Studies suggest that many persons with painful osteoarthritis already have extensive structural disease including malalignment, which may preclude successful stabilization or reversal of disease; this provides a strong rationale for developing strategies to prevent disease or to identify and treat it early. This article reviews a variety of approaches likely to capture those at high risk of or with early disease. However, given the absence of effective treatments, it is unclear whether structural disease could be successfully slowed or prevented in those with early symptoms or at high risk of disease.
Key points
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The limited efficacy of current nonsurgical treatments for osteoarthritis (OA) may be due partly to their use at a late point in the evolution of disease when structural deterioration is often advanced; this provides a rationale for identifying persons with early disease or those at high risk.
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Persons at especially high risk of later disease who would be good targets for treatment are those with sports-related major knee injuries, those with anatomic abnormalities of their hips associated with a high rate of later OA, and those from families with an unusually high risk of early disease.
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Chronic knee pain is a harbinger of knee OA.
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Evolving imaging approaches using magnetic resonance imaging hold promise in identifying joints with reversible structural findings that represent early lesions of OA.
Introduction
Osteoarthritis (OA) is the most common form of arthritis. Although prevalence estimates differ depending on the country and how disease is assessed, OA clearly affects millions of persons in the United States and a similar number in Europe. In developing countries it is also the most common form of arthritis. OA prevalence increases with age and with obesity, and the rapidly increasing demand for knee and hip replacements is due in part to the burgeoning population of those with OA because of the aging of the population and increasing rates of obesity. OA is the most common cause of mobility disability in the world, and its overall impact as a cause of years lived with disability and limited quality of life is rising.
One of the central reasons for the increase in demand for knee and hip replacements is that medical and rehabilitative treatments for OA are not very effective. There are no treatments that have been shown consistently to delay the structural progression of disease, and none is approved by regulatory agencies for this purpose. Meta-analyses suggest that nonsurgical treatments such as exercise, anti-inflammatory medications, and others all have modest efficacy at best. New more effective treatments for established disease are badly needed.
One major reason why treatments are not delaying joint replacement surgery may be that treatment begins too late in the course of OA to have an effect. Many of the structural findings uncovered in recent comprehensive cohort studies of persons with knee OA have suggested that most persons with disease have advanced structural findings in the knee by the time they are clinically diagnosed, and have frequent knee pain. Varus or valgus malalignment, meniscal damage such as tears, and prevalent cartilage loss are all common features of middle-aged and older persons with new-onset chronic knee pain. Radiographic evidence of OA is a relatively late phenomenon in the structural evolution of this disease. For example, alterations in the shape of the periarticular bones often precede the development of disease by 5 to 10 years radiographically. Abnormalities seen on magnetic resonance imaging (MRI) are present several years before disease development in most cases. Many of these structural changes are not known to be reversible and, to the extent that they drive disease progression, a patient presenting with knee pain is often on the downslope of such a trajectory.
A recent focus on changes in the peripheral and central nervous system that develop as part of osteoarthritic pain suggests that nervous system–related changes have also occurred in many persons by the time they develop the chronic pain of OA. These changes in the nervous system make treatment more challenging and pain more severe than might have occurred had the disease been identified and treated earlier.
Therefore, the rationale for focusing on early OA is that irreversible structural changes may not yet be established and that chronic nervous system sensitization to pain has not yet evolved. To target early OA, the choice might include those with early disease and those at high risk of disease who do not yet have symptoms or early disease.
The evolution of OA from the earliest evidence of joint injury to end-stage disease is shown in Fig. 1 . Early osteochondral lesions are usually unaccompanied by symptoms in middle-aged and elderly persons. Even meniscal tears, which are common and occur incidentally, are often not associated with knee pain or other symptoms. The initial defect in cartilage or initial meniscal tear or extrusion is followed by a constellation of features including more damage in the initial location leading to asymmetry of the joint and malalignment, bony remodeling, and damage to adjacent tissues. For example, an incidental meniscal tear puts a knee at high risk of adjacent cartilage damage and of meniscal extrusion. There is tissue loss between the 2 bones and narrowing of the joint on that side, initially to a subtle degree that is not visible on the radiograph. First symptoms occur only after this process is far advanced, and are mild and intermittent. The patient usually does not seek care until symptoms including pain are more troublesome or frequent. By the time symptoms are present, roughly 80% of knees have clinically important frontal plane malalignment (varus or valgus) and even knees without frontal plane malalignment often have patellofemoral malalignment. This malalignment increases stress or focal loading across the affected region of the joint. Cartilage loss and/or meniscal damage is the rule.
Other features of disease that can coexist at the time include ligamentous laxity, proprioceptive deficiencies, muscle weakness, and synovitis. Whereas some of these, such as muscle weakness and synovitis, may be amenable to therapy, for others there is no known therapy. Thus, for early treatment approaches to be successful, at least for knee OA, patients need to be identified at a point before the development of meniscal damage, substantial cartilage loss, or malalignment. Waiting for radiographic evidence of disease for diagnosis is almost certainly too late because many of the irreversible structural findings accompany radiographic changes. Ideally an approach that targets either those at high risk who are willing to consider preventive therapy or those with very early disease constitute the most likely route to success.
Introduction
Osteoarthritis (OA) is the most common form of arthritis. Although prevalence estimates differ depending on the country and how disease is assessed, OA clearly affects millions of persons in the United States and a similar number in Europe. In developing countries it is also the most common form of arthritis. OA prevalence increases with age and with obesity, and the rapidly increasing demand for knee and hip replacements is due in part to the burgeoning population of those with OA because of the aging of the population and increasing rates of obesity. OA is the most common cause of mobility disability in the world, and its overall impact as a cause of years lived with disability and limited quality of life is rising.
One of the central reasons for the increase in demand for knee and hip replacements is that medical and rehabilitative treatments for OA are not very effective. There are no treatments that have been shown consistently to delay the structural progression of disease, and none is approved by regulatory agencies for this purpose. Meta-analyses suggest that nonsurgical treatments such as exercise, anti-inflammatory medications, and others all have modest efficacy at best. New more effective treatments for established disease are badly needed.
One major reason why treatments are not delaying joint replacement surgery may be that treatment begins too late in the course of OA to have an effect. Many of the structural findings uncovered in recent comprehensive cohort studies of persons with knee OA have suggested that most persons with disease have advanced structural findings in the knee by the time they are clinically diagnosed, and have frequent knee pain. Varus or valgus malalignment, meniscal damage such as tears, and prevalent cartilage loss are all common features of middle-aged and older persons with new-onset chronic knee pain. Radiographic evidence of OA is a relatively late phenomenon in the structural evolution of this disease. For example, alterations in the shape of the periarticular bones often precede the development of disease by 5 to 10 years radiographically. Abnormalities seen on magnetic resonance imaging (MRI) are present several years before disease development in most cases. Many of these structural changes are not known to be reversible and, to the extent that they drive disease progression, a patient presenting with knee pain is often on the downslope of such a trajectory.
A recent focus on changes in the peripheral and central nervous system that develop as part of osteoarthritic pain suggests that nervous system–related changes have also occurred in many persons by the time they develop the chronic pain of OA. These changes in the nervous system make treatment more challenging and pain more severe than might have occurred had the disease been identified and treated earlier.
Therefore, the rationale for focusing on early OA is that irreversible structural changes may not yet be established and that chronic nervous system sensitization to pain has not yet evolved. To target early OA, the choice might include those with early disease and those at high risk of disease who do not yet have symptoms or early disease.
The evolution of OA from the earliest evidence of joint injury to end-stage disease is shown in Fig. 1 . Early osteochondral lesions are usually unaccompanied by symptoms in middle-aged and elderly persons. Even meniscal tears, which are common and occur incidentally, are often not associated with knee pain or other symptoms. The initial defect in cartilage or initial meniscal tear or extrusion is followed by a constellation of features including more damage in the initial location leading to asymmetry of the joint and malalignment, bony remodeling, and damage to adjacent tissues. For example, an incidental meniscal tear puts a knee at high risk of adjacent cartilage damage and of meniscal extrusion. There is tissue loss between the 2 bones and narrowing of the joint on that side, initially to a subtle degree that is not visible on the radiograph. First symptoms occur only after this process is far advanced, and are mild and intermittent. The patient usually does not seek care until symptoms including pain are more troublesome or frequent. By the time symptoms are present, roughly 80% of knees have clinically important frontal plane malalignment (varus or valgus) and even knees without frontal plane malalignment often have patellofemoral malalignment. This malalignment increases stress or focal loading across the affected region of the joint. Cartilage loss and/or meniscal damage is the rule.
Other features of disease that can coexist at the time include ligamentous laxity, proprioceptive deficiencies, muscle weakness, and synovitis. Whereas some of these, such as muscle weakness and synovitis, may be amenable to therapy, for others there is no known therapy. Thus, for early treatment approaches to be successful, at least for knee OA, patients need to be identified at a point before the development of meniscal damage, substantial cartilage loss, or malalignment. Waiting for radiographic evidence of disease for diagnosis is almost certainly too late because many of the irreversible structural findings accompany radiographic changes. Ideally an approach that targets either those at high risk who are willing to consider preventive therapy or those with very early disease constitute the most likely route to success.
Risk factors: identifying those at high risk of early osteoarthritis
Age
The major risk factor for OA is older age. In all joints and among both genders, OA prevalence increases steeply with age, starting at around age 50 to 55 years. A multitude of factors contributes to this increase, including the senescence of cartilage leading to its fragility, the failure of periarticular structures that provide protection against joint damage during weight bearing, increasing muscle weakness with age, neurosensory failure with age, and ligamentous laxity. Because of these changes (many of which are age-related) and the challenge in reversing them, targeting early OA may need to focus on persons of middle age who may be at high risk of developing OA earlier than expected. Because knee and hip replacements are often reserved for older persons, early onset of OA when a person is in their 30s or 40s poses special therapeutic challenges, and the reward for any prevention strategy may be great.
Obesity
Obesity plays a major role in increasing the risk of OA of the knee and, to a lesser extent, the hip. Jiang and colleagues have suggested that eliminating the problem of obesity might prevent up to 50% of knee OA in the United States and a lesser proportion in countries where obesity is not as prevalent. Effects of obesity in causing OA may be complex. Obesity not only increases the risk of knee and hip OA but also increases the risk of hand OA, suggesting that its effects on disease are not completely mediated by effects on mechanical load. Indeed, adipokines have been linked with OA occurrence, although there are no clear-cut data as yet to suggest that the effects of leptin or other adipokines are independent of the loading effect of weight. Convincing evidence demonstrating the role of adipokines might point to an opportunity for slowing the rate of progression of disease in those who are obese.
Gender
Women are at substantially higher risk than men of contracting OA in all joints except the hips. Women are more likely than men to develop structural disease in their joints, and, for a given level of structural disease, women are also more likely to have joint pain. Although women have higher rates of OA than men, this gender difference does not develop until the sixth decade, when women have just gone through or are going through the menopause. This fact has obviously raised questions about whether estrogen or hormonal loss triggers OA, a matter as yet unresolved despite many studies.
Traumatic Joint Injury
Among the most potent risk factors for OA is major injury, such as from sports, leading to an anterior cruciate ligament (ACL) or meniscal tear. In the knee, such major injuries account for approximately 10% of all OA, but in joints that are rarely affected by OA such as the ankles, injuries account for more than 70% of OA cases. Meniscal damage, including tears and extrusion, has been consistently shown to be among the most potent risk factors for later development of OA. Even incidental tears with no recollected injury pose a very high risk of later disease, and a partial meniscectomy does not necessarily reduce this risk. Similarly, ACL tears even without concomitant meniscal tears increase the risk of OA later, and surgical treatment does not seem to lessen this risk.
Injuries such as ACL and meniscal tears may represent a special opportunity to prevent OA. These injuries occur in young persons whose joints are otherwise normal, without the coexisting pathomechanics and bone-shape alterations that typify clinical OA. Animal studies have identified a superhealer strain of mouse which, faced with traumatic joint injury, heals without arthritis. Characteristics of these mice include a blunted inflammatory response, suggesting that prolific inflammation may be a major cause of permanent joint damage after an injury, and that ablating this inflammatory response may lessen the ultimate joint damage. There are ongoing trials testing whether disease can be prevented by administering potent anti-inflammatory treatments at an early stage after either ACL or meniscal tears.
In the knee, frontal plane malalignment ( Fig. 2 ), in either the varus or valgus direction, is a major cause of disease progression. Usually malalignment develops as a consequence of disease when cartilage loss or meniscal extrusion narrows one side of the joint. However, even among normal prediseased knees there is a modest variation in alignment status, and some normal people have varus or valgus knees without any preexisting knee damage. Recent studies have shown definitively that prediseased knees with malalignment are at modestly increased risk of developing OA, probably because such knees experience increased focal loads at the site of malalignment and these loads ultimately lead to tissue breakdown, especially as a person becomes older and their intra-articular soft tissue becomes more fragile.
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