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Tibial subchondral trabecular volumetric bone density in medial knee joint osteoarthritis using peripheral quantitative computed tomography technology.

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ARTHRITIS & RHEUMATISM
Vol. 58, No. 9, September 2008, pp 2776–2785
DOI 10.1002/art.23795
© 2008, American College of Rheumatology
Tibial Subchondral Trabecular Volumetric Bone Density
in Medial Knee Joint Osteoarthritis Using
Peripheral Quantitative Computed Tomography Technology
Kim L. Bennell,1 Mark W. Creaby,1 Tim V. Wrigley,1 and David J. Hunter2
higher vBMD in the medial compartment compared
with the lateral compartment, but these ratios were not
influenced by disease status.
Conclusion. Subregional vBMD changes were evident beneath the medial and lateral compartments of
those with moderate medial knee OA. Of import, the
posterior subchondral trabecular regions of the medial
tibial plateau have markedly lower vBMD.
Objective. Knee osteoarthritis (OA) is an organlevel failure of the joint involving pathologic changes in
articular cartilage and bone. This cross-sectional study
compared apparent volumetric bone mineral density
(vBMD) of proximal tibial subchondral trabecular bone
in people with and without knee OA, using peripheral
quantitative computed tomography (pQCT).
Methods. Seventy-five individuals with mild or
moderate medial compartment knee OA and 41 asymptomatic controls were recruited. Peripheral QCT was
used to measure vBMD of trabecular bone beneath
medial and lateral tibiofemoral compartments at levels
of 2% and 4% of tibial length, distal to the tibial plateau.
Results. There was no significant difference in
vBMD beneath the overall medial and lateral compartments between the 3 groups. However, in the affected
medial compartment of those with moderate OA, lower
vBMD was seen in the 2 posterior subregions compared
with controls and those with mild knee OA, while higher
vBMD was seen in the anteromedial subregion. Beneath
the unaffected or lesser affected lateral compartment,
significantly lower vBMD was seen at the 2% level in the
anterior and lateral subregions of those with moderate
disease. Volumetric BMD ratios showed relatively
Knee osteoarthritis (OA), which most commonly
affects the medial tibiofemoral compartment, is a prevalent chronic, localized joint disease (1) that involves
pathologic changes in articular cartilage and subchondral bone (2). However, there is debate about the role
and timing of bone and cartilage changes in disease
initiation and progression. It also appears that the
various subchondral bony layers beneath the articular
cartilage (calcified cartilage, subchondral cortical plate,
and subchondral trabecular bone) respond differently
and play different roles in knee OA (2,3). Much of our
understanding of bone changes in knee OA has come
from studies using specimens obtained at autopsy, from
animals, or from patients undergoing total knee joint
arthroplasty, and thus having end-stage disease. There is
limited in vivo research evaluating tibial subchondral
bone changes, particularly in those with less severe
disease and as the disease progresses. Our goal was to
focus on the subchondral trabecular bone, since an
improved understanding of the role of this tissue in knee
OA may assist in developing more targeted treatment
interventions.
Trabecular bone has traditionally been investigated using a number of key measures that assess the
quantity of bone in a fixed volume, the mineral density
of that bone tissue itself, and the mass of bone mineral
within the fixed volume; these are the bone volume
fraction (bone volume over the total, fixed, sample
Supported by an Australian Research Council Large Infrastructure Equipment grant (LEO453623), a grant from the William
Buckland Foundation (ANZ Trustees), and a National Health and
Medical Research Council project grant (350297).
1
Kim L. Bennell, BAppSci(Physio), PhD, Mark W. Creaby,
BSc (Hons), PhD, Tim V. Wrigley, BSc (Hons), MSc: The University
of Melbourne, Melbourne, Victoria, Australia; 2David J. Hunter,
MBBS, PhD: New England Baptist Hospital, Boston, Massachusetts.
Dr. Bennell has received speaking fees from the Hong Kong
Association of Rehabilitation Medicine (less than $10,000).
Address correspondence and reprint requests to Kim L.
Bennell, PhD, Centre for Health, Exercise and Sports Medicine
(CHESM), The University of Melbourne, 202 Berkeley Street, Melbourne, Victoria 3010, Australia. E-mail: k.bennell@unimelb.edu.au.
Submitted for publication October 18, 2007; accepted in
revised form May 23, 2008.
2776
VOLUMETRIC BONE DENSITY IN KNEE OA
measurement volume [BV/TV]), the material density
(bone mass over bone volume [BM/BV]), and apparent
bone mineral density (BMD) (bone mass over fixed total
volume [BM/TV]). The bone volume fraction also determines the porosity (1 ⫺ [BV/TV]), that is, the proportion of space not occupied by bone tissue. It is also
clear from the above that the apparent BMD (BM/TV)
is equal to the bone volume fraction (BV/TV) multiplied
by the material density (BM/BV).
A range of imaging technologies has been used to
evaluate some or all of these parameters or related
indices in subchondral tibial trabecular bone in knee
OA. These technologies include high-resolution magnetic resonance imaging (MRI) (4), macroradiography
(5) and micro–computed tomography (6), the latter of
which is generally limited to in vitro applications (7).
While unable to distinguish trabecular from cortical
bone, dual energy x-ray absorptiometry (DXA) has also
been used to assess the subchondral proximal tibia,
where both cortical and trabecular bone are found.
However, DXA does not assess any of the traditional
parameters of trabecular bone. Rather, it derives the
areal BMD (aBMD; gm/cm2) by dividing the bone
mineral content by the projected area. As such, it is not
sensitive to size differences in the third dimension (8)
and may lead to erroneous conclusions (9).
These imaging technologies have demonstrated a
number of changes in trabecular bone associated with
knee OA in vivo. MRI studies have correlated cartilage
volume loss with increased bone volume fraction beneath the affected compartment, and decreased bone
volume fraction beneath the unaffected compartment
(4,10,11). Fractal signature analysis of macroradiographs
has shown thinning of vertical trabeculae, in particular,
to be characteristic of the predominantly less dense
subchondral trabecular bone in OA (5,12,13). The few
DXA studies, however, are contradictory, with reports
of no difference (5,14), and lower (15) or higher (16,17)
apparent aBMD in the OA groups compared with controls.
Peripheral quantitative computed tomography
(pQCT) is a broad class of x-ray–based tomographic scanners that can operate at pixel resolutions from ⬍100 ␮m
to ⬃500 ␮m. However, the larger scanners that can
accommodate a human limb tend to operate in the range
from 200 ␮m to 500 ␮m. At this resolution, which is not
high enough to identify individual trabeculae, pQCT
measures the apparent volumetric density of the mineral
fraction of each fixed-volume, 3-dimensional voxel (BM/
2777
TV) (8). Thus, it cannot measure such parameters as the
bone volume fraction (BV/TV).
Peripheral QCT has several advantages over
DXA, in particular for evaluating BMD of subchondral
trabecular bone in knee OA. First, it provides
3-dimensional vBMD rather than aBMD and thus is not
influenced by differences in bone size. Second, it allows
for separate examination of trabecular and cortical
bone. This is not merely an issue of delineation. Because
cortical bone is much denser than trabecular bone (i.e.,
there is more of it), changes in trabecular bone are
difficult to detect with DXA, in which both types of bone
are present within the sampled region, i.e., cortical bone
dominates. Third, because pQCT uses thin crosssectional slices, bone density profiles can be examined in
subregions across a particular level. This is important for
knee OA because loading varies across the tibial plateaus, and articular cartilage wear is greater in particular
regions (18). Thus, it is likely that subchondral bone
density will be heterogeneous across a given level beneath the plateau. However, to date, there have been no
studies of in vivo proximal tibial subchondral bone in
knee OA using the low ionizing technology (19) of
pQCT.
The specific aim of this study was to compare,
using pQCT, the tibial subchondral trabecular vBMD
beneath the medial and lateral joint compartments in
patients with medial knee OA of varying severity and in
subjects without OA.
PATIENTS AND METHODS
Study participants. One hundred sixteen participants
were recruited, including 75 patients with medial compartment
knee OA (39 women, 36 men) and 41 asymptomatic, healthy
controls (24 women, 17 men).
Diagnosis of knee OA was based on the American
College of Rheumatology classification criteria (20). Participants were included if they were ⬎50 years of age and had
knee pain on most days of the previous month (average level
⬎3 cm on a 10-cm visual analog scale). Other inclusion criteria
were a predominance of pain/tenderness over the medial
region of the knee and medial radiographic OA (defined as at
least grade 1 medial joint space narrowing [more narrowing in
the medial than in the lateral compartment] and grade 1
medial tibial or femoral osteophytes) (21). The exclusion
criteria were as follows: questionable presence of or advanced
radiographic knee OA (Kellgren/Lawrence [K/L] score of 1 or
4, respectively) (22), predominant patellofemoral joint symptoms based on clinical examination, knee surgery or intraarticular corticosteroid injection within the past 6 months, current or past (within 4 weeks) oral corticosteroid use, systemic
arthritic conditions, a history of tibiofemoral/patellofemoral
2778
joint replacement or tibial osteotomy, or taking medication or
having any condition that could affect bone density. Participants with either unilateral and bilateral disease were included,
with the more painful knee studied.
Controls were excluded if they reported a history of
knee pain that interfered with function or caused them to seek
treatment within the past year, had prior knee surgery, had any
condition that affected mobility for ⬎1 week in the past 12
months, or had any condition or were taking any medications
that could affect bone density.
The research was approved by the University of Melbourne Human Research Ethics Committee and the Department of Human Services Radiation Safety Committee. All
participants provided written informed consent.
Tibial subchondral trabecular vBMD. A Stratec XCT
3000 pQCT scanner (Stratec, Pforzheim, Germany) was used
to measure apparent vBMD (mg/cm3; not to be confused with
bone mineral apparent density, a DXA-derived measure).
Participants were seated with the extended leg placed in the
scanner gantry (Figure 1a). A scout scan of the tibiofemoral
joint was performed first, after which 1 medial and 1 lateral
reference line were interactively placed on the scout image at
half the depth of the region of highest radio-opacity near the
surface of the tibia (indicating the highest cortical bone
density), midway between the medial and lateral borders of the
respective compartments (Figure 1b). Four transverse CT
scans were then obtained at 2% and 4% of tibial length
(defined as the distance from the medial joint line to the tip of
the medial malleolus) distal to the reference lines. These levels
were designed to sample subchondral trabecular bone deep to
the subchondral cortical plate, consistent with our objective.
The 2% level in our participants corresponded to ⬃6.4–8.6
mm from the reference line, while the 4% level corresponded
to ⬃12.7–17.1 mm from the reference line. The XCT 3000 has
a fixed slice thickness of 2.3 mm. The voxel size was set at
500 ⫻ 500 ␮m, and the scan speed was 20 mm/second. Total
scan time was ⬃15 minutes.
The analysis was conducted using custom-written
MatLab software (MathWorks, Natick, MA) because currently
available commercial software is not suited to subregional analysis
of subchondral trabecular bone. With our custom software (23),
soft tissue was removed and the outer tibial cortex was identified.
Ellipses were then automatically placed to define the regions of
interest (ROIs) in the slices taken from beneath the medial and
lateral compartments. The width of the ellipses was 0.35 of the
maximum medial–lateral tibial outer cortical dimension, and the
height was 0.40 of the maximum anteroposterior dimension at the
medial–lateral centroid of each compartment. These dimensions
ensured that cortical regions and osteophytes were not included.
Six subregions of interest within each ellipse were then created
(anteromedial, anterolateral, middle medial, middle lateral, posteromedial, and posterolateral) at the 2% and 4% levels (Figure
1c). The variable of interest was the mean trabecular apparent
vBMD (mg/cm3), in the whole medial and lateral ellipses and in
each of the subregions.
Test–retest reliability was established in 16 subjects
with and without knee OA, who were measured twice with
repositioning. Intraclass correlation coefficients (ICC 2.1)
BENNELL ET AL
Figure 1. a, Patient positioning for measurement of tibial subchondral trabecular volumetric bone mineral density. b, Scout view, showing medial and lateral reference lines and measurement positions at
2% and 4% tibial length distal to each reference line. c, Transverse
peripheral quantitative computed tomography scan of the subchondral
tibia, showing the medial and lateral ellipses and demarcation of
lateral and medial subregions of interest.
ranged from 0.86 to 0.99 for the 2% level ROIs and from 0.83
to 0.99 for the 4% ROIs.
Disease severity and knee alignment. In patients with
knee OA, standardized semiflexed posteroanterior knee radiographs were obtained with the participant standing barefoot.
Radiographic severity of tibiofemoral OA was assessed using
the K/L scale, where 0 ⫽ normal, 1 ⫽ possible osteophytes, 2 ⫽
minimal osteophytes and possible joint space narrowing, 3 ⫽
moderate osteophytes, some narrowing, and possible sclerosis,
and 4 ⫽ large osteophytes, definite joint space narrowing, and
VOLUMETRIC BONE DENSITY IN KNEE OA
2779
Table 1. Characteristics of the control and OA groups*
Age, years
Female, no. (%)
Height, meters
Body mass, kg
BMI, kg/m2
Knee alignment,
degrees§
Controls
(n ⫽ 41)
Mild OA
(n ⫽ 40)
Moderate OA
(n ⫽ 35)
60.5 ⫾ 8.5
24 (58.5)
1.67 ⫾ 0.1
74.6 ⫾ 14.0
26.5 ⫾ 3.5
–
62.8 ⫾ 7.6
23 (57.5)
1.67 ⫾ 0.1
80.6 ⫾ 15.1
28.8 ⫾ 4.4‡
179.6 ⫾ 1.3
67.4 ⫾ 7.9†
19 (54.3)
1.70 ⫾ 0.1
91.0 ⫾ 12.6†
31.9 ⫾ 4.6†
177.7 ⫾ 1.9¶
* Except where indicated otherwise, values are the mean ⫾ SD. OA ⫽
osteoarthritis; BMI ⫽ body mass index.
† P ⱕ 0.05 versus controls and versus mild OA.
‡ P ⱕ 0.05 versus controls.
§ Lower numbers indicate greater varus.
¶ P ⱕ 0.05 versus mild OA.
severe sclerosis (21,22). The radiographs were assessed by an
experienced musculoskeletal researcher and physiotherapist
(KLB) whose intrarater reliability was 0.87 (linearly incremental weighted kappa statistic).
Anatomic knee alignment was measured using the
posteroanterior radiographs. Alignment measured in this manner is strongly correlated with the mechanical axis obtained
from a long leg radiograph (ICC 0.86; data from 40 patients in
our laboratory) (24) and avoids the additional cost and radiation associated with a long leg radiograph. A prediction
equation was used for conversion (24). The intrarater and
interrater reliability of this technique was excellent (ICC ⫽
0.98 and 0.97, respectively).
Statistical analysis. Results are expressed as the adjusted mean and SE. Data were analyzed using SPSS, version
13.0 (SPSS, Chicago, IL). Checks were made for normality and
violation of statistical assumptions. Patients with OA were
divided into 2 groups based on the K/L score; those with a K/L
score of 2 were categorized as having mild disease, while those
with a K/L score of 3 were categorized as having moderate
disease. Differences between the mild OA, moderate OA, and
control groups in each ROI at 2% and 4% levels were
determined using generalized linear models (GLMs). Group
was included as a fixed factor, while age, body mass, and sex
were included as covariates. The adjusted models were followed by pairwise contrasts to locate the source of any
significant differences. Differences between groups in the ratio
of vBMD beneath the medial and lateral compartments were
also calculated, using the same GLM approach as described
above. P values less than 0.05 were considered significant.
RESULTS
Characteristics of the OA and control groups
are shown in Table 1. The groups were similar in sex
representation and were comparable in height. However, the moderate OA group was significantly older,
heavier, and had a higher body mass index (BMI)
compared with the control and mild OA groups. The
mild OA group had a significantly higher BMI than the
control group. The moderate OA group had greater
varus malalignment than the mild OA group.
Table 2. Trabecular volumetric bone mineral density (mg/cm3) overall and in each subregion of interest in the affected medial
compartment
Controls (n ⫽ 41)
2% level
Whole ellipse
Posteromedial
Posterolateral
Middle medial
Middle lateral
Anteromedial
Anterolateral
4% level
Whole ellipse
Posteromedial
Posterolateral
Middle medial
Middle lateral
Anteromedial
Anterolateral
Mild OA (n ⫽ 40)
Moderate OA (n ⫽ 35)
Adjusted
mean
SE
Adjusted
mean
SE
Adjusted
mean
SE
205.419
221.120
150.362
254.990
151.671
244.256
213.647
4.990
7.512
5.490
8.134
4.125
7.684
6.702
205.655
217.544
149.790
258.902
151.372
249.730
208.267
4.656
7.009
5.123
7.589
3.849
7.170
6.254
198.931
190.428*
131.647*
257.093
143.295
271.351†
199.758
5.601
8.430
6.162
9.129
4.629
8.624
7.522
193.459
240.491
166.103
251.043
122.112
224.164
164.454
5.213
8.743
5.995
7.584
4.950
6.919
5.095
189.261
225.439
155.215
240.351
123.949
227.755
169.880
4.864
8.158
5.593
7.077
4.619
6.456
4.754
182.779
200.588†
149.897
229.082
114.243
241.262
170.901
5.851
9.812
6.728
8.512
5.556
7.765
5.718
* P ⱕ 0.05 versus controls and versus mild osteoarthritis (OA) (generalized linear model with age, sex, and body mass as
covariates).
† P ⱕ 0.05 versus controls (generalized linear model with age, sex, and body mass as covariates).
2780
BENNELL ET AL
Figure 2. Percentage difference in subchondral trabecular volumetric bone mineral density beneath the medial (a) and lateral (b) compartments
at 2% distal to the tibial plateau reference line, in the osteoarthritis (OA) patient groups compared with the control group. The color bar provides
a visual representation of increasingly greater differences in bone density in the mild and moderate OA groups compared with controls. ⴱ indicates
P ⱕ 0.05 versus controls; † indicates P ⱕ 0.05 versus mild OA.
Beneath the medial compartment, the trabecular
vBMD of the whole ellipse was similar in the OA and
control groups at both the 2% and 4% levels. However,
subregional differences in vBMD existed between
groups (Table 2). At the 2% level, the moderate OA
group had a significantly lower vBMD than both the
controls and the mild OA group in the posteromedial
and posterolateral subregions. These differences ranged
from 12.1% lower to 13.9% lower than in the control
and mild OA groups, respectively. However, the moderate OA group had a significantly higher vBMD than the
controls in the anteromedial subregion, with a similar
trend also observed when compared with the mild OA
group (P ⫽ 0.06). The percentage differences in vBMD
in the OA groups compared with controls are shown in
Figure 2. At the 4% level, the deficit in posteromedial
vBMD was seen in the moderate OA group compared
with controls, with bone density being 16.6% lower (P ⫽
0.006). No other significant subregional differences in
bone density were noted between groups at the 4% level.
Beneath the unaffected or less affected lateral
compartment (Table 3), trabecular vBMD of the whole
ellipse at the 2% level was 10% lower in the moderate
OA group compared with controls, which almost
reached significance (P ⫽ 0.057). Subregional vBMD
differences existed between the groups at the 2% level.
Volumetric BMD was significantly less in the moderate
OA group compared with controls in the posteromedial
(14% less), posterolateral (13.1% less), and middle
lateral (11.4% less) subregions. It was also significantly
lower when compared with the mild OA group in the
posterolateral subregion (9.4% less). Overall and subregional vBMD at the 4% level was similar between groups.
The medial to lateral vBMD ratios from the
whole ellipse at both the 2% and 4% levels were ⬎1,
indicating a relatively higher vBMD beneath the medial
VOLUMETRIC BONE DENSITY IN KNEE OA
2781
Table 3. Trabecular volumetric bone mineral density (mg/cm3) overall and in each subregion of interest in the unaffected or
less affected lateral compartment
Controls (n ⫽ 36)
2% level
Whole ellipse
Posteromedial
Posterolateral
Middle medial
Middle lateral
Anteromedial
Anterolateral
4% level
Whole ellipse
Posteromedial
Posterolateral
Middle medial
Middle lateral
Anteromedial
Anterolateral
Mild OA (n ⫽ 37)
Moderate OA (n ⫽ 29)
Adjusted
mean
SE
Adjusted
mean
SE
Adjusted
mean
SE
187.032
219.545
241.276
158.126
199.318
143.585
167.436
5.515
8.014
7.227
5.435
6.019
5.777
6.394
179.449
206.942
231.357
155.442
188.579
137.245
164.290
4.959
7.207
6.499
4.887
5.413
5.195
5.749
168.924
188.885*
209.563†
149.916
176.568*
138.718
155.291
6.524
9.482
8.550
6.430
7.121
6.835
7.564
160.034
222.370
212.501
108.718
171.841
123.927
137.964
5.239
7.123
7.358
5.972
6.470
5.256
7.026
155.218
207.536
206.771
108.094
164.417
118.566
143.106
4.711
6.405
6.616
5.371
5.818
4.726
6.318
151.840
200.833
191.246
112.947
161.266
119.805
139.069
6.198
8.427
8.705
7.066
7.655
6.218
8.312
* P ⱕ 0.05 versus controls (generalized linear model with age, sex, and body mass as covariates).
† P ⱕ 0.05 versus controls and versus mild osteoarthritis (OA) (generalized linear model with age, sex, and body mass as
covariates).
compartment compared with the lateral compartment in
all 3 groups (Figure 3). The ratios ranged from 1.1 to 1.2,
indicating 10–20% greater vBMD beneath the medial
compartment. Consistent with the findings that vBMD
in the whole medial and lateral ellipse was similar
between groups, there was no difference in ratios between groups (P ⬎ 0.05).
Figure 3. Ratio of overall medial to lateral trabecular volumetric
bone mineral density in the osteoarthritis (OA) and control groups,
shown as the adjusted mean and SE at 2% and 4% distal to the tibial
plateau reference line.
DISCUSSION
This study is the first to assess apparent vBMD of
tibial subchondral trabecular bone in patients with medial knee OA using pQCT, and the first to assess in vivo
regional variations in vBMD. In general, it showed no
differences in apparent vBMD beneath the whole medial and lateral compartment, or in their ratio, when
comparing medial knee OA and control groups. However, an examination of subregional vBMD beneath
each compartment revealed significant group differences. Beneath the affected medial compartment of
those with moderate OA disease, subregions of both
lower and higher vBMD were found when compared
with controls and those with mild knee OA. Beneath the
less affected or unaffected lateral compartment, subregions of significantly lower vBMD were seen in patients
with moderate OA disease. A greater number of vBMD
differences between groups were noted at the 2% rather
than the 4% tibial level, which makes intuitive sense,
since its closer proximity to the diseased joint surface
makes it more likely to be implicated in the OA process.
Apparent trabecular vBMD beneath the medial
compartment as a whole did not differ between groups.
This finding is consistent with some DXA studies (14),
but not others, in which both increased and decreased
2782
aBMD have been reported in those with knee OA
(15–17). However, it is difficult to make direct comparisons given the differences between DXA and pQCT. In
particular, the differences may relate to the inability of
DXA to distinguish between cortical and trabecular
bone and to its measurement of aBMD. Since the latter
measure may be associated with bone size–related artifact (25), size differences between individuals and
changes in bone size with OA disease may be important
(26) and may subsequently influence DXA results.
Given these issues, we believe that our results using
pQCT provide a more accurate reflection of proximal
tibial trabecular BMD in patients with knee OA.
Our results indicate that assessment of apparent
vBMD in the compartment as a whole can mask subregional variations that exist. In those with moderate knee
OA, we found significantly lower vBMD in the posteromedial and posterolateral subregions of the affected
medial compartment compared with controls and those
with mild OA. In fact, two-thirds of the subregions
exhibited a similar pattern. However, in the anteromedial subregion, we found significantly higher vBMD in
the group with moderate knee OA. These variations
could reflect regional differences in mechanical load and
cartilage degeneration. Overall, the medial knee joint
compartment experiences greater load than the lateral
compartment (27). This load differential is exacerbated
by more severe disease (28) and joint malalignment
(17,29). However, within the medial compartment, the
actual distribution of loading and cartilage wear patterns
across the tibial plateau are complex, heterogeneous,
and not consistently established.
Loading and cartilage wear within the medial
compartment appear to vary depending on factors such
as the integrity of the anterior cruciate ligament
(18,30,31), meniscal status (32,33), and joint malalignment (18,31). For example, one study found the greatest
cartilage wear in the anterior regions in medial knee OA
(34), whereas others have shown greater involvement in
the posterior regions (18,31). Subregional vBMD differences between groups might reflect these loading variations given that bone responds to the loads that are
placed upon it. We must be somewhat cautious in these
interpretations, since it is also conceivable that some
differences may actually originate in the subchondral
trabecular bone prior to development of OA.
One difficulty in understanding the trabecular
bone changes in OA is reconciling results derived from
different measures. An increase in trabecular bone
volume fraction (BV/TV) is a characteristic finding in
BENNELL ET AL
OA. This has been shown in the late stages of OA (35),
as well as early in its course (36). However, the material
density of this tissue typically indicates relative undermineralization. Thus, at the tissue level, OA is actually
associated with reduced material bone density (2). Remembering that the apparent BMD (BM/TV) is equal to
the bone volume fraction (BV/TV) multiplied by the
material density (BM/BV), changes in either of the latter
2 quantities will change the vBMD. The exact effect
depends on the relative magnitude and direction of the
changes in bone volume and material density, although
only to the extent that these change bone mass (given
that total volume is fixed in vBMD). Studies that have
shown an increase in subchondral trabecular bone (e.g.,
BV/TV) have also generally investigated the region very
close to the subchondral cortical plate (36–38). A reduction in bone may be more characteristic of trabecular
bone at a greater distance from the cortical plate (5,38).
In this study, the localized lower vBMD beneath
the affected medial compartment was marked (up to
17% lower), particularly in the posterior subregions. The
interpretation of this result is that it is due to reduced
mineral mass. This is most likely related to a decrease in
bone tissue volume (e.g., thinning of trabeculae); however, if remodeling is occurring, reduced mineralization
of the new bone could also partly explain a loss of overall
mineral mass. Remodeling is likely to be driven by
changes in loading, which would result in remodeling
due to either direct bone effects or the production of
microdamage (39). If the posterior subregions are directly exposed to lower load, then the subchondral
trabecular bone would respond by remodeling with
greater bone resorption, thus reducing its bone mass and
hence its apparent vBMD.
In contrast, although seemingly counterintuitive,
there are possible mechanisms by which increased joint
loading could also lead to localized lower subchondral
trabecular vBMD. One is related to the thickening of the
interposed subchondral cortical plate that occurs in OA,
and has been shown in animal studies to occur prior to
cartilage deterioration (6,40). This new, thickened bone
may be poorly mineralized (41) due to the increased
bone remodeling. This may, in turn, reduce the stiffness
of the cortical plate (42–44). However, the timing of
these cortical plate changes is complex and not particularly well understood (3,38). However, it has been
suggested that the thickened but less stiff cortical bone
would absorb more of the load through the knee joint,
thus potentially shielding the underlying subchondral
trabecular bone (2,3,5,13). In response to this reduced
VOLUMETRIC BONE DENSITY IN KNEE OA
loading, the trabecular bone may undergo increased
remodeling with subsequent loss of mass and therefore
apparent vBMD. This effect has been likened to “stress
shielding” of bone around a metal implant. Another
possibility is that high loading could lead to microdamage accumulation (39) and a transient reduction in
apparent vBMD. However, given that our results were
seen in those with more advanced disease, this is a less
likely explanation. Regardless of the mechanism, the
timing of these reductions in bone density is also not
well understood (3,6,13,38).
While vBMD differences with tibiofemoral OA
have not previously been reported in vivo, our finding of
lower vBMD has recently been shown by pQCT in
patellae of human cadavers (45). In 14 patellae, those with
advanced or moderate cartilage degeneration had reductions in vBMD of ⬃25% and ⬃10%, respectively, compared with those patellae with no or minimal degeneration.
Also consistent with our results, loss of trabeculae (5,13)
and reductions in aBMD (15) have been found in human in
vivo studies using other technologies.
The area of higher vBMD beneath the anteromedial subregion in the group with moderate OA could
reflect an area subjected to increased loading. Since this
increased density was isolated to 1 region confined to
the 2% level, it is possible that some regions of subchondral trabecular bone closer to the cortical plate may
experience increased density similar to that of the
cortical plate (5,37). Regional variations in the thickness
and depth of the cortical plate (46) might have contributed to the finding being limited to this subregion. Also,
as the disease progresses, changes that may initially
occur more proximally, closer to the cortical plate, may
extend more distally (37). This may occur at different
rates in different regions.
The findings of altered subregional vBMD were
only significant in those with moderate knee OA. While
similar trends were seen in the group with mild OA, the
differences were of a lesser magnitude. This suggests
that vBMD changes as detected by pQCT become more
apparent as the disease progresses. This is consistent
with findings using other techniques, such as macroradiography (13). Further investigation is required to
elucidate the pattern of vBMD change in humans
through longitudinal studies.
Beneath the less affected or unaffected lateral
compartment, the adjusted mean overall vBMD was
10% lower in the group with moderate OA, with the
result just failing to reach significance (P ⫽ 0.057). This
group also demonstrated substantially lower vBMD at
2783
the 2% level in half the subregions. It has been surmised
that lower bone density beneath the lateral compartment may simply represent disuse osteopenia (4,47).
This could be due to the fact that more of the load is
shifted to the medial compartment due to increasing
varus malalignment and joint changes as the disease
progresses (17,28,29). It is also possible that reduced
physical activity levels as a person’s disease severity
worsens (48) could lower the overall amount of loading
taken through the knee.
The medial:lateral vBMD ratios of all 3 groups at
both the 2% and the 4% levels were ⬎1, reflecting
relatively higher vBMD beneath the medial tibial compartment compared with the lateral compartment. This
is consistent with some DXA studies of aBMD ratios
(17,49–51). However, it is important to note that medial:
lateral ratios ⬎1 are unable to distinguish between
increased density on the medial side and decreased
density on the lateral side. Since both phenomena seem
to be apparent in OA, precise interpretation of this
measure is problematic. Despite the findings of regional
variations in the extent of the relative increased or
decreased trabecular vBMD among OA participants and
controls, our pQCT-based medial:lateral vBMD ratios,
which are not subject to the possible artifacts of DXA,
did not show any differences between controls and those
with mild or moderate OA. Thus, while several DXA
studies have found that those with more severe disease
and greater joint space narrowing have higher aBMD
ratios (17,50), we do not believe that interpretation of
such findings is clearcut in relation to changes beneath
either the medial or the lateral compartment. We would
therefore advise that medial:lateral density ratios not be
used as primary outcome measures. Our results indicate
that the relative proportion of trabecular vBMD beneath
the compartments as a whole at the 2 levels we measured
is not altered in those with mild to moderate OA.
In summary, subregional vBMD changes in the
proximal tibia are apparent in those with moderate
medial knee OA compared with those with mild OA and
in healthy controls. Of import, the posterior subchondral
trabecular regions beneath the affected medial tibial
plateau, as well as a number of regions beneath the
unaffected lateral compartment, appear to have markedly lower vBMD. In general, our findings using pQCT
to measure vBMD are consistent with results of some in
vitro studies and some in vivo studies, for example, those
using macroradiography. It is apparent that further
studies are needed. In particular, more focused attention
on subregional vBMD as it relates to regional alterations
2784
BENNELL ET AL
in cartilage and mechanical loading, as well as measurement of longitudinal changes in vBMD as the disease
progresses, would provide important data.
12.
ACKNOWLEDGMENTS
We wish to thank Associate Professor Mark R. Forwood for his valuable feedback on an earlier revision of the
manuscript, Sue Kantor and Ben Metcalf for assisting with
pQCT measurements, and Kelly-Ann Bowles and Georgina
Morrow for assisting with participant recruitment.
AUTHOR CONTRIBUTIONS
Dr. Bennell had full access to all of the data in the study and
takes responsibility for the integrity of the data and the accuracy of the
data analysis.
Study design. Bennell, Wrigley, Hunter.
Acquisition of data. Creaby.
Analysis and interpretation of data. Bennell, Creaby, Wrigley, Hunter.
Manuscript preparation. Bennell, Creaby, Wrigley, Hunter.
Statistical analysis. Creaby.
Acquisition of funding. Bennell, Creaby, Wrigley.
13.
14.
15.
16.
17.
18.
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