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

6.12­1

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

6.12­2

weight loss and physical therapy (i. and the development of disease modifying drugs that have the potential to halt or reverse the disease. and surgical treatments. 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.12: Osteoarthritis Summary Osteoarthritis (OA) is the most common type of arthritis or degenerative joint disease. Finally. 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.2. The management of OA is broadly divided into non-pharmacological. The disease most commonly affects the middle-aged and elderly. 3 At present. although younger people may be affected as a result of injury or overuse. severity and progression of disease. these include: epidemiology. and several studies are also evaluating alternative therapies. Surgical management is generally reserved for failed medical management where functional disability affects a patient’s quality of life. there is no cure for OA. environmental risk factors. 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. Furthermore.6. 3 6. patient response to drugs. pharmacological. biomarkers and imaging technology. There are several drugs on the market whose clinical effectiveness and long-term safety still need to be determined. There are also several areas where information is still lacking. Patients affected by this disease suffer from pain and loss of function.2. Experts in this field suggest that appropriate therapy for OA combines one or more pharmacological agents with exercise.e. most experts emphasize that more research efforts need to be directed towards new diagnostics. This is an essential area of research in OA since it will help to determine who is likely to get OA. non-pharmacological therapy). OA is regarded as a complex disease whose cause is not completely understood. and for whom the potential for drug interactions are high. There are a number of drugs under development for symptomatic and disease modification. genetic predisposition and lifestyle factors.1 It is a leading cause of chronic disability. Pharmacological management includes control of pain and improvement in function and quality of life while limiting drug toxicity. diagnostic aids and imaging technology are not available to assist in the management of OA.12­3 . pathophysiology. effective biomarkers.

00% 0-4 5-14 15-29 30-44 6.8% of total years of living with disability. The disease most commonly affects the middle-aged and elderly. Worldwide estimates indicate that 9.00% 1. OA was estimated to be the eighth leading non-fatal burden of disease. hip. 4 2. with significant indirect costs.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).00% 6. progressive musculoskeletal disorder characterized by gradual loss of articular cartilage. In 1990.5 OA is a major cause of impaired mobility.1.6% of men and 18% of women ≥ 60 years have symptomatic OA. or if they have been damaged from fractures or other injuries. and spine than in the wrist. It is often more painful in weight bearing joints such as the knee. 2002) 7. All joints may be more affected if they are used extensively in work or sports. It is a common chronic.00% 3.6.00% 2. accounting for 2. Figure 1 Burden of disease of OA by age groups and regions    Osteoarthritis (DALYs. although it may begin earlier as a result of injury or overuse. by age groups & regions. and shoulder joints.1 The most common type of arthritis is osteoarthritis (OA) or degenerative joint disease.12: Osteoarthritis 1. Size and Nature of Disease Burden Musculoskeletal conditions are a major burden on individuals as well as health and social care systems. Introduction There are more than 100 different types of arthritis.00% 0. Incidence and prevalence  Literature is limited on the incidence and prevalence of OA because of the problems of defining it and determining its onset. elbow.00% % of total 4. Overall disease burden ranking according to this compiled data shows a ranking of 12 for combined 25 EU countries.00% 5.12­4 EU15-M 45-59 60-69 70-79 80+ Age groups EU15-F EU-10-M EU-10-F W-M W-F EU25-M EU25-F . 15th ranked for old EU and 9th rank for the 10 EU accession countries.

According to expert opinions presented in the EULAR committee report.   6. statistical highlights and the impact of arthritis from individual countries that have reported information are presented.6. EU25.4 Figure 2. EU15.000 hip or knee replacements were performed at a cost of £405 million. perhaps resulting in more disability.75 million people have symptomatic OA.2 OA contributes to a higher disease burden in men below the age of 50 and in women over the age of 50. the onset of OA is at an earlier age. In 2000 more than 80. Altogether 10% to 15% of adults over 60 have some degree of OA. Therefore.5 In general OA is more prevalent in Europe and USA than in other parts of the world. Prevalence of osteoarthritis5     Country impact Aggregate numbers on the overall impact of OA are not available.2 Figure 2 shows the prevalence of OA of the knee by age group. radiographic evidence of knee OA in men and women over 65 is found in 30% of patients.12: Osteoarthritis  Note from Figure 1. Knee OA is likely to become the fourth most important global cause of disability in women and eighth most important in men. loss of productivity and increased health care costs. As a cause of disability (such as walking and climbing stairs) in the elderly OA is second to cardiovascular disease.12­5 . sex and region. In EU 10. and EU10 are different. the peak in the burden of disease (DALYs) in each of the three regions: Global.3 and 1. UK4  In England and Wales between 1.

access to rheumatology care.6. An estimated 50 million people will be diagnosed with arthritis by 2013. doctors. The key issues in the fight against arthritis facing Japan include access to medications. Direct costs are $34. 9          6. The occurrence of the OA increases with age.12­6 . Only 24% of people with arthritis report and achieve levels of physical activity that are recommended for health. transportation. There are approximately 37. 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.to 10-fold in people from 30 to 65 years of age. uncoordinated treatment. access to speciality care. The key issues in the fight against arthritis include access to medications. The direct and indirect costs of arthritis in Canada equates to approximately $18 billion per year. 150 of them are close to retirement leaving 120 rheumatologists to care for 4 million suffering arthritis patients.4 billion. Arthritis is a greater factor in limiting activity than heart disease. funding for research and illness disability.000 people have arthritis. The current economic burden of arthritis in its various forms is approximately $82. Canada6      Japan6     US7.000 hip and knee replacement surgeries every year in Canada. 5% of the population has some form of arthritis. and diminished state budgets. access to speciality care. however. Indirect costs are $47.12: Osteoarthritis Germany6    Four million people out of 82 million people suffer from some form of autoimmune conditions affecting joints. Currently there are approximately 270 rheumatologists in Canada. 17% of population is over 65 (this percentage is expected to grow by 25% in the next three decades). Most people participate in a universal medical health insurance system.014. access to orthopaedic care. Population of 127 million people. It is estimated that over 41 million people out of 285 million people in the United States have arthritis. blindness. The remainder are essentially inactive or insufficiently active. or diabetes.6 billion (hospitals. The key issues in the fight against arthritis facing Canada include: access to medications. Over four million Canadians out of 31. 8. hypertension. Figure 3 shows the levels of physical activity reported by women with arthritis in the US. rising 2. nursing homes) Only 3% of the cost is for drugs.8 billion (primarily lost wages and lost productivity).

identify and note OA progression.  Plain radiographs are the current most common way of assessing disease progression. However. 2. non-pharmacological OA therapies. 7. 7 3. 12. Therefore management of the patient with OA should be comprehensive and individualized.  Comorbid conditions such as cardiac disease.15  An assessment of effect of a therapy should include a measure of health status in addition to radiological assessments. and interests. peptic ulcer disease or renal disease must be taken into account.  Biochemical markers of disease activity are not yet available for routine clinical care. 6. Levels of physical activity reported by women with arthritis in the US10. the phase and the progression rate of the disease. Objectives of OA management are to reduce the level of pain. 4. 13  The aetiology of OA is multifactorial. functional goals.12: Osteoarthritis Figure 3.  A radiographic grading system is used to define. The WHO recommends a definition of OA based on symptoms and a symptom-based grading system would be preferred for disease progression. Control Strategy Patients with OA suffer from pain and loss of function. reduce inflammation.  Persons with OA are a heterogeneous population. improve function and reduce disability. 11.6. However. ranging widely in age. This section reviews pharmacological and nonconventional. hypertension. Diagnosis and medical management 1. X-rays are not readily available in many parts of the world. there are currently no validated tools in this area.12­7 . disease impairment. as well as the patient’s needs and expectations. 3. although there are problems with standardization of joint positioning with respect to the knee. taking into account the anatomical distribution. slow cartilage degradation.

Goals of these prevention strategies are to reduce. Access to health care facilities and availability of X-rays is problematic in many parts of the world. radiographic evidence is often needed to identify and mark disease progression. There are only a few effective primary prevention strategies for arthritis. This involves early diagnosis so that appropriate early intervention can be utilized.13.  Occupational injury prevention: Avoiding repetitive joint use and its injuries can help prevent arthritis. pharmacological. physical activity. 14 • Primary prevention. • Secondary prevention.  Sports injury prevention: Taking the necessary precautions to prevent injury such as warming up and using proper equipment can help reduce joint injuries. home help programs.12: Osteoarthritis  The management plan of OA patients also needs to be regularly reviewed and adjusted in light of their response and adherence. maintaining or reducing weight can lower the risk for certain arthritic conditions.12­8 . This will vary between patients and location. education). Surgical treatment is generally reserved for failed medical management with functional disability affecting a patient’s quality of life. The following encompass tertiary prevention strategies: self-management (weight control.  Prevention Preventing the onset of OA requires lifestyle changes. and surgical treatments. Furthermore. The management of OA is broadly divided into non-pharmacological. This focuses on reducing the consequences of a disease. and improving quality of life.6. However. 15 • Tertiary prevention. this is difficult in OA since no effective biomarkers are available to determine the progression of the disease. These are measures to prevent the condition from occurring. These include:  Weight control: Obesity is considered a risk factor for OA. delay the onset of complications and disability. cognitive behavioural interventions.14.14 6. rehabilitation services and medical surgical treatments. Tertiary prevention strategies for arthritis are aimed at reducing pain and disability. Thus.

13. 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. 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 antiinflammatory drugs) Opioid analgesics Hormones Psychotropic drugs [comment. Non-pharmacological therapy review According to various recommendations. 3. 4. exercise. 16.2. non-pharmacological treatment of OA should include education.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). insoles and knee braces) and weight reduction.12­9 . chondroitin. 3 6. physical aids (such as canes.6.12: Osteoarthritis Table 1. Therapeutic options in osteoarthritis 2.

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. Pharmacological management of OA remains control of pain and improvement in function and quality of life while limiting drug toxicity. 6. 20  Both the American College of Rheumatology (ACR) and European League Against Rheumatism Guidelines (EULAR) recommend paracetamol/acetaminophen as the first list line agent. 16  A metaanalysis concluded that patient education in disease management.12: Osteoarthritis Education2.2. the effect of weight loss on OA has only been evaluated in two studies. regular telephone calls.3   There is limited data on the effects of physical aids on OA. physical aids are considered a sensible approach in the management of OA. and spouse assisted coping skills. Exercise builds muscle strength and endurance. reduced pain and improved function. 3.12.13 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.16 There are several studies that demonstrate the benefits of education in reducing pain. Effective educational techniques include individualized education. 19  Annex 6. improves joint flexibility and motion. 3. Most authors conclude that while the evidence is poorly documented weight loss is a sensible recommendation in the management of OA.2 Exercise2.  Below are the summarized highlights of the literature findings. 12. Physical aids2.paracetamol/acetaminophen2. there is no cure for OA. Weight loss2. increasing coping skills. 18  Exercise is considered the most important intervention in the management of OA. weight reduction and exercise was 20% as effective as NSAID therapy in reducing joint pain. 18. These studies showed that weight loss reduced the risk of developing symptomatic OA in women.12­10 . 9  Although weight loss is recommended. The review also found that there was insufficient evidence to compare the effects of different insoles. Pharmacological therapy review At present. Analgesics. Experts in this field suggest that appropriate therapy for OA combines one or more pharmacological agents with exercise and other biomechanical techniques.1 provides a detailed analysis on the current effectiveness of medical management of OA. 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.6. although. EULAR recommendations also state that based on it overall cost. it should be the preferred long-term oral analgesic. and reducing visits to the primary care. group education. 3. patient coping skills. efficacy and toxicity profile.

concomitant use of anticoagulants and glucocorticoids and history of peptic ulcer disease or upper gastrointestinal bleed. systematic reviews of RCTs by BMJ. 19 ACR and EULAR recommend that NSAIDs should be considered in patients unresponsive to paracetamol. 4. Risk factors for renal failure include: age greater than 65.11 Gastroduodenal ulcers occur in 15% to 30% of patients who take NSAIDs. The study suggests that high dose acetaminophen may results in an increased risk of gastrointestinal toxicity equivalent to NSAIDs. There is limited evidence that these agents vary in efficacy within this therapeutic drug category.12: Osteoarthritis  A BMJ clinical evidence review found limited evidence that simple analgesics such as paracetamol. 11      6. hypertension. found no good evidence that oral NSAIDS differ from paracetamol/acetaminophen in pain relief. According to systematic reviews conducted by BMJ. however. A recent study has also raised concern about the safety of acetaminophen in doses of greater than 2g/day.11. There is evidence that misoprostol.3. concomitant use of angiotensin-converting enzyme inhibitors. However. NSAIDs would be the ‘logical drugs in patients unresponsive to paracetamol’. the cost utility or prophylactic use of these agents is controversial and requires pharmaco-eoconomic analysis. 16. 22 In the US an estimated 20% to 30% of all hospitalisations due to peptic ulcer disease are secondary to NSAID use.18 According to the 2003 EULAR review. their long-term efficacy (past 2 years) has not been studied. it can be taken safely over the long term. reduced pain compared with placebo. smoking and alcohol consumption. the expert committee states that there is evidence that NSAIDs are more efficacious than paracetamol for some patients. 18    NSAIDs have both anti-inflammatory and analgesic properties.20. proton pump inhibitors and H2 blockers may reduce the gastrointestinal adverse effects induced by NSAIDs.6. Also.19 Another serious complication associated with NSAIDS includes renal failure. 21  Non-steroidal anti-inflammatory drugs (NSAIDs)2.2 Risk factors for NSAID-induced upper gastrointestinal adverse effects include: patient’s greater than 65 years.20. and patients who are at risk of gastrointestinal toxicity should use effective gastroprotective agents or selective COX-2 inhibitors. NSAIDs are more effective than placebo in reducing pain. 3. 11. However. but there is no evidence that they modify the course of OA. and existing renal failure. concomitant use of diuretics. Furthermore. The recommendations suggest that given the low-grade inflammatory component of OA. a review by EULAR reports that paracetamol is as effective as NSAIDS in the management of OA.12­11 . congestive heart failure.

and are currently ‘block buster’ drugs on the pharmaceutical market. However. 21  Intra-articular.4 injections per year and should be reserved for disease flares only.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. however limited evidence was found that capsaicin improves pain compared to placebo. 19.  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. 18   According to ACR and EULAR guidelines.19  Concern about loss of antiplatelet activity with COX-2 inhibitor group may contribute to excess cardiovascular complication. COX-2 inhibitors or NSAIDs plus a gastroprotective agent may be used. especially in the elderly who are at a higher risk of cerebral and vascular thrombosis.  There are no RCTs comparing the effectiveness of combination therapy.2. 4.11  Both ACR and EULAR state that patients who are at an increased risk of gastrointestinal complications.16. 20 Topical agents2. Topical treatment is an additional option for patients who have inadequate control with oral agents or who require local treatment.  Injections may be used as monotherapy or in combination with systemic drugs. 13. BMJ clinical review concludes that topical NSAIDs reduce pain compared to placebo. 6. 3.2  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). further wellconducted trials are needed in this area. however the most cost effective strategy for their use is still unclear.  Corticosteroids/glucocorticoids2. topical NSAIDs and topical capsaicin have clinical efficacy and are safe.6. 3.  There is evidence that intra-articular injections are effective with short-term relief. long acting corticosteroids are widely used in the management of knee OA. ulcers and bleeding.  The short-term therapy is considered to be beneficial in patients who have local inflammation and swollen joints.  ACR guidelines recommend no more than 3.  Infection into the OA joint is considered to be a rare complication associated with this intra-articular corticosteroid therapy.  A systematic review and one RCT found limited evidence that intra-articular corticosteroids reduced pain for 1-4 weeks. 17  COX-2 inhibitors have been found to be more effective than placebo in relieving pain in OA. the evidence for predictors of response remains unclear and further studies are needed to determine this.12: Osteoarthritis Cyclooxygenase-2 (COX-2) Inhibitors2.12­12 .4  COX-2 inhibitors are widely used in the US and Europe. 3.2. However.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  This class is just as efficacious as NSAIDs for pain relief but with a reduction of up to 50% in perforation.

there is limited literature on the adverse effects or long-term effects of these drugs. cost and logistical issues can offset its use in OA management. 23. transient local swelling. in the US. English and non-English. 27 6.  Hyaluronan is unaltered hyaluronic acid.  A EULAR review of 20 studies showed that 18/20 trials showed that hyaluronic acid to be more effective than placebo in relieving pain. randomised controlled trials comparing intra-articular hyaluronic acid with intra-articular placebo injection for the treatment of knee OA. the highest-molecular-weight hyaluronic acid may be more efficacious in treating knee OA’. 24  The injection of viscosupplements. There is a very recent metaanalysis evaluating published or unpublished. single.25  Current evidence suggests that it is not known whether different glucosamine. can be administered orally.  Hylan G-F 20 is hyaluronic acid but with a higher molecular weight. but further research is necessary. Viscosupplements-hyaluronic acid19. and well conducted RCT are needed to determine the long-term effects and safety of these drugs.24  The potential of hyaluronic acid preparations to preserve cartilage still remains to be determined. However.26 Further research is also needed in the following areas: assessment of the long-term efficacy and safety. chondroitin. effectiveness.6. there are no formal requirements for nutritional supplements to prove their efficacy and claims cannot be made for the treatment of medical conditions. Most studies have evaluated glucosamine sulfate.19.or double-blinded. who would most benefit from glucosamine and finally. Most common reported adverse effects include: localized reactions.12­13 . Most of these studies have shown a variable response in the relief of pain compared to placebo with various dosage forms. This preparation is injected weekly over a three-week period. Compared with lowermolecular-weight hyaluronic acid. Glucosamine also has a slower onset of action compared to NSAIDs and the pharmacology by which it exerts pain relief still remains unclear. EULAR states while there is evidence for its use. The presence of publication bias suggests even this effect may be overestimated. what are the appropriate doses and routes of administration to both maximize efficacy while limiting adverse effects.2 SYADOA (Symptomatic Slow Acting Drugs for OA (avocado/soybean unsaponifiables (ASU). relative purity and content of the different glucosamine preparations. which include hyaluronan and hylan G-F 20. is being used in the treatment of knee OA.  The clinical effectiveness of viscosupplements remains controversial. or intra-articularly. There are numerous glucosamine preparations on the market. chondroitin sulfate and collagen hydrolysate  Glucosamine and chondroitin sulfate are regulated as drugs in European countries and as a nutritional supplement in the US. an aminosaccharide.18. 26  Glucosamine.  Intra-articular viscosupplements have few side effects. 19.24 ‘Intra-articular hyaluronic acid has a small effect when compared with an intra-articular placebo. intramuscularly. or glucosamine chondroitin preparations by different manufacturers are equally effective in the therapy of OA.12: Osteoarthritis  Current recommendations are to use intra-articular steroids when other analgesics and NSAIDs are ineffective or contraindicated. Given this. diacerein and glucosamine) Glucosamine.26. pain and erythema. its delayed onset. 27 A Cochrane review of RCTs evaluating the effectiveness and toxicity of glucosamine determined there is evidence that glucosamine is effective. which is injected weekly for 5-weeks. Further evidence. Glucosamine.

28 Collagen hydrolysate: Collagen hydrolysate may be beneficial in the treatment of OA. Studies in the review examined: articulin F.  Future trials should focus on clinical effectiveness of herbal therapies. The compound is available and used in France. Also. very limited evidence showing its effectiveness.  Well-designed RCT are needed to determine the effectiveness. Studies should also compare and assess the impact of herbals medicines on allopathic medication. Boron. Avocado/Soybean extract and Articulin F. diseasemodifying potential.27 Diacerein: Reviews of RCTS of diacerein.12­14 . Diacerein’s role in the management of OA still needs to be determined. in the form of food supplements and there is very limited evidence to clinically demonstrate their effectiveness. 32  A number of alternatives exist for the treatment and prevention of OA.19  Vitamin A.19. however. since it contains amino acids that may play a role in the development of collagen. 27. there is some evidence that these preparations may reduce the use of NSAIDS. 6. the reviewed herbal medicines appear to be safe. gitadyl. Compared to NSAIDS. eaymov. Some of these include Vitamin E. and E have antioxidant properties that may be beneficial in the management of OA. 33  Long L et al. Manganese. reumalex and stinging nettle leaf. Invitro studies have shown that this compound has an inhibitory effect on a number of molecules that may affect OA. recommended dosage guidelines and adverse effects in OA management.  Promising evidence was found for the effective use of some herbal preparations in the treatment of OA. Furthermore.31. Herbals31. 32. There is. devils claw. but further investigation in larger RCTs for longer time periods are needed to prove its effectiveness as a symptom modifying drug in OA. The drug may have the potential as an add-on therapy to NSAIDs or viscosupplements. SAdenosylmethionine.30    Vitamins19  A review of the role of vitamins in the management of OA states that oxidative damage may accelerate OA progression. C. Ascorbic acid.29 Avacado/Soybean unsaponifiable residues (ASU):ASU is a compound consisting of avocado oil and soybean. derived from bovine and calf cartilage has an oral bioavailability of about 10%. chondroitin has a delayed onset and therapeutic response. They are available.29 There have been few reported adverse effects with this drug. Very limited evidence is presented on the safety and effectiveness of these agents and further well-conducted studies are needed. Chondroitin. Vitamin D.33 Surgical treatment Surgical treatment of osteoarthritis is usually considered after failure of nonsurgical therapies. outcome measures and valid measures of OA. specifically NSAIDs. phytodolor. an interleukin-1 inhibitor showed that it was effective in reducing pain. capsaicin cream. There are four surgical procedures: osteotomy.31.19 A metaanalysis of chondroitin sulphate concluded that this product may be effective in OA. however. conducted a systematic review of herbal medicines for the treatment of osteoarthritis.6. Well-conducted trials are needed to evaluate the potential of this compound in the management of OA.12: Osteoarthritis  Chondroitin sulfate. 32  The area of herbal medicines in OA is under-researched and merits further attention.

and health care provisions).6. the expert committee recommends that predictors of response.12­15 . which include physician visits and hospitalisations. indications for joint replacement. and disability of end-stage OA can be eliminated.69. after heart disease. economics. This is approximately 21% of the total musculoskeletal disorders expenditure. feasibility and sustainability Limited literature is available on the affordability. independent of known environmental or demographic confounders. physical disability arising from pain and loss of functional capacity reduces quality of life and increases the risk of further morbidity and mortality. 34 OA is associated with pain and functional disability and as the disease progresses. restoring patients to near-normal function. accessibility and cost of currently approved therapies and their impact and management of OA.2 Affordability.15  The total cost. Of this. postoperative care and outcome assessment should also be studied for these procedures. sex. heredity. complications and the disability that result from arthritis is estimated at $65 billion. is the mainstay of surgical treatments.14  Economic indicators for OA are difficult to develop. which have compared surgery with nonsurgical intervention.39 to 0. ageing. This is because data can be collected on the medical resources (which is dependent on cultural. trauma. The remaining balances are indirect costs resulting from wage losses. as a cause of missed work in the developed world. Studies need to asses (1) the cost of drug therapy for disease management and (2) the combination of nonpharmacological and pharmacological treatment modalities. occupational and recreational usage).13 Total joint replacement is highly successful and by most measures among the most effective of all medical interventions.14 4.12 Risk factors for incidence and progression of osteoarthritis Age is the strongest predictor of the development and progression of OA.g. The four procedures have different indications and variable benefits. and reproductive variables) and local adverse mechanical factors (e. Further studies are required to address this issue. arthrodesis and arthroplasty.  The estimated health-care cost of OA was US $624 million in 1993-94. and loss of income resulting from disability or limitations on work. obesity. Pain. treatment. Arthritis is ranked second. 6. which occur as a result of the corrosion between the implanted material and the cells. the estimated medical costs are $15 billion annually.13 Currently there are no RCTs. a large population affected are elderly and not working.13 The most common failures of total joint replacement surgery include aseptic loosening and osteolysis. Total joint arthroplasty.7. than on the condition itself. 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. Also. Although EULAR acknowledges the difficulties in study design. There are also genetic components in the prevalence of OA. the most surgically advanced in OA treatment. while lost days of work may be determined. with heritability estimates from twin studies of 0. Furthermore.  The economic implications of arthritis include the financial burden of health care costs.g.12: Osteoarthritis arthroscopy. and this operation is highly cost-effective. effect of different surgical techniques and long-term effect of joint prosthesis should be examined.

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 There is genetic susceptibility to the disease Children of parents with early onset OA are at a higher risk of developing OA themselves Strongest modifiable risk factor Being overweight at an average age of 36-37 is a risk factor for developing knee OA Threefold increase risk of progression of OA for people in the lower decile of vitamin C and D blood levels 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.12. These enzymes have been shown to increase in activity after joint 6. 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 More common in those performing heavy physical work Dockers. 16 5. The following section (and Annex 6. Unfortunately. hips and hands.1 evaluates therapies currently used or have been indicated in the management of OA.12­16 . a family of degradative enzymes. Annex 6.5. Risk factor Age     Trauma Occupation Exercise Gender ethnicity    and   Genetics         Obesity Diet Bone density Normal ageing process causes increases progression 27% of those aged 63-70 had radiographic evidence of knee OA. Risk Factors for Incidence and Progression of Osteoarthritis1. have been identified as occurring in the development and normal turnover of tissues.12: Osteoarthritis  Table 2 shows the risk factors for incidence and progression of OA of the knees.12. halt or reverse OA progression. 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.  Inhibition of breakdown of cartilage by collagenolytic enzymes or matrix metalloproteinases (MMPs). 12 Table 2. miners and farmers found to have OA High impact sports present an increase for OA Men under the age of 50 have a higher prevalence and incidence Women over 50 have a higher prevalence and incidence (menopause may be a trigger. 4. increasing to 44% in over 80 age group Collateral ligament. 5. although pharmaceutical companies are actively pursuing development of such therapies. The burden will be greatest in developing countries where life expectancy is increasing.6.2) provides information on the areas of current research. but access to therapy is not readily available. there have been no new drugs that can prevent. MMPs.

12: Osteoarthritis injury. for more information. For example.12­17 . New medications in development for osteoarthritis Investigation al drug name Indication and description Company 37 Developme nt status 462795 (Cathepsin K inhibitor) ABT 963 CP-544. MMPs present an important target for potential pharmacological development.439 Osteoarthritis Osteoporosis • Cathepsin K is believed to play a role in degrading bone.12.20     6. 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. 36 Refer to Annex 6.12. 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. 36 Bisphosphonates. which have prevented their continued development.3 shows the new medications in development for OA. through biomechanical factors and increased chondrocytes loading has resulted in increased proteoglycan synthesis and an increased release of degradative enzyme activity. Resorptive agents or bisphosphonates (such as alendronate and clodronate) may provide important benefits in the symptomatic relief of OA. in individuals with OA provides evidence that MMP inhibitions may be effective in slowing down cartilage loss in OA. a potent MMP. The drug is intended for the symptomatic treatment of OA40. this class of drugs are not clinically approved for OA therapy. MMP-13 has been shown to play a central role in cartilage degradation. Unfortunately all the new MMPs tested in humans to date have resulted in toxicity in other organ systems.35.39 Osteoarthritis Rheumatoid arthritis • ABT 963 is a COX-2 inhibitor like celecoxib and rofecoxib already on the market. Also. Initial results of the studies have not been made available yet. Hence. 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.6. The release of MMPs. since these enzymes may alter disease process. 35. Table 6. increased weight and preceding joint injury can increase the risk of OA. Table 3.11. Growth factors are being evaluated in the management of OA and its affect on cartilage. these molecules have also become a potential target for pharmacological intervention and studies of such agents are planned or ongoing. Osteoarthritis GlaxoSmithKlin e Phase I Abbott Laboratories Phase II Pfizer Phase II 6. 35 Therapy that stimulates repair activity by chondrocytes. A recent study with doxycycline. Alternative medicines: The US Congress created The National Center of Complementary and Alternative Medicine (NCCAM) given the growing use of alternative medicines. which are believed to affect the degradative process in OA.35 Growth factors. Current Pharmaceutical Product “Pipeline” for OA Treatment Currently there are a limited number of pharmaceutical products in the pipeline. Specific MMPs have been identified. Studies that have attempted to mimic these effects in vitro. by chondrocytes appears to be affected by a wide range of conditions and processes. 38 • Cathepsin K inhibitors have the potential to provide a new therapeutic agent for the treatment of OA.11.

45 • A number of companies are developing new COX-2 inhibitors with the intention of achieving greater responder rates and/or reduction in pain score. Differences within the COX-2 class have not yet been established.44. This drug has the potential to become a disease-modifying drug for the treatment of OA and inflammatory diseases.12: Osteoarthritis Investigation al drug name Indication and description Company Developme nt status ML-3000 Pennsaid Topical Solution Pralnacasan Various COX2 inhibitors • No available information Osteoarthritis • A new class of anti-inflammatory and analgesic drugs. 43 Osteoarthritis • An orally bioavailable inhibitor of interleukin (IL)-1beta converting enzyme. 42 Osteoarthritis Rheumatoid arthritis • Pennsaid is a topical formulation of diclofenac. which is used for the treatment of the symptoms of osteoarthritis. Forest Laboratories Phase III Dimethaid Research Application submitted to FDA Aventis Pharmaceutical s Phase II Various companies 6. a non-steroidal antiinflammatory drug (NSAID). This class are inhibitors of both cyclooxygenase and leukotrienes and have the potential to reduce gastrointestinal toxicity.12­18 .41. Also known as COX/LOX inhibitors.6.

Most experts in this field have articulated that this is particularly an area where research into new diagnostics. vitamins. and nutraceuticals) whose clinical effectiveness still needs to be determined through better-conducted clinical trials.        These studies bridge the range of research from basic science to Phase IV studies. and long term effects of SYADOA drugs. Several questions remain unanswered in the areas of epidemiology. damage and quality of life. effectiveness. Compare the effectiveness between paracetamol-acetaminophen and cox-2 inhibitors. Only when the patients develop pronounced inflammations are the symptoms of pain noticeable to the patient. pathophysiology and diagnosis of the disease. Conduct pharmaco-economic studies to determine the cost effectiveness of OA therapy and its long term management. There are also a large number of drugs (including alternative therapies. reverse or halt the disease.12: Osteoarthritis 7. Explore the effectiveness of alternative therapies in reducing symptoms of OA. such as local delivery of anti-inflammatory cytokines. Investigate the efficacy of topical NSAIDS and conduct comparative trials. Investigate pooled/combination treatments.12­19 . since it will help the medical community to determine: . efficacy and safety of COX-2 inhibitor use. which reflect everyday clinical practice. Study the gastrointestinal safety of high-dose acetaminophen. Opportunities for Research into New Pharmaceutical Intervention See Annex 6. 8. Biomarkers are an essential area of research in OA and arthritis as a whole. because although there is inflammation in the joint it occurs much less than in rheumatoid arthritis. biomarkers and imaging technology is going to be important and useful for the management of OA. Current therapies on the market only help to improve pain and function. Determine the long-term effects.12 The area of drug development in OA is of a significant public health consequence.Severity and progression of disease 6. Evaluate the safety.6.Who is likely to get arthritis? . Development of disease modifying osteoarthritis drugs. 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. There are no drugs that can prevent. 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. 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. These need to be studied to support the effective development of novel disease modifying agents.

12­20 .46 While exciting breakthrough treatments continue to become available for rheumatoid arthritis. researchers and drug companies require effective biochemical and imaging markers to assess disease progression. called the osteoarthritis Initiative (OAI).12: Osteoarthritis 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.25 The position of many recent health authorities has facilitated improvement in the level of evidence and the observed treatment effect of drugs. 3  Strengthen evidence-based medicine by closing the gap between molecular research and clinical disease research for OA. such as glucosamine and chondroitin sulphate are considered drugs in parts of Europe.  Class of compounds: Certain compounds.47 A number of other issues need to be resolved. On the other hand. which will include evaluation data. The difference in the availability of drugs may result in differences in clinical practice and level of patient expectation of OA drugs. progress may be achieved in the development of medications to effectively control the symptoms and disease progression of OA as well. with better understanding through research of the molecular process.  Level of evidence of efficacy: Despite certain drugs being on the market for several decades. Current evaluation methods of x-rays and blood tests are insufficient to determine the progression and outcome of new treatments. Interestingly. their efficacy was not determined until recently. GlaxoSmithKline. such as ASU (Avocado/Soybean unsaponifiable) residues in France.  Drug development in OA has been lacking. There is substantial research opportunity potential in this area. Merck.46 The following are areas that need research:2. however. highly effective therapies do not exist for OA. radiological images and a biospecimen repository. All the data will be available to researchers worldwide.46 This discovery may potentially be helpful since some of the knowledge about rheumatoid arthritis may be transferred and applied to osteoarthritis. Currently.Differences in quality assurance. because in order to diagnose. whereas others are not available in other countries or the US. Furthermore. As a result. 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. 6. the research to support treatments in OA is not as advanced as compared to rheumatoid arthritis. a recent US-based public private partnership.6. These differences may have the following consequences:25 . monitor and develop treatments for OA. This data will be used for the development of potential new OA treatments. OAI will provide approximately 8 million dollars annually to six clinical research centres to establish and maintain a database of OA. intends to combine resources for the purpose of finding biological markers related to the progression of OA.No requirements to determine the efficacy or the safety of food supplement products.25  Inter country differences: Certain drugs are available in parts of Europe. .20 In the US. complementary and alternative medicines are the most rapidly growing area at the NIH (National Institute of Health). Novartis Pharmaceuticals Corporation and Pfizer. OAI will collect data over the next 5-7 years on individuals at high risk for the development of OA. OAI is a combined effort in the US by NIH (National Institute of Health). in the US they are considered food supplements.

there are no drugs that can cure. trials should compare the observed effect of new treatments to conventional drugs such as NSAIDs. however. OA. OA is also now regarded as a complex disease whose etiology is not completely understood. 6. data is lacking about the therapeutic effectiveness of certain drugs within a class as well as between classes. Emphasis on most peer review journals is about the statistically significant effect of these treatments. several drugs on the market whose clinical effectiveness and long-term safety still need to be determined. Information related to these topics may assist in the overall management and planning of this disabling condition. while there is substantial research in this area. these include epidemiology. 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. In addition there are also several areas where information is still lacking.12­21 . This is especially important since OA requires long disease management and the disease primarily affects people over the age of 60. the most common arthritis condition. Conclusion The prevalence of OA is increasing and this places a globally major burden on individuals. environmental risk factors. To answer this and to determine the level of efficacy.12: Osteoarthritis there are numerous unpublished studies. Finally. path physiology.6. While there are several drugs available on the market that mitigate pain and improve function. reverse or halt disease progression. genetic predisposition and lifestyle. In addition. There are. health systems. is a major cause of impaired mobility and disability for the ageing populations. There are a number of drugs in the pipeline under development and several studies also evaluating alternative therapies. and social care systems. who are most prone to drug toxicity. 9. biomarkers and imaging technology is going to be important and useful for the management of OA and the development of disease modifying drugs. most experts emphasize that research into new diagnostics.

12­22 .12: Osteoarthritis 10. References 6.6.

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