Ther Adv Musculoskel Dis
(2012) 4(4) 259 –267
© The Author(s), 2012.
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Therapeutic Advances in Musculoskeletal Disease Review
Osteoarthritis (OA) is the most common form of
arthritis, and knee OA in particular is a leading
cause of disability among older adults [Guccione
et al. 1994; Lawrence et al. 2008]. With the aging
of the population, rising prevalence of obesity,
and lack of definitive treatments to prevent the
disease or halt its progression, the public health
impact of OA continues to grow. A better under-
standing of the pathophysiology of OA and devel-
opment of more sensitive biomarkers is needed
to identify and test rational treatment targets to
reduce the burden of this common condition.
While OA has traditionally been considered a dis-
ease of cartilage degeneration, it is being increas-
ingly recognized as a disease of the whole joint
involving all joint tissues [Dieppe, 2011]. Specific
pathologic changes, such as osteophytes, the first
definitive sign of radiographic OA, are a clear indi-
cation that bone changes occur in early OA.
However, radiography is relatively insensitive in
detecting the earliest changes. With the advent of
magnetic resonance imaging (MRI) of the knee, it
has become apparent that the majority of radio-
graphically ‘normal’ knees have some abnormality
detectable on MRI. For example, in the Framingham
Osteoarthritis Study, knees without any evidence of
radiographic OA (i.e. Kellgren and Lawrence grade
0), 88% have at least one abnormality on MRI
(unpublished data). With the use of newer imaging
modalities and advances in the understanding of
molecular mechanisms and disease pathology, OA
is now known to involve an active repair process and
is therefore not solely degenerative or destructive
[Brandt et al. 2006, 2008, 2009].
Clinical significance of bone changes
Abstract: Osteoarthritis (OA), the most common form of arthritis, is now understood to
involve all joint tissues, with active anabolic and catabolic processes. Knee OA in particular
is considered to be a largely mechanically-driven disease. As bone adapts to loads by
remodeling to meet its mechanical demands, bone alterations likely play an important role
in OA development. Subchondral bone changes in bone turnover, mineralization, and volume
result in altered apparent and material density of bone that may adversely affect the joint’s
biomechanical environment. Subchondral bone alterations such as bone marrow lesions (BMLs)
and subchondral bone attrition (SBA) both tend to occur more frequently in the more loaded
knee compartments, and are associated with cartilage loss in the same region. Recently, MRI-
based 3D bone shape has been shown to track concurrently with and predict OA onset.
The contributions of structural abnormalities to the clinical manifestations of knee OA are
becoming better understood as well. While a structure-symptom discordance in knee OA
is thought to exist, such observations do not take into account all potential factors that can
contribute to between-person differences in the pain experience. Using novel methodology, pain
fluctuation has been associated with changes in BMLs, synovitis and effusion. SBA has also
been associated with knee pain, but the relationship of osteophytes to pain has been conflicting.
Understanding the pathophysiologic sequences and consequences of OA pathology will guide
rational therapeutic targeting. Importantly, rational treatment targets require understanding
what structures contribute to pain as pain is the reason patients seek medical care.
Keywords: bone, osteoarthritis
Tuhina Neogi, MD, PhD,
Sections of Clinical
and Training Unit,
Department of Medicine,
Boston University School
of Medicine, 650 Albany
Street, Suite X200, Clin
Epi Unit, Boston, MA
Therapeutic Advances in Musculoskeletal Disease 4 (4)
Supporting the recognition that OA is a disease of
the whole joint, there is mounting evidence that
subchondral bone plays an important role in OA.
Bone remodeling in the OA joint occurs preferen-
tially in the subchondral plate. Surgical specimens
from persons with OA have demonstrated that
subchondral bone changes, including subchon-
dral bone attrition which is a flattening or depres-
sion of the subchondral bony surface unrelated
to gross fracture, are common [Bullough, 1998].
Further, in radiographically normal tibiofemoral
knee joints, subchondral bone changes on MRIs,
such as bone marrow lesions (BMLs), are common.
Changes in bone turnover, mineralization, and
bone volume result in altered apparent and
material density of bone [Burr, 2003, 2004].
Specifically, subchondral bone in OA has increased
thickness and volume, but is weaker and less
mineralized than normal bone [Buckland-Wright,
2004; Grynpas et al. 1991; Li and Aspden, 1997a,
1997b; Radin and Rose, 1986]. With alterations
in its properties, subchondral bone may be less able
to absorb and dissipate energy, thereby increasing
forces transmitted through the joint and predis-
posing the articular surface to deformation.
It has been proposed that these changes in the
subchondral bone could adversely affect the
biomechanical environment of the overlying car-
tilage, predisposing the cartilage to subsequent
loss of integrity [Radin and Rose, 1986].
Whether these bony changes are a cause or conse-
quence of other changes in OA remains contro-
versial. The potential for alterations in subchondral
bone to contribute to the early pathology of OA is
supported by a number of animal models that
demonstrate cartilage lesions in relation to dam-
age to subchondral bone through loading [Carlson
et al. 1994; Radin et al. 1972, 1984; Radin and
Rose, 1986; Wu et al. 1990]. Other experimental
animal models demonstrate subchondral bone
changes very early after induction of disease
[Anderson-MacKenzie et al. 2005; Hayami et al.
2006]. In humans, increased subchondral bone
turnover, as measured by bone scintigraphy, has
been associated with progression of radiographic
OA and with pain upon joint loading [Dieppe
et al. 1993; McCrae et al. 1992]. Recent MRI
studies have demonstrated increased tibial plateau
size and alterations of the bony surface contour
(subchondral bone attrition), even at the preradi-
ographic OA stage [Ding et al. 2006; Dore et al.
2010; Reichenbach et al. 2008]. Further, such
MRI studies have also demonstrated that these
bone lesions themselves are associated with
development and worsening of cartilage loss
[Davies-Tuck et al. 2010; Felson et al. 2003;
Hunter et al. 2006; Neogi et al. 2009a; Roemer
et al. 2009; Wluka et al. 2008, 2009].
It has been hypothesized that cartilage loss is a
mechanically mediated process that is more likely
to occur in regions subjected to high stress; such
areas of high stress are influenced by bone shape
[Williams et al. 2010]. Understanding the impli-
cations of bony alterations on the biomechanical
environment of the joint is critical as biomechan-
ics are known to play an important role in knee
OA. The association of static malalignment and
higher dynamic knee adduction moments with
knee OA progression supports the importance of
mechanical influences in knee OA pathogenesis
[Miyazaki et al. 2002; Sharma et al. 2001]. Yet lit-
tle beyond that is known about the potential full
range of mechanical effects in knee OA. Pertinent
to the recognition of the importance of biome-
chanics in knee OA, bone is known to be a
dynamic tissue that adapts to loads by remodeling
to meet its mechanical demands (Wolff’s Law)
[Chen et al. 2010; Goldring, 2008]. The normal
functioning of a diarthroidal joint is dependent
upon stability provided by ligaments, tendons and
musculature; appropriate load distribution across
the joint surfaces which is dependent upon the
geometry and material properties of the articu-
lating joint tissues; and joint congruity. While
chondrocytes can modulate their functional state
in response to loading [Hunziker, 2002], their
capacity to do so is limited compared with bone
[Goldring, 2008]. This loss of synchronous
adaptation to the biomechanical environment is
likely important in contributing to the eventual
pathologic changes that occur in the setting of
inadequate repair responses. Since alterations in
joint geometry can affect load distribution and
joint congruity, this can lead to maldistribution
of biomechanical loads to previously relatively
underloaded regions of cartilage and may contribute
to cartilage breakdown [Bullough, 1981].
Joint geometry has an obvious role in predispos-
ing to OA in conditions such as developmental
hip dysplasia. Femoroacetabular impingement
has also been recognized as contributing to hip
OA [Doherty et al. 2008]. Recently, more subtle
morphologic differences have been studied for
their relation to risk of OA. Two-dimensional
modeling of the hip joint shape demonstrated
particular shapes to be associated with radio-
graphic OA changes, supporting the importance
of joint geometry to the normal functioning of the
joint [Gregory et al. 2007; Lynch et al. 2009].
Given the spherical nature of the hip joint, study-
ing the morphology of the hip joint is relatively
easier than the more complex shape of the knee
joint. Nonetheless, joint shape modeling has now
also been extended to three-dimensional evalua-
tion of the knee [Bredbenner et al. 2010; Neogi
et al. 2011]. MRI-based three-dimensional bone
shape of the knee has been shown to track con-
currently with knee OA onset, and to predict the
incidence of radiographic knee OA 12 months
before its onset [Neogi et al. 2011]. The potential
effects of altered bone shape and resultant altered
biomechanical load can be inferred from investi-
gations of the impact of articular contact stress
on knee OA. Using discrete element analysis,
higher baseline contact stress was associated with
increased risk of incident symptomatic knee OA
in a longitudinal cohort study of persons with
knees at risk for OA [Segal et al. 2009]. Such
investigations highlight the critical importance of
abnormal biomechanics on joint pathology. It is
likely that some aspects of the joint shape are
reflective of biomechanical stresses, such as
habitual activities that may influence bone shape
during development and beyond, whereas other
aspects are likely genetically determined. For
example, differences in hip morphology have been
demonstrated to exist between White and Asian
(Chinese) women, which is a plausible explanation
for the difference in hip OA prevalence [Dudda
et al. 2011]. These differences may be related to
genetic differences, differences in frequency of
activities such as squatting, or both.
In addition to bone shape or morphology, the
pathologic bone abnormalities found in OA are
also thought to be important biomechanically.
The bony lesion most studied to date in this
regard is BMLs. These subchondral bony lesions
have been shown to occur more commonly at
sites of increased biomechanical loading [Felson
et al. 2003; Hunter et al. 2006]. That is, medial
BMLs are more likely to occur and to progress in
varus aligned knees, while similar relationships
are seen for lateral BMLs in valgus aligned knees.
It has been hypothesized that microfractures and
subchondral remodeling, as evidenced by altera-
tions in the apparent and material properties of
subchondral bone, are due to chronic overload
and are reflected by the presence of BMLs on
MRI [Roemer et al. 2010]. Radiologically, BMLs
in OA are noncystic subchondral areas of ill-
defined hyperintensity on T2-weighted or
proton-density-weighted fast spin echo images on
MRI [Bergman et al. 1994; Zanetti et al. 2000].
Histologically, BMLs appear to have features
suggestive of a localized infarction reaction,
with active and chronic remodeling processes
[Bergman et al. 1994; Hunter et al. 2009a; Zanetti
et al. 2000]. Histomorphometric evaluation has
demonstrated BMLs to have many of the same
features noted to occur in OA bone, but to a
greater extent; these changes include increased
bone volume fraction, decreased tissue mineral
density, increased trabecular thickness and
spacing but decreased number, and to be more
plate-like than bone in other areas of the same
(osteoarthritic) knee [Hunter et al. 2009a]. Such
alterations may make these areas more mechani-
In keeping with this hypothesis, subchondral
bone attrition, a depression or flattening of the
bony surface, tends to occur concomitantly and/or
develop in the same subregions as where BMLs
are present [Roemer et al. 2010]. Similar to BMLs,
subchondral bone attrition is also associated with
malalignment, occurring more frequently medially
when there is varus alignment, and laterally when
there is valgus alignment [Neogi et al. 2010a].
BMLs and subchondral bone attrition have also
been demonstrated to have effects on the overlying
cartilage. BML presence, incidence and progres-
sion have been associated with development and
worsening of cartilage loss, including in locations
adjacent to the BMLs [Davies-Tuck et al. 2010;
Felson et al. 2003; Hunter et al. 2006; Roemer
et al. 2009; Wluka et al. 2008, 2009]. Subchondral
bone attrition itself also increases the risk for
cartilage loss to occur in the same subregion
[Neogi et al. 2009a]. In contrast to subchondral
bone attrition, BMLs not only increase in size,
but have been shown to also regress over time
[Davies-Tuck et al. 2009; Hunter et al. 2006;
Kornaat et al. 2007; Roemer et al. 2009].
The biomechanical implications of the fluctuation
of BMLs are not clear presently. However, the
fluctuating nature of BMLs provides an opportu-
nity to determine whether such fluctuations
correspond to the fluctuating nature of pain in
knee OA. Based upon qualitative data, symptoms
in knee OA are thought to progress through
various stages, with pain initially occurring with
activity, later becoming more constant in nature,
and finally also being punctuated by unpredicta-
ble episodes of intense pain [Hawker et al. 2008].
The intermittent nature of pain has been noted in
Therapeutic Advances in Musculoskeletal Disease 4 (4)
large-scale knee OA cohort studies as well [Neogi
et al. 2010b]. As pain is the most common symp-
tom associated with knee OA, and is the primary
reason that patients seek medical attention,
whether there are pathologic features that under-
lie such fluctuating pain experiences are impor-
tant to understand as they may be rational targets
for treatment development. This is particularly of
relevance since successful treatments must not
only address the underlying pathologic processes,
but also be clinically relevant.
One of the difficulties in understanding patho-
logic features contributing to pain in knee OA
is the observed so-called structure–symptom
discordance. That is, persons with radiographic
knee OA may have minimal or no symptoms,
while others without radiographic changes may
have substantial knee symptoms [Hannan et al.
2000]. However, such observational studies have
been unable to account for potential confounders
that may limit the ability to discern a relationship
between structure and symptoms. For example,
the pain experience is influenced by many factors
that differ from person to person, such as
genetics, psychosocial factors and sociocultural
environment, among others, many of which are
unmeasurable. Without accounting for such dif-
ferences, the true relationship between structure
and symptoms cannot be validly evaluated. When
such between-person variability and confound-
ing factors are accounted for by using a within-
person knee-matched study design (i.e. naturally
paired knees in which one knee has pain, whereas
the other does not; both knees are influenced by
the same person-level factors), a strong associa-
tion between radiographic severity and knee pain
can be discerned, even at the earliest stages of
knee OA [Neogi et al. 2009b]. Such findings
suggest that certain structural lesions within the
knee are a cause of knee pain. Experimental
injection of a local anesthetic into the knee joint
leading to pain reduction is further direct evi-
dence that some structural pathology within the
knee must be responsible, at least in part, for
knee pain [Creamer et al. 1996].
Which tissues are likely sources of pain is becom-
ing better understood. Cartilage is unlikely to
be an important source of pain in early OA since
it is aneural, although at later stages neurovascu-
lar invasion may contribute to pain. An awake
arthroscopic evaluation of the knee demonstrated
that probing of the cartilage itself was not pain-
ful, but other structures such as synovium and
ligaments were painful; bone itself was not probed
as it is known to be painful [Dye et al. 1998].
A number of studies have demonstrated an asso-
ciation of BMLs and subchondral bone attrition
with pain [Felson, 2005; Felson et al. 2001, 2007;
Hernandez-Molina et al. 2008; Torres et al.
2006]. In a systematic review, in addition to
BMLs, synovitis was noted to be related to pain
[Yusuf et al. 2011]. Both features (BMLs and
synovitis) are known to fluctuate in nature. This
fluctuation in pathologic features can be consid-
ered a natural experimental condition, providing
a unique opportunity to determine whether the
changes in these lesions are associated with
changes in pain, thereby providing compelling
evidence of their link to pain short of conducting
intervention studies. Using novel analytic meth-
odology, the fluctuation in these features was
indeed shown to be associated with fluctuation in
knee pain; an increase in the size or number of
the lesion was associated with increased knee
pain, while a decrease was associated with
decreased knee pain [Zhang et al. 2011]. Such
data provide support to pursuit of therapeutics
that can target BMLs and synovitis as one poten-
tial strategy for treating and/or preventing pain
The possibility of targeting bone for OA treat-
ment is attractive given the known pathologic
changes and the capacity for bone to be modu-
lated. Despite the potential importance of bone
remodeling and consequent alterations in bone
geometry and material properties to OA patho-
genesis, bone remodeling as a therapeutic target
remains controversial. In the high bone turnover
state of OA, mineral deposition may be attenu-
ated, leading to relative hypomineralization and
weaker bone that is more easily deformed [Day
et al. 2001; Li and Aspden, 1997b]. Thus, OA
bone may have increased stiffness overall due
to increased subchondral bone thickness and
volume, despite its inferior material properties
[Radin and Rose, 1986]. These properties of bone
have implications for whether antiresorptive
therapies (e.g. bisphosphonates), would be poten-
tially beneficial in OA. In addition, the timing of
such intervention is likely important as they
should ideally be considered during phases of
high bone turnover, rather than during phases
with minimal bone turnover, in which case bis-
phosphonate therapy could theoretically increase
stiffness and interfere with potentially necessary
bone remodeling. Animal data has supported the
potential for agents to be beneficial in OA [Saag,
2008]. While not directly relevant for knee OA,
a secondary analysis of spinal OA in a trial of
alendronate demonstrated less spinal osteophyte
and disc space narrowing progression [Neogi
et al. 2008]. Consistent with this finding, in an
observational study of knee OA, alendronate use
was associated with less BMLs, subchondral bone
attrition, and knee pain than those not using
alendronate; however, interpretation of such
observational data is limited by potential residual
confounding [Carbone et al. 2004]. A randomized
controlled trial of risedronate suggested potential
benefit on knee symptoms and structure [Spector
et al. 2005], but a subsequent larger trial failed to
demonstrate any such benefits [Bingham et al.
2006]. More recently, a trial of intravenous zolen-
dronic acid resulted in a 6-month reduction in
BMLs and pain, and maintained the BML reduc-
tion at 12 months, although the pain effect was
no longer noted [Laslett et al. 2011]. A trial of
another agent that has potential bone-modifying
effects, calcitonin, was recently reported to improve
pain, function, and cartilage volume, but not radi-
ographic joint-space width [Karsdal et al. 2011].
These recent trials provide hope for the feasibility
of developing and testing disease-modifying
OA drugs (DMOADS). Randomized controlled
trials in OA have been hampered by slow X-ray
and MRI-based cartilage changes. In two large
knee OA cohorts, the Multicenter Osteoarthritis
(MOST) Study and Osteoarthritis Initiative, ~6%
of knees develop incident OA over a 30–36 month
period (unpublished data). In the initial risedro-
nate trial, the joint-space width progression in the
placebo arm was ~0.085 mm/year [Spector et al.
2005]. These data highlight the difficulty in using
radiographic endpoints for trials, necessitating
long followup and large sample sizes to detect
differences between treatment arms. Cartilage
assessments on MRI have not substantially
improved these issues, with cartilage volume change
estimated to be approximately 1% per year [Hunter
et al. 2009b]. Given the capacity of bone to change
more rapidly than radiographic features or
cartilage, further investigation of bone imaging
biomarkers appears warranted. Further, given the
recognition of bone pathology as being of rele-
vance for both the biomechanical abnormalities
and pain in OA, specific targeting of bone for OA
disease modification should continue to be pur-
sued. A recent study demonstrated changes
(increase and decrease) in BML size even as early
as 6 and 12 weeks [Felson et al. 2011]. Such
findings support the feasibility of pursuing thera-
peutic interventions for BMLs with shorter dura-
tion trials. Despite its promise, though, a greater
understanding is needed regarding the implica-
tions of altering bone remodeling and adaptive
responses to stresses as some responses are
appropriate and necessary, while others may be
maladaptive and contribute to abnormal biome-
chanics; these effects may also differ by stage of
disease. In addition, targeting structural pathol-
ogy without addressing concomitant biomechani-
cal abnormalities contributing to the disease may
not allow effects of successful treatments to be
In summary, the shift in thinking about OA as a
degenerative disease of cartilage to one of a
dynamic pathology process involving all of the
tissues of the joint is an important step towards
identifying treatment targets that can address the
disease of the whole joint. The study of bone in
OA not only provides a potentially more sensitive
tissue to continue developing as an imaging bio-
marker and indicator of biomechanical stresses in
the joint, but also a rational therapeutic target.
This work received no specific grant from any
funding agency in the public, commercial, or
not-for-profit sectors. Dr. Neogi is supported by
NIH AR055127 and the Arthritis Foundation
Arthritis Investigator Award.
Conflict of interest statement
The authors declare no conflicts of interest in
preparing this article.
Anderson-MacKenzie, J.M., Quasnichka, H.L., Starr,
R.L., Lewis, E.J., Billingham, M.E. and Bailey, A.J.
(2005) Fundamental subchondral bone changes in
spontaneous knee osteoarthritis. Int J Biochem Cell
Biol 37: 224–236.
Bergman, A.G., Willen, H.K., Lindstrand, A.L. and
Pettersson, H.T. (1994) Osteoarthritis of the knee:
correlation of subchondral MR signal abnormalities
with histopathologic and radiographic features.
Skeletal Radiol 23: 445–448.
Bingham, C.O., III, Buckland-Wright, J.C., Garnero,
P., Cohen, S.B., Dougados, M., Adami, S. et al. (2006)
Risedronate decreases biochemical markers of cartilage
degradation but does not decrease symptoms or slow
Therapeutic Advances in Musculoskeletal Disease 4 (4)
radiographic progression in patients with medial
compartment osteoarthritis of the knee: results of the
two-year multinational knee osteoarthritis structural
arthritis study. Arthritis Rheum 54: 3494–3507.
Brandt, K.D., Dieppe, P. and Radin, E.L. (2008)
Etiopathogenesis of osteoarthritis. Rheum Dis Clin
North Am 34: 531–559.
Brandt, K.D., Dieppe, P. and Radin, E.L. (2009)
Commentary: is it useful to subset “primary”
osteoarthritis? A critique based on evidence regarding
the etiopathogenesis of osteoarthritis. Semin Arthritis
Rheum 39: 81–95.
Brandt, K.D., Radin, E.L., Dieppe, P.A. and van
de Putte, L. (2006) Yet more evidence that
osteoarthritis is not a cartilage disease. Ann Rheum Dis
Bredbenner, T.L., Eliason, T.D., Potter, R.S.,
Mason, R.L., Havill, L.M. and Nicolella, D.P. (2010)
Statistical shape modeling describes variation in tibia
and femur surface geometry between Control and
Incidence groups from the osteoarthritis initiative
database. J Biomech 43: 1780–1786.
Buckland-Wright, C. (2004) Subchondral bone
changes in hand and knee osteoarthritis detected by
radiography. Osteoarthritis Cartilage 12(Suppl. A):
Bullough, P.G. (1981) The geometry of diarthrodial
joints, its physiologic maintenance, and the possible
significance of age-related changes in geometry-
to-load distribution and the development of
osteoarthritis. Clin Orthop Relat Res 156: 61–66.
Bullough, P.G. (1998) Osteoarthritis and related
disorders: pathology. In: Klippel, J.H. and Dieppe, P.
(eds), Rheumatology, 2nd ed. London: Mosby,
Burr, D.B. (2003) Subchondral bone in the
pathogenesis of osteoarthritis. Mechanical aspects. In:
Brandt, K.D., Doherty, M. and Lohmander, L.S.O.
(eds), Bone, 2nd ed. Oxford: Oxford University Press,
Burr, D.B. (2004) The importance of subchondral
bone in the progression of osteoarthritis. J Rheumatol
Suppl 70: 77–80.
Carbone, L.D., Nevitt, M.C., Wildy, K., Barrow,
K.D., Harris, F., Felson, D. et al. (2004) The
relationship of antiresorptive drug use to structural
findings and symptoms of knee osteoarthritis. Arthritis
Rheum 50: 3516–3525.
Carlson, C.S., Loeser, R.F., Jayo, M.J., Weaver,
D.S., Adams, M.R. and Jerome, C.P. (1994)
Osteoarthritis in cynomolgus macaques: a primate
model of naturally occurring disease. J Orthop Res
Chen, J.H., Liu, C., You, L. and Simmons, C.A.
(2010) Boning up on Wolff’s Law: mechanical
regulation of the cells that make and maintain bone.
J Biomech 43: 108–118.
Creamer, P., Hunt, M. and Dieppe, P. (1996) Pain
mechanisms in osteoarthritis of the knee: effect of
intraarticular anesthetic. J Rheumatol 23: 1031–1036.
Davies-Tuck, M.L., Wluka, A.E., Forbes, A.,
Wang, Y., English, D.R., Giles, G.G. et al. (2010)
Development of bone marrow lesions is associated
with adverse effects on knee cartilage while resolution
is associated with improvement—a potential target for
prevention of knee osteoarthritis: a longitudinal study.
Arthritis Res Ther 12: R10.
Davies-Tuck, M.L., Wluka, A.E., Wang, Y., English,
D.R., Giles, G.G. and Cicuttini, F. (2009) The
natural history of bone marrow lesions in community-
based adults with no clinical knee osteoarthritis.
Ann Rheum Dis 68: 904–908.
Day, J.S., Ding, M., van der Linden, J.C., Hvid, I.,
Sumner, D.R. and Weinans, H. (2001) A decreased
subchondral trabecular bone tissue elastic modulus
is associated with pre-arthritic cartilage damage.
J Orthop Res 19: 914–918.
Dieppe, P. (2011) Developments in osteoarthritis.
Rheumatology (Oxford) 50: 245–247.
Dieppe, P., Cushnaghan, J., Young, P. and Kirwan,
J. (1993) Prediction of the progression of joint space
narrowing in osteoarthritis of the knee by bone
scintigraphy. Ann Rheum Dis 52: 557–563.
Ding, C., Cicuttini, F., Scott, F., Cooley, H., Boon,
C. and Jones, G. (2006) Natural history of knee
cartilage defects and factors affecting change. Arch
Intern Med 166: 651–658.
Doherty, M., Courtney, P., Doherty, S., Jenkins, W.,
Maciewicz, R.A., Muir, K. et al. (2008) Nonspherical
femoral head shape (pistol grip deformity), neck shaft
angle, and risk of hip osteoarthritis: a case-control
study. Arthritis Rheum 58: 3172–3182.
Dore, D., Quinn, S., Ding, C., Winzenberg, T.,
Cicuttini, F. and Jones, G. (2010) Subchondral bone
and cartilage damage: a prospective study in older
adults. Arthritis Rheum 62: 1967–1973.
Dudda, M., Kim, Y.J., Zhang, Y., Nevitt, M.C.,
Xu, L., Niu, J. et al. (2011) Morphologic differences
between the hips of Chinese women and white
women: could they account for the ethnic difference
in the prevalence of hip osteoarthritis? Arthritis Rheum
Dye, S.F., Vaupel, G.L. and Dye, C.C. (1998)
Conscious neurosensory mapping of the internal
structures of the human knee without intraarticular
anesthesia. Am J Sports Med 26: 773–777.
Felson, D.T. (2005) The sources of pain in knee
osteoarthritis. Curr Opin Rheumatol 17: 624–628.
Felson, D.T., Callaghan, M.J., Parkes, M.,
Marjanovic, E.J., Lunt, M., Oldham, J.A. et al.
(2011) Bone marrow lesions in knee osteoarthritis
change in 6 to 12 weeks. Osteoarthritis Cartilage
19(Suppl. 1): S10.
Felson, D.T., Chaisson, C.E., Hill, C.L., Totterman,
S.M., Gale, M.E., Skinner, K.M. et al. (2001) The
association of bone marrow lesions with pain in knee
osteoarthritis. Ann Intern Med 134: 541–549.
Felson, D.T., McLaughlin, S., Goggins, J., LaValley,
M.P., Gale, M.E., Totterman, S. et al. (2003) Bone
marrow edema and its relation to progression of knee
osteoarthritis. Ann Intern Med 139: 330–336.
Felson, D.T., Niu, J., Guermazi, A., Roemer, F.,
Aliabadi, P., Clancy, M. et al. (2007) Correlation of
the development of knee pain with enlarging bone
marrow lesions on magnetic resonance imaging.
Arthritis Rheum 56: 2986–2992.
Goldring, S.R. (2008) The role of bone in
osteoarthritis pathogenesis. Rheum Dis Clin North Am
Gregory, J.S., Waarsing, J.H., Day, J., Pols, H.A.,
Reijman, M., Weinans, H. et al. (2007) Early
identification of radiographic osteoarthritis of the
hip using an active shape model to quantify changes
in bone morphometric features: can hip shape tell
us anything about the progression of osteoarthritis?
Arthritis Rheum 56: 3634–3643.
Grynpas, M.D., Alpert, B., Katz, I., Lieberman,
I. and Pritzker, K.P. (1991) Subchondral bone in
osteoarthritis. Calcif Tissue Int 49: 20–26.
Guccione, A.A., Felson, D.T., Anderson, J.J.,
Anthony, J.M., Zhang, Y., Wilson, P.W. et al. (1994)
The effects of specific medical conditions on the
functional limitations of elders in the Framingham
Study. Am J Public Health 84: 351–358.
Hannan, M.T., Felson, D.T. and Pincus, T. (2000)
Analysis of the discordance between radiographic
changes and knee pain in osteoarthritis of the knee.
J Rheumatol 27: 1513–1517.
Hawker, G.A., Stewart, L., French, M.R., Cibere, J.,
Jordan, J.M., March, L. et al. (2008) Understanding
the pain experience in hip and knee osteoarthritis—an
OARSI/OMERACT initiative. Osteoarthritis Cartilage
Hayami, T., Pickarski, M., Zhuo, Y., Wesolowski,
G.A., Rodan, G.A. and Duong le, T. (2006)
Characterization of articular cartilage and subchondral
bone changes in the rat anterior cruciate ligament
transection and meniscectomized models of
osteoarthritis. Bone 38: 234–243.
Hernandez-Molina, G., Neogi, T., Hunter, D.J., Niu,
J., Guermazi, A., Roemer, F.W. et al. (2008) The
association of bone attrition with knee pain and other
MRI features of osteoarthritis. Ann Rheum Dis
Hunter, D.J., Gerstenfeld, L., Bishop, G., Davis,
A.D., Mason, Z.D., Einhorn, T.A. et al. (2009a)
Bone marrow lesions from osteoarthritis knees
are characterized by sclerotic bone that is less well
mineralized. Arthritis Res Ther 11(1): R11.
Hunter, D.J., Niu, J., Zhang, Y., Totterman, S.,
Tamez, J., Dabrowski, C. et al. (2009b) Change in
cartilage morphometry: a sample of the progression
cohort of the Osteoarthritis Initiative. Ann Rheum Dis
Hunter, D.J., Zhang, Y., Niu, J., Goggins, J.,
Amin, S., LaValley, M.P. et al. (2006) Increase
in bone marrow lesions associated with cartilage
loss: a longitudinal magnetic resonance imaging
study of knee osteoarthritis. Arthritis Rheum
Hunziker, E.B. (2002) Articular cartilage repair:
basic science and clinical progress. A review of the
current status and prospects. Osteoarthritis Cartilage
Karsdal, M.A., Alexandersen, P., John, M.R.,
Loeffler, J., Arnold, M., Azria, M. et al. (2011) Oral
calcitonin demonstrated symptom-modifying efficacy
and increased cartilage volume: Results from a 2-year
phase 3 trial in patients with osteoarthritis of the knee.
Osteoarthritis Cartilage 19(Suppl. 1): S35.
Kornaat, P.R., Kloppenburg, M., Sharma, R., Botha-
Scheepers, S.A., Le Graverand, M.P., Coene, L.N.
et al. (2007) Bone marrow edema-like lesions
change in volume in the majority of patients with
osteoarthritis; associations with clinical features.
Eur Radiol 17: 3073–3078.
Laslett, L.L., Dore, D.A., Quinn, S.J., Winzenberg,
T.M., Boon, P. and Jones, G. (2011) Zolendronic
acid reduces bone marrow lesions and knee pain over
one year. Ann Rheum Dis 70(Suppl. 3): 138.
Lawrence, R.C., Felson, D.T., Helmick, C.G.,
Arnold, L.M., Choi, H., Deyo, R.A. et al. (2008)
Estimates of the prevalence of arthritis and other
rheumatic conditions in the United States. Part II.
Arthritis Rheum 58: 26–35.
Li, B. and Aspden, R.M. (1997a) Composition
and mechanical properties of cancellous bone from
the femoral head of patients with osteoporosis or
osteoarthritis. J Bone Miner Res 12: 641–651.
Li, B. and Aspden, R.M. (1997b) Mechanical and
material properties of the subchondral bone plate
from the femoral head of patients with osteoarthritis
or osteoporosis. Ann Rheum Dis 56: 247–254.
Therapeutic Advances in Musculoskeletal Disease 4 (4)
Lynch, J.A., Parimi, N., Chaganti, R.K., Nevitt,
M.C. and Lane, N.E. (2009) The association of
proximal femoral shape and incident radiographic
hip OA in elderly women. Osteoarthritis Cartilage
McCrae, F., Shouls, J., Dieppe, P. and Watt, I.
(1992) Scintigraphic assessment of osteoarthritis of
the knee joint. Ann Rheum Dis 51: 938–942.
Miyazaki, T., Wada, M., Kawahara, H., Sato, M.,
Baba, H. and Shimada, S. (2002) Dynamic load at
baseline can predict radiographic disease progression
in medial compartment knee osteoarthritis. Ann
Rheum Dis 61: 617–622.
Neogi, T., Bowes, M., Niu, J., De Souza, K.,
Goggins, J., Zhang, Y. et al. (2011) MRI-based 3D
bone shape predicts incident knee OA 12 months
prior to its onset. Osteoarthritis Cartilage 19(Suppl. 1):
Neogi, T., Felson, D., Niu, J., Lynch, J., Nevitt, M.,
Guermazi, A. et al. (2009a) Cartilage loss occurs in
the same subregions as subchondral bone attrition: a
within-knee subregion-matched approach from the
Multicenter Osteoarthritis Study. Arthritis Rheum
Neogi, T., Felson, D., Niu, J., Nevitt, M.,
Lewis, C.E., Aliabadi, P. et al. (2009b) Association
between radiographic features of knee osteoarthritis
and pain: results from two cohort studies. BMJ 339:
Neogi, T., Nevitt, M., Niu, J., Sharma, L., Roemer,
F., Guermazi, A. et al. (2010a) Subchondral bone
attrition may be a reflection of compartment-specific
mechanical load: the MOST Study. Ann Rheum Dis
Neogi, T., Nevitt, M.C., Ensrud, K.E., Bauer, D.
and Felson, D.T. (2008) The effect of alendronate
on progression of spinal osteophytes and disc-space
narrowing. Ann Rheum Dis 67: 1427–1430.
Neogi, T., Nevitt, M.C., Yang, M., Curtis, J.R.,
Torner, J. and Felson, D.T. (2010b) Consistency of
knee pain: correlates and association with function.
Osteoarthritis Cartilage 18: 1250–1255.
Radin, E.L., Martin, R.B., Burr, D.B., Caterson,
B., Boyd, R.D. and Goodwin, C. (1984) Effects of
mechanical loading on the tissues of the rabbit knee.
J Orthop Res 2: 221–234.
Radin, E.L., Paul, I.L. and Rose, R.M. (1972) Role
of mechanical factors in pathogenesis of primary
osteoarthritis. Lancet 1: 519–522.
Radin, E.L. and Rose, R.M. (1986) Role of
subchondral bone in the initiation and progression of
cartilage damage. Clin Orthop Relat Res 213: 34–40.
Reichenbach, S., Guermazi, A., Niu, J., Neogi, T.,
Hunter, D.J., Roemer, F.W. et al. (2008) Prevalence
of bone attrition on knee radiographs and MRI in a
community-based cohort. Osteoarthritis Cartilage
Roemer, F.W., Guermazi, A., Javaid, M.K., Lynch,
J.A., Niu, J., Zhang, Y. et al. (2009) Change in
MRI-detected subchondral bone marrow lesions is
associated with cartilage loss: the MOST Study. A
longitudinal multicentre study of knee osteoarthritis.
Ann Rheum Dis 68: 1461–1465.
Roemer, F.W., Neogi, T., Nevitt, M.C., Felson,
D.T., Zhu, Y., Zhang, Y. et al. (2010) Subchondral
bone marrow lesions are highly associated with, and
predict subchondral bone attrition longitudinally: the
MOST study. Osteoarthritis Cartilage 18: 47–53.
Saag, K.G. (2008) Bisphosphonates for osteoarthritis
prevention: “Holy Grail” or not? Ann Rheum Dis
Segal, N.A., Anderson, D.D., Iyer, K.S., Baker,
J., Torner, J.C., Lynch, J.A. et al. (2009) Baseline
articular contact stress levels predict incident
symptomatic knee osteoarthritis development in the
MOST cohort. J Orthop Res 27: 1562–1568.
Sharma, L., Song, J., Felson, D.T., Cahue, S.,
Shamiyeh, E. and Dunlop, D.D. (2001) The role of
knee alignment in disease progression and functional
decline in knee osteoarthritis. JAMA 286: 188–195.
Spector, T.D., Conaghan, P.G., Buckland-Wright,
J.C., Garnero, P., Cline, G.A., Beary, J.F. et al.
(2005) Effect of risedronate on joint structure and
symptoms of knee osteoarthritis: results of the BRISK
randomized, controlled trial [ISRCTN01928173].
Arthritis Res Ther 7: R625–R633.
Torres, L., Dunlop, D.D., Peterfy, C., Guermazi, A.,
Prasad, P., Hayes, K.W. et al. (2006) The relationship
between specific tissue lesions and pain severity
in persons with knee osteoarthritis. Osteoarthritis
Williams, T.G., Vincent, G., Bowes, M., Cootes,
T.F., Balamoody, S., Hutchinson, C.E. et al.
(2010) Automatic segmentation of bones and
inter-image anatomical correspondence by
volumetric statistical modeling of knee MRI.
In: Proceedings of the 2010 IEEE International
Conference on Biomedical Imaging: From nano
to macro. Rotterdam: IEEE Press
Wluka, A.E., Hanna, F., Davies-Tuck, M., Wang,
Y., Bell, R.J., Davis, S.R. et al. (2009) Bone marrow
lesions predict increase in knee cartilage defects
and loss of cartilage volume in middle-aged women
without knee pain over 2 years. Ann Rheum Dis
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Wluka, A.E., Wang, Y., Davies-Tuck, M., English,
D.R., Giles, G.G. and Cicuttini, F.M. (2008) Bone
marrow lesions predict progression of cartilage defects
and loss of cartilage volume in healthy middle-aged
adults without knee pain over 2 yrs. Rheumatology
(Oxford) 47: 1392–1396.
Wu, D.D., Burr, D.B., Boyd, R.D. and Radin,
E.L. (1990) Bone and cartilage changes following
experimental varus or valgus tibial angulation.
J Orthop Res 8: 572–585.
Yusuf, E., Kortekaas, M.C., Watt, I., Huizinga, T.W.
and Kloppenburg, M. (2011) Do knee abnormalities
visualised on MRI explain knee pain in knee
osteoarthritis? A systematic review. Ann Rheum Dis
Zanetti, M., Bruder, E., Romero, J. and Hodler, J.
(2000) Bone marrow edema pattern in osteoarthritic
knees: correlation between MR imaging and histologic
findings. Radiology 215: 835–840.
Zhang, Y., Nevitt, M., Niu, J., Lewis, C., Torner, J.,
Guermazi, A. et al. (2011) Fluctuation of knee pain
and changes in bone marrow lesions, effusions and
synovitis on MRI: The Most Study. Arthritis Rheum