Age and Ageing 2001; 30: 374±378
#
2001, British Geriatrics Society
COMMENTARY
The role of bone in osteoarthritis
Osteoarthritis ranks with cancer and heart disease
as a major cause of disability in elderly people. The
prevalence in the UK is 20 per 1000. There is a strong
age relationship and it is more common in women
[1]. Unfortunately research into osteoarthritis has
been largely ignored by many rheumatologists, partly
because the disease was considered to be an inevitable
consequence of `wear and tear' in old age.
Although it is the most common joint disease,
osteoarthritis is dif®cult to de®ne. The disease develops
and changes slowly, and its heterogeneity has resulted
in controversy as to its aetiology and progression. The
absence of objective biochemical markers has also been
a major barrier to clinical and therapeutic research. The
characteristic pathological feature of osteoarthritis is
the focal destruction of the articular cartilageÐhence
for several decades biochemical investigations into the
pathogenesis of osteoarthritis have concentrated on
the mechanisms involved in the destruction of the
articular cartilage.
However, bone changes also occur in osteoarthritis,
with osteophyte formation and, more importantly, subchondral plate sclerosis. Radin and Rose [2] postulated
that increased bone mass and thickening of the subchondral bone plate would cause stiffening of the bone
and, as a consequence, cartilage destruction on repeated
loading. More recently, studies have re-emphasized the
importance of bone changes. In radiographic studies
of patients with osteoarthritis of the knee and hand,
Buckland-Wright et al. [3, 4] reported thickening of the
subchondral bone, while Carlson et al. [5] used histological techniques to detect increased bone thickening
with osteoarthritis progression in the cyanomolgus
macaque. Both techniques revealed marked increase
in bone formation before cartilage ®brillation. Using
labelled bisphosphonate in a scintigraphic study,
Dieppe et al. [6] demonstrated elevated bone cell activity
in those patients that progressed to severe osteoarthritis, while Mansell and Bailey [7, 8] demonstrated
increased metabolism of the subchondral bone collagen.
The occurrence of these bone changes is not
disputed, but, their importance in the pathogenesis
of osteoarthritis remains contentious, and the mechanisms involved in these changes have received scant
attention. There is now emerging evidence to suggest
that changes in bone precede changes in cartilage, so
that bone rather than cartilage may be the site of the
causally most signi®cant pathophysiological events.
New treatments (such as injections to lubricate the
joint or cartilage implants) may therefore be at best
short-term palliative measures.
374
Resolution of the question of the importance of bone
in osteoarthritis requires a multidisciplinary approach,
including the disciplines of biomechanics, imaging,
collagen biochemistry and cell biology, as well as the
development of animal models.
This brief review is based on work reviewed at an
AgeNet workshop, which took place on 15±16 June 1999
in Bath, UK, and aimed to assess the relative importance
of bone and cartilage changes in the pathogenesis of
osteoarthritis and whether bone ®brosis precedes or is
a consequence of cartilage degradation, and to identify
research priorities, develop methodologies and promote
collaborative projects.
Monitoring disease progression
Several techniques are available for the effective
monitoring of progression of osteoarthritis. Techniques
in radiography have become more sophisticated.
Buckland-Wright et al. [3, 4, 9] have used quantitative
microfocal radiography to demonstrate that the earliest
anatomical change in osteoarthritic joints is thickening of the subchondral cortical plate which precedes
changes in the articular cartilage thickness measured
radiographically as joint space narrowing (Figure 1).
Scintigraphy of osteoarthritic joints can be predictive of the severity of osteoarthritis, indicating that
bone pathology is a major, relatively early feature in the
evolution of hand and knee osteoarthritis [6].
Potentially most important are the developments in
magnetic resonance imaging. Its ability to detect changes
in both the hard and soft tissues will make it a powerful
technique for future studies of osteoarthritis progression. Studies on the guinea pig have demonstrated that
thickening of the subchondral bone precedes cartilage
hyperplasia and changes at the ligament±bone insertion
site occur early in the development of osteoarthritis
[10, 11].
Genetic determinants
The identi®cation of relevant genes promises earlier
diagnosis of individuals at risk and the possibility of
novel therapeutic strategies. To date, the study of
mutations has not provided any major advances, but
it is probably only a question of time. Spector and
co-workers' studies in twins and in families have demonstrated a strong genetic in¯uence on the development
of all the common forms of osteoarthritis [12], although
the interplay between genetic and environmental
Commentary
factorsÐsuch as obesity, occupation and recreational
activitiesÐis also likely to be important [13, 14].
Genetic analysis can determine whether genes that
are important in bone biology are also susceptibility loci
for osteoarthritis. Candidate genes can be targeted in
linkage analyses of affected sibling pairs or case±control
associate analysis of unrelated individuals. Loughlin et al.
[15] have detected a high-impact susceptibility locus for
osteoarthritis on chromosome 11q, which is close to
the regulator of bone mass. In contrast to the reports of
others, this group found no evidence for association of
the vitamin D receptor Taq1 or the oestrogen receptor
with osteoarthritis. There was, however, moderate
evidence of an association of Col1A1 in women with
osteoarthritis, collagen type I being the major collagen
of bone.
Bone structure and metabolism
Collagen structure
Simplistically, bone can be considered as a two-phase
system of a collagenous supporting framework that
provides strength and calcium apatite that confers
rigidity [16, 17], both phases being removed during
remodelling. Biochemical studies have revealed a
several-fold increase in metabolism of the subchondral
bone collagen in osteoarthritis, along with decreased
mineralization in human femoral heads [8].
Bailey et al. [18] have reported changes in the
composition of collagen, with the type I collagen a1
homotrimer identi®ed in osteoarthritic subchondral
bone, indicating a changed phenotypic expression in
the osteoblasts. Studies of transgenic mice with deleted
a2 chain [19] suggest that such changes would have
a deleterious effect on the mechanical properties and
mineralization of bone due to the loose packing of
the ®bres.
Cellular activity
Many growth factors which act to promote cell
differentiation and activity are stored in bone matrix,
suggesting that these may be important in the coupling
of the resorptive and formation processes of bone.
Transforming growth factor b is related to bone
turnover [20] and has been shown to be increased
several-fold in osteoarthritic subchondral bone [8].
Growth factors may also act as potential mediators of
communication between bone and adjacent cartilage
cells: for example, cells derived from osteoarthritic joints
promoted the degradation of non-arthritic cartilage
biopsies in vitro, whereas cells from normal joints did
not do so [21].
Figure 1. Radiograph of a patient's knee with moderately advanced osteoarthritis showing marked bone formation in the
medial diseased, tibio-femoral compartment. Osteophytes (O) can be seen at the margins of the joint and there is marked
subchondral sclerosis visible as a thickened cortical plate (small arrowheads) and increase of depth of subchondral trabecular
bone (large arrowheads).
375
A. J. Bailey et al.
The turnover of the collagenous network in bone
involves collagenases MMP-1, MMP-8 and MMP-13 of
the matrix metalloproteinase family [22]; this suggests
therapeutic strategies to block production of these
enzymes [23]. However, the cathepsins, particularly
cathepsin K, are also involved in the degradation of
bone collagen [24], and the relative importance of the
cathepsins and the matrix metalloproteinases remains
to be determined.
Blake and co-workers [25, 26] have proposed that
chronic hypoxia and anoxia, resulting in the generation
of free radicals, initiate bone erosion, and that they
should be considered a target for therapeutic manipulation. Hypoxia induces the production of xanthine
oxidoreductase, which generates superoxide and nitric
oxide, which lead to bone resorption.
In short, there is an increase in metabolism of bone,
but an imbalance in favour of synthesis over degradation. Osteoarthritis could therefore be rede®ned as a
®brotic disease, and therapies should be aimed at developing agents to control increased synthesis of bone
collagen.
Biomechanics of bone in osteoarthritis
The results of studies of the mechanical properties of
bone in osteoarthritis have been con¯icting. Bone taken
from patients with osteoarthritis varies both in its
properties and according to location. The subchondral
bone from such patients is less stiff and dense, shows
greater porosity and has a reduced mineral content
[27]. These results complement the ®ndings of biochemical studies [8, 18], but are contrary to those of
earlier studies which suggested that subchondral bone
was stiffer [2].
Bone is formed in response to mechanical loading,
and disuse results in bone loss, allowing the skeleton to
achieve suf®cient strength without excessive mass, which
would be energetically costly to build, maintain or use
[28, 29]. There is emerging evidence that different cell
types in bone communicate though effector molecules
and receptors that are similar to those that operate at
synapses in the central nervous system. Studies by Skerry
and co-workers, based on a differential display of osteocyte RNA following bone loading, have shown regulation of a glutamate transporter previously thought to
be expressed only in the central nervous system [30].
Such an arrangement would allow response to rapidly
changing transient strains. Manipulation of such signalling pathways could provide a way of controlling bone
mass in disease.
In a different approach, bone cells cultured in vitro
can be subjected to physiological levels of mechanical
strain with resulting changes to proliferative response
and prostaglandin production [31]. Suggestive differences between cells from osteoarthritic and normal
patients have been observed, for example, in proliferative responses and prostaglandin production [32]. The
376
mechanical effects on osteoprogenetor and osteogenic
cells warrant further investigation.
The current consensus is that subchondral bone in
osteoarthritic subjects increases in material content but
is mechanically weaker.
Animal models
Bone changes occur in non-human species which
naturally develop osteoarthritis [33, 34]. These animal
models allow the opportunity to examine the early
stages of bone changes, as well as to test potential
therapies. In macaques, where striking similarities to
the slow human disease are seen, Carlson et al. [5]
demonstrated histological evidence for thickening of
the subchondral bone before cartilage ®brillation. In
the case of the STR/ORT mouse, the onset of bone
sclerosis and cartilage ®brillation was dif®cult to assess
because of the complication of early calci®cation of the
ligaments and tendons [35]. Recent studies by Bailey and
co-workers [36] on spontaneous guinea pig osteoarthritis
suggest that bone density alterations accompanied by
bone collagen remodelling are important in early disease
progression.
The hypothesis that bone sclerosis results from a
change in tension on the bone which in turn could be
due to metabolic changes in the cruciate ligament [34]
is supported by evidence from the STR/ORT mouse [37]
and the guinea pig [36], where ligament remodelling is
seen before cartilage ®brillation.
The different animal models appear to con®rm that
bone changes precede cartilage damage. Further studies
are required to con®rm that changes in the ligaments are
a major initiating event in idiopathic osteoarthritis.
Conclusions
The ®rst decade of the new millennium has been
designated Decade of the Bone and Joint by the World
Health Organisation and the United Nations, and the
US National Institute of Health has set up the Osteoarthritis Initiative for the detailed study of human
osteoarthritis. By the year 2012, osteoarthritis will be the
disease with the fourth greatest impact upon the health
of women and have the eighth greatest impact for men.
The changed view of the pathogenesis of osteoarthritis from cartilage to the involvement of the whole
synovial joint, and the recognition of early changes in
the bone and ligaments, provide the potential for a new
approaches to the understanding and treatment of this
painful and debilitating disease.
Changes in bone and collagen play an integral part in
osteoarthritis of the joint. Much work has already been
done to clarify the changes in articular cartilage, but
a greater effort must now be directed towards research
into bone to redress the balance in our understanding of
the role of osteoarthritic changes at the osteochondral
junction within synovial joints.
Commentary
The AgeNet Workshop established both a collective
view that bone is important in the pathogenesis of
osteoarthritisÐnot hitherto a widely held opinionÐand
a desire to collaborate across disciplinary and geographical boundaries in the expectation that this will
bring faster progress. We hope that this opportunity will
not be missed.
ALLEN J. BAILEY
CHRISTOPHER BUCKLAND-WRIGHT1
DAVID METZ2
Collagen Research Group,
Division of Molecular and Cellular Biology,
University of Bristol, Bristol BS40 5DS, UK
Fax: (q44) 117 928 9505
Email: [email protected]
1
Department of Applied Clinical Anatomy,
King's College, London, UK
2
AgeNet,
London School of Hygiene and
Tropical Medicine, London, UK
AgeNet is an initiative sponsored by Medical Research
Council, Research into Ageing, BUPA, SmithKline Beecham
and the UK government's Foresight Challenge, with a mission
to create a research network stimulating multidisciplinary
partnerships bene®cial to the quality of life of older people.
The organizers are indebted to the University of Bath
for providing conference and accommodation facilities.
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