Osteoarthritis "Opportunities To Address Pharmaceutical Gaps"

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
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6.12: Osteoarthritis
Table of Contents
Summary................................................................................................................3
1. Introduction........................................................................................................4
2. Size and Nature of Disease Burden....................................................................4
Incidence and prevalence ..................................................................................4
Country impact ...................................................................................................5
3. Control Strategy ................................................................................................7
Prevention........................................................................................................... 8
Table 1. Therapeutic options in osteoarthritis 2, 3, 4, 13, , ...............................9
Non-pharmacological treatment.............................................................................9
Pharmacological treatment....................................................................................9
Intra-articular treatment........................................................................................9
Surgical.................................................................................................................. 9
Non-pharmacological therapy review..................................................................9
Pharmacological therapy review.......................................................................10
Affordability, feasibility and sustainability.........................................................15
4. Major Problems and Challenges for Disease Control
(Why Does the Disease Burden Persist?).................................................15
Risk factors for incidence and progression of osteoarthritis..............................15
Trends............................................................................................................... 16
5. Past/Current Research into Pharmaceutical Interventions for OA....................16
6. Current Pharmaceutical Product “Pipeline” for OA Treatment.........................17
7. Opportunities for Research into New Pharmaceutical Intervention..................19
8. Gaps Between Current Research and Potential Research Issues that Could
Make a Difference....................................................................................19
9. Conclusion ......................................................................................................21
10. References.....................................................................................................22
Annexes
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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.2, 3
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1. Introduction
There are more than 100 different types of arthritis.1 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.1, 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.5
 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
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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

 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.2
 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.2
 Figure 2 shows the prevalence of OA of the knee by age group, sex and
region.5 In general OA is more prevalent in Europe and USA than in other
parts of the world.4
Figure 2. Prevalence of osteoarthritis5
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.
UK4
 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.
 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.
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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.
Canada6
 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.
Japan6
 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 physical activity that are recommended
for health. The remainder are essentially inactive or insufficiently active.
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Figure 3. Levels of physical activity reported by women with arthritis in

the US10, 7
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 1, 2, 3, 4, 7, 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.15
 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.
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 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.13, 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.14, 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.14
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Table 1. Therapeutic options in osteoarthritis 2, 3, 4, 13, 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.
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.2, 3
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Education2, 16
 A metaanalysis concluded that patient education in disease management,
weight reduction and exercise was 20% as effective as NSAID therapy in
reducing joint pain.16 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.2
Exercise2, 3, 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 loss2, 12, 9

 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 aids2,3
 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.13 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.2, 3, 19
 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/acetaminophen2, 3, 18, 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.
6.1210
 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.20, 21
Non-steroidal anti-inflammatory drugs (NSAIDs)2, 3, 4, 11, 16, 18

 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.18
 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’.2
 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.20, 22
- In the US an estimated 20% to 30% of all hospitalisations due to
peptic ulcer disease are secondary to NSAID use.11
- Gastroduodenal ulcers occur in 15% to 30% of patients who take
NSAIDs.19
 Another serious complication associated with NSAIDS includes renal failure.
Risk factors for renal failure include: age greater than 65, hypertension,
congestive heart failure, concomitant use of diuretics, concomitant use of
angiotensin-converting enzyme inhibitors, and existing renal failure.11, 19
 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.3, 11
6.1211
Cyclooxygenase-2 (COX-2) Inhibitors2, 4, 13,16, 17
 COX-2 inhibitors have been found to be more effective than placebo in
relieving pain in OA.2, 13
 This class is just as efficacious as NSAIDs for pain relief but with a reduction of
up to 50% in perforation, ulcers and bleeding.2
 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).19
 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.7
 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.13
 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.4
 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.11
 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.2, 3, 20
Topical agents2, 3, 18
 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/glucocorticoids2, 3, 19, 21
 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.
 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.
6.1212
 Current recommendations are to use intra-articular steroids when other

analgesics and NSAIDs are ineffective or contraindicated.
Viscosupplements-hyaluronic acid19, 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.24 ‘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’.24
 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.2
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.18, 19, 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 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.19, 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.26 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.26, 27
6.1213
 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.19 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.19, 27, 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.27
 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.29
 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
Vitamins19
 A review of the role of vitamins in the management of OA states that
oxidative damage may accelerate OA progression.19
 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 of NSAIDS. Furthermore, the reviewed
herbal medicines appear to be safe.31, 32
 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.31, 32
 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.33
Surgical treatment
Surgical treatment of osteoarthritis is usually considered after failure of
nonsurgical therapies. There are four surgical procedures: osteotomy,
6.1214
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.13 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.13 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.13 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.2
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.14
 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.15
 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.14
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.7, 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.12
Risk factors for incidence and progression of osteoarthritis
Age is the strongest predictor of the development and progression of OA.
6.1215
 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 Osteoarthritis1, 4, 5,

12
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
ethnicity incidence
 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 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.5, 16
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
6.1216
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.11, 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.11, 35, 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.35
 Growth factors. Growth factors are being evaluated in the management of OA
and its affect on cartilage.35, 36 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.20
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.
37
Table 3. New medications in development for osteoarthritis
Investigation Indication and description Company Developme
al drug name nt status
462795 Osteoarthritis GlaxoSmithKlin Phase I
(Cathepsin K Osteoporosis e
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
6.1217
Investigation Indication and description Company Developme
al drug name nt status
• 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
Solution • Pennsaid is a topical formulation of to 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 Pharmaceutical
interleukin (IL)-1beta converting s
enzyme. This drug has the potential to
become a disease-modifying drug for
the treatment of OA and inflammatory
diseases.44, 45
Various COX- • A number of companies are developing Various
2 inhibitors new COX-2 inhibitors with the intention companies
of achieving greater responder rates
and/or reduction in pain score.
Differences within the COX-2 class have
not yet been established.
6.1218
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
6.1219
- Response to drugs and what types of drugs are effective

- Populations at risk of developing toxicity
Complementary and alternative medicines are of great interest to consumer

groups affected with OA.20 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.46 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.46
The following are areas that need research:2, 3

 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.25

 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 improvement in the level of
evidence and the observed treatment effect of drugs. On the other hand,
6.1220
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.
6.1221
10. References
6.1222
1
http://www.arthritis.org/conditions. Arthritis Foundation. Accessed February 11, 2004.
2
Jordan KM, Arden NK, Doherty M, Bannwarth B, et al. EULAR Recommendations 2003: An
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Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann
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American College of Rheumatology (ACR). Last accesses February 18, 2004. Altman RD, Hochberg
MC, Moskowitz RW, Schnitzer TJ. Recommendations for the medical management of Osteoarthritis
of the hip and knee. Arthritis and Rheumatism. 2000; 43(9) 1905-1915.
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http://www.arthritis.org/ari/state/default.asp. Arthritis and Rheumatism International. State of the
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Brandt KD Non-surgical Treatment of Osteoarthritis: A Half Century of “Advances”. Ann. Rheum.
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Prevalence and impact of arthritis among women—United States 1989–1991. MMWR Morb
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Manek N. Medical Management of Osteoarthritis. Mayo Clin Proc 2001;76:533-539.
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Jordan JM, Kingston RS, Lane NE, Nevitt MC et al., Systemic risk factors for osteoarthritis. In
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conference chair. Osteoarthritis: New insights. Part 2: Treatment approaches. Ann Intern Med.
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http://www.cdc.gov/nccdphp/pdf/naap.pdf. The Center for Disease Control. National Center for
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6.

By Saloni Tanna, Pharm.D. MPH

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

At present, there is no cure for OA. The management of OA is broadly divided

2. Size and Nature of Disease Burden

Incidence and prevalence

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

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

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

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

Figure 2. Prevalence of osteoarthritis5

Aggregate numbers on the overall impact of OA are not available. Therefore,

Figure 3. Levels of physical activity reported by women with arthritis in

Diagnosis and medical management 1, 2, 3, 4, 7, 11, 12, 13

 The management plan of OA patients also needs to be regularly reviewed and

Preventing the onset of OA requires lifestyle changes.13, 14

• Primary prevention. These are measures to prevent the condition from

• Secondary prevention. This involves early diagnosis so that appropriate

• Tertiary prevention. This focuses on reducing the consequences of a disease.

Non-pharmacological therapy review

According to various recommendations, non-pharmacological treatment of OA

Weight loss2, 12, 9

Pharmacological therapy review

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

Analgesics- paracetamol/acetaminophen2, 3, 18, 20

Non-steroidal anti-inflammatory drugs (NSAIDs)2, 3, 4, 11, 16, 18

 Current recommendations are to use intra-articular steroids when other

Viscosupplements-hyaluronic acid19, 23, 24

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

Affordability, feasibility and sustainability

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

4. Major Problems and Challenges for Disease Control

Risk factors for incidence and progression of osteoarthritis

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

Table 2. Risk Factors for Incidence and Progression of Osteoarthritis1, 4, 5,

5. Past/Current Research into Pharmaceutical

6. Current Pharmaceutical Product “Pipeline” for OA

7. Opportunities for Research into New Pharmaceutical

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

 Clinical predictors of response to pharmacological and non-pharmacological

8. Gaps Between Current Research and Potential

- Response to drugs and what types of drugs are effective

Complementary and alternative medicines are of great interest to consumer

While exciting breakthrough treatments continue to become available for

The following are areas that need research:2, 3

A number of other issues need to be resolved.25

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