tissue that is constantly undergoing remodeling,17 thereby per-
alignment is a risk factor for OA or comes about as a result haps contributing to OA, but also offering potential points of
of the disease, and more longitudinal data are required to de- intervention.
termine the link. Congenital dysplasia or dislocation of the hip,
whether occurring as a result of perinatal dislocation or con- Microstructural changes in bone in osteoarthritis
genitally incorrect morphology of the acetabulum or femoral The microstructure of subchondral bone differs in osteoarthrit-
head, can give rise to hip OA because of the lack of congru- ic bone compared with nonosteoarthritic bone, particularly
ency of the joint and the concentration of load in a small re- with respect to the subchondral plate and adjacent trabec-
gion of the joint. Genetics may play an important role in OA ular bone, but also in regions more distal from the affected
that has bone deformity as its underlying cause. Waarsing et joint.18,19 For example, Kumarasinghe et al20 reported increased
al9 have described a range of shape modes for the proximal bone volume fraction in cancellous bone from the intertro-
femur, several of which predispose to OA, but apparently only chanteric region in individuals with OA compared with those
in carriers of susceptibility alleles of genes that associate with with normal or osteoporotic bone, with increased trabecular
OA. Haverkamp et al10 have obtained similar data for the knee, number and decreased trabecular spacing. Reduced hard-
suggesting that a larger tibial plateau area associates with OA. ness of trabecular bone from the femoral head was also not-
Pincer deformities of the acetabulum and cam deformities of ed in hip OA compared with normal subjects,21 probably due
the femoral neck,11 which result in various degrees of impinge- to decreased mineralization of the bone in OA.22 These changes
ment of the hip joint, are thought to lead to OA. Nicholls et combine to produce bone that is stiffer and stronger than
al12 examined the relationship between cam deformity and the normal or osteoporotic bone.22 It is not known at which stage
19-year risk of total hip arthroplasty (THA) for end-stage hip of human disease these changes appear, and whether they
OA. Their intriguing results showed that individuals with THA are, in some way, causative of the disease process or sim-
had a higher prevalence of cam deformity than their respec- ply describe it. For the most part, animal models show that
tive controls, although the study was limited by small num- changes in the subchondral bone occur in parallel with carti-
bers of subjects after exclusions. Further studies in this area lage degradation.23 Longitudinal mouse studies that used high-
are warranted given the prospect that it might be possible to resolution imaging to investigate joints in a mouse strain that
predict the risk of hip OA from hip shape. Two recent stud- spontaneously develops knee OA compared with one that
ies addressed the important question of whether such defor- does not showed that susceptible mice developed more tra-
mities are inevitable or whether they may be preventable. It becular bone in a region-specific manner, and particularly in
was found that cam deformity seemed to arise from vigorous the tibial compartment, in parallel with arthritic changes in the
articular cartilage.24

In addition to the generalized changes in subchondral bone in
ACLT anterior cruciate ligament transection OA, areas of subchondral bone that appear bright with MRI,
BML bone marrow lesion which are termed BMLs, are commonly observed in both es-
ES/BS eroded surface/bone surface ratio tablished OA and early OA, but rarely in symptom-free individ-
MRI magnetic resonance imaging uals.25,26 BMLs have not been extensively characterized, but
OA osteoarthritis they arise in regions of predicted high loading and contain ab-
OARSI Osteoarthritis Research Society International normal bone with areas of osteocyte death and areas of bone
OPG osteoprotegerin sclerosis with reduced mineral density.27 Subchondral bone
OS/BS osteoid surface/bone surface ratio attrition28 and repair of fractured trabeculae have also been
TGF transforming growth factor observed.29 BMLs are interesting clinically due to the fact that
THA total hip arthroplasty longitudinal studies have shown that their presence is a po-
WOMAC Western Ontario and McMaster Universities Osteo- tent risk factor for structural deterioration in knee OA30-32 and
arthritis index for future joint replacement.5 BMLs have been shown to be
dynamic, increasing and decreasing in size, and they have
222 MEDICOGRAPHIA, Vol 35, No. 2, 2013 The role of subchondral bone in osteoarthritis pathophysiology and pain Findlay
FOCUS
also been found to disappear over a 2-year period.33 In a com- (RANKL), in mature bone.48,49 Osteocytes also produce scle-
munity-based population of older males and females, similar rostin, a Wnt inhibitor that negatively regulates bone forma-
proportions of BMLs were found to worsen and improve (as- tion.50 Individuals and animals deficient in sclerostin show bone
sessed by measuring maximal area).34 Importantly, a change overgrowth.51 Sclerostin appears to mediate the actions of a
in BML size was associated with changes in pain, perhaps number of factors that influence bone formation, so that load-
linking fluctuating knee pain to BML changes, at least in in- ing of bone, a known anabolic influence, decreases sclerostin
dividuals with early-stage disease. Enlargement of BMLs has expression in bone,52,53 and unloading of bone, which is cata-
been strongly associated with increased cartilage loss.5,31 Sub- bolic for bone, increases its expression.52 Both of these con-
chondral cysts, which are characteristic of established and ditions might apply at different times during the progression
severe OA, arise at the same sites as BMLs.35 A number of of OA. Interestingly, increased sclerostin expression has been
studies have indicated possible causal factors for BMLs, in- observed in cartilage overlying sclerotic bone, while the latter
cluding mechanical loading,36 dietary fatty acid intake,37 and by contrast shows decreased sclerostin expression.54,55 Since
total serum cholesterol and triglycerides.38 osteocytes have such a strong influence on bone metabolism
and turnover, it may be an important finding that in osteo-
Bone remodeling in osteoarthritis arthritic subchondral bone, osteocyte morphology was altered,
As stated, bone is constantly being remodeled, and this may showing rough and rounded cell bodies with fewer and disor-
have special significance in OA in ways that require more at- ganized dendrites compared with the osteocytes in control
tention.17 Understanding bone remodeling in the particular samples.56 In addition, and this has been particularly noted
context of OA is complex. The topic was recently the subject in BMLs, there is evidence of osteocyte apoptosis, which, as
of an excellent review by Burr and Gallant,39 who cited evi- stated, can be a stimulus for osteoclastic resorption and bone
dence for increased remodeling, accompanied by increased turnover.46
vascularity, in the subchondral bone in early OA. By contrast,
late-stage disease is characterized by reduced bone resorp- Differential gene expression in osteoarthritic bone
tion, with a bias toward bone formation. In addition to these The structural changes in osteoarthritic bone follow changes
temporal variations, it is likely that bone remodeling varies in bone cell activity, which are in turn driven by, and evidenced
spatially within the joint; for example, medially versus lateral- as, altered gene expression in osteoarthritic bone compared
ly in the knee. There is histological and biochemical evidence with bone from age- and sex-matched controls or osteoporot-
of increased bone remodeling in subchondral bone contain- ic individuals. The opportunity to investigate bone in OA is
ing BMLs.40 Increased subchondral bone remodeling as de- essentially limited to sampling during joint replacement sur-
tected by bone scans has been described in established OA, gery in end-stage disease, and the gene expression observed
where it has been reported to predict joint space narrowing.41 at this time likely represents the decrease in remodeling de-
In contrast, a report by Berry et al42 concluded that higher lev- scribed in late-stage OA. In fact, both the gene and protein
els of bone remodeling (assessed by serum bone turnover expression that have been described in human late-stage OA
markers) is associated with reduced cartilage loss (assessed are largely consistent with the reduced bone turnover, scle-
by MRI). It is difficult to determine whether changes in bone rosis, and lower bone mineralization that have been described
turnover are a cause or effect in human OA; however, work in in OA bone tissue at this time.39 Kuliwaba et al57 measured RNA
Hartley guinea pigs showed that subchondral cancellous bone extracted from the cancellous bone in the intertrochanteric
was fragile before the onset of cartilage degeneration.43 In the region of the proximal femur, a site distal from the articular sur-
rat anterior cruciate ligament transection model of OA, in- face of the femur, and compared patients with end-stage OA
creased subchondral bone resorption was associated with with age-matched autopsy controls. Differential gene expres-
early development of cartilage lesions, which preceded sig- sion was found in OA bone, which had the hallmarks of re-
nificant cartilage thinning and subchondral bone sclerosis.44 duced inflammatory cytokines and bone resorption markers
and increased bone formation. Messenger RNA species en-
At the level of the bone cell, remodeling is a function of the coding interleukin (IL)-6 and IL-11 and RANKL were signifi-
actions of osteoclasts, which resorb bone, and osteoblasts, cantly less abundant in the OA group, while osteoprotegerin
which are the bone-forming cells. The activities of both of (OPG) mRNA expression was no different from controls.58 In
these cell types are regulated by osteocytes embedded with- a separate study, an additional increase in the anti-osteoclas-
in the bone matrix.45 There is good evidence that osteocytes togenic cytokine interferon gamma was also observed in OA.59
detect damage within the mineralized bone matrix and di- Both RANKL mRNA levels and the ratio of RANKL:OPG mRNA
rect its repair by initiating targeted osteoclastic resorption of were strongly associated with eroded surface/bone surface
the affected bone,46 and in OA, there is evidence of increased ratio (ES/BS) and osteoid surface/bone surface ratio (OS/BS)
microdamage and microfractures in subchondral bone in over- in trabecular bone from control individuals; the former would
loaded areas of the joint.47 Recent evidence suggests that be expected for this cytokine, which is a potent driver of bone
osteocytes are the major source of the osteoclast differenti- resorption, and the latter is likely due to the fact that bone re-
ating cytokine, receptor activator of nuclear factor -B ligand sorption and formation are coupled in healthy adult bone.58
FOCUS
Intriguingly, these relationships were not apparent in osteo- Massicotte et al66 performed measurements of conditioned
arthritic bone, suggesting that bone turnover is regulated dif- media from osteoblasts derived from osteoarthritic subchon-
ferently in OA. In terms of bone formation, osteocalcin mRNA dral bone, and reported two subgroups of cells based on
expression was significantly greater in OA and, curiously, in- production of IL-6 and prostaglandin E2, while TGF levels
creased significantly with age in the OA group but not in con- were increased in all osteoarthritic osteoblasts compared
trols.57 In addition, there was a significant positive correlation with normal osteoblasts. Kumarasinghe et al20 performed an
between the osteocalcin mRNA levels and OS/BS in OA bone, extensive analysis of gene expression in primary osteoblasts
which was not seen in the control cohort. Work by the same derived from OA and control femoral bone. They found that
group showed elevated alkaline phosphatase, osteocalcin, os- the dysregulated expression of TWIST1 (twist-related pro-
teopontin, and COL1A1 (collagen, type I, alpha 1) and COL1A2 tein 1), TGF1, and SMAD3 (mothers against decapentaplegic
(collagen, type I, alpha 2) mRNA in osteoarthritic bone com- homolog 3) mRNA observed by Hopwood et al62 in OA bone
pared with control,60 which the authors suggested reflects an is also present in OA osteoblasts when these cells are cul-
increase in osteoblastic biosynthetic activity in OA. tured ex vivo, and they proposed that at least part of the eti-
ology of OA is due to altered intrinsic properties of the os-
Hopwood et al61,62 performed gene microarray analysis on teoblasts.
bone from the same region of the femur, and identified a large
number of differentially expressed genes in OA compared with Directing treatments for osteoarthritis to the
control or osteoporotic bone. A substantial number of the top- subchondral bone
ranking differentially expressed genes are known to play roles It is clear that changes in subchondral bone parallel the pro-
in bone formation, and many of these genes are targets of gression of OA and may even be causally involved. The sub-
either the Wnt or transforming growth factor (TGF)/bone chondral compartment may therefore be a treatment target to
morphogenetic protein signaling pathways. These findings are delay or prevent progression of the disease. Since this com-
consistent with the increased amounts of insulin-like growth partment is richly innervated, and cartilage is devoid of nerves,
factor types I and II and TGF protein measured in osteoarthrit- bone is also a legitimate treatment target for joint pain. How-
ic bone from the iliac crest.63 This latter result, and the findings ever, treatments designed to normalize the bone changes in
from bone derived from the intertrochanteric region, are con- OA are controversial, largely because the promise of efficacy
sistent with both increased anabolic stimulus in osteoarthritic seen in animal models has not been matched by human stud-
bone and the notion that bone metabolism may be system- ies. It would seem reasonable that treatment with antiresorp-
ically disturbed in OA. tive agents in early disease might be effective, since this phase
of the disease is characterized by increased bone remodel-
Osteoblasts from osteoarthritic bone ing. Accordingly, in two rat models of knee OA, the bispho-
Gene expression has also been explored in osteoblasts taken sphonate alendronate suppressed both subchondral bone
from osteoarthritic subchondral bone. Interestingly, these cells resorption and the later development of OA symptoms in the
appear to retain their phenotypic differences from control cells knee joint.67 Similarly, calcitonin reduced the levels of circu-
in culture. Thus, one group showed that cultured OA osteo- lating bone turnover markers and the severity of OA lesions
blasts produced a similar degree of mineralization to control in the dog model of anterior cruciate ligament transection
cells, but with dramatically variable calcium:phosphate ratios (ACLT).68 Kadri et al69 used OPG to block RANKL-mediated
compared with control osteoblasts and normal bone (ap- bone resorption and remodeling in a mouse menisectomy
proximately 1.6).20 A second group showed that mineraliza- model of OA, and observed protection from meniscectomy-
tion by OA osteoblasts was reduced compared with control related bone loss, lower OA scores, and reduced ADAMTS-4
osteoblasts, which they found to be due to a threefold higher and ADAMTS-5 expression following meniscectomy. In a high
COL1A1:COL1A2 mRNA ratio in the OA cells.64 This finding in bone turnover version of the same mouse model, pamidronate
cells was similar to the differential expression of these genes dramatically preserved the bone mass and reduced the Os-
in osteoarthritic bone.60 Alkaline phosphatase and osteocal- teoarthritis Research Society International (OARSI) score
cin levels were also found to be elevated in OA osteoblasts while at the same time almost normalizing the expression of
compared with normal osteoblasts, whereas osteopontin lev- ADAMTS-4 and ADAMTS-5 in the overlying joint cartilage.70
els were similar.64 In this study, the authors obtained evidence
that TGF1 levels are approximately fourfold higher in OA os- Such marked effects of antiresorptive agents have not been
teoblasts than in normal osteoblasts, and that inhibiting TGF1 consistently observed in human trials of antiresorptive agents
in OA osteoblasts corrected the abnormal COL1A1:COL1A2 in OA subjects, where symptom relief, radiographic joint space
ratio and increased cell mineralization. It was subsequently narrowing, or Western Ontario and McMaster Universities
shown that the increased TGF in OA cells induces increased Arthritis index (WOMAC) were used as end points,71 and it
Dickkopf-related protein 2 (DKK-2), and that silencing of either has been argued that such agents are unlikely to show effi-
TGF or DKK2 in these cells normalized the OA phenotype, in- cacy in late-stage OA because bone resorption is already sup-
cluding the decreased mineralization of OA osteoblasts.65 pressed at this stage.39 Interestingly, results of a trial in which
FOCUS
postmenopausal women were treated with strontium ranelate Conclusion

indicated that subjects with early OA (C-terminal crosslinked Changes in the bone of articulating joints are apparent from
telopeptide type II collagen [CTX-II] was used as a surrogate the time of the earliest symptoms of OA, and are due to al-
marker of disease) obtained the greatest benefit, again in tered bone structure, altered biochemistry, and altered bio-
terms of CTX-II reduction.72 It is thus clear that earlier defin- mechanics, which in turn cause altered gene expression in
itive diagnosis of OA is required so that these treatments bone. This altered bone remodeling needs to be better under-
might be applied during periods of high bone turnover.6 In ad- stood temporally, spatially, mechanistically, and molecularly,
dition, more informative outcome measures for human clin- so that informed treatments can be developed for application
ical trials will assist in determining efficacy. A recent trial of at a time point when efficacy can be achieved, starting as
zolendronic acid showed a reduction over 6 months in BML early in the disease course as possible. In the evaluation of ap-
area as well as in pain,73 showing the potential utility of BMLs proaches that target the bone in OA, end points will be re-
as informative markers. Although there are likely several sources quired that are based on better imaging and that are much
of pain in OA, it seems logical that antiresorptives should re- more informative of all the compartments of the joint, carti-
duce bone pain caused by elevated levels of bone remod- lage, synovium, tendon and muscle, and bone. I
eling, since this is the case in the high bone turnover states
Acknowledgements. Funding from the National Health and Medical Re-
of Pagets disease,74 osteogenesis imperfecta,75 and cancer- search Council of Australia and the support of the Department of Or-
induced bone pain.76 The results of the trial by Laslett et al73 thopaedics and Trauma, Royal Adelaide Hospital and the University of
suggest that this is a possibility in OA. Adelaide, Adelaide, Australia is gratefully acknowledged.
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Characterization of articular cartilage and subchondral bone changes in the 65. Chan TF, Couchourel D, Abed E, Delalandre A, Duval N, Lajeunesse D. Elevat-
rat anterior cruciate ligament transection and meniscectomized models of os- ed Dickkopf-2 levels contribute to the abnormal phenotype of human osteo-
teoarthritis. Bone. 2006;38:234-243. arthritic osteoblasts. J Bone Miner Res. 2011;26:1399-1410.
45. Atkins GJ, Findlay DM. Osteocyte regulation of bone mineral: a little give and 66. Massicotte F, Lajeunesse D, Benderdour M, et al. Can altered production of in-
take. Osteoporos Int. 2012;23:2067-2079. terleukin-1beta, interleukin-6, transforming growth factor-beta and prostaglandin
46. Cardoso L, Herman BC, Verborgt O, Laudier D, Majeska RJ, Schaffler MB. Os- E(2) by isolated human subchondral osteoblasts identify two subgroups of
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bone fatigue. J Bone Miner Res. 2009;24:597-605. 67. Hayami T, Pickarski M, Wesolowski GA, et al. The role of subchondral bone
47. Taljanovic MS, Graham AR, Benjamin JB, et al. Bone marrow edema pattern remodeling in osteoarthritis: reduction of cartilage degeneration and preven-
in advanced hip osteoarthritis: quantitative assessment with magnetic reso- tion of osteophyte formation by alendronate in the rat anterior cruciate liga-
nance imaging and correlation with clinical examination, radiographic findings, ment transection model. Arthritis Rheum. 2004;50:1193-1206.
and histopathology. Skeletal Radiol. 2008;37:423-431. 68. Manicourt DH, Altman RD, Williams JM, et al. Treatment with calcitonin sup-
48. Nakashima T, Hayashi M, Fukunaga T, et al. Evidence for osteocyte regulation presses the responses of bone, cartilage, and synovium in the early stages of
of bone homeostasis through RANKL expression. Nat Med. 2011;17:1231- canine experimental osteoarthritis and significantly reduces the severity of the
1234. cartilage lesions. Arthritis Rheum. 1999;42:1159-1167.
49. Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O'Brien CA. Matrix- 69. Kadri A, Ea HK, Bazille C, Hannouche D, Liot F, Cohen-Solal ME. Osteopro-
embedded cells control osteoclast formation. Nat Med. 2011;17:1235-1241. tegerin inhibits cartilage degradation through an effect on trabecular bone in
50. Winkler DG, Sutherland MK, Geoghegan JC, et al. Osteocyte control of bone murine experimental osteoarthritis. Arthritis Rheum. 2008;58:2379-2386.
formation via sclerostin, a novel BMP antagonist. EMBO J. 2003;22:6267- 70. Funck-Brentano T, Lin H, Hay E, et al. Targeting bone alleviates osteoarthritis
6276. in osteopenic mice and modulates cartilage catabolism. PLoS One. 2012;7:
51. Balemans W, Patel N, Ebeling M, et al. Identification of a 52 kb deletion down- e33543.
stream of the SOST gene in patients with van Buchem disease. J Med Genet. 71. Saag KG. Bisphosphonates for osteoarthritis prevention: "Holy Grail" or not?
2002;39:91-97. Ann Rheum Dis. 2008;67:1358-1359.
52. Robling AG, Niziolek PJ, Baldridge LA, et al. Mechanical stimulation of bone in 72. Alexandersen P, Karsdal MA, Byrjalsen I, Christiansen C. Strontium ranelate ef-
vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem. 2008;283: fect in postmenopausal women with different clinical levels of osteoarthritis. Cli-
5866-5875. macteric. 2011;14:236-243.
53. Moustafa A, Sugiyama T, Prasad J, et al. Mechanical loading-related changes 73. Laslett LL, Dor DA, Quinn SJ, et al. Zoledronic acid reduces knee pain and
in osteocyte sclerostin expression in mice are more closely associated with bone marrow lesions over 1 year: a randomised controlled trial. Ann Rheum Dis.
the subsequent osteogenic response than the peak strains engendered. Os- 2012;71:1322-1328.
teoporos Int. 2012;23:1225-1234. 74. Reid IR. Pharmacotherapy of Paget's disease of bone. Expert Opin Pharmaco-
54. Power J, Poole KE, van Bezooijen R, et al. Sclerostin and the regulation of ther. 2012;13:637-646.
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Miner Res. 2010;25:1867-1876. diatrics. 2007;119(suppl II):S163-S165.
55. Chan BY, Fuller ES, Russell AK, et al. Increased chondrocyte sclerostin may 76. Sittig HB. Pathogenesis and bisphosphonate treatment of skeletal events and
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2011;19:874-885. 380-387.
Keywords: antiresorptive; gene expression; osteoarthritis; remodeling; subchondral bone
FOCUS
UN GRAND OUBLI : LE RLE DE LOS SOUS-CHONDRAL

DANS LA PHYSIOPATHOLOGIE ET LA DOULEUR ARTHROSIQUES
Larthrose a longtemps t considre comme tant uniquement une pathologie de dgnrescence du cartilage.
Il est dsormais reconnu que toutes les structures articulaires sont touches par la maladie, et notamment los sous-
chondral, qui subit des modifications caractristiques tout au long de la maladie. Ces modifications osseuses
semblent suivre la progression de la maladie et sassocient une douleur articulaire. Cet article porte sur le rle jou
par le remodelage osseux sous-chondral dans la pathogense de larthrose et lexpression de la douleur dans cette
pathologie. Il examine les arguments en faveur de laltration des fonctions ostoblastique et ostoclastique et lim-
plication probable des ostocytes dans les modifications de lenvironnement osseux sous-chondral dans larthrose.
Il explore aussi les influences biomcaniques et gntiques qui peuvent modifier linteraction entre los et le cartilage.
De nombreux gnes sexpriment de faon diffrentielle dans los sous-chondral au cours de larthrose par rapport
los normal ou ostoporotique, et nombre de ces changements persistent dans les ostoblastes issus de los ar-
throsique. On peut donc se poser les questions suivantes : comment les modifications cellulaires et molculaires don-
nent-elles naissance aux changements structuraux dans los sous-chondral, y compris aux lsions mdullaires ? Les
lsions mdullaires sont-elles des signes avant-coureurs ou mme la cause de la progression de la maladie ? Enfin,
les traitements ciblant los sous-chondral peuvent-ils tre efficaces pour diffrer ou inverser la dgnrescence du
cartilage articulaire sous-jacent ?
U P DAT E
The concept of osteoarthritis

as organ failure with multitissue
damage opens up novel therapeu-
tic perspectives Current treat-
ments for osteoarthritis are es-
sentially aimed at controlling the
painful symptoms, thereby reduc-
Clinical research in
ing the disability that is essentially
related to the pain in osteoarthri-
osteoarthritis: whats new?
tis. The real therapeutic goal for
osteoarthritis in the coming years
will be to find a treatment that can
permanently reduce cartilage de-
struction.
by X. Chevalier and F. Eymard, France
N
ew therapeutic perspectives in osteoarthritis are focused on blocking
the degradative process by inhibiting tissue remodeling in the bone
and cartilage and inflammation of the synovial membrane. None of the
so-called slow-acting drugs that are currently available for the management
of osteoarthritis can be considered to be targeted treatments. A great hope
surfaced after initial trials with antinerve growth factor therapy showed a dra-
matic effect on pain in patients with knee osteoarthritis. Unfortunately, trials
were later stopped because of unexplained rapidly destructive arthropathies.
Biotherapies involving interleukin-1 blockers have been used in knee osteo-
arthritis, but so far have shown no efficacy on pain. Biotherapy for hand osteo-
L
arthritis involving the use of tumor necrosis factor blockers to slow down dis-
Xavier CHEVALIER, MD, PhD
ease progression has failed. Nitric oxide inhibitors also failed to demonstrate
Florent EYMARD
a chondroprotective effect in a large trial involving patients with knee osteo-
Service de Rhumatologie
Hpital Henri Mondor arthritis. Inhibitors of enzymes involved in cartilage matrix degradation are in
Universit Paris XII UPEC a preclinical phase of development, but constitute an appealing approach.
Crteil, FRANCE
Targeting of subchondral bone is also a promising approach. Although pre-
vious chondroprotective trials using bisphosphonates have produced nega-
tive results, a recent large trial with strontium ranelate showed diminished joint
space narrowing over 3 years of follow-up. Another therapeutic approach cur-
rently under consideration is stimulation of chondrocyte anabolism. Intra-artic-
ular injection of growth factors is in the initial development phase. Finally, a new
lubricant called lubricin has shown very attractive results in animal models.
steoarthritis is the most common form of joint disease, affecting millions of
O people throughout the world, and it represents a major and recognized cause
of pain and disability, particularly in the elderly.1 The aim of this review is to
provide an update on potentially chondroprotective molecules, as well as disease-
modifying antirheumatic drugs in clinical trials. Other therapeutic approaches such
as chondrocyte transplantation, stem cells, gene therapy, and intra-articular injec-
tions of conditioned media or platelet concentrates are very interesting possibilities
Address for correspondence: for the future in terms of chondroprotection, but as they are still in the early stages
Professor Xavier Chevalier, Service of clinical development, they will not be discussed in this article.
de Rhumatologie, Hpital Henri
Mondor, Universit Paris XII UPEC,
Crteil, France Understanding the disease in order to treat it
(e-mail: [email protected]) Osteoarthritis is often wrongly considered to simply be the slow and inexorable
www.medicographia.com wear of cartilage, hence the term degenerative disease. Actually, it is a disease of a
228 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Clinical research in osteoarthritis: whats new? Chevalier and Eymard
U P DAT E
whole organ, the joint.2,3 The tissue changes observed in os- Targeting proinflammatory mediators and other
teoarthritis include not only cartilage degradation, but also players in osteoarthritis
sclerosis of subchondral bone, osteophyte formation, and N Biotherapy
to varying degrees over time and space, inflammation of the Biotherapy involves specifically blocking a molecule (cytokine
synovial membrane.3 The concept of osteoarthritis as organ or growth factor) involved in the inflammatory and/or painful
failure with multitissue damage opens up novel therapeutic process in osteoarthritis.11
perspectives whereby not only the cartilage damage can be
targeted, but also synovitis and remodeling of subchondral N Targeting pain by inhibiting nerve growth factor
bone, the latter two participating in a major way in the de- Nerve growth factor (NGF) is a molecule directly involved in
struction of cartilage.4,5 the pathways responsible for pain transmission.12 This mol-
ecule was first described in the nervous system. It acts by
Current treatments for osteoarthritis, as defined by the latest means of two tyrosine kinasetype receptors.12 By binding to
international consensus conferences, are essentially aimed at its receptor, it may modify the phosphorylation of vanilloid-
controlling the painful symptoms, thereby reducing the disabil- like pain receptors (nociceptors).12
ity that is essentially related to the pain in osteoarthritis.6,7 The
real therapeutic goal for osteoarthritis in the coming years will NGF has been identified in the joint, particularly the osteo-
be to find a treatment that can permanently reduce cartilage arthritic joint, and it is present at detectable levels in synovial
destruction. fluid.13 It was therefore logical to investigate the use of an in-
hibitor of NGF as a potential treatment. Tanezumab (TNZ) is
Data on the currently available treatments a fully human monoclonal antibody directed against NGF; it
For the purposes of slowing down the progression of osteo- was used in a randomized trial versus placebo that involved
arthritis, a therapeutic class of drugs known as slow-acting perfusions every 8 weeks at different doses in patients suffer-
anti-arthritic agents is used. These drugs include derivatives ing from painful knee osteoarthritis (n=450). The results at 16
of avocado and soya, diacerein, chondroitin sulfate and glu- weeks were impressive, with a very substantial reduction in
cosamine sulfate, and hydroxychloride salts. The status of pain of between 45% to 62% in the TNZ groups compared
some of these molecules is that of a nutrient rather than a true with 21% in the placebo group.14 Unfortunately, in addition to
medicine. These molecules have shown a favorable risk-ben- some adverse neurological side effects, phase 3 clinical trials
efit ratio in lower limb osteoarthritis, but their analgesic effec- revealed an increased number of rapidly destructive arthro-
tiveness remains modest and controversial.7,8 A recent trial pathies (similar to neurological arthropathies) that led to the
using 800 mg of chondroitin sulfate for osteoarthritis of the implementation of prostheses, resulting in the suspension of
fingers showed that it could significantly reduce the painful trials with this type of antibody.14 Use of nonsteroidal anti-in-
symptoms over a period of 6 months.9 In terms of chondro- flammatory drugs in conjunction with anti-NGF seems to in-
protection, these molecules have been shown in various trials crease this risk. Since the publication of a recent report by the
to slow the narrowing of the joint space by about 0.1 mm per US Food and Drug Administration, however, the use of NGF
year, especially in osteoarthritis of the knee, and to reduce the inhibitors under specific conditions and without the concomi-
number of patients defined as rapid progressors.8 Such a min- tant use of nonsteroidal anti-inflammatory drugs has again
imal annual slowdown still needs to be translated in terms been authorized.
of clinical relevance. The end point could be, for example,
whether this annual slowdown can delay the need for the im- N Biotherapies targeting proinflammatory cytokines
plementation of a total prosthesis of the treated joint.10 Osteoarthritis is in part an inflammatory disease, as indicated
by its name. The inflammation is localized mainly in the synovial
membrane, but also in the subchondral bone and cartilage,
and involves a cascade of proinflammatory mediators (frag-
DORA Digital Osteoarthritis in Refractory hand OA (study) ments of the matrix, cytokines, complement components).15,16
FGF18 fibroblast growth factor 18 These mediators not only contribute to the degradation of the
IL-1 interleukin 1 cartilage matrix during attacks of synovitis, but are also in-
MRI magnetic resonance imaging volved in pain transmission pathways.17,18
NGF nerve growth factor
NO nitric oxide Two proinflammatory cytokines play a major role in osteoarthri-
TIMP tissue inhibitor of metalloproteinase tis: interleukin 1 (soluble form of interleukin 1[IL-1]) and tumor
TNF- tumor necrosis factor necrosis factor (TNF-).2,3,15 Through in vitro studies, and
TNZ tanezumab later with the use of animal models in vivo, it was demon-
WOMAC Western Ontario and McMaster Universities Arthritis strated that IL-1 is a key molecule favoring cartilage degra-
index dation, inhibition of chondrocyte synthesis, and apoptosis.15
Use of an IL-1 inhibitor through local intra-articular adminis-
Clinical research in osteoarthritis: whats new? Chevalier and Eymard MEDICOGRAPHIA, Vol 35, No. 2, 2013 229
U P DAT E
tration in experimental animal models of osteoarthritis showed no evidence of a decrease in the structural evolution of digi-
a slowdown in chondrolysis.19-22 Two randomized trials have tal osteoarthritis compared with placebo over a period of 1
been conducted on two different inhibitors of IL-1 versus pla- year.28 Only the subgroup of patients with clinically detectable
cebo in patients with knee osteoarthritis. We conducted the effusion at baseline at the interphalangeal joints showed a
first biotherapy trial in osteoarthritis using an IL-1 antagonist lower incidence of new erosions.28 In other words, it seems
(anakinra) administered by a single intra-articular injection (dose that anti-TNF may be active on the structural progression of
of 50 mg or 150 mg) versus a placebo injection of physiolog- the disease in a subgroup of patients suffering clinically from
ical saline.23 In this trial, there was no significant difference in a more inflammatory disease. The French study, Digital Os-
the Western Ontario and McMaster Universities Arthritis Index teoarthritis in Refractory hand OA (DORA), aimed to assess
(WOMAC) global score or level of pain at 1 month, 3 months, the symptomatic effect of two injections of a monoclonal an-
and 6 months. However, at 4 days, there was a small but sig- tibody directed against TNF-.
nificant difference in the level of pain reported in the patient
group that received 150 mg of the IL-1 receptor antagonist.23 N Nitric oxide inhibition
In fact, pharmacokinetic studies have shown a very short half- Nitric oxide (NO) is a gas that plays many physiological roles,
life of about 6 hours for IL-1 receptor antagonists in serum, particularly in terms of regulation of arterial vasodilation, but it
which is incompatible with having a residual effect on pain.23 may also play a deleterious role when produced in excess.
It has been demonstrated that NO produced in excess dur-
The second randomized trial compared repeated systemic ing osteoarthritis could contribute to cartilage destruction
injections (by subcutaneous injection) of a monoclonal anti- through protein nitrosylation, but could also favor apoptosis
body blocking the type 1 receptor of IL-1 with placebo.24 The of chondrocytes through combined action with free radicals.29
injections were administered monthly. Again, up to 3 months, It was therefore logical to consider that inhibition of NO could
IL-1 inhibition demonstrated no significant analgesic effect. reduce the progression of osteoarthritis. A recent randomized
In addition, constant neutropenia was reported and a case placebo-controlled trial used two doses of an inhibitor of NO
of death from severe pneumonia was also observed.24 On administered orally (50 mg and 200 mg). The trial investigated
the other hand, functional magnetic resonance imaging (MRI) chondroprotection in knee osteoarthritis, with the main out-
demonstrated changes in the subgroup of patients showing come criterion being evolution of radiographic joint space nar-
a beneficial effect from IL-1 inhibition.24 rowing observed at 2 years.30 This study showed no difference
in the overall study population at 2 years in terms of reducing
From these two trials, we can conclude that at present, in- progression of radiographic joint space narrowing. There was
hibition of IL-1 has not enabled observation of an analgesic only a trend favoring the molecule in the subgroup of patients
effect in knee osteoarthritis. However, IL-1 seems to be a good with a Kellgren-Lawrence grade superior to 2 at 48 weeks.30
therapeutic target. Thus, in the future, it will be necessary to To sum up, this trial does not allow us to conclude on the ef-
think about modes of administration, including the intra-ar- ficacy of NO inhibition in reducing the progression of knee os-
ticular mode, which can prolong the action of this inhibitor, teoarthritis.
and to see whether prolonged inhibition of this cytokine can
delay the progression of osteoarthritis. N Inhibition of metalloproteases and enzymes involved
in cartilage degradation
The second potentially interesting molecule to target is TNF-, Degradation of the extracellular matrix of cartilage is due to
which has an important proinflammatory effect and whose the increased activity of enzymes such as metalloproteases,
effect on cartilage degradation potentiates that of IL-1.15 A as well as aggrecanase enzymes and a number of serine pro-
recent study conducted in a rabbit model of osteoarthritis teases.3 These enzymes are activated in situ by the action of
involving cross-section of the medial meniscus showed that proinflammatory mediators such as cytokines. It seems log-
monthly intra-articular injections of infliximab (10 mg/kg or ical, therefore, to block these enzymes in order to slow the
20 mg/kg) over a 3-month period significantly decreased car- progression of osteoarthritis. The first trials to be conducted
tilage lesions compared with saline injections.25 In a case re- in this area used nonselective inhibitors with many side effects,
port, repeated subcutaneous injections of a blocking mon- including skeletal muscle disorders and tendinitis, which led
oclonal antibody against TNF (adalimumab) in a patient with to discontinuation of their production.31 Highly selective inhib-
congestive knee osteoarthritis was able to reduce pain and de- itors are currently available, however, including matrix metal-
crease subchondral edema observed with MRI at 6 months.26 loproteinase (MMP)-13 inhibitor. The major role of MMP-13 has
been well demonstrated in knockout mouse models of os-
TNF- is mainly used as a target in digital osteoarthritis, which teoarthritis.32 In an experimental model of osteoarthritis in dogs,
can involve a more painful and inflammatory condition called a selective inhibitor of this enzyme showed a convincing chon-
erosive osteoarthritis.27 Systemic administration of a TNF- droprotective effect.33 The use of these kinds of inhibitors could
inhibitor is logical in this polyarticular form of osteoarthritis. thus be tested clinically in future.34 Similarly, one can consider
Repeated subcutaneous injections of adalimumab produced the use of natural inhibitors of these metalloproteases, which
U P DAT E
are designed as tissue inhibitors of metalloproteinase (TIMPs). was negative; however, patients also underwent MRI. A sig-
Indeed, it has already been demonstrated that intra-articular nificant difference in cartilage volume favoring calcitonin was
injections of TIMP3 could slow the evolution of degenerative observed at 12 months compared with placebo. It is difficult
lesions in experimental animal models of osteoarthritis.35 to interpret the observed effect solely on the basis of MRI data.
Moreover, the rate of side effects observed with calcitonin was
Targeting subchondral bone very high and led to patient discontinuation on the grounds
There are many arguments in favor of a major role for subchon- of intolerance in nearly 20% of cases.41
dral bone in the genesis and progression of degenerative joint
disease (see article by Professor David Findlay in this issue). N Use of strontium ranelate
In animal models, there are early lesions of the subchondral The use of strontium ranelate for OA treatment has two ad-
plate (microcracks) in vivo, with accelerated bone remodel- vantages; on the one hand, there is an indirect effect on bone,
ing. In situ, there is a break in the bone-cartilage calcified di- but there is also a potential direct effect on cartilage. Indeed,
viding line, leading to neovascularization of the deep layers the use of strontium ranelate specifically (the same effect was
of cartilage and a change in chondrocyte phenotype under not observed with calcium ranelate) produced increased syn-
the influence of factors such as vascular endothelial growth thesis of proteoglycans in vitro, and a synergistic effect with
factor. In vivo, MRI has revealed subchondral bone lesions insulin-like growth factor-1 on the anabolism of chondrocytes
(bone marrow lesions) in the form of a hypersignal next to the in vitro.42 On the basis of this observation, the largest-ever
affected cartilage, which can predict the progression of knee chondroprotection study was conducted using two doses of
osteoarthritis. Finally, radiographs reveal late subchondral scle- strontium ranelate (1 g and 2 g) compared with placebo over
rosis.36,37 a period of 3 years in patients with symptomatic knee osteo-
arthritis.43 Over 1600 patients were recruited. The proportion
The use of treatments designed to slow remodeling of the sub- of patients who completed the study was approximately 55%
chondral bone appears appropriate in order to preserve the and 60%, respectively, which is consistent with what has been
adjacent cartilage. The use of parathyroid hormone (either in observed in previous trials.44 The results of this trial were pos-
a curative or preventive capacity) in an experimental model of itive, and showed an annual slowdown of 0.14 mm in the
osteoarthritis in mice has shown very promising results in terms group receiving 1 g of strontium ranelate and 0.10 mm in the
of chondroprotection.38 A few clinical trials have been con- group receiving 2 g of strontium ranelate. In addition, the group
ducted using various anti-osteoporotic drugs to examine their of patients defined as radiological progressors (ie, those with
possible chondroprotective effect. a loss of more than 0.5 mm over the 3-year period) was sig-
nificantly reduced in the strontium ranelate groups compared
N Use of bisphosphonates with placebo: 33% in the placebo group compared with 22%
The use of risedronate at different doses in a randomized tri- and 26% in the strontium ranelate groups, respectively.44
al versus placebo conducted over 2 years was not able to
demonstrate any chondroprotective effect.39 The poor pro- Finally, for the highest dose of 2 g, a combined effect on pain
gression in patients included in this study may account for was also observed, especially in patients experiencing a painful
the failure of bisphosphonates. However, decreased urinary condition as well as rapid progression of their disease.44 This
levels of collagen CTX2 (Human C-telopeptide of Type II Col- large-scale study opens up interesting perspectives, and could
lagen) were observed in this trial, perhaps indicating a reduc- eventually lead to the use of anti-osteoporotic agents such as
tion in joint remodeling.39 strontium ranelate for the prevention of cartilage loss.
A recent randomized placebo-controlled trial used a single Stimulating anabolism by the use of growth factors
perfusion of zoledronic acid in 30 patients with symptomatic There is another interesting therapeutic option whose aim is
osteoarthritis of the knee and subchondral edema revealed not to limit the destruction of cartilage, but rather to favor car-
by MRI.40 At 6 months, there was a significant decrease in tilage repair, even when it is naturally weak. The possibility of
pain and bone edema observed on MRI in the patients re- direct intra-articular injection of growth factors (bone mor-
ceiving zoledronic acid. However, at 12 months, there was no phogenetic protein-7 or fibroblast growth factor 18; FGF18)
longer any significant difference.40 is still in its early stages, and phase 1/2 trials are currently on-
going.45,46 One study, published only as an abstract, used in-
N Use of oral calcitonin tra-articular injections of FGF18 (either a single injection or
A large-scale trial involving nearly 1200 patients with knee os- two cycles of three intra-articular injections) in knee osteo-
teoarthritis compared the use of two doses of oral calcitonin arthritis.46 There was no evidence of a slowdown in the nar-
with placebo. Patients were followed up over a 2-year period. rowing of the joint space compared with placebo, but there
The main purpose of the study was to assess the ability of was a benefit in terms of cartilage volume gain as assessed by
oral calcitonin to slow joint space narrowing as assessed by a MRI at 1 year.46 With regard to local injections of either platelet-
standard knee x-ray.41 On the basis of this criterion, the test rich autologous plasma or autologous conditioned serum, the
U P DAT E
principle of which is to concentrate growth factors or contra- Conclusion

inflammatory cytokines, clinical efficacy on pain still needs to A better understanding of the physiopathogenesis of degen-
be validated in large-scale placebo-controlled trials, and no erative disease in osteoarthritis, particularly the involvement
chondroprotection study has been conducted thus far.47,48 of different tissues of the joint such as the synovial membrane
and the subchondral bone, has allowed us to consider some
Protecting the superficial layers of cartilage very interesting prospective therapeutic options. Combina-
Protection of the superficial layers of cartilage is the princi- tion of different treatments may also eventually be consid-
ple behind the use of hyaluronic acid, which serves as a pro- ered, which at different time points could target the synovial
tective gel. Lubricin is a glycoprotein present in the synovial membrane, stem cell cartilage repair, and limitation of long-
fluid, which acts by adhering to the most superficial layers of term remodeling of the subchondral bone. Nevertheless, it will
cartilage. Animal tests have shown the ability of this molecule also be necessary to demonstrate that modulatory effects on
to prevent cartilage degradation when it is administered by in- these structural components can also have an impact on and
tra-articular injection.49 The future may involve combined ther- a clinical relevance for a hard criterion, such as delaying the
apy using lubricin and hyaluronic acid. need for total joint replacement surgery. I
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and knee osteoarthritis. An OMERACT 10 Special Interest Group. J Rheumatol. 27. Punzi L, Ramonda R, Sfriso P. Erosive osteoarthritis. Best Pract Res Clin Rheu-
2011;38:1765-1769. matol. 2004;18:739-758.
9. Bruyre O, Burlet N, Delmas PD, Rizzoli R, Cooper C, Reginster JY. Evaluation 28. Verbruggen G, Wittoek R, Cruyssen BV, Elewaut D. Tumour necrosis factor
of symptomatic slow-acting drugs in osteoarthritis using the GRADE system. blockade for the treatment of erosive osteoarthritis of the interphalangeal finger
BMC Musculoskelet Disord. 2008;9:165. joints: a double blind, randomised trial on structure modification. Ann Rheum
10. Gabay C, Medinger-Sadowski C, Gascon D, Kolo F, Finckh A. Symptomatic Dis. 2012;71:891-898.
effects of chondroitin 4 and chondroitin 6 sulfate on hand osteoarthritis: a ran- 29. Abramson SB. Nitric oxide in inflammation and pain associated with osteo-
domized, double-blind, placebo-controlled clinical trial at a single center. Arthri- arthritis. Arthritis Res Ther. 2008;10(suppl 2):S2.
tis Rheum. 2011;63:3383-3391. 30. Hellio Le Graverand MP, Clemmer R, Redifer P, et al. A 2-year randomized, dou-
11. Chevalier X. Evolution of the pharmacological management of osteoarthritis: the ble-blind, placebo-controlled, multicentre study of oral selective iNOS inhibitor,
biologics. Presse Med. 2010;39:1164-1171. cindunistat (5SD-6010), in patients with symptomatic osteoarthritis of the knee.
12. Wood JN. Nerve growth factor and pain. N Engl J Med. 2010;363:1572-1573. Ann Rheum Dis. 2013;72:187-195.
13. Barthel C, Yeremenko N, Jacobs R, et al. Nerve growth factor and receptor ex- 31. Krzeski P, Buckland-Wright C, Blint G, et al. Development of musculoskeletal
pression in rheumatoid arthritis and spondyloarthritis. Arthritis Res Ther. 2009; toxicity without clear benefit after administration of PG-116800, a matrix met-
11:R82. alloproteinase inhibitor, to patients with knee osteoarthritis: a randomized, 12-
14. Lane NE, Schnitzer TJ, Birbara CA, et al. Tanezumab for the treatment of pain month, double-blind, placebo-controlled study. Arthritis Res Ther. 2007;9:R109.
from osteoarthritis of the knee. N Engl J Med. 2010;363:1521-1531. 32. Little CB, Barai A, Burkhardt D, et al. Matrix metalloproteinase 13-deficient mice
15. Pelletier JP, Martel-Pelletier J, Abramson SE. Osteoarthritis, an inflammatory dis- are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertro-
ease: potential implication for the selection of new therapeutic targets. Arthritis phy or osteophyte development. Arthritis Rheum. 2009;60:3723-3733.
Rheum. 2001;44:1237-1247. 33. Settle S, Vickery L, Nemirovskiy O, et al. Cartilage degradation biomarkers pre-
16. Scanzello CR, Goldring SR. The role of synovitis in osteoarthritis pathogenesis. dict efficacy of a novel, highly selective matrix metalloproteinase 13 inhibitor in
Bone. 2012;51:249-257. a dog model of osteoarthritis: confirmation by multivariate analysis that mod-
17. Sachs D, Cunha FQ, Poole S, Ferreira SH. Tumour necrosis factor-alpha, inter- ulation of type II collagen and aggrecan degradation peptides parallels patho-
leukin-1beta and interleukin-8 induce persistent mechanical nociceptor hyper- logic changes. Arthritis Rheum. 2010;62:3006-3015.
sensitivity. Pain. 2002;96:89-97. 34. Li H, Feng F, Bingham CO 3rd, Elisseeff JH. Matrix metalloproteinases and inhib-
18. Ayral X, Pickering EH, Woodworth TG, Mackillop N, Dougados M. Synovitis: itors in cartilage tissue engineering. J Tissue Eng Regen Med. 2012;6:144-154.
a potential predictive factor of structural progression of medial tibiofemoral knee 35. Black RA, Castner B, Slack J, Tocker J, Eisenman J. Injected TIMP-3 protects
osteoarthritis: results of a 1 year longitudinal arthroscopic study in 422 patients. cartilage in a rat meniscal tear model. Osteoarthritis Cartilage. 2006;14(sup-
Osteoarthritis Cartilage. 2005;13:361-367. pl B S23):A14.
U P DAT E
36. Pesesse L, Sanchez C, Henrotin Y. Osteochondral plate angiogenesis: a new ranelate for the treatment of knee osteoarthritis: rationale and design of randomised,
treatment target in osteoarthritis. Joint Bone Spine. 2011;78:144-149. double-blind, placebo-controlled trial. Curr Med Res Opin. 2012;28:231-239.
37. Hunter DJ, Zhang W, Conaghan PG, et al. Systematic review of the concur- 44. Reginster JY, Badurski J, Bellamy N, et al. Efficacy and safety of strontium
rent and predictive validity of MRI biomarkers in OA. Osteoarthritis Cartilage. ranelate in the treatment of knee osteoarthritis: results of a double-blind, ran-
2011;19:557-588. domised placebo-controlled trial. Ann Rheum Dis. 20113;72:179-186.
38. Sampson ER, Hilton MJ, Tian Y, et al. Teriparatide as a chondroregenerative 45. Hunter DJ, Pike MC, Jonas BL, Kissin E, Krop J, McAlindon T. Phase 1 safety
therapy for injury-induced osteoarthritis. Sci Transl Med. 2011;3:101ra93. and tolerability study of BMP-7 in symptomatic knee osteoarthritis. BMC Mus-
39. Bingham CO 3rd, Buckland-Wright JC, Garnero P, et al. Risedronate de- culoskelet Disord. 2010;11:232.
creases biochemical markers of cartilage degradation but does not decrease 46. McPherson R, Flechenshar K, Hellot S, Eckstein F. A randomized, double blind,
symptoms or slow radiographic progression in patients with medial compart- placebo-controlled, multicenter study of RHFGF18 administered intraarticular-
ment osteoarthritis of the knee: results of the two-year multinational knee os- ly using single or multiple ascending doses in patients with primary knee osteo-
teoarthritis structural arthritis study. Arthritis Rheum. 2006;54:3494-3507. arthritis (OZA), not expected to require knee surgery within a year. Osteoar-
40. Laslett LL, Dor DA, Quinn SJ, et al. Zoledronic acid reduces knee pain and thritis Cartilage. 2011;19(suppl S35):65.
bone marrow lesions over 1 year: a randomised controlled trial. Ann Rheum 47. Kon E, Mandelbaum B, Buda R, et al. Platelet-rich plasma intra-articular injec-
Dis. 2012;71:1322-1328. tion versus hyaluronic acid viscosupplementation as treatments for cartilage
41. Karsdal MA, Alexandersen P, Dam EB, et al. Oral calcitonin demonstrated symp- pathology: from early degeneration to osteoarthritis. Arthroscopy. 2011;27:
tom-modifying efficacy and decreased cartilage volume loss: results from a 2 1490-1501.
year phase 3 trial in patients with osteoarthritis of the knee. Presented at: Amer- 48. Baltzer AW, Moser C, Jansen SA, Krauspe R. Autologous conditioned serum
ican College of Rheumatology Scientific Meeting; November 8, 2011; Chicago, (Orthokine) is an effective treatment for knee osteoarthritis. Osteoarthritis Car-
IL. Late breaking abstract L9. tilage. 2009;17:152-160.
42. Henrotin Y, Labasse A, Zheng SX, et al. Strontium ranelate increases cartilage 49. Jay GD, Elsaid KA, Kelly KA, et al. Prevention of cartilage degeneration and gait
matrix formation. J Bone Miner Res. 2001;16:299-308. asymmetry by lubricin tribosupplementation in the rat following anterior cruci-
43. Cooper C, Reginster JY, Chapurlat R, et al. Efficacy and safety of oral strontium ate ligament transection. Arthritis Rheum. 2012;64:1162-1171.
Keywords: anti-osteoporotic drug; biotherapy; cartilage; metalloprotease; nitric oxide; osteoarthritis; strontium ranelate
LA RECHERCHE CLINIQUE DANS LARTHROSE : QUOI DE NEUF ?

Les nouvelles perspectives de traitement de larthrose se concentrent sur le blocage du processus de dgradation
en inhibant le remodelage tissulaire dans los et le cartilage, ainsi que linflammation de la membrane synoviale. Au-
cun des mdicaments anti-arthrosiques daction lente actuellement disponibles ne peut tre considr comme un
traitement cibl. Les premires tudes sur le traitement par antagonisme du facteur de croissance du nerf ayant
montr un effet spectaculaire sur la douleur des patients souffrant darthrose du genou, ont soulev un grand es-
poir. Malheureusement, ces tudes ont par la suite t arrtes en raison de la survenue inexplique darthropathies
rapidement destructives. Des biothrapies utilisant des bloqueurs de linterleukine 1 ont t utilises dans larthrose
du genou mais se sont jusqu maintenant montres inefficaces sur la douleur. La biothrapie de larthrose de la
main par blocage du facteur de ncrose tumorale pour ralentir la progression de la maladie, a galement chou. De
mme, les inhibiteurs du monoxyde dazote nont pas russi montrer deffet protecteur du cartilage dans une large
tude sur des patients souffrant darthrose du genou. Lutilisation dinhibiteurs des enzymes impliques dans la d-
gradation de la matrice cartilagineuse est en phase prclinique et reprsente une approche intressante. Cibler los
sous-chondral reprsente galement une approche prometteuse. Alors que les rsultats dtudes antrieures sur
la protection du cartilage par les bisphosphonates ont t ngatifs, une grande tude rcente a montr une diminu-
tion du rtrcissement de lespace interarticulaire aprs 3 ans de traitement par le ranlate de strontium. Le traite-
ment par stimulation de lanabolisme du chondrocyte est galement ltude. Linjection intra-articulaire de facteurs
de croissance est en phase initiale de dveloppement. Enfin, un nouveau lubrifiant appel lubricine a montr des
rsultats trs intressants dans des modles animaux.
A TOUCH
OF FRANCE
y inventing the film camera,
B and perforations to advance

the film through a camera
and a projector, France, through
the Lumire brothers, gave birth
to the cinema. On 19 March 1895,
they produced the first footage
ever made, albeit on an admit-
tedly dull topic, that of workers
leaving a factory after their days
work. Touch of France looks at
the early history of the motion pic-
ture and its developments in the
fields of science and medicine
(Christian Rgnier), and at the gi-
gantic effort to preserve the lega-
cy of the cinema, with the French
Cinmathque founded by Henri
Langlois (Isabelle Spaak). And re-
member, the love affair between
France and the cinema is still alive
and kicking: do The Artist and Au-
drey Tautou mean anything to you?
Cinema, science, and

medicine in France
C . R g n i e r, Fra n c e Page 237
Children of the Cinmathque

I . S p a a k , Fra n c e Page 246
A TOUCH OF FRANCE
ublic health propaganda us-
P ing moving pictures spread

in France during World War I
after the setting up of an extra-
parliamentary commission to study
how to extend the use of cinema-
Cinema, science, and
tography to other areas of teaching.
Most films shown by the Rocke-
feller mission, some 150 in all,
medicine in France
were produced by Path and by
Gaumont. Their titles left little to
the imagination: Dont Spit on the
Ground, Beware the Fly, Dont Lick
your Fingers to Turn the Page, The
Slums Must be Vanquished, Fin-
gernails in Mourning.
b y C . R g n i e r, Fra n c e
I
n the 1870s, a forerunner of the motion picture settled a bothersome ques-
tion. Does a galloping horse ever become airborne? More prosaically, are
all four of its hooves ever off the ground at the same time? It fell to the Eng-
lish photographer Eadweard Muybridge to find the answer. Hired by a former
governor of California and racehorse owner, Muybridge placed glass-plate
cameras along the edge of a race track. As the horse passed each camera it
All rights reserved
broke a thread and triggered the shutter, thus generating a series of photo-
graphs. Muybridge copied these as silhouettes onto a disc and, using his in-
vention the zoopraxiscope, showed that there was indeed unsupported tran-
sit, a fleeting moment when the horse was airborne. The zoopraxiscope later
Christian RGNIER, MD came to be regarded as an early movie projector, and with it Muybridge wrote
Praticien Attach Consultant a page in the history of early cinematography. So too did the French astron-
de lHtel-Dieu de Paris
Socit Internationale omer Jules Janssen, with his photographic revolver, which he used in Japan
dHistoire de la Mdecine in 1874 to record the transit of Venus across the face of the sun. And above
9 rue Bachaumont all there was tienne-Jules Marey, a French doctor and physiologist who de-
75002 Paris
(e-mail: veloped the chronophotograph and other instruments for pioneering analy-
[email protected]) sis in humans and animals of locomotion and physiological processes like
blood flow, breathing, and the beating heart. These and other pioneers were
driven by their thirst for scientific understanding. Others, meanwhile, had their
eyes on the immense commercial and artistic potential of the new technique
of motion pictures. At the close of the 19th century, the American engineer
Thomas Edison, the French industrialists Louis and Auguste Lumire, and
the French illusionist Georges Mlis joined the adventure of the new cine-
matography. Industrial logic, the drive for profitability, and the lure of wealth
drove them, and led to clashes with scientists who saw cinematography pure-
ly as a research and educational tool. From its beginnings in the laboratories
of science, cinema had become a show, a leisure activity accessible to every-
one. Dubbed the seventh art (after architecture, sculpture, painting, music,
poetry, and dance) by the Italian film theoretician Ricciotto Canudo, the motion
picture was able to portray all aspects of life whether scientific or fictional.
Left page: Louis Lumire,

inventor of the cinematograph
together with his brother
Augusteinspecting a film
(photo dated 1935).
AKG-images/Walter Limot.
www.medicographia.com
Cinema, science, and medicine in France Rgnier MEDICOGRAPHIA, Vol 35, No. 2, 2013 237
A TOUCH OF FRANCE
odays cinemagoers, accustomed as they are to com- their cinematograph, which combined a camera and projec-
T puter-generated three-dimensional images full of sound

and fury, would have scant regard for a 45-second silent
film with the humdrum title Workers Leaving the Lumire Fac-
tor to recreate movement. Not everyone present was thrilled.
tienne-Jules Marey, the President of the Academy of Sci-
ences, was sickened by what he saw: intellectual theft. The
tory. Yet motion pictures were born that March day in 1895, Lumire brothers projector, he said, was his invention, the
when the Lumire brothers Louis and Auguste showed their chronophotograph, hijacked and poorly disguised by the ad-
film to a gathering of scientists at the Grand Caf on the Bou- dition of a cam for perforated films. Marey was interested sole-
levard des Capucines in Paris. Sons of a manufacturer of pho- ly in science and biology, and was hostile to the commercial
tographic equipment, the Lumires screened the film using exploitation of moving pictures.1,2 As a pioneer of the analy-
sis of movement, he developed a chronophotographic pro-
jector using unperforated film to record and study normal and
abnormal human gait, the beating of a perfused frog heart,
airborne birds and insects, swimming rays, even the move-
ment of smoke trails.
Cinema, a godsend for showmen and

industrialists
The principle of moving images was not new and various an-
imation devices were invented in the middle years of the 19th
century. The thaumatrope, beloved of every child, relies on the
persistence of vision to combine two separate images into
one: a bird on one side of a spinning card, its cage on the
Charles-mile Reynauds praxinoscope projector (invented in

1877) and projection image (1887). Bettmann/CORBIS.
Frames from Moving Horse, filmed by physiologist tienne-Jules

Marey (left) and Workers Leaving the Lumire Factory, filmed by
the Lumire Brothers in 1895. Album/Oronoz/akg-images.
238 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Cinema, science, and medicine in France Rgnier
A TOUCH OF FRANCE
Left: Thomas Edison (1847-1931), inventor of the phonograph, the light bulb, and the motion picture camera, and holder of 1093
patents, in his laboratory, ca 1915. Bettmann/CORBIS. Right: Thomas Edisons first motion picture camera (1891). CORBIS.
other. The phenakistiscope, zootrope, kinetiscope, and prax- Sprinkler Sprinkled that December day was the illusionist
inoscope (the latter invented in France in 1877 by Charles- Georges Mlis. He quickly acquired a camera and in 1897
mile Reynaud) all created the illusion of movement, and in opened a film studio at Montreuil-sous-Bois, near Paris, where
1891 Thomas Edison patented his kinetoscope and a cam- he founded his company Star-Film. A pioneer in special effects,
era, the kinetograph, which used perforated 35-mm film. The Mlis made one thousand 125-meter (4-minute) films, and
kinetoscopes continuous lighting offered closed loop images won worldwide acclaim with his masterpiece Le Voyage Dans
for one viewer at a time. This wealth of ideas and inventions la Lune (A Trip to the Moon). Mlis trod not the cinematic road
knew no limit; nor, it should be added, did intellectual prop- of the quest for knowledge, but that of a storyteller making
erty disputes or wrangling over patent applications (nearly 150 films for the general public.1
in France in 1896).1
In December 1895, the Lumire broth-

ers screened what was probably the
first ever comedy film. LArroseur Ar-
ros (The Sprinkler Sprinkled) was
shown to an audience of 33 in the In-
dian Salon of the Grand Caf, on the
boulevard des Capucines in Paris.
The entry charge was 1 francto put
this into context, the salon could be
rented for a whole year for 30 francs.
The success was immediate, and last-
ing as word of mouth ensured that
for weeks on end people came to the
film show at the Grand Cafbe-
tween 2000 and 2500 every day. Em-
boldened by their triumph, the Lumire
brothers trained operators and sent
them on filming trips around the world,
while use of their cameras spread
among fairground cinemas. Among Poster for LArroseur Arros (The Sprinkler Sprinkled) screened in 1895 by the Lumire
those at the first screening of The Brothers. Bettmann/CORBIS.
A TOUCH OF FRANCE
Film still from A Trip to the Moon, a movie by Georges Mlis (1902), based on the novel From the Earth to the Moon, by Jules Verne.
Mlis directed 555 films between 1896 and 1914. Bettmann/CORBIS.
Industrialists, too, sought to exploit the potential of moving production company L. Gaumont et Cie, which manufactured
images. Georges Demen, Mareys assistant at the physiol- projection equipment and cameras. Demen fared badly in
ogy annex of the Collge de France, started out studying the the venture and his process was bought by Gaumont, thus
movements of the mouth during speech. In May 1892, at bringing to an untimely end this first marriage between sci-
the first International Exhibition of Photography in Paris, he ence and industry.1,3
presented thirty or so moving images mouthing the phrase
je vous aime (I love you). Demen also invented the phono- Birth of the French scientific film
scope, which recorded both images and sound, to teach In 1898, Dr Eugne Doyen, a well-known surgeon, paid some-
deaf-mutes how to speak. He soon recognized, though, the one to film him performing a hysterectomy and a craniotomy
commercial potential of his invention, changed tack, and set (his specialties) in his private clinic on the rue Piccini in Paris.
up a company (Socit Gnrale du Phonoscope) to focus When his surgeon colleagues of the Academy of Medicine
on the industrial exploitation of his process.3 balked at showing his films in public, Doyen himself paid for
their projection. They showed medium-close shots, with no
Using an improved version of his phonoscope, Demen then dcor, and were intended for teaching purposes, though
filmed short photograms, living portraits of people uttering Doyen did not hesitate to show them to an impressionable
a few words, and everyday scenes unrelated to his original sci- public. The surgeon Jean-Louis Faure, another pioneer of sur-
entific endeavors. The breach with Marey, who was opposed gical films, said of Doyens films that they were of great edu-
to the commercial exploitation of moving pictures, was not cational value, but tended to showiness, which, he felt, marred
long in coming, and in 1894 Demen was forced to resign from the demonstration of the surgical technique.
the Collge de France. Unfazed, Demen is believed to have
filmed the national funeral of Louis Pasteur on 5 October 1895 A few years later Doyen hired a camera operator to film his
using 6-mm film, and two years later invented the 35-mm ver- surgical separation of Doodica and Radica, conjoined twins
sion of his camera. Unversed in the ways of business, Demen who starred in Barnum and Baileys touring cabinet of curiosi-
sought help from Lon Gaumont, the founder of the French ties. The sober staging and style seemed to invite viewers to
A TOUCH OF FRANCE
forces with genuine laboratories with animal facilities, an aquar-

ium, a vivarium, biology, chemistry, and physics departments,
their films acquired an educational purpose. Some 450 one-
reelers popularizing science were produced in the four years
before the war. To kindle the interest of younger viewers and
to overcome any mind-wandering, the films showed odd or
unfamiliar creatures and insects. The industrialist Charles Path
was convinced of their educational value, saying that the
cinematograph will be the theater, newspaper, and school
of tomorrow. douard Petit, the chief inspector of schools,
begged to differ, believing that in the cinema the somewhat
rushed sequence of images deforms the slow and progres-
sive work of nature.7-9
To adapt to the large variations in the duration of natural or bi-

ological phenomena, the scientific film from the outset used
techniques that would later be adopted by those making films
The conjoined twins Doodica and Radica, joined at the chest for cinematic storytelling: slow motion and time-lapse pho-
(xiphopagus twins), surgically separated by Eugne Doyen in 1902. tography. One of Mareys collaborators, the photographer Lu-
Although the operation itself was a success, Doodica died shortly cien Bull, originated high-speed cameras which, in the early
after the separation, and Radica succumbed to tuberculosis in
1903. IAM/akg/World History Archive.
1900s, filmed at 1200 and then 4000 images per second, and
over the years he refined them until by 1951 they could record
abandon their role as onlookers and become protagonists. one million images per second. Bull also invented a camera for
The resulting scientific filmLa Sparation des Surs Sia- microcinematography capable of 8- to 10-fold magnification.7,8
moises Doodica et Radicatrespassed into the realm of show
business. Worse was to come. Negatives of the film were kept Interest in scientific films waned at the start of the First World
by the camera operator and distributed in France and be- War and laboratories were dismantled and their staff laid off.
yond for projection at cafs chantants. What had started life Scientific documentaries took their place, but were less pop-
as a medical demonstration, ended in ghoulishness. Tarnished ular and designed for a different purpose: the dissemination
by this unseemly episode, and by the resulting legal tussles of scientific knowledge to prepared minds and the creation
and controversy, Doyen fell from grace. of audiences keen on this type of film.
Then there was the question of copyright. Who exactly owned Using itinerant film shows to teach public hygiene
such films? The filmmaker or the surgeon? And what of the In 1917, as the United States of America joined forces with
patient, without whom there would be no film? The fifty or the Allies in World War I, the Rockefeller Foundation sent a
so films of Doyens surgical procedures were leased to the commission to France to aid that country in organizing a fight
clipse company, later transferred to
Gaumont, and then acquired by Doyens
heirs, only to go up in smoke during a
bombing raid in World War II.4-6
Up to the outbreak of war in 1914, in-

dustrial scientific films were highly pop-
ular in France. Most French production
companiesPath, Gaumont, clair,
clipseopened studios to make short
films which in general were shown in cin-
emas, before the newsreel and the main
feature. When the production units joined
One of the Rockefeller Foundations trav-

eling educational units (roulottes dhygiene),
which crisscrossed France from 1917
to 1925 as part of a mission to fight tuber-
culosis. Photo published in Cinmagazine
No. 49, on 23 December 1921.
A TOUCH OF FRANCE
upon tuberculosis, by which under ex- Doctor Jean Comandon (1877-1970), a

isting conditions the population was se- precursor of medical and hygiene documen-
riously menaced.10 The Commission for taries, with more than 400 films to his credit.
the Prevention of Tuberculosis in France
was solemnly welcomed by French Pres- Dont Spit on the Ground, Beware the
ident Raymond Poincar on 9 August Fly, Dont Lick your Fingers to Turn the
1917. It was funded by The Rockefeller Page, The Slums Must be Vanquished,
Foundation to the tune of $522 459 (the Fingernails in Mourning.11 These and like
equivalent today of roughly 45 million eu- films were aimed at teachers and univer-
ros), and included training courses for sity lecturers, the middle classes, soldiers,
doctors and health visitors, the running housewives, and workers. And above all
of dispensaries throughout France (70% children, for whom the Rockefeller lectur-
of the population lived in rural areas), ers ran health crusades with the added
and a campaign of popular education incentive of prizes. Between 1917 and
by means of traveling exhibits, lectures, 1922, the Rockefeller mission organized
slides, moving pictures, posters, pam- 6800 talks, distributed 15 million leaflets,
phlets, and press articles.10 Five circu- and launched extensive American-style
lating educational units known as the press campaigns. Close to three million
roulottes dhygine (hygiene caravans) French people attended the talks and
traveled the length and breadth of France. lectures.11 After World War I, public health
Aboard each were an electrical generator, film projection equip- education using films continued, notably in the fight against
ment, films, documents, 42 exhibition posters, and five peo- tuberculosis through the National Committee for Defense
ple: the (American) film director, a female lecturer, a male lec- Against Tuberculosis (which took over the films of the Rocke-
turer, a mailman, and a driver-cinematographer. feller mission). The task of making new films was entrusted
to Jean Benot-Lvy, who between 1920 and 1944 made to
Public health propaganda using moving pictures spread in order for various governmental ministries almost 300 one-
France during World War I after the setting up of an extra- reelers and 15 features. These scientific and educational films
parliamentary commission to study how to extend the use of were made in consultation with medical officers, notably Dr
cinematography to other areas of teaching. Most films shown Louis Devraigne, head of the maternity ward at the Lariboi-
by the Rockefeller mission, some 150 in all, were produced by sire Hospital in Paris, who gave advice (and provided scripts).
Path and by Gaumont. Their titles left little to the imagination: In 1927 alone ten million French people attended these film
shows, which were the educational medi-
um most popular with the working class-
es and rural populations.12,13
Designed to appeal to, and so to edu-

cate, the general public, Benot-Lvys
films extolled the values of humanism and
of republican science. Produced by the
Socit ddition cinmatographique
franaise, which Benot-Lvy created in
1922, there were films on cancer, the pre-
vention of syphilis, and alcoholism. The
first great film recounted the life and work
of Louis Pasteur. Others followed, like
The Mother-To-Be on infant care, The Sa-
cred Veil on visiting nurses, and Mater-
nity, which advocated a pro-birth policy.
In a December 1932 interview, Benot-

Lvy spoke of his belief that education-
al films have much in common, and of-
Jean Painlev (1902-1989) filming an aquarium for his documentary LHippocampe, tentimes are confused, with drama films,
with a high-speed Debrie GV camera, in Port-Blanc, Brittany, around 1925. from which they borrow ideas on how
Les Documents cinmatographiques, Paris. to be more compelling. Benot-Lvy felt
A TOUCH OF FRANCE
that educational films fall into two clearly distinct genres: erthe world of science scoffed at Painlevs eclecticism,
those used to illustrate a talk and to transmit understanding, unconvinced that cinema was a tool of scientific research.
and those shown in ordinary film theaters and intended to Painlev was one of the founders of the Institut de Cinma-
appeal to heart and soul. Education, Benot-Lvy believed, tographie Scientifique and of the Commission Suprieure de
speaks above all to the intellect in the first genre, and to the lImage et du Son, which allied science and cinema. He even
sentiments in the second, provided, that is, mind and heart acted in the film The Unknown Woman of Six Days direct-
can be partitioned so neatly.12,14 ed by Ren Sti to fund the anatomy and histology laborato-
ry of the Sorbonne. He gave talks illustrated by films at the
Making the transition to the talkies, Benot-Lvy produced French Academy of Sciences on the larvae of midges of the
two realistic filmsItto and Hlnein which the image of the Chironomidae family (which contains some 5000 species).
rebellious woman, mistress of her own destiny, contrasted Also a diver, Painlev made numerous scientific documen-
sharply with the silent images of Maternity.12 He also made taries of aquatic animal life, like the landmark documentary on
films for the teaching of surgery, as part of a medical-surgical sea horses LHippocampe ou Cheval Marin (filmed through
cinematographic encyclopedia, a project curtailed by the out- an aquarium!).
break of war in 1939.
A new genre: the independent

science documentary
Dr Jean Comandon filmed the invisible.
A maker of scientific films before World
War I, Comandon later moved on to doc-
umentaries. His research on microcine-
matography at the Saint Louis Hospital
in Paris was given technical backup by
Path, which he joined in 1906 to work
its laboratory. There he made films like
Crystallization, The Curious Soldier Flies:
The Stratiomyidae, and The Movement
of Plants.
Beset by financial difficulties, Path

stopped producing scientific films in
1926 and closed the laboratory where
Comandon worked. Already the recip-
ient of various distinctions and awards
for his work, Comandon set up a scien-
tific cinematography lab at the Institut
Pasteur in Garches (near Paris) where
he made films like The Phagocytosis of
Trypanosomes by White Blood Cells and
The Circulation of Blood.15,16
In the 1920s, film clubs, educational cin-

ema offices, and specialized projection
rooms ensured the survival of scientific
cinema in a new form where mostly doc-
umentary films were shown to the pub-
lic. Jean Painlev bestrode French sci-
entific cinema of the 1920s. Biologist,
scriptwriter, friend of the surrealists, hu-
manist, jewelry designer, racing car driv-
Buste d'Hippocampe (sea horse bust),

photographed by Jean Painlev, around 1930.
Les Documents cinmatographiques, Paris.
A TOUCH OF FRANCE
Painlev was friends with renowned film Doctor Albert Calmette (1863-1933), who,
directors like Jacques Prvert, Henri Lan- together with his assistant Camille Gurin,
glois, Georges Franju, Sergei Eisenstein, developed the BCG vaccine against tuber-
culosis. Wellcome Library, London.
Luis Buuel, Jean Vigo, and Abel Gance.
He used musicians in the making of his
documentaries like LHippocampe, for an uninterrupted series of science doc-
which Darius Milhaud wrote the music, umentaries and films, some of which won
and in The Vampire, in which the life of a awards: Beware of Vipers, Ultrasound,
vampire bat was illustrated by the music The Killer Mushroom, The True Culprit, a
of Duke Ellington, including Echoes of the drama commissioned by the French wel-
Jungle (Painlev was a jazz pianist too!). fare system to warn of the dangers of in-
duced abortion, The Question of Cancer,
In all, Painlev took part in the making of an encyclopedic review in thirteen reels,
almost 200 films, using the latest tech- and The Adventures of a Bluebottle. A
nologies: underwater filming, special ef- good number of Thvenards films were
fects, steadycam. In 1930, he made a set to music by Andr Jolivet, while pop-
militant four-minute film in which he de- ular actors and members of the Com-
clared his support for the use of citrate in die-Franaise did the voiceovers. After
anticoagulation to stem massive bleed- Thvenard joined the scientific cinema-
ing, as recommended by a physician with the rank of gen- tography laboratory of the Institut Pasteur, he was commis-
eral in the French military, but recently refused by the French sioned to make a documentary on Albert Calmette, co-dis-
Defense Health Service Authorities.17,18 Dr Pierre Thvenard coverer of the bacillus Calmette-Gurin, used in vaccination
started his career as a film scientific director in 1934 by mak- against tuberculosis. This and other films brought Thvenard
ing 35-mm films on urologic surgery and followed this up with international renown.8,19
CINEMOPHTHALMIA, THE BANE OF EARLY CINEMAGOERS
In the early 20th century, a visit to the newfangled cinema which were stained and scratched, by celluloid of uneven
was a risky affair. Eighteen-year-old Miss R. of Bordeaux thickness and grain, by poor shots dotted with fuzzy and
paid for her cinematic passion with conjunctivitis after every indistinct details that force the viewers eye constantly to
show. And M. C., a barber of that same French city, was change focus (accommodation), and by deterioration of
unable to read his newspaper for days after every visit to the film perforations resulting in slippage of the film.
a film theater. What was happening? In 1909, local oph-
thalmologist Dr Ginestous provided the answer when he Cinemophthalmia had several clinical variants: simple eye
gave a paper on a new medical phenomenon he had dis- watering with photophobia, inflammatory erythema of the
covered: cinemophthalmia. eyelids and of the conjunctiva, problems focusing, exhaus-
tion of ocular reflexes, notably fatigue of the internal eye
In the early years of cinematography, the persistence of muscles, and retinal asthenopia without loss of visual acu-
luminous impressions on the retina was calculated to last ity or abnormal refraction. Despite this alarming list of dis-
2/25 of a second, and so filmmakers adopted a projection orders, Dr Ginestous sought to hearten, saying that in fact
speed of 16 images/second for 35-mm film. To produce ophthalmias of this type had a good prognosis and usu-
the cinematographic illusion, the succeeding images must ally resolved quickly, even without treatment. As for pro-
remain superimposed on the retina for long enough to phylaxis, Dr Ginestous had the answers: choose a better
give the impression of movement. Each projected image class of film theater where they use new reels of film (no slip-
requires an illumination phase and a phase during which page) and the correct projection speed; wear blue-tinted
the film is advanced at a fixed speed by one frame. The glasses; peer at the screen through fanned fingers or fi-
resulting scintillation of the image generated eye strain, par- brous palm leaves; use eyedrops containing cocaine or
ticularly as knavish film theater directors tended to slow adrenaline.
the projection speed so as to lengthen the show: a 1000-
meter film lasted 54 minutes when projected at 16 images/ Cinemophthalmia receded after World War I, like a fad-
second and 62 minutes at 14 images/second. This new ing retinal image, pushed into a footnote on the history of
ailment of cinemophthalmia discovered by Dr Ginestous medicine by improvements in cinema projection equip-
was believed to be triggered by the poor quality of films, ment, filming techniques, and celluloid film.21-24
A TOUCH OF FRANCE
Epilogue
Movies have long depicted stories of medical practitioners fragile and vulnerable heart patient, the erratic mental patient,
in a bewildering array of guises: the hospital bigwig, a coun- the consumptive condemned to a slow death, loathsome mis-
try doctor, a physician and humanist, the doomed hero, the shapenness and disfigurement, the chilling diagnosis of can-
medic guilty of malpractice, a doctor in the colonies, murder- cer, traumatic childbirth. The sick and the lame have served
ers, cranks. Illness and the afflicted too have well served many as a mirror, a conceit, a vehicle for a social conception of dis-
an intrigue on the silver screen: the Machiavellian gimp, the ease and suffering.20 I
References
1. Sicard M. LAnne 1895: lImage cartele Entre Voir et Savoir. Paris, France: 13. Viborel L. ducation populaire et cinmatographe. La Vie Saine. 1957;44.
Les Empcheurs de Penser en Rond: 1994. 14. Laot F et al. LImage dans lHistoire de la Formation des Adulte. Paris, France:
2. Leuba M. Marey, Pionnier de la Synthse du Mouvement, Beaune: Muse Marey, LHarmattan; 2010.
1995. 15. Do OGomes I. Luvre de Jean Comandon In: Martinet A et al. Le Cinma et
3. Drevon A. Les travaux de Georges Demen In: Martinet A et al. Le Cinma et la Science; Paris, France: ditions du CNRS; 1994.
la Science; Paris, France: ditions du CNRS; 1994. 16. Comandon J. Pierre de Fondbrune (1901-1963). Annales de lInstitut Pasteur.
4. Lefebvre T. La Chair et le CellulodLe Cinma Chirurgical du Docteur Doyen. 1964;106(4):515-518.
Brionne, France: Jean Doyen; 2004. 17. Berg B. De charmants petits rien. In: Leuba M et al. Marey, Pionnier de la Syn-
5. Doyen E. LEnseignement de la Technique Opratoire par les Projections Ani- thse du Mouvement. Beaune, France: Muse Marey; 1995.
mes. Paris, France: Socit Gnrale des Cinmatographes clipses; 1911. 18. Millet R. Jean Painlev cinaste. In: Martinet A et al. Le Cinma et la Science;
6. Faure JL. Les films chirurgicaux. Bull Soc Fr Hist Med. 1937;31:245-248. Paris, France: ditions du CNRS; 1994.
7. Lefebvre T. De la science lavant garde. In: Berthoz A et al. Images, Science, 19. Raynal A. Le docteur Thvenard, cinaste et scientifique. In: Martinet A et al.
Mouvement. Paris, France: LHarmattan-SMIA; 2003. Le Cinma et la Science. Paris, France: ditions du CNRS; 1994.
8. Thvenard P, Tassel G. Le Cinma Scientifique Franais. Paris, France: La Jeune 20. Broussouloux C. Cinma et Mdecine. Le Mdecin lcran. Paris, France:
Parque; 1948. Ellipses; 2001.
9. Petit E. Lcole et le cinma. Film-Revue. 1913;53:1-2. 21. Cahan D. Hermann von Helmholtz and the Foundation of Nineteenth-Century
10. The Rockefeller Foundation Annual Report 1920. www.rockefellerfoundation.org/ Science. Berkeley, CA: University of California; 1994.
.../annual-reports. 22. Helmholtz H. Handbuch der Physiologischen Optik. Leipzig, Germany: Leopold
11. Picard JF. La Fondation Rockefeller et la Recherche Mdicale. Paris, France: Voss; 1867.
PUF; 1999. 23. Lefebvre T. Une maladie au tournant du sicle: la cinmaophtalmie. In: Mari
12. Vignaux V. Jean Benot-Lvy ou le Corps Comme Utopie, une Histoire du Cin- M et al. Cinma des premiers temps: Nouvelles contributions franaises. Tho-
ma Educateur Dans lEntre-Deux-Guerres en France, Paris,France: AFRHC; rme. 1996;4:131-145.
2007. 24. Ginestous E. Hygine Oculaire de la Premire Enfance. Paris, France: Vigot; 1909.
CINMA, SCIENCE ET MDECINE EN FRANCE

Le cinma demeure avant tout un procd technique scientifique dexploration des mouvements des tres vivants.
Cest la capacit dinventer des appareils capables de saisir des images grande vitesse puis de les assembler
qui constitue limage anime. Les grands dcouvreurs furent lastronome franais Jules Janssen, inventeur du revol-
ver astronomique (1874), le photographe anglais Eadweard Muybridge qui mit au point le zoopraxiscope pour d-
composer les mouvements du cheval (1879) et surtout le mdecin franais tienne-Jules Marey qui dveloppa le
chronophotographe et la pellicule souple non perfore (1882). Ces hommes demeurrent des hommes de science
qui produisirent donc des films vise exclusivement scientifique. Dun autre ct, lingnieur amricain Thomas
Edison (1894), les industriels franais Louis et Auguste Lumire (1895), le magicien franais Georges Mlis (1895)
comprirent que cette nouvelle technique de limage anime offrait des perspectives commerciales et artistiques
immenses. Ils se lancrent alors dans le cinma-spectacle qui connut immdiatement un immense succs. La lo-
gique industrielle, la rentabilit animaient ces pionniers qui sopposrent souvent aux savants. Le cinma devint un
art, un spectacle, un loisir accessible tous. Cet art nouveau, le septime ainsi dsign par le critique franco-italien
Ricciotto Canudo, intgrait toutes les composantes de la vie. La mdecine, le mdecin, la maladie et le malade fi-
gurent en bonne place dans la thmatique des films franais tant comme acteurs de fiction ou comme agents din-
trigues. Pour autant, le cinma scientifique, le documentaire, le film de propagande hyginique connurent aussi,
en France, de belles heures de gloire. Attachs la propagation de la science, de la mdecine, de lhygine par
limage, ces faiseurs dimages bouleversrent souvent la technique cinmatographique au plus grand bnfice du
film de fiction.
A TOUCH OF FRANCE
ecause Langlois considered
B film images as reflecting how

people dressed, moved, ate,
entertained themselvesin short
livedat a particular time and
place, determining how those
Children of
coming after it would view it, he
viewed every frame as testimony. the Cinmathque
His motto was Everything must
be saved. It was thanks to him
that the work of the Lumire broth-
ers and Georges Mlis was res-
cued from oblivion, that pre-War
cinema has been handed down to
posterity, and that the French New
Wave was made possible.
b y I . S p a a k , Fra n c e
A
s with film institutes or cinematheques the world over, the vocation
of the Cinmathque, founded in Paris in 1936, was to preserve, re-
store, research, and show films, playing the same role for the moving
image as libraries for books or museums for paintings. That the Cinmathque
is perhaps the best endowed of its kind, holding around 40 000 films, is large-
ly down to one man, Henri Langlois. Born in Izmir in 1914 and a devotee of film
from childhood, Langlois founded a silent film preservation club in Paris in
1935. A year later, aged 22, he became the first director of the Cinmathque,
which he and two friends set up to save and preserve every film wherever
made, whether masterpiece or middling. His ambition also extended to rescu-
Isabelle SPAAK ing from oblivion anything related to film, including scenarios, sets, costumes,
Journalist and projectors. Larger than life, a law unto himselfthe archetypal sacred
(e-mail:
[email protected]) monsterHenri Langlois let nothing stand between himself and film. During
the Second World War and the Occupation, he saved the Cinmathques
collection from destruction. His obsession was his strength. He forged close
friendships with Chaplin and Hitchcock, and encouraged New Wave directors
on both sides of the Atlantic. As the soul and archeologist of the moving im-
age, he was for the poet Jean Cocteau the dragon standing guard over our
treasure, all of which is now on exhibition in the rejuvenated 12th arrondisse-
ment of Paris to the delectation of modern movie-lovers.
re cinephiles an extant species in the 21st century? Are there still people
A who take moviegoing so seriously that they are prepared to spend whole
days in dark theaters watching endless reruns of grainy reels of celebrated
or often completely unknown films when they could be consuming avalanches of
technically superior images in the comfort of their own homes thanks to DVDs, the
Internet, social networking sites, and other forms of video on demand? And what
meaning does cinephiliaa word coined in the early 1950s by the philosophizing
champions of an art form touted as the equal of painting or literaturehave in the
21st century? It was the young cinephiles of the 1950s grouped around the ex-
travagant figure of Henri Langlois, cofounder (with Georges Franju, Jean Mitry, and
Paul-Auguste Harl) of the Paris Cinmathque in 1936, who went on to revitalize
French cinema. Franois Truffaut, Eric Rohmer, Claude Chabrol, Jacques Rivette,
Jean Rouch, and Jean-Luc Godard were all nurtured at the Cinmathque: they
were each so entranced with cinema that they had to make films themselves. All
www.medicographia.com of them discovered gems at the Cinmathque that they would never otherwise
246 MEDICOGRAPHIA, Vol 35, No. 2, 2013 Children of the Cinmathque Spaak
A TOUCH OF FRANCE
have seen had not Langlois, driven (Truffaut) by his mono-

maniacal obsession, spent his days, nights, and entire life at-
tempting to preserve everything that had been filmed since
images were first made to move. Langlois was a larger than
life figure, a law unto himselfthe archetypal sacred monster.
Had he not been obsessed by the urgent necessity of saving
everything, what would have become of the Lumire broth-
ers archive or the cinemagic of Georges Mlis? Who, but for
him, would have seen Marlene Dietrich in The Blue Angel were
it not for its miraculous escape from destruction from Ger-
man wartime censorship? How else would France have been
introduced to Soviet cinema, Hollywood epics, and Japan-
ese masterpieces? Filmmakers the world over are indebted
to the dragon, as the poet Jean Cocteau called him, for
having been there to stand guard over the treasures of their
profession.
But Langlois was not content to track films down, identify

them, and show them. He also saw himself as an archeol-
ogist. His aim was to save everything and anything that was
related directly or indirectly to cinema, including scenarios, ob-
Henri Langlois (1914-1977): cofounder and iconic figure of the
jects, costumes, sets, and projectors. His collection had more
French Cinmathque. Cond Nast Archive/Corbis.
than a hint of Ali Babas cave to it. But who else was able to
forge links of mutual respect and friendship so strong that Our spiritual home
Charlie Chaplin himself donated part of the cogwheels from When the Cinmathque left the Palais de Chaillot and moved
Modern Times, Martine Carol the dresses she wore in Max to the new quarters in the 12th arrondissement, in a build-
Ophuls Lola Monts, Louise Brooks the buckles from her ing designed by Frank Gehry, Martin Scorsese declared at
stage shoes, Fritz Lang the robot he dreamed up for Metro- the opening: Filmmakers the world over are familiar with the
polis, or Alfred Hitchcock the death head of Anthony Perkins French Cinmathque, even if they have never been here.
mother in Psycho, posted in a large cardboard box? Its our spiritual home.
The new
Cinma-
thque
Franaise
building,
designed by
Frank Gehry
(the same
architect who
designed the
Guggenheim
Musem in
Bilbao) and
opened to
the public on
28 Septem-
ber 2005.
Ginies/
epa/Corbis.
Children of the Cinmathque Spaak MEDICOGRAPHIA, Vol 35, No. 2, 2013 247
A TOUCH OF FRANCE
Charlie
Chaplin in
the satire
of the dehu-
manizing in-
dustrialized
world, Mod-
ern Times
(1936).
Bettmann/
CORBIS.
This moving testimony reflected the reputation of an institu- Franju and Langlois had met in the early 30s at a printers
tion brought into being in 1936 by three devotees of what where the young Langlois had been apprenticed by his fa-
in France is commonly referred to as the seventh art: direc- ther after failing his exams. Born in Izmir, ex-Smyrna, in 1914
tor Georges Franju (1912-1987), film critic Jean Mitry (1907- to French parents forced to return to France after the Greek
1988), and Henri Langlois (1914-1977). city was taken by Turkey in 1922, Henri Langlois had only one
interest: cinema. It was the one and only pas-
sion in his life, to the extent that he chose to go
to the movies rather than sit for his baccalau-
reat, to the great despair of his father. Franju and
Langlois found themselves partners in the same
passion.
Together they borrowed 500 francs (equivalent

to 375 euros in 2013 [INSEE indicator]) from
Henris parents to set up a sort of film club, Le
Cercle du Cinma (The Cinema Circle), where
they showed silent films, encouraged by the film
historian Jean Mitry who was convinced that
the advent of the talkies would condemn the
masterpieces of silent cinema to oblivion if no-
body bothered to preserve the reels. There was
no institution of any kind devoted to the protec-
Brigitte Helm as the Robot Maria in Metropolis,

directed by Fritz Lang in 1926, in Germany.
Bettmann/CORBIS
A TOUCH OF FRANCE
tion or preservation of what was yet to be acknowledged as

the seventh art. The founding principle of the Cinmathque
was the desire to preserve a heritage under threat. Barely 22,
yet already steeped in film history and culture, there was no
one more fitting to preside over such an institution than Henri
Langlois.
His ambition was to preserve everything: the good along with

the not so good, final cuts along with outtakes. He excluded
nothing: scale models, scenarios, stills, sets, costumes, pro-
jectors, etc. Langlois was the first to look beyond, or beneath,
the masterpieces of cinema and take an interest in all films.
He saved everything, even the stinkers. Bad films too are a
record of their time. That is what drove Langlois. I wanted
the shades of the living to mingle with those of the dead,
said Langlois in justifying his approach under the triple guise
of archeologist, sociologist, and historian, because that is
The Palais de Chaillot, which housed the Cinmathque from
what cinema is about. 1963 to 2005. Bettmann/CORBIS.
Everything must be saved The Cinmathques first home, like its current home, was
Because Langlois considered film images as reflecting how in the 12th arrondissement, but in the rue Marsoulan. From
people dressed, moved, ate, entertained themselvesin short the start it was designed as both museum and cinema. Lan-
livedat a particular time and place, determining how those glois had the appetite of an ogre. He increased the Cinma-
coming after it would view it, he viewed every frame as tes- thques archive from ten films in 1936 to over 60 000 in 1970.
timony. His motto was Everything must be saved. It was But if anything he was even keener to show them. Langlois
thanks to him that the work of the Lumire brothers and saved films by recovering them, but also by restoring them
Georges Mlis was rescued from oblivion, that pre-War cin- when they had begun to decompose. Most were made of cel-
ema has been handed down to posterity, and that the French luloid, a fragile material that disintegrates under adverse stor-
New Wave was made possible. age conditions.
Director
Abel Gance
and crew
filming scene
in Napoleon,
in 1927.
Bettmann/
CORBIS
A TOUCH OF FRANCE
The Cinmathque was built on the donation of films by film- reels around in the mtro. It sounds funny now, but at the
makers and producers thanks to a relationship with Langlois time it was dangerous. Without Langlois and his daring in-
based on mutual gratitude and admiration. Langlois was able genuity, Robert Wienes The Cabinet of Dr Cagliari (1919), or
to show the films without paying fees, but they remained the Georges Mlis Joan of Arc (1900), or Josef von Sternbergs
property of those who entrusted them with him. Perhaps the The Blue Angel with Marlene Dietrich, to take but three ex-
bulk of the collection belonged to Langlois himself, a com- amples, would have been lost to history. Many items in the
pulsive collector and inspired flea-market trawler, who was Cinmathque archive were under threat during the Occu-
snapping up items long before governments recognized the pation, and Langlois managed to hide them by secreting his
need to establish cinematographic archives. films in any number of hiding places in Paris, burying some in
Marlene
Dietrich on
the set of The
Blue Angel,
directed by
Joseph von
Sternberg,
based on
Heinrich
Manns novel
Professor Un-
rat (Professor
Garbage).
John
Springer
Collection/
CORBIS.
Americans in particular were grateful to the Cinmathques Michel Simons garden, and hiding othersthose by Chaplin
director for having preserved works that would no longer have and Soviet directorsin a Bordeaux wine estate. By 1944,
existed without his intervention. It is thanks to Langlois, for in- Langlois had saved 40 000 films. As soon as the War ended
stance, that we still have Abel Gances magnificent Napoleon he set out to find a home for them.
(1927), one of the masterpieces of silent cinema.
The German Occupation deprived the Cinmathque of a The small theater on the rue de Messine
home of its own. To get round the censor, Langlois organized In 1948, he found premises at 8 rue de Messine, near the
clandestine viewings at his mothers, attended in particular by Champs-Elyses. Keeping to the same fundamentals: pre-
Simone Signoret, who had no hesitation, despite her Polish- serve and show, he decided to show only once. The single-
Jewish father, in crossing Paris under the Occupiers nose showing idea was simple, and caught on. It was the key to his
pushing a pram full of reels. The first time I saw Battleship Po- success.
temkin, remembered Signoret, was in 1941, rue Troyon, in
the dining room at Langlois mothers. All the Soviet films, and Hungry to catch the one-off showings of Langlois rare finds,
all the films by Renoir or Prvert that were banned under the cinephiles were assiduous in their attendance, meeting up
Occupation, in fact the only great films that I saw during this for each weeks program of unmissable films that Langlois
period, were shown to me by Langlois who used to carry his used to stencil on a single sheet of paper. They included the
A TOUCH OF FRANCE
young Claude Chabrol, Franois Truffaut,

Eric Rohmer, Jean-Luc Godard, Alain
Resnais, Jacques Rivette, and others,
all irrevocably committed to film, with
Langlois as their spiritual godfather. Its
thanks to Langlois that they saw their
first undubbed Japanese film and their
first Buster Keaton (subtitled in Czech).
It was Langlois who trained and sharp-
ened their eye. Enjoying cinema, Lan-
glois used to say, means enjoying life.
Competition was fierce for the sixty seats

of the little theater on the rue de Mes-
sine. Jean-Paul Sartre and Simone de
Beauvoir were regulars, as were Andr
Gide, Georges Braque, Fernand Lger,
and the future French president Georges
Pompidou. After each showing discus-
sion would go on for hours in the street
outside as Langlois had no time for the
French director Franois Truffaut shooting La Sirne du Mississippi (Mississippi Mermaid)
staged dissection of films after they were in 1969. Alain Dejean/Sygma/Corbis.
shown. Langlois did not only rescue rich-
es from the past. He also celebrated, made known and en- That didnt stop him being warm, provided you agreed to
couraged the directors of the future, such as the French New board the train of his conversation, which was more exactly
Wave, the violently controversial Rainer Werner Fassbinder, a conspiracy-centered monologuethe conspiracy being
and Nicholas Ray, one of the leading post-War Hollywood di- the constant threat of a State stranglehold over his collection.
rectors (Johnny Guitar, 1954, and Rebel Without a Cause,
1955, with James Dean). The work by the French Cinma- Langlois was paranoid. But he was not mad. He knew that
thque was without doubt the most important individual ef- the Cinmathque had outgrown the era of heroic one-man
fort in cinema history, said Ray in support of Langlois in Feb- effort. Its riches had become an incitement to State lust. An-
ruary 68. dr Malraux, the then Minister of Culture, made a first attempt
at modifying the status and management of the Cinmathque
A man driven in 1963, more exactly to convert it from a private association
Langlois was characterful to have only attracted admirers. His to a fully State-funded institution. In exchange for State sup-
detractors accused him of being muddle-headed, a hope- port, a theater in the Palais de Chaillot, and increased fund-
less manager, and a thief to boot. Langlois behaved like a ing, Malraux wanted a leading role on the board of directors
scavenger, with the ethics and clothing to match. He was ac- and the power to appoint a regular and dependable financial
cused of keeping negatives any old how, of letting reels rust officer. In February 1968, Malraux stopped beating about the
in his bath (a rumor which only compounded his unwashed bush: he dismissed Langlois.
image), and of alarming nontransparency as to both the pre-
cise methods by which he acquired some of the items in his World cinema takes to the street
collection or their exact location. He was shielded by a close The events of May 68, when the country rose up against a
guard of volunteers who were prepared, like Langlois himself, deaf and authoritarian government, were only weeks away,
for any sacrifice that would enrich or protect his collection, and Malraux underestimated the stature and loyalty of the
especially as they were convinced that the whole world was troops at Langlois command. Indeed, so spontaneous was
out to wrest them from him. The renowned film critic Serge the loyalty that command was unnecessary. Within twenty-
Daney sketched a realistic portrait of the poet of film: Like four hours, world cinema had taken to the street: Abel Gance,
all driven men, Henri Langlois divided the world, people and Franois Truffaut, Jean-Luc Godard, Jean Renoir, and Robert
events into two blocks: 1. Those that were good for the Ci- Bresson banned the State from showing their films. They were
nmathque. 2. Those that were not good for the Cinma- joined by dozens of other filmmakers, including Charlie Chap-
thque. Even if hed known you for ten years, he didnt waste lin, Roberto Rossellini, Fritz Lang, Richard Lester, Carl Dreyer,
time asking after your health or your family because the very Orson Welles, and Jerry Lewis. Three thousand people demon-
notions of health or family only had meaning in terms of the strated outside the Palais de Chaillot. The police charged.
health of the Cinmathque or the family of the Cinmathque. Godard was wounded, and Franois Truffaut used scenes
A TOUCH OF FRANCE
Filmmakers demonstrating in the streets of Paris in February 1968to reinstate Henri Langlois who had just been fired by the French
Minister of Culture Andr Malraux. Georges Pierre/Sygma/Corbis.
from the demonstration in Stolen Kisses, which he dedicated Antonioni, Ingmar Bergman, Luis Buuel, Peter Brook, Alfred
to the Cinmathque when it came out the following year. Hitchcock, Elia Kazan, Akira Kurosawa, Pier Paolo Pasolini,
There were riots outside the Cinmathque offices in the rue Claude Berri, Satyajit Ray, and Andy Warhol; actors such as
de Courcelles. A petition gathered 700 signatures from the Jean-Paul Belmondo, Brigitte Bardot, Catherine Deneuve,
international cinematographic elite: the directors Michelangelo Michel Simon, Simone Signoret, Marlene Dietrich, Jane Fonda,
Katharine Hepburn, Peter OToole, and Gloria Swan-
son; as well as writers, artists and philosophers, such
as Roland Barthes, Samuel Beckett, Alexander Calder,
Truman Capote, Max Ernst, Eugene Ionesco, Pablo
Picasso, Paul Ricoeur, Jean-Paul Sartre, Henri Cartier-
Bresson, and Norman Mailer. The power of this Whos
Who of world culture was such that the government
climbed down and Langlois could only be reinstated.
He spent his remaining years on his singular creation,
leaving behind him a Cinmathque envied by the rest
of the world.
The Cinmathque was duly rescued from the jaws of

the State, but paid for it by having its subsidies reduced
to a minimum. Langlois fought to the end of his life to
maintain his artistic ideal: a film museum designed to
turn people into filmmakers rather than to satisfy con-
French director and producer Caude Berri (left), actor Michel Simon
(middle), and screenwriter and producer Claude Chabrol (right) during a sumers. He always maintained that true cinema was
demonstration at the Cinmathque on 12 February 1968. James made by mauvais lves, bad pupils who refuse to sit
Andanson/Sygma/Corbis. dutifully at their desks swallowing the teachers curricu-
A TOUCH OF FRANCE
Ingrid
Bergman
handing reel
to Roberto
Rossellini
(left) in 1949.
Bettmann/
CORBIS.
lum. Once an ardent defender of the sacred monster, Truffaut

eventually moved away, finding it increasingly difficult to tol-
erate Langlois ever more autocratic behavior and his ten-
dency to show commercial films to bring in much-needed
cash. In 1974, Henri Langlois received an honorary Oscar for
his contribution to cinema. He and his wife Mary Meerson man-
aged to keep the Cinmathque afloat by dint of round-the-
clock work. After his death on January 13 1977, his friends
clubbed together to build a fitting monument over his grave in
the Montparnasse cemeterya sloping slab that reproduces
scenes from iconic films.
From dormancy to rebirth

Bereft of its creator, the Cinmathque and Museum of Cin-
ema entered a dark period of semi-dormancy lasting two
decades compounded in 1997 by a fire and the subsequent Alfred Hitchcock receiving the French Legion of Honor from the
hands of Henri Langlois in 1971. Michel Ginfray/Apis/Sygma/
flood caused by the firemens hoses directed onto the roof Corbis.
of the Palais de Chaillot. The collections were saved, but the
Cinmathque found itself confined to a little theater on the the great classics, but also organize retrospectives and fes-
Grands Boulevards until it was reborn and rehoused in 2005 tivals dedicated to specific filmmakers, actors, producers, and
in the building designed by Frank Gehry. technicians, archive the collections, display some of the fab-
ulous objects in the museum, mount temporary exhibitions to
Our turn now to push open the door of this reincarnation. We give glimpses into the wealth of its holdings, and reinforce the
find a Cinmathque that has modern technologies to help links between film and the other arts. The Cinmathque
it fulfill its timeless mission: to preserve and put on films, run also has a library and archive at the disposal of students and
A TOUCH OF FRANCE
researchers. After its record 300 000 visitors in the summer of DVD. It was made under pressure during the German Occu-
2012 for the temporary exhibition on the director Tim Burton, pation by those wholike the films writer Jacques Prvert and
with over 500 drawings, photographs, and scale models, the the actors Jean-Louis Barrault, Arletty, and Pierre Brasseur
Cinmathque staged an exhibition in honor of Marcel Carn, were out to prove that the French spirit was still free even if
another monument in the history of film. Generations of cine- France itself was not, much as Langlois always remained a
philes were raised on Carns cult film, Children of Paradise free spirit even when his Cinmathque appeared threatened
(1945), which has since been re-released in theaters and on by chains. I
LA CINMATHQUE FRANAISE
51 rue de Bercy
75012 Paris
Monday to Saturday 12 AM to 7 PM
Sunday 10 AM to 8 PM
www.cinematheque.fr
Paris burning? Raging flames engulf

the Palais de Chaillot on 22 July 1997,
threatening to destruct the collections of
the Cinmathque. AFP.
LES ENFANTS DE LA C INMATHQUE

Comme toutes les cinmathques au monde, la Cinmathque franaise fonde en 1936 a pour vocation dorga-
niser un lieu de conservation et de dcouverte des films comme les bibliothques le sont pour les livres ou les
muses pour les tableaux. Mais, si la Cinmathque Franaise est lune des plus riches qui existe avec quelque
40 000 films, elle le doit surtout la volont et lnergie dun seul homme : Henri Langlois (1914-1977). Fou de ci-
nma ds son plus jeune ge, ce natif de Smyrne se lance partir de 1935 dans laventure dun cinclub consa-
cr la prservation des films muets. A vingt-deux ans, il devient le premier directeur de la Cinmathque quil a
initie avec deux amis. Son but : tout sauver, tout conserver. Les chefs-duvre comme les films moins bons, les
franais mais aussi les russes, les japonais. Il entend aussi prserver de loubli tout ce qui touche aux films : d-
cors, scnarios, matriel de projection, costumes. Monstre sacr, Henri Langlois ddie sa vie son projet. Durant
la seconde guerre mondiale et lOccupation, il sauve les films de la destruction. La force de Langlois est son ob-
session. Il noue des amitis fortes avec Charlie Chaplin ou Alfred Hitchcock, encourage les jeunes ralisateurs de
la Nouvelle Vague et du renouveau Hollywoodien. Monstre sacr qui veille sur nos trsors dira de lui le pote
Jean Cocteau, il est lme et larchologue de limage anime. Ses trsors sont exposs Paris dans le douzime
arrondissement et continuent denchanter les cinphiles daujourdhui.
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Vol 35, No.

152 Osteoarthritis and comorbidities

158 Osteoarthritis pathophysiology: similarities and dissimilarities with other

164 Role of imaging in osteoarthritis: diagnosis, prognosis, and follow-up

172 Osteoarthritis treatments: where do we stand at the moment?

181 Knee replacement for osteoarthritis: facts, hopes, and fears

189 Disease-modifying osteoarthritis drugs (DMOADs): what are they and

197 The economic weight of osteoarthritis in Europe

Contents continued on next page

Kingdom - S. Blkba i, Turkey - O. P. Bortkevych, Ukraine - P. Hork,

Czech Republic - A. El Maghraoui, Morocco - A. Mahmoud Ali Elsayed,

246 Children of the Cinmathque

In early phases of OA, there

O tilage. The Osteoarthritis Research Society International Disease State

Keywords: osteoarthritis, pathophysiology, risk factors, treatment

Dans les phases prcoces de

Larthrose, la forme la plus frquente darthropathie, est une cause importante de

BETWEEN BONE AND CARTILAGE

A systematic review and

SELECTED ABBREVIATIONS AND ACRONYMS

1000 1000 clinical osteo-

N Knee OA could not be fully explained by increasing obesity. According

Figure 5. Varying prevalence of radiographic

41.9 Abbreviations: BMI, body mass index; OA, osteoarthritis.

N Genetics smoking may be associated with a greater risk of both car-

osteoporotic fractures in men study. Arthritis Rheum. 2010;62:511-514. 2009;121:9-20.

Keywords: burden; epidemiology; osteoarthritis; risk factor

BETWEEN BONE AND CARTILAGE

Adipose tissue is an active

OA and CVD are both considered to be age-related diseases.

BETWEEN BONE AND CARTILAGE

A complex and paradoxical

steoarthritis (OA) is a multifactorial disease that affects not only articular

Disease mechanism/phenotypic feature

Keywords: inflammatory arthritis; osteoarthritis; subchondral bone

PHYSIOPATHOLOGIE DE LARTHROSE : RESSEMBLANCES ET DIFFRENCES AVEC

BETWEEN BONE AND CARTILAGE

Radiography is the only EMA-

steoarthritis (OA) is a highly prevalent joint disorder and is becoming in-

aging (MRI) in OA imaging, and also

Magnetic resonance imaging

Figure 4. Visualiza- Knee Score (MOAKS).22 MOAKS is a recent effort to combine

On the other hand, GRE-type sequences

Figure 6. Biochemical magnetic resonance imaging.

Keywords: magnetic resonance imaging, osteoarthritis, radiography, ultrasound

RLE DE L IMAGERIE DANS LARTHROSE : DIAGNOSTIC , PRONOSTIC , ET SUIVI

BETWEEN BONE AND CARTILAGE

Guidelines for the medical

N Patient education of weight at a lower level seems to reduce osteoarthritis-re-

Treatment type Adverse effect/safety profile

arthroplasty [UKA] and total joint replacement).61 Arthroscopy

Treatment type Component

Nonpharmacological Education; exercise; injury prevention; weight loss; orthotic devices

Acetaminophen Table II.

OARSI effect size*

Education 0.06 (0.03, 0.10)

Acetaminophen 0.14 (0.05, 0.22)

Arthroscopic lavage and debridement 0.21 (0.12, 0.54)

ful treatment for end-stage symptomatic knee osteoarthritis, Conclusion