CME Objectives:

On completion of this article, the reader

should be able to: (1) identify patients
who have systemic risk factors that will Osteoarthritis
predispose them to osteoarthritis, (2)
recognize the role of local
biomechanical factors in the
development of osteoarthritis, and (3)
describe normal joint structure and
function and the pathophysiologic CME ARTICLE • 2006 SERIES • NUMBER 8
changes that occur in osteoarthritis.
Level: Advanced.
Accreditation: The Association of
Academic Physiatrists is accredited by
Osteoarthritis
the Accreditation Council for Epidemiology, Risk Factors, and Pathophysiology
Continuing Medical Education to
provide continuing medical education
for physicians. The Association of
Academic Physiatrists designates this
continuing medical education activity
for a maximum of 1.5 credits in ABSTRACT
Category 1 of the Physician’s Garstang SV, Stitik TP: Osteoarthritis: epidemiology, risk factors, and pathophys-
Recognition Award of the American
Medical Association. Each physician iology. Am J Phys Med Rehabil 2006;85(Suppl):S2–S11.
should claim only those credits that he Key Words: Osteoarthritis, Arthritis, Epidemiology, Pathophysiology
or she actually spent in the education
activity.
Disclosures: This activity was
supported by an educational grant from
Sanofi-Aventis. Disclosure statements
have been obtained regarding the
O steoarthritis (OA) is the most prevalent form of arthritis and a major cause
of disability in people aged 65 and older.1 Current estimates are that 40 million
authors’ relationships with financial
supporters of this activity. The people in the United States have OA, and this number is expected to reach 60
supplement editor, Todd P. Stitik, MD, million by the year 2020.2 Among persons aged 70 and older, 58% report having
is currently performing research that symptomatic arthritis.3 In addition to the high prevalence of OA in the United
has been funded by a grant from Sanofi- States, approximately 10 –30% of those affected with OA have significant pain
Aventis, Inc. Susan V. Garstang, MD, has
and disability.4 By 2020, an estimated 12 million Americans will have limitation
no apparent conflicts of interest related
to the context of participation of the in some aspect of function because of OA.2 The estimated cost of this disability
authors of this article. is nearly $65 billion annually.2 Because of the public health impact of arthritis,
0894-9115/06/8511(Suppl)-00S2/0 President George Bush signed a proclamation designating the years 2002–2011
American Journal of Physical Medicine as the Bone and Joint Decade in the United States.
& Rehabilitation OA is not a single disease; rather, it is a group of overlapping yet distinct
Copyright © 2006 by Lippincott diseases with different etiologies. Nuki5 best describes OA as “the clinical and
Williams & Wilkins pathologic outcome of a range of disorders that results in structural and
functional failure of synovial joints. OA occurs when the dynamic equilibrium
DOI: 10.1097/01.phm.0000245568.69434.1a
between the breakdown and repair of joint tissues is overwhelmed.” Thus,
understanding OA requires knowledge of the disorders that contribute to the
development of OA as well as the structure and function of synovial joints. This
paper will being by reviewing the epidemiology of OA and then will review the
systemic and local biomechanical factors that contribute to the development of
OA. Next, normal joint structure and function will be discussed, followed by a
review of the pathophysiology of the OA joint.

Epidemiology
The incidence and prevalence of OA vary by whether clinical or radiographic
definitions are used. Not all patients with radiographic evidence of OA have
symptoms, and patients may report having arthritis without radiographic con-
firmation.6 Despite this, an overall picture of the epidemiology of the disorder
has been described. Approximately 30% of adults over 30 have radiographic
evidence of hand OA. At least 33% (and up to 68% in some studies) of persons
over 55 have radiographic evidence of knee OA. Clinically, 6% of adults over 30
have symptomatic knee OA, and 10 –15% of adults over 60 have symptoms.6 –9

S2 Am. J. Phys. Med. Rehabil. ● Vol. 85, No. 11 (Supplement)

Authors:
Susan V. Garstang, MD
Todd P. Stitik, MD
Affiliations:
From the Department of Physical Medicine and
Rehabilitation, University of Medicine and Dentistry of
New Jersey–New Jersey Medical School, Newark, New
Jersey.
Correspondence:
All correspondence and requests for reprints should be
addressed to Dr Susan Garstang , MD, University of
Medicine and Dentistry of New Jersey–New Jersey
Medical School, Physical Medicine & Rehabilitation,
30 Bergen Street, ADMC 101, Newark, NJ 07039.
Symptomatic hip OA occurs in 1– 4% of adults.6
Symptomatic hand OA occurs in 10 –15% of the
elderly.9
Analysis of the causes of OA reveals a disorder
that is multifactorial, with primary and secondary
forms that likely represent differing disease pro-
cesses. Data that support the concept of OA as a
group of diseases include studies showing that OA
of the hip and knee are associated with different
risk factors and have varying prevalence in differ-
ent ethnic groups.10,11 In addition, generalized OA
may be a distinct disease and can be clearly differ-
entiated from secondary OA, some forms of which
develop in persons with prior injuries or develop-
mental abnormalities.6,9 Another disease pattern
pointing to more than one etiology for OA is that
hip OA may be hypertrophic or atrophic, and these
two types likely have different underlying patho-
physiologic mechanisms.6 Understanding the risk
factors associated with OA can aid in clarifying the
disease processes that lead to the eventual outcome
of synovial joint failure.
Risk Factors
Risk factors can be divided into two major
categories: systemic factors, which are associated
with the development of OA; and local factors,
which tend to result in abnormal biomechanical
loading of affected joints (Table 1). Systemic fac-
tors include ethnicity, age, gender and hormonal
status, genetic factors, bone density, nutritional
factors, and other factors. Local biomechanical fac-
tors include obesity (which also has a systemic
component), altered joint biomechanics (including
ligamentous laxity, malalignment, impaired pro-
prioception, and muscle weakness), prior joint in-
juries, occupational factors, the effects of sports
and physical activities, and the result of develop-
November 2006
mental abnormalities. The pathophysiology of OA
is almost certainly multifactorial, with interplay
between systemic and local factors. Both systemic
and local factors affect the likelihood that a joint
will develop OA; for example, genetics may increase
the likelihood that joint damage will progress to
OA.12 If systemic factors are in place, the joint may
be thought of as vulnerable, and thus local biome-
chanical factors will have more of an impact on
joint degeneration.
Systemic Factors
Systemic risk factors are the factors thought to
contribute to the development of OA by creating a
systemic environment where the joint is vulnerable.
As mentioned above, these systemic risk factors in-
clude ethnicity, age, gender and hormonal status,
genetic factors, bone density, nutritional factors, and
other factors, some which have yet to be identified.
Each of these will be discussed in detail.
Ethnicity
Studies of the patterns and incidence of OA in
different racial and ethnic groups support the role
of ethnicity in the development of OA. For example,
hip OA is rare in China and in those of Chinese
descent in the United States.13,14 Anatomic abnor-
malities that are prevalent in the United States are
rare in the hips of persons of Chinese descent,
which may indicate that genetic predisposition to
developmental abnormalities is a factor in this eth-
nic variation (although other factors, including
nutrition, cannot be excluded).15 However, knee
OA is more prevalent in older persons in Beijing
than in the United States, particularly in women,
who have a 44% higher rate of knee OA than did
women in the Framingham study.16 This may be
attributable in part to activities thought to be more
prevalent in Chinese women, such as squatting and
manual labor.17 Interestingly, the prevalence of OA
is 50% lower in hand joints in the Chinese than in
persons in the United States, for unclear reasons.18
In the United States, there are also differences
seen in some studies in the prevalence and patterns of
TABLE 1 Risk factors
Local Biomechanical
Systemic Risk Factors Risk Factors
Ethnicity Joint injury
Age Obesity
Gender and hormonal Occupation
status
Genetics Sports and physical activity
Bone density Joint biomechanics
Nutritional factors Muscle weakness
Osteoarthritis Epidemiology S3
 OA in different ethnic groups. One study showed a
higher rate of knee OA in African American women
but not in men compared with their Caucasian coun-
terparts; however, another study showed no differ-
ence between these groups.19,20 In a study looking at
hip OA in men, there was no change in the prevalence
of hip OA between groups, but another study showed
that African American men were 35% more likely
than white men to have hip OA.21,22 Several studies
show that African Americans with hip or knee OA
have more severe radiographic features of disease and
more frequent bilateral involvement and mobility im-
pairment.20,23 These ethnic differences may be related
not only to underlying genetic factors but also other
variables including variations in body mass index
(BMI), nutritional factors, and the impact of lifestyle
differences and healthcare disparities between popu-
lations, which confound interpretation of this data.
Age
The prevalence and incidence of OA correlates
with age. The general incidence of radiographic OA in
the United States population is 1–3% in persons over
55 yrs of age.7,8 A community-based survey revealed
that the incidence and prevalence of OA increased 2-
to 10-fold from 30 to 65 yrs of age. This association
with age continues until the age of 80, when the
curve levels off.24 It is unclear how much of this effect
is attributable to decreased reporting of the disease in
the elderly, perhaps because they are more sedentary
or because of the increase in pain threshold with age.
The presence of radiographic OA rises with age at all
joint sites. In a Dutch study, by 40 yrs of age, 10 –20%
of women had evidence of severe radiographic OA of
their hands or feet, and by age 70, approximately 75%
of women had evidence of radiographic OA in their
hands or feet.25
The increase in OA with age is likely a conse-
quence of biological changes that occur with aging.
These include a decreased responsiveness of chondro-
cytes to growth factors that stimulate repair.26 There
is also an age-related accumulation of advanced gly-
cation end products in cartilage that affect the syn-
thetic and reparative abilities of the chondrocytes.27
In addition, aging is often associated with decreased
strength and slower neurologic responses attribut-
able in part to a decline in proprioception.28 Not only
are both of these joint-protective mechanisms im-
paired, but the cartilage also thins, increasing shear
stress and hastening joint degeneration.10
Gender and Hormonal Status
Men younger than 50 have a higher incidence
of OA than women, whereas after the age of 50
women have a higher incidence of the disease.6
This gender difference is also seen in prevalence,
and it increases with advancing age.25 Hip OA is
more frequent in men, whereas knee, hand, and
S4 Garstang and Stitik Am. J. Phys. Med. Rehabil.
foot OA are more frequent in women.11 Many fac-
tors may influence gender differences in the inci-
dence and prevalence of OA, including differing
occupational histories or choice of sports and lei-
sure activities. In addition, some developmental
abnormalities (such as Legg–Calves–Perthes dis-
ease) are linked to gender, and these conditions are
also known to predispose persons to OA as they age.
The evidence regarding the influence of hor-
monal status on the incidence of OA is mixed. The
higher incidence of OA in women who are post-
menopausal suggests that estrogen deficiency in-
creases the risk of OA. OA has also been associated
with previous hysterectomy in one study, but not in
another.29,30 Estrogen replacement therapy is associ-
ated with a reduction in the risk of knee and hip OA
in several studies.30 –32 However, high lifetime estro-
gen exposure correlates with high bone density. Stud-
ies of the relationship between high bone density and
the development of OA show that high bone mineral
density is associated with an increased prevalence of
hip, hand, and knee OA.33,34 Despite potentially in-
creasing the risk of OA, women with higher bone
density that have OA may actually have a decrease in
the rate of disease progression.35 Thus, the role of
estrogen in OA is mixed and may exert protective or
deleterious effects on the disease in different patients.
Genetics
Studies show that OA has a major genetic com-
ponent.36 –38 Primary OA is a late-onset disease that
can be classified as polygenic and multifactorial,
meaning that environmental factors play a significant
role in gene expression.39 A large-scale female twin
study showed a heritability rate for hand and knee OA
between 39 and 65%, with a concordance rate of 0.64
in monozygotic pairs compared with 0.38 in the dizy-
gotic pairs.40 Focusing on hip OA, the heritability was
58% in female twins.41 Although sibling studies
clearly support a strong genetic component to the
development of OA, this association is much weaker
in male twins than in females, with a correlation for
development of OA of 0.62 in female monozygotic
twins and only 0.34 in male monozygotic twins.38 A
relatively recent study suggests that generalized ra-
diographic OA is inherited and that the most likely
pattern is that of a major Mendelian gene with a
residual multifactorial component.42 The study found
that heritability of generalized OA was stronger
among women in the family than among men.
There are studies of rare Mendelian families in
which OA was transmitted as a dominant trait with
incomplete penetrance.39 However, affected individu-
als had mild osteochondrodysplasias, which predis-
pose them to OA, and thus this type of OA would be
considered secondary rather than primary. Several
extended families whose members had chondrodys-
plasia in conjunction with severe OA with an early
● Vol. 85, No. 11 (Supplement)
onset have been described.43,44 In some cases the
disease development has been tied to an autosomal
dominant mutation in type II procollagen, the pre-
cursor to type II collagen, which is the most prevalent
form of collagen in joint cartilage. A recent analysis of
affected sibling pairs and an evaluation of 45 families
affected by generalized OA have found that type II
collagen defects may not account for a large propor-
tion of inherited OA in the community.45,46
Many studies of rare pedigrees and affected
sibling pairs have been conducted, and genome-
wide scans have been performed to determine
which chromosome regions link to OA. Although
many chromosomes have been identified in small
studies, chromosomes 2, 4, and 16 were positive in
several studies and are therefore the chromosomes
most likely to harbor primary OA susceptibility.39
Syntenic genes for type II collagen, cartilage oligo-
meric protein, and the vitamin D receptor may also
encode for OA susceptibility.39
Bone Density
The association between bone density and OA
remains unclear. Osteoporosis and OA have been
shown to be inversely associated in many studies in
which individuals with osteoporosis exhibit a lower
than expected rate of OA.47–52 In addition, women
with hypertrophic hip OA and osteophyte formation
have an 8 –12% increase in bone density compared
with women without OA.33 Patients with generalized
OA have also been found to have increased BMD of
the lumber spine.49 Although it might be that osteo-
phyte formation and not cartilage loss is linked to the
high bone mass, bone density in patients with OA is
greater than in age-matched controls, even at sites
distant from the joints affected by OA.33 However,
despite the preponderance of evidence linking in-
creased bone density to OA, there are studies that
show either no association or a reverse associa-
tion.53–56 How much of this is attributable to meth-
odological study issues (such as careful analysis to
eliminate confounding risk factors) is unclear.
Nutritional Factors
Theoretically, exposure to dietary antioxidants
could have a protective role in the development of
OA. The Framingham Knee OA Cohort Study
showed a threefold reduction in risk for radio-
graphic OA in persons in the middle and highest
tertiles of vitamin C intake compared with those
whose intake was in the lowest.57 The Framingham
Study demonstrated that the risk for progression of
OA was increased threefold for persons in the mid-
dle and lower tertiles of both vitamin D intake and
serum level, but there was no association with the
risk of new-onset OA.58 High levels of vitamin D
where found in another study to be protective
against both incident and progressive hip OA.59
November 2006
Local Biomechanical Factors
Besides the systemic risk factors discussed above,
another clear set of risk factors that play a role in the
development of OA are the local biomechanical fac-
tors. These include prior joint injuries, obesity, occu-
pation, sports and physical activity, joint biomechan-
ics and malalignment, and muscle weakness. These
risk factors will be discussed in detail below.
Joint Injury
OA is clearly associated with a variety of joint
injuries and damage, including fractures of the
articular surface, prior joint dislocations, and liga-
ment and meniscal ruptures. Studies of both hu-
man and animal models convincingly demonstrate
that a loss of anterior cruciate ligament integrity,
damage to the meniscus, and meniscectomy lead to
knee OA.60 Follow-up studies of patients with cru-
ciate rupture have reported cartilage loss, even in
young patients. The risk rises with advanced age,
presence of a systemic risk factor for OA, and time
since meniscectomy. Major injuries that alter me-
chanical function or joint alignment may also pre-
dispose individuals to OA at other sites.
Factors that are associated with altered joint
shape lead to increased local stresses on the carti-
lage and predispose individuals to cartilage loss and
early disease. Articular surface incongruities can
also increase local contact stress and predispose
the joint to accelerated development of OA.61 Other
risk factors for posttraumatic arthritis include high
body mass, high level of activity, and residual joint
instability or malalignment.11,60,61
Obesity
Obesity is associated with a high prevalence of
knee OA in both genders. However, its association
with hand and hip OA is less clear. Overweight per-
sons, particularly women, develop knee OA more of-
ten than people who are not overweight.6,62 Although
it is likely that body weight generally increases fur-
ther after the development of knee OA, increased
body weight has been shown to precede the occur-
rence of knee OA.62,63 In the Framingham study, the
body mass index measured at entry into the study
predicted the presence of radiographic knee OA 36 yrs
later.62 The risks of developing knee OA or experienc-
ing progression of the knee OA are not attenuated by
adjustments for factors correlated with obesity.6 Be-
ing overweight also increases the risk for radio-
graphic progression of knee OA. Interestingly, weight
loss of 11 pounds in women of average height was
associated with an approximately 50% reduction in
the risk of developing symptomatic knee OA.64
The association between OA at other joints and
obesity is less clear. Unilateral hip OA has not been
clearly associated with obesity. However, bilateral hip
Osteoarthritis Epidemiology S5
 OA is associated with obesity, even when adjusted for
age and gender.11,65 Some studies have shown that
there is an association between obesity and hand OA,
with body mass index being directly proportional to
carpometacarpal OA in both genders, suggesting that
obesity may predispose to OA, perhaps via an inflamma-
tory or metabolic intermediary that has not yet been
identified.66,67 This means that obesity plays a role not
only as a local process but systemically as well.
Occupation
Although the development of OA is clearly mul-
tifactorial, there seems to be an association between
the pattern of joint involvement in OA and repetitive
use.68,69 Occupational activities are often character-
ized by repetitive use of particular joint groups. Ac-
tivities performed by jackhammer operators, shipyard
workers, coal miners, and others lead to OA in the
joints exposed to repetitive occupational use.68,69
Women whose jobs involved repetitive pincer grip
motions had a much higher rate of distal interpha-
langeal joint OA than did other female workers whose
jobs did not involve repetitive grasp.6 Studies dem-
onstrate a significant increase in knee OA in men and
women who engage in jobs that are associated with
high physical demands such as miners, dock workers,
concrete workers and shipyard workers, when com-
pared with clerical or office staff.17,70,71 Jobs requiring
kneeling and squatting also predispose individuals to
knee OA, and jobs with heavy lifting can lead to hip
OA.68 Hip OA occurs two to eight times more fre-
quently than expected among agricultural laborers.6
This most probably relates to regular lifting of very
heavy loads and walking over rough ground. Data from
the Framingham Study suggest that such job activities
are associated with 15–30% of cases of OA in men.72
Sports and Physical Activity
Certain types of sporting activity have been
associated with an increased risk of OA. However,
repetitive activities associated with some types of
athletics, such as moderate running, do not seem
to cause joint degeneration in the absence of other
factors.73 The only group of runners who do seem
to have a higher risk of developing OA are male
athletes under 50 who run more than 20 miles
per week.74 The risk of OA increases with joint
damage, ligamentous damage, or meniscal injury
sustained during sports participation. High-inten-
sity, acute, direct joint impact as a result of contact
with other players or equipment can increase the
risk of OA in the affected joint.75 Torsional loading
also seems to be associated with joint degenera-
tion, such as in the elbows of throwing athletes.75
Early diagnosis and treatment of sports-related in-
juries, with a goal of maintaining joint-surface
integrity, should help decrease the subsequent risk
of developing OA at the injured joint.
S6 Garstang and Stitik Am. J. Phys. Med. Rehabil.
Joint Biomechanics
A loss of normal joint biomechanics results in
increased joint vulnerability. Individuals who have
abnormal joint anatomy or function, including dis-
ruption or incongruity of the articular surface,
dysplasia, malalignment, instability, disturbances
of innervation of the joint or muscles, and inade-
quate muscle strength or endurance may have a
greater risk of OA.76 Developmental conditions that
have been associated with subsequent OA include
developmental hip dysplasia, Legg–Calves–Perthes
disease, and slipped capital femoral epiphysis.10
Although in theory the biomechanical alter-
ations that are a result of ligamentous laxity, joint
malalignment, or proprioceptive deficits predis-
pose the joint to the development of OA, there are
few data to support most of these effects. Those
with knee OA and varus alignment of the lower
limb have a marked increase in the risk of medial-
joint disease progression, and those with valgus
malalignment have an extremely high risk of lat-
eral-joint space progression.10 A higher incidence
of varus–valgus laxity is seen bilaterally in the
knees of those with OA (both the involved and
nonarthritic knee), suggesting that laxity may pre-
cede disease development and contribute to the dis-
ease process.77 Impaired proprioception has been
seen in patients with OA compared with age-matched
controls, which may also indicate that proprioceptive
loss preceded disease development.78
The role of mechanical loading in the develop-
ment of OA is clearer. Moderate cyclic joint loading
has been shown to be beneficial by enhancing pro-
teoglycan synthesis and making cartilage thicker,
but continuous compression of the cartilage sup-
presses metabolic activity including collagen and
proteoglycan synthesis and causes tissue damage.79,80
Joint immobilization has also been shown to be det-
rimental, reducing cartilage thickness and proteogly-
can content. In addition, intense exercise or a sudden
increase in exercise, particularly in older persons,
produces catabolic changes in cartilage.79
Muscle Weakness
Muscle weakness, particularly of the quadri-
ceps, is often seen in people with OA of the knee.
People with radiographic evidence of OA have been
shown to have weaker quadriceps than those with-
out knee OA.81 In addition, patients with OA who
are obese, despite having overall greater quadriceps
muscle mass, have weaker quadriceps than obese
patients without OA.11 Quadriceps muscle weak-
ness has generally been attributed to disuse atro-
phy due to pain or to the altered joint biomechan-
ics as discussed above.
However, women in a longitudinal study who
had no initial radiographic evidence of OA but who
● Vol. 85, No. 11 (Supplement)
did have knee-extensor weakness were more likely
to develop OA than women with no initial weak-
ness.82 This suggests that weakness, although not
necessarily the primary insult to the joint, may
predispose individuals to the development of OA.
Muscle weakness may permit transmission of more
load onto affected OA joints, thereby accelerating
joint damage.83
Normal Joint Structure and Function
OA develops when the normal synovial joint
structure and function is disrupted or damaged by
interplay of the risk factors mentioned above. The
normal synovial joint has multiple structures that
act to protect the joint, including the surrounding
muscles, ligaments, synovium, and menisci, and
factors intrinsic to the cartilage and subchondral
bone. In addition, joint biomechanics protect the
joint when functioning normally. Knowledge of
normal joint structure and function is important
for understanding the development of OA in an
impaired joint.
Normal Anatomy and Physiology
The normal synovial joint consists of subchon-
dral bone, articular cartilage, the synovial mem-
brane, synovial fluid, and the joint capsule. Some
joints also have labral tissue, interosseous liga-
ments, menisci, and fat pads. In addition, joints are
supported by the periarticular muscles, tendons,
and ligaments. These structures are all important
in ensuring proper joint function. The articular
surface consists of articular cartilage supported by
subchondral bone and metaphyseal trabecule.61
Normal cartilage has a surface zone, a middle
zone, a deep zone, and then a zone of calcified
cartilage, where the cartilage attaches to the un-
derlying subchondral bone. In the surface zone,
collagen content is the highest and the collagen
fibers are oriented parallel to the joint surface. In
the middle zone, collagen fibers are oriented in
multiple directions, and proteoglycan content is
increased. In the deep zone, collagen fibers are
oriented perpendicular to the articular surface.
Collagen fibers attach to the subchondral bone
after a transition through the zone of calcified
cartilage.84
The articular cartilage has several roles in the
normal joint, including friction reduction, shock
absorption, and the spread and transmission of
weight loads to the underlying bone. Articular car-
tilage is composed of an extracellular matrix and
chondrocytes. The extracellular matrix is primarily
composed of water (65– 80% by weight), collagen,
and proteoglycans. The other constituents of car-
tilage are Type II collagen (10 –20%), proteogly-
cans (4 –7%), and cellular elements and proteins
November 2006
(1–10%).84 Proteoglycans have a protein core (the
most common of which is aggrecan) and one or
more glycosaminoglycan side chains (which in-
clude hyaluronic acid, chondroitin sulfate, and ker-
atin sulfate). Chondrocytes are the only cells of the
articular cartilage, and they are dispersed through-
out the extracellular matrix. Cartilage is avascular,
and therefore the chondrocytes receive nutrients
and eliminate waste by diffusion through the syno-
vial fluid and by facilitated imbibition.85
The subchondral bone also plays a role in nor-
mal joint protection. The deepest layer of cartilage
is calcified and attached to the subchondral bone
plate (cortical end plate). The cartilage and bone
are interdigitated at their interface, which serves to
transform shear forces into tensile and compres-
sive stresses.85 Subchondral bone can attenuate
about 30% of the loads through the joint, whereas
articular cartilage attenuates only 1–3% of load
forces.85 In addition to its shock-absorbing func-
tion, the subchondral bone plays a supportive role
in maintaining the joint environment. The sub-
chondral bone contains not only bone marrow and
trabecular bone but also end arteries and veins. The
subchondral bone has marked porosity, with ves-
sels penetrating the calcified cartilage zone. These
help provide nutrients to the cartilage and facilitate
the removal of metabolic waste products.
The synovial membrane is another joint struc-
ture providing protection to the joint. It consists of
a thin synoviocyte layer, which forms synovial fluid
by plasma ultrafiltration and produces hyaluro-
nate. Synovial fluid is viscoelastic (shock absorp-
tion and friction reduction), provides a barrier for
inflammatory cell and debris movement within the
joint, and shields articular nociceptors from in-
flammatory mediators.84
Mechanisms Protecting the Joint
Normal loads on articular cartilage include
forces imposed by the action of muscles around the
joint, as well as the force of the body weight that is
transmitted through the joint. Muscle contractions
that stabilize or move the joint provide a major
component of the load on the articular cartilage.86
In addition, during normal walking, three to four
times the weight of the body is transmitted
through the knee joint. This force increases dra-
matically during maneuvers such as a deep knee
bend, during which the patellofemoral joint is sub-
jected to a load 9 –10 times the body’s weight.87
Although articular cartilage is an excellent shock
absorber, it is only 3– 6 mm thick at maximum, and
thus provides limited joint protection.10 Thus, the
joint must have other protective mechanisms,
which include the action of muscles around the
joint and the protection of the subchondral bone
Osteoarthritis Epidemiology S7
 and the shock-absorbing functions of the synovial
fluid mentioned above.
The surrounding muscles play a key role in
imposing forces on the joint and also act as shock-
absorbing mechanisms. Muscles store energy when
stretched during joint motion, and they dissipate
or absorb this energy rather than transferring it to
the vulnerable joint structures.86 Thus, adequate
muscle strength and bulk are protective to the
joint. In addition, rapid neuromuscular (reflex) re-
sponses also serve to shield the joint from unex-
pected forces.
Pathology
The primary pathologic changes seen in OA
include fibrillations and loss of the articular carti-
lage, accompanied by thickening and remodeling
of the subchondral bone and, finally, full thickness
loss of joint space.84 It is still unclear whether
cartilage and bony changes occur concomitantly or
whether one tissue is involved before the other.84
However, OA typically progresses to involve many
or all the of tissues that form the synovial joint,
including the articular cartilage, subchondral
bone, synovial tissue, ligaments, joint capsule, and
muscles that act across the joint.
In the early stages of OA, fibrillation and irreg-
ularities of the superficial zone of the articular
cartilage develop and extend into the transitional
zone.88 After this, focal regions of cartilage loss
with clefts and fissure develop, along with changes
in the deepest layer of cartilage, the calcified car-
tilage layer. In late-stage OA, the loss of articular
cartilage may be of full thickness, and the bone
may become exposed.
One of the first pathologic signs of bony in-
volvement in OA is the formation of new extra bone
on trabeculae in the subchondral bone.89 Articular
cartilage degeneration is accompanied by these al-
terations of the subchondral bone, which may in-
clude subchondral sclerosis, formation of cystlike
bone cavities, and development of osteophytes.
Growth of osteophytes accompanies changes in the
articular cartilage and in subchondral bone in most
synovial joints. These fibrous, cartilaginous, and
osseous prominences usually develop around the
periphery of the joints, but they also occur along
insertions of the joint capsule or protruding from
the degenerating joint surfaces.
Subchondral bone alterations are thought to
be a result of abnormal osteoblast function.4,89
Microfractures of the highly elastic cancellous sub-
chondral bone can occur if the load is excessive,
leading to fracture of the subchondral trabeculae.
These microfractures heal with callous formation
and remodeling. The remodeled trabeculae may be
stiffer than normal and, therefore, may reduce the
shock-absorbing ability of the subchondral bone.89
S8 Garstang and Stitik Am. J. Phys. Med. Rehabil.
However, other work shows that the subchondral
bone is in fact less dense than normal bone.90 Thus,
the role of subchondral bone changes in the gen-
esis of OA is not completely clear because these
changes caused by remodeling precede the degen-
eration of articular cartilage but may not actually
cause the cartilage degeneration.85,90
The loss of articular cartilage leads to second-
ary changes in synovial tissue, ligaments, and the
muscles that surround the involved joint. Thus, the
normal protective role played by muscles can be
diminished by these secondary effects because de-
creased use of the joint and decreased range of
motion may lead to muscle atrophy, with concom-
itant loss of joint protection.
On a cellular level, OA is thought to represent
an imbalance between the destructive and repara-
tive or synthetic processes of the articular carti-
lage. The mechanisms responsible for progressive
loss of cartilage in OA include alteration of the
cartilage matrix, decline of the chondrocytic syn-
thetic response, and progressive cartilage loss.
Early changes in the cartilage include an increase
in the water content, and progressive disease is
marked by loss of the extracellular matrix.84 Ini-
tially, chondrocytes multiply and become metabol-
ically active. They also produce increased quanti-
ties of collagen and proteoglycans, but the quality
is abnormal. The type II collagen fibers in the
osteoarthritic cartilage are smaller than normal,
and the normally tight weave in the midzone be-
comes distorted.84 In addition, with advancing dis-
ease, the proteoglycan concentration decreases to
50% or less.84 As the disease worsens, less aggrecan
is present and the glycosaminoglycan chains be-
come shorter.84 These cartilage matrix changes
lead to increased matrix permeability and de-
creased matrix stiffness, which then predisposes
the joint to further damage.
Failure of chondrocytic responses to restore or
maintain tissue leads to loss of articular cartilage
accompanied or preceded by a decline in chondro-
cytic response. This decline leads to the last step in
the development of OA. The causes for this decline
are poorly understood. The decline could result
from the mechanical damage and death of chon-
drocytes no longer stabilized and protected by a
functional matrix, but it also seems to be related to,
or initiated by, a downregulation of the chondro-
cytic response to anabolic cytokines.26 Chondro-
cyte senescence is also thought to be the result of
chronic oxidative stress.
OA is considered a noninflammatory arthritis,
but there is evidence that as the cartilage destruc-
tion proceeds, changes in the joint occur that are
associated with inflammation. The synovial mem-
brane may have mild to moderate inflammatory
reaction, which is thought to be partly attributable
● Vol. 85, No. 11 (Supplement)
to the inflammatory effects of loose fragments of
articular cartilage in the synovial fluid.4 Once the
synovium is inflamed, the synoviocytes produce
cartilage-degrading enzymes, such as matrix met-
allotoproteins, and cytokines, including interleu-
kin-1, interleukin-6, and tumor necrosis factor-
alpha. These stimulate the chondrocyte to produce
more degrading enzymes. Enzymatic degradation
contributes to further decreased cartilage volume.88
In addition to the catabolic processes described
above, potent inflammatory mediators are also re-
leased into the joint. Interleukin-1 stimulates the
synoviocytes to make prostaglandin E2. Interleu-
kin-1 downregulates extracellular matrix synthesis
and upregulates matrix metallotoproteins synthe-
sis through the production of nitric oxide in chon-
drocytes. Interleukin-1 seems to be more potent at
causing cartilage degradation, whereas tumor ne-
crosis factor-alpha seems to be responsible for
inflammatory events.88 Nitric oxide and prosta-
glandin E2 seem to regulate the activity of the
cytokines, which may be one mechanism by which
prostaglandin E2 causes pain and inflammation, in
addition to its actions on blood vessels. Indepen-
dent of these other factors, joint impact has been
shown to cause upregulation of arachadonic acid,
interleukin-1, tumor necrosis factor-alpha, and
matrix metallotoprotein-3, even in the absence of
fracture.92 Thus, it is likely that a variety of stimuli
trigger the events that lead to joint destruction
after trauma and to OA in general.
CONCLUSION
OA is the most prevalent form of arthritis in
the United States, affecting a majority of adults
over 55 yrs of age. OA is not one disease but a group
of overlapping diseases with different etiologies but
similar pathologic, morphologic, and clinical out-
comes. Both systemic and local biomechanical fac-
tors contribute to the development of the disease,
with systemic factors also making the joint vulner-
able and resulting in a greater impact of local joint
factors. Systemic risk factors include ethnicity,
gender, age, genetic factors, hormonal status, bone
density, and nutritional factors. Local biomechani-
cal factors include altered joint biomechanics,
prior injuries, the effects of physical activities,
sports participation, occupation, developmental ab-
normalities, and obesity. The normal joint is pro-
tected by biomechanical factors such as alignment
and muscle strength, the lubrication provided by
the synovial fluid, and the shock-absorbing func-
tion of bone and cartilage. When these functions
are altered, changes occur at both the macroscopic
and cellular levels, with derangements in any
structure contributing to further joint destruction.
Further studies of both risk-factor modification
and cellular changes in OA will hopefully continue
November 2006
to enhance our understanding of this complex dis-
ease and lead to improved outcomes.
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