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ARTHRITIS & RHEUMATISMVol. 58, No. 6, June 2008, pp 1716–1726DOI 10.1002/art.23462© 2008, American College of Rheumatology
Relationship of Meniscal Damage, Meniscal Extrusion,Malalignment, and Joint Laxity to Subsequent Cartilage Loss in
Osteoarthritic Knees
Leena Sharma,1 Felix Eckstein,2 Jing Song,1 Ali Guermazi,3 Pottumarthi Prasad,4
Dipali Kapoor,1 September Cahue,1 Meredith Marshall,1 Martin Hudelmaier,2
and Dorothy Dunlop1
Objective. Progressive knee osteoarthritis (OA) isbelieved to result from local factors acting in a systemicenvironment. Previous studies have not examined thesefactors concomitantly or compared quantitative andqualitative cartilage loss outcomes. The aim of thisstudy was to test whether meniscal damage, meniscalextrusion, malalignment, and laxity each predicted tib-iofemoral cartilage loss after controlling for the otherfactors.
Methods. Laxity and alignment were measured atbaseline in individuals with knee OA. Magnetic reso-nance imaging included spin-echo coronal and sagittalimaging for meniscal scoring and axial and coronalspoiled gradient echo sequences with water excitationfor cartilage quantification. Tibial and weight-bearingfemoral condylar subchondral bone area and cartilagesurface were segmented. Cartilage volume, denudedbone area, and cartilage thickness were quantified ineach plate, with progression defined as cartilage loss >2
times the coefficient of variation for each plate. Quali-tative outcome was assessed as worsening of the carti-lage score. Logistic regression analysis with generalizedestimating equations yielded odds ratios for each factor,adjusting for age, sex, body mass index, and the otherfactors.
Results. We studied 251 knees in 153 persons.After full adjustment, medial meniscal damage pre-dicted medial tibial cartilage volume loss and tibial andfemoral denuded bone increase, while varus malalign-ment predicted medial tibial cartilage volume and thick-ness loss and tibial and femoral denuded bone increase.Lateral meniscal damage predicted every lateral out-come. Laxity and meniscal extrusion had inconsistenteffects. After full adjustment, no factor except mediallaxity predicted qualitative outcome.
Conclusion. Using quantitative cartilage loss as-sessment, local factors that independently predictedtibial and femoral loss included medial meniscal dam-age and varus malalignment (medially) and lateralmeniscal damage (laterally). A measurement of quanti-tative outcome was more sensitive at revealing theserelationships than a qualitative approach.
Progressive knee osteoarthritis (OA) is believedto result from local mechanical factors acting in asystemic environment (1,2), although there is as yet littledirect evidence of this from magnetic resonance imaging(MRI)–based natural history studies. Healthy menisci,more neutral alignment, and joint stability all protect thearticular cartilage from concentrations of stress (3–5).When these factors are altered or impaired, stress is notwell distributed, and it increases focally, potentiallyleading to articular cartilage damage. Meniscal damage,meniscal extrusion, varus–valgus malalignment, andmedial–lateral laxity are local factors that may be
Supported by the NIH (National Institute of Arthritis andMusculoskeletal and Skin Diseases grants R01-AR-48216, R01-AR-48748, and P60-AR-48098, and National Center for Research Re-sources grant M01-RR-00048).
1Leena Sharma, MD, Jing Song, MS, Dipali Kapoor, MD,MPH, September Cahue, MPH, Meredith Marshall, BA, DorothyDunlop, PhD: Feinberg School of Medicine, Northwestern University,Chicago, Illinois; 2Felix Eckstein, MD, Martin Hudelmaier, MD:Paracelsus Medical University, Salzburg, Austria, and Chondromet-rics, Ainring, Germany; 3Ali Guermazi, MD: Boston University Med-ical Center, Boston, Massachusetts; 4Pottumarthi Prasad, PhD: Evan-ston Northwestern Healthcare, Evanston, Illinois.
Dr. Eckstein has received consulting fees, speaking fees,and/or honoraria (less than $10,000) from Wyeth and AstraZeneca,and (more than $10,000) from Pfizer, Virtual Scopics, and Glaxo-SmithKline.
Address correspondence and reprint requests to LeenaSharma, MD, Division of Rheumatology, Feinberg School of Medi-cine, Northwestern University, 240 East Huron, M300, Chicago, IL60611. E-mail: [email protected].
Submitted for publication October 4, 2007; accepted in re-vised form February 15, 2008.
1716
present in primary knee OA (6–15). Their effect on loaddistribution and attenuation are especially important inthe damaged and more vulnerable OA knee.
Natural history studies of knee OA ideally shouldconsider meniscal damage, malalignment, and laxitytogether to determine if any effect on cartilage losspersists after adjusting for the other local factors, andthereby address the strong possibility of confounding. Inthe very few progression studies that have evaluatedthese factors, either meniscal damage (16–18) or align-ment (12) has been considered, but not both together,and no studies have included laxity.
The emphasis on the radiographic joint space inthe literature on knee OA progression reflects the intentto capture cartilage loss. However, radiographic out-comes are inherently limited in their ability to detect theimpact of certain local factors. Without contrast, radi-ography cannot distinguish articular cartilage and me-niscal tissue; since the meniscus contributes to theradiographic joint space, joint space change cannot beused to study the effect of meniscal damage on OAprogression. Medial laxity (medial joint line opening)and lateral laxity (lateral joint line opening) eachstresses cartilage in the compartment opposite the sideof opening. A separate assessment of medial laxity effectversus lateral laxity effect requires an outcome toolcapable of detecting progression equally well in themedial and lateral tibiofemoral compartment of thesame knee. Knee radiography can only reveal progres-sion in the tibiofemoral compartment that is predomi-nantly involved; reciprocal widening of the other com-partment makes it impossible to gauge progressionthere. MRI approaches, in contrast, reveal outcomeequally well in each tibiofemoral compartment andsurface within the same knee.
Notably, almost all published knee OA progres-sion studies with MRI outcome measures have usedqualitative cartilage assessment to define cartilage loss.It is unclear at present whether a more quantitativeassessment of cartilage loss is more sensitive than thequalitative approach previously used. To date, no studyof OA risk factors has included both outcomes.
Using MRI-based quantitative measures of carti-lage loss, we tested 2 hypotheses. First, the local factorsof medial meniscal damage, medial meniscal extrusion,varus malalignment, and lateral laxity are each associ-ated with a reduction in cartilage volume and thicknessand an increase in denuded bone area in the medialtibial and medial femoral surfaces after adjusting forage, sex, body mass index (BMI), and the other localfactors. Second, the local factors of lateral meniscaldamage, lateral meniscal extrusion, valgus malalign-
ment, and medial laxity are each associated with areduction in cartilage volume and thickness and anincrease in denuded bone area on the lateral tibial andlateral femoral surfaces after adjusting for age, sex, BMI,and the other local factors. We then tested both hypoth-eses by applying a qualitative MRI outcome measure,i.e., worsening of the cartilage integrity score.
PATIENTS AND METHODS
Sample. Study participants were members of a cohortparticipating in a natural history study of knee OA, the MAK-2(Mechanical Factors in Arthritis of the Knee, second cycle).MAK-2 participants were recruited from community sources,e.g., through advertising in periodicals targeting elderly per-sons, neighborhood organizations, letters to members of theregistry of the Beuhler Center on Aging at NorthwesternUniversity, and via medical center referrals.
Inclusion criteria were the definite presence of tib-iofemoral osteophytes (grade �2 on the Kellgren/Lawrence[K/L] radiographic scale [19]) in 1 or both knees, and a Likertcategory of at least “a little difficulty” for �2 items on theWestern Ontario and McMaster Universities OsteoarthritisIndex physical function scale (20). Exclusion criteria werehaving received a corticosteroid injection within the previous 3months; a history of avascular necrosis, rheumatoid or otherinflammatory arthritis, periarticular fracture, Paget’s disease,villonodular synovitis, joint infection, ochronosis, neuropathicarthropathy, acromegaly, hemochromatosis, gout, pseudogout,osteopetrosis, or meniscectomy; or meeting exclusion criteriafor MRI, such as the presence of a pacemaker, artificial heartvalve, aneurysm clip or shunt, metallic stent, implanted device(e.g., pain control/nerve stimulator, defibrillator, insulin/drugpump, or ear implant), or any metallic fragment in an eye.
Approval was obtained from the Office for the Protec-tion of Research Subjects and the Institutional Review Boardsof Northwestern University and Evanston NorthwesternHealthcare. Written consent was obtained from all partici-pants.
Meniscal damage and meniscal extrusion. Images ofboth knees of all participants were obtained using a commer-cial knee coil and 1 of 2 whole-body scanners, a 1.5T Symphony(Siemens, Erlangen, Germany) or a 3T Genesis Signa (GEHealthcare, Waukesha, WI). The protocol included coronalT1-weighted spin-echo (SE), sagittal fat-suppressed dual-echoturbo SE, and axial and coronal T1-weighted, fat-suppressed3-dimensional fast low-angle shot sequences.
Meniscal damage and extrusion were graded in eachknee using the Whole-Organ MRI Score (WORMS) (21). Theanterior horn, posterior horn, and body of the medial andlateral meniscus were each graded on a scale of 0–4, where 0 �intact, 1 � minor radial or parrot-beak tear, 2 � nondisplacedtear, 3 � displaced tear or partial maceration, and 4 �complete maceration and destruction. The highest grade foreach meniscus was used in the analysis. Extrusion of the bodysegments of the medial and lateral menisci was graded (0 ifnone, 1 if less than half of the meniscus, or 2 if more than half)using coronal images at the level of the medial collateralligament and lateral collateral ligament, respectively. MRIswere read by 1 of 3 experienced readers (AG). The interob-
RELATIONSHIP BETWEEN LOCAL FACTORS AND CARTILAGE LOSS IN OA KNEES 1717
server reliability of the readers applying this scoring system hasbeen published previously (21); the intraclass correlation co-efficient (ICC) was 0.94 for medial meniscal damage and 0.81for lateral meniscal damage. Readers were blinded with regardto all outcome data.
Varus–valgus alignment. To assess the hip–knee–ankle angle, a single anteroposterior radiograph of both lowerextremities was obtained using a 51 � 14–inch graduated gridcassette (Reina Imaging, Crystal Lake, IL) to include the fulllimb of tall participants. By filtering the x-ray beam in agraduated manner, this cassette accounted for the unique softtissue characteristics of the hip and ankle. The tibial tubercle,a site adjacent to the knee that was not distorted by OA, wasused as the positioning landmark. Participants stood withoutfootwear, with the tibial tubercles facing forward. The x-raybeam was centered at the knee at a distance of 2.4 meters.Settings of 100–300 mA/second and 80–90 kV were used,depending on limb size and tissue characteristics. All radio-graphs were obtained in the same unit by 2 trained technicians.
Alignment, i.e., the hip–knee–ankle angle, was mea-sured as the angle formed by the intersection of the lineconnecting the centers of the femoral head and the intercon-dylar notch with the line connecting the centers of the surfaceof the ankle talus and the tips of the tibial spines. Our readingreliability, in image sets including both varus- and valgus-aligned knees, was excellent (ICC 0.98–0.99) (12). Alignmentwas analyzed as a continuous variable.
Medial–lateral laxity. Medial and lateral laxity weremeasured using a previously described device (15), consistingof a bench and an attached arc-shaped, low-friction track (30-cm in radius measured from the center of the knee and runningmedially and laterally) and providing thigh and ankle immo-bilization and a stable knee flexion angle. The distal shank(30 cm from the knee) was immobilized in a sled that traveledwithin the track. A hand-held dynamometer fitted into eitherside of the sled was used to apply a fixed varus and valgus load.Laxity was measured in degrees as the angular deviation afterfixed load in each direction. All laxity measurements wereperformed by the same examiner and assistant (DK and MM).Our reliability with this device testing persons with knee OAand varying body habitus was very good (within-session ICC0.85–0.96, between-session ICC 0.84–0.90) (15). Medial andlateral laxity were separately analyzed as continuous variables.
Quantitative measurement of cartilage loss. Articularcartilage was quantified at baseline and 2 years later. Forquantitative measurements, coronal spoiled gradient echosequences with water excitation were acquired, with a slicethickness of 1.5 mm and an in-plane resolution of 0.31 mm(field of view 16 cm, 512 � 512–pixel matrix, number ofexcitations 1). The repetition time, echo time, and flip angle,respectively, were 18.6 msec/9.3 msec/15° on the 1.5T scanner,and 12.2 msec/5.8 msec/9° on the 3T scanner. The total area ofsubchondral bone and the area of the cartilage surface weresegmented for the medial tibial and lateral tibial surfaces, andin the weight-bearing portion of the medial and lateral femoralcondyle using proprietary software (Chondrometrics, Ainring,Germany) (22–24). Cartilage volume, percentage of subchon-dral bone covered with cartilage, denuded subchondral bonearea, and the average thickness of cartilage, including areas ofdenuded subchondral bone as 0 mm, were quantified. Baselineand 2-year scans were read together, with the reader blindedwith regard to the order of acquisition.
Using the methodology applied here (image acquisi-tion at 1.5T, double-oblique coronal acquisitions, 1.5-mm slicethickness, image analysis by experienced readers, and Chon-drometrics software), the precision errors (coefficient of vari-ation [CV] for 2 acquisitions with repositioning) for cartilagevolume, cartilage thickness, and denuded bone area, respec-tively, were as follows: for the medial tibia 2.6%/2.1%/1.1%,for the medial weightbearing femur 3.2%/3.0%/1.4%, forthe lateral tibia 2.1%/2.1%/1.2%, and for the lateral weight-bearing femur 3.7%/3.0%/1.7% (23). These reliability mea-sures are consistent with those reported in the literature andrecently summarized (25); in other studies, interscan (intra-observer) precision errors for cartilage volume have rangedfrom 2.1% in the medial tibia to 6.7% in the lateral tibia.
Qualitative assessment of cartilage loss. Specifically, 3regions (anterior, central, and posterior) of the medial andlateral femoral condyles and tibial plateaus were each scoredseparately for cartilage morphology following a detailed read-ing protocol, including visual illustrations of each grade (21).In each region, cartilage morphology was graded on a scale of0–6, where 0 � normal thickness and signal, 1 � normalthickness but increased signal on T2-weighted images, 2 �solitary focal partial- or full-thickness defect �1 mm in width,3 � multiple areas of partial-thickness loss or a grade 2 lesion�1 mm, with areas of preserved thickness, 4 � diffuse, �75%,partial-thickness loss, 5 � multiple areas of full-thicknessloss, or a full-thickness lesion �1 mm, with areas of partial-thickness loss, and 6 � diffuse, �75%, full-thickness loss. TheICC for these readers was 0.98 for cartilage integrity in themedial regions and 0.99 in the lateral regions (21).
Acquisition and reading of radiographs. All partici-pants had bilateral, anteroposterior, weight-bearing knee ra-diographs performed at baseline in the semiflexed positionwith fluoroscopic confirmation of superimposition of the an-terior and posterior tibial plateau lines and centering of thetibial spines within the femoral notch (for full protocol, see ref.26). To describe the knees, the K/L global radiographic scorewas used (0 � normal, 1 � possible osteophytes, 2 � definiteosteophytes without definite joint space narrowing, 3 � defi-nite joint space narrowing, some sclerosis, and possible attri-tion, and 4 � large osteophytes, marked narrowing, severesclerosis, and definite attrition). Reliability of radiographicgrading for the single reader was high (� � 0.85–0.86).
Statistical analysis. Two-year progression was definedas cartilage loss �2 times the CV (previously determined foreach measure of cartilage loss in each cartilage plate; see ref.23). This definition of progression yielded the following cutpoints: in the medial tibia, cartilage volume loss 5.2%, cartilagethickness loss 4.2%, denuded bone area 2.2%; in the medialweight-bearing femur, cartilage volume loss 6.4%, cartilagethickness loss 6.0%, denuded bone area 2.8%; in the lateraltibia, cartilage volume loss 4.2%, cartilage thickness loss 4.2%,denuded bone area 2.4%; and in the lateral weight-bearingfemur, cartilage volume loss 7.4%, cartilage thickness loss6.0%, denuded bone area 3.4%. The unit of analysis was theknee. Generalized estimating equations were used to estimatelogistic regression models that validly included potentiallycorrelated observations between knees in the same individual.Separate modeling was performed for each tibiofemoral carti-lage surface. The effects of baseline meniscal damage, menis-cal extrusion, medial–lateral laxity, and varus–valgus malalign-ment on cartilage loss measurements were expressed as odds
1718 SHARMA ET AL
Tab
le1.
Bas
elin
ean
d2-
year
chan
gein
cart
ilage
mea
sure
men
ts*
Med
ialc
ompa
rtm
ent
Lat
eral
com
part
men
t
Bas
elin
eB
asel
ine
to2-
year
chan
geB
asel
ine
Bas
elin
eto
2-ye
arch
ange
Mea
n�
SDM
edia
n(I
QR
)M
ean
�SD
Med
ian
(IQ
R)
Mea
n�
SDM
edia
n(I
QR
)M
ean
�SD
Med
ian
(IQ
R)
Tib
ia Car
tilag
evo
lum
e,m
m3
1,94
3.30
�55
1.79
1,87
9(1
,610
,2,2
86)
53.6
3�
160.
3537
(�17
,114
)1,
861
�68
6.83
1,77
3(1
,361
,2,2
81)
41.7
1�
122.
1430
(�21
,108
)C
artil
age
thic
knes
s,m
m1.
64�
0.32
1.68
(1.4
8,1.
83)
0.05
�0.
110.
04(�
0.01
,0.0
9)1.
83�
0.49
1.88
(1.5
4,2.
17)
0.05
�0.
110.
04(�
0.01
,0.0
1)A
rea
ofde
nude
dbo
ne,c
m2
0.41
�1.
160
(0,0
)†0.
23�
0.62
0(0
,0)‡
0.45
�1.
320
(0,0
)†0.
08�
0.49
0(0
,0)‡
Fem
ur(w
eigh
t-be
arin
gpo
rtio
n)C
artil
age
volu
me,
mm
31,
028.
13�
371.
261,
016
(787
,1,2
38)
32.0
6�
91.0
916
(�21
,64)
1,18
4.63
�33
4.74
1,16
1(9
29,1
,429
)22
.13
�93
.67
12(�
40,8
0)C
artil
age
thic
knes
s,m
m1.
62�
0.47
1.66
(1.3
8,1.
96)
0.05
�0.
140.
03(�
0.02
,0.1
)1.
77�
0.35
1.76
(1.5
6,2)
0.03
�0.
120.
02(�
0.05
,0.1
)A
rea
ofde
nude
dbo
ne,c
m2
0.33
�0.
960
(0,0
)†0.
09�
0.31
0(0
,0)‡
0.13
�0.
420
(0,0
)†0.
07�
0.25
0(0
,0)‡
*C
hang
eis
desc
ribe
d/de
fined
asa
decr
ease
for
the
cart
ilage
volu
me
and
thic
knes
san
dan
incr
ease
for
the
area
ofde
nude
dbo
ne.D
ata
are
from
the
righ
tkn
eeof
each
part
icip
ant.
IQR
�in
terq
uart
ilera
nge.
†T
hepr
opor
tion
ofkn
ees
with
node
nude
dbo
neat
base
line
was
79%
for
the
med
ialt
ibia
,82%
for
the
med
ialf
emur
,79%
for
the
late
ralt
ibia
,and
83%
for
the
late
ralf
emur
.‡
The
prop
ortio
nof
knee
sw
ithno
denu
ded
bone
atbo
thba
selin
ean
dth
e2-
year
follo
wup
was
74%
for
the
med
ialt
ibia
,78%
for
the
med
ialf
emur
,77%
for
the
late
ralt
ibia
,and
78%
for
the
late
ralf
emur
.
RELATIONSHIP BETWEEN LOCAL FACTORS AND CARTILAGE LOSS IN OA KNEES 1719
ratios (ORs) with the associated 95% confidence intervals(95% CIs).
All logistic regression models controlled for age, sex,and BMI. Full logistic models for the lateral cartilage surfaceoutcomes additionally controlled for lateral meniscal damage,lateral meniscal extrusion, valgus malalignment severity (con-tinuous variable), and medial laxity (continuous variable). Fulllogistic models for the medial cartilage surface outcomesadditionally controlled for medial meniscal damage, medialmeniscal extrusion, varus malalignment severity, and laterallaxity.
Two-year progression was then examined, based onqualitative cartilage integrity scores. First, the originalWORMS system was used, and then the recently introducedmodification (18). In this modification, the original WORMSvalues of 0 and 1 were collapsed to 0, the original scores of 2and 3 were collapsed to 1, and the original scores of 4, 5, and6 were considered to be 2, 3, and 4, respectively. For both ofthese qualitative approaches, progression was defined as aworsening of the cartilage integrity score in 1 or more regionsof a given compartment from the baseline to the followupevaluation.
RESULTS
Of 165 persons evaluated at baseline, 12 (7%)were lost to followup because of poor health or becausethey had moved away or had undergone bilateral totalknee replacement. We studied 251 knees in 153 personswith knee OA. The mean � SD age of the participantswas 66.4 � 11.0 years and the mean � SD BMI was30.1 � 5.9 kg/m2. The K/L score in most knees was 2(41%) or 3 (33%) at baseline. Mean � SD varus–valgusalignment at baseline was 0.11 � 4.8 degrees in the varusdirection. Baseline medial and lateral meniscal damagescores were 1.29 � 1.59 and 0.77 � 1.46, respectively,and the medial and lateral meniscal extrusion scoreswere 0.52 � 0.74 and 0.25 � 0.57, respectively. Mean �SD medial laxity at baseline was 2.52 � 1.28 degrees andmean lateral laxity was 4.14 � 1.53 degrees. Baselinevalues and values for the 2-year change in cartilagevolume, cartilage thickness, and area of denuded bone atbaseline are described in Table 1. Tables 2 and 3 show
the correlations between local factors at baseline. Al-though some factors were moderately correlated, theirassociation did not introduce harmful multicollinearityinto our multiple regression models based on standardcriteria (27).
As shown in Table 4, in models adjusted for age,sex, and BMI, medial meniscal damage significantlyincreased the likelihood of cartilage volume loss, carti-lage thickness decrease, and denuded bone increase inboth the medial tibial and the medial weight-bearingfemoral cartilage plates. In the fully adjusted models(i.e., adjusted for age, sex, BMI, medial meniscal extru-sion, varus malalignment, and lateral laxity), a signifi-cant relationship between medial meniscal damage andthe following outcomes persisted: medial tibial cartilagevolume loss, medial tibial denuded bone increase, andmedial weight-bearing femoral denuded bone increase.Medial meniscal extrusion was significantly associatedwith every outcome for both plates in the modelsadjusted for age, sex, and BMI, but in none of the fullyadjusted models, although the relationship approachedsignificance for medial weight-bearing femoral cartilagethickness loss and denuded bone increase.
Varus malalignment was significantly associatedwith every outcome for the medial tibial and femoralplates after adjusting for age, sex, and BMI. In the fullyadjusted models, a significant relationship persisted be-tween varus malalignment and each of the followingmedial outcomes: tibial cartilage volume loss, tibialcartilage thickness loss, tibial denuded bone increase,and weight-bearing femoral denuded bone increase. Incontrast, lateral laxity was associated only with medialtibial cartilage volume loss.
In the lateral compartment, lateral meniscal dam-age was significantly associated with every outcome inboth the lateral tibial and the lateral femoral surfaces inthe models adjusted for age, sex, and BMI, and therelationship persisted in all of the fully adjusted models(i.e., adjusted for age, sex, BMI, lateral meniscal extru-
Table 2. Spearman’s correlation coefficients for associations be-tween local medial compartment factors at baseline*
Medialmeniscaldamage
Medialmeniscalextrusion
Varusmalalignment
Laterallaxity
Medial meniscal damage 1.00 0.62 0.49 �0.09Medial meniscal extrusion 0.62 1.00 0.36 �0.07Varus malalignment 0.49 0.36 1.00 �0.27Lateral laxity �0.09 �0.07 �0.27 1.00
* Coefficients were determined using data from the right knee of eachparticipant.
Table 3. Spearman’s correlation coefficients for associations be-tween local lateral compartment factors at baseline*
Lateralmeniscaldamage
Lateralmeniscalextrusion
Valgusmalalignment
Mediallaxity
Lateral meniscal damage 1.00 0.54 0.29 0.13Lateral meniscal extrusion 0.54 1.00 0.28 0.002Valgus malalignment 0.29 0.28 1.00 0.14Medial laxity 0.13 0.002 0.14 1.00
* Coefficients were determined using data from the right knee of eachparticipant.
1720 SHARMA ET AL
Tab
le4.
Rel
atio
nshi
pbe
twee
nlo
calm
echa
nica
lfac
tors
and
quan
titat
ive
cart
ilage
loss
outc
omes
inth
em
edia
ltib
iofe
mor
alca
rtila
gepl
ates
*
Mea
sure
ofca
rtila
gelo
ss,b
asel
ine
to2
year
s(d
epen
dent
vari
able
)
Med
ialt
ibia
Med
ialw
eigh
t-be
arin
gfe
mur
Loc
alm
echa
nica
lfa
ctor
,at
base
line
(ind
epen
dent
vari
able
)
Car
tilag
evo
lum
elo
ss,
OR
(95%
CI)
Car
tilag
eth
ickn
ess
loss
,O
R(9
5%C
I)D
enud
edbo
nein
crea
se,
OR
(95%
CI)
Car
tilag
evo
lum
elo
ss,
OR
(95%
CI)
Car
tilag
eth
ickn
ess
loss
,O
R(9
5%C
I)D
enud
edbo
nein
crea
se,
OR
(95%
CI)
Adj
uste
dfo
rag
e,se
x,an
dB
MI
Adj
uste
dfo
ral
lco
vari
ates
Adj
uste
dfo
rag
e,se
x,an
dB
MI
Adj
uste
dfo
ral
lco
vari
ates
Adj
uste
dfo
rag
e,se
x,an
dB
MI
Adj
uste
dfo
ral
lco
vari
ates
Adj
uste
dfo
rag
e,se
x,an
dB
MI
Adj
uste
dfo
ral
lco
vari
ates
Adj
uste
dfo
rag
e,se
x,an
dB
MI
Adj
uste
dfo
ral
lco
vari
ates
Adj
uste
dfo
rag
e,se
x,an
dB
MI
Adj
uste
dfo
ral
lco
vari
ates
Med
ialm
enis
cal
dam
age†
1.57
(1.2
9,1.
91)
1.29
(1.0
2,1.
64)
1.40
(1.1
6,1.
69)
1.07
(0.8
4,1.
37)
3.44
(2.3
7,5.
01)
2.42
(1.5
6,3.
75)
1.32
(1.0
9,1.
60)
1.10
(0.8
7,1.
38)
1.39
(1.1
6,1.
68)
1.19
(0.9
4,1.
50)
2.42
(1.7
6,3.
32)
1.69
(1.2
5,2.
28)
Med
ialm
enis
cal
extr
usio
n†1.
99(1
.36,
2.91
)1.
21(0
.79,
1.87
)1.
81(1
.23,
2.65
)1.
27(0
.78,
2.06
)4.
98(2
.94,
8.43
)1.
77(0
.82,
3.85
)1.
68(1
.15,
2.44
)1.
28(0
.84,
1.96
)1.
93(1
.35,
2.77
)1.
46(0
.97,
2.20
)3.
55(2
.25,
5.61
)1.
62(0
.98,
2.68
)V
arus
mal
alig
nmen
t‡1.
16(1
.07,
1.26
)1.
11(1
.01,
1.21
)1.
20(1
.10,
1.31
)1.
18(1
.07,
1.30
)1.
41(1
.20,
1.65
)1.
22(1
.06,
1.41
)1.
12(1
.04,
1.20
)1.
09(1
.00,
1.18
)1.
10(1
.02,
1.17
)1.
05(0
.97,
1.14
)1.
35(1
.22,
1.50
)1.
21(1
.10,
1.32
)L
ater
alla
xity
‡1.
24(1
.02,
1.51
)1.
22(1
.00,
1.49
)1.
17(0
.95,
1.44
)1.
17(0
.94,
1.44
)1.
11(0
.87,
1.42
)1.
04(0
.75,
1.43
)1.
03(0
.85,
1.25
)1.
02(0
.83,
1.24
)0.
94(0
.77,
1.15
)0.
91(0
.74,
1.12
)1.
01(0
.82,
1.24
)0.
91(0
.72,
1.15
)
*O
dds
ratio
s(O
Rs)
and
95%
conf
iden
cein
terv
als
(95%
CIs
)fo
rth
eba
selin
eto
2-ye
arqu
antit
ativ
eca
rtila
gelo
ssou
tcom
eas
soci
ated
with
each
loca
lfac
tor
wer
efir
stad
just
edfo
rag
e,se
x,an
dbo
dym
ass
inde
x(B
MI)
,and
wer
eth
enad
just
edfo
ral
lcov
aria
tes
(age
,sex
,BM
I,m
edia
lmen
isca
ldam
age,
med
ialm
enis
cale
xtru
sion
,var
usm
alal
ignm
ent,
and
late
ral
laxi
ty).
Prog
ress
ion,
defin
edas
cart
ilage
loss
�2
times
the
coef
ficie
ntof
vari
atio
n,w
asob
serv
edin
67kn
ees
(27%
)fo
rtib
ial
cart
ilage
volu
me,
77kn
ees
(31%
)fo
rtib
ial
cart
ilage
thic
knes
s,49
knee
s(2
0%)
for
tibia
lare
aof
denu
ded
bone
,68
knee
s(2
7%)
for
fem
oral
cart
ilage
volu
me,
75kn
ees
(30%
)fo
rfe
mor
alca
rtila
geth
ickn
ess,
and
39kn
ees
(16%
)fo
rfe
mor
alar
eaof
denu
ded
bone
.Dat
aar
efr
om25
1kn
ees
in15
3pa
rtic
ipan
ts.
†O
Rpe
run
itsc
ore.
‡O
Rpe
r1
degr
ee.
RELATIONSHIP BETWEEN LOCAL FACTORS AND CARTILAGE LOSS IN OA KNEES 1721
Tab
le5.
Rel
atio
nshi
pbe
twee
nlo
calm
echa
nica
lfac
tors
and
quan
titat
ive
cart
ilage
loss
outc
omes
inth
ela
tera
ltib
iofe
mor
alca
rtila
gepl
ates
*
Mea
sure
ofca
rtila
gelo
ss,b
asel
ine
to2
year
s(d
epen
dent
vari
able
)
Lat
eral
tibia
Lat
eral
wei
ght-
bear
ing
fem
ur
Loc
alm
echa
nica
lfa
ctor
,at
base
line
(ind
epen
dent
vari
able
)
Car
tilag
evo
lum
elo
ss,
OR
(95%
CI)
Car
tilag
eth
ickn
ess
loss
,O
R(9
5%C
I)D
enud
edbo
nein
crea
se,
OR
(95%
CI)
Car
tilag
evo
lum
elo
ss,
OR
(95%
CI)
Car
tilag
eth
ickn
ess
loss
,O
R(9
5%C
I)D
enud
edbo
nein
crea
se,
OR
(95%
CI)
Adj
uste
dfo
rag
e,se
x,an
dB
MI
Adj
uste
dfo
ral
lco
vari
ates
Adj
uste
dfo
rag
e,se
x,an
dB
MI
Adj
uste
dfo
ral
lco
vari
ates
Adj
uste
dfo
rag
e,se
x,an
dB
MI
Adj
uste
dfo
ral
lco
vari
ates
Adj
uste
dfo
rag
e,se
x,an
dB
MI
Adj
uste
dfo
ral
lco
vari
ates
Adj
uste
dfo
rag
e,se
x,an
dB
MI
Adj
uste
dfo
ral
lco
vari
ates
Adj
uste
dfo
rag
e,se
x,an
dB
MI
Adj
uste
dfo
ral
lco
vari
ates
Lat
eral
men
isca
lda
mag
e†1.
54(1
.26,
1.87
)1.
45(1
.14,
1.85
)1.
69(1
.39,
2.06
)1.
62(1
.28,
2.06
)2.
46(1
.96,
3.09
)2.
11(1
.64,
2.72
)1.
78(1
.43,
2.20
)1.
62(1
.27,
2.07
)1.
75(1
.42,
2.17
)1.
66(1
.30,
2.12
)1.
97(1
.54,
2.53
)1.
80(1
.37,
2.37
)L
ater
alm
enis
cal
extr
usio
n†2.
11(1
.28,
3.47
)1.
41(0
.80,
2.48
)2.
25(1
.36,
3.73
)1.
33(0
.74,
2.40
)4.
54(2
.66,
7.74
)2.
19(1
.18,
4.04
)2.
30(1
.38,
3.85
)1.
22(0
.66,
2.27
)1.
93(1
.21,
3.06
)0.
95(0
.52,
1.75
)2.
95(1
.81,
4.81
)1.
66(0
.95,
2.87
)V
algu
sm
alal
ignm
ent‡
1.05
(0.9
9,1.
12)
0.99
(0.9
3,1.
05)
1.07
(1.0
0,1.
15)
0.99
(0.9
3,1.
06)
1.20
(1.0
8,1.
34)
1.02
(0.9
2,1.
12)
1.13
(1.0
1,1.
26)
1.02
(0.9
3,1.
13)
1.14
(1.0
3,1.
26)
1.04
(0.9
6,1.
14)
1.12
(0.9
7,1.
30)
0.97
(0.8
7,1.
08)
Med
iall
axit
y‡1.
12(0
.90,
1.38
)1.
07(0
.85,
1.35
)1.
08(0
.86,
1.34
)1.
01(0
.79,
1.29
)1.
11(0
.86,
1.43
)0.
99(0
.72,
1.36
)1.
26(0
.97,
1.65
)1.
18(0
.82,
1.67
)1.
32(1
.04,
1.69
)1.
25(0
.91,
1.71
)1.
50(1
.16,
1.95
)1.
48(1
.06,
2.07
)
*O
Rs
and
95%
CIs
for
the
base
line
to2-
year
quan
titat
ive
cart
ilage
loss
outc
ome
asso
ciat
edw
ithea
chlo
calf
acto
rw
ere
first
adju
sted
for
age,
sex,
and
BM
I,an
dw
ere
then
adju
sted
for
allc
ovar
iate
s(a
ge,s
ex,B
MI,
late
ralm
enis
cald
amag
e,la
tera
lmen
isca
lext
rusi
on,v
algu
sm
alal
ignm
ent,
and
med
iall
axit
y).T
hepr
opor
tion
ofkn
ees
with
prog
ress
ion
was
97of
251
(39%
)fo
rtib
ialc
artil
age
volu
me,
95of
251
(38%
)fo
rtib
ialc
artil
age
thic
knes
s,49
of25
1(2
0%)
for
tibia
lare
aof
denu
ded
bone
,53
of25
1(2
1%)
for
fem
oral
cart
ilage
volu
me,
61of
251
(24%
)fo
rfe
mor
alca
rtila
geth
ickn
ess,
and
37of
251
(15%
)fo
rfe
mor
alar
eaof
denu
ded
bone
.Dat
aar
efr
om25
1kn
ees
in15
3pa
rtic
ipan
ts.S
eeT
able
4fo
rde
finiti
ons.
†O
Rpe
run
itsc
ore.
‡O
Rpe
r1
degr
ee.
1722 SHARMA ET AL
sion, valgus malalignment, and medial laxity) (Table 5).Lateral meniscal extrusion was significantly associatedwith every outcome for both joint surfaces after adjust-ment for age, sex, and BMI; in the fully adjusted models,a significant relationship persisted only for lateral tibialdenuded bone increase. In the models adjusted for age,sex, and BMI, valgus malalignment was significantlyassociated with lateral tibial denuded bone increase,lateral weight-bearing femoral cartilage volume loss, andlateral weight-bearing femoral cartilage thickness loss,but the relationship did not persist in any of the fullyadjusted models. In the fully adjusted models, mediallaxity was significantly associated only with an increasein lateral weight-bearing femoral denuded bone.
Considering the medial tibiofemoral progressionoutcome identified from the 2 qualitative approaches,the original and the modified WORMS systems, signif-icant relationships were detected for medial meniscaldamage, medial meniscal extrusion, and varus malalign-ment after adjusting for age, sex, and BMI but not afterfurther adjustment for the other local factors (Table 6).In the lateral compartment, a significant relationshipwas not detected for any of the local factors other thanmedial laxity (Table 7).
DISCUSSION
After considering other local factors, medial me-niscal damage and varus malalignment were indepen-
Table 6. Relationship between local mechanical factors and qualitative cartilage loss outcomes in themedial tibiofemoral compartment*
WORMS score of cartilage integrity,OR (95% CI)
Modified WORMS score,OR (95% CI)
Adjusted for age,sex, and BMI
Adjusted for allcovariates
Adjusted for age,sex, and BMI
Adjusted for allcovariates
Medial meniscaldamage†
1.38 (1.12, 1.71) 1.22 (0.90, 1.66) 1.51 (1.21, 1.88) 1.32 (0.95, 1.83)
Medial meniscalextrusion†
1.91 (1.21, 3.01) 1.48 (0.82, 2.68) 2.07 (1.27, 3.38) 1.42 (0.75, 2.70)
Varusmalalignment‡
1.06 (0.98, 1.15) 1.01 (0.91, 1.11) 1.09 (1.01, 1.17) 1.02 (0.93, 1.12)
Lateral laxity‡ 1.11 (0.89, 1.37) 1.09 (0.88, 1.36) 1.15 (0.93, 1.43) 1.14 (0.91, 1.42)
* Odds ratios (ORs) and 95% confidence intervals (95% CIs) for the baseline to 2-year qualitativecartilage loss outcome associated with each local factor were first adjusted for age, sex, and body massindex (BMI), and were then adjusted for all covariates (age, sex, BMI, medial meniscal damage, medialmeniscal extrusion, varus malalignment, and lateral laxity). The proportion of knees with progression was42 of 251 (17%) using the Whole-Organ Magnetic Resonance Imaging Score (WORMS) and 35 of 251(14%) using the modified WORMS. Data are from 251 knees in 153 participants.† OR per unit score.‡ OR per 1 degree.
Table 7. Relationship between local mechanical factors and qualitative cartilage loss outcomes in thelateral tibiofemoral compartment*
WORMS score of cartilage integrity,OR (95% CI)
Modified WORMS score,OR (95% CI)
Adjusted for age,sex, and BMI
Adjusted for allcovariates
Adjusted for age,sex, and BMI
Adjusted for allcovariates
Lateral meniscaldamage†
1.10 (0.87, 1.38) 0.93 (0.70, 1.24) 1.22 (0.96, 1.54) 1.09 (0.84, 1.43)
Lateral meniscalextrusion†
1.07 (0.56, 2.03) 0.93 (0.47, 1.83) 1.28 (0.68, 2.41) 1.03 (0.52, 2.06)
Valgusmalalignment‡
1.10 (1.00, 1.20) 1.09 (0.98, 1.22) 1.09 (0.98, 1.21) 1.05 (0.95, 1.17)
Medial laxity‡ 1.62 (1.22, 2.14) 1.59 (1.21, 2.08) 1.49 (1.16, 1.93) 1.45 (1.12, 1.88)
* ORs and 95% CIs for the baseline to 2-year qualitative cartilage loss outcome associated with each localfactor were first adjusted for age, sex, and BMI, and were then adjusted for all covariates (age, sex, BMI,lateral meniscal damage, lateral meniscal extrusion, valgus malalignment, and medial laxity). Theproportion of knees with progression was 30 of 251 (12%) using the WORMS and 23 of 251 (9%) usingthe modified WORMS. Data are from 251 knees in 153 participants. See Table 6 for definitions.
RELATIONSHIP BETWEEN LOCAL FACTORS AND CARTILAGE LOSS IN OA KNEES 1723
dently associated with baseline to 2-year quantitativelymeasured cartilage loss from each medial surface, bothtibial and weight-bearing femoral. In the fully adjustedmodels, neither medial meniscal extrusion nor laterallaxity was associated with cartilage loss in either plate(although the relationship between meniscal extrusionand femoral cartilage loss measurements approachedsignificance). Lateral meniscal damage predicted carti-lage loss in each of the lateral surfaces after adjusting forthe other local factors. In these fully adjusted models,lateral meniscal extrusion was linked to one outcome forthe tibial surface, valgus malalignment was not signifi-cantly associated with cartilage loss in either surface, andmedial laxity was linked to one outcome for the femoralsurface.
In these analyses, which used the more quantita-tive cartilage assessment, factors bearing the strongestrelationship to cartilage loss were medial meniscal dam-age and varus malalignment for the medial surfaces andlateral meniscal damage for the lateral surfaces. Usingthe qualitative cartilage assessment, no significant rela-tionship with outcome was detected for these localfactors (except medial laxity) in the fully adjustedmodels.
The findings for meniscal damage are not surpris-ing, especially given that the menisci function to reducecontact stresses by enlarging the contact surface, distrib-uting load, and increasing stability (28–31). Meniscec-tomy reduces the contact area, with a corresponding2–3-fold increase in stress (32). Total meniscectomycauses knee OA changes; the risk of OA is high, evenafter partial meniscectomy (33).
In a study of patients with knee injury, 22% ofcartilage lesions in the presence of a meniscal tearworsened, as compared with 14.9% of lesions in theabsence of a meniscal tear (16). Berthiaume et al foundthat knees in a severe medial meniscal tear group hadgreater medial cartilage volume loss than did kneeswithout a tear (3.0% versus 2.7%) (17). In analysesadjusting for medial meniscal extrusion, extrusion, butnot tear, predicted loss. A trend toward more lateralcartilage loss in knees with lateral meniscal tear ap-proached significance. In the Boston Osteoarthritis ofthe Knee Study, meniscal damage and extrusion inde-pendently predicted worsening in the cartilage mor-phology score (18). Our study uniquely considered mal-alignment and laxity; meniscal damage relationshipspersisted, but extrusion was not linked to cartilage loss inany surface after controlling for the other local factors.
A compelling biomechanical rationale also existsfor the relationship between malalignment and cartilageloss. Malalignment (i.e., when the center of the knee
does not lie close to the mechanical axis of the limb,which is represented by a line from the center of the hipto the center of the ankle) alters stress distribution in theknee (4,5,10). Varus malalignment is a major determi-nant of the adduction moment at the knee during gait(11,34), which, in turn, is strongly related to medial load(35), a correlate of the medial to lateral subchondralbone density ratio, and a predictor of OA progression(36). We previously found that varus and valgus mal-alignment increased the likelihood of radiographic me-dial and lateral tibiofemoral OA progression, respec-tively (12). Cicuttini et al found an average annual loss ofmedial femoral cartilage of 17.7 �l (95% CI 6.5–28.8) forevery 1 degree of increase in baseline varus angulation,with a trend toward a similar relationship with medialtibial cartilage volume loss (37). For every 1 degree ofincrease in valgus angle, there was an average loss oflateral tibial cartilage volume of 8.0 �l (95% CI 0.0–16.0). After adjusting for the other local factors, wefound a consistent and independent effect of varusmalalignment, but not valgus malalignment, as a contin-uous variable on cartilage loss. The valgus impact on thelateral joint surfaces may be weaker than the varusimpact, which is consistent with previous findings sug-gesting that compartment load distribution is moreequitable in valgus than in varus knees (38–40).
We did not find consistent evidence of a relation-ship between medial or lateral laxity and cartilage loss.The effect of frontal plane laxity on primary knee OAprogression has not been previously reported. Instabilityleads to abrupt motion, with larger displacements, al-tered fit and contact regions of opposing joint surfaces,and an increase in regional shear and compressive forces(41). Several studies support a link between instabilityand posttraumatic OA development (42). The stableknee is a result of several interacting systems: articularand periarticular restraints (e.g., condylar geometry,tibial tubercle, iliotibial tract, cruciate and collateralligaments, capsule, menisci, and muscle); contact forcesgenerated by muscle activity and gravitational forces;mechanoreceptors providing proprioceptive input forreflex and centrally driven muscle activity, with feedfor-ward and feedback neuromuscular control mechanisms;and visual, vestibular, and somatosensory subsystems(3,43–45). In the OA setting, dynamic instability mayoriginate, in theory, from any combination of impair-ments in these systems. Our results raise the possibilitythat static and non–weight-bearing frontal plane laxitydoes not capture key aspects of joint-protective dynamicstability.
MRI enhances the ability to assess local factorimpact; the impact of meniscal damage and laxity, as
1724 SHARMA ET AL
described above, could not be examined using kneeradiography. Several studies (25,46–49) summarize evi-dence of the validity and long-term reliability of carti-lage quantification in OA knees. Whether qualitative orquantitative cartilage loss outcomes are superior is anarea of great interest; this is the first study to includemeasures of both. Previous studies examining local riskfactors have often showed progression as a cartilageintegrity score that worsens in any region within thetibiofemoral compartment of interest, relying on theoriginal or modified WORMS scoring system. We in-cluded these outcomes to be able to compare our resultswith those published reports and to be able to comparea quantitative approach with the previously appliedqualitative approach. The WORMS scoring system isinvaluable in characterizing an array of tissue lesions inthe OA knee joint organ comprehensively and reliably.For outcome assessment, however, the quantitative ap-proach was more sensitive in revealing independentrelationships in the fully adjusted models.
From these results, we cannot conclude that thisquantitative approach is superior to any qualitativeapproach. It is possible that other qualitative approachesmay be more sensitive. The skewed distribution ofquantified cartilage loss precluded handling it as acontinuous variable (Table 1). Cartilage loss in a largepopulation may be better distributed, allowing for explo-ration of additional ways to handle longitudinal quanti-tative cartilage data. In addition to its ability to revealrelationships, advantages of the quantitative approach ofthe current study include interpretability, i.e., as anamount of change �2 times the measurement error, asopposed to change as a continuous measure, which maybe difficult to interpret. The current study had a 2-yearfollowup; findings may or may not be the same over alonger period of time.
Finally, it is important to note that local factors,such as those examined in this study, may participate invicious circles with the worsening of knee OA. In a kneewith OA and any of these impairments, it is often notpossible to determine which came first, local impairmentor knee OA. Whenever along the OA disease timeline alocal impairment develops, it may contribute to subse-quent OA progression and cartilage loss, especially giventhe vulnerable milieu of the already damaged OA knee.Local change has mechanical consequences, which maylead to other structural changes, in a vicious circle ofprogressive damage. This and amplification loops fur-ther increase the impact of local factors. Ultimately,strategies that interrupt these vicious circles may beespecially powerful.
The absence of disease-modifying therapy in-
creases the need to identify factors underlying progres-sive cartilage loss as potential targets for intervention.These factors may modify the effect of drugs thatemerge in the future; targeting them may enhance drugresponse. Their presence also defines higher-risk sub-sets, useful at the individual level and at the publichealth level in the development of progression-prevention programs. These results support further workto define optimal interventions for meniscal tears in thesetting of knee OA and the study of emerging interven-tions targeting the varus-malaligned OA knee.
In conclusion, using quantitative approaches toassess cartilage loss, local factors that independentlypredict tibial and femoral cartilage loss included medialmeniscal damage and varus malalignment for the medialcompartment and lateral meniscal damage for the lat-eral compartment. Quantitative cartilage loss outcomemeasures were more sensitive in revealing these rela-tionships than a previously applied qualitative approach.
AUTHOR CONTRIBUTIONS
Dr. Sharma had full access to all of the data in the study andtakes responsibility for the integrity of the data and the accuracy of thedata analysis.Study design. Sharma, Song, Cahue, Dunlop.Acquisition of data. Sharma, Guermazi, Prasad, Kapoor, Cahue,Marshall.Analysis and interpretation of data. Sharma, Eckstein, Song,Guermazi, Hudelmaier, Dunlop.Manuscript preparation. Sharma, Eckstein, Song, Guermazi, Dunlop.Statistical analysis. Song, Dunlop.
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