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MICROSCOPY RESEARCH AND TECHNIQUE 37:358–371 (1997)
Bone Density and Local Growth Factors
in Generalized Osteoarthritis
JAN DEQUEKER,* LUC MOKASSA, JEROEN AERSSENS, AND STEVEN BOONEN
Arthritis and Metabolic Bone Disease Research Unit, K.U. Leuven, U.Z. Pellenberg, B-3212 Pellenberg, Belgium
KEY WORDS
osteoarthritis; bone density; growth factors; subchondral bone; osteoporosis
ABSTRACT
Osteoarthritis is usually considered to be a primary disorder of chondrocyte
function with secondary changes in bones. However, a defect in the subchondral bone resulting in
loss of its shock absorbing capacity could transfer the stress of loading directly to the articular
cartilage with secondary changes in the cartilage.
Review of histomorphometric and bone densitometric studies at sites of osteoarthritis at the hip or
knee revealed that cartilage fibrillation could not be dissociated from bony changes even in the
earliest stages of osteoarthritis and that subchondral trabeculae are thickened and more spaced in
osteoarthritis. Microfractures of subchondral trabecular bone were less frequently seen in osteoarthritis compared to controls.
Changes of the tidemark were found to be multiform and metabolically active in the osteoarthritic
process. Endochondral ossification depletes the calcified cartilage at the cartilage/bone interface and
the tidemark has been thought of as a calcification front advancing in the direction of non-calcified
cartilage. Duplication of the tidemark is cited as evidence of this advancement.
In the few experimental animal studies of subchondral bone in osteoarthritis, thicker trabeculae
which were closer together were found in guinea pigs already when only mild cartilage changes were
present. In the dog, with cruciate ligament transection, changes in bone were later than in the
cartilage, but the changes in bone could still contribute to the progression of osteoarthritis.
To study if bone changes may precede injury to the cartilage and if metabolic and systemic
influences can also alter the subchondral bone, rendering it less able to withstand normal
mechanical stresses, bone at different sites in the body has been studied extensively by the authors.
Epidemiological and case control studies have revealed that osteoarthritis cases have more bone at
all sites than expected and that bone in cases with generalized osteoarthritis shows both
quantitative and qualitative differences, including increased contents of growth factors and
hypermineralization. These findings suggest that a more generalized bone alteration may be the
basis of the pathogenesis of osteoarthritis. Microsc. Res. Tech. 37:358–371, 1997. r 1997 Wiley-Liss, Inc.
INTRODUCTION
The damage to articular cartilage that is characteristic of osteoarthritis is accompanied by changes in the
subchondral bone. It is not certain whether the bony
changes precede or follow injury to the cartilage. Osteoarthritis is usually considered to be a primary disorder
of chondrocyte function with secondary changes in
bone. However, a defect in the subchondral bone resulting in loss of its shock absorbing capacity could transfer
the stress of loading directly to the articular cartilage
with secondary changes in the cartilage.
Changes in the subchondral bone may occur as a
result of local factors, such as altered weight bearing, or
as part of a generalized disease of bone, such as Paget’s
disease. Simon et al. (1972) induced cartilage damage
in rabbits by repetitive excessive impulse loading. The
damage was preceded by changes in the subchondral
bone. Radin and Paul (1970) postulated that excessive
impulse loading of the joint causes thickening of the
subchondral bone as a result of repair of numerous
microfractures. This bone is stiffer and less pliable so
that the impact of loading is borne principally by the
overlying cartilage, which, as a result, degenerates.
r 1997 WILEY-LISS, INC.
The morphological appearances in osteoarthritis are
well known: the subchondral bone undergoes a number
of changes. Sclerosis occurs in areas of thinning and
loss of the cartilage, particularly in the central area
lateral to the fovea of the femoral head. Osteophyte
production occurs around the circumference of the joint
margin, and the so-called cysts, which contain fibrovascular tissue or metaplastic cartilage, are often surrounded by bone showing active new bone formation
(Amir et al., 1992).
What initiates this subchondral remodeling? Wolff’s
law states that the structure of any bone is a function of
the mechanical demands made on that bone. The load
applied to any joint can be modified by many factors,
such as weight, amount and type of exercise, occupation, integrity of neuromuscular control. Metabolic and
systemic influences can also alter the subchondral
bone, rendering it less able to withstand normal mechanical demands. The latter hypothesis will be dis*Correspondence to: Prof. Dr. J. Dequeker, Arthritis and Metabolic Bone
Disease, Research Unit, U.Z. Pellenberg, Weligerveld 1, B-3212 Pellenberg,
Belgium.
Received 22 January 1995; Accepted 18 March 1995
BONE DENSITY AND LOCAL GROWTH FACTORS IN OA
cussed here in more detail and illustrated by means of
fundamental studies on bone.
OSTEOARTHRITIS OF THE HIP
Changes in Bone Mechanics
In 1969, Sokoloff studied the pathology of osteoarthritis in human hip joints and found that cartilage fibrillation could not be dissociated from bony changes, even in
the earliest stage of osteoarthritis. Radin and Paul
(1970) were the first investigators to propose that
subchondral bone stiffening, due to healing microfractures, might be the primary pathogenic event in osteoarthritis. They performed biomechanical tests on subchondral bone plugs, removed at autopsy, from the
weight-bearing portion of the medial femoral condyle in
43 male patients with varying degrees of osteoarthritis,
as well as normal controls. There was a significant
decrease in the energy-absorbing capacity of the subchondral bone in mild osteoarthritis vs. normal energy
absorption in moderate and severe cases as well as in
the controls. It was suggested that in mild osteoarthritis, the articular cartilage would be exposed to increased forces and eventually wear, due to the decreased energy attenuating properties of the underlying
subchondral bone. Further support for the above mechanism was provided by Ewald et al. (1982) when they
replaced the subchondral bone in living dogs with
methacrylate cement which was 2.6 times stiffer than
normal cancellous bone. After 2 years of normal abulation, there was uniform loss of the articular cartilage in
the weight-bearing regions of all the femoral heads.
Other studies of osteoarthritic human hips noted that
the bony changes (including trabecular bone volume,
ash mineral, alkaline and acid phosphatase activity)
were greater in the weight-bearing region (Cameron
and Fornasier 1979; Reinmann and Christensen 1979;
Reinmann et al., 1977). In 67% of osteoarthritic femoral
heads studied histologically by Batra and Charnley
(1969), osteoid was found exclusively in the pressure
zones.
Histomorphometric Alterations
Amir et al. (1992), studying quantitative histomorphometry after double tetracycline labeling in human
osteoarthritic femoral heads, found that remodeling of
subchondral bone in osteoarthritis is fairly constant
and is not related to weight-bearing. They also stated
that endochondral ossification is an unlikely mechanism for bone sclerosis in osteoarthritis. In order to
determine whether subchondral bone in osteoarthritis
differs from that seen in normal human aging osteoarthritic femoral heads removed for total hip arthroplasty
compared with normal age-matched and young autopsy
controls, Grynpas et al. (1991) studied extensively the
femoral head. Standardized, 1-cm deep, weight-bearing
and nonweight-bearing subchondral bone blocks, as
well as cancellous core bone, 2–4 cm deep to the
articular surface, were examined in each femoral head.
Mineralization was assessed using density fractionation and chemical analyses, and compared to histomorphometry. In osteoarthritis, both weight-bearing and
nonweight-bearing surface subchondral bone showed a
lower degree of mineralization than age-matched and
young controls. Histomorphometric analysis showed
that subchondral bone thickness, as well as all osteoid
359
parameters and eroded surfaces, were increased in
osteoarthritic samples vs. controls. Mineralization in
the deep cancellous core bone increased with normal
aging but underwent less change with osteoarthritis.
Histomorphometry of the cancellous core showed that
osteoid parameters, but not bone volume, were increased in osteoarthritis vs. controls. They concluded
that advanced osteoarthritis of the femoral head is
associated with a thickening of the subchondral bone
with an abnormally low mineralization pattern.
The observations of Grynpas are in line with those of
Kusakabe (1977), who found that bone remodeling is
increased in the subchondral proximal femoral head
bone of osteoarthritis cases and that the osteoid surface
and osteoblastic activity are so great that trabeculae
and larger relative bone area are produced.
Bone volume in the femoral head of osteoarthritis
cases and controls has also been studied by Moore et al.
(1994). They found that the cartilage overlying the
subchondral compressive and tensile regions was significantly thinner and that bone volume was increased at
the principal compressive region and diminished at
both of the tensile regions. Figure 1 illustrates the
structural differences between osteoarthritis and controls at the compression and tensile regions of the
femoral head subchondral bone.
In an earlier study of the same group, Fazzalari et al.
(1985) studied histomorphometric changes in the trabecular structures of the principal compressive stress
regions in the femoral head of patients with osteoarthritis and patients with femoral neck fracture. They found
that the trabeculae in osteoarthritis were significantly
thicker than in femoral neck fracture and that spacing
in osteoarthritis was significantly greater than in femoral neck fracture.
The different relationships indicate, therefore, that
the structural arrangement of the cancellous bone in
each group is unique and reflects the different pathophysiology and biomechanics of the femoral head in
osteoarthritis and femoral neck fracture. Taking the
derived parameters of trabecular thickness and trabecular spacing, it was possible to draw the average trabecular dimensions for each group that reflect the differences of architecture in the principal compressive stress
region (Fig. 2).
Trabecular Microfractures
In Radin’s concept on the cause of stiffening of the
subchondral bone is the healing of trabecular microfractures. When the joint is subjected to repetitive impulsive loading, the bone underlying the joint, especially
the well-vascularized subchondral area, responds by
microfracturing and remodeling of its internal architecture to better resist these stresses. This stiffer bone is
no longer as effective a shock-absorber as it was before.
The articular cartilage is now relatively unprotected
and the peak dynamic forces it is subjected to are
increased.
Fazzalari and co-workers (1987) examined the head
of the femur from 67 patients who had joint replacement for advanced osteoarthritis and 66 autopsy controls without discernible joint disease. They used a
microscopic approach to ascertain fractures in coronal
slabs and to quantify the mineralization and thickness
of trabecular bone in a principal compressive zone (Fig.
360
J. DEQUEKER ET AL.
A.
B.
Fig. 1. A: Sections from the subchondral principal compressive
region of control (a) and osteoarthritic (b) cases, which show the
differences in the structural variables. From Fazzalari et al. (1992). B:
Sections taken from the subchondral principal tensile region of control
(a) and osteoarthritic (b) cases, which show more complex structural
changes than occur in the subchondral principal compressive region.
From Fazzalari et al. (1992).
3). There was a reduction in the number of trabecular
microfractures in osteoarthritis patients, compared with
the controls, with a lack of correlation between numbers of microfractures and age in osteoarthritis patients (Fig. 4). There was no evidence for the hypothesis
that increased numbers of microfractures led to the
increase of bone to support the view that microfractures
play a role in maintaining osteoarthritic joint structure.
This study confirms earlier studies of trabecular stress
fractures in early and advanced osteoarthritis of the hip
(Cameron and Fornasier, 1975). Koszyca et al. (1989)
evaluated the role of healing trabecular microfractures
by studying their nature and distribution in femoral
heads from patients with osteoarthritis of the hip and
subcapital fracture of the femoral neck. The nature and
distribution of healing trabecular fractures of femoral
heads were studied in 50 autopsy specimens, 30 patients with osteoarthritis of the hip, and 45 patients
with subcapital fractures of the femoral neck. Macerated coronal slices were examined with a dissecting
microscope, and the trabecular microfractures were
identified where there was callus formation, either
nodular or smooth. The number of trabecular microfractures did not differ significantly in the subcapital
fractures of the femoral neck and age-matched control
groups. The number of trabecular microfractures in the
osteoarthritis group was lower than in subcapital fractures of the femoral neck and age-matched control
groups. The numbers of nodular trabecular microfractures in the control and subcapital fractures of the
femoral neck groups did not differ significantly but
were fewer in the osteoarthritis group. Smooth trabecular microfractures were present in similar numbers in
osteoarthritis, control, and subcapital fractures of the
femoral neck groups.
The low number of trabecular microfractures in
osteoarthritic bone may indicate that the proposed
pathologic remodeling of bone following repeated impact loading has already occurred and that the trabecular network has become stronger as a result of trabecu-
BONE DENSITY AND LOCAL GROWTH FACTORS IN OA
Fig. 2. Schematic drawings of histologic sections showing the
average trabecular dimensions in the selected stress region of the
femoral neck for control, osteoarthritis, and fractured neck of femur
samples. The drawings show the correct relative relationships among
the three groups. From Fazzalari et al. (1985).
lar thickening and increased connectivity, decreasing
the likelihood of fracture. Another possibility is that the
thicker trabeculae were already present as part of a
constitutional stronger bone built up during adolescence.
OSTEOARTHRITIS OF THE KNEE
The tibial subchondral bone in osteoarthritis of the
tibia was extensively studied histologically and microradiographically by Havdrup et al. (1976). They found
that the tidemark was double or multiple as has also
been described by Green et al. (1970). The borderline
between the mineralized cartilage and the subchondral
bone was very irregular and each tissue showed extensions which fitted in between one another as has been
described by Stougård (1974). The subchondral bone
had a strong tendency to undergo sclerosis in the form
of thickening and confluence of the trabeculae to form
massive blocks of bone containing single vessel canals.
361
When the bone was completely denuded the surface
layer exhibited necrotic osteocytes. The severity of the
sclerosis clearly varied with damage to the overlying
cartilage. When the cartilage was relatively intact the
underlying trabeculae were of normal appearance. The
thinner the cartilage the more massive the sclerosis.
The sclerosis was clearly focal. The sclerotic changes
varied in depth from 500 to 3,000 µ but were often
abruptly bordered by spongy bone of normal appearance. No microscopic fractures or nodular aggregates
(‘‘birds nests’’) (Todd et al., 1972) were found in this
spongy bone. Mostly the trabeculae were highly mineralized without appreciable signs of remodeling of the
bone. Where the osteoarthritis was severe, it had
locally broken through the mineralized cartilage, which
otherwise appeared to be very resistant. In such cases
resorption cavities extending downwards from the surface and filled with granulation tissue were visible. The
spaces between the bone trabeculae contained fatty
marrow, except where the trabeculae were sclerotic;
here the tissue was fibromyxotic and poor in cells. The
resorption cysts contained highly cellular tissue.
Osteoblasts were observed on the sclerotic trabeculae
and to a lesser extent on the normal trabeculae. The
osteoblasts were invariably flattened, suggesting low
activity (so called resting osteoblasts). Only in the
resorption cavities (cysts) the osteoblasts were more
active and protrudent. The amount of osteoid tissue
found in osteoarthritic bone stained ad modum Goldner
was small, but increased with the severity of the
osteoarthritis and was found particularly on trabeculae
surrounding granulation tissue and in resorption cavities. These cavities also contained osteoclasts which
were hardly ever seen elsewhere. New bone formation
occurred inside the cysts. The specimens contained very
few osteophytes, but where they were found, they were
seen to form on the remains of the mineralized cartilage, frequently with a persisting tidemark.
As shown for the femoral head, Pugh et al. (1974)
have found at the femoral condyle evidence of changes
in geometric pattern of trabeculae in the early stages of
degenerative arthritis in the subchondral bone; changes
in the spatial arrangement of the trabeculae (rather
than the gross density of bone) were shown to correlate
with the observed increase in subchondral bone stiffening associated with loss of cartilage mucopolysaccharides.
Data on bone mineral density (BMD) of the proximal
tibia in osteoarthritic knees assessed in vivo by photon
absorption were recently reported by Madsen et al.
(1994). Compared to the controls, BMD of the subchondral plate, BMD of the medial condyle, the medial to
lateral distribution ratio of subchondral BMD, and the
ratio between BMD of the subchondral plate and of the
immediately underlying region were significantly increased in patients with predominantly medial osteoarthritis of the knee. The BMD of the lateral condyle was
lower in patients with osteoarthritis of the knee than in
controls. After adjustment for weight differences between patients with osteoarthritis of the knee and
controls, the differences in bone density were still
present.
Mokassa et al. (1993) studied the effect of body
weight and osteoarthritis grade on the mineralization
pattern of subchondral trabecular bone of cadaveric
362
J. DEQUEKER ET AL.
Fig. 3. Trabecular microfractures on trabecular bone in macerated coronal slabs of the femoral head.
a, nodular lesion; b, fusiform lesion. Original magnification 325. From Fazzalari et al. (1987).
opposite to the effect of body weight. As shown in Figure
5, the mineralization profile is shifted to higher density
in the high osteoarthritis grade while in the obese a
shift to a lower density mineralization profile was
found, indicating that despite a positive relation between obesity and osteoarthritis they have opposite
effects on bone quality.
Fig. 4. Pooled male and female data for trabecular microfractures
vs. age for both normal controls and osteoarthritis patients. No
significant relationship was found for osteoarthritis patients. Their
scatter with respect to the 95% confidence interval for controls is
shown. Controls, trabecular microfractures 0.47 3 Exp (0.064 3 Age).
Osteoarthritis, NS. From Fazzalari et al. (1987).
proximal tibial epiphyses. The effect of osteoarthritis
grade on mineralization degree as defined by gradient
density separation of trabecular bone powder was
THE SUBCHONDRAL PLATE AND TIDEMARK
IN OSTEOARTHRITIS
Subchondral Plate and Tidemark in Tibial Bone
The subchondral plate consists of two mineralized
layers which together act as a single unit, separating
the articular cartilage from the bone marrow cavity. On
the articular side at the line of contact between subchondral plate and articular cartilage is a discrete band of
mineralized cartilage which is more radiodense than
adjacent bone, has affinity for numerous histological
stains, and is recognized as the ‘‘tidemark’’ in hematoxylin stained sections (Green et al., 1970). From the
tidemark, the calcified cartilage extends for a varying
distance toward the bone marrow cavity, where it is
remodeled and replaced with woven, or lamellar bone
similar to the supporting trabeculae. The thickness of
the subchondral plate varies in different places and in
different joints. In most joints where the bones have a
concave and convex component, the dome-shaped convex subarticular bone structures are thinner and more
uniform in shape than the complementary part of the
joint where the center of the concavity is associated
with a much thicker subchondral plate than at the
periphery (Simkin et al., 1980). In the case of the tibial
plateau, some modification of these general observations is noted since the bony plateau is almost flat; the
presence of the wedge-shaped meniscal cartilage (measuring thickness from 0 mm at the center of the plateau
to 5 to 7 mm at the periphery) produces a functional
BONE DENSITY AND LOCAL GROWTH FACTORS IN OA
363
Fig. 5. Opposite effect of body weight and osteoarthritis grade of the knee on distribution of trabecular
bone density of the proximal tibia. From Mokassa (1993).
concavity in which the condylar end of the femur
articulates. At the center—contact area—of each plateau the subchondral bone is thicker than at the more
peripheral regions.
The hyaline articular cartilage is closely attached to
the irregular surface of the subchondral bone at the
tidemark. This cartilage is traversed from the tidemark
to its surface by ‘‘arcades’’ of collagen fibers which
emanate at approximately 90° from the calcified cartilage in bundles 55 µ in diameter (Minns and Stevens,
1977). Deep to the surface and anchoring these collagen
bundles at the tidemark level is a ramification or ‘‘root
system’’ as they penetrate deeper into the calcified
cartilage (Broom and Poole, 1982; Inove, 1981). Whilst
not all collagen fibers are directed in this fashion, some
are known to be aligned at more acute or obtuse angles.
The chondrocytes buried between the collagen fibers
maintain control over a region or domain in their
proximity and appear to control the turnover of the
noncollagenous matrix. The mechanisms of repair, if
any, of the collagen fibers themselves is uncertain.
Subchondral Plate Including
Tidemark in Osteoarthritis
The role of subchondral plate in the development of
osteoarthritis is of particular interest and has not
received much attention in the search for the pathogenesis of osteoarthritis. Its role in the development of
osteoarthritis may depend not only upon its own mechanical and metabolic properties, but also upon its
influence on the nutrition of the adjacent cartilage.
While it is stated (Schubert and Hamerman, 1968) that
the nutrition of cartilage is facilitated by the compression and relaxation during normal joint use, and that
the influx and expulsion of synovial fluid from the
interstices of spongelike hyaline cartilage provides the
essential nutrition, other authors have suggested that
some of the deeper layers of cartilage cells are metabolically influenced by the subchondral capillaries (Ekholm
and Norbäck, 1951; Ingemark, 1950; Sokoloff, 1969;
Trueta and Harrison, 1953; Woods et al., 1970). If one
presumes that both the superficial diffusion and also
the permeation of nutrients from beneath the subchondral plate may control the metabolism of the cartilage,
then the development of osteoarthritis might follow
nutritional interference by 1) primary damage and
disintegration of the surface of the articular cartilage
due to compression or excessive use independently of
the subchondral plate structure, 2) remodeling of the
subchondral plate may interfere with the nutrition of
the deeper cartilage layer, or 3) combinations of both.
According to Duncan et al. (1985), injury to the
subchondral plate may generate a response which
alters the access of nutrients to the deeper cartilage
layers either by 1) fracture of the subchondral plate and
its immediate local metabolic effect on the adjacent
cartilage; 2) the occlusion of the vascular channel by the
repair process, giving rise to relative ischemia; 3)
perforations and identations of the nonarthritic tibial
plateau may be the sites of increased damage penetration and cyst formation seen in the osteoarthritic joint;
or 4) a stiffened joint architecture predisposes to direct
cartilage damage.
Oettmeier et al. (1989) further analysed the tidemark
changes in osteoarthritic and control femoral heads.
Histological and histomorphometric examinations were
carried out on 88 human femoral heads, 63 from
patients with osteoarthritis and 25 controls. The
changes of the tidemark were found to be multiform in
the osteoarthritic process and could be classified into
three degrees of severity. Low-grade tidemark changes
were characterized by reduplications of the tidemark
and discontinuities of the tidemark line, occurring also
in about one third of the controls. Vascular invasion
into the tidemark as well as incipient calcification of
basal hyaline cartilage were observed in middle-grade
tidemark alterations. High-grade changes were distinguished by the disappearance of the tidemark, advanced mineralization and ossification of basal hyaline
and calcified cartilage and finally by the ‘‘tidemark and
bald bone.’’
Increased Metabolic Activity
at the Tidemark in Osteoarthritis
Differences of metabolic activity in the calcified zone
of cartilage in particular at the tidemark might be of
importance in the development of osteoarthritis. Active
though slow remodeling takes place at the articular
cartilage/subchondral bone interface in adult humans
(Green et al., 1970) and in rabbits (Lemperg, 1971).
Lane et al. (1977) showed that this endochondral
ossification increases in late middle age, especially in
more loaded areas. Lemperg (1971) and Bullough and
Jagannath (1983) showed that the tidemark is a metabolically active area involved in mineralization of the
overlying noncalcified hyaline cartilage. Endochondral
364
J. DEQUEKER ET AL.
ossification depletes the calcified cartilage at the cartilage/bone interface and the tidemark has been thought
of as a calcification front advancing in the direction of
the noncalcified cartilage. Duplication of the tidemark
is cited as evidence for this advancement and indeed
duplication is increased in normal late middle age and
in osteoarthritic femoral heads (Lane and Bullough,
1980). Apart from this activity at the calcified-hyaline
cartilage interface, the calcified zone of cartilage has
been considered inactive.
Revell et al. (1990) studied tetracycline labelled
articular cartilage of 50 osteoarthritic femoral heads in
an attempt to understand the mechanisms of endochondral ossification and tidemark advancement. They confirmed that the tidemark is a metabolically active part
of calcified cartilage with a much higher level of activity
than previously suspected. That there was tetracycline
incorporation in 20 of 43 tidemarks during the 18-day
period before joint replacement is testimony to the
extent to which the tidemark and calcified cartilage
represent a metabolically active zone.
The metabolic role of the tidemark zone in the
pathogenesis is further emphasized by Gannon et al.
(1991), who detected type X collagen in the pericellular
matrix of the chondrocytes at or just above the tidemark, and this expression was immediately before
mineralization. They suggest that the expression of
growth platelike properties would allow the deep chondrocytes of mature articular cartilage to play a role in
the remodeling of the joint with age and in the pathogenesis of osteoarthritis.
Rees and Ali (1988) examined the distribution of
alkaline phosphatase activity in human articular cartilage from normal and osteoarthritic joints by an electron
microscope technique. Chondrocytes and matrix vesicles
close to the tidemark were positive for alkaline phosphatase activity in osteoarthritic cartilage within the extracellular matrix of osteoarthritic cartilage. Large numbers of matrix vesicles were found. Because there is a
specific relation between alkaline phosphatase activity,
number of matrix vesicles, and initial mineral formation in the tidemark region of articular cartilage, these
results give evidence for increased metabolic activity in
articular damage in osteoarthritic joints.
SUBCHONDRAL BONE DENSITY
AT THE SITE OF OSTEOARTHRITIC JOINTS
Remodeling of subchondral bone has been considered
to have a key role in the pathogenesis and perpetuation
of the changes in osteoarthritis. Bone sclerosis can
result from an increased rate of appositional bone
formation or decreased resorptive activity, an increased
amount of bone forming surface (increased osteoid), and
increased endochondral ossification of the calcified layer
of the articular cartilage. Ossification also occurs in
plugs of metaplastic cartilage within the eburnated
bone at the joint surface, but this mechanism probably
has a minor role, if any at all, in the alteration of the
bony contour.
SUBCHONDRAL BONE DENSITY
IN EXPERIMENTAL MODELS
OF OSTEOARTHRITIS
Subchondral bone density has been studied in a few
animal models for osteoarthritis. Layton et al. (1988)
used microscopic computed axial tomography to evaluate the subchondral bone structure in femoral heads
from a guinea pig model of spontaneous osteoarthritis.
Their findings showed that trabecular remodeling occurs deep within the femoral heads in this animal
model of early osteoarthritis. These changes occurred
when only mild cartilage changes were present. The
trabecular bone changes consisted of thicker trabeculae
that were closer together. These findings are consistent
with the notion that bone changes are an early event in
this model of osteoarthritis.
Dedrick et al. (1993) evaluated the sequence of
changes in articular cartilage, trabecular bone, and
subchondral plate in dogs with osteoarthritis, 3 months,
18 months, and 54 months after anterior cruciate
ligament transection. Specimens of the medial tibial
plateau were analyzed with microscopic computed tomography (micro-CT) at a resolution of 60 µm, and
biochemical and morphologic changes in the femoral
articular cartilage were assessed.
At 3 months and 18 months after anterior cruciate
ligament transection, the articular cartilage in the
unstable knee showed histologic changes typical of
early osteoarthritis and increased water content and
uronic acid concentration; by 54 months, full-thickness
ulceration had developed. Micro-CT analysis showed a
loss of trabecular bone in the unstable knee, compared
with the contralateral knee, at all time points. At both
18 and 54 months, the differences in trabecular thickness and surface-to-volume ratio were greater than at 3
months. Although the mean subchondral plate thickness, especially in the medial aspect of the medial tibial
plateau, was greater in the osteoarthritic knee than in
the contralateral knee 18 months and 54 months after
anterior cruciate ligament transection, these differences were not statistically significant; however, the
difference was significantly greater at 54 months than
at 3 months.
They concluded that thickening of the subchondral
bone is not required for the development of cartilage
changes of osteoarthritis in this model. The bony
changes that develop after anterior cruciate ligament
transection, however, could result in abnormal transmission of stress to the overlying cartilage and thereby
contribute to the progression of cartilage degeneration.
OVERALL BONE DENSITY
AND OSTEOARTHRITIS
In line with Radin’s aetiological ‘‘impulse loading’’
concept of osteoarthritis and the role of subchondral
bone, we have studied the hypothesis that the subchondral bone stiffness is part of a more general bone
alteration instead of local microfractures in patients
sufferering from generalized osteoarthritis.
Osteoporosis Protects Against Osteoarthritis
It is known that osteoporosis spares osteoarthritis
(Smith and Rizek, 1966; Urist, 1960), and that osteopetrosis, on the contrary, is highly associated with osteoarthritis in the few patients with this condition who reach
adulthood (Milgram and Jasty, 1982). Osteoporotic
bone would be relatively soft and would act as an
excellent shock-absorber easily sustaining compression
fracture of its relatively weak structure. The osteoporotic bone simply lacks the mass, even in the presence
BONE DENSITY AND LOCAL GROWTH FACTORS IN OA
of numerous micro- and macrofractures, to stiffen sufficiently and lose its protective shock-absorbing role
vis-à-vis the overlaying cartilage. Fracture is a very
effective alternative way of absorbing energy.
Although much has been studied about the possible
causes of osteoarthritis, we are still unable to readily
explain why some individuals remain free from the
disease throughout life while others are affected. The
observation that not everyone will develop osteoarthritis or osteoporotic fractures with ageing, and that
primary osteoarthritis and primary osteoporosis rarely
coexist (Verstraeten et al., 1991), stimulated us to study
these two conditions in order to elucidate pathogenetic
pathways.
Osteoporosis and osteoarthritis are two common agerelated musculoskeletal disorders associated with considerable morbidity and mortality. Patients with postmenopausal osteoporosis and those with osteoarthritis
appear to represent anthropometrically different populations (Dequeker et al., 1983). The osteoporotic women
were shorter, more slender, and had less fat, muscle
girth, and strength, while the women with osteoarthritis, although of comparable age and skeletal size, were
more obese and had more fat, muscle mass, and
strength. General clinical experience is that, although
both common in elderly patients, osteoporosis and
osteoarthritis (Christiansen et al., 1981; Cooper et al.,
1991; Dequeker et al., 1975; de Sèze et al., 1962; Foss
and Byers, 1972; Roh et al., 1974; Urist, 1960; Verstraeten et al., 1991), and, in particular, fractures and
osteoarthritis of the hip, seldom occur together (Aström
and Beertema, 1992; Pogrund et al., 1982). Osteoarthritis of the hip is in addition a negative risk factor for hip
fracture (Dequeker et al., 1993a) and for compression
fractures of the spine (Healy et al., 1985).
Despite strong evidence that osteoarthritis protects
against or retards the development of osteoporosis, the
biological explanation for this link is not yet clear.
Osteoarthritis is usually considered as a disease of
cartilage failure with secondary bone changes such as
osteophytes and subchondral sclerosis. Osteoporosis,
on the other hand, is considered to be an age-related
condition characterized by a reduced amount of bone,
leading to diminished physical strength of the skeleton
and an increased susceptibility to fracture.
Primary Osteoarthritis: Initially a Bone Disease?
At present, evidence is accumulating that primary
osteoarthritis might initially be a bone disease rather
than a cartilage disease. Osteoarthritis cases have a
better preserved bone mass (Carlsson et al., 1979; Foss
and Byers, 1972; Hannan et al., 1993; Moore et al.,
1994; Roh et al., 1974), even independently of body
weight (Belmonte-Serrano et al., 1993; Gotfriedsen et
al., 1990; Hart et al., 1994; Hordon et al., 1993; Lane
and Nevitt, 1994; Mokassa et al., 1993; Nevitt et al.,
1992; Vandermeersch et al., 1990). No significant differences in calcitropic hormones, PTH, 25(OH) and
1.25(OH)2 vitamin D3 metabolite levels could be established (Geusens et al., 1983), but fasting growth hormone levels and growth hormone levels after stimulation with hypoglycaemia were above normal in
osteoarthritis (Dequeker et al., 1982). Calcium excretion, both over 24 hours and when fasting, was significantly higher in osteoporotic cases.
365
Dynamic tests for osteoblast function stimulation of
osteocalcin production by 1.25 dihydroxyvitamin D3
treatment revealed no difference between osteoarthritis and osteoporosis cases and between osteoarthritisosteoporosis and young controls, indicating that osteoblasts remain responsive to stimulation in both
conditions (Geusens et al., 1991).
Serum levels of IGF-I are elevated in patients with
acromegaly, a disease associated with the development
of secondary osteoarthritis (Bluestone et al., 1972).
New bone formation has also been related to increased
serum levels of IGF-I in patients with diffuse idiopathic
skeletal hyperostosis (Littlejohn et al., 1986), and, in
one study, both the size and the growth of osteophytes
were directly correlated with serum levels of IGF-I in
subjects with osteoarthritis of the knee (Schouten et al.,
1993). Other studies, however, have yielded conflicting
results (Denko et al., 1990; Hochberg et al., 1994;
McAlindon et al., 1992).
Hochberg et al. (1994) examined the relationship
between serum levels of IGF-I and the presence and
severity of radiographic changes of knee osteoarthritis
in subjects participating in the Baltimore Longitudinal
Study of Aging. Mean serum IGF-I levels were significantly lower in subjects with knee osteoarthritis; however, after adjustment for age-related changes in IGF-I
levels, these differences were no longer significant.
We examined serum levels of IGF-I in osteoarthritis
and osteoporosis cases and did not find significant
differences and also not after stimulation with growth
hormone releasing factor (Dequeker et al., 1994). We
also studied serum osteocalcin levels as marker of
osteoblast function and bone turnover and bone mineral content in the spine and radius in osteoarthritis
and osteoporosis cases. Bone mineral content in the
spine (corrected for excessive osteophyte formation)
and in the radius was significantly higher in osteoarthritis cases. No difference in serum osteocalcin levels was
found between osteoarthritis and osteoporosis but osteocalcin levels were significantly negatively correlated
with bone mineral content in the spine in osteoporosis,
but no correlation was found in osteoarthritis (Gevers
et al., 1988).
In a study of 19 cases in whom there was a coexistence of spinal osteoarthritis and osteoporosis, we found
that these cases compared to cases with osteoarthritis
alone, had the following characteristics: older age, more
menopausal years, smaller stature and lower body
weight, a higher serum PTH level, and more nulliparity
than both other groups. They have less osteoarthritis of
the hip than osteoarthritis alone cases, and less forearm and other fragility fractures than osteoporosis
alone cases, though the incidence of femoral neck
fractures was comparable. These results suggest that
osteoarthritis might have a protective or retarding
effect on the development of osteoporosis (Verstraeten
et al., 1991).
The observed differences in bone mass and bone
metabolism parameters between osteoarthritis and osteoporosis raises the possibility that the physiopathology of osteoarthritis might be linked rather to bone
changes with secondary cartilage suffering. The increase in bone mass and change in bone quality might
alter the mechanical properties of subchondral bone
resulting in a reduced shock absorbing efficiency and
366
J. DEQUEKER ET AL.
Fig. 6.
Osteoarthritis grades of the hand. From Kellgren (1963).
leading to subchondral fracture and cartilage degeneration. This hypothesis might explain why in osteoporotic
cases osteoarthritic changes at the joints and the spine
are rarely seen (Dequeker et al., 1975; Pogrund et al.,
1982; Weintroub et al., 1982).
These data are in support of the hypothesis of Radin
and Paul (1970), who postulated that the primary
defect in osteoarthritis is not in the articular cartilage,
but rather in the subchondral bone. According to Radin
et al. (1973), the initial process of bone thickening in
osteoarthritis is due to callus formation at the sites of
multiple fatigue fractures. Our hypothesis is that in
osteoarthritis there is a generalised bone alteration
which might be accentuated in weight bearing areas.
BONE QUALITY OF THE ILIAC
CREST IN OSTEOARTHRITIS
In order to study the hypothesis that osteoarthritis
and osteoporosis are part of a generalised bone disease,
we decided to study bone at the iliac crest, because this
is a part of the skeleton where no effect of local joint
destruction can be expected. Data on the analysis of
iliac crest bone, consecutively removed in the autopsy
room of a large university hospital, will now be reported. Iliac crest specimens, obtained from 38 women,
aged 60–75 years, were analysed for biochemical, quantitative histomorphological, and biomechanical characteristics. For each subject, an X-ray of the right hand
was obtained in the necropsy room for the grading of
osteoarthritis in the small hand joints. The osteoarthritic changes were graded 0 to 4 according to the
criteria of the Atlas of Standard Radiographs of Arthritis (Kellgren, 1963) by two independent readers (Fig. 6).
Eleven patients had grade 0, 10 had grade I, and 17 had
grade II to IV. Grouping of patients was done before
TABLE 1. Physical characteristics of the iliac crest in women graded
according to the degree of osteoarthritis
Grade 0
(n 5 8)
Grade I
(n 5 10)
Grade II–IV
(n 5 14)
Apparent density (trabecular)
Fat-free dry weight/crude
bone (g/cm3)
16.9 6 4.8 23.8 6 3.6*** 26.27 6 8.97**
Pure bone density (trabecular)
Fat-free dry weight/crude
bone
2.1 6 0.1
2.2 6 0.1
2.1 6 0.3
% Pure/crude bone
Trabecular
8.03 6 2.80 10.9 6 2.2*
16.76 6 9.0**
Trabecular 1 cortical
31.8 6 9.4 36.3 6 3.9
42.6 6 8.5**
Mean 6 SD.
Significance compared to osteoarthritis grade 0: *P , 0.05; **P , 0.02; ***P ,
0.005, Student’s t test.
results of the different tests were available. One patient
was excluded because of local metastasis in the iliac
crest.
Bone Density
Pure crude bone volume and iliac crest density of
bone cylinders were determined, using the principle of
Archimedes, with carbon tetrachloride as a medium
(Dequeker et al., 1971). Apparent density (fat-free dry
weight/pure bone volume) was significantly higher in
the osteoarthritis group (Table 1).
Since analysis on whole bone samples represents a
weighted average of microscopic portion of tissue of
different physiological maturity, metabolic changes occurring in a small portion of the total bone mass may
367
BONE DENSITY AND LOCAL GROWTH FACTORS IN OA
Fig. 7. Distribution of cortical bone of various densities in young adult control (A) 60- to 75-year-old
control (B) and osteoarthritis (C) patients. Values are expressed as weight of the fraction per total bone
volume (%). Bars indicate SEM. Significant differences: *vs. control 60–75 years; Q vs. control young
adults; *Q P , 0.05; **QQ P , 0.01; QQQ P , 0.001. From Raymaekers et al. (1992).
TABLE 2. Bone histomorphometry of the iliac crest in women graded according to the degree of osteoarthritis
Osteoarthritis grade
0
I
n58
n 5 10
II–IV
n 5 14
Iliac bone
thickness (mm)
Cortical
thickness (µm)
Cortical thickness/iliac
bone thickness (%)
Cortical bone
volume (%)
Trabecular bone
volume (%)
Trabecular
width (µm)
6.09 6 1.18
6.99 6 2.43
NS
7.53 6 0.92
P , 0.01
521.68 6 188.96
731.12 6 494.7
NS
893.41 6 210.06
P , 0.001
8.68 6 3.15
9.68 6 3.67
NS
11.67 6 2.02
P , 0.02
89.71 6 1.67
89.77 6 2.51
NS
88.19 6 3.38
NS
12.67 6 3.28
13.2 6 5.4
NS
17.87 6 5.98
P , 0.05
116.41 6 18.4
129.31 6 36.67
NS
158.82 6 12.33
P , 0.015
Mean 6 SD.
Significance compared to osteoarthritis grade 0.
not be detected. Pathogenetic mechanisms behind diseases can thus be overlooked, especially in the elderly,
when phases of low and high turnover bone may be
mixed. The density fractionation technique of bone
powder gives us an unique procedure to study ageing in
situ and to disclose early pathogenetic events. The
distribution pattern of cortical bone powder from the
iliac crest (Raymaekers et al., 1992) shows a shift to
higher density fractions in the osteoarthritis cases,
which implies more mineralized bone with lower proportions of young osteons (Fig. 7).
histomorphometric changes in the trabecular structure
of a selected stress region in the femur in patients with
osteoarthritis: thicker trabeculae were found in osteoarthritis compared to normals and femoral neck fracture
cases (Fazzalari et al., 1985). Thus, in osteoarthritis not
only is cortical bone mass increased, but so is trabecular bone as shown by our studies using two different
techniques for trabecular bone measurement. Figure 8
illustrates the striking difference in iliac crest bone
density in a case with osteoarthritis at the hand (grade
II–IV) (B) and a case without hand osteoarthritis (A).
Histomorphometry
Using quantitative histomorphological methods, it
was found that in the osteoarthritis patients of grades
II–IV, the cortical thickness, percentage of trabecular
bone, and trabecular thickness of iliac bone were significantly higher compared to the group which had no
osteoarthritic changes on X-ray at the hands (Gevers et
al., 1989a) (Table 2). The latter finding confirms the
Bone Mechanical Properties
Mechanical properties of iliac crest trabecular bones
have been tested in 21 specimens. A significant difference in stiffness elastic modulus as measured by compression tests was found, the osteoarthritic trabecular
bone being significantly stiffer than non-osteoarthritic
trabecular bone (Fig. 9). A significant correlation was
found between elastic modulus, apparent density, the
368
J. DEQUEKER ET AL.
A
B
Fig. 8. Microradiographs of iliac crest sections (310). A: Osteoarthritis grade 0; B: Osteoarthritis grade II–IV. From Gevers et al.
(1989a).
percentage pure to crude bone volume, and cortical
thickness and trabecular width, the latter two evaluated by quantitative histomorphometry. Compressive
strength was higher in osteoarthritic bone but not
significantly. A significant correlation between trabecular bone volume and trabecular width and maximum
compressive strength was established (Gevers et al.,
1989b).
Biochemical Composition—Growth
Factors in Bone
Iliac crest bone matrix composition in the osteoarthritis group differs significantly in several aspects from
the control group without osteoarthritis at the hand
joints (Gevers and Dequeker, 1987). In the EDTA,
significantly less glycoproteins and proteoglycans could
be extracted, while the osteocalcin content was found to
be significantly increased in the osteoarthritis group
(Gevers and Dequeker, 1987).
We also found that IGF-I and IGF-II and TGF-b
concentrations are increased in the matrix of the iliac
crest (Dequeker et al., 1993b). IGF-I concentrations
were measured by radioimmunoassay (RIA) using a
recombinant human IGF-I (Ciba-Geigy Basel, Switserland). IGF-II concentrations were determined by radioreceptor assay (RRA) using H-35 rat hepatoma cells
(American Type Culture Collection CRL 1548) as the
receptor source. TGF-b concentrations were determined by bioassay, measuring the inhibition of DNA
synthesis by mink lung epithelial cells (Mv. ILU American type Culture Collection CL64). Osteocalcin was
measured in the supernatants of the EDTA extracts by
RIA.
Because these locally produced growth factors are
resistant to an acidic milieu, they can be released and
activated during bone resorption and act on osteoblast
and osteoclast progenitor cells in a paracrine or autocrine fashion.
It has been suggested that the IGFs and TGF-b in
bone may act to link bone formation to resorption in the
remodeling cycle (Baylink et al., 1990; Canalis et al.,
1988; Farley et al., 1987). Many biologic properties
attributed to the IGFs and TGF-b make them ideal
‘‘coupling factors.’’ In addition to their well-recognized
anabolic activity on bone cells, these growth factors are
deposited in large quantities in human bone, where
they would be available for action after osteoclastic
resorption. Because the IGFs (Mohan et al., 1986) and
TGF-b (Jennings, personal communication) are stable
at acidic pH, they may be released during resorption in
a bioactive form to act on either osteoblasts or osteoblast precursor cells. The higher concentrations of
these growth factors in bone in osteoarthritis would
predict the observed findings that, in general, patients
with osteoarthritis would maintain a greater bone
mass.
The increased density of bone in patients with osteoarthritis may have a negative impact. This increased
density may impair the resilience of the bone immediately adjacent to the articular space, reducing the
shock-absorbing capacity and contributing to the pathogenesis of osteoarthritis and further degeneration of
the cartilage.
These quantitative and qualitative biochemical differences according to the presence of osteoarthritis of the
hands confirm our earlier findings and suggest that
bone matrix alterations may play a role in biomechanical behavior of subchondral bone.
CONCLUSION
The multiplicity of significant alterations found in
patients with primary osteoarthritis and in osteoarthritic bone far away from the articular lesion indicates
that osteoarthritis is part of a more generalised bone
disease.
These findings support the hypothesis that quantitative and qualitative differences in bone may explain the
inverse relationship between osteoarthritis and osteoporosis. These quantitative and qualitative differences in
bone may produce disease by increasing subchondral
bone stiffness and by making subchondral bone less
deformable to impact loads. This stiff bone transmits
more force to overlying cartilage, making it more
vulnerable. In contrast to Radin’s hypothesis (Radin et
al., 1970; Radin and Rose, 1986), we hypothesize that
subchondral bone stiffness is part of a more general
bone alteration instead of healing of local microfractures.
In line with our observations of a generalized change
in bone in osteoarthritis, Doherty et al. (1983) demonstrated that the predisposition to ‘‘primary’’ osteoarthritis influences the development and severity of ‘‘secondary’’ osteoarthritis. Patients who had undergone
unilateral meniscectomy 19 years or more before and
who had X-ray changes in the hands consistent with
generalised osteoarthritis showed more frequently a
BONE DENSITY AND LOCAL GROWTH FACTORS IN OA
369
Fig. 9. Mechanical properties of iliac crest trabecular bone in women 56–80 years according to
osteoarthritis grade of the hands. From Gevers et al. (1989b).
more severe knee osteoarthritis, judged clinically and
radiologically, in both unoperated and operated knees.
Furthermore, if osteoporosis spares osteoarthritis,
osteopetrosis should be a risk factor for osteoarthritis.
In the few patients with osteopetrosis who reach adulthood, osteoarthritis has been reported (Milgram and
Jasty, 1982). The higher body weight and associated
increased subcutaneous fat in the osteoarthritis group,
in addition to increased force on cartilage and bone,
may also affect the bone density by preserving a better
postmenopausal oestrogen status due to peripheral
conversion of androstenedione to oestrone in subcutaneous fat.
The inverse relationship between osteoarthritis and
osteoporosis is not only of academic interest in explaining pathophysiological mechanisms of both diseases, it
is also of interest in clinical practice and in decisionmaking on preventive measures. General osteoarthritis
usually becomes manifest around the age of the menopause, before major bone loss occurs. Therefore, osteoarthritis could be a good negative indicator for selecting
patients at risk for osteoporosis. The anthropometric,
biological, and biochemical differences between primary osteoarthritis and osteoporosis reflect that systemic and metabolic factors are involved in the pathophysiology of this disease and that these common,
crippling diseases are not a simple consequence of
ageing.
Osteoarthritis is a physiologic imbalance, a ‘‘joint
failure’’ similar to ‘‘heart failure’’ in which mechanical
as well as constitutional factors play a role. The initiation and progression of cartilage damage are distinct
phenomena. One of the mechanisms of initiation of
osteoarthritis is subchondral bone stiffness, often a part
of generalized (heridited) increased bone density. Once
cartilage damage is initiated, the stiffness of the subchondral bone may contribute further to progression
and chondrocyte dysfunction because cartilage repair
cannot follow the repeated sequence of events. From
then onwards, a cascade of catabolic factors interferes
because wear debris excites a synovial inflammation
with protease, collagenase, interleukin 1, and prostaglandin E2 production.
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