6.

12: Osteoarthritis

Priority Medicines for Europe and the World

"A Public Health Approach to Innovation"

Background Paper

Osteoarthritis
“Opportunities to Address Pharmaceutical Gaps”

By Saloni Tanna, Pharm.D. MPH

7 October 2004

6.12-1
 6.12: Osteoarthritis

Table of Contents

Summary..............................................................................................................................................3
1. Introduction..........................................................................................................................4
2. Size and Nature of Disease Burden....................................................................................4
3. Control Strategy...................................................................................................................8
4. Major Problems and Challenges for Disease Control
(Why Does the Disease Burden Persist?).........................................................................16
5. Past/Current Research into Pharmaceutical Interventions for OA...............................17
6. Current Pharmaceutical Product “Pipeline” for OA Treatment..................................18
7. Opportunities for research into new pharmaceutical intervention..............................20
8. Gaps Between Current Research and Potential Research Issues
that Could Make a Difference...........................................................................................21
9. Conclusion..........................................................................................................................22
10. References...........................................................................................................................23

Annexes

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 6.12: Osteoarthritis

Summary
Osteoarthritis (OA) is the most common type of arthritis or degenerative joint disease. 1 It is a
leading cause of chronic disability. The disease most commonly affects the middle-aged and
elderly, although younger people may be affected as a result of injury or overuse. Age is the
strongest predictor of the disease and therefore increasing age and extended life expectancy
will result in a greater occurrence of the disease. Patients affected by this disease suffer from
pain and loss of function.

OA is regarded as a complex disease whose cause is not completely understood.

Furthermore, effective biomarkers, diagnostic aids and imaging technology are not available
to assist in the management of OA. There are also several areas where information is still
lacking; these include: epidemiology, pathophysiology, environmental risk factors, genetic
predisposition and lifestyle factors.2, 3

At present, there is no cure for OA. The management of OA is broadly divided into non-
pharmacological, pharmacological, and surgical treatments. Surgical management is
generally reserved for failed medical management where functional disability affects a
patient’s quality of life. Pharmacological management includes control of pain and
improvement in function and quality of life while limiting drug toxicity. Experts in this field
suggest that appropriate therapy for OA combines one or more pharmacological agents with
exercise, weight loss and physical therapy (i.e. non-pharmacological therapy).

There are a number of drugs under development for symptomatic and disease modification,
and several studies are also evaluating alternative therapies. There are several drugs on the
market whose clinical effectiveness and long-term safety still need to be determined. This
assessment is especially important since OA requires long-term disease management and the
disease primarily affects people over the age of 60 who are most prone to drug toxicity, and
for whom the potential for drug interactions are high. Information on the impact of the
disease to society and the cost of disease management (including pharmacological and non-
pharmacological treatments) needs to be re-evaluated. Finally, most experts emphasize that
more research efforts need to be directed towards new diagnostics, biomarkers and imaging
technology. This is an essential area of research in OA since it will help to determine who is
likely to get OA; severity and progression of disease; patient response to drugs, and the
development of disease modifying drugs that have the potential to halt or reverse the
disease.Error: Reference source not found, Error: Reference source not found

6.12-3
 6.12: Osteoarthritis

1. Introduction
There are more than 100 different types of arthritis.Error: Reference source not found The
most common type of arthritis is osteoarthritis (OA) or degenerative joint disease. It is a
common chronic, progressive musculoskeletal disorder characterized by gradual loss of
articular cartilage. The disease most commonly affects the middle-aged and elderly,
although it may begin earlier as a result of injury or overuse. It is often more painful in
weight bearing joints such as the knee, hip, and spine than in the wrist, elbow, and shoulder
joints. All joints may be more affected if they are used extensively in work or sports, or if
they have been damaged from fractures or other injuries.Error: Reference source not found, 4
2. Size and Nature of Disease Burden
Musculoskeletal conditions are a major burden on individuals as well as health and social
care systems, with significant indirect costs.

Incidence and prevalence

 Literature is limited on the incidence and prevalence of OA because of the problems of

defining it and determining its onset. Worldwide estimates indicate that 9.6% of men and
18% of women  60 years have symptomatic OA.5
 OA is a major cause of impaired mobility. In 1990, OA was estimated to be the eighth
leading non-fatal burden of disease, accounting for 2.8% of total years of living with
disability.Error: Reference source not found
 OA is the highest-ranking disease among the musculoskeletal diseases and contributes to
approximately 50% of the disease burden in this disease group (See Background Chapter
5).
 Overall disease burden ranking according to this compiled data shows a ranking of 12 for
combined 25 EU countries; 15th ranked for old EU and 9th rank for the 10 EU accession
countries.

Figure 1 Burden of disease of OA by age groups and regions

Osteoarthritis (DALYs, by age groups & regions, 2002)

7.00%

6.00%

5.00%

4.00%
% of total

3.00%

2.00%

1.00%

0.00%
0-4 5-14 15-29 6.12-4
30-44 45-59 60-69 70-79 80+
Age groups

EU25-M EU25-F EU15-M EU15-F EU-10-M EU-10-F W-M W-F

 6.12: Osteoarthritis

 Note from Figure 1, the peak in the burden of disease (DALYs) in each of the three
regions: Global, EU15, EU25, and EU10 are different. In EU 10, the onset of OA is at an
earlier age, perhaps resulting in more disability, loss of productivity and increased health
care costs.
 Knee OA is likely to become the fourth most important global cause of disability in
women and eighth most important in men.Error: Reference source not found
 OA contributes to a higher disease burden in men below the age of 50 and in women
over the age of 50.
 According to expert opinions presented in the EULAR committee report, radiographic
evidence of knee OA in men and women over 65 is found in 30% of patients.Error:
Reference source not found
 Figure 2 shows the prevalence of OA of the knee by age group, sex and region.Error:
Reference source not found In general OA is more prevalent in Europe and USA than in
other parts of the world.Error: Reference source not found

Figure 2. Prevalence of osteoarthritisError: Reference source not found

Country impact

Aggregate numbers on the overall impact of OA are not available. Therefore, statistical
highlights and the impact of arthritis from individual countries that have reported
information are presented.
UKError: Reference source not found

 In England and Wales between 1.3 and 1.75 million people have symptomatic OA. In
2000 more than 80,000 hip or knee replacements were performed at a cost of £405 million.

6.12-5
 6.12: Osteoarthritis

 As a cause of disability (such as walking and climbing stairs) in the elderly OA is second
to cardiovascular disease.
 Altogether 10% to 15% of adults over 60 have some degree of OA.
Germany6

 Four million people out of 82 million people suffer from some form of autoimmune
conditions affecting joints.
 Most people participate in a universal medical health insurance system.
 The key issues in the fight against arthritis include access to medications, access to
speciality care, uncoordinated treatment, and diminished state budgets.
CanadaError: Reference source not found

 The direct and indirect costs of arthritis in Canada equates to approximately $18 billion
per year.
 Over four million Canadians out of 31,014,000 people have arthritis.
 Currently there are approximately 270 rheumatologists in Canada; however, 150 of them
are close to retirement leaving 120 rheumatologists to care for 4 million suffering arthritis
patients.
 There are approximately 37,000 hip and knee replacement surgeries every year in
Canada.
 The key issues in the fight against arthritis facing Canada include: access to medications,
access to rheumatology care, access to orthopaedic care, funding for research and illness
disability.
JapanError: Reference source not found

 Population of 127 million people.

 17% of population is over 65 (this percentage is expected to grow by 25% in the next three
decades).
 5% of the population has some form of arthritis.
 The key issues in the fight against arthritis facing Japan include access to medications,
access to speciality care.
US7, 8, 9

 It is estimated that over 41 million people out of 285 million people in the United States
have arthritis.
 In the United States about 6 percent of adults over 30 have OA of the knee and about
3 percent have OA of the hip.
 The occurrence of the OA increases with age, rising 2- to 10-fold in people from 30 to
65 years of age.
 An estimated 50 million people will be diagnosed with arthritis by 2013.
 The current economic burden of arthritis in its various forms is approximately
$82.4 billion.
 Direct costs are $34.6 billion (hospitals, doctors, transportation, nursing homes)
 Only 3% of the cost is for drugs.
 Indirect costs are $47.8 billion (primarily lost wages and lost productivity).
 Arthritis is a greater factor in limiting activity than heart disease, hypertension,
blindness, or diabetes. Figure 3 shows the levels of physical activity reported by women
with arthritis in the US. Only 24% of people with arthritis report and achieve levels of

6.12-6
 6.12: Osteoarthritis

physical activity that are recommended for health. The remainder are essentially inactive
or insufficiently active.

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 6.12: Osteoarthritis

Figure 3. Levels of physical activity reported by women with arthritis in the US 10, Error: Reference
source not found

3. Control Strategy
Patients with OA suffer from pain and loss of function. Objectives of OA management are to
reduce the level of pain, reduce inflammation, slow cartilage degradation, improve function
and reduce disability. This section reviews pharmacological and nonconventional, non-
pharmacological OA therapies.

Diagnosis and medical management Error: Reference source not found, Error: Reference source not found,
Error: Reference source not found, Error: Reference source not found, Error: Reference source not found, 11, 12, 13

 The aetiology of OA is multifactorial.

 Biochemical markers of disease activity are not yet available for routine clinical care.
 Plain radiographs are the current most common way of assessing disease progression,
although there are problems with standardization of joint positioning with respect to the
knee.
 A radiographic grading system is used to define, identify and note OA progression.
However, X-rays are not readily available in many parts of the world. The WHO
recommends a definition of OA based on symptoms and a symptom-based grading
system would be preferred for disease progression. However, there are currently no
validated tools in this area.Error: Reference source not found
 An assessment of effect of a therapy should include a measure of health status in
addition to radiological assessments.
 Persons with OA are a heterogeneous population, ranging widely in age, disease
impairment, functional goals, and interests. Therefore management of the patient with
OA should be comprehensive and individualized, taking into account the anatomical
distribution, the phase and the progression rate of the disease.
 Comorbid conditions such as cardiac disease, hypertension, peptic ulcer disease or renal
disease must be taken into account, as well as the patient’s needs and expectations.

6.12-8
 6.12: Osteoarthritis

 The management plan of OA patients also needs to be regularly reviewed and adjusted
in light of their response and adherence. This will vary between patients and location.
 The management of OA is broadly divided into non-pharmacological, pharmacological,
and surgical treatments. Surgical treatment is generally reserved for failed medical
management with functional disability affecting a patient’s quality of life.

Prevention

Preventing the onset of OA requires lifestyle changes.Error: Reference source not found, 14
 Primary prevention. These are measures to prevent the condition from occurring. There are
only a few effective primary prevention strategies for arthritis. These include:
 Weight control: Obesity is considered a risk factor for OA. Thus, maintaining or
reducing weight can lower the risk for certain arthritic conditions.
 Occupational injury prevention: Avoiding repetitive joint use and its injuries can
help prevent arthritis.
 Sports injury prevention: Taking the necessary precautions to prevent injury such
as warming up and using proper equipment can help reduce joint injuries.

 Secondary prevention. This involves early diagnosis so that appropriate early intervention
can be utilized. However, this is difficult in OA since no effective biomarkers are
available to determine the progression of the disease. Furthermore, radiographic
evidence is often needed to identify and mark disease progression. Access to health care
facilities and availability of X-rays is problematic in many parts of the world.Error:
Reference source not found, 15

 Tertiary prevention. This focuses on reducing the consequences of a disease. Goals of these
prevention strategies are to reduce, delay the onset of complications and disability.
Tertiary prevention strategies for arthritis are aimed at reducing pain and disability, and
improving quality of life. The following encompass tertiary prevention strategies: self-
management (weight control, physical activity, education); home help programs;
cognitive behavioural interventions; rehabilitation services and medical surgical
treatments.Error: Reference source not found

6.12-9
 6.12: Osteoarthritis

Table 1. Therapeutic options in osteoarthritis Error: Reference source not found, Error: Reference source not found, Error: Reference source not found, Error:

Reference source not found, 16, 17

Non-pharmacological treatment
Education (patient and spouse or family)
Social support
Physiotherapy (physical therapy)
Occupational therapy
Weight loss
Exercise
Orthotic devises
Laser
Pulsed EMF (Electromagnetic field therapy)
Ultrasound
Transcutaneous electrical nerve stimulation (TENS)
Acupuncture
Nutrients
Herbal remedies
Vitamins/minerals
Pharmacological treatment
Paracetamol/Acetaminophen
NSAIDS (Non-steroidal anti-inflammatory drugs) [plus misoprostol or a proton
pump inhibitor]*
COX-2 inhibitors (cyclo-oxygenase-2 selective non-steroidal anti-inflammatory
drugs)
Opioid analgesics
Hormones
Psychotropic drugs [comment- can this be elaborated using a couple of examples?
These are also not covered in pharmacological treatment sections below]
SYSADOA (Symptomatic Slow Acting Drugs for OA (avocado/soybean
unsaponifiables (ASU), chondroitin, diacerein and glucosamine)
Topical NSAIDS
Topical capsaicin
Intra-articular treatment
Corticosteroids
Hyaluronans
Tidal irrigation
Surgical
Arthroscopy
Osteomy
UKR (unicompartmental knee replacement)
TKR (total knee replacement)

*Misoprostol and proton pump inhibitors are recommendations by ACR and are
recommended in patients who are at increased risk of gastrointestinal adverse effects.

6.12-10
 6.12: Osteoarthritis

Non-pharmacological therapy review

According to various recommendations, non-pharmacological treatment of OA should

include education, exercise, physical aids (such as canes, insoles and knee braces) and weight
reduction.Error: Reference source not found, Error: Reference source not found
EducationError: Reference source not found, Error: Reference source not found

 A metaanalysis concluded that patient education in disease management, weight

reduction and exercise was 20% as effective as NSAID therapy in reducing joint
pain.Error: Reference source not found There are several studies that demonstrate the
benefits of education in reducing pain, increasing coping skills, and reducing visits to the
primary care. Effective educational techniques include individualized education; regular
telephone calls, group education, patient coping skills, and spouse assisted coping
skills.Error: Reference source not found

ExerciseError: Reference source not found, Error: Reference source not found, 18

 Exercise is considered the most important intervention in the management of OA.

Exercise builds muscle strength and endurance, improves joint flexibility and motion.
The British Medical Journal (BMJ) systematic review of randomized controlled trials
(RCTs) on the effect of exercise on OA concluded that both exercise and physical therapy
reduce pain and disability in people with hip and knee OA.

Weight lossError: Reference source not found, Error: Reference source not found, Error: Reference source not found

 Although weight loss is recommended, the effect of weight loss on OA has only been
evaluated in two studies. These studies showed that weight loss reduced the risk of
developing symptomatic OA in women, reduced pain and improved function. Most
authors conclude that while the evidence is poorly documented weight loss is a sensible
recommendation in the management of OA.

Physical aidsError: Reference source not found,Error: Reference source not found

 There is limited data on the effects of physical aids on OA, although, physical aids are
considered a sensible approach in the management of OA.
 A BMJ Clinical review concluded that RCTs in people with knee OA found limited
evidence that joint bracing or taping improves quality of life and symptoms. The review
also found that there was insufficient evidence to compare the effects of different insoles.

Pharmacological therapy review

At present, there is no cure for OA. Pharmacological management of OA remains control of

pain and improvement in function and quality of life while limiting drug toxicity. Experts in
this field suggest that appropriate therapy for OA combines one or more pharmacological
agents with exercise and other biomechanical techniques.Error: Reference source not found
A risk-benefit analysis of these must be considered when prescribing these drugs since
adverse effects are common and the long-term efficacy of these drugs is variable or yet to be
determined.Error: Reference source not found, Error: Reference source not found, 19

6.12-11
 6.12: Osteoarthritis

 Annex 6.12.1 provides a detailed analysis on the current effectiveness of medical

management of OA.
 Below are the summarized highlights of the literature findings.

Analgesics- paracetamol/acetaminophenError: Reference source not found, Error: Reference source not
found, Error: Reference source not found, 20

 Both the American College of Rheumatology (ACR) and European League Against
Rheumatism Guidelines (EULAR) recommend paracetamol/acetaminophen as the first
list line agent. EULAR recommendations also state that based on it overall cost, efficacy
and toxicity profile, it should be the preferred long-term oral analgesic.
 A BMJ clinical evidence review found limited evidence that simple analgesics such as
paracetamol, reduced pain compared with placebo. However, a review by EULAR
reports that paracetamol is as effective as NSAIDS in the management of OA.
Furthermore, it can be taken safely over the long term.
 A recent study has also raised concern about the safety of acetaminophen in doses of
greater than 2g/day. The study suggests that high dose acetaminophen may results in an
increased risk of gastrointestinal toxicity equivalent to NSAIDs.Error: Reference source
not found, 21

Non-steroidal anti-inflammatory drugs (NSAIDs)Error: Reference source not found , Error:

Reference source not found, Error: Reference source not found, Error: Reference source not found, Error: Reference source not found, Error: Reference source not

found


NSAIDs have both anti-inflammatory and analgesic properties, but there is no evidence
that they modify the course of OA.

There is limited evidence that these agents vary in efficacy within this therapeutic drug
category.

According to systematic reviews conducted by BMJ, NSAIDs are more effective than
placebo in reducing pain; however, their long-term efficacy (past 2 years) has not been
studied. Also, systematic reviews of RCTs by BMJ, found no good evidence that oral
NSAIDS differ from paracetamol/acetaminophen in pain relief.Error: Reference source
not found

According to the 2003 EULAR review, the expert committee states that there is evidence
that NSAIDs are more efficacious than paracetamol for some patients. The
recommendations suggest that given the low-grade inflammatory component of OA,
NSAIDs would be the ‘logical drugs in patients unresponsive to paracetamol’.Error:
Reference source not found

Risk factors for NSAID-induced upper gastrointestinal adverse effects include: patient’s
greater than 65 years, concomitant use of anticoagulants and glucocorticoids and history
of peptic ulcer disease or upper gastrointestinal bleed, smoking and alcohol
consumption.Error: Reference source not found, 22
- In the US an estimated 20% to 30% of all hospitalisations due to peptic ulcer disease
are secondary to NSAID use.Error: Reference source not found
- Gastroduodenal ulcers occur in 15% to 30% of patients who take NSAIDs.Error:
Reference source not found

Another serious complication associated with NSAIDS includes renal failure. Risk factors
for renal failure include: age greater than 65, hypertension, congestive heart failure,
6.12-12
 6.12: Osteoarthritis

concomitant use of diuretics, concomitant use of angiotensin-converting enzyme

inhibitors, and existing renal failure.Error: Reference source not found, Error: Reference source not
found


ACR and EULAR recommend that NSAIDs should be considered in patients
unresponsive to paracetamol, and patients who are at risk of gastrointestinal toxicity
should use effective gastroprotective agents or selective COX-2 inhibitors.

There is evidence that misoprostol, proton pump inhibitors and H2 blockers may reduce
the gastrointestinal adverse effects induced by NSAIDs. However, the cost utility or
prophylactic use of these agents is controversial and requires pharmaco-eoconomic
analysis.Error: Reference source not found, Error: Reference source not found

6.12-13
 6.12: Osteoarthritis

Cyclooxygenase-2 (COX-2) InhibitorsError: Reference source not found, Error: Reference source not found,
Error: Reference source not found,Error: Reference source not found, Error: Reference source not found

 COX-2 inhibitors have been found to be more effective than placebo in relieving pain in
OA.Error: Reference source not found, Error: Reference source not found
 This class is just as efficacious as NSAIDs for pain relief but with a reduction of up to 50%
in perforation, ulcers and bleeding.Error: Reference source not found
 There are reports that the cardiovascular and renal adverse effects are comparable to
NSAIDs and the risk factors associated with renal failure are the same as NSAIDs (listed
above).Error: Reference source not found

Concern about loss of antiplatelet activity with COX-2 inhibitor group may contribute to
excess cardiovascular complication, especially in the elderly who are at a higher risk of
cerebral and vascular thrombosis.Error: Reference source not found

Concomitant use of low dose aspirin for cardiovascular prophylaxis appears to diminish
COX-2 inhibitor gastroprotective effect.

There are no RCTs to compare the efficacy of different COX-2 inhibitors.Error: Reference
source not found

Haq et al report that the estimated cost of switching high-risk patients with OA to COX-2
inhibitors would lead to an estimated incremental cost of £25 million to the NHS.Error:
Reference source not found

COX-2 inhibitors are widely used in the US and Europe, and are currently ‘block buster’
drugs on the pharmaceutical market, however the most cost effective strategy for their
use is still unclear.Error: Reference source not found

Both ACR and EULAR state that patients who are at an increased risk of gastrointestinal
complications, COX-2 inhibitors or NSAIDs plus a gastroprotective agent may be
used.Error: Reference source not found, Error: Reference source not found, Error: Reference source not found

Topical agentsError: Reference source not found, Error: Reference source not found, Error: Reference source not found

According to ACR and EULAR guidelines, topical NSAIDs and topical capsaicin have
clinical efficacy and are safe.

BMJ clinical review concludes that topical NSAIDs reduce pain compared to placebo,
however limited evidence was found that capsaicin improves pain compared to placebo.

Topical treatment is an additional option for patients who have inadequate control with
oral agents or who require local treatment. However, further well-conducted trials are
needed in this area.

Corticosteroids/glucocorticoidsError: Reference source not found, Error: Reference source not found, Error:

Reference source not found, Error: Reference source not found

 Intra-articular, long acting corticosteroids are widely used in the management of knee
OA.
 The short-term therapy is considered to be beneficial in patients who have local
inflammation and swollen joints.
 Injections may be used as monotherapy or in combination with systemic drugs.
 There are no RCTs comparing the effectiveness of combination therapy.
 Most review articles that have evaluated intra-articular corticosteroids studies conclude
that there appears to be a short-term efficacy lasting 2-4 weeks compared to placebo.
 A systematic review and one RCT found limited evidence that intra-articular
corticosteroids reduced pain for 1-4 weeks.

6.12-14
 6.12: Osteoarthritis

 There is evidence that intra-articular injections are effective with short-term relief.
However, the evidence for predictors of response remains unclear and further studies are
needed to determine this.
 ACR guidelines recommend no more than 3- 4 injections per year and should be reserved
for disease flares only.
 Infection into the OA joint is considered to be a rare complication associated with this
intra-articular corticosteroid therapy.
 Current recommendations are to use intra-articular steroids when other analgesics and
NSAIDs are ineffective or contraindicated.

Viscosupplements-hyaluronic acidError: Reference source not found, 23, 24

 The injection of viscosupplements, which include hyaluronan and hylan G-F 20, is being
used in the treatment of knee OA.
 Hyaluronan is unaltered hyaluronic acid, which is injected weekly for 5-weeks.
 Hylan G-F 20 is hyaluronic acid but with a higher molecular weight. This preparation is
injected weekly over a three-week period.
 Intra-articular viscosupplements have few side effects. Most common reported adverse
effects include: localized reactions, transient local swelling, pain and erythema.
 The clinical effectiveness of viscosupplements remains controversial. There is a very
recent metaanalysis evaluating published or unpublished, English and non-English,
single- or double-blinded, randomised controlled trials comparing intra-articular
hyaluronic acid with intra-articular placebo injection for the treatment of knee OA.Error:
Reference source not found ‘Intra-articular hyaluronic acid has a small effect when
compared with an intra-articular placebo. The presence of publication bias suggests even
this effect may be overestimated. Compared with lower-molecular-weight hyaluronic
acid, the highest-molecular-weight hyaluronic acid may be more efficacious in treating
knee OA’.Error: Reference source not found
 The potential of hyaluronic acid preparations to preserve cartilage still remains to be
determined.
 A EULAR review of 20 studies showed that 18/20 trials showed that hyaluronic acid to be
more effective than placebo in relieving pain. EULAR states while there is evidence for its
use, its delayed onset, cost and logistical issues can offset its use in OA
management.Error: Reference source not found

SYADOA (Symptomatic Slow Acting Drugs for OA (avocado/soybean unsaponifiables

(ASU), chondroitin, diacerein and glucosamine)
Glucosamine, chondroitin sulfate and collagen hydrolysate

Glucosamine and chondroitin sulfate are regulated as drugs in European countries and
as a nutritional supplement in the US. Given this, in the US, there are no formal
requirements for nutritional supplements to prove their efficacy and claims cannot be
made for the treatment of medical conditions.25

Current evidence suggests that it is not known whether different glucosamine, or
glucosamine chondroitin preparations by different manufacturers are equally effective in
the therapy of OA. Further evidence, and well conducted RCT are needed to determine
the long-term effects and safety of these drugs.Error: Reference source not found , Error:
Reference source not found, 26


Glucosamine. Glucosamine, an aminosaccharide, can be administered orally,
intramuscularly, or intra-articularly. There are numerous glucosamine preparations on
the market. Most studies have evaluated glucosamine sulfate. Most of these studies have
6.12-15
 6.12: Osteoarthritis

shown a variable response in the relief of pain compared to placebo with various dosage
forms. However, there is limited literature on the adverse effects or long-term effects of
these drugs. Glucosamine also has a slower onset of action compared to NSAIDs and the
pharmacology by which it exerts pain relief still remains unclear.Error: Reference source
not found, 27 A Cochrane review of RCTs evaluating the effectiveness and toxicity of
glucosamine determined there is evidence that glucosamine is effective, but further
research is necessary.Error: Reference source not found Further research is also needed
in the following areas: assessment of the long-term efficacy and safety; effectiveness,
relative purity and content of the different glucosamine preparations; who would most
benefit from glucosamine and finally, what are the appropriate doses and routes of
administration to both maximize efficacy while limiting adverse effects.Error: Reference
source not found, Error: Reference source not found

Chondroitin sulfate. Chondroitin, derived from bovine and calf cartilage has an oral
bioavailability of about 10%. Compared to NSAIDS, chondroitin has a delayed onset and
therapeutic response.Error: Reference source not found A metaanalysis of chondroitin
sulphate concluded that this product may be effective in OA, but further investigation in
larger RCTs for longer time periods are needed to prove its effectiveness as a symptom
modifying drug in OA.Error: Reference source not found, Error: Reference source not found, 28

Collagen hydrolysate: Collagen hydrolysate may be beneficial in the treatment of OA, since
it contains amino acids that may play a role in the development of collagen. They are
available, however, in the form of food supplements and there is very limited evidence to
clinically demonstrate their effectiveness.Error: Reference source not found

Diacerein: Reviews of RCTS of diacerein, an interleukin-1 inhibitor showed that it was
effective in reducing pain.29 There have been few reported adverse effects with this drug.
Diacerein’s role in the management of OA still needs to be determined. The drug may
have the potential as an add-on therapy to NSAIDs or viscosupplements.Error: Reference
source not found

Avacado/Soybean unsaponifiable residues (ASU):ASU is a compound consisting of avocado
oil and soybean. Invitro studies have shown that this compound has an inhibitory effect
on a number of molecules that may affect OA. There is, however, very limited evidence
showing its effectiveness. The compound is available and used in France. Well-conducted
trials are needed to evaluate the potential of this compound in the management of OA. 30

VitaminsError: Reference source not found

 A review of the role of vitamins in the management of OA states that oxidative damage
may accelerate OA progression.Error: Reference source not found
 Vitamin A, C, and E have antioxidant properties that may be beneficial in the
management of OA.
 Well-designed RCT are needed to determine the effectiveness, disease-modifying
potential, recommended dosage guidelines and adverse effects in OA management.

Herbals31, 32, 33

Long L et al, conducted a systematic review of herbal medicines for the treatment of
osteoarthritis. Studies in the review examined: articulin F, capsaicin cream, devils claw,
eaymov, gitadyl, phytodolor, reumalex and stinging nettle leaf.

Promising evidence was found for the effective use of some herbal preparations in the
treatment of OA. Also, there is some evidence that these preparations may reduce the use

6.12-16
 6.12: Osteoarthritis

of NSAIDS. Furthermore, the reviewed herbal medicines appear to be safe.Error:

Reference source not found, Error: Reference source not found

The area of herbal medicines in OA is under-researched and merits further attention.

Future trials should focus on clinical effectiveness of herbal therapies, outcome measures
and valid measures of OA. Studies should also compare and assess the impact of herbals
medicines on allopathic medication, specifically NSAIDs.Error: Reference source not
found, Error: Reference source not found

A number of alternatives exist for the treatment and prevention of OA. Some of these
include Vitamin E, Boron, Vitamin D, Ascorbic acid, Manganese, S-Adenosylmethionine,
Avocado/Soybean extract and Articulin F. Very limited evidence is presented on the
safety and effectiveness of these agents and further well-conducted studies are
needed.Error: Reference source not found

Surgical treatment
Surgical treatment of osteoarthritis is usually considered after failure of nonsurgical
therapies. There are four surgical procedures: osteotomy, arthroscopy, arthrodesis and
arthroplasty. The four procedures have different indications and variable benefits. Total joint
arthroplasty, the most surgically advanced in OA treatment, is the mainstay of surgical
treatments.Error: Reference source not found Total joint replacement is highly successful
and by most measures among the most effective of all medical interventions. Pain, and
disability of end-stage OA can be eliminated, restoring patients to near-normal function, and
this operation is highly cost-effective.Error: Reference source not found The most common
failures of total joint replacement surgery include aseptic loosening and osteolysis, which
occur as a result of the corrosion between the implanted material and the cells.Error:
Reference source not found Currently there are no RCTs, which have compared surgery with
nonsurgical intervention. Although EULAR acknowledges the difficulties in study design,
the expert committee recommends that predictors of response, indications for joint
replacement, effect of different surgical techniques and long-term effect of joint prosthesis
should be examined. Furthermore, postoperative care and outcome assessment should also
be studied for these procedures.Error: Reference source not found

Affordability, feasibility and sustainability

Limited literature is available on the affordability, accessibility and cost of currently

approved therapies and their impact and management of OA. Further studies are required to
address this issue. Studies need to asses (1) the cost of drug therapy for disease management
and (2) the combination of non-pharmacological and pharmacological treatment modalities.
 The economic implications of arthritis include the financial burden of health care costs,
and loss of income resulting from disability or limitations on work. Arthritis is ranked
second, after heart disease, as a cause of missed work in the developed world.Error:
Reference source not found
 Economic indicators for OA are difficult to develop. This is because data can be collected
on the medical resources (which is dependent on cultural, economics, and health care
provisions), than on the condition itself. Also, while lost days of work may be
determined, a large population affected are elderly and not working.
 The estimated health-care cost of OA was US $624 million in 1993-94. This is
approximately 21% of the total musculoskeletal disorders expenditure.Error: Reference
source not found

6.12-17
 6.12: Osteoarthritis

 The total cost, treatment, complications and the disability that result from arthritis is
estimated at $65 billion. Of this, the estimated medical costs are $15 billion annually,
which include physician visits and hospitalisations. The remaining balances are indirect
costs resulting from wage losses.Error: Reference source not found

4. Major Problems and Challenges for Disease Control

(Why Does the Disease Burden Persist?)
The aetiology of OA is multifactorial and includes both generalized and constitutional
factors (e.g. ageing, sex, obesity, heredity, and reproductive variables) and local adverse
mechanical factors (e.g. trauma, occupational and recreational usage). There are also genetic
components in the prevalence of OA, with heritability estimates from twin studies of 0.39 to
0.69, independent of known environmental or demographic confounders.Error: Reference
source not found, 34 OA is associated with pain and functional disability and as the disease
progresses, physical disability arising from pain and loss of functional capacity reduces
quality of life and increases the risk of further morbidity and mortality.Error: Reference
source not found

Risk factors for incidence and progression of osteoarthritis

Age is the strongest predictor of the development and progression of OA.

 Table 2 shows the risk factors for incidence and progression of OA of the knees, hips and
hands.

Table 2. Risk Factors for Incidence and Progression of OsteoarthritisError: Reference source not found, Error: Reference source not found, Error: Reference

source not found, Error: Reference source not found

Risk factor
Age  Normal ageing process causes increases progression
 27% of those aged 63-70 had radiographic evidence of knee OA,
increasing to 44% in over 80 age group
Trauma  Collateral ligament, meniscal tears and joint fractures lead to
increased risk for OA
 Men with a history of known injury were at 5-6 fold increased risk of
developing OA
Occupation  More common in those performing heavy physical work
 Dockers, miners and farmers found to have OA
Exercise  High impact sports present an increase for OA
Gender and  Men under the age of 50 have a higher prevalence and incidence
ethnicity  Women over 50 have a higher prevalence and incidence (menopause
may be a trigger. However there is conflicting evidence if hormone
replacement therapy protects against OA)
 Difference is less marked after the age of 80
 Generally more common in Europeans than in Asians
Genetics  There is genetic susceptibility to the disease
 Children of parents with early onset OA are at a higher risk of
developing OA themselves
Obesity  Strongest modifiable risk factor
 Being overweight at an average age of 36-37 is a risk factor for
6.12-18
 6.12: Osteoarthritis

Risk factor
developing knee OA
Diet  Threefold increase risk of progression of OA for people in the lower
decile of vitamin C and D blood levels
Bone density  Increasing bone density may lead to increased loading through
weight bearing joint cartilage
Trends

Increasing age and extended life expectancy will most likely result in greater incidence
and prevalence of OA. The burden will be greatest in developing countries where life
expectancy is increasing, but access to therapy is not readily available.Error: Reference
source not found, Error: Reference source not found

5. Past/Current Research into Pharmaceutical Interventions for OA

Currently all the treatment advances in OA offer palliative care and help to reduce the
symptoms of pain. Unfortunately, there have been no new drugs that can prevent, halt or
reverse OA progression, although pharmaceutical companies are actively pursuing
development of such therapies. Annex 6.12.1 evaluates therapies currently used or have been
indicated in the management of OA. The following section (and Annex 6.12.2) provides
information on the areas of current research.
 Inhibition of breakdown of cartilage by collagenolytic enzymes or matrix metalloproteinases
(MMPs). MMPs, a family of degradative enzymes, have been identified as occurring in
the development and normal turnover of tissues. These enzymes have been shown to
increase in activity after joint injury. Specific MMPs have been identified, which are
believed to affect the degradative process in OA. MMP-13 has been shown to play a
central role in cartilage degradation. MMPs present an important target for potential
pharmacological development, since these enzymes may alter disease process.
Unfortunately all the new MMPs tested in humans to date have resulted in toxicity in
other organ systems, which have prevented their continued development. A recent study
with doxycycline, a potent MMP, in individuals with OA provides evidence that MMP
inhibitions may be effective in slowing down cartilage loss in OA.Error: Reference source
not found, 35

Therapy that stimulates repair activity by chondrocytes. The release of MMPs, by
chondrocytes appears to be affected by a wide range of conditions and processes. For
example, increased weight and preceding joint injury can increase the risk of OA. Studies
that have attempted to mimic these effects in vitro, through biomechanical factors and
increased chondrocytes loading has resulted in increased proteoglycan synthesis and an
increased release of degradative enzyme activity. A number of cytokines and cell-
signalling molecules such as interleukin-1 (IL-1) and nitric oxide (NO) have also been
shown to play an important role in chondrocytes activity. Hence, these molecules have
also become a potential target for pharmacological intervention and studies of such
agents are planned or ongoing.Error: Reference source not found, Error: Reference source not found, 36
 Bisphosphonates. Resorptive agents or bisphosphonates (such as alendronate and
clodronate) may provide important benefits in the symptomatic relief of OA. Initial
results of the studies have not been made available yet. Also, this class of drugs are not
clinically approved for OA therapy.Error: Reference source not found

6.12-19
 6.12: Osteoarthritis

 Growth factors. Growth factors are being evaluated in the management of OA and its
affect on cartilage.Error: Reference source not found , Error: Reference source not found Refer to Annex
6.12. for more information.
 Alternative medicines: The US Congress created The National Center of Complementary
and Alternative Medicine (NCCAM) given the growing use of alternative medicines.
Currently NCCAM and the National Institute of Health (NIH) are supporting a large
RCT evaluating the effectiveness of glucosamine and chondroitin in the treatment of
OA.Error: Reference source not found

6. Current Pharmaceutical Product “Pipeline” for OA Treatment

Currently there are a limited number of pharmaceutical products in the pipeline. Both the
European Agency for the Evaluation of Medicinal Products (EMEA) and the US Food and
Drug Administration (FDA) were reviewed to determine this information. Table 6.12.3 shows
the new medications in development for OA.

Table 3. New medications in development for osteoarthritis 37

Investigational Indication and description Company Development

drug name status
462795 Osteoarthritis GlaxoSmithKline Phase I
(Cathepsin K Osteoporosis
inhibitor)  Cathepsin K is believed to play a role in
degrading bone. 38
 Cathepsin K inhibitors have the potential to
provide a new therapeutic agent for the
treatment of OA.39
ABT 963 Osteoarthritis Abbott Phase II
Rheumatoid arthritis Laboratories
 ABT 963 is a COX-2 inhibitor like celecoxib
and rofecoxib already on the market. The
drug is intended for the symptomatic
treatment of OA40.
CP-544,439 Osteoarthritis Pfizer Phase II
 No available information
ML-3000 Osteoarthritis Forest Phase III
 A new class of anti-inflammatory and Laboratories
analgesic drugs. Also known as COX/LOX
inhibitors. This class are inhibitors of both
cyclooxygenase and leukotrienes and have the
potential to reduce gastrointestinal toxicity.41,
42

Pennsaid Osteoarthritis Dimethaid Application

Topical Rheumatoid arthritis Research submitted to
Solution  Pennsaid is a topical formulation of FDA
diclofenac, a non-steroidal anti-inflammatory
drug (NSAID), which is used for the
treatment of the symptoms of osteoarthritis. 43
Pralnacasan Osteoarthritis Aventis Phase II
 An orally bioavailable inhibitor of interleukin Pharmaceuticals
(IL)-1beta converting enzyme. This drug has
the potential to become a disease-modifying

6.12-20
 6.12: Osteoarthritis

Investigational Indication and description Company Development

drug name status
drug for the treatment of OA and
inflammatory diseases.44, 45
Various COX-2  A number of companies are developing new Various
inhibitors COX-2 inhibitors with the intention of companies
achieving greater responder rates and/or
reduction in pain score. Differences within the
COX-2 class have not yet been established.

6.12-21
 6.12: Osteoarthritis

7. Opportunities for Research into New Pharmaceutical Intervention

See Annex 6.12

The area of drug development in OA is of a significant public health consequence. Current

therapies on the market only help to improve pain and function. There are no drugs that can
prevent, reverse or halt the disease. Several questions remain unanswered in the areas of
epidemiology, pathophysiology and diagnosis of the disease. These need to be studied to
support the effective development of novel disease modifying agents. There are also a large
number of drugs (including alternative therapies, vitamins, and nutraceuticals) whose
clinical effectiveness still needs to be determined through better-conducted clinical trials. The
following are highlights for opportunities for research in OA as put forward by various
expert members on ACR and EULAR and authors:

 Clinical predictors of response to pharmacological and non-pharmacological

interventions need to be determined.
 Determine the long-term effects, efficacy and safety of COX-2 inhibitor use.
 Investigate pooled/combination treatments, which reflect everyday clinical practice.
 Further investigate the difference between efficacy (trial data) and clinical effectiveness of
many pharmacological treatments using validated and reliable outcomes measures that
reflect disease activity, damage and quality of life.
 Investigate the efficacy of topical NSAIDS and conduct comparative trials.
 Development of disease modifying osteoarthritis drugs, such as local delivery of anti-
inflammatory cytokines.
 Explore the effectiveness of alternative therapies in reducing symptoms of OA.
 Study the gastrointestinal safety of high-dose acetaminophen.
 Compare the effectiveness between paracetamol-acetaminophen and cox-2 inhibitors.
 Conduct pharmaco-economic studies to determine the cost effectiveness of OA therapy
and its long term management.
 Evaluate the safety, effectiveness, and long term effects of SYADOA drugs.

These studies bridge the range of research from basic science to Phase IV studies.

8. Gaps Between Current Research and Potential Research Issues that

Could Make a Difference
Most rheumatologists have suggested that osteoarthritis is often considered a silent disease,
because although there is inflammation in the joint it occurs much less than in rheumatoid
arthritis. Only when the patients develop pronounced inflammations are the symptoms of
pain noticeable to the patient. Most experts in this field have articulated that this is
particularly an area where research into new diagnostics, biomarkers and imaging
technology is going to be important and useful for the management of OA. Biomarkers are
an essential area of research in OA and arthritis as a whole, since it will help the medical
community to determine:
- Who is likely to get arthritis?
- Severity and progression of disease
- Response to drugs and what types of drugs are effective
- Populations at risk of developing toxicity

6.12-22
 6.12: Osteoarthritis

Complementary and alternative medicines are of great interest to consumer groups affected
with OA.Error: Reference source not found In the US, complementary and alternative
medicines are the most rapidly growing area at the NIH (National Institute of Health). There
is substantial research opportunity potential in this area.46

While exciting breakthrough treatments continue to become available for rheumatoid

arthritis, highly effective therapies do not exist for OA. Currently, the research to support
treatments in OA is not as advanced as compared to rheumatoid arthritis. Interestingly, it
has been discovered that the cytokines that are driving inflammation and destruction of bone
and cartilage in rheumatoid arthritis may also drive the destructive process in OA.Error:
Reference source not found This discovery may potentially be helpful since some of the
knowledge about rheumatoid arthritis may be transferred and applied to osteoarthritis.
Furthermore, with better understanding through research of the molecular process, progress
may be achieved in the development of medications to effectively control the symptoms and
disease progression of OA as well.Error: Reference source not found

The following are areas that need research:Error: Reference source not found, Error: Reference source not
found

 Strengthen evidence-based medicine by closing the gap between molecular research and
clinical disease research for OA.
 Drug development in OA has been lacking, because in order to diagnose, monitor and
develop treatments for OA, researchers and drug companies require effective
biochemical and imaging markers to assess disease progression. Current evaluation
methods of x-rays and blood tests are insufficient to determine the progression and
outcome of new treatments. As a result, a recent US-based public private partnership,
called the osteoarthritis Initiative (OAI), intends to combine resources for the purpose of
finding biological markers related to the progression of OA. OAI will collect data over
the next 5-7 years on individuals at high risk for the development of OA. This data will
be used for the development of potential new OA treatments. OAI is a combined effort in
the US by NIH (National Institute of Health), GlaxoSmithKline, Merck, Novartis
Pharmaceuticals Corporation and Pfizer. OAI will provide approximately 8 million
dollars annually to six clinical research centres to establish and maintain a database of
OA, which will include evaluation data, radiological images and a biospecimen
repository. All the data will be available to researchers worldwide. 47

A number of other issues need to be resolved.Error: Reference source not found


Inter country differences: Certain drugs are available in parts of Europe, whereas others are
not available in other countries or the US. The difference in the availability of drugs may
result in differences in clinical practice and level of patient expectation of OA drugs.

Class of compounds: Certain compounds, such as glucosamine and chondroitin sulphate
are considered drugs in parts of Europe, however, in the US they are considered food
supplements. These differences may have the following consequences: 25
- Differences in quality assurance.
- No requirements to determine the efficacy
or the safety of food supplement products.
 Level of evidence of efficacy: Despite certain drugs being on the market for several decades,
such as ASU (Avocado/Soybean unsaponifiable) residues in France, their efficacy was not
determined until recently.25 The position of many recent health authorities has facilitated
6.12-23
 6.12: Osteoarthritis

improvement in the level of evidence and the observed treatment effect of drugs. On the
other hand, there are numerous unpublished studies. Emphasis on most peer review
journals is about the statistically significant effect of these treatments. To answer this and
to determine the level of efficacy, trials should compare the observed effect of new
treatments to conventional drugs such as NSAIDs.

9. Conclusion
The prevalence of OA is increasing and this places a globally major burden on individuals;
health systems, and social care systems. OA, the most common arthritis condition, is a major
cause of impaired mobility and disability for the ageing populations. While there are several
drugs available on the market that mitigate pain and improve function, there are no drugs
that can cure, reverse or halt disease progression. OA is also now regarded as a complex
disease whose etiology is not completely understood. In addition there are also several areas
where information is still lacking; these include epidemiology, path physiology,
environmental risk factors, genetic predisposition and lifestyle. Information related to these
topics may assist in the overall management and planning of this disabling condition. There
are a number of drugs in the pipeline under development and several studies also evaluating
alternative therapies. There are, however, several drugs on the market whose clinical
effectiveness and long-term safety still need to be determined. This is especially important
since OA requires long disease management and the disease primarily affects people over
the age of 60, who are most prone to drug toxicity. In addition, data is lacking about the
therapeutic effectiveness of certain drugs within a class as well as between classes.
Information on the impact of the disease to society and both the cost of medicines and cost of
disease management (including pharmacological and non pharmacological treatments) need
to be evaluated. Finally, while there is substantial research in this area, most experts
emphasize that research into new diagnostics, biomarkers and imaging technology is going
to be important and useful for the management of OA and the development of disease
modifying drugs.

6.12-24
 6.12: Osteoarthritis

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