VIEWPOINT
T ansla ion o clinical p oblems in
os eoa h i is in o pa hophysiological
esea ch goals
Pe e M an de K aan,
1
F ancis Be enbaum,
2
F ancisco J Blanco,
3
de Ba i Cosimo,
4
Flo is La ebe ,
5
Ellen Hauge,
6
Adele Higginbo om,
7
And eea Ioan-Facsinay,
8
John Loughlin,
9
Ing id Meulenbel ,
10
Ee a Moilanen,
11
I ene Pi sillidou,
12
Aspasia Tsezou,
13
Joyce an Meu s,
14
Tonia Vincen ,
15
Ru h Wi oek,
16
Rik Lo ies,
17
On behal o he EULAR S udy g oup in OA (h p://
www.eula .o g/in es iga i e_ heuma ology_s udy_g oups.c m)
To ci e: an de K aan PM,
Be enbaum F, Blanco FJ,
e al. T ansla ion o clinical
p oblems in os eoa h i is
in o pa hophysiological
esea ch goals. RMD Open
2016;2:e000224.
doi:10.1136/ mdopen-2015-
000224
▸P epublica ion his o y o
his pape is a ailable online.
To iew hese iles please
isi he jou nal online
(h p://dx.doi.o g/10.1136/
mdopen-2015-000224).
Recei ed 8 Decembe 2015
Re ised 29 Feb ua y 2016
Accep ed 7 Ma ch 2016
Fo numbe ed a ilia ions see
end o a icle.
Co espondence o
D Pe e M an de K aan;
pe e . ande k aan@
adboudumc.nl
ABSTRACT
Os eoa h i is (OA) accoun s o mo e disabili y among
he elde ly han any o he disease and is associa ed
wi h an inc eased mo ali y a e. The p e alence in
Eu ope will ise in he u u e since his con inen has a
s ongly ageing popula ion and an obesi y epidemic;
obesi y and age bo h being majo isk ac o s o OA.
No adequa e he apeu ic op ions, besides join
eplacemen , a e a ailable, al hough hey a e g ea ly
needed and should be acqui ed by adequa e esea ch
in es men s. Howe e , he pe spec i e on OA om a
esea che ’s poin o iew is no always aligned wi h
he pe spec i e o a pa ien wi h OA. Resea che s base
hei iews on OA mainly on abno mali ies in s uc u e
and unc ion while pa ien s conside OA as a collec ion
o symp oms. In his iewpoin pape , we discuss he
possibili y o ansla ing he mos impo an clinical
p oblems in o pa hophysiological esea ch goals o
acili a e he ansla ion om bench o bedside and ice
e sa. This iewpoin is he ou come o a dialogue
wi hin he ‘Eu opean League Agains Rheuma ism
s udy g oup on OA’and People wi h A h i is/
Rheuma ism ac oss Eu ope (PARE) ep esen a i es.
OSTEOARTHRITIS (OA) IS A HUGE AND EVER
INCREASING PROBLEM
OA is he mos p e alen join disease and
accoun s o mo e disabili y among he
elde ly han any o he disease. I is es ima ed
ha OA a ec s abou 40 million people in
Eu ope.
12
OA can a ec each and e e y
join bu is mos common in he knee, hip,
spine and hand. Clinically, i is cha ac e ised
by join pain, limi a ion o mo emen , en-
de ness, s i ness, c epi us and a ious
deg ees o inflamma ion. OA is conside ed a
disease o he whole join o gan; s uc u al
changes include ca ilage fib illa ion,
fissu es, ull hickness loss o a icula ca il-
age, os eophy e o ma ion, changes in he
subchond al bone pla e, syno i is and fib osis
in syno ium o capsule.
To p o ide exac numbe s on he inci-
dence and p e alence o disease is a di ficul
ask. A majo cause o his is he ac ha
adiog aphic changes a e no always asso-
cia ed wi h join pain and ice e sa.
Mo eo e , OA is gene ally a slow p og essi e
disease. Epidemiological s udies a e di ficul
o compa e due o di e ences in s udy popu-
la ion and disease c i e ia. OA is ela i ely
in equen in people unde he age o
40 yea s bu defini ely inc eases wi h age.
Unde he age o 45 yea s, women a e less
a ec ed han males, bu his gende di e -
ence e e ses abo e 45 yea s. Eu ope has an
inc easingly ageing popula ion as well as an
obesi y epidemic; old age and obesi y a e
bo h majo isk ac o s o OA. Since cu -
en ly no he apeu ic op ions o he han
pain con ol and join eplacemen a e a ail-
able, he bu den o OA will con inue o ise
in he coming decades.
ABSENCE OF EFFECTIVE PHARMACOLOGICAL
TREATMENT
Analgaesics, anging om pa ace amol and
opia es o non-s e oidal an i-inflamma o y
d ugs (NSAIDs), and in a-a icula hyalu o-
nan, a e p esc ibed o ea ing pain bu
hei e ec is o en small (mean e ec -size
om 0.15 o 0.30) and in many pa ien s no
su ficien . Os eoa h i ic join s ha show
signs o inflamma ion a e o en ea ed wi h
in a-a icula co icos e oid. Ano he e y
impo an oppo uni y in OA managemen is
an de K aan PM, e al.RMD Open 2016;2:e000224. doi:10.1136/ mdopen-2015-000224 1
Os eoa h i is
change in li es yle, mainly by inc easing physical ac i i y
and imp o ing physical condi ion, o example, by
weigh loss. T ials a e ongoing wi h newe ea men s o
join pain ha a e p omising bu some imes wi h limi a-
ions due o unexpec ed d awbacks, o ins ance, unex-
pec ed apid disease p og ession in some pa ien s
ea ed wi h an an i ne e g ow h ac o s a egy.
3
T ea men o s uc u al disease p og ession in OA
join s is s ill a big challenge. Nu aceu icals, symp oma ic
slow ac ing d ugs o OA (SYSADOAs) and iscosupple-
men a ion a e p esc ibed wi h his aim in mind,
al hough he e is li le e idence o ully suppo his
claim. S udies wi h s on ium anela e show e ec s on
join space wid h, bu he clinical ele ance o he
epo ed small di e ence and he po en ial ca dio ascu-
la side e ec s ha e jus ified hal ing i s u he de elop-
men o pa ien s wi h OA.
4
Ul ima ely, join
eplacemen is he op ion o pa ien s wi h se e e symp-
oms and end-s age OA. Join eplacemen is a apidly
inc easing p ocedu e and o e 90% o join s a e
eplaced due o OA. Howe e , his is a cos ly p ocedu e
and is, especially in ela i ely young people, no a pe -
manen solu ion. Mo eo e , a ound 20% o he pa ien s
con inue o expe ience some o m o join pain e en
a e he p ocedu e has been success ully pe o med.
Thus, he unme needs in pa ien s wi h OA a e high
and he de elopmen o OA ea men s ha can bo h
p e en o ea s uc u al b eak down and imp o e
symp oms is inc easingly needed. Pe sonalised ea -
men , wi h a pa ien -specific s a egy, equi es bioma -
ke s ha s a i y pa ien s based on OA sub ype and
specific pa hophysiological p ocesses in ol ed, also
aking in o accoun ha hese p ocesses e ol e in a pe -
sonal manne du ing he p og ession o disease.
PATIENT AND RESEARCHER PERSPECTIVE ON OA
As is adequa ely exemplified by he pape o K aus e al,
he pe spec i e on OA om a esea che ’s poin o iew
is qui e di e en om he pe spec i e o a pa ien wi h
OA.
5
While he main ocus o he esea che is on
genes, p o eins and cells, signalling, and me abolic pa h-
ways and s uc u al aspec s, he ocus o he pa ien is on
pain, unc ional limi a ions, aes he ic damage due o
bony p oli e a ions and loss o daily and social ac i i ies.
A esea che iews OA as a ‘disease’based on i s abno -
mali ies in s uc u e and unc ion o igina ing om bio-
logical o (bio)chemical e idence while a pa ien
conside s OA as an illness, ‘ he human esponse o
disease’.
6
S a ing om basic pa hophysiological esea ch ques-
ions, esea che s ha e aken majo s eps in unde s and-
ing OA. We ha e come om he opinion on OA as a
simple wea and ea p ocess o a icula ca ilage o a
concep o OA as an o gan disease in complex in e -
ac ion wi h he human body as a whole. Ou unde -
s anding is inc easing eno mously and only some
gene al insigh s can be men ioned he e. Gene ic s udies
ha e shown ha specific gene a ian s (Smad3, Dio2
and GDF5, e c) a e associa ed wi h OA p e alence and
o se e i y.
78
The ole o ageing and cell senescence has
been implica ed in OA.
9
Fu he mo e, i has been
shown ha changes in chond ocy e beha iou , such as
inc eased p oduc ion o p o eoly ic enzymes, and e en
mos likely changes in chond ocy e di e en ia ion, play
a c ucial ole in deg ada ion o he a icula ca ilage
ma ix.
10 11
These changes in chond ocy e beha iou
a e go e ned by changes in ac i a ed signalling pa hways
and changed esponses o aged and senescen chond o-
cy es o hese s imuli.
12 13
Changes in he subchond al
bone can p edic subsequen symp oms o s uc u al
p og ession, and, ecen ly, i has been shown ha no
only local join inflamma ion bu also low-g ade sys emic
inflamma ion could con ibu e o he OA disease
p ocess.
14–16
To gain a u he and mo e obus unde s anding o
p ocesses ha occu in OA, i is impo an o ake in o
accoun in e ac ions be ween gene exp ession, epigen-
e ic egula ion and en i onmen in clinically well-
defined pa ien s.
RECOGNITION OF DIFFERENT OA PHENOTYPES
OA has been his o ically classified based on join loca-
ion bu no on he unde lying pa hophysiological
p ocess.
17
I becomes mo e and mo e clea ha OA,
e en in a specific join , is be e classified acco ding o
specific ea u es ha a e p esumably a esul o specific
unde lying disease p ocesses.
18
End-s age OA in a pa -
icula join in di e en pa ien s can be iewed as he
final common ou come o a a ie y o pa hophysiological
p ocesses ha di e , o ha e di e ed, be ween hese
pa ien s. Classifica ion, no based on loca ion bu on he
unde lying disease p ocess, will be a aluable ins umen
no only o u he elucida e OA pa hophysiology and
also o op imise clinical ials, in pa icula pa ien
selec ion.
No only migh be e classifica ion o pa ien s by OA
pheno ype be a majo ad ance, bu imp o ed me hods
o ea ly de ec ion o OA a e o c ucial impo ance as
well. As ea ly OA has an ex ended subclinical disease
phase ea ly changes in an OA-a ec ed join emain
unde he ada . As a consequence, in e en ion is
in a iably delayed un il se e e, and maybe e en i e e s-
ible, s uc u al damage has occu ed. To imp o e
disease-modi ying in e en ions, me hods and s a egies
ha e o be de eloped ha can de ec ea ly, meaning ul
and p edic i e OA-associa ed changes in he join and
ha can ack he esul o an e en ual in e en ion.
THE OSTEOARTHRITIS RESEARCH SOCIETY
INTERNATIONAL DEFINITION OF OA
OA is a he e ogeneous disease and in his iewpoin and
p eceding discussions wi hin he Eu opean League
Agains Rheuma ism (EULAR) s udy g oup, we use he
d a defini ion o he Os eoa h i is Resea ch Socie y
2 an de K aan PM, e al.RMD Open 2016;2:e000224. doi:10.1136/ mdopen-2015-000224
RMD Open
In e na ional
5
as a wo king defini ion. The au ho s o his
defini ion and he OA s udy g oup a e ully awa e ha his
defini ion will be modified acco ding o he u he eluci-
da ion o OA p ocess(es) and disease pheno ypes.
Os eoa h i is is a diso de in ol ing mo able join s cha ac-
e ised by cell s ess and ex acellula ma ix deg ada ion
ini ia ed by mic o- and mac o-inju y ha ac i a es maladap-
i e epai esponses including p o-inflamma o y pa hways
o inna e immuni y. The disease mani es s fi s as a molecu-
la de angemen (abno mal join issue me abolism) ol-
lowed by ana omic, and/o physiologic de angemen s
(cha ac e ised by ca ilage deg ada ion, bone emodelling,
os eophy e o ma ion, join inflamma ion and loss o
no mal join unc ion) ha can culmina e in illness.
5
TRANSLATION OF CLINICAL PROBLEMS INTO
PATHOPHYSIOLOGICAL RESEARCH GOALS
A ecen EULAR ini ia i e iden ified ou esea ch p io -
i y a eas: epidemiology, imaging and bioma ke s, pa ho-
genesis and he apy,
2
which se ed as he basis o he
fi s call o p ojec s issued by Founda ion o esea ch
in heuma ology. In his iewpoin pape , classifica ion
o ele an pa hophysiological esea ch goals is based on
hese p io i y a eas (box 1). The esea ch goals ha
we e iden ified wi hin he s udy g oup a e no p io i-
ised, as in ou opinion he esea ch goals ha e o be
eached in pa allel. Fo example, iden ifica ion and al-
ida ion o a ge s o he apy a e no achie able wi hou
be e insigh in o he OA pa hogenesis and imp o e-
men o ea ly de ec ion and disease s a ifica ion.
Mo eo e , ea ly de ec ion and disease s a ifica ion
canno be accomplished wi hou us wo hy imaging
and unc ional bioma ke s.
EPIDEMIOLOGY
Epidemiology is, in a s ic sense, no he majo me hod-
ology o pa hophysiological esea ch. Howe e , due o
he in eg a ion o epidemiology and gene ics (gene ic
epidemiology) and he ecogni ion o di e en OA phe-
no ypes, esea ch in his a ea is o high alue in b inging
oge he clinical p oblems, and pa hophysiological
esea ch goals and unde s anding. Iden ifica ion o
gene ic a ian s in pa ien s wi h OA, bo h genomic and
mi ochond ial, will iden i y pheno ype-specific pa ho-
genic pa hways ha will be undamen o pheno ype-
specific OA he apies. Mo eo e , elucida ion o he ole
o epigene ic changes in specific OA pheno ypes has he
po en ial o p o ide a oadmap o a ge ed and pa ien
g oup-specific he apy.
IMAGING AND BIOMARKERS
Iden ifica ion and alida ion o imaging echnologies
and bioma ke s is o u mos impo ance o ea ly disease
de ec ion, o classifica ion o OA pheno ypes, disease
ac i i y and p ognosis and o e alua ion o he apy
esponse. Imaging and bioma ke s should bo h o m a
eliable eflec ion o unde lying disease p ocesses.
Ideally, a bioma ke i sel should be an in eg al pa o
he ac ual disease p ocess in OA and a sign o a specific
OA pheno ype. Iden ifica ion o OA pheno ypes and he
esponse o s a ified in e en ions will mos likely
depend on he combina ion o join imaging and bio-
ma ke quan ifica ion.
PATHOGENESIS
The pa hogenesis o OA is a om unde s ood and will
be di e en in he a ious OA pheno ypes. I has
become mo e and mo e clea ha he whole join is
a ec ed in OA and ha he di e en issues o he join
communica e and influence each o he ’s eac ions. To
eally comp ehend he OA disease p ocess, he commu-
nica ion be ween he a ious join issues should be
unde s ood in a pheno ype-specific con ex and be
s udied in he e y ea ly s ages o OA de elopmen .
In many pa ien g oups, a causal ela ionship be ween
mechanical changes in he join and OA is p obable.
Box 1 Majo pa hophysiological esea ch goals
Epidemiology (gene ic epidemiology)
▸To iden i y and elucida e he ole o gene ic a ian s in
Os eoa h i is (OA) pheno ypes;
▸To iden i y and elucida e he ole o epigene ics in OA
pheno ypes;
▸To iden i y and elucida e he ole o mi ochond ial gene ic a -
ian s in OA pheno ypes.
Imaging and bioma ke s
▸Iden i y ma ke s o ea ly OA;
▸Iden i y ma ke s o OA pheno ypes;
▸Iden i y ma ke s o disease ac i i y;
▸Iden i y ma ke s o disease p og ession;
▸Iden i y p edic i e ma ke s o he apeu ic esponse;
▸Iden i y ma ke s o e alua e he he apeu ic esponse.
Pa hogenesis
▸To unde s and issue communica ion in OA (be ween ca ilage,
subchond al bone, syno ium, essels, adipose issue);
▸To unde s and non-ca ilage pa hology in OA;
▸To unde s and he ole o chond ocy e di e en ia ion in OA;
▸To unde s and he ole o join auma and epai in OA;
▸To unde s and he mechanism o mechanical join inju y and
he ansla ion o in lamma ion and epai ;
▸To unde s and he ela ionship be ween syno i is and adio-
g aphic p og ession;
▸To unde s and he ea lies s ages o OA;
▸To unde s and he di e ence be ween OA pheno ypes;
▸To unde s and he o igins o pain;
▸To unde s and he ela ionship be ween pain and s uc u e;
▸To unde s and he ela ionship be ween syno i is and pain;
▸To unde s and he ela ionship be ween ageing and OA;
▸To unde s and he ela ionship be ween gende and OA;
▸To unde s and he ole o sys emic ac o s in OA;
▸To de ine he mechanisms by which como bidi ies in luence
he OA p ocess ( a and glucose me abolism).
The apy
▸To iden i y and alida e a ge s o he apy (symp oms and
s uc u e).
an de K aan PM, e al.RMD Open 2016;2:e000224. doi:10.1136/ mdopen-2015-000224 3
Os eoa h i is
Howe e , he exac ole o mechanical (o e ) load in
no mal join physiology and OA is no ye known.
Mo eo e , he ole o in insic join epai o ailing
in insic join epai in OA is s ill obscu e. The ela ion-
ship be ween s uc u al join changes and symp oms,
among o he s, pain, is s ill an enigma. I is no clea
which issues a e he majo sou ce o join pain, pe haps
bone o syno ium o whe he he e is a ole o p o-
duc s eleased by damaged ca ilage in join pain.
The ela ionship be ween una oidable ac o s, such as
ageing and gende , and OA pheno ype-specific pa ho-
physiology has s ill o be elucida ed. Fu he mo e, how
sys emic ac o s and como bidi ies, such as obesi y and
diabe es, a ec he de elopmen and p og ession o OA,
needs u he insigh .
THERAPY
The majo goal o pa hophysiological esea ch in OA is
he iden ifica ion and alida ion o a ge s o he apy.
These a ge s can ei he be s uc u al a ge s o symp-
oma ic a ge s, mainly pain. Ideally, hese a ge s should
be combined as a single agen , albei wi hou igno ing
he ac ha di e en OA pheno ypes may equi e di e -
en a ge ed he apies.
This iewpoin a icle a emp s o b idge he gap
be ween majo clinical p oblems o OA wi h pa ho-
physiological esea ch goals o he OA esea ch commu-
ni y, o acili a e he ansla ion om bed o bench and
ice e sa. I is an icipa ed ha his a icle can be a
guide o OA esea che s, in e na ional o ganisa ions
and unding agencies o acili a e hei discussions on
di ec ions o esea ch and unding.
Au ho a ilia ions
1
Depa men o Expe imen al Rheuma ology, Radboud Uni e si y Medical
Cen e , Nijmegen, The Ne he lands
2
Facul y o Medicine Pie e and Ma ie Cu ie Pa is VI, INSERM UMR-S938,
Sain -An oine Hospi al, Pa is, F ance
3
Rheuma ology Di ision, Ins i u o de In es igación Biomédica de A Co uña
(INIBIC), Complexo Hospi ala io Uni e si a io de A Co uña (CHUAC), Se gas,
Uni e sidade da Co uña (UDC), A Co uña, España
4
Musculoskele al Resea ch P og amme, Ins i u e o Medical Sciences,
Fo es e hill, Abe deen, UK
5
Depa men o Rheuma ology and Clinical Immunology, Uni e si y Medical
Cen e U ech , U ech , The Ne he lands
6
Depa men o Clinical Medicine, The Sec ion o Rheuma ology, Aa hus,
Denma k
7
EULAR PARE Pa ien Resea ch Pa ne and Keele Uni e si y, Newcas le-
unde -Lyme, UK
8
Depa men o Rheuma ology, Leiden Uni e si y Medical Cen e , Leiden,
The Ne he lands
9
Musculoskele al Resea ch G oup, Newcas le Uni e si y, Ins i u e o Cellula
Medicine, The Medical School, Newcas le upon Tyne, UK
10
Depa men o Molecula Epidemiology, LUMC, Leiden, The Ne he lands
11
The Immunopha macology Resea ch G oup, Uni e si y o Tampe e School
o Medicine and Tampe e Uni e si y Hospi al, Tampe e, Finland
12
EULAR PARE Pa ien Resea ch Pa ne , Nicosia, Cyp us
13
Depa men o Biology, Uni e si y o Thessaly, School o Medicine, La issa,
G eece
14
Gene ic Labo a o y, Depa men o In e nal Medicine, E asmus MC,
Ro e dam, The Ne he lands
15
ARUK Cen e o OA Pa hogenesis, Uni e si y o Ox o d, Ox o d, UK
16
Depa men o Rheuma ology, Uni e si y Hospi al Ghen , Ghen , Belgium
17
Labo a o y o Tissue Homeos asis and Disease, Depa men o De elopmen
and Regene a ion, KU Leu en and Di ision o Rheuma ology, Skele al Biology
and Enginee ing Resea ch Cen e , Uni e si y Hospi als Leu en, Leu en,
Belgium
Compe ing in e es s None decla ed.
P o enance and pee e iew No commissioned; ex e nally pee e iewed.
Da a sha ing s a emen No addi ional da a a e a ailable.
Open Access This is an Open Access a icle dis ibu ed in acco dance wi h
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comme cially, and license hei de i a i e wo ks on di e en e ms, p o ided
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