Osteoarthritis: Treatment, Clinical Features and Risk Factors


Osteoarthritis (OA) is the most common type of arthritis. Its high prevalence, especially in the elderly, and the high rate of disability related to disease make it a leading cause of disability in the elderly. Because of the aging of Western populations and because obesity, a major risk factor, are increasing in prevalence, the occurrence of osteoarthritis is on the rise. In the United States, osteoarthritis prevalence will increase from 66–100% by the year 2020.
OA affects certain joints, yet spares others (Fig. 326-1). Commonly affected joints include the cervical and lumbosacral spine, hip, knee, and first metatarsal phalangeal joint (MTP). In the hands, the distal and proximal interphalangeal joints and the base of the thumb are often affected. Usually spared are the wrist, elbow, and ankle. Our joints were designed in an evolutionary sense, when humans were still brachiating apes. We thus develop OA in joints that were ill designed for these tasks, i.e., joints involved in pincer grip in the hands and lower extremity weight-bearing joints. Some joints, like the ankles, may be spared because their articular cartilage may be uniquely resistant to loading stresses.

Figure 326-1
Joints affected by osteoarthritis.

OA can be diagnosed based on structural abnormalities or on the symptoms these abnormalities evoke. Based on cadaveric studies, structural changes of OA are nearly universal by the elderly years. These include cartilage loss (seen as joint space loss on x-rays) and osteophytes. Many persons with x-ray evidence of OA have no joint symptoms and, while the prevalence of structural abnormalities is of interest in understanding disease pathogenesis, what matters more from a clinical and public health perspective is the prevalence of symptomatic OA. Symptoms, usually joint pain, determine disability, visits to clinicians, and disease costs.
Symptomatic OA of the knee (pain on most days of a recent month in a knee plus x-ray evidence of OA in that knee) occurs in ~12% of persons age 60 in the United States and 6% of all adults age 30. Symptomatic hip OA is roughly one-third as common as disease in the knee. While radiographically evident hand OA and the appearance of bony enlargement in affected hand joints (Fig. 326-2) are extremely common in older persons, most cases are often not symptomatic. Even so, recent studies suggest that symptomatic hand OA occurs in ~10% of elderly individuals and often produces measurable physical functional limitation.

Figure 326-2
Severe osteoarthritis of the hands affecting the distal interphalangeal joints (Heberden's nodes) and the proximal interphalangeal joints (Bouchard's nodes). There is no clear bony enlargement of the other common site in the hands, the thumb base.
The prevalence of OA correlates strikingly with age. Regardless of how it is defined, OA is uncommon in adults under age 40 and highly prevalent in those over age 60. It is also a disease that, at least in middle-aged and elderly persons, is much more common in women than in men, and sex differences in prevalence increase with age. X-ray evidence of OA is common in the lower back and neck, but back pain and neck pain have not been tied to findings of OA on x-ray. Thus, back pain and neck pain are treated separately

OA is joint failure, a disease in which all structures of the joint have undergone pathologic change, often in concert. The pathologic sine qua non of disease is hyaline articular cartilage loss, present in a focal and, initially, nonuniform manner. This is accompanied by increasing thickness and sclerosis of the subchondral bony plate, by outgrowth of osteophytes at the joint margin, by stretching of the articular capsule, by mild synovitis in many affected joints, and by weakness of muscles bridging the joint. In knees, meniscal degeneration is part of the disease. There are numerous pathways that lead to joint failure, but the initial step is often joint injury in the setting of a failure of protective mechanisms.

Joint Protective Mechanisms and Their Failure
Joint protectors include: joint capsule and ligaments, muscle, sensory afferents, and underlying bone. Joint capsule and ligaments serve as joint protectors by providing a limit to excursion, thereby fixing the range of joint motion.
Synovial fluid reduces friction between articulating cartilage surfaces, thereby serving as a major protector against friction-induced cartilage wear. This lubrication function depends on the molecule lubricin, a mucinous glycoprotein secreted by synovial fibroblasts whose concentration diminishes after joint injury and in the face of synovial inflammation.
The ligaments, along with overlying skin and tendons, contain mechanoreceptor sensory afferent nerves. These mechanoreceptors fire at different frequencies throughout a joint's range of motion, providing feedback by way of the spinal cord to muscles and tendons. As a consequence, these muscles and tendons can assume the right tension at appropriate points in joint excursion to act as optimal joint protectors, anticipating joint loading.
Muscles and tendons that bridge the joint are key joint protectors. Their co-contractions at the appropriate time in joint movement provide the appropriate power and acceleration for the limb to accomplish its tasks. Focal stress across the joint is minimized by muscle contraction that decelerates the joint before impact and assures that when joint impact arrives, it is distributed broadly across the joint surface.
The bone underneath the cartilage may also provide a shock-absorbing function, as it may give way subtly to an oncoming impulse load.
Failure of these joint protectors increases the risk of joint injury and OA. For example, in animals, OA develops rapidly when a sensory nerve to the joint is sectioned and joint injury induced. Similarly, in humans, Charcot arthropathy, which is a severe and rapidly progressive OA, develops when minor joint injury occurs in the presence of posterior column peripheral neuropathy. Another example of joint protector failure is rupture of ligaments, a well-known cause of the early development of OA.

Cartilage and Its Role in Joint Failure
In addition to being a primary target tissue for disease, cartilage also functions as a joint protector. A thin rim of tissue at the ends of two opposing bones, cartilage is lubricated by synovial fluid to provides an almost frictionless surface across which these two bones move. The compressible stiffness of cartilage compared to bone provides the joint with impact-absorbing capacity. Both the smooth frictionless surface and the compressive stiffness of cartilage serve as protective mechanisms preventing joint injury.
Since the earliest changes of OA may occur in cartilage and abnormalities there can accelerate disease development, understanding the structure and physiology of cartilage is critical to an appreciation of disease pathogenesis. The two major macromolecules in cartilage are type 2 collagen, which provides cartilage its tensile strength, and aggrecan, a proteoglycan macromolecule linked with hyaluronic acid, which consists of highly negatively charged glycosaminoglycans. In normal cartilage, type 2 collagen is woven tightly, constraining the aggrecan molecules in the interstices between collagen strands, forcing these highly negatively charged molecules into close proximity with one another. The aggrecan molecule, through electrostatic repulsion of its negative charges, gives cartilage its compressive stiffness. Chondrocytes, the cells within this avascular tissue, synthesize all elements of the matrix. In addition, they produce enzymes that break down the matrix and cytokines and growth factors, which in turn provide autocrine/paracrine feedback that modulates synthesis of matrix molecules (Fig. 326-3). Cartilage matrix synthesis and catabolism are in a dynamic equilibrium influenced by the cytokine and growth factor environment and by mechanical stress. While chondrocytes synthesize numerous enzymes, especially matrix metalloproteinases (MMP), there are only a few that are critical in regulating cartilage breakdown. Type 2 cartilage is degraded primarily by MMP-13 (collagenase 3), with other collagenases playing a minor role. Aggrecan degradation is complex but appears to be a consequence, in part, of activation of aggrecanase 1 (ADAMTS-4) and perhaps of MMPs. Both collagenase and aggrecanase act primarily in the territorial matrix surrounding chondrocytes; however, as the osteoarthritic process develops, their activities and effects spread throughout the matrix, especially in the superficial layers of cartilage.
Figure 326-3
The chondrocyte and its products, type II collagen, aggrecan and enzymes which degrade these structures along with molecules stimulating chondrocytes.

The synovium and chondrocytes synthesize numerous growth factors and cytokines. Chief among them is interleukin (IL) 1, which exerts transcriptional effects on chondrocytes, stimulating production of proteinases and suppressing cartilage matrix synthesis. In animal models of OA, IL-1 blockade prevents cartilage loss. Tumor necrosis factor (TNF)  may play a similar role to that of IL-1. These cytokines also induce chondrocytes to synthesize prostaglandin E2, nitric oxide, and bone morphogenic protein 2 (BMP-2), which together have complex effects on matrix synthesis and degradation. Nitric oxide inhibits aggrecan synthesis and enhances proteinase activity, whereas BMP-2 is a potent stimulator of anabolic activity. At early stages in the matrix response to injury and in the healthy response to loading, the net effect of cytokine stimulation may be matrix turnover but, ultimately, excess IL-1 triggers a process of matrix degradation. Enzymes in the matrix are held in check by activation inhibitors, including tissue inhibitor of metalloproteinase (TIMP). Growth factors are also part of this complex network, with insulin-like growth factor type 1 and transforming growth factor  playing prominent roles in stimulating anabolism by chondrocytes.
While healthy cartilage is metabolically sluggish, with slow matrix turnover and a net balance of synthesis and degradation, cartilage in early OA or after an injury is highly metabolically active. In the latter situation, stimulated chondrocytes synthesize enzymes and new matrix molecules, with those enzymes becoming activated in the matrix, causing release of degraded aggrecan and type 2 collagen into cartilage and into the synovial fluid. OA cartilage is characterized by gradual depletion of aggrecan, an unfurling of the tightly woven collagen matrix, and loss of type 2 collagen. With these changes comes increasing vulnerability of cartilage, which no longer has compressive stiffness.

Risk Factors
Joint vulnerability and joint loading are the two major factors contributing to the development of OA. On the one hand, a vulnerable joint whose protectors are dysfunctional can develop OA with minimal levels of loading, perhaps even levels encountered during ever day activities. On the other hand, in a young joint with competent protectors, a major acute injury or long-term overloading is necessary to precipitate disease. Risk factors for OA can be understood in terms of their effect either on joint vulnerability or on loading (Fig. 326-4).

Figure 326-4
Risk factors for osteoarthritis either contribute to the susceptibility of the joint (systemic factors or factors in the local joint environment) or they increase risk by the load they put on the joint. Usually a combination of loading and susceptibility factors is required to cause disease or its progression.

Systemic Risk Factors
Age is the most potent risk factor for OA, with prevalence and incidence of disease rising dramatically with age. Radiographic evidence of OA is rare in individuals under age 40; however, in some joints, such as the hands, OA occurs in >50% of persons over age 70. Aging increases joint vulnerability through several mechanisms. Whereas dynamic loading of joints stimulates cartilage matrix by chondrocytes in young cartilage, aged cartilage is less responsive to these stimuli. Indeed, because of the poor responsiveness of older cartilage to such stimulation, cartilage transplant operations are far more challenging in older than in younger persons. Partly because of this failure to synthesize matrix with loading, cartilage thins with age, and thinner cartilage experiences higher shear stress at basal layers and is at greater risk of cartilage damage. Aging also increases the likelihood of failure of major joint protectors. Muscles that bridge the joint become weaker with age and also respond less quickly to oncoming impulses. Sensory nerve input slows with age, retarding the feedback loop of mechanoreceptors to muscles and tendons related to their tension and position. Ligaments stretch with age, making them less able to absorb impulses. A combination of all of these factors work in concert to increase the vulnerability of older joints to OA.
Older women are at high risk of OA in all joints, a risk that emerges as women reach their sixth decade. While hormone loss with menopause may contribute to this risk, there is little understanding of the vulnerability of older women's joints to OA.

Heritability and Genetics
OA is a highly heritable disease, but its heritability varies by joint. Fifty percent of the hand and hip OA in the community is attributable to inheritance, i.e., to disease present in other members of the family. However, the heritable proportion of knee OA is at most 30%, with some studies suggesting no heritability at all. Whereas many people with OA have disease in multiple joints, this "generalized OA" phenotype is rarely inherited and is more often a consequence of aging.
Emerging evidence suggests that persons with genetic mutations in proteins that regulate the transcription of major cartilage molecules are at high risk of OA. One gene implicated is FRZB, in which a mutation may put a woman at high risk of hip OA. FRZB is a gene for a Frizzle protein that antagonizes an extracellular Wnt ligand, and the Wnt signaling pathway plays a critical role in matrix synthesis and joint development.

Global Considerations
Hip OA is rare in China and in immigrants from China to the United States. However, OA in the knees, is at least as common, if not more so, in Chinese than in Caucasians from the United States, and knee OA represents a major cause of disability in China. Anatomic differences between Chinese and Caucasian hips may account for much of the difference in prevalence, with Caucasian hips having a higher prevalence of anatomic predispositions to the development of OA. Persons from Africa, but not African Americans, may also have a very low rate of hip OA.

Risk Factors in the Joint Environment
Some risk factors increase vulnerability of the joint through local effects on the joint environment. With changes in joint anatomy, for example, load across the joint is no longer distributed evenly across the joint surface, but rather shows an increase in focal stress. In the hip, three uncommon developmental abnormalities occurring in utero or childhood, congenital dysplasia, Legg-Perthes disease, and slipped femoral capital epiphysis, leave a child with distortions of hip joint anatomy that often lead to OA later in life. Girls are predominantly affected by acetabular dysplasia, a mild form of congenital dislocation, whereas the other abnormalities more often affect boys. Depending on the severity of the anatomic abnormalities, hip OA occurs either in young adulthood (severe abnormalities) or middle age (mild abnormalities).
Major injuries to a joint also can produce anatomic abnormalities that leave the joint susceptible to OA. For example, a fracture through the joint surface often causes OA in joints in which the disease is otherwise rare such as the ankle and the wrist. Avascular necrosis can lead to collapse of dead bone at the articular surface, producing anatomic irregularities and subsequent OA.
Tears of ligaments that protect the joints, such as the anterior cruciate ligament in the knee and the labrum in the hip, can increase joint susceptibility and lead to premature OA. While meniscal tears may increase the risk of OA, meniscectomy operations, including selective ones, increase the risk of later disease, perhaps independent of the tear that led to the operation. Even injuries that do not produce diagnosed joint injuries may increase risk of OA, perhaps because the structural injury was not detected at the time. For example, in the Framingham study subjects, men with a history of major knee injury, but no surgery, had a 3.5-fold increased risk for subsequent knee OA.
Another source of anatomic abnormality is malalignment across the joint (Fig. 326-5). This factor has been best studied in the knee, which is the fulcrum of the longest lever arm in the body. Varus (bowlegged) knees with OA are at exceedingly high risk of cartilage loss in the medial or inner compartment of the knee, whereas valgus (knock-kneed) malalignment predisposes to rapid cartilage loss in the lateral compartment. Malalignment causes this effect by decreasing contact area during loading, increasing stress on a focal area or cartilage, which then breaks down. There is evidence that malalignment in the knee not only causes cartilage loss but leads to underlying bone damage, producing bone marrow lesions seen on MRI.

Figure 326-5
The two types of limb malalignment in the frontal plane: varus, in which the stress is placed across the medial compartment of the knee joint, and valgus, which places excess stress across the lateral compartment of the knee.
While it is likely that the weakness in muscles bridging a joint increase the risk of OA in that joint, there is no definitive evidence in this regard.
Patients with knee OA have impaired proprioception across their knees, and this may predispose them to further disease progression. The role of bone in serving as a shock absorber for impact load is not well understood, but persons with increased bone density are at high risk of OA, suggesting that the resistance of bone to impact during joint use may play a role in disease development.

Loading Factors

Three to six times body weight is exerted across the knee during single leg stance. Any increase in weight may be multiplied by this factor to reveal the excess force across the knee in overweight persons during walking. Obesity is a well-recognized and potent risk factor for the development of knee OA and, less so, for hip OA. Obesity precedes the development of disease and is not just a consequence of the inactivity present in those with disease. Obesity is a stronger risk factor for disease in women than in men, and in women, the relationship of weight to the risk of disease is linear, so that with each increase in weight, there is a commensurate increase in risk. Weight loss in women lowers the risk of developing symptomatic disease. Not only is obesity a risk factor for OA in weight-bearing joints, but obese persons have more severe symptoms from the disease.
Obesity's effect on the development and progression of disease is mediated mostly through the increased loading in weight-bearing joints that occurs in overweight persons. However, a modest association of obesity with an increased risk of hand OA suggests that there may be a systemic metabolic factor circulating in obese persons that affects disease risk also.

Repeated Use of Joint
There are two categories of repetitive joint use, occupational use and leisure time physical activities. Workers performing repetitive tasks as part of their occupations for many years are at high risk of developing OA in the joints they use repeatedly. For example, farmers are at high risk for hip OA, miners have high rates of OA in knees and spine, and shipyard and dockyard workers have a higher prevalence of disease in knees and fingers than do office workers. Even within a textile mill, women whose jobs required fine pincer grip [increasing the stress across the interphalangeal (IP) joints] had much more distal IP (DIP) joint OA than women of the same age whose jobs required repeated power grip, a motion that does not stress the DIP joints. Workers whose jobs require regular knee bending or lifting or carrying heavy loads have a high rate of knee OA. One reason why workers may get disease is that during long days at work, their muscles may gradually become exhausted, no longer serving as effective joint protectors.
While exercise is a major element of the treatment of OA, certain types of exercise may paradoxically increase the risk of disease. While recreational runners are not at increased risk of knee OA, studies suggest that they do have a modest increased risk of disease in the hip. However, persons who have already sustained major knee injuries are at increased risk of progressive knee OA as a consequence of running. Compared to nonrunners, elite runners (professional runners and those on Olympic teams) have high risks of both knee and hip OA. Given the widespread recommendation to adopt a healthier, more exercise-filled lifestyle; longitudinal epidemiologic studies of exercise contain cautionary notes. For example, women with increased levels of physical activity, either as teenagers or at age 50, had a higher risk of developing symptomatic hip disease later in life than women who were sedentary. Other athletic activities that pose high risks of joint injury, such as football, may thereby predispose to OA.

The pathology of OA provides evidence of the panarticular involvement of disease. Cartilage initially shows surface fibrillation and irregularity. As disease progresses, focal erosions develop there, and these eventually extend down to the subjacent bone. With further progression, cartilage erosion down to bone expands to involve a larger proportion of the joint surface, even though OA remains a focal disease with nonuniform loss of cartilage (Fig. 326-6).

Figure 326-6
Pathologic changes of osteoarthritis in a toe joint. Note the nonuniform loss of cartilage (arrowhead vs. solid arrow), the increased thickness of the subchondral bone envelope (solid arrow), and the osteophyte (open arrow).

After an injury to cartilage, chondrocytes undergo mitosis and clustering. While the metabolic activity of these chondrocyte clusters is high, the net effect of this activity is to promote proteoglycan depletion in the matrix surrounding the chondrocytes. This is because the catabolic activity is greater than the synthetic. As disease develops, collagen matrix becomes damaged, the negative charges of proteoglycans get exposed, and cartilage swells from ionic attraction to water molecules. Because in damaged cartilage proteoglycans are no longer forced into close proximity, cartilage does not bounce back after loading as it did when healthy, and cartilage becomes vulnerable to further injury. Chondrocytes at the basal level of cartilage undergo apoptosis.
With loss of cartilage come alterations in subchondral bone. Stimulated by growth factors and cytokines, osteoclasts and osteoblasts in the subchondral bony plate, just underneath cartilage, become activated. Bone formation produces a thickening and stiffness of the subchondral plate that occurs even before cartilage ulcerates. Trauma to bone during joint loading may be the primary factor driving this bone response, with healing from injury (including microcracks) producing stiffness. Small areas of osteonecrosis usually exist in joints with advanced disease. Bone death may also be caused by bone trauma with shearing of microvasculature, leading to a cutoff of vascular supply to some bone areas.
At the margin of the joint, near areas of cartilage loss, osteophytes form. These start as outgrowths of new cartilage and, with neurovascular invasion from the bone, this cartilage ossifies. Osteophytes are an important radiographic hallmark of OA. In malaligned joints, osteophytes grow larger on the side of the joint subject to most loading stress (e.g., in varus knees, osteophytes grow larger on the medial side).
The synovium produces lubricating fluids that minimize shear stress during motion. In healthy joints, the synovium consists of a single discontinuous layer filled with fat and containing two types of cells, macrophages and fibroblasts, but, in OA, it can sometimes become edematous and inflamed. There is a migration of macrophages from the periphery into the tissue, and cells lining the synovium proliferate. Enzymes secreted by the synovium digest cartilage matrix that has been sheared from the surface of the cartilage.
Additional pathologic changes occur in the capsule, which stretches, becomes edematous, and can become fibrotic.
The pathology of OA is not identical across joints. In hand joints with severe OA, for example, there are often cartilage erosions in the center of the joint probably produced by bony pressure from the opposite side of the joint. Bone remodeling is a prominent feature of hand OA, in part because of the thin cartilage in each hand joint. In hand OA, pathology has also been noted in ligament site insertions, which may help propagate disease.
Basic calcium phosphate and calcium pyrophosphate dihydrate crystals are present microscopically in most joints with end-stage OA. Their role in osteoarthritic cartilage is unclear, but their release from cartilage into the joint space and joint fluid likely triggers synovial inflammation, which can, in turn, produce release of enzymes and trigger nociceptive stimulation.

Sources of Pain
Because cartilage is aneural, cartilage loss in a joint is not accompanied by pain. Thus, pain in OA likely arises from structures outside the cartilage. Innervated structures in the joint include the synovium, ligaments, joint capsule, muscles, and subchondral bone. Most of these are not visualized by the x-ray, and the severity of x-ray changes in OA correlates poorly with pain severity.
Based on MRI studies in osteoarthritic knees comparing those with and without pain and on studies mapping tenderness in unanesthetized joints, likely sources of pain include synovial inflammation, joint effusions, and bone marrow edema. Modest synovitis develops in many but not all osteoarthritic joints. Some diseased joints have no synovitis, whereas others have synovial inflammation that approaches the severity of joints with rheumatoid arthritis (Chap. 314). The presence of synovitis on MRI is correlated with the presence and severity of knee pain. Capsular stretching from fluid in the joint stimulates nociceptive fibers there, inducing pain. Increased focal loading as part of the disease not only damages cartilage but probably also injures the underlying bone. As a consequence, bone marrow edema appears on the MRI; histologically, this edema may signal the presence of microcracks and scar, which are the consequences of trauma. These lesions may stimulate bone nociceptive fibers. Also, hemostatic pressure within bone rises in OA, and the increased pressure itself may stimulate nociceptive fibers, causing pain. Lastly, osteophytes themselves may be a source of pain. When osteophytes grow, neurovascular innervation penetrates through the base of the bone into the cartilage and into the developing osteophyte.
Pain may arise from outside the joint also, including bursae near the joints. Common sources of pain near the knee are anserine bursitis and iliotibial band syndrome.

Clinical Features
Joint pain from OA is activity-related. Pain comes on either during or just after joint use and then gradually resolves. Examples include knee or hip pain with going up or down stairs, pain in weight-bearing joints when walking, and, for hand OA, pain after cooking. Early in disease, pain is episodic, triggered often by a day or two of overactive use of a diseased joint, such as a person with knee OA taking a long run and noticing a few days of pain thereafter. As disease progresses, the pain becomes continuous and even begins to be bothersome at night. Stiffness of the affected joint may be prominent, but morning stiffness is usually brief (less than 30 min)
In knees, buckling may occur, in part, due to weakness of muscles crossing the joint. Mechanical symptoms, such as buckling, catching, or locking, could also signify internal derangement, such as meniscal tears, and need to be evaluated. In the knee, pain with activities requiring knee flexion, such as stair climbing and arising from a chair, often emanates from the patellofemoral compartment of the knee, which does not actively articulate until the knee is bent ~35°.
OA is the most common cause of chronic knee pain in persons over age 45, but the differential diagnosis is long. Inflammatory arthritis is likely if there is prominent morning stiffness and many other joints are affected. Bursitis occurs commonly around knees and hips. A physical examination should focus on whether tenderness is over the joint line (at the junction of the two bones around which the joint is articulating) or is outside of it. Anserine bursitis, medial and distal to the knee, is an extremely common cause of chronic knee pain that may respond to a glucocorticoid injection. Prominent nocturnal pain in the absence of end-stage OA merits a distinct workup. For hip pain, OA can be detected by loss of internal rotation on passive movement, and pain isolated to an area lateral to the hip joint usually reflects the presence of trochanteric bursitis.
No blood tests are routinely indicated for workup of patients with OA unless less symptoms and signs suggest inflammatory arthritis. Examination of the synovial fluid is often more helpful diagnostically than an x-ray. If the synovial fluid white count is more than 1000 per L, inflammatory arthritis or gout or pseudogout are likely, the latter two being also identified by the presence of crystals.
X-rays are indicated to evaluate chronic hand pain and hip pain thought to be due to OA, as the diagnosis is often unclear without confirming radiographs. For knee pain, x-rays should be obtained if symptoms or signs are not typical of OA or if knee pain persists after effective treatment. In OA, radiographic findings (Fig. 326-7) correlate poorly with the presence and severity of pain. Further, radiographs may be normal in early disease as they are insensitive to cartilage loss and other early findings.
While MRI may reveal the extent of pathology in an osteoarthritic joint, it is not indicated as part of the diagnostic workup. Findings such as meniscal tears in cartilage and bone lesions occur in most patients with OA in the knee, but almost never warrant a change in therapy.
Figure 326-7
X-ray of knee with medial osteoarthritis. Note the narrowed joint space on medial side of the joint only (white arrow), the sclerosis of the bone in the medial compartment providing evidence of cortical thickening (black arrow), and the osteophytes in the medial femur (white wedge).

Osteoarthritis: Treatment
The goals of the treatment of OA are to alleviate pain and minimize loss of physical function. To the extent that pain and loss of function are consequences of inflammation, of weakness across the joint, and of laxity and instability, the treatment of OA involves addressing each of these impairments. Comprehensive therapy consists of a multimodality approach including nonpharmacologic and pharmacologic elements.
Patients with mild and intermittent symptoms may need only reassurance or nonpharmacologic treatments. Patients with ongoing, disabling pain are likely to need both nonpharmaco- and pharmacotherapy.
Treatments for knee OA have been more completely evaluated than those for hip and hand OA or for disease in other joints. Thus, while the principles of treatment are identical for OA in all joints, we shall focus below on the treatment of knee OA, noting specific recommendations for disease in other joints, especially when they differ from those for disease in the knee.

Since OA is a mechanically driven disease, the mainstay of treatment involves altering loading across the painful joint and improving the function of joint protectors, so they can better distribute load across the joint. Ways of lessening focal load across the joint include
1.    avoiding activities that overload the joint, as evidenced by their causing pain;
2.   improving the strength and conditioning of muscles that bridge the joint, so as to optimize their function; and
3.   unloading the joint, either by redistributing load within the joint with a brace or a splint or by unloading the joint during weight bearing with a cane or a crutch.
The simplest effective treatment for many patients is to avoid activities that precipitate pain. For example, for the middle-aged patient whose long-distance running brings on symptoms of knee OA, a less demanding form of weight-bearing activity may alleviate all symptoms. For an older person whose daily constitutionals up and down hills bring on knee pain, routing the constitutional away from hills might eliminate symptoms.
Each pound of weight increases the loading across the knee three- to sixfold. Weight loss may have a commensurate multiplier effect, unloading both knees and hips. Thus, weight loss, especially if substantial, may lessen symptoms of knee and hip OA.
In hand joints affected by OA, splinting, by limiting motion, often minimizes pain for patients with involvement either in the base of the thumb or in the DIP or proximal IP joints. With an appropriate splint, function can often be preserved. Weight-bearing joints such as knees and hips can be unloaded by using a cane in the hand opposite to the affected joint for partial weight bearing. A physical therapist can help teach the patient how to use the cane optimally, including ensuring that its height is optimal for unloading. Crutches or walkers can serve a similar beneficial function.

Osteoarthritic pain in knees or hips during weight bearing results in lack of activity and poor mobility and, because OA is so common, the inactivity that results represent a public health concern, increasing the risk of cardiovascular disease and of obesity. Aerobic capacity is poor in most elders with symptomatic knee OA, worse than others of the same age.
The development of weakness in muscles that bridge osteoarthritic joints is multifactorial in etiology. First, there is a decline in strength with age. Second, with limited mobility comes disuse muscle atrophy. Third, patients with painful knee or hip OA alter their gait so as to lessen loading across the affected joint, and this further diminishes muscle use. Fourth, "arthrogenous inhibition" may occur, whereby contraction of muscles bridging the joint is inhibited by a nerve afferent feedback loop emanating in a swollen and stretched joint capsule; this prevents maximal attainment of voluntary maximal strength. Since adequate muscle strength and conditioning are critical to joint protection, weakness in a muscle that bridges a diseased joint makes the joint more susceptible to further damage and pain. The degree of weakness correlates strongly with the severity of joint pain and the degree of physical limitation. One of the cardinal elements of the treatment of OA is to improve the functioning of muscles surrounding the joint.
At least for knee OA, trials have shown that exercise lessens pain and improves physical function. Most effective exercise regimens consist of aerobic and/or resistance training, the latter of which focuses on strengthening muscles across the joint. Exercises are likely to be effective, especially if they train muscles for the activities a person performs daily. Some exercises may actually increase pain in the joint; these should be avoided, and the regimen needs to be individualized to optimize effectiveness and minimize discomfort. Range-of-motion exercises, which do not strengthen muscles, and isometric exercises that strengthen muscles, but not through range of motion, are unlikely to be effective by themselves. Isokinetic and isotonic strengthening (strengthening that occurs when a person flexes or extends the knees against resistance) have been shown consistently to be efficacious. Low-impact exercises, including water aerobics and water resistance training, are often better tolerated by patients than exercises involving impact loading, such as running or treadmill exercises. A patient should be referred to an exercise class or to a therapist who can create an individualized regimen, and then an individualized home-based regimen can be crafted.
There is no strong evidence that patients with hip or hand OA benefit from therapeutic exercise, although for any patient with OA, individualized exercise programs should be tried. Adherence to exercise over the long term is the major challenge to an exercise prescription. In trials involving patients with knee OA who are interested in exercise treatment, a third to over a half of patients stopped exercising by 6 months. Less than 50% continued regular exercise at 1 year. The strongest predictor of continued exercise in a patient is a previous personal history of successful exercise. Physicians should reinforce the exercise prescription at each clinic visit, help the patient recognize barriers to ongoing exercise, and identify convenient times for exercise to be done routinely. The combination of exercise with calorie restriction is especially effective in lessening pain.
One clinical trial has suggested that, among those with very early OA, participating in a strengthening and multimodality exercise program led to improvement in cartilage biochemistry, as evidenced by MRI imaging. There is little other evidence, however, that strengthening or other exercise has an effect on joint structure.

Correction of Malalignment
Malalignment in the frontal plane (varus-valgus) markedly increases the stress across the joint, which can lead to progression of disease and to pain and disability (Fig. 326-5). Correcting malalignment, either surgically or with bracing, can relieve pain in persons whose knees are maligned. Malalignment develops over years as a consequence of gradual anatomic alterations of the joint and bone, and correcting it is often very challenging. One way is with a fitted brace, which takes an often varus osteoarthritic knee and straightens it by putting valgus stress across the knee. Unfortunately, many patients are unwilling to wear a realigning knee brace, plus in patients with obese legs, braces may slip with usage and lose their realigning effect. They are indicated for willing patients who can learn to put them on correctly and on whom they do not slip.
Other ways of correcting malalignment across the knee include the use of orthotics in footwear. Unfortunately, while they may have modest effects on knee alignment, trials have heretofore not demonstrated efficacy of a lateral wedge orthotic vs. placebo wedges.
Pain from the patellofemoral compartment of the knee can be caused by tilting of the patella or patellar malalignment with the patella riding laterally (or less often, medially) in the femoral trochlear groove. Using a brace to realign the patella, or tape to pull the patella back into the trochlear sulcus or reduce its tilt, has been shown, when compared to placebo taping in clinical trials, to lessen patellofemoral pain. However, patients may find it difficult to apply tape, and skin irritation from the tape is common. Commercial patellar braces may be a solution, but they have not been tested.
While their effect on malalignment is questionable, neoprene sleeves pulled to cover the knee lessen pain and are easy to use and popular among patients. The explanation for their therapeutic effect on pain is unclear.
In patients with knee OA, acupuncture produces modest pain relief compared to placebo needles and may be an adjunctive treatment.

While nonpharmacologic approaches to therapy constitute its mainstay, pharmacotherapy serves an important adjunctive role in OA treatment. Available drugs are administered using oral, topical, and intraarticular routes.

Acetaminophen, Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), and COX-2 Inhibitors
Acetaminophen (paracetamol) is the initial analgesic of choice for patients with OA in knee, hip, or hands. For some patients, it is adequate to control symptoms, in which case more toxic drugs such as NSAIDs can be avoided. Doses up to 1 g 4 times daily can be used (Table 326-1).
Table 326-1 Pharmacologic Treatment for Osteoarthritis
Up to 1 g qid
Prolongs half-life of warfarin
Take with food. High rates of gastrointestinal side effects, including ulcers and bleeding, occur. Patients at high risk for gastrointestinal side effects should also take either a proton-pump inhibitor or misoprostol.b There is an increased concern about side effects (gastrointestinal or bleeding) when taken with acetylsalicylic acid. Can also cause edema and renal insufficiency.
375–500 mg bid
1500 mg bid
600–800 mg 3–4 times a day
Cyclooxygenase-2 inhibitors
100–200 mg/d
High doses are associated with an increased risk of myocardial infarction and stroke. Can cause edema and renal insufficiency.
Common side effects include dizziness, sedation, nausea or vomiting, dry mouth, constipation, urinary retention, and pruritis. Respiratory and central nervous system depression can occur.
0.025–0.075% cream 3–4 times a day
Can irritate mucous membranes.
Intraarticular injections
Varies from 3 to 5 weekly injections depending on preparation
Mild to moderate pain at injection site. Controversy exists re: efficacy.

aNSAIDs denotes nonsteroidal anti-inflammatory drugs.
bPatients at high risk include those with previous gastrointestinal events, persons 60 years, and persons taking glucocorticoids. Trials have shown the efficacy of proton-pump inhibitors and misoprostol in the prevention of ulcers and bleeding. Misoprostol is associated with a high rate of diarrhea and cramping; therefore, proton-pump inhibitors are more widely used to reduce NSAID-related gastrointestinal symptoms.

NSAIDs are the most popular drugs to treat osteoarthritic pain. In clinical trials, NSAIDs produce ~30% greater improvement in pain than high-dose acetaminophen. Occasional patients treated with NSAIDs experience dramatic pain relief, whereas others experience little improvement. Initially, NSAIDs should be taken on an "as needed" basis because side effects are less frequent with low intermittent doses, which may be highly efficacious. If occasional medication use is insufficiently effective, then daily treatment with NSAIDs is indicated, with an anti-inflammatory dose selected (Table 326-1). Patients should be reminded to take low-dose aspirin and NSAIDs at different times to eliminate drug interactions.
NSAIDs have substantial and frequent side effects, the most common of which is upper gastrointestinal toxicity, including dyspepsia, nausea, bloating, gastrointestinal bleeding, and ulcer disease. Some 30–40% of patients experience upper gastrointestinal (GI) side effects so severe as to require discontinuation of medication. Strategies to avoid or minimize the risk of nonsteroidal related GI side effects include:
·         Take medications after food.
·         Avoid use of two NSAIDs.
·         Use a relatively safe NSAID. In terms of GI toxicity, meta-analyses have suggested that nonacetylated salicylates, ibuprofen and nabumetone, are among the safer NSAIDs; more dangerous ones include piroxicam, ketorolac, and ketoprofen.
·         For persons at high risk of GI bleeding and/or complications, prescribe a gastroprotective agent (Table 326-1).
Major NSAID-related GI side effects can occur in patients who do not complain of upper GI symptoms. In one study of patients hospitalized for GI bleeding, 81% had no premonitory symptoms.
There are other common side effects of NSAIDs, including the tendency to develop edema, because of prostaglandin inhibition of afferent blood supply to glomeruli in the kidneys and, for similar reasons, a predilection toward reversible renal insufficiency. Blood pressure may increase modestly in some NSAID-treated patients.
Alternative anti-inflammatory medications are cyclooxygenase-2 (COX-2) inhibitors. While their rate of GI side effects may be less than for conventional NSAIDs, their risk of causing edema and renal insufficiency is similar. In addition, COX-2 inhibitors, especially at high dose, increase the risk of myocardial infarction and of stroke. This is because selective COX-2 inhibitors reduce prostaglandin I2 production by vascular endothelium, but do not inhibit platelet thromboxane A2 production, leading to an increased risk of intravascular thrombosis.

Intraarticular Injections: Glucocorticoids and Hyaluronic Acid
Since synovial Inflammation is likely to be a major cause of pain in patients with OA, local anti-inflammatory treatments administered intraarticularly may be effective in ameliorating pain, at least temporarily. Glucocorticoid injections provide such efficacy, but work better than placebo injections for only 1 or 2 weeks. This may be because the disease remains mechanically driven and, when a person begins to use the joint, the loading factors that induce pain return. Glucocorticoid injections are useful to get patients over acute flares of pain and may be especially indicated if the patient has coexistent OA and crystal deposition disease, especially from calcium pyrophosphate dihydrate crystals (Chap. 327). There is no evidence that repeated glucocorticoid injections into the joint are dangerous.
Hyaluronic acid injections can be given for treatment of symptoms in knee and hip OA, but there is controversy as to whether they have efficacy vs. placebo (Table 326-1).
Optimal therapy for OA is often achieved by trial and error, with each patient having idiosyncratic responses to specific treatments. When medical therapies have failed and the patient has an unacceptable reduction in their quality of life and ongoing pain and disability, then at least for knee and hip OA, total joint arthroplasty is indicated.

For knee OA, several operations are available. Among the most popular surgeries, at least in the United States, is arthroscopic debridement and lavage. A well done randomized trial evaluating this operation showed that its efficacy was no greater than that of sham surgery for relief of pain or disability. There is controversy as to whether mechanical symptoms such as buckling, which are extremely common in patients with knee OA, respond to arthroscopic debridement. While buckling is usually due to muscle weakness, a history of a recent injury, along with knee catching or locking, may suggest a meniscal tear is contributing to this symptom. In such cases arthroscopic debridement with partial meniscal resection might be warranted.
For patients with knee OA isolated to the medial compartment, operations to realign the knee to lessen medial loading can relieve pain. These include a high tibial osteotomy, in which the tibia is broken just below the tibial plateau and realigned so as to load the lateral, nondiseased compartment, or a unicompartmental replacement with realignment. Each surgery may provide the patient with years of pain relief before they require a total knee replacement.
Ultimately, when the patient with knee or hip OA has failed medical treatment modalities and remains in pain, with limitations of physical function that compromise the quality of life, the patient should be referred for total knee or hip arthroplasty. These are highly efficacious operations that relieve pain and improve function in the vast majority of patients. Currently failure rates are ~1% per year, although these rates are higher in obese patients. The chance of surgical success is greater in centers where at least 50 such operations are performed yearly or with surgeons who perform a similar number annually. The timing of knee or hip replacement is critical. If the patient suffers for many years until their functional status has declined substantially, with considerable muscle weakness, postoperative functional status may not improve to a level achieved by others who underwent operation earlier in their disease course.

Cartilage Regeneration
Chondrocyte transplantation has not been found to be efficacious in OA, perhaps because OA includes pathology of joint mechanics, which is not corrected by chondrocyte transplants. Similarly, abrasion arthroplasty (chondroplasty) has not been well studied for efficacy in OA, but it produces fibrocartilage in place of damaged hyaline cartilage. Both of these surgical attempts to regenerate and reconstitute articular cartilage may be more likely to be efficacious early in disease when joint malalignment and many of the other noncartilage abnormalities that characterize OA have not yet developed.

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