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Volume 04 / Issue 03 / September 2016
Page 60
JTO Peer-Reviewed Articles
Advances in osteoarthritis
imaging: What will make it
into clinical practice?
Stephen McDonnell
Tom Turmezei, Martin Graves, Andrew McCaskie & Joshua Kaggie
Osteoarthritis is one of the fastest increasing global health
problems, causing pain and disability. End stage disease is
treated effectively with joint replacement, but the number of
replacements is increasing year-on-year, with increased costs for
already stretched healthcare systems.
population, less than 1% by
mass. Therefore, compositional
techniques rely on the ability to
quantitatively measure changes in
this macromolecular environment.
A critical question is whether these
techniques will have relevance to
global joint health and treatment
decisions in future clinical practice?
Structural imaging
Surgical interventions for
early stage disease, such as
regenerative treatments1, are
currently limited, in part due to
the lack of diagnostic imaging
methods to accurately quantify
disease severity and select
patients for treatment. Looking
ahead, cutting-edge imaging
technologies may provide
detailed assessments of the
arthritic joint at an early stage,
allowing the development and
improvement of treatment
strategies in early disease.
Stephen McDonnell
Improvements in regular clinical
imaging techniques, such as
x-ray, computed tomography (CT)
and magnetic resonance imaging
(MRI) will give more detailed
anatomical resolution and be
combined with assessment
of biological function. In this
review article we explore imaging
techniques likely to impact on
clinical practice, focusing on plain
radiography, CT and MRI. Other
techniques such as ultrasound
and nuclear medicine may also
play an important role.
The difference
between structural and
compositional imaging
One important distinction in
imaging osteoarthritis is whether
the technique provides structural
or compositional information.
Structural imaging is the basis of
current clinical imaging and depicts
joint morphology from a limited
range of tissue characteristics
such as mineralisation, fat and
water content. This can be used
to assess the early features that
might predispose to later disease,
or for monitoring progression
towards end-stage joint failure.
Compositional imaging techniques
assess joint tissue characteristics
beyond the macroscopic structural
level, identifying early changes,
prior to cartilage loss, that would
otherwise be considered irreversible
(OARSI grade IV2). Cartilage is an
avascular, aneural and alymphatic
extracellular matrix formed
predominantly from collagen
and glycosaminoglycans (GAG)
networks, with a small chondrocyte
X-ray Radiography
Planar X-rays have been the
mainstay of clinical and research
osteoarthritis imaging. It is
low cost, accessible, quick
and relatively easy to interpret.
Thus it will continue to inform
clinical assessment and
decision-making, particularly
in monitoring progression and
following up therapies, such as
joint replacement. However,
compared to other modalities its
two-dimensional nature makes it
insensitive to structural change and
unlikely to have an extended role.
Computed Tomography (CT)
CT is excellent at imaging bone.
As such, it has mainly been used
as a tool for the pre-operative
planning of surgery, for example
alignment, dysplasia, patientspecific implants. Similar to
radiography, CT is low cost,
accessible and can be acquired
rapidly. Although the relatively
higher exposure to ionising
radiation compared to radiography,
is a concern, particularly if planning
multiple exposures for follow-up
Volume 04 / Issue 03 / September 2016
Page 61
© 2016 British Orthopaedic Association
Journal of Trauma and Orthopaedics: Volume 04, Issue 03, pages 60-63
Title: Advances in osteoarthritis imaging: What will make it into clinical practice?
Authors: Stephen McDonnell, Tom Turmezei, Martin Graves, Andrew McCaskie & Joshua Kaggie
Division of Trauma and Orthopaedics, University of Cambridge
Arthritis Research UK Tissue Engineering Centre
Figure 1: Quantitative measurement of cortical thickness at the hip in 3D from clinical CT
imaging data using Stradwin software ( displayed
as a colour map on a 3D mesh framework. Note increased thickness compared to other
articular regions at the femoral superior subchondral bone plate, a key load-bearing site
imaging or if used in a younger
population. Increasingly low-dose
protocols are being developed that
will make this less of an issue3. CT
can also be used to quantitatively
map structural features of disease
such as subchondral bone
thickness, density, and joint space
width (JSW) in three-dimensions
(Figure 1)4. Given their association
with recognised tissue changes in
the development of osteoarthritis5,
changes in these parameters are
likely to be meaningful in disease
progression or response to therapy.
Magnetic resonance imaging (MRI)
MRI has traditionally been used
to supplement radiography in the
clinical evaluation of osteoarthritis,
mainly in the characterisation
of structural joint damage and
cartilage health. One of the main
strengths of structural MRI is its
ability to evaluate early soft tissue
features, such as synovitis6 and
bone marrow edema7 whilst also
detecting ligament, fibrocartilage
and hyaline cartilage damage.
Semi-quantitative systems exist for
scoring these features, but these
scores are mainly used as research
tools. The MOCART system has
been used to assess cartilage
repair technique viability and is
likely to be become more familiar
as these surgical techniques
become more established. We
refer readers with an interest in
semi-quantitative MRI scoring on
to an in-depth review by Guermazi
et al.8. In addition to observergenerated scoring, there are a
variety of 3D MRI methods that
can create contrast between
cartilage and bone, allowing
3D visualisation and structural
quantification9,10. These can be
used for measurement of cartilage
thickness and volume (Figure
2). Such measures are likely to
become increasingly important
with the advent of whole joint
therapies, which look to reverse
deterioration in cartilage health.
MRI is the forerunner in
compositional imaging. Although
many compositional techniques
are not used clinically as a result
of the lack of early osteoarthritis
management options, this is
likely to change as new therapies
become available. There is a
range of techniques that have
been validated in small, specific
cohorts of early osteoarthritis
which are beginning to be used in
clinical practice: here we look at
the most relevant#.
Delayed Gadonlinium Enhanced
MRI with Contrast (dGEMRIC)
measures the T1 relaxation
time in cartilage before and 90
minutes after the intravascular
injection of a gadolinium-based
contrast agent12-14. Damage to
articular cartilage is associated
with Glycosaminoglycans (GAG)
loss, so decreased GAG levels
allow greater penetration of
gadolinium from synovial fluid
into the cartilage matrix, leading
to reduced T1 relaxation times.
dGEMRIC has proven ability to
identify cartilage damage relevant to
disease outcome before structural
changes13-17. However, the long
times required for joint perfusion
has so far kept it from widespread
clinical application. dGEMRIC’s use
of gadolinium is also a concern due
to recently discovered retention in
the brain and established toxicity
in patients with renal impairment18.
As a result, non-gadolinium-based
measures of cartilage integrity may
well play a wider role (Figure 319).
Proton Relaxation MRI: T2,
T1rho and T2* mapping
Other types of quantitative
MRI acquisition are sensitive to
compositional changes that can
be probed through relaxation
time measurements. Four
main relaxation times can be
measured: T1 (as in dGEMRIC),
T2, T1rho, and T2*. Each of these
creates different image contrasts
between tissues types, with
additional post-processing to give
quantitative results that can be
mapped in 2D or 3D.
T2 mapping using spin echo
based MRI sequences has been
the most common method for
identifying changes relevant to
osteoarthritis (Figure 4)20,21, with
T2 values shown to correlate
Figure 2: Quantitative cartilage thickness at the femoral articular surface in 3D
as measured from segmentation in a 3D T1-weighted MRI series using Stradwin
software. The tibial articular surfaces are shown in grey
# For in depth reading into the full range of compositional MRI techniques currently available, we refer readers on to a recent review by Guermazi et al.11
Volume 04 / Issue 03 / September 2016
Page 62
JTO Peer-Reviewed Articles
MRI systems, and while T1rho is
becoming increasingly available
it does require additional
specialised software.
Figure 3: dGEMRIC of articular cartilage at the knee joint (sagittal). Note the
increased T1 values at the weight-bearing surfaces of the femur and tibia
(dashed lines) compared to the rest of the cartilage19
with water levels in cartilage,
synovial fluid, and muscle22. The
underlying principle is that since
damaged cartilage has increased
water content, T2 values will
be higher in unhealthy regions.
However, changes in these values
are not correlated with acute injury.
T1rho images appear similar to T2,
but use a special technique that
measures relaxation dominated
by macromolecular correlation
times. It has the advantage over
T2 of being more sensitive to early
microscopic change23, and more
repeatable in one study involving
anterior cruciate ligament injuries24.
Both T2 and T1rho correlate with
age, which is a strong indication
of their sensitivity to related
proteoglycan changes25,26. T2
maps can be acquired on many
Figure 4: Sagittal T1rho image (a) and map (b, T2 image (c) and map (d), and
T2* image (e) and map (f) in a healthy knee. All three techniques can be used
to quantitatively assess the state of cartilage health. Maps can be masked to
provide values exclusive to cartilage regions
The principle of T2* mapping is
similar to T2 mapping, except that
it is based on gradient-echo based
MRI sequences that demonstrate
susceptibility to local magnetic field
inhomogeneities. Using a similar
effect as harnessed in T2 mapping,
T2* maps similar properties of
cartilage as T2 but using much
faster acquisitions. T2* mapping is
available on many clinical imaging
systems, and as with T2 and T1rho
mapping, we are likely to see this
in clinical practice once the clinical
relevance of these quantitative
cartilage measures is established.
Ultrashort Echo Time (UTE) MRI
MRI signals decay rapidly (T2 <
10 ms) in bone or near the bonecartilage interface27-29 so they are
unseen on conventional MR images.
Ultra-short echo time (UTE) MRI
captures this fast-decaying signal by
using novel acquisition methods30,31.
UTE MRI can therefore image the
deep cartilage layers31. Subtracted
UTE images can also be used
to highlight differences at the
osteochondral junction (Figure 5)31.
UTE techniques are becoming
more clinically available, although
commercial implementation
has been slow partially due
to increased computational
requirements30,32. The relevance
of UTE imaging is yet to be
established in disease progression.
Sodium MRI
Instead of using hydrogen
atoms as the basis for tissue
signal, it is possible to use other
atoms. Sodium MRI can create
image contrast not available
with other standard protonbased methods33,34 (Figure 6).
Positively-charged sodium is
attracted to negatively charged
proteoglycans, such that healthy
cartilage contains more sodium
than osteoarthritic cartilage35-37.
Sodium MRI requires specialised
software and hardware that is not
widely available on clinical MRI
systems, but these can be found
at various research institutions38,39
and is likely that it will ultimately
be used in disease assessment40.
Orthopaedics is continually
evolving and is our diagnostic
resource. Even the very familiar
MRI examination will, as 3T
field strength imaging becomes
routinely available, provide
quantitative structural and
compositional imaging techniques
described here, which will in
turn provide realistic diagnostic
and prognostic options. In the
coming decade it is likely that
patients with early osteoarthritis
will have access to quantitative
imaging methods. This will be an
unprecedented opportunity for
the clinician to refine and develop
new treatments for cartilage repair
and early osteoarthritis.
Figure 5: Sagittal UTE image of a healthy knee. The short TE of the first image
(32 µs) allows UTE structures to be visualised; these signals have decayed by the
late echo image (4.5 ms). The subtraction image shows the delineation of deep
cartilage (arrow), which is usually an undefined low-signal structure in standard MRI
Volume 04 / Issue 03 / September 2016
Page 63
© 2016 British Orthopaedic Association
Journal of Trauma and Orthopaedics: Volume 04, Issue 03, pages 60-63
Title: Advances in osteoarthritis imaging: What will make it into clinical practice?
Authors: Stephen McDonnell, Tom Turmezei, Martin Graves, Andrew McCaskie & Joshua Kaggie
Division of Trauma and Orthopaedics, University of Cambridge
Arthritis Research UK Tissue Engineering Centre
Figure 6: Standard sagittal proton T2 image (a), sodium MRI image (b), in a
healthy knee. The sodium image gives an indirect measurement of proteoglycan
content, which has been shown to be an indicator of cartilage health
The UTE images are courtesy of Dr.
James MacKay. Dr. Joshua Kaggie
is funded by GlaxoSmithKline.
The work was supported by the
Addenbrooke’s Charitable Trust
and the NIHR comprehensive
Biomedical Research Centre award
to Cambridge University Hospitals
NHS Foundation Trust in partnership
with the University of Cambridge. n
Email: [email protected]
Stephen McDonnell is a
University Lecturer and Honorary
Consultant Orthopaedic Surgeon
in Cambridge. He has an interest
in early arthritis phenotypes, novel
radiology techniques, patient
stratification and treatments.
References can be found online at
or by scanning the QR Code.
1. Pers YM, Rackwitz L, Ferreira R, et al. Adipose Mesenchymal Stromal Cell-Based Therapy for Severe Osteoarthritis
of the Knee: A Phase I Dose-Escalation Trial. Stem cells translational medicine. 2016.
2. Pritzker KP, Gay S, Jimenez SA, et al. Osteoarthritis cartilage histopathology: grading and staging. Osteoarthritis
and cartilage / OARS, Osteoarthritis Research Society. 2006;14:13-29.
3. Henckel J, Richards R, Lozhkin K, et al. Very low-dose computed tomography for planning and outcome
measurement in knee replacement. The imperial knee protocol. The Journal of bone and joint surgery British volume.
4. Turmezei TD, Treece GM, Gee AH, et al. Quantitative 3D analysis of bone in hip osteoarthritis using clinical
computed tomography. Eur Radiol. 2015.
5. Bousson V, Lowitz T, Laouisset L, et al. CT imaging for the investigation of subchondral bone in knee osteoarthritis.
Osteoporosis international : a journal established as result of cooperation between the European Foundation for
Osteoporosis and the National Osteoporosis Foundation of the USA. 2012;23 Suppl 8:S861-865.
6. Hill CL, Hunter DJ, Niu J, et al. Synovitis detected on magnetic resonance imaging and its relation to pain and
cartilage loss in knee osteoarthritis. Annals of the rheumatic diseases. 2007;66:1599-1603.
7. Graif M, Schweitzer M, Deely D, et al. The septic versus nonseptic inflamed joint: MRI characteristics. Skeletal
radiology. 1999;28:616-620.
8. Guermazi A, Roemer FW, Haugen IK, et al. MRI-based semiquantitative scoring of joint pathology in osteoarthritis.
Nature Reviews Rheumatology. 2013;9:236-251.
9. Hardy PA, Recht MP, Piraino D, et al. Optimization of a dual echo in the steady state (DESS) free‐precession
sequence for imaging cartilage. Journal of Magnetic Resonance Imaging. 1996;6:329-335.
10. Eckstein F, Hudelmaier M, Wirth W, et al. Double echo steady state magnetic resonance imaging of knee articular
cartilage at 3 Tesla: a pilot study for the Osteoarthritis Initiative. Annals of the rheumatic diseases. 2006;65:433-441.
11. Guermazi A, Alizai H, Crema MD, et al. Compositional MRI techniques for evaluation of cartilage degeneration in
osteoarthritis. Osteoarthritis Cartilage. 2015;23:1639-1653.
12. Tiderius CJ, Svensson J, Leander P, et al. dGEMRIC (delayed gadolinium‐enhanced MRI of cartilage) indicates
adaptive capacity of human knee cartilage. Magnetic resonance in medicine : official journal of the Society of
Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. 2004;51:286-290.
13. Trattnig S, Mlyńarik Vr, Breitenseher M, et al. MRI visualization of proteoglycan depletion in articular cartilage via
intravenous administration of Gd-DTPA. Magnetic resonance imaging. 1999;17:577-583.
14. Bashir A, Gray ML, Boutin RD, et al. Glycosaminoglycan in articular cartilage: in vivo assessment with delayed Gd
(DTPA)(2-)-enhanced MR imaging. Radiology. 1997;205:551-558.
15. Bittersohl B. Delayed gadolinium-enhanced magnetic resonance imaging of hip joint cartilage (dGEMRIC): pearls
and pitfalls. Orthopedic reviews. 2011;3:11.
16. Burstein D, Velyvis J, Scott KT, et al. Protocol issues for delayed Gd (DTPA) 2–‐enhanced MRI (dGEMRIC) for
clinical evaluation of articular cartilage. Magnetic resonance in medicine : official journal of the Society of Magnetic
Resonance in Medicine / Society of Magnetic Resonance in Medicine. 2001;45:36-41.
17. Cunningham T, Jessel R, Zurakowski D, et al. Delayed gadolinium-enhanced magnetic resonance imaging of
cartilage to predict early failure of Bernese periacetabular osteotomy for hip dysplasia. J Bone Joint Surg Am.
18. Kanda T, Ishii K, Kawaguchi H, et al. High signal intensity in the dentate nucleus and globus pallidus on
unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast
material. Radiology. 2013;270:834-841.
19. Williams, A., Sharma, L., McKenzie, C. A., Prasad, P. V. and Burstein, D. (2005), Delayed gadolinium-enhanced
magnetic resonance imaging of cartilage in knee osteoarthritis: Findings at different radiographic stages of disease
and relationship to malalignment. Arthritis & Rheumatism, 52: 3528–3535. doi: 10.1002/art.21388
20. Kijowski R, Blankenbaker DG, Munoz del Rio A, et al. Evaluation of the articular cartilage of the knee joint: value
of adding a T2 mapping sequence to a routine MR imaging protocol. Radiology. 2013;267:503-513.
21. Dunn TC, Lu Y, Jin H, et al. T2 Relaxation Time of Cartilage at MR Imaging: Comparison with Severity of Knee
Osteoarthritis 1. Radiology. 2004;232:592-598.
22. Liess C, Lüsse S, Karger N, et al. Detection of changes in cartilage water content using MRI T 2-mapping in vivo.
Osteoarthritis and Cartilage. 2002;10:907-913.
23. Akella SV, Reddy Regatte R, Gougoutas AJ, et al. Proteoglycan‐induced changes in T1ρ‐relaxation of articular
cartilage at 4T. Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine /
Society of Magnetic Resonance in Medicine. 2001;46:419-423.
24. Nishioka H, Hirose J, Nakamura E, et al. Detecting ICRS grade 1 cartilage lesions in anterior cruciate ligament
injury using T1ρ and T2 mapping. European journal of radiology. 2013;82:1499-1505.
25. Wang Y-XJ, Griffith JF, Leung JC, et al. Age related reduction of T1rho and T2 magnetic resonance relaxation times
of lumbar intervertebral disc. Quantitative imaging in medicine and surgery. 2014;4:259.
26. Mosher TJ, Liu Y, Yang QX, et al. Age dependency of cartilage magnetic resonance imaging T2 relaxation times in
asymptomatic women. Arthritis & Rheumatism. 2004;50:2820-2828.
27. Freeman DM, Bergman G, Glover G. Short TE MR microscopy: accurate measurement and zonal differentiation of
normal hyaline cartilage. Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in
Medicine / Society of Magnetic Resonance in Medicine. 1997;38:72-81.
28. Xia Y, Farquhar T, Burton‐Wurster N, et al. Diffusion and relaxation mapping of cartilage‐bone plugs and excised
disks using microscopic magnetic resonance imaging. Magnetic resonance in medicine : official journal of the Society
of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. 1994;31:273-282.
29. Williams A, Qian Y, Bear D, et al. Assessing degeneration of human articular cartilage with ultra-short echo time
(UTE) T 2* mapping. Osteoarthritis and Cartilage. 2010;18:539-546.
30. Gold GE, Thedens DR, Pauly JM, et al. MR imaging of articular cartilage of the knee: new methods using
ultrashort TEs. AJR American journal of roentgenology. 1998;170:1223-1226.
31. Bae WC, Dwek JR, Znamirowski R, et al. Ultrashort Echo Time MR Imaging of Osteochondral Junction of the Knee
at 3 T: Identification of Anatomic Structures Contributing to Signal Intensity 1. Radiology. 2010;254:837-845.
32. Samsonov A, Block WF, Field AS. Reconstruction of MRI data using sparse matrix inverses. Signals, Systems and
Computers, 2007 ACSSC 2007 Conference Record of the Forty-First Asilomar Conference on: IEEE; 2007:1884-1887.
33. Madelin G, Regatte RR. Biomedical applications of sodium MRI in vivo. Journal of Magnetic Resonance Imaging.
34. Zbýň Š, Mlynárik V, Juras V, et al. Evaluation of cartilage repair and osteoarthritis with sodium MRI. NMR in
Biomedicine. 2016;29:206-215.
35. Shapiro EM, Borthakur A, Gougoutas A, et al. 23Na MRI accurately measures fixed charge density in articular
cartilage. Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine /
Society of Magnetic Resonance in Medicine. 2002;47:284-291.
36. Reddy R, Insko EK, Noyszewski EA, et al. Sodium MRI of human articular cartilage in vivo. Magn Reson Med.
37. Madelin G, Babb J, Xia D, et al. Articular cartilage: evaluation with fluid-suppressed 7.0-T sodium MR imaging in
subjects with and subjects without osteoarthritis. Radiology. 2013;268:481-491.
38. Wiggins GC, Brown R, Lakshmanan K. High-performance radiofrequency coils for 23Na MRI: brain and
musculoskeletal applications. NMR in Biomedicine. 2016;29:96-106.
39. Bangerter NK, Kaggie JD, Taylor MD, et al. Sodium MRI radiofrequency coils for body imaging. NMR in
Biomedicine. 2016;29:107-118.
40. de Bruin PW, Versluis MJ, Koken P, et al. Time-efficient interleaved 23Na and 1H acquisition at 7T. Milan, Italy:
Proc. Intl. Soc. Mag. Reson. Med.; 2014:0034.