ࡱ> q` 0^bjbjqPqP  ::!j < < < < 4RޗޗޗhF$jLR8› N4=gDe8g8g8g8g8g8g8$;h>p8Lߪ^=LL8< Z]8222Le82Le822U-P2 +ޗ1t4T8082t>v^>22>2p2U988^8LLLLRRDBVARRVRRR< < <   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 Table of Contents  TOC \o "1-2" \h \z \u  HYPERLINK \l "_Toc79994342" Summary  PAGEREF _Toc79994342 \h 3  HYPERLINK \l "_Toc79994343" 1. Introduction  PAGEREF _Toc79994343 \h 4  HYPERLINK \l "_Toc79994344" 2. Size and Nature of Disease Burden  PAGEREF _Toc79994344 \h 4  HYPERLINK \l "_Toc79994347" 3. Control Strategy  PAGEREF _Toc79994347 \h 8  HYPERLINK \l "_Toc79994357" 4. Major Problems and Challenges for Disease Control (Why Does the Disease Burden Persist?)  PAGEREF _Toc79994357 \h 16  HYPERLINK \l "_Toc79994360" 5. Past/Current Research into Pharmaceutical Interventions for OA  PAGEREF _Toc79994360 \h 17  HYPERLINK \l "_Toc79994361" 6. Current Pharmaceutical Product Pipeline for OA Treatment  PAGEREF _Toc79994361 \h 18  HYPERLINK \l "_Toc79994362" 7. Opportunities for research into new pharmaceutical intervention  PAGEREF _Toc79994362 \h 20  HYPERLINK \l "_Toc79994363" 8. Gaps Between Current Research and Potential Research Issues that Could Make a Difference  PAGEREF _Toc79994363 \h 21  HYPERLINK \l "_Toc79994364" 9. Conclusion  PAGEREF _Toc79994364 \h 22  HYPERLINK \l "_Toc79994365" 10. References  PAGEREF _Toc79994365 \h 23   HYPERLINK "../annexes/osteo_listanx.htm" Annexes Summary Osteoarthritis (OA) is the most common type of arthritis or degenerative joint disease. 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.,  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 patients 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. NOTEREF _Ref65992257 \f \h  \* MERGEFORMAT 2,  NOTEREF _Ref65992279 \f \h  \* MERGEFORMAT 3 1. Introduction There are more than 100 different types of arthritis. NOTEREF _Ref65992333 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref65992333 \f \h  \* MERGEFORMAT 1,  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. 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. NOTEREF _Ref66001838 \f \h  \* MERGEFORMAT 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 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. NOTEREF _Ref66001871 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66001871 \f \h  \* MERGEFORMAT 2 Figure 2 shows the prevalence of OA of the knee by age group, sex and region. NOTEREF _Ref66001838 \f \h  \* MERGEFORMAT 5 In general OA is more prevalent in Europe and USA than in other parts of the world. NOTEREF _Ref66001959 \f \h  \* MERGEFORMAT 4 Figure 2. Prevalence of osteoarthritis NOTEREF _Ref66001838 \f \h  \* MERGEFORMAT 5 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. UK NOTEREF _Ref66001959 \f \h  \* MERGEFORMAT 4 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. Germany 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. Canada NOTEREF _Ref65989867 \f \h  \* MERGEFORMAT 6 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. Japan NOTEREF _Ref65989867 \f \h  \* MERGEFORMAT 6 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. US, ,  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 3percent have OA of the hip. The occurrence of the OA increases with age, rising 2- to 10-fold in people from 30 to 65years 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 $82.4billion. 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. Figure 3. Levels of physical activity reported by women with arthritis in the US,  NOTEREF _Ref66002304 \f \h  \* MERGEFORMAT 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  NOTEREF _Ref65992333 \f \h  \* MERGEFORMAT 1,  NOTEREF _Ref66001871 \f \h  \* MERGEFORMAT 2,  NOTEREF _Ref65992279 \f \h  \* MERGEFORMAT 3,  NOTEREF _Ref66001959 \f \h  \* MERGEFORMAT 4,  NOTEREF _Ref66002304 \f \h  \* MERGEFORMAT 7, , ,  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. NOTEREF _Ref66087801 \f \h  \* MERGEFORMAT 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 patients needs and expectations. 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 patients quality of life. Prevention Preventing the onset of OA requires lifestyle changes. NOTEREF _Ref66003761 \f \h  \* MERGEFORMAT 13,  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. NOTEREF _Ref66087686 \f \h  \* MERGEFORMAT 14,  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. NOTEREF _Ref66087686 \f \h  \* MERGEFORMAT 14 Table 1. Therapeutic options in osteoarthritis  NOTEREF _Ref66001871 \f \h  \* MERGEFORMAT 2,  NOTEREF _Ref65992279 \f \h  \* MERGEFORMAT 3,  NOTEREF _Ref66001959 \f \h  \* MERGEFORMAT 4,  NOTEREF _Ref66003761 \f \h  \* MERGEFORMAT 13, ,  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. NOTEREF _Ref66001871 \f \h  \* MERGEFORMAT 2,  NOTEREF _Ref65992279 \f \h  \* MERGEFORMAT 3 Education NOTEREF _Ref66001871 \f \h  \* MERGEFORMAT 2,  NOTEREF _Ref66003975 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66003975 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref65992257 \f \h  \* MERGEFORMAT 2 Exercise NOTEREF _Ref66001871 \f \h  \* MERGEFORMAT 2,  NOTEREF _Ref65992279 \f \h  \* MERGEFORMAT 3,  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 loss NOTEREF _Ref66001871 \f \h  \* MERGEFORMAT 2,  NOTEREF _Ref66004216 \f \h  \* MERGEFORMAT 12,  NOTEREF _Ref66004226 \f \h  \* MERGEFORMAT 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 aids NOTEREF _Ref66001871 \f \h  \* MERGEFORMAT 2, NOTEREF _Ref65992279 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66003761 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66001871 \f \h  \* MERGEFORMAT 2,  NOTEREF _Ref65992279 \f \h  \* MERGEFORMAT 3,  HYPERLINK "../annexes/osteo_anx_1.doc"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/acetaminophen NOTEREF _Ref66001871 \f \h  \* MERGEFORMAT 2,  NOTEREF _Ref65992279 \f \h  \* MERGEFORMAT 3,  NOTEREF _Ref66004519 \f \h  \* MERGEFORMAT 18,  Both the American College of Rheumatology (ACR) and European League Against Rheumatism Guidelines (EULAR) recommend paracetamol/acetaminophen as the first list line agent. EULAR recommendations also state that based on it overall cost, efficacy and toxicity profile, it should be the preferred long-term oral analgesic. A BMJ clinical evidence review found limited evidence that simple analgesics such as paracetamol, reduced pain compared with placebo. However, a review by EULAR reports that paracetamol is as effective as NSAIDS in the management of OA. Furthermore, it can be taken safely over the long term. A recent study has also raised concern about the safety of acetaminophen in doses of greater than 2g/day. The study suggests that high dose acetaminophen may results in an increased risk of gastrointestinal toxicity equivalent to NSAIDs. NOTEREF _Ref66004564 \f \h  \* MERGEFORMAT 20,  Non-steroidal anti-inflammatory drugs (NSAIDs) NOTEREF _Ref66001871 \f \h  \* MERGEFORMAT 2,  NOTEREF _Ref65992279 \f \h  \* MERGEFORMAT 3,  NOTEREF _Ref66001959 \f \h  \* MERGEFORMAT 4,  NOTEREF _Ref66005536 \f \h  \* MERGEFORMAT 11,  NOTEREF _Ref66003975 \f \h  \* MERGEFORMAT 16,  NOTEREF _Ref66004519 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66004519 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66001871 \f \h  \* MERGEFORMAT 2 Risk factors for NSAID-induced upper gastrointestinal adverse effects include: patients greater than 65 years, concomitant use of anticoagulants and glucocorticoids and history of peptic ulcer disease or upper gastrointestinal bleed, smoking and alcohol consumption. NOTEREF _Ref66004564 \f \h  \* MERGEFORMAT 20,  In the US an estimated 20% to 30% of all hospitalisations due to peptic ulcer disease are secondary to NSAID use. NOTEREF _Ref66005536 \f \h  \* MERGEFORMAT 11 Gastroduodenal ulcers occur in 15% to 30% of patients who take NSAIDs. NOTEREF _Ref66006291 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66005536 \f \h  \* MERGEFORMAT 11,  NOTEREF _Ref66006291 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref65992279 \f \h  \* MERGEFORMAT 3,  NOTEREF _Ref66005536 \f \h  \* MERGEFORMAT 11 Cyclooxygenase-2 (COX-2) Inhibitors NOTEREF _Ref66001871 \f \h  \* MERGEFORMAT 2,  NOTEREF _Ref66001959 \f \h  \* MERGEFORMAT 4,  NOTEREF _Ref66003761 \f \h  \* MERGEFORMAT 13, NOTEREF _Ref66003975 \f \h  \* MERGEFORMAT 16,  NOTEREF _Ref66006157 \f \h  \* MERGEFORMAT 17 COX-2 inhibitors have been found to be more effective than placebo in relieving pain in OA. NOTEREF _Ref66001871 \f \h  \* MERGEFORMAT 2,  NOTEREF _Ref66003761 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66001871 \f \h  \* MERGEFORMAT 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). NOTEREF _Ref66006291 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66002304 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66003761 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66001959 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66005536 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66001871 \f \h  \* MERGEFORMAT 2, NOTEREF _Ref65992279 \f \h  \* MERGEFORMAT 3, NOTEREF _Ref66004564 \f \h  \* MERGEFORMAT 20 Topical agents NOTEREF _Ref66001871 \f \h  \* MERGEFORMAT 2,  NOTEREF _Ref65992279 \f \h  \* MERGEFORMAT 3,  NOTEREF _Ref66004519 \f \h  \* MERGEFORMAT 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/glucocorticoids NOTEREF _Ref66001871 \f \h  \* MERGEFORMAT 2,  NOTEREF _Ref65992279 \f \h  \* MERGEFORMAT 3,  NOTEREF _Ref66006291 \f \h  \* MERGEFORMAT 19,  NOTEREF _Ref66013212 \f \h  \* MERGEFORMAT 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. Current recommendations are to use intra-articular steroids when other analgesics and NSAIDs are ineffective or contraindicated. Viscosupplements-hyaluronic acid NOTEREF _Ref66006291 \f \h  \* MERGEFORMAT 19, ,  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. NOTEREF _Ref66006539 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66006539 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66001871 \f \h  \* MERGEFORMAT 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. 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. NOTEREF _Ref66004519 \f \h  \* MERGEFORMAT 18,  NOTEREF _Ref66006291 \f \h  \* MERGEFORMAT 19,  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. NOTEREF _Ref66006291 \f \h  \* MERGEFORMAT 19,  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. NOTEREF _Ref66077264 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66077264 \f \h  \* MERGEFORMAT 26,  NOTEREF _Ref66077676 \f \h  \* MERGEFORMAT 27 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. NOTEREF _Ref66006291 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66006291 \f \h  \* MERGEFORMAT 19,  NOTEREF _Ref66007928 \f \h  \* MERGEFORMAT 27,  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. NOTEREF _Ref66007928 \f \h  \* MERGEFORMAT 27 Diacerein: Reviews of RCTS of diacerein, an interleukin-1 inhibitor showed that it was effective in reducing pain. There have been few reported adverse effects with this drug. Diacereins 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. NOTEREF _Ref66262909 \f \h  \* MERGEFORMAT 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. Vitamins NOTEREF _Ref66006291 \f \h  \* MERGEFORMAT 19 A review of the role of vitamins in the management of OA states that oxidative damage may accelerate OA progression. NOTEREF _Ref66006291 \f \h  \* MERGEFORMAT 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. Herbals, ,  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. NOTEREF _Ref66263099 \f \h  \* MERGEFORMAT 31,  NOTEREF _Ref66263115 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66263099 \f \h  \* MERGEFORMAT 31,  NOTEREF _Ref66263115 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66263081 \f \h  \* MERGEFORMAT 33 Surgical treatment Surgical treatment of osteoarthritis is usually considered after failure of nonsurgical therapies. There are four surgical procedures: osteotomy, arthroscopy, arthrodesis and arthroplasty. The four procedures have different indications and variable benefits. Total joint arthroplasty, the most surgically advanced in OA treatment, is the mainstay of surgical treatments. NOTEREF _Ref66003761 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66003761 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66003761 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66001871 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66087686 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66087801 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66087686 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66002304 \f \h  \* MERGEFORMAT 7,  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. NOTEREF _Ref66004216 \f \h  \* MERGEFORMAT 12 Risk factors for incidence and progression of osteoarthritis Age is the strongest predictor of the development and progression of OA. Table 2 shows the risk factors for incidence and progression of OA of the knees, hips and hands. Table 2. Risk Factors for Incidence and Progression of Osteoarthritis NOTEREF _Ref66003224 \f \h  \* MERGEFORMAT 1,  NOTEREF _Ref66001959 \f \h  \* MERGEFORMAT 4,  NOTEREF _Ref66001838 \f \h  \* MERGEFORMAT 5,  NOTEREF _Ref66004216 \f \h  \* MERGEFORMAT 12 Risk factorAgeNormal ageing process causes increases progression 27% of those aged 63-70 had radiographic evidence of knee OA, increasing to 44% in over 80 age groupTraumaCollateral 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 OAOccupationMore common in those performing heavy physical work Dockers, miners and farmers found to have OAExerciseHigh impact sports present an increase for OAGender and ethnicityMen 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. 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 AsiansGeneticsThere is genetic susceptibility to the disease Children of parents with early onset OA are at a higher risk of developing OA themselvesObesityStrongest modifiable risk factor Being overweight at an average age of 36-37 is a risk factor for developing knee OADietThreefold increase risk of progression of OA for people in the lower decile of vitamin C and D blood levelsBone densityIncreasing bone density may lead to increased loading through weight bearing joint cartilageTrends 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. NOTEREF _Ref66001838 \f \h  \* MERGEFORMAT 5,  NOTEREF _Ref66003975 \f \h  \* MERGEFORMAT 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. HYPERLINK "../annexes/osteo_listanx.htm"Annex 6.12.1 evaluates therapies currently used or have been indicated in the management of OA. The following section (and HYPERLINK "../annexes/osteo_anx_2.doc"Annex 6.12.2) provides information on the areas of current research. Inhibition of breakdown of cartilage by collagenolytic enzymes or matrix metalloproteinases (MMPs). MMPs, a family of degradative enzymes, have been identified as occurring in the development and normal turnover of tissues. These enzymes have been shown to increase in activity after joint injury. Specific MMPs have been identified, which are believed to affect the degradative process in OA. MMP-13 has been shown to play a central role in cartilage degradation. MMPs present an important target for potential pharmacological development, since these enzymes may alter disease process. Unfortunately all the new MMPs tested in humans to date have resulted in toxicity in other organ systems, which have prevented their continued development. A recent study with doxycycline, a potent MMP, in individuals with OA provides evidence that MMP inhibitions may be effective in slowing down cartilage loss in OA. NOTEREF _Ref66005536 \f \h  \* MERGEFORMAT 11,  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. NOTEREF _Ref66005536 \f \h  \* MERGEFORMAT 11,  NOTEREF _Ref66009363 \f \h  \* MERGEFORMAT 35,  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. NOTEREF _Ref66009363 \f \h  \* MERGEFORMAT 35 Growth factors. Growth factors are being evaluated in the management of OA and its affect on cartilage. NOTEREF _Ref66009363 \h  \* MERGEFORMAT 35,  NOTEREF _Ref66687460 \h  \* MERGEFORMAT 36 HYPERLINK "../annexes/osteo_listanx.htm"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. NOTEREF _Ref66004564 \f \h  \* MERGEFORMAT 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. Table 3. New medications in development for osteoarthritis  Investigational drug nameIndication and descriptionCompanyDevelopment status462795 (Cathepsin K inhibitor)Osteoarthritis Osteoporosis Cathepsin K is believed to play a role in degrading bone.  Cathepsin K inhibitors have the potential to provide a new therapeutic agent for the treatment of OA.GlaxoSmithKlinePhase IABT 963Osteoarthritis Rheumatoid arthritis ABT 963 is a COX-2 inhibitor like celecoxib and rofecoxib already on the market. The drug is intended for the symptomatic treatment of OA. Abbott LaboratoriesPhase IICP-544,439Osteoarthritis No available informationPfizerPhase IIML-3000Osteoarthritis A new class of anti-inflammatory and 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., Forest LaboratoriesPhase IIIPennsaid Topical SolutionOsteoarthritis Rheumatoid arthritis Pennsaid is a topical formulation of diclofenac, a non-steroidal anti-inflammatory drug (NSAID), which is used for the treatment of the symptoms of osteoarthritis.  Dimethaid ResearchApplication submitted to FDAPralnacasanOsteoarthritis An orally bioavailable inhibitor of interleukin (IL)-1beta converting enzyme. This drug has the potential to become a disease-modifying drug for the treatment of OA and inflammatory diseases., Aventis PharmaceuticalsPhase IIVarious COX-2 inhibitorsA 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.Various companies 7. Opportunities for Research into New Pharmaceutical Intervention HYPERLINK "../annexes/osteo_listanx.htm"See Annex 6.12 The area of drug development in OA is of a significant public health consequence. Current therapies on the market only help to improve pain and function. There are no drugs that can prevent, reverse or halt the disease. Several questions remain unanswered in the areas of epidemiology, pathophysiology and diagnosis of the disease. These need to be studied to support the effective development of novel disease modifying agents. There are also a large number of drugs (including alternative therapies, vitamins, and nutraceuticals) whose clinical effectiveness still needs to be determined through better-conducted clinical trials. The following are highlights for opportunities for research in OA as put forward by various expert members on ACR and EULAR and authors: Clinical predictors of response to pharmacological and non-pharmacological interventions need to be determined. Determine the long-term effects, efficacy and safety of COX-2 inhibitor use. Investigate pooled/combination treatments, which reflect everyday clinical practice. Further investigate the difference between efficacy (trial data) and clinical effectiveness of many pharmacological treatments using validated and reliable outcomes measures that reflect disease activity, damage and quality of life. Investigate the efficacy of topical NSAIDS and conduct comparative trials. Development of disease modifying osteoarthritis drugs, such as local delivery of anti-inflammatory cytokines. Explore the effectiveness of alternative therapies in reducing symptoms of OA. Study the gastrointestinal safety of high-dose acetaminophen. Compare the effectiveness between paracetamol-acetaminophen and cox-2 inhibitors. Conduct pharmaco-economic studies to determine the cost effectiveness of OA therapy and its long term management. Evaluate the safety, effectiveness, and long term effects of SYADOA drugs. These studies bridge the range of research from basic science to Phase IV studies. 8. Gaps Between Current Research and Potential Research Issues that Could Make a Difference Most rheumatologists have suggested that osteoarthritis is often considered a silent disease, because although there is inflammation in the joint it occurs much less than in rheumatoid arthritis. Only when the patients develop pronounced inflammations are the symptoms of pain noticeable to the patient. Most experts in this field have articulated that this is particularly an area where research into new diagnostics, biomarkers and imaging technology is going to be important and useful for the management of OA. Biomarkers are an essential area of research in OA and arthritis as a whole, since it will help the medical community to determine: Who is likely to get arthritis? Severity and progression of disease Response to drugs and what types of drugs are effective Populations at risk of developing toxicity Complementary and alternative medicines are of great interest to consumer groups affected with OA. NOTEREF _Ref66004564 \f \h  \* MERGEFORMAT 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. 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. NOTEREF _Ref66010052 \f \h  \* MERGEFORMAT 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. NOTEREF _Ref66010052 \f \h  \* MERGEFORMAT 46 The following are areas that need research: NOTEREF _Ref65992257 \f \h  \* MERGEFORMAT 2,  NOTEREF _Ref65992279 \f \h  \* MERGEFORMAT 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. A number of other issues need to be resolved. NOTEREF _Ref66078813 \f \h  \* MERGEFORMAT 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, 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. 10. References     6.12: Osteoarthritis PAGE  6.12- PAGE 18 6.12: Osteoarthritis 6.12- PAGE 20   HYPERLINK http://www.arthritis.org/conditions http://www.arthritis.org/conditions. Arthritis Foundation. Accessed February 11, 2004.  Jordan KM, Arden NK, Doherty M, Bannwarth B, et al. 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