REVIEW ARTICLE

UPDATED THERAPY IN ELDERLY PATIENTS WITH

KNEE OSTEOARTHRITIS
Der-Yuan Chen1,2,3,4*
1
National Yang-Ming University, Taipei, 2National Chung-Hsing University, and 3Department of Allergy,
Immunology and Rheumatology, and 4Center for Geriatrics and Gerontology,
Taichung Veterans General Hospital, Taichung, Taiwan.

SUMMARY
In 2005, 9.6% of the Taiwan population were 65 years of age or older. Osteoarthritis (OA) is the most common
form of chronic arthritis, which is a common cause of functional limitation and dependency in the elderly in
Taiwan. The age-related changes in muscle strength and knee OA increase susceptibility to falls, which are asso-
ciated with significant morbidity and mortality in the elderly. The plan for management should be tailored to
the individual elderly patient and should be a multidisciplinary approach that includes nonpharmacologic
modalities combined with pharmacologic measures. Our understanding of the etiopathogenesis of knee OA
has grown significantly in recent decades, which has led to targeted and more effective approaches to disease
management. Therapeutic advances include the introduction of safer agents for symptomatic relief, as well
as agents with potential for disease or structure modification. [International Journal of Gerontology 2007;
1(1): 3139]

Key Words: disease-modifying osteoarthritis drug, elderly, knee osteoarthritis, Taiwan, therapy

Introduction ROM is associated with abnormal posture and may

About 9.6% of the Taiwan population are 65 years of age
or older1. By the year 2020, it is predicted that more
than 14% of the population will fall into this age range.
Osteoarthritis (OA) is the most common form of chronic
arthritis in the elderly in Taiwan; it is a major disease
associated with significant morbidity, and is one of the
most common causes of functional limitation and
dependency24. The prevalence of radiographic knee
OA is 42.8% in elderly Chinese women and 21.5% in
men5. Knee OA is particularly disabling due to symptoms
such as pain, stiffness, muscle weakness, and limited
range of motion (ROM)6. Furthermore, restricted joint
*Correspondence to: Dr Der-Yuan Chen, Department of Allergy,
Immunology and Rheumatology, Taichung Veterans General
Hospital, 160, Section 3, Taichung-Kang Road, Taichung 40705,
Taiwan.
E-mail: dychen@vghtc.gov.tw
Accepted: November 30, 2006
exacerbate disability. The age-related changes in muscle
strength and knee OA increase susceptibility to falls,
which are associated with significant morbidity and
mortality in the elderly7,8.
Risk Factors for Knee OA
OA is a slowly developing multifactorial disorder in
which aging, genetic, hormonal, and mechanical fac-
tors are major contributors to its onset and progres-
sion9,10. The incidence and prevalence of this disease
increase directly with age. By the age of 60 years, nearly
100% of the population will have histologic changes of
degeneration in their knee cartilage, over 80% will have
radiographic evidence of OA in at least 1 joint, about
40% will report having clinical symptoms of arthritis,
and about 10% will report activity limitation caused by
arthritis10. In an elderly cohort in the Framingham OA
study (age range, 6394 years), radiographic knee OA

International Journal of Gerontology | March 2007 | Vol 1 | No 1 31

2007 Elsevier.
 D.Y. Chen
was present in 27% of those below 70 years of age, and
44% in those aged 80 years or above11. Symptomatic
knee OA was less common than radiographic OA, with
7% of those below 70 years of age, and 11.2% of those
80 years or above reporting knee pain on most days
for at least a month11. The rate of incident radio-
graphic OA of the knee was about 2% per year in
women, and progressive disease occurred at 4% per
year with approximately 1% per year developing new
knee pain11.
Previous studies have found that the female sex is
associated with an increased risk of OA12,13. At 50 years
of age, women have higher rates of incident knee OA
compared to men14, and a higher prevalence of radio-
graphic and symptomatic OA3,15,16. The Framingham
OA study showed that women had rates of incident
disease 1.7 times higher than that in men15. Recent
epidemiologic studies suggested that postmenopausal
estrogen deficiency could play a role in the develop-
ment of knee OA in older women1719.
After age, obesity is the strongest modifiable risk
factor for the development of knee OA, particularly in
women10. For incident radiographic knee OA in the eld-
erly Framingham group, higher body mass index (BMI)
was associated with an odds ratio of 1.6 per 5-unit
increase in BMI20,21. Weight change also correlated with
risk such that an increase in risk of knee OA of 40%
was noted per 10-lb weight gain and a similar decrease
in risk was noted for weight loss. Among the elderly,
the combination of obesity and heavy physical activity
is associated with an enhanced risk of knee OA. Data
from the Framingham heart study showed that elderly
individuals in the upper tertile of BMI who performed
at least 3 hours of significant physical activity daily had
an odds ratio of 13 for developing knee OA22.
A prior history of knee injury is also a risk factor for
knee OA15,23,24. In a 21-year follow-up of 107 patients
who had undergone meniscectomy for management of
an isolated meniscus tear, the relative risk of develop-
ing radiographic knee OA compared with that of age-
and sex-matched controls was 1424. Recent studies have
also suggested that quadriceps weakness is associated
with radiographic and symptomatic knee OA in com-
munity-dwelling elderly individuals25. In addition,
knee proprioception declines with age, and muscle
weakness as well as reduced proprioception may con-
tribute to the development of knee OA. These factors
could certainly be expected to be involved in the effect
of knee OA on physical function26.
32
Pathobiology of OA
Pathologically, OA is characterized by fibrillation and
loss of articular cartilage, hypertrophic changes in the
neighboring bone including subchondral thickening
and osteophyte formation, some degree of synovial
change with patchy areas of synovitis and areas of
hypertrophy, and thickening of the joint capsule27.
The earliest changes involve roughening of the carti-
lage surface in areas of the knee joint that receive the
greatest stress, such as regions of the tibial condyles not
covered by the menisci and vertical ridge of the patella28.
The morphologic changes become more common and
more extensive with advancing age.
The pathobiology of OA is much more complicated
than either simple joint aging or wear and tear from
repetitive use. OA has traditionally been regarded as
noninflammatory arthritis, but improved detection
methods show that the inflammatory pathways are
upregulated29. OA results from articular cartilage failure
caused by a complex interplay of genetic, metabolic,
and biomechanical factors with secondary compo-
nents of synovitis. The increased catabolic activity is
caused by increased levels of several matrix metallopro-
teases (MMP), including MMP 1, 2, 8, 9, and 13, and the
newly discovered enzyme, aggrecanase30,31. Inadequate
repair of damaged matrix may be caused by age-related
increase in apoptosis32, decrease in mitogenic response
to insulin-like growth factor-I and other growth factor
stimulation with age33,34, and decline in proteoglycan
synthesis, which has been shown to be correlated with
an age-associated increase in pentosidine levels sug-
gesting accumulation of advanced glycation end prod-
ucts35. Cytokines and other signaling molecules released
from the cartilage, synovium, and bone affect chondro-
cyte function36. Levels of inflammatory cytokines such
as interleukin (IL)-1 are increased in OA cartilage and
are thought to be important in stimulating catabolism
and inhibiting anabolic processes37. Age-related changes
in the overall composition of the cartilage matrix also
result in a tissue that is less able to handle mechanical
stress.
Thickening of the subchondral bone, a consistent
finding in OA38,39, places additional stress on the over-
lying cartilage during joint loading resulting in mechan-
ical failure of the cartilage40. Multiple factors such as
body weight, joint stability, and muscle strength influ-
ence the rate at which age-related changes result in
the development and progression of OA.
International Journal of Gerontology | March 2007 | Vol 1 | No 1
 Updated Therapy in Elderly Knee OA
Clinical Manifestations of Knee OA
The principal symptom associated with knee OA is artic-
ular pain, which is typically exacerbated by activity and
relieved by rest41. In a more advanced stage of the dis-
ease, pain may be noted with progressively less activ-
ity, eventually occurring at rest and at night. Articular
pain is an important issue in the care of elderly peo-
ple, and perhaps the most important problem in their
daily lives. Morning stiffness is also a common com-
plaint in knee OA patients. It typically resolves less
than 30 minutes after patients awaken, but may recur
following periods of inactivity. Joint effusions may be
present, which typically exhibit a mild pleocytosis and
normal viscosity42. Limitation of ROM is a common sign
of knee OA41,42. In advanced cases, malalignment may
be apparent (genu varus or genu valgus), particularly
when medial and lateral compartments are affected
unequally. A fluctuant swelling along the posterior
aspect of the knee, or Bakers cyst, is also a common
complication. The most common clinical problem is
differentiation of painful OA from other common causes
of regional or generalized joint pain in elderly people,
referred pain, periarticular (soft-tissue) conditions, and
somatization. The diagnosis of knee OA remains prima-
rily clinical, and the American College of Rheumatology
(ACR) has developed classification criteria for this dis-
ease to assist the clinician in identifying patients with
symptomatic OA43.
Management of Knee OA in
Elderly Patients
The goals of management of elderly patients with knee
OA are to control articular pain and swelling, minimize
disability, improve the quality of life, prevent progres-
sion of the process, and educate the patient about
lifestyle modification. The initial plan for management
should be tailored to the individual patient but usually
includes nonpharmacologic modalities combined with
pharmacologic measures44.
Nonpharmacologic modalities
The ACR has recently developed guidelines for the
management of knee OA that stress the importance of
nonpharmacologic measures45. The multidisciplinary
team approach often used in geriatric medicine clearly
applies to managing elderly patients with knee OA4446.
International Journal of Gerontology | March 2007 | Vol 1 | No 1
Epidemiologic studies suggested that obesity is strongly
associated with the development of elderly OA2022, so
clinicians should encourage their obese patients with
knee OA to lose weight. Even moderate weight loss
may relieve joint pain, produce improvement in phys-
ical function, and reduce progression of OA. Patients
can be encouraged by the finding that an average
10-lb weight loss reduced the risk of knee OA by almost
50% in the Framingham cohort47. To achieve weight loss
in older adults with knee OA, dietary intervention to
reduce caloric intake should be recommended.
Given the importance of muscle strength in the
pathogenesis of knee OA25, exercises to strengthen the
quadriceps are particularly important. Individualized
strengthening programs developed by therapists have
been shown to improve strength and function and
relieve pain in subjects with knee OA48. Studies have
shown that elderly subjects are capable of increasing
their quadriceps strength using weights49,50. If available,
weight-training equipment, such as a leg extension
machine, is beneficial since the weight can more easily
be controlled and advanced as the patient improves in
strength. In the Fitness and Arthritis Seniors Trial51, aero-
bic walking was compared with a low-level strength
training program with comparable results in terms of
relief of pain and improvement in physical function.
The optimal exercise plan may be a combination of
lower extremity strengthening exercises and aerobic
walking. However, several factors must be considered
when creating an individualized exercise program for
an elderly patient with knee OA. As an example, a rel-
atively high intensity aerobic exercise program should
not be employed for patients with moderate-to-severe
OA. The American Geriatrics Society, which supports exer-
cise for elderly OA, has released guidelines for exercise
regimens for such individuals52.
Patient education and psychosocial support have
been shown to relieve pain in OA patients53,54. Patient
education should include informative discussions of the
disease and of physical disability, therapeutic options,
and the risks and benefits of the different approaches
to management53. Institution of appropriate counsel-
ing and antidepressant therapy when indicated are also
important issues for the management of elderly patients
with knee OA55.
There is evidence that physical therapy improves
clinical outcome in knee OA56. Physical therapists help
by developing an exercise program, and occupational
therapists provide guidance in using assistant devices.
33
 D.Y. Chen
Physical modalities to improve function can be just as
important as those that relieve pain. The application of
warm or cold packs to the symptomatic joint can also be
helpful. Therapeutic ultrasound has been used to treat
knee OA, and is reputed to reduce edema, relieve pain,
increase ROM, and accelerate joint tissue repair57.
Finally, braces and splints may be useful for symp-
tomatic relief for those with knee OA. As an example,
valgus bracing of the knee not only reduces pain, but
also improves function in patients with OA of the knee
that predominantly affects the medial compartment58.
In patients with more advanced disease, assistive devices
such as a cane should be recommended.
Pharmacologic therapy
The focus in managing patients with knee OA should
not only be centered on pain relief but also on func-
tion improvement. When medications are needed, the
least toxic drugs should be used for older adults
who have increased susceptibility to unwanted side
effects. Choices to this end include acetaminophen,
non-narcotic analgesics, nonsteroidal anti-inflammatory
drugs (NSAIDs), topical analgesics, intra-articular corti-
costeroids, and disease-modifying osteoarthritis drugs
(DMOADs).
Acetaminophen has been shown to be as effica-
cious as NSAIDs in many patients with knee OA59,60.
Given its better side effect profile, acetaminophen is a
good choice as an analgesic for OA patients, and is the
recommended first drug of choice in the ACR guide-
lines for the management of knee OA45,46, and in the
guidelines for management of chronic pain in older
adults from the American Geriatrics Society61. It is
important that patients are instructed to use the
proper dosage of acetaminophen, which is 1 g 34
times a day.
The new ACR guidelines include the non-NSAID anal-
gesic drug tramadol for the treatment of pain associ-
ated with knee OA46. Tramadol has a dual mechanism
of action, binding to the -opioid receptor and inhibit-
ing the reuptake of norepinephrine and serotonin62.
A recently developed drug, Ultracet (tramadol 37.5 mg/
acetaminophen 325 mg), is indicated for the short-term
management of acute pain in elderly knee OA63.
In older adults who are at increased risk of side
effects from NSAIDs, local treatments should be tried
before NSAIDs. Local treatments, including arthrocen-
tesis and corticosteroid injections, are effective for eld-
erly OA patients with synovitis64,65. A general guideline
34
is not to inject the same joint within 6 weeks of a pre-
vious injection or more than 34 times a year.
If simple analgesics and local treatments in com-
bination with nonpharmacologic agents have not
provided adequate pain relief, then NSAIDs may be
prescribed44,46. Although widely used in the manage-
ment of OA, NSAIDs do not provide an obvious advan-
tage over the other types of analgesics but have greater
potential for causing serious side effects, particularly
in the elderly population66,67. Numerous studies have
documented the increased risk of gastrointestinal (GI)
ulceration, bleeding, and death in elderly NSAID
users66,67. Other potential problems from NSAIDs, which
appear more commonly in older adults, include dete-
rioration of renal function68 and central nervous sys-
tem (CNS) symptoms, such as confusion, headache, and
vertigo. Therefore, indomethacin should not be used
to treat older adults with OA because it may exert
deleterious effects on the cartilage matrix, seems to be
the most toxic of the available NSAIDs, and causes
more CNS symptoms than the other NSAIDs66. A new
class of NSAIDs, the selective COX-2 inhibitors, has less
GI toxicity than conventional NSAIDs and provide an
alternative choice for elderly patients with knee
OA6972. A cost-effective analysis by Yen et al. showed
that among selective COX-2 inhibitors, celebrex was
found to be a more cost-effective or even cost-saving
strategy if the probability of serious GI complications
from conventional NSAIDs was considered73. However,
COX-2 inhibitors potentially cause vascular thrombosis
and heart failure in the elderly population74,75. In
patients with known cardiovascular disease or those
with multiple risk factors for coronary heart disease,
COX-2 inhibitors should be reduced in dosage and
duration, or even be avoided. Since the symptoms of
knee OA are often intermittent, physicians should try to
discontinue NSAIDs when the patients symptoms have
been stably quiescent. Nonpharmacologic modalities,
such as exercise and weight reduction, should be
continued.
Topical NSAIDs offer efficacy similar to that of orally
administered NSAIDs, reducing some aspects of GI and
renal toxicity. However, the efficacy of topical NSAIDs
appears to be of relatively short duration. A 2004 meta-
analysis, which included 13 trials involving almost 2,000
patients, showed a significant short-term (12 weeks)
efficacy of topical NSAIDs for pain relief and functional
improvement compared to that of placebo76. Topical
usage of capsaicin (which exerts its therapeutic effect
International Journal of Gerontology | March 2007 | Vol 1 | No 1
 Updated Therapy in Elderly Knee OA
by enhancing the release of substance P from unmyeli-
nated C nerve fibers) is recommended for patients who
do not respond to analgesics or who do not wish to
take systemic therapy77.
Disease- or structure-modifying osteoarthritis
drugs (DMOADs)
New therapeutic strategies for treating OA based on
present knowledge of its pathogenesis are evolving and
a new class of antiarthritis agents, known as DMOADs,
has been defined78. Clinical research studies are cur-
rently underway using other pharmacologic agents that
have been shown to favorably slow the disease process
in OA.
Tetracyclines have a variety of anti-inflammatory
effects that are mediated by inactivation of MMPs,
including collagenases, stromelysins, and gelatinases,
which degrade all components of the articular extra-
cellular matrix and can cause destruction of articular
cartilage79. Doxycycline may slow the rate of OA pro-
gression. A study showed that the rate of joint space
narrowing was significantly less in those treated with
doxycycline than in the placebo group79,80.
Glucosamine is important for the repair and main-
tenance of cartilage. A recent in vitro study provided
evidence that glucosamine could potentially inhibit
the activity of aggrecanase, which is responsible for
the cleavage of the large aggregating proteoglycan in
cartilage81. A 2005 meta-analysis of 20 controlled trials
of glucosamine including a total of 2,570 patients with
OA82 showed that a significant advantage over placebo
was noted in the efficacy of glucosamine for pain relief
and functional improvement, and there was a modest
benefit of glucosamine sulfate on slowing the rate of
joint space narrowing. However, a post hoc analysis did
not show any significant correlation between the degree
of pain relief and the change in joint space width. For
patients whose symptoms improve with glucosamine,
there is some evidence to suggest that regular use for
more than 6 months is no more effective in controlling
symptoms of OA than placebo. Adverse effects of glu-
cosamine are not significantly greater than for placebo,
but glucosamine should not be administered to patients
who are allergic to shellfish.
Chondroitin sulfate is composed of repeating units
of galactosamine sulfate and glucuronic acid. It is the
predominant glycosaminoglycan found in articular car-
tilage. A 2003 meta-analysis that involved 755 patients
with OA of the knee who were randomly assigned to
International Journal of Gerontology | March 2007 | Vol 1 | No 1
receive chondroitin sulfate or placebo showed that a
significant advantage over placebo was noted in the
efficacy of chondroitin sulfate for pain relief83. Some tri-
als also had a glucosamine arm, which showed that
the efficacy of chondroitin sulfate was similar to that
of glucosamine84. Despite the promising results noted
above, a large double-blind, placebo-controlled ran-
domized trial showed no significant difference in pain
relief between those receiving chondroitin sulfate alone
or the combination of glucosamine and chondroitin
sulfate and those receiving selective COX-2 inhibitor
(celecoxib)84.
Diacerein is metabolized to rhein, an agent that has
anti-inflammatory and analgesic properties85. An in vitro
study of cultured chondrocytes showed that rhein stim-
ulated prostaglandin E2 synthesis while inhibiting pro-
duction of IL-186,87. A 2006 systematic review of 7
clinical trials that included 2,069 patients with knee
OA noted a clinically modest pain relief compared to
placebo88. Diarrhea was a frequent adverse effect and
was reported in those taking diacerein. Another ther-
apy that has been found to relieve pain in knee OA is
avocado and soya unsaponifiables (ASU)89. They are
supposed to stimulate repair of extracellular matrix
components, thus enhancing the expression of trans-
forming growth factors 1 and 2 in cultured articular
chondrocytes. The majority of trial data available to date
suggest that ASU is effective for the symptomatic treat-
ment of OA90. However, the only real long-term trial
yielded a largely negative result.
Hyaluronic acid (HA), a major component of syno-
vial fluid (SF) and cartilage, is a high molecular weight
polysaccharide made of long nonsulfated straight
chains of variable disaccharide lengths composed of
N-acetylglucosamine and glucuronic acid. Its unique vis-
coelastic properties confer remarkable shock-absorbing
and lubricating abilities to SF91. In addition, HA can form
a pericellular coat around cells, interact with proin-
flammatory mediators, and bind to cell receptors to
modulate cell proliferation and migration91,92. It is now
believed that biologic activation of multiple protective
mechanisms may explain the long-term clinical bene-
fits. A 2005 meta-analysis showed a statistically signifi-
cant advantage for intra-articular HA injection in rest
pain between 2 and 6 weeks when compared to the
placebo group93,94. Recently, the ACR guidelines have
been updated to include recommendations for the use
of intra-articular hyaluronans46. However, there was no
statistically significant difference between those who
35
 D.Y. Chen
received HA injections and those who received oral
NSAID (naproxen)93. Considering the limited resources
available for health care in Taiwan, intra-articular HA
treatment may not be an economical choice73.
When patients with symptomatic knee OA have failed
to respond to nonpharmacologic and pharmacologic
treatment approaches, surgery should be considered.
For those with severe knee OA, joint replacement is very
effective95.
Conclusion
Knee OA is a common and debilitating condition asso-
ciated with pain and loss of mobility that undermines
quality of life in the elderly population. Our under-
standing of the etiopathophysiology of knee OA has
grown significantly in recent decades, which has led to
targeted and more effective approaches to disease
management. Therapeutic advances include the intro-
duction of safer agents for symptomatic relief, as well as
agents with potential for disease (structure) modification.
Maintaining or restoring functional capacity in elderly
knee OA is an important public health issue. Cartilage
replacement by bone marrow stem cells and implan-
tation of autologous chondrocytes or bioengineered
tissues continue as important areas of therapeutic
interest.
References
1. (2005, 7 19 )
http://sowf.moi.gov.tw/04/07/
.xls
2. Centers for Disease Control and Prevention (CDC). Arthritis
prevalence and activity limitationsUnited States, 1990.
MMWR Morb Mortal Wkly Rep 1994; 43: 4338.
3. Lawrence RC, Helmick CG, Arnett FC, Deyo RA, Felson DT,
Giannini EH, et al. Estimates of the prevalence of arthri-
tis and selected musculoskeletal disorders in the United
States. Arthritis Rheum 1998; 41: 77883.
4. Zhang Y, Xu L, Nevitt MC, Aliabadi P, Yu W, Qin M, et al.,
eds. Principles of Geriatric Medicine and Gerontology,
4th edition. New York: McGraw Hill, 1999: 1097111.
5. Zhang Y, Xu L, Nevitt MC, Aliabadi P, Yu W, Qin M, et al.
Comparison of the prevalence of knee osteoarthritis
between the elderly Chinese population in Beijing and
whites in the United States: The Beijing Osteoarthritis
Study. Arthritis Rheum 2001; 44: 206571.
36
6. Messier SP, Loeser RF, Hoover JL, Semble EL, Wise CM.
Osteoarthritis of the knee: effects on gait, strength, and
flexibility. Arch Phys Med Rehab 1992; 73: 2936.
7. Tinetti ME, Inouye SK, Gill TM, Doucette JT. Shared risk
factors for falls, incontinence, and functional depen-
dence. Unifying the approach to geriatric syndromes.
JAMA 1995; 273: 134853.
8. Ho SC, Woo J, Chan SS, Yuen YK, Sham A. Risk factors for
falls in the Chinese elderly population. J Gerontol A Biol
Sci Med Sci 1996; 51: M1958.
9. Creamer P, Hochberg MC. Osteoarthritis. Lancet 1997;
350: 5039.
10. Loeser RF. Aging and the etiopathogenesis and treatment
of osteoarthritis. Rheum Dis Clin North Am 2000; 26:
54767.
11. Felson DT, Naimark A, Anderson J, Kazis L, Castelli W,
Meenan RF. The prevalence of knee osteoarthritis in the
elderly. The Framingham Osteoarthritis Study. Arthritis
Rheum 1987; 30: 9148.
12. Jordan JM, Luta G, Renner JB, Linder GF, Dragomir A,
Hochberg MC, et al. Self-reported functional status in
osteoarthritis of the knee in a rural southern community:
the role of sociodemographic factors, obesity, and knee
pain. Arthritis Care Res 1996; 9: 2738.
13. Davis MA, Ettinger WH, Neuhaus JM, Hauck WW. Sex dif-
ferences in osteoarthritis of the knee. The role of obesity.
Am J Epidemiol 1988; 127: 101930.
14. Oliveria SA, Felson DT, Reed JI, Cirillo PA, Walker AM.
Incidence of symptomatic hand, hip, and knee osteo-
arthritis among patients in a health maintenance organ-
ization. Arthritis Rheum 1995; 38: 113441.
15. Felson DT, Zhang Y, Hannan MT, Naimark A, Weissman
BN, Aliabadi P, et al. The incidence and natural history
of knee osteoarthritis in the elderly. The Framingham
Osteoarthritis Study. Arthritis Rheum 1995; 38: 15005.
16. Felson D, Zhang Y. An update on the epidemiology of
knee and hip osteoarthritis with a view to prevention.
Arthritis Rheum 1998; 41: 13436.
17. Nevitt M, Felson D. Sex hormones and the risk of
osteoarthritis in women: epidemiological evidence. Ann
Rheum Dis 1996; 55: 6737.
18. Spector TD, Nandra D, Hart DJ, Doyle DV. Is hormone
replacement therapy protective for hand and knee
osteoarthritis in women? The Chingford study. Ann
Rheum Dis 1997; 56: 4324.
19. Zhang Y, McAlindon TE, Hannan MT, Chaisson CE, Klein R,
Wilson PW, et al. Estrogen replacement therapy and
worsening of radiographic knee osteoarthritis: the
Framingham Study. Arthritis Rheum 1998; 41: 186773.
20. Felson DT, Anderson JJ, Naimark A, Walker AM, Meenan RF.
Obesity and knee osteoarthritis. The Framingham Study.
Ann Intern Med 1988; 109: 1824.
International Journal of Gerontology | March 2007 | Vol 1 | No 1
 Updated Therapy in Elderly Knee OA
21. Felson DT, Zhang Y, Hannan MT, Naimark A, Weissman B,
Aliabadi P, et al. Risk factors for incident radiographic
knee osteoarthritis in the elderly: the Framingham Study.
Arthritis Rheum 1997; 40: 72833.
22. McAlindon TE, Wilson PW, Aliabadi P, Weissman B, Felson
DT. Level of physical activity and the risk of radiographic
and symptomatic knee osteoarthritis in the elderly: the
Framingham study. Am J Med 1999; 106: 1517.
23. Roos H, Adalberth T, Dahlberg L, Lohmander LS. Osteo-
arthritis of the knee after injury to the anterior cruciate
ligament or meniscus: the influence of time and age.
Osteoarthritis Cartilage 1995; 3: 2617.
24. Roos H, Lauren M, Adalberth T, Roos EM, Jonsson K,
Lohmander LS. Knee osteoarthritis after meniscectomy:
prevalence of radiographic changes after twenty-one
years, compared with matched controls. Arthritis Rheum
1998; 41: 68793.
25. Slemenda C, Brandt KD, Heilman DK, Mazzuca S,
Braunstein EM, Katz BP, et al. Quadriceps weakness and
osteoarthritis of the knee. Ann Intern Med 1997; 127:
97104.
26. Pai YC, Rymer WZ, Chang RW, Sharma L. Effect of age and
osteoarthritis on knee proprioception. Arthritis Rheum
1997; 40: 22605.
27. Buckwalter J, Mankin H. Articular cartilage: Part II.
Degeneration and osteoarthrosis, repair, regeneration,
and transplantation. J Bone Joint Surg 1997; 79A: 6127.
28. Ryu J, Treadwell BV, Mankin HJ. Biochemical and meta-
bolic abnormalities in normal and osteoarthritic human
articular cartilage. Arthritis Rheum 1984; 27: 4954.
29. Pelletier JP, Martel-Pelletier J, Howell DS. Etiopathogen-
esis of osteoarthritis. In: Koopman WJ, ed. Arthritis and
Allied Conditions: A Textbook of Rheumatology, 13th edi-
tion. Baltimore: Williams & Wilkins, 1997; 1969.
30. Tortorella MD, Burn TC, Pratta MA, Abbaszade I, Hollis JM,
Liu R, et al. Purification and cloning of aggrecanase-1:
a member of the ADAMTS family of proteins. Science
1999; 284: 16646.
31. Dean DD, Martel-Pelletier J, Pelletier JP, Howell DS,
Woessner JF Jr. Evidence for metalloproteinase and met-
alloproteinase inhibitor imbalance in human osteo-
arthritic cartilage. J Clin Invest 1989; 84: 67885.
32. Sharif M, Whitehouse A, Sharman P, Perry M, Adams M.
Increased apoptosis in human osteoarthritic cartilage
corresponds to reduced cell density and expression of
caspase-3. Arthritis Rheum 2004; 50: 50715.
33. Martin J, Ellerbroek S, Buckwalter J. Age-related decline
in chondrocyte response to insulin-like growth factor-I:
the role of growth factor binding proteins. J Orthop Res
1997; 15: 4917.
34. Guerne PA, Blanco F, Kaelin A, Desgeorges A, Lotz M.
Growth factor responsiveness of human articular chon-
drocytes in aging and development. Arthritis Rheum
1995; 38: 9608.
International Journal of Gerontology | March 2007 | Vol 1 | No 1
35. Barone-Varelas J, Schnitzer TJ, Meng Q, Otten L, Thonar EJ.
Age-related differences in the metabolism of proteogly-
cans in bovine articular cartilage explants maintained
in the presence of insulin-like growth factor 1. Connect
Tissue Res 1991; 26: 10120.
36. Westacott CI, Sharif M. Cytokines in osteoarthritis: medi-
ators or markers of joint destruction? Semin Arthritis
Rheum 1996; 25: 25460.
37. Dodge GR, Foole AR. Immunohistochemical detection
and immunochemical analysis of type 2 collagen degra-
dation in human normal, rheumatoid, and osteoarthritic
articular cartilages and in explants of bovine articular
cartilage cultured with interleukin-1. J Clin Invest 1989;
83: 64753.
38. Bailey A, Mansell J. Do subchondral bone changes
exacerbate or precede articular cartilage destruction
in osteoarthritis of the elderly? Gerontology 1997; 43:
296301.
39. Carlson CS, Loeser RF, Purser CB, Gardin JF, Jerome CP.
Osteoarthritis in cynomolgus macaques. III: Effects of
age, gender, and subchondral bone thickness on the
severity of disease. J Bone Miner Res 1996; 11: 120917.
40. Radin E, Paul I, Rose R. Role of mechanical factors in
pathogenesis of primary osteoarthritis. Lancet 1972; 2:
51923.
41. Moskowitz RW, Holderbaum D. Clinical and laboratory
findings in osteoarthritis. In: Koopman WJ, ed. Arthritis
and Allied Conditions: A Textbook of Rheumatology,
13th edition. Baltimore: Williams & Wilkins, 2001; 2216.
42. Schumacher HR, Gordon G, Paul H, Reginato AJ.
Osteoarthritis, crystal deposition, and inflammation.
Semin Arthritis Rheum 1971; 1: 11620.
43. Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K,
et al. Development of criteria for the classification and
reporting of osteoarthritis. Classification of osteoarthri-
tis of the knee. Diagnostic and Therapeutic Criteria
Committee of the American Rheumatism Association.
Arthritis Rheum 1986; 29: 103949.
44. Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma
JW, Dieppe P, et al. EULAR Recommendations 2003: an
evidence-based approach to the management of knee
osteoarthritis: Report of a Task Force of the Standing
Committee for International Clinical Studies Including
Therapeutic Trials (ESCISIT). Ann Rheum Dis 2003; 62:
114555.
45. Hochberg MC, Altman RD, Brandt KD, Clark BM, Dieppe PA,
Griffin MR, et al. Guidelines for the medical management
of osteoarthritis. Part II. Osteoarthritis of the knee.
American College of Rheumatology. Arthritis Rheum
1995; 38: 15416.
46. American College of Rheumatology Subcommittee on
Osteoarthritis Guidelines. Recommendation for the medi-
cal management of osteoarthritis of the hip and knee:
2000 update. Arthritis Rheum 2000; 43: 190515.
37
 D.Y. Chen
47. Felson DT, Zhang Y, Anthony JM, Naimark A, Anderson JJ.
Weight loss reduces the risk for symptomatic knee
osteoarthritis in women. The Framingham Study. Ann
Intern Med 1992; 116: 5359.
48. Fisher NM, Gresham GE, Abrams M, Hicks J, Horrigan D,
Pendergast DR. Quantitative effects of physical therapy
on muscular and functional performance in subjects
with osteoarthritis of the knees. Arch Phys Med Rehabil
1993; 74: 8407.
49. Fiatarone MA, Marks EC, Ryan ND, Meredith CN, Lipsitz LA,
Evans WJ. High-intensity strength training in nonagenari-
ans. Effects on skeletal muscle. JAMA 1990; 263: 302934.
50. Morganti CM, Nelson ME, Fiatarone MA, Dallal GE,
Economos CD, Crawford BM, et al. Strength improve-
ments with 1 year of progressive resistance training in
older women. Med Sci Sports Exerc 1995; 27: 90612.
51. Ettinger WH Jr, Burns R, Messier SP, Applegate W, Rejeski WJ,
Morgan T, et al. A randomized trial comparing aerobic
exercise and resistance exercise with a health education
program in older adults with knee osteoarthritis. The
Fitness Arthritis and Seniors Trial (FAST). JAMA 1997;
277: 2531.
52. Exercise prescription for older adults with osteoarthritis
pain: consensus practice recommendations. A supple-
ment to the AGS Clinical Practice Guidelines on the man-
agement of chronic pain in older adults. J Am Geriatr Soc
2001; 49: 80813.
53. Rene J, Weinberger M, Mazzuca SA. Reduction of joint pain
in patients with knee osteoarthritis who have received
monthly telephone calls from lay personnel and whose
medical treatment regimens have remained stable.
Arthritis Rheum 1992; 35: 5116.
54. Weinberger M, Hiner SL, Teirney WM. Improving func-
tional status in arthritis: the effect of social support. Soc
Sci Med 1986; 23: 899905.
55. Lin EH, Katon W, Von Korff M, Tang L, Williams JW Jr,
Kroenke K, et al. Effect of improving depression care on
pain and functional outcomes among older adults with
arthritis: a randomized controlled trial. JAMA 2003; 290:
24289.
56. Fransen M, Crosbie J, Edmonds J. Physical therapy is
effective for patients with osteoarthritis of the knee: a
randomized controlled clinical trial. J Rheumatol 2001;
28: 15661.
57. Huang MH, Lin YS, Lee CL, Yang RC. Use of ultrasound
to increase effectiveness of isokinetic exercise for knee
osteoarthritis. Arch Phys Med Rehabil 2005; 86: 154551.
58. Draper ER, Cable JM, Sanchez-Ballester J, Hunt N,
Robinson JR, Strachan RK. Improvement in function
after valgus bracing of the knee. An analysis of gait
symmetry. J Bone Joint Surg Br 2000; 82: 10015.
59. Bradley JD, Brandt KD, Katz BP, Kalasinski LA, Ryan SI.
Comparison of an antiinflammatory dose of ibuprofen,
38
an analgesic dose of ibuprofen, and acetaminophen in
the treatment of patients with osteoarthritis of the knee.
N Engl J Med 1991; 325: 8791.
60. Williams HJ, Ward JR, Egger MJ, Neuner R, Brooks RH,
Clegg DO, et al. Comparison of naproxen and aceta-
minophen in a two-year study of treatment of
osteoarthritis of the knee. Arthritis Rheum 1993; 36:
1196206.
61. American Geriatrics Society Panel on Chronic Pain in
Older Persons. The management of chronic pain in older
persons. J Am Geriatr Soc 1998; 46: 6359.
62. Raffa RB, Friderichs E. The basic science aspect of tra-
madol hydrochloride. Pain Rev 1996; 3: 24971.
63. Emkey R, Rosenthal N, Wu SC, Jordan D, Kamin M;
CAPSS-114 Study Group. Efficacy and safety of tramadol/
acetaminophen tablets (Ultracet) as add-on therapy for
osteoarthritis pain in subjects receiving a COX-2 non-
steroidal antiinflammatory drug: a multicenter, random-
ized, double-blind, placebo-controlled trial. J Rheumatol
2004; 31: 1506.
64. Bellamy N, Campbell J, Robinson V, Gee T, Bourne R,
Wells G. Intra-articular corticosteroid for treatment of
osteoarthritis of the knee. Cochrane Database Syst Rev
2006; 2: CD005328.
65. Arroll B, Goodyear-Smith F. Corticosteroid injections
for osteoarthritis of the knee: meta-analysis. BMJ 2004;
328: 86974.
66. Fries J, Williams C, Bloch D. The relative toxicity of non-
steroidal anti-inflammatory drugs. Arthritis Rheum 1991;
34: 13538.
67. Smalley WE, Ray WA, Daugherty JR, Griffin MR.
Nonsteroidal anti-inflammatory drugs and the inci-
dence of hospitalizations for peptic ulcer disease in eld-
erly persons. Am J Epidemiol 1995; 141: 53945.
68. Gurwitz JH, Avorn J, Ross-Degnan D, Lipsitz LA. Non-
steroidal anti-inflammatory drug-associated azotemia in
the very old. JAMA 1990; 264: 4715.
69. Hawkey CJ. COX-2 inhibitors. Lancet 1999; 353: 30714.
70. Singh G, Fort JG, Goldstein JL, Levy RA, Hanrahan PS,
Bello AE, et al. Celecoxib versus naproxen and diclofenac
in osteoarthritis patients: SUCCESS-1 Study. Am J Med
2006; 119: 25566.
71. Bjordal JM, Ljunggren AE, Klovning A, Slordal L. Nonsteroi-
dal anti-inflammatory drugs, including cyclooxygenase-2
inhibitors, in osteoarthritic knee pain: meta-analysis
of randomized placebo-controlled trials. BMJ 2004;
329: 1317.
72. Mamdani M, Rochon PA, Juurlink DN, Kopp A,
Anderson GM, Naglie G, et al. Observational study of
upper gastrointestinal haemorrhage in elderly patients
given selective cyclo-oxygenase-2 inhibitors or conven-
tional non-steroidal anti-inflammatory drugs. BMJ 2002;
325: 624.
International Journal of Gerontology | March 2007 | Vol 1 | No 1
 Updated Therapy in Elderly Knee OA
73. Yen ZS, Lai MS, Wang CT, Chen LS, Chen SC, Chen WJ, et al.
Cost-effectiveness of treatment strategies for osteoarthritis
of the knee in Taiwan. J Rheumatol 2004; 31: 1797803.
74. Couzin J. Drug safety. Withdrawal of Vioxx casts a shadow
over COX-2 inhibitors. Science 2004; 306: 3845.
75. Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B,
Horgan K, et al; Adenomatous Polyp Prevention on Vioxx
(APPROVe) Trial Investigators. Cardiovascular events asso-
ciated with rofecoxib in a colorectal adenoma chemo-
prevention trial. N Engl J Med 2005; 352: 1092102.
76. Lin J, Zhang W, Jones A, Doherty M. Efficacy of topical
non-steroidal anti-inflammatory drugs in the treatment
of osteoarthritis: meta-analysis of randomized controlled
trials. BMJ 2004; 329: 3247.
77. Deal CL, Schnitzer TJ, Lipstein E, Seibold JR, Stevens RM,
Levy MD, et al. Treatment of arthritis with topical cap-
saicin: a double-blind trial. Clin Ther 1991; 13: 38395.
78. Verbruggen G. Chondroprotective drugs in degenerative
joint diseases. Rheumatology (Oxford) 2006; 45: 12938.
79. Brandt KD, Mazzuca SA, Katz BP, Lane KA, Buckwalter KA,
Yocum DE, et al. Effects of doxycycline on progression
of osteoarthritis: results of a randomized, placebo-
controlled, double-blind trial. Arthritis Rheum 2005; 52:
201525.
80. Brandt KD, Mazzuca SA. Experience with a placebo-
controlled, randomized clinical trial of a disease-
modifying drug for osteoarthritis: the doxycycline trial.
Rheum Dis Clin North Am 2006; 32: 21734.
81. Richy F, Bruyere O, Ethgen O, Cucherat M, Henrotin Y,
Reginster JY. Structural and symptomatic efficacy of glu-
cosamine and chondroitin in knee osteoarthritis: a com-
prehensive meta-analysis. Arch Intern Med 2003; 163:
151422.
82. Towheed TE, Maxwell L, Anastassiades TP, Shea B,
Houpt J, Robinson V, et al. Glucosamine therapy for
treating osteoarthritis. Cochrane Database Syst Rev 2005;
2: CD002946.
83. Michel BA, Stucki G, Frey D, De Vathaire F, Vignon E,
Bruehlmann P, et al. Chondroitins 4 and 6 sulfate in
osteoarthritis of the knee: a randomized, controlled
trial. Arthritis Rheum 2005; 52: 77986.
84. Clegg DO, Reda DJ, Harris CL, Klein MA, ODell JR,
Hooper MM, et al. Glucosamine, chondroitin sulfate, and
the two in combination for painful knee osteoarthritis.
N Engl J Med 2006; 354: 795808.
International Journal of Gerontology | March 2007 | Vol 1 | No 1
85. Spencer CM, Wilde MI. Diacerein. Drugs 1997; 53: 98107.
86. Pelletier JP, Mineau F, Fernandes JC, Duval N, Martel-
Pelletier J. Diacerhein and rhein reduce the interleukin
1-beta-stimulated inducible nitric oxide synthesis level
and activity while stimulating cyclooxygenase-2 synthe-
sis in human osteoarthritis chondrocytes. J Rheumatol
1998; 25: 241724.
87. Yaron M, Shirazi I, Yaron I. Anti-interleukin-1 effects
of diacerein and rhein in human osteoarthritis synovial
tissue and cartilage cultures. Osteoarthritis Cartilage
1999; 7: 2728.
88. Fidelix TS, Soares BG, Trevisani VF. Diacerein for osteo-
arthritis. Cochrane Database Syst Rev 2006; 1: CD005117.
89. Cake MA, Read RA, Guillou B, Ghosh P. Modification of
articular cartilage and subchondral bone pathology in an
ovine meniscectomy model of osteoarthritis by avocado
and soya unsaponifiables (ASU). Osteoarthritis Cartilage
2000; 8: 40411.
90. Ernst E. Avocado-soybean unsaponifiables (ASU) for
osteoarthritisa systematic review. Clin Rheumatol 2003;
22: 2858.
91. Abatangelo G, ORegan M. Hyaluronan: biological role
and function in articular joints. Eur J Rheumatol Inflamm
1995; 15: 916.
92. Takahashi K, Hashimoto S, Kubo T, Hirasawa Y, Lotz M,
Amiel D. Effect of hyaluronan on chondrocyte apoptosis
and nitric oxide production in experimentally induced
osteoarthritis. J Rheumatol 2000; 27: 171320.
93. Adams ME, Atkinson MH, Lussier AJ, Schulz JI,
Siminovitch KA, Wade JP, et al. The role of viscosupple-
mentation with hylan G-F 20 (Synvisc) in the treatment
of osteoarthritis of the knee: a Canadian multicenter
trial comparing hylan G-F 20 alone, hylan G-F 20 with
nonsteroidal anti-inflammatory drugs (NSAIDs) and
NSAIDs alone. Osteoarthritis Cartilage 1995; 3: 21325.
94. Day R, Brooks P, Conaghan PG, Petersen M; Multicenter
Trial Group. A double-blind, randomized, multicenter,
parallel group study of the effectiveness and tolerance
of intraarticular hyaluronan in osteoarthritis of the
knee. J Rheumatol 2004; 31: 77582.
95. Dieppe P, Basler HD, Chard J, Croft P, Dixon J, Hurley M,
et al. Knee replacement surgery for osteoarthritis: effec-
tiveness, practice variations, indications and possible
determinants of utilization. Rheumatology (Oxford) 1999;
38: 7383.
39