Osteoarthritis
June 1, 2013
Osteoarthritis
Authors: Terrence C. Tan, DO, Rheumatology Fellow, Loma Linda University, Loma Linda, CA
Shahim Zahara, MD, Medicine Resident, Loma Linda University, Loma Linda, CA
Keith K. Colburn, MD, FACP, FACR, Professor of Medicine, Chief of Rheumatology, Loma Linda University and Loma Linda VA Medical Center, Loma Linda, CA
Peer Reviewer: Robert A. Hawkins, MD, FACR, Associate Professor of Medicine, Wright State University, Dayton, OH; Associate Residency Program Director, Internal Medicine Residency Program, Kettering Medical Center, Kettering, OH
Osteoarthritis (OA) can be described as the failed repair of damage that has been caused by excessive mechanical stress (defined as force/unit area) on joint tissues.1 This implies that although multiple factors may lead to OA, mechanical impact (either as a major single event or as repetitive micro trauma) is central to all of these, and that the sequence of events that ensues represents the intrinsic repair process, which may either fail or be successful in restoring joint function. Also known as osteoarthrosis or degenerative joint disease, OA is the most important chronic musculoskeletal disorder in both humans and horses.
Although not a life-threatening disease, OA is considered one of the major concerns in human health care because of the vast number of people involved and the severe impact this literally crippling disease can have on quality of life. In the United States alone, total OA costs were estimated at $89.1 billion in 2001.2 A more recent article estimates that, compared with 2005, total hip replacements will have gone up by 673% in 2030 to a total of 3.5 million surgeries per year.3 In France, direct costs of OA exceeded $2 billion in 2002 and accounted for 13 million physician visits. That year’s figures represented a 156% increase in costs over 1993, which was because of an increase in the number of patients rather than the increase of costs per patient.4 In horses, articular disorders, most of which are related to osteoarthritic pain, account for the greatest single economic loss to the equine industry, and likewise form a major animal welfare concern.5
Contribution of Osteoarthritis to Functional Limitations and Disability
It is widely stated that arthritis is the leading cause of disability among adults.6-14 Indeed, there is no question that OA in particular is related to disability as adults age. The risk of OA increases with age, so that by the age of 80 years, radiographic evidence of joint degeneration is found in nearly everyone. However, much remains unknown about the specific contributions of osteoarthritis and intervening variables to the development of disability. As people age, a larger proportion of disability occurs along a slower, progressive course compared with a more rapid onset, “catastrophic disability.”15
Research supports the classification of OA as one example of a condition that is characterized by the slow progression of disability.16-19 OA pathology results in the degeneration of cartilage, bone, and soft tissues integral to joints; most commonly the hand, knee, hip, spine, and foot. Discordance between OA pathology and resultant disability highlight opportunities to identify modifiable factors in the pathway from pathology to disability. Although OA is associated with joint-related symptoms such as pain and stiffness, there is wide variation in symptoms for those with radiographic evidence of joint degeneration changes, and many with radiographic changes report no pain.20 Studies of OA and disability use a range of definitions for OA and for disability, which presents challenges to summarizing and interpreting the literature. Often, diagnosis of OA is made based on radiographic signs and joint symptoms; however, the former is considered to be associated with later stages of disease.
Pathogenesis
One of the main mechanisms for the development of OA is damage to the articular cartilage by trauma, which in turn causes chrondrocytes to release degradative enzymes leading to abnormal repair of the matrix.21-24 This in turn causes the subsequent development of OA. Cartilage from osteoarthritic joints is thought to deform more easily compared to normal joint tissue in response to the same mechanical load.25 This changes the perception of normal mechanical load into a larger load of longer duration.26
Chondrocytes maintain homeostasis of the articular cartilage by synthesizing collagens, proteoglycans, and proteinases. OA develops when there is failure of these chondrocytes to maintain this homeostasis between synthesis and degradation.
Most of the time, this homeostasis is disturbed by alteration in the differentiation of chondrocytes. For example, hypertrophied chondrocytes will have abnormal matrix repair secondary to increased collagen II and aggrecan, increased expression of collagen X, upregulation of matrix metalloproteinase 13, and promotion of calcification. Chondrocyte dedifferentiation can also occur when types I, III, and IV collagen are present in higher amounts than normal. These types of collagen are not normally seen in adult cartilage.
There is also an increase in the degradation of the matrix secondary to increased production of proteinases due to tissue activation by cytokines, prostaglandins, nitric oxide, peroxide, and fibronectin fragments. Inflammation is further produced by synovial cells ingesting fragments of cartilage which are released into the joint causing these cells to release metalloproteinases, cytokines, and other inflammatory mediators activating chondrocytes.
Osteoblasts also play a role in the formation of OA. These osteoblasts in OA patients produce more alkaline phosphatase, osteocalcin, insulin-like growth factor, and urokinase in comparison to normal osteoblasts leading to degradation of the cartilage matrix.
The main proteases involved in OA are the metalloproteases which are active in the degradation of cartilage. The three main metalloproteases are the collagenase, stromelysin, and gelatinase usually limited by tissue inhibitors of metalloproteases. The balance of these proteases is altered in OA, which in turn leads to cartilage destruction. Collagenases will cleave both type II and type X cartilage by activating interleukin-1 (IL-1) produced by chondrocytes.27,28 The main collagenases are thought to be collagenase-1 (MMP-1), collagensae-2 (MMP-8), and collagenae-3 (MMP-13). Stromelysin degrades collagen byproducts and type IX collagen.29 These proteases are found in increased numbers in osteoarthritic knees. Gelatinase is known to cleave type 1 cartilage.
Certain cytokines such as IL-1, tumor necrosis factor alpha, insulin-like growth factor, transforming growth factor-beta, and interleukin-6 were shown to play a role in OA. IL-1 is involved in cartilage degradation. It is shown to decrease the synthesis of type 1 cartilage, induce stromelysin and collagenase, and also suppress prostaglandin synthesis. Studies show there is an increased level of IL-1 in the joints of patients with knee OA vs those without OA. Tumor necrosis factor alpha has a role in osteoarthritis with similar effects as IL-1, and is increased in the joints of OA patients.30 Insulin-like growth factor increases cartilage and matrix synthesis, and is decreased in the joints of OA patients. Another cytokine known to maintain cartilage, called transforming growth factor-beta, is found in low levels in osteoarthritic joints.31 Interleukin-6 has a complex role in OA and more studies need to be done to confirm its role in the breakdown of cartilage. This cytokine, which is a modulator in cartilage remodeling and degradation, was shown to be increased in osteoarthritic joints, to increase TNF receptors (which causes breakdown of cartilage), and to increase the production of tissue metalloproteinase-1 (which inhibits breakdown of cartilage).
Nitric oxide also plays a role in the pathogenesis of OA. In OA patients, nitric oxide is produced in the joints in large amounts. Nitric oxide is partly responsible for blocking glycosaminoglycan and collagen synthesis by IL-1and activating metalloproteinases. Data suggested that the risk of OA progression increased three-fold in patients with low vitamin D intake.32 However, low intake and serum levels of vitamin D did not increase the risk for developing OA.
Etiology, Incidence, and Risk Factors
OA is a normal result of aging.33 It is also caused by “wear and tear” on a joint. Cartilage is the firm, rubbery tissue that cushions the bones at the joints, and allows bones to glide over one another. If the cartilage breaks down and wears away, the bones rub together. This causes pain, swelling, and stiffness. Bony spurs or extra bone may form around the joint. The ligaments and muscles around the joint become weaker and stiffer.
OA symptoms usually appear in middle age. Almost everyone has some symptoms by age 70. However, these symptoms may be minor. Before age 55, OA occurs equally in men and women. After age 55, it is more common in women.33 Often, the cause of OA is unknown. It is mainly related to aging.
Other factors can also lead to OA. OA tends to run in families. Being overweight increases the risk of OA in the hip, knee, ankle, and foot joints because extra weight causes more wear and tear. Fractures or other joint injuries can lead to OA later in life. This includes injuries to the cartilage and ligaments in joints. Jobs involving kneeling or squatting for more than an hour a day have the highest risk of the development of OA. Jobs that involve lifting, climbing stairs, or walking increase the risk of this disease. Playing sports that involve direct impact on the joint (such as football), twisting (such as basketball or soccer), or throwing also increase the risk of OA.
Medical conditions such as hemophilia can also lead to OA because of bleeding in the joint. Disorders that block the blood supply near a joint lead to avascular necrosis. Other types of arthritis, such as chronic gout, pseudogout, or rheumatoid arthritis lead to “secondary” OA. Certain systemic diseases also are associated with the development of secondary OA, including Wilson’s disease and hemochromatosis. As an example, hemochromatosis may cause chondrocalcinosis with secondary OA in many joints, especially with a predilection for the second and third metacarpophalangeal joints. OA of non-weight-bearing joints is almost always the result of “secondary” OA with the exception of some hand joints.
Classification of Osteoarthritis
First, there is idiopathic OA which is further divided into localized or generalized forms of the disease. Localized OA most commonly affects the hands, feet, knee, hip, and spine. Generalized OA consists of involvement of three or more joint sites. In secondary OA, specific conditions may cause or enhance the risk of developing OA as mentioned above. Secondary OA may also result from trauma, congenital or developmental disorders, septic arthritis, Paget disease of bone, and other diseases such as diabetes mellitus, acromegaly, hypothyroidism, or neuropathic (Charcot) arthropathy.
Clinical Manifestations
The cervical and lumbar spine is commonly affected. Spinal involvement in OA is most common at C5, T8, and L3, which represent the areas of greatest spinal flexibility. Two syndromes of clinical importance are due to OA of the lumbar apophyseal joints.34 In the cervical spine, osteophytes arising from the margins of a vertebral body (cervical spondylosis) may compromise the spinal canal. When sufficiently advanced, cervical spinal cord compression may result. Uncovertebral osteophytes can compromise the neural foramen and impinge on the exiting nerve root. Lumbar apophyseal osteophytes (lumbar spondylosis) can cause spinal stenosis if they encroach into the intervertebral foramina and/or the spinal canal. The resultant symptoms of low back pain radiating to the lower extremity worsens with exertion, thereby mimicking vascular claudication, but resolves more rapidly with rest. Spondylolisthesis, a slipping of one vertebral body on another, typically affecting the apophyseal joints at L4 to L5, may occur with severe OA. Diffuse idiopathic skeletal hyperostosis (DISH) is a syndrome of inappropriate bone formation at the insertions and along the course of ligaments and tendons. Although osteoarthritis is frequently present in patients with the DISH syndrome, the latter is thought to represent a distinct clinical entity.
Hands: Osteoarthritic enlargements of the distal and proximal interphalangeal joints are referred to as Heberden’s and Bouchard’s node, respectively. The first carpometacarpal joint is also a common area affected by OA. Enlargement of this joint causes a squared appearance to the hand.
Hip: Pain around the hip is common in patients with OA. It may be due to OA of the hip or to pain referred to the hip area from other structures, such as the lumbosacral spine. Similarly, OA of the hip may result in pain that is referred to distant structures (such as the knee).34 Another potential diagnostic problem is that patients frequently confuse the pain of greater trochanteric bursitis with OA of the hip. The pain from bursitis is felt laterally and does not limit motion; by comparison, OA of the hip is associated with pain in the groin and upper posterior buttock with limited range of motion.
Knee: Osteophytes, effusions, crepitus, and limitation of range of motion are all common signs of OA of the knee. However, findings on physical examination alone may underestimate the degree of knee involvement. In advanced cases, malalignment may be apparent (genu varus or genu valgus), particularly when medial and lateral compartments are affected unequally. Cartilage loss due to OA usually begins in the medial aspect of the tibiofemoral joint; as a result, varus angulation (“bow-legged”) occurs more commonly than valgus (“knock-kneed”). Femorotibial malalignment may be a risk factor for more rapid progression of OA of the knee. A fluctuant swelling along the posterior aspect of the knee, or popliteal (Baker’s) cyst, is a common complication. Involvement of the patellofemoral portions of the joint may be affected by malalignment. Among patients with established radiographic OA of the knee, genu varus and genu valgus are associated with more rapid progression of medial and lateral patellofemoral OA, respectively.34
Feet: The first metatarsophalangeal joint often is affected by OA, resulting in hallux valgus or hallux rigidus. Involvement of the subtalar joint may be particularly troublesome during ambulation; pain is often elicited by inversion and eversion of the foot.34
Uncommonly affected joints: Shoulder OA is almost always secondary OA, and results in varied clinical manifestations range from mild discomfort to destruction. Symptoms of a diseased glenohumeral joint typically include anterior shoulder pain that gradually worsens over years that is aggravated by movement. Involvement of the acromioclavicular joint may cause vague shoulder pain, which may present a diagnostic dilemma. Osteophytes located along the undersurface of the acromioclavicular joint may result in rotator cuff tendonitis or tears due to the juxtaposition of tendons with the inferior portion of the acromioclavicular joint. The shoulder may rapidly deteriorate because of an aggressive form of OA that occurs in association with calcium crystalline disease.34 The wrist and elbow may also be affected.
Symptoms
Pain is the principal symptom associated with OA, typically exacerbated by activity and relieved by rest. With more advanced disease, pain may be felt with progressively less activity, eventually occurring at rest and at night. Episodic increases in pain and inflammation suggest synovitis caused by crystalline disease or trauma. Some patients ascribe fluctuating symptoms to changes in the weather, but the evidence for effects of varying barometric pressure, precipitation, and outdoor temperature is conflicting. Pain in OA is not caused directly by cartilage damage since cartilage is aneural. As a result, osteoarthritic radiologic changes are often incidentally noted in patients without symptoms at affected sites. For the perception of pain, two general conditions need to be met. First, a pain stimulus must be generated, and second this stimulus must be detected, transduced, and transmitted by the nervous system to the brain where pain perception can take place. Two general types of pain stimuli in synovial joints can be distinguished: mechanical stimuli, generated by mechanical changes in the environment of the joint (i.e., by direct trauma) and chemical stimuli resulting from tissue inflammation. These stimuli are detected and forwarded by different types of receptors, referred to as mechanoreceptors, and nocioceptors, the distribution and relative abundance of which differ in various joint tissues. The signal is then carried by Aδ or C-nociceptive nerve fibers in peripheral nerves to the dorsal horn of the spinal cord, where neuromodulators and neurotransmitters are located within synapses between primary and secondary neurons. The latter decussate within the spinal cord and travel to the brain where the signal is further processed, modulated, and finally perceived.35 Stiffness is also a common complaint in patients with OA. Morning stiffness typically resolves in less than 30 minutes after a patient awakens, but may recur following periods of inactivity.
Findings on Physical Examination
Crepitus is a common finding and is probably due to the disruption of the normally smooth articulating surfaces of the joints. Bony enlargement and osteophytes may be palpable as nodules along the periphery of the joint. Tenderness to palpation of involved joints may be evident with or, more often, without associated signs of inflammation. There may also be decreased range of motion and joint malalignment.
Differential Diagnosis:
- Calcium pyrophosphate crystal deposition disease (CPPD disease) — Osteoarthritis of non-weight bearing joints except distal interphalangeal joint and proximal interphalangeal joints of hands is most frequently CPPD disease. Involvement of the second and third metacarpophalangeal (MCP) joints of hands with OA and the presence of chondrocalcinosis on x-rays of especially knees, the triangular cartilage of the wrist, hips, shoulders, symphasis pubis, and MCPs is frequently due to CPPD disease.
- Rheumatoid arthritis — Unlike OA, rheumatoid arthritis is primarily an inflammatory joint disease with symmetrical joint involvement, and x-ray findings of marginal erosions of joints and juxta-articular osteoporosis. It is a systemic disease involing more organ systems than just joints.
- Infectious monoarticular disease — every time only one joint is inflamed it must have arthrocentesis performed to rule out infection.
- Most other forms of arthritis — can end up with OA as the final common pathway for each disease.
Diagnosis: Clinical diagnosis of OA should be entertained in a patient who presents with joint pain. An essential component to the diagnosis is the correct attribution of signs and symptoms to the affected site. As an example, pain and other symptoms resulting from OA can be confused with soft tissue processes such as bursitis at periarticular sites. Additionally, pain in a particular area may be referred from OA at other sites or may be due to a nonarticular process.
Pain and other symptoms of OA can be confused with soft tissue processes like bursitis at periarticular sites. Pain in a particular area may be referred from OA at other site or may be due to a nonarticular process. Thus, an important first step in management is to be reasonably certain that pain in a particular joint is indeed due to OA at that site.
A nonspecific complaint of joint pain may be due to a wide range of disorders. Such patients should undergo a complete history and physical examination and, if clinically indicated, radiographic examination of affected joints in combination with selected tests:
- Erythrocyte sedimentation rate or a C-reactive protein
- Rheumatoid factor titers
- Anti-cyclic citrulinated peptide antibody
- Uric acid
- Microscopic evaluation of the synovial fluid
Certain clinical features are more suggestive of idiopathic OA than other disorders. As an example, OA does not affect all joints equally; it has a predilection for the fingers, knees, hips, and spine, and rarely affects the elbow, wrist, and ankle. If the atypical joints are involved in a patient suspected of having OA, the clinician should initiate a search for secondary causes of the disorder. The joints are usually asymmetrically involved in OA (particularly the large joints), and a synovial effusion, if present, most commonly has mild inflammatory characteristics (i.e., synovial WBC < 2000/mm3).
However, the disorder has no absolutely specific characteristics. Radiographic findings may be misleading and disproportionately severe when compared to the findings on clinical examination. As a result, the diagnosis of idiopathic OA is not made based upon a few specific findings, but upon a constellation of clinical, historical, and laboratory features.
Joint effusions may be present. The synovial fluid analysis might show a clear fluid, WBC < 2000/mm3 and normal viscosity.
Imaging: Imaging can assist in making a diagnosis of OA by refuting other diagnoses when the clinical picture from history and physical examination leaves this diagnosis unclear.36 However, the diagnosis is a clinical one made by assessing the constellation of presenting clinical features. Currently, there is an overuse of inappropriate imaging to make a diagnosis that can be made clinically. In light of the current lack of therapy that can modify the disease course and measurement imprecision, there is currently no rationale for obtaining serial radiographs if the clinical state remains unchanged. Plain radiographs are helpful in assessing for the presence and severity of OA. Radiographic changes in OA are insensitive, particularly with early disease, and correlate poorly with symptoms. When present, however, the specificity of the radiographic changes of OA often renders further diagnostic imaging unnecessary. The major radiographic features of OA include:
- Joint space narrowing
- Subchondral sclerosis
- Osteophytes
- Subchondral cysts
The clinical relevance of each radiographic finding in OA appears to vary by joint. Minimal joint space of the hip is most closely correlated with hip pain while osteophytes arising from the patellofemoral and tibiofemoral joints of the knee correlate best with knee pain. Knee joint space narrowing best predicts disease progression.
Magnetic Resonance Imaging (MRI): is not necessary for most patients with suggestive symptoms of OA and/or typical plain radiographic features. Magnetic resonance imaging is used primarily in a research setting but may have some clinical value in assessing for cartilage defects and bone marrow “edema.” However, MRI of the knee has a diagnostic role in patients with joint pain and symptoms such as locking, popping, or instability that suggest meniscal or ligamentous damage. MRI should only be used in infrequent circumstances to facilitate the diagnosis of other causes of knee pain that can be confused with osteoarthritis (e.g., osteochondritis dissecans, avascular necrosis, etc.). The presence of a meniscal tear viewed by MRI in a person with knee osteoarthritis is not necessarily a cause of increased symptoms.36 The presence of two MRI findings concomitantly correlates with painful OA of the knee; partial or full-thickness cartilage defects, and bone marrow “edema” as indicated by decreased T1 and increased T2 signal from the subchondral bone. In contrast, marrow edema alone does not appear to be closely associated with knee pain in patients with generalized osteoarthritis.
Patterns of Joint Involvement: OA can be monoarticular in young adults and pauciarticular, affecting large joints in middle-aged individuals. OA can also be polyarticular and generalized. The specific set of joints involved in a given patient with OA tends to conform to one of several recognized clinical patterns. It is unknown whether these subsets, each with unique clinical features, reflect the alterations of a common disease process or are alternative syndromes with similarities of expression.34
- The occurrence of monoarticular osteoarthritis in a young adult is often secondary to a congenital abnormality or previous trauma.37
- A pauciarticular form of OA is common in middle age and usually affects the large, weight-bearing joints of the lower extremities.
- Polyarticular or generalized OA is the most common form, typically affecting middle-aged or elderly women. The presence of Heberden’s and Bouchard’s nodes (hereditary or nodal OA) and involvement of the first carpometacarpal joint are common in these patients. The knees, hips, metatarsophalangeal joints, and spine may also be involved.38
- The onset of the arthritis may be heralded by an initial, inflammatory phase. Erosive, inflammatory OA is a variant of this polyarticular form that follows a more aggressive course and frequently results in joint deformities.
Management of Osteoarthritis
The management goals for patients with osteoarthritis include patient education about the disease and its therapy, pain control, improving function, and decreasing disability so as to alter the disease process and its consequences. Optimal management of OA requires a combination of nonpharmacological and pharmacological modalities.
Nonpharmacologic Therapy
Nonpharmacologic therapies for OA of the knee for which there is reasonably strong evidence of efficacy include exercise programs, weight loss, and patient education. Nonpharmacologic interventions, other than surgical approaches, are generally begun before medications.
Lifestyle Changes:
1. Exercise. A pivotal and frequently ignored aspect of conservative treatment of OA is exercise.39-41 Exercise increases aerobic capacity, muscle strength, and endurance, and also facilitates weight loss.42,43 All individuals capable of exercise should be encouraged to partake in a low-impact aerobic exercise program (walking, biking, swimming, or other aquatic exercise). Quadriceps strengthening exercises have been demonstrated to lead to improvements in knee pain and function.44-46 Guidelines routinely advocate exercise;33,47-51 however, clinical practice does not often reflect this recommendation.39-41 Staying active and getting exercise helps maintain joint and overall movement. Water exercises, such as swimming, are especially helpful. Low load effect exercise, warm-up, and stretching prior to exercise, and use of splints for joint immobilization can be of benefit for joint protection and reduction in symptoms. Multiple factors should be considered in designing details of exercise regiments for patients with OA, including the pattern of joint involvement, presence or absence of inflammation, muscle condition, range of motion, exercise capacity, and comorbid medical conditions. All exercise programs include range of motion and isometric strengthening. For patients with active joint inflammation, advanced disease, or profound functional impairment, these interventions may be the highest level of exercise that can initially be safely achieved. Patients with less severe or more quiescent disease may progress sequentially through isotonic strengthening, aerobic exercises, and, ultimately, recreational exercise. Low impact exercises to avoid excessive joint loading are preferable for patients with OA. Aquatic exercises are of particular benefit for those with severe arthritis and/or marked deconditioning.
2. Other lifestyle recommendations: Obesity management and weight loss if overweight are extremely important. The majority of patients with OA are either overweight or obese. There is good evidence for the efficacy of weight management,42 which is advocated by most OA guidelines. However, in practice, weight management is not frequently implemented.39-41 In patients with OA who are overweight, weight loss of even modest degree may produce improvement in lower extremity joint pain and function. Other methods of unloading an osteoarthritic joint include canes and walkers, which can reduce joint forces at the hip by as much as 50%. A trial of soft, elastic heeled sports shoes or the use of insoles for patients with knee OA diminishes impact loading. Moist, superficial heat can raise the threshold for pain, produce analgesia by acting on free nerve endings and decrease muscle spasm.52-54 Ultrasound therapy appears to have no proven benefit in treating OA. Superficial cooling decreases muscle spasm and increases the threshold of pain. Data concerning the efficacy of transcutaneous electrical nerve stimulation (TENS) in patients with OA are conflicting.55-57 Eating a healthy, balanced diet is important. Vitamin D supplementation is indicated in patients at high risk for osteoporosis, such as postmenopausal women. Resting affected joints may alleviate pain. Rest is recommended for only short periods of time, typically 12-24 hours for acute pain and inflammation, because prolonged rest may lead to muscle atrophy and decreased joint mobility. Protecting joints may include the use of braces and splints for symptomatic relief for OA of certain joints such as the knee58 and OA of the carpometacarpal and interphalangeal joints of the thumb.59 Therapeutic arthrocentesis of the knee for pain in the patellofemoral syndrome is controversial, but may be useful for OA of the knee.60 As the pain from OA becomes worse, keeping up with everyday activities may become more difficult or painful. Making changes around the home, such as side bars in bathtubs and showers, may take some stress off of joints and relieve some pain. If work is causing stress in certain joints, it may be necessary to adjust the work area or change work tasks.
Physical Therapy:
Physical therapy can help improve muscle strength and the motion of stiff joints, as well as sense of balance. Therapists have many techniques for treating OA. Physical therapy and exercise improves functional outcome and pain in OA by improving flexibility and by strengthening muscles that support the affected joints.61 An appropriate exercise program can safely reverse deficiencies in gait, strength, flexibility, aerobic power, and exercise capacity. Compliance with exercise programs varies dramatically according to the regimen selected and the setting, but can be maximized through the use of supervised rather than home exercise programs.
Management of Joint Pain:
Pain is the most salient clinical feature of OA and has the biggest impact on both the welfare and performance of patients. Pain management is therefore of great importance when managing osteoarthritis. However, it should be realized that treatment aimed at pain reduction does not necessarily treat the underlying primary disease process and may even interfere negatively with it. In fact, it has been suggested that long-term use of nonsteroidal anti-inflammatory drugs might enhance the pathologic process of cartilage degeneration by removing the regulatory role of PGE2 on IL-1 synthesis.62 On the other hand, treatment aimed primarily at pain relief may, through anti-inflammatory actions, also positively affect the articular cartilage by means of inhibition of release of catabolic factors.63 Chronic pain attributable to OA is most frequently managed pharmacologically. Other ways of modulating joint pain are also available and may prove efficacious.
Systemic Treatment of Joint Pain:
The goals of management of OA patients with are to control pain and swelling, minimize disability, improve the quality of life, and educate the patient about his or her role in the management team. Management should be individualized to the patient’s expectations, level of function and activity; to the joints involved; to the severity of the patient’s disease; to occupational and vocational needs; and to the nature of any coexisting medical problems. Subjective complaints and objective findings may guide the clinician in designing appropriate therapeutic goals. There are, at present, no specific pharmacologic therapies that can prevent the progression of joint damage due to OA. The goal of finding disease modifying agents for OA that can prevent radiographic joint space narrowing, indicative of progressive articular cartilage loss is being addressed through ongoing research.
Analgesics: Pain relief is the primary indication for the use of pharmacologic agents in patients with OA who do not respond to nonpharmacologic interventions. In patients with noninflammatory OA, this goal is generally achieved by the administration of a non-opioid, simple analgesic.
Acetaminophen: At doses of up to 3 g/day, acetaminophen is the drug of choice for pain relief in this setting.64,65 Clinical trials found evidence that acetaminophen is superior to placebo, but less effective in relieving pain due to OA of the hip or knee than nonsteroidal anti-inflammatory drugs (NSAIDs).66 Adverse effects of therapeutic doses of acetaminophen are seldom seen. Hepatotoxicity can occur but, at these doses, is primarily seen only in patients who concurrently consume excessive amounts of alcohol. Acetaminophen in doses of 2 g/day or greater can increase the risk for gastrointestinal (GI) complications, including bleeding and perforation, but these complications are not increased at lower acetaminophen doses. Additionally, the risk of GI complications is greater with the combination of acetaminophen and an NSAID than with either alone.67 There is suggestive but not definitive evidence that chronic, especially daily, acetaminophen use has dose-dependent, long-term nephrotoxicity.33
Tramadol: Tramadol alone or in combination with acetaminophen may also be useful when added to ongoing treatment with an NSAID or COX-2 inhibitor.68
Opioid analgesics: Opioid analgesics may be beneficial for short-term use in patients with acute exacerbations of pain. In a controlled study, a long acting narcotic, oxycodone, was synergistic with NSAIDs for reducing pain in patients with OA.69 Many patients with OA are ≥ 65 years of age and some are much older. In the geriatric population, the use of opioid analgesics is discouraged due to increased sensitivity to adverse side effects, particularly sedation, confusion, and constipation, except the use in these populations with cancer pain. Arguments have also been made for the use of opioids in patients who are not candidates for surgery and who continue to have moderate to severe pain despite being administered NSAIDs or selective cyclooxygenase (COX-2) inhibitors.70 Opioids may also be considered for patients who are at high risk for adverse effects of both selective COX-2 inhibitors and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs).65,71
NSAIDs: NSAIDs are by far the most important class of compounds in this category. NSAIDs may be indicated in patients with noninflammatory OA who fail to respond to acetaminophen or for those with moderate to severe pain. The majority of experience is with oral administration of NSAIDs, and topical preparations are available as well. NSAIDs should be given prior to oral analgesics in patients with inflammatory OA who do not respond to nonpharmacologic interventions. The demonstration of superinduction of prostaglandin E2 in human OA cartilage suggests that PGE2 may contribute to the local inflammation72,73 and provides a specific rationale for the use of NSAIDs in inflammatory OA.
Oral NSAIDs: NSAIDs are effective pain relievers in OA patients.74 The efficacy of acetaminophen has also been demonstrated to be superior to placebo in relief of pain due to OA, but is less effective than NSAIDs. Many different NSAIDs can be used in patients with symptomatic OA, including over-the-counter agents (aspirin, ibuprofen, and naproxen) and prescription drugs. There is immense variability in patients’ responses to the different agents in terms of both efficacy and toxicity.75
- Low dose ibuprofen (< 1600 mg/day) may have less serious gastrointestinal side effects.76
- Nonacetylated salicylates (salsalate, choline magnesium trisalicylate), sulindac, and perhaps nabumetone appear to have less renal toxicity.
- The nonacetylated salicylates and nabumetone have less antiplatelet activity.77
- Indomethacin should probably be avoided for long-term use in patients with hip OA since it may be associated with accelerated joint destruction in this setting.78
- The selective cyclooxygenase-2 (COX-2) inhibitors (e.g., celecoxib and etoricoxib) appear to be as effective as the traditional nonspecific NSAIDs. Although they are associated with less gastroduodenal toxicity, concerns about an increased risk of cardiovascular adverse events has limited their use. Furthermore, the concomitant use of low dose aspirin for an antithrombotic effect may negate the gastroduodenal sparing effects of COX-2 inhibitors.79
- Patients at increased risk of gastroduodenal damage who are receiving low-dose aspirin and a COX-2 selective agent may benefit from anti-ulcer prophylaxis.
Topical NSAIDs: The topical application of NSAIDs may reduce the risk of side effects that are seen with oral use. Topical NSAIDs, such as aspirin and diclofenac, are available as well.
COX-2 inhibitors: These drugs have at least a 200- to 300-fold selectivity for inhibition of COX-2 over COX-1. However, two selective COX-2 inhibitors, rofecoxib and valdecoxib, were withdrawn from the worldwide market because of an increased risk of serious cardiovascular adverse events associated with their use. Increased cardiovascular risks preclude use of coxibs unless the GI risk is very high and the cardiovascular risk is low (e.g., there are no known cardiovascular disease and absence of multiple cardiovascular risk factors). Some NSAID therapy is considered unavoidable, and the patient should be informed of the potential benefits and risks of coxib use. As an example, selective COX-2 inhibitors are an option for patients at low cardiovascular risk who have a history of peptic ulcer, GI bleeding, or GI intolerance to NSAIDs (including salicylates) and whose joint pain is inadequately controlled using acetaminophen. An alternative approach is the use of a nonselective NSAID and a gastroprotective agent such as a proton pump inhibitor or misoprostol. Selective COX-2 inhibitors are not effective as prophylactic therapy for ulcers. Thus, in patients with a history of peptic ulcer disease that was unrelated to NSAID use, continued use of effective antiulcer agents, such as a proton pump inhibitor, may be necessary. NSAIDs should not be used in combination because of the greater risk of adverse events and the lack of evidence that the use of two or more NSAIDs is associated with improved efficacy. NSAIDs should be avoided in patients with aspirin sensitivity. The selective COX-2 inhibitor, celecoxib, may be less likely to provoke symptoms in aspirin sensitive reactive airways disease.64
Choice of NSAID: There is no convincing evidence that any of the available NSAIDs is more effective than any other for osteoarthritis of the knee or hip.80,81 Thus, the choice of a NSAID is based upon a variety of other factors including adverse effect profile, cost, type of OA, and frequency of dosage. It is preferable to use an NSAID on a periodic basis in patients with noninflammatory OA since the presence and intensity of symptoms usually vary with time. A short-acting agent is ideal in this setting.64 Continuous therapy is indicated if this regimen does not provide adequate symptom control. Because of the pathophysiology, continuous NSAID therapy works better in patients with inflammatory osteoarthritis.
Factors to be considered when selecting from the available NSAIDs and COX-2 selective agents:
- When NSAID use is considered, the patient should be informed of the potential cardiovascular risk.
- If there is a history of gastroduodenal disease, a selective COX-2 inhibitor may be considered in patients at low cardiovascular risk or a nonselective NSAID can be combined with anti-ulcer prophylaxis.
- A short-acting NSAID is generally used initially. It usually takes about 2-4 weeks to evaluate the efficacy of a NSAID.75
- If there is inadequate control with the initial dose, then the dose should be gradually increased toward the maximum for that drug. The patient’s renal, liver, and bone marrow function should be monitored more closely as the dose is increased. The patient should be educated to monitor for symptoms indicative of side effects mentioned in this article.
- If one NSAID is not effective after 2-4 weeks on a maximal dosage, then another NSAID or nonacetylated salicylate could be tried.
Intraarticular Glucocorticoid Injections: Intra-articular glucocorticoids were first used in human medicine in the early 1950s.82 Glucocorticoids inhibit inflammatory mediator production by inhibiting phospholipase A2 through the production of anti-phospholipase proteins called lipocortins.83 Because of their mode of action upstream in the arachidonic acid cascade, glucocorticoids not only inhibit COX-1/2 derived mediators (including prostaglandins, thromboxanes, and lipoxins), but also the LOX-derived mediators like leukotrienes. Glucocorticoids are primarily potent anti-inflammatory agents, exerting their analgesic action indirectly via the suppression of inflammation. Intraarticular glucocorticoid injections may be appropriate in patients with OA who have one or a few joints that are painful despite the use of an NSAID, and in patients with monoarticular or pauciarticular inflammatory osteoarthritis in whom NSAIDs are contraindicated.84 Intraarticular glucocorticoid injections are effective for short-term pain relief and can increase quadriceps strength after knee injection.85 Intra-articular glucocorticoids injected in the hip is a technically difficult procedure that generally requires fluoroscopic guidance under the direction of a rheumatologist, orthopedist, or radiologist.64 A trial of fluoroscopically guided glucocorticoid injection for osteoarthritis of the hip demonstrated benefits lasting up to 3 months in many cases.86 Synovial fluid, if aspirated, should be sent for cell count, Gram stain, and culture if an infection is suspected. The joint should not be injected with a corticosteroid until there is certainty that an infection is not present.87 Clinical findings suggestive of possible joint infection include fever, leukocytosis, or the rapid onset of a large effusion. Glucocorticoids formulated for intraarticular injection are in crystalline suspension. Steroid crystals rarely may lead to a transient mild flare of synovitis. Common synthetic glucocorticoid suspensions used for intraarticular injection include triamcinolone acetonide, triamcinolone hexacetonide, and microcrystalline methylprednisolone. The amount of these agents generally used depends upon joint size:
- 10 mg for small joints (interphalangeal, metacarpophalangeal, and metatarsophalangeal joints)
- 20 mg for medium-sized joints (wrists, elbows, ankles, and acromioclavicular joints)
- 40 mg for larger joints (shoulders, knees, hips).
Intraarticular Hyaluronans: Hyaluronic acid (HA), also called hyaluronan, is a large unsulphated glycosaminoglycan that consists of repeating units of D-gluronic acid and N-acetylglucosamine. It has been used extensively as an intraarticular (IA) treatment in horses88 initially as visco-supplementation, but later on the basis of its anti-inflammatory capacities.89 Although HA is supposed to treat the primary disease process not to provide analgesia, as is the case with corticosteroids or NSAIDs, it reportedly also has some analgesic effect itself.90 In humans, there are various reports on the analgesic effects of HA in OA but publication bias and flaws in experimental design may have overestimated the beneficial effects in many studies. A meta-analysis showed only a relatively small positive effect of HA application compared with placebo.91 In the horse, there are various studies reporting reduction of lameness following IA HA treatment, but many of these suffer from flaws in the experimental design, such as lack of randomization and blinding, and absence of a control group or use of an inappropriate control group.92 A well-controlled study comparing the effects of IA polysulphated glycosaminoglycans and IA HA in an osteochondral chip model showed positive effects of HA at the tissue level, but failed to substantiate any clinical effect.93 The combination of IA corticosteroids and HA is popular in equine practice, as it permits the reduction of the dose of corticosteroids and, at least intuitively, may counteract the possible deleterious effects of these drugs on the cartilage either through such dose reduction and/or through a possible “chondroprotective” action of HA.88 Unfortunately, no controlled trials have been reported to date that compare the clinical (analgesic) efficacy and cartilage matrix effects of IA HA, IA steroids, and IA steroid plus HA. Although it can indeed be assumed that the combination will have a substantial analgesic effect, in vitro studies so far have not provided support for the premise that HA might counteract potentially negative steroid effects on the articular cartilage.94,95
There may be subpopulations of patients with osteoarthritis that respond well to this type of therapy. Commercial hyaluronan preparations currently are available in the United States include sodium hyaluronate.
Glucosamine and Chondroitin: The use of glucosamine and chondroitin for OA has been controversial, and results of randomized trials have varied.96-110 The balance of evidence from high-quality trials has shown little to no evidence of clinically meaningful benefit.96-98
Colchicine: The basis for the use of colchicine in inflammatory OA that is refractory to NSAIDs and/or intraarticular glucocorticoids is that the majority of such patients have evidence of calcium pyrophosphate dihydrate crystals.111 Inflammation is attenuated by colchicine via microcrystal-induced tyrosine phosphorylation.112 Adding colchicine to ongoing NSAID therapy may produce an additional benefit. This was illustrated in a small study in which 36 patients with OA of the knee were randomly assigned to receive nimesulide plus colchicine (0.5 mg twice daily) or nimesulide plus placebo.113 Significantly more patients receiving the NSAID plus colchicine combination had at least 30% improvement in osteoarthritis scores (57.9% vs 23.5%, respectively). In view of these findings, it may be reasonable to use prophylactic colchicine (0.6 mg twice daily) in patients with OA if the patient has frequent acute inflammatory episodes that do not respond well to NSAIDs, intraarticular steroid injections, and/or joint irrigation. Chronic colchicine therapy is generally safe in patients who do not have underlying hepatic or renal disease.
Anti-Malarial Drugs: Hydroxychloroquine has been used infrequently in patients with inflammatory or erosive OA. One report retrospectively reviewed charts of patients with erosive OA who were treated with hydroxychloroquine because of symptoms that were unresponsive to NSAIDs. Hydroxychloroquine was felt to be effective in six of eight patients.114 Prospective, randomized, double-blind studies of large numbers of patients are needed in order to confirm these initial observations.
Pharmacologic and nonpharmacologic modalities commonly used to manage individual joints such as knee, hip, and hand OA
Surgery
Severe cases of OA often need surgery to replace or repair damaged joints. The typical indications for surgery are debilitating pain and major limitation of functions, such as walking, working, or sleeping not controlled by other means.115
Surgical options include:
- Arthroscopic surgery to trim torn and damaged cartilage, the most common orthopedic surgery performed on the knee has no demonstrable efficacy.116 Arthroscopic debridement and meniscal resection remains the most frequently performed procedure by orthopedic surgeons in the United States.117,118
- Changing the alignment of a bone to relieve stress on the bone or joint (osteotomy)
- Surgical fusion of bones, usually in the spine (arthrodesis)
- Total or partial replacement of the damaged joint with an artificial knee, hip, shoulder, first carpometacarpal, ankle, or elbow joint are regularly done. The development of modern total hip arthroplasty in the 1960s by John Charnley, a British surgeon, represents a milestone in orthopedic surgery and was the most important treatment advancement in arthritis therapy throughout most of the 20th Century. Currently, the most common indication for knee and hip replacement is OA (approximately 85% of all cases). The general consensus among orthopedic surgeons on indications for joint replacement were (1) severe daily pain and (2) radiographic evidence of joint space narrowing.115 With proper patient selection, good to excellent results can be expected in 95% of patients. The survival rate of the implant is expected to be 95% at 15 years.119 When overall health improvement is used to assess the cost effectiveness of total joint arthroplasty, the hip and knee arthroplasty have similar excellent results.120
Complications of OA
- Side effects of drugs used for treatment, including virtually all organ systems in the body
- Decreased ability to perform everyday activities, such as personal hygiene, household chores, or cooking
- Decreased ability to walk
Prognosis
The prognosis seems to differ according to the affected joint121
- Hand OA: older age appears to be the strongest risk factor for progression.
- Hip OA: risk factors for progression to total hip replacement include female gender, night pain, and lower baseline functional capacity.
- Knee OA: a higher body mass index and polyarticular arthritis predict radiographic deterioration. Varus or valgus deformity of the knee correlates with later radiographic worsening of OA of the medial and lateral compartments, respectively.122,123
Patients with OA also experience varying degrees of physical disability, and OA can adversely affect quality of life.124,125 OA is estimated to be the most common cause of disability in adults. Worsening disability may be correlated with coping styles, in particular, avoidance of activity due to pain may lead to muscle weakness that may impact upon joint stability. Exercise may help to prevent such loss of strength and decrease disability.126 Joint laxity, impaired proprioception, greater body mass index, and more severe joint pain were each predictive of subsequent worsening in function in patients with OA of the knee. In contrast, patients with better muscle strength, better mental health, stronger social supports, and those who are better able to perform aerobic exercise experience less disability than those with lesser amounts of these factors. Every person with OA is different. Pain and stiffness may prevent one person from performing simple daily activities, while others are able to maintain an active lifestyle that includes sports and other activities. Patient movement may become very limited over time. Doing everyday activities, such as personal hygiene, household chores, or cooking may become a challenge. Treatment usually improves function.
Mortality
There are some studies showing OA associated with excess mortality risk, although the exact cause could not be determined.127,128 Risk factors for death included a history of diabetes, cancer, or cardiovascular disease, and the presence of walking disability.
Summary
OA management should consider all quality of care domains; that care is safe, effective, patient-centered, timely, efficient, and equitable.129 Several papers document widespread support for OA guidelines, but there are delays in utilization of these standards, particularly of non-pharmacological recommendations, and variance in the application of recommendations by clinicians in different specialty areas.130-134 Additionally, qualitative information suggests that the needs of patients are not being met with regard to the quantity and quality of information provided about OA and its treatment, the emotional needs of patients, and patient clinician communication.135,136
Future research should be directed toward overcoming patient and provider barriers to the use of OA guidelines and their documentation, guideline implementation, and evaluation of outcomes. Although the evidence for many OA treatments is good, the complexity and high number of treatment recommendations available for OA may be a hindrance to use of the guidelines. Many available strategies have been evaluated and can improve implementation of evidence of efficacy into practice.137-141
References
1. Brandt KD, et al. Etiopathogenesis of osteoarthritis. Med Clin North Am 2009;93:1-24.
2. Leigh JP, et al. Estimating the costs of job related arthritis. J Rheumatol 2001;28:1647-1654.
3. Bitton R. The economic burden of osteoarthritis. Am J Manag Care 2009;15(Suppl 8):S230-S235.
4. Le Pen J, et al. Financial costs of osteoarthritis in France. The “COART” France study. Joint Bone Spine 2005;72:567/70.
5. Frisbie DD. Synovial joint biology and pathology. In: Auer JA, Stick JA, editors. Equine Surgery. 3rd edition. St. Louis, MO: Saunders; 2006: 1037-1055.
6. Covinsky K. Aging, arthritis, and disability. Arthritis Rheum 2006;55:175-176.
7. Covinsky KE, et al. Effect of arthritis in middle age on older-age functioning. J Am Geriatr Soc 2008;56:23-28.
8. Dunlop D, et al. Disability in activities of daily living: Patterns of change and a hierarchy of disability. Am J Public Health 1997;87:378-383.
9. Dunlop D, et al. Arthritis prevalence and activity limitations in older adults. Arthritis Rheum 2001;44:212-221.
10. Felson D, et al. Osteoarthritis: New insights. Part 1: the disease and its risk factors [review]. Ann Intern Med 2000;133:635-646.
11. Institute of Medicine. The Future of Disability in America. Washington, DC: The National Academies Press; 2007.
12. Ling SM, et al. Transitions to mobility difficulty associated with lower extremity osteoarthritis in high functioning older women: Longitudinal data from the Women’s Health and Aging Study II. Arthritis Rheum 2006;55: 256-263.
13. Song J, et al. Population impact of arthritis on disability in older adults. Arthritis Rheum 2006;55:248-255.
14. Verbrugge LM, Juarez L. Profile of arthritis disability: II. Arthritis Rheum 2006;55:102-113.
15. van Saase JL, et al. Epidemiology of arthritis: Zoetermeer survey. Comparison of radiological arthritis in a Dutch population with that of 10 other populations. Ann Rheum Dis 1989;20:351-369.
16. Mallen CD, et al. Predicting poor functional outcome in community-dwelling older adults with knee pain: Prognostic value of generic indicators. Ann Rheum Dis 2007;66:1456-1461.
17. Roos EM, et al. Change in self-reported outcomes and objective physical function over 7 years in middle-aged subjects with or at high risk of knee osteoarthritis. Ann Rheum Dis 2008;67:505-510.
18. Sharma L, et al. Physical functioning over three years in knee osteoarthritis: Role of psychosocial, local mechanical, and neuromuscular factors. Arthritis Rheum 2003;48:3359-3370.
19. van Dijk GM, et al. Course of functional status and pain in osteoarthritis of the hip or knee: A systematic review of the literature. Arthritis Rheum 2006;55:779-785.
20. Lawrence J, et al. Prevalence in the population and relationships between symptoms and x-ray changes. Ann Rheum Dis 1966;25:1-24.
21. Mow VC, et al. Cartilage and diarthrodial joints as paradigms for hierarchical materials and structures. Biomaterials 1992;13:67.
22. Mankin HJ, Brandt KD. Biochemistry and metabolism of articular cartilage in osteoarthritis. In: Osteoarthritis: Diagnosis and Management, 2nd edition. Moskowitz RW, eds. Philadelphia: WB Saunders; 1992: 109.
23. Byer PD, et al. Hypothesizing about joints. In: Studies in Joint Diseases 2. Maroudas A, Holborow EJ, eds. London: Pitman; 1983: 241.
24. Jimenez SA, et al. Type II collage gene mutations in familial osteoarthritis. In: Articular Cartilage and Osteoarthritis (workshop). Kuettner KE, et al, eds. New York: Raven Press; 1992: 167.
25. Mizrahi J, et al. The “instantaneous” deformation of cartilage: effects of collagen fiber orientation and osmotic stress. Biorheology 1986;23:311.
26. Buckwalter JA. Osteoarthritis and articular cartilage use, disuse, and abuse: Experimental studies. J Rheumatol Suppl 1995;43:13.
27. Miller EJ, et al. Cleavage of Type II and III collagens with mammalian collagenase: Site of cleavage and primary structure at the NH2-terminal portion of the smaller fragment released from both collagens. Biochemistry 1976;15:787.
28. Vincenti MP, et al. Using inhibitors of metalloproteinases to treat arthritis. Easier said than done? Arthritis Rheum 1994;37:1115.
29. Okada Y, et al. Degradation of type IX collagen by matrix metalloproteinase 3 (stromelysin) from human rheumatoid synovial cells. FEBS Lett 1989; 244.
30. Smith MD, et al. Synovial membrane inflammation and cytokine production in patients with early osteoarthritis. J Rheumatol 1997;24:365.
31. Fava R, et al. Active and latent forms of transforming growth factor beta activity in synovial effusions. J Exp Med 1989;169:291.
32. McAlindon TE, et al. Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study. Ann Intern Med 1996;125:353.
33. Hunter D. In the clinic. Osteoarthritis [review]. Ann Intern Med 2007;147. ITC8-1-16.
34. Moskowitz RW, Holderbaum D. Clinical and laboratory findings in osteoarthritis. In: Arthritis and Allied Conditions. Koopman WJ, ed. Baltimore: Williams & Wilkins; 2001: 2216.
35. Raffa RB. Mechanism of action of analgesics used to treat osteoarthritis pain. Rheum Dis Clin North Am 2003;29:733-745.
36. Altman R, et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and therapeutic criteria committee of the American rheumati association. Arthritis Rheum 1986;29:1039-1049.
37. Solomon L. Clinical features of osteoarthritis. In: Textbook of Rheumatology. Kelley WN, et al; eds. Philadelphia: WB Saunders; 1996: 1383.
38. Cooper C, et al. Generalized osteoarthritis in women: Pattern of joint involvement and approaches to definition for epidemiological studies. J Rheumatol 1996;23:1938.
39. DeHaan MN, et al. Knee osteoarthritis clinical practice guidelines — how are we doing? J Rheumatol 2007;34:2099-2105.
40. Hutchings A, et al. The Longitudinal Examination of Arthritis Pain (LEAP) study: Relationships between weekly fluctuations in patient-rated joint pain and other health outcomes. J Rheumatol 2007;34:2291-2300.
41. Jordan KM, et al. The use of conventional and complementary treatments for knee osteoarthritis in the community. Rheumatology 2004;43: 381-384.
42. Messier SP, et al. Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis: The arthritis, diet, and activity promotion trial [see comment]. Arthritis Rheum 2004;50:1501-1510.
43. Ettinger WHJ, et al. A randomized trial comparing aerobic exercise and resistance exercise with a health education program in older adults with knee osteoarthritis. The Fitness Arthritis and Seniors Trial (FAST). JAMA 1997;277:25-31.
44. Roddy E, et al. Aerobic walking or strengthening exercise for osteoarthritis of the knee? A systematic review. Ann Rheum Dis 2005;64:544-548.
45. Roddy E, et al. Evidence-based recommendations for the role of exercise in the management of osteoarthritis of the hip or knee—the MOVE consensus. Rheumatology 2005;44:67-73.
46. Schattner A. Review: Both aerobic and home-based quadriceps strengthening exercises reduce pain and disability in knee osteoarthritis. ACP J Club 2005;143:71.
47. Jordan KM, et al. EULAR recommendations 2003: An evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis 2003;62:1145-1155.
48. Zhang W, et al. EULAR evidence based recommendations for the management of hip osteoarthritis: Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2005;64:669-681.
49. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum 2000;43:1905-1915.
50. Zhang W, et al. OARSI recommendations for the management of hip and knee osteoarthritis, part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 2008;16:137-162.
51. Hunter D, Felson D. Osteoarthritis. BMJ 2006;332:639-642.
52. Hollander JL, Horvath SM. The influence of physical therapy procedures on the intra-articular temperature of normal and arthritic subjects. Am J Med Sci 1949;218:543.
53. Fischer E, Solomon S. Physiological responses to heat and cold. In: Therapeutic Heat and Cold. Licht S, Ed, E Licht, New Haven, CT; 1965:126.
54. Hicks JE, Gerber LH. Rehabilitation in the management of patients with osteoarthritis. In: Osteoarthritis: Diagnosis and Medical/Surgical Management, Moskowitz RW, et al. eds. Philadelphia: WB Saunders; 1992:433.
55. Zizic TM, et al. The treatment of osteoarthritis of the knee with pulsed electrical stimulation. J Rheumatol 1995;22:1757.
56. Taylor P, et al. Treatment of osteoarthritis of the knee with transcutaneous electrical nerve stimulation. Pain 1981;11:233.
57. Lewis B, et al. The comparative analgesic efficacy of transcutaneous electrical nerve stimulation and a non-steroidal anti-inflammatory drug for painful osteoarthritis. Br J Rheumatol 1994;33:455.
58. Draper ER, et al. Improvement in function after valgus bracing of the knee. An analysis of gait symmetry. J Bone Joint Surg Br 2000;82:1001.
59. Rannou F, et al. Splint for base-of-thumb osteoarthritis: A randomized trial. Ann Intern Med 2009;150:661.
60. Hinman RS, et al. Efficacy of knee tape in the management of osteoarthritis of the knee: Blinded randomised controlled trial. BMJ 2003;327:135.
61. Fransen M, et al. Physical therapy is effective for patients with osteoarthritis of the knee: A randomized controlled clinical trial. J Rheumatol 2001;28:156.
62. Landoni MF, et al. Effects of flunixin, tolfenamic acid, R(-) and S (1) ketoprofen on the response of equine synoviocytes to Lipopolysaccharide stimulation. Equine Vet J 1996;28:468-475.
63. De Grauw JC, et al. In vivo effects of meloxicam on inflammatory mediators, MMP activity and cartilage biomarkers in equine joints with acute synovitis. Equine Vet J 2009;41:693-699.
64. Hochberg MC, et al. Guidelines for the medical management of osteoarthritis. Part I. Osteoarthritis of the hip. American College of Rheumatology. Arthritis Rheum 1995;38:1535.
65. Jordan KM, et al. EULAR Recommendations 2003: An evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis 2003;62:1145.
66. Towheed TE, et al. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev 2006;CD004257.
67. Doherty M, et al. A randomised controlled trial of ibuprofen, paracetamol or a combination tablet of ibuprofen/paracetamol in community-derived people with knee pain. Ann Rheum Dis 2011;70:1534.
68. Cepeda MS, et al. Tramadol for osteoarthritis. Cochrane Database Syst Rev 2006;CD005522.
69. Caldwell JR, et al. Treatment of osteoarthritis pain with controlled release oxycodone or fixed combination oxycodone plus acetaminophen added to nonsteroidal antiinflammatory drugs: A double blind, randomized, multicenter, placebo controlled trial. J Rheumatol 1999;26:862.
70. Peloso PM. Opioid therapy for osteoarthritis of the hip and knee: Use it or lose it? J Rheumatol 2001;28:6.
71. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum 2000;43:1905.
72. Amin AR, et al. Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage. Influence of nitric oxide. J Clin Invest 1997;99:1231.
73. Li X, et al. Expression and regulation of microsomal prostaglandin E synthase-1 in human osteoarthritic cartilage and chondrocytes. J Rheumatol 2005;32:887.
74. Bjordal JM, et al. Non-steroidal anti-inflammatory drugs, including cyclo- oxygenase-2 inhibitors, in osteoarthritic knee pain: Meta-analysis of randomised placebo controlled trials. BMJ 2004;329:1317.
75. Batchlor EE, Paulus HE. Principles of drug therapy. In: Osteoarthritis: Diagnosis and Medical/Surgical Management. Moskowitz RW, et al, eds. Philadelphia: WB Saunders Co.; 1992:465.
76. Griffin MR, et al. Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons. Ann Intern Med 1991;114:257.
77. Furst DE. Are there differences among nonsteroidal antiinflammatory drugs? Comparing acetylated salicylates, nonacetylated salicylates, and nonacetylated nonsteroidal anti-inflammatory drugs. Arthritis Rheum 1994;37:1.
78. Huskisson EC, et al. Effects of anti-inflammatory drugs on the progression of osteoarthritis of the knee. LINK Study Group. Longitudinal Investigation of Nonsteroidal Antiinflammatory Drugs in Knee Osteoarthritis. J Rheumatol 1995;22:1941.
79. Silverstein FE, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000;284:1247.
80. Watson MC, et al. Non-aspirin, nonsteroidal anti-inflammatory drugs for osteoarthritis of the knee. Cochrane Database Syst Rev 2000; CD000142.
81. Towheed T, et al. Analgesia and non-aspirin, non-steroidal anti-inflammatory drugs for osteoarthritis of the hip. Cochrane Database Syst Rev 2000; CD000517.
82. Hollander JL, et al. Hydrocortisone and cortisone injected into arthritic joints; comparative effects of and use of hydrocortisone as a local antiarthritic agent. JAMA 1951;147:1629-1635.
83. Di Rosa RJ, et al. Nomenclature announcement. Anti-phospholipase proteins. Prostaglandins 1984;28:441-442.
84. Newstadt DH. Intraarticular steroid therapy. In: Osteoarthritis: Diagnosis and Medical/Surgical Management. Moskowitz RW, et al., eds. Philadelphia: WB Saunders Co; 1992:493.
85. Arroll B, Goodyear-Smith F. Corticosteroid injections for osteoarthritis of the knee: Meta-analysis. BMJ 2004;328:869.
86. Lambert RG, et al. Steroid injection for osteoarthritis of the hip: A randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2007;56:2278.
87. Gatter RA, et al. American college of rheumatology guidelines for performing office synovial fluid examinations. J Clin Rheumatol 1995;1:194.
88. Caron JP. Intra-articular injections for joint disease in horses. Vet Clin North Am Equine Pract 2005;21:559-573.
89. Goodrich LR, Nixon AJ. Medical treatment of osteoarthritis in the horse—a review. Vet J 2006;171:51-69.
90. Moskowitz RW. Hyaluronic acid supple mentation. Curr Rheumatol Rep 2000;2:466-471.
91. Lo GH, et al. Intra-articular hyaluronic acid in treatment of knee osteoarthritis: A meta-analysis. JAMA 2003;290:3115-1121.
92. Richardson DW, Loinaz R. An evidence-based approach to selected joint therapies in the horse. Vet Clin North Am Equine Pract 2007;23:443-460.
93. Frisbie DD, et al. Evaluation of the effect of extracorporeal shock wave treatment on experimentally induced osteoarthritisin middle carpal joints of horses. Am J Vet Res 2009;70:449-454.
94. Yates AC, et al. Effects of sodium hyaluronate and methylprednisolone acetate on proteoglycan metabolism in equine articular chondrocytes treated with interleukin-1. Am J Vet Res 2006;67:1980-1986.
95. Doyle AJ, et al. Effects of sodium hyaloronate and methylprednisolone acetate on proteoglycan synthesis in equine articular cartilage explants. Am J Vet Res 2005;66:48-53.
96. Clegg DO, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006;354:795.
97. Sawitzke AD, et al. Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT. Ann Rheum Dis 2010;69:1459.
98. Wandel S, et al. Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: Network meta-analysis. BMJ 2010;341:c4675.
99. Setnikar I, et al. Antiarthritic effects of glucosamine sulfate studied in animal models. Arzneimittelforschung 1991;41:542.
100. Biggee BA, et al. Low levels of human serum glucosamine after ingestion of glucosamine sulphate relative to capability for peripheral effectiveness. Ann Rheum Dis 2006;65:222.
101. Towheed TE, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev 2005; CD002946.
102. Vlad SC, et al. Glucosamine for pain in osteoarthritis: Why do trial results differ? Arthritis Rheum 2007;56:2267.
103. Reginster JY. The efficacy of glucosamine sulfate in osteoarthritis: Financial and nonfinancial conflict of interest. Arthritis Rheum 2007;56:2105.
104. Reginster JY, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: A randomised, placebo-controlled clinical trial. Lancet 2001;357:251.
105. Mazzuca SA, et al. Knee pain reduces joint space width in conventional standing anteroposterior radiographs of osteoarthritic knees. Arthritis Rheum 2002;46:1223.
106. Pavelká K, et al. Glucosamine sulfate use and delay of progression of knee osteoarthritis: A 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med 2002;162:2113.
107. Rozendaal RM, et al. Effect of glucosamine sulfate on hip osteoarthritis: A randomized trial. Ann Intern Med 2008;148:268.
108. Rozendaal RM, et al. Effect of glucosamine sulphate on joint space narrowing, pain and function in patients with hip osteoarthritis; subgroup analyses of a randomized controlled trial. Osteoarthritis Cartilage 2009;17:427.
109. Cibere J, et al. Randomized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis. Arthritis Rheum 2004;51:738.
110. Reichenbach S, et al. Meta-analysis: Chondroitin for osteoarthritis of the knee or hip. Ann Intern Med 2007;146:580.
111. Klashman DJ, et al. Occult presence of CPPD crystals in patients undergoing arthroscopic knee irrigation for refractory pain related to osteoarthritis (abstract). Arthritis Rheum 1994;37:S240.
112. Roberge CJ, et al. Crystal-induced neutrophil activation. IV. Specific inhibition of tyrosine phosphorylation by colchicine. J Clin Invest 1993;92:1722.
113. Das SK, et al. A randomized controlled trial to evaluate the slow-acting symptom-modifying effects of colchicine in osteoarthritis of the knee: A preliminary report. Arthritis Rheum 2002;47:280.
114. Bryant LR, et al. Hydroxy-chloroquine in the treatment of erosive osteoarthritis. J Rheumatol 1995;22:1527.
115. Mancuso CA, et al. Indications for total hip and total knee arthroplasties. Results of orthopaedic surveys. J Arthroplasty 1996;11:34-46.
116. Moseley JB, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med 2002;347:81–88.
117. Hall MJ, Lawrence L. Ambulatory surgery in the United States, 1996. Adv Data 1998;(300):1-16.
118. Brinker MR, et al. Utilization of orthopaedic services in a capitated population. J Bone Joint Surg Am 2002;84:1926-1932.
119. Callahan CM, et al. Patient outcomes following tricompartmental total knee replacement. A meta-analysis. JAMA 1994;271:1349-1357.
120. Ethgen O, et al. Health-related quality of life in total hip and total knee arthroplasty. A qualitative and systematic review of the literature. J Bone Joint Surg Am 2004;86:963-974.
121. Hochberg MC. Prognosis of osteoarthritis. Ann Rheum Dis 1996;55:685.
122. Cahue S, et al. Varus-valgus alignment in the progression of patellofemoral osteoarthritis. Arthritis Rheum 2004;50:2184.
123. Sharma L, et al. The role of knee alignment in disease progression and functional decline in knee osteoarthritis. JAMA 2001;286:188.
124. Dominick KL, et al. Health-related quality of life among older adults with arthritis. Health Qual Life Outcomes 2004;2:5.
125. Losina E, et al. Impact of obesity and knee osteoarthritis on morbidity and mortality in older Americans. Ann Intern Med 2011;154:217.
126. Steultjens MP, et al. Avoidance of activity and disability in patients with osteoarthritis of the knee: The mediating role of muscle strength. Arthritis Rheum 2002;46:1784.
127. van Dijk GM, et al. Course of functional status and pain in osteoarthritis of the hip or knee: A systematic review of the literature. Arthritis Rheum 2006;55:779.
128. Hochberg MC. Mortality in osteoarthritis. Clin Exp Rheumatol 2008;26:S120.
129. Brand C. Translating evidence into practice for people with osteoarthritis of the hip and knee. Clin Rheumatol 2007;26:1411-1420.
130. DeHaan MN, et al. Knee osteoarthritis clinical practice guidelines — how are we doing? J Rheumatol 2007;34:2099-2105.
131. Jawad AS. Analgesics and osteoarthritis: Are treatment guidelines reflected in clinical practice? Am J Ther 2005;12:98-103.
132. Denoeud L, et al. First line treatment of knee osteoarthritis in out-patients in France: Adherence to the EULAR 2000 recommendations and factors influencing adherence. Ann Rheum Dis 2005;64:70-74.
133. Mazieres B, et al. Level of acceptability of EULAR recommendations for the management of knee osteoarthritis by practitioners in different European countries. Ann Rheum Dis 2005;64:1158-1164.
134. Sarzi-Puttini P, et al. Do physicians treat symptomatic osteoarthritis patients properly? Results of the AMICA experience. Semin Arthritis Rheum 2005;35:38-42.
135. Chard J, et al. A comparison of the views of rheumatologists, general practitioners and patients on the treatment of osteoarthritis. Rheumatology 2002;41:1208-1210.
136. Rosemann T, et al. Problems and needs for improving primary care of osteoarthritis patients: The views of patients, general practitioners and practice nurses. BMC Musculoskelet Disord 2006;7:48.
137. Grol R, Grimshaw J. From best evidence to best practice: Effective implementation of change in patients’ care. Lancet 2003;362:1225-1230.
138. Grimshaw JM, et al. Changing provider behavior: An overview of systematic reviews of interventions. Med Care 2001;39:42-45.
139. Grimshaw JM, et al. Changing physicians’ behavior: What works and thoughts on getting more things to work. J Contin Educ Health Prof 2002;22:237-243.
140. Eccles MP, Grimshaw JM. Selecting, presenting and delivering clinical guidelines: Are there any ‘‘magic bullets’’? Med J Aust 2004;180:S52-S54.
141. Grimshaw J, et al. Toward evidence-based quality improvement. Evidence (and its limitations) of the effectiveness of guideline dissemination and implementation strategies 1966–1998. J Gen Intern Med 2006;21(Suppl 2):S14-S20.
Osteoarthritis (OA) can be described as the failed repair of damage that has been caused by excessive mechanical stress (defined as force/unit area) on joint tissues.1 This implies that although multiple factors may lead to OA, mechanical impact (either as a major single event or as repetitive micro trauma) is central to all of these, and that the sequence of events that ensues represents the intrinsic repair process, which may either fail or be successful in restoring joint function. Also known as osteoarthrosis or degenerative joint disease, OA is the most important chronic musculoskeletal disorder in both humans and horses.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content