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Sections of Clinical Epidemiology Research, Training Unit and Rheumatology, 650 Albany Street, Suite X200, Boston University School of Medicine, Boston, MA, 02118, USA
Osteoarthritis (OA) is the most common form of arthritis, with OA of the knee, hand, or hip having a similar prevalence of approximately 20% to 30% of adults in various populations.
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Person-level factors associated with OA include increasing age, female sex, overweight/obesity, and race/ethnicity, which may represent genetic or sociocultural influences.
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Joint-level factors associated with OA are reflective of mechanisms related to abnormal loading of the joints.
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Several methodologic challenges to the study of OA exist, which have affected our ability to identify important relationships.
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There is a need for ongoing epidemiologic and intervention studies regarding the prevention of incident and progressive OA and related pain.
Introduction
Osteoarthritis (OA) is the most common form of arthritis,
OA is frequently defined by radiography, with the most commonly used radiographic grading system being the Kellgren and Lawrence (KL) grade, which scores OA severity on a scale of 0 to 4; definite radiographic OA is KL grade 2 or greater.
The KL grading system has been used for the hand, hip, and knee; however, at the knee it is only used to define tibiofemoral OA. Patellofemoral radiographic OA can also be assessed if appropriate radiographic views are obtained. The Osteoarthritis Research Society International Atlas provides a means to score individual radiographic features, such as osteophytes and joint-space narrowing, in a semi-quantitative manner,
Joint space width measures cartilage thickness in osteoarthritis of the knee: high resolution plain film and double contrast macroradiographic investigation.
Numerous joint structures that are not otherwise visualized on radiographs can be examined by magnetic resonance imaging (MRI). An MRI definition of OA has been proposed, but requires validation.
However, individual structural lesions on MRI are well described, including cartilage lesions, osteophytes, bone marrow lesions, synovitis, effusion, and subchondral bone attrition.
Of knees without radiographic evidence of tibiofemoral OA (KL 0) in adults 50 years or older, the enhanced sensitivity of MRI revealed that 89% had at least 1 such abnormality in the tibiofemoral joint, with similar prevalences in painful and painless knees.
Prevalence of abnormalities in knees detected by MRI in adults without knee osteoarthritis: population based observational study (Framingham Osteoarthritis Study).
Symptomatic OA indicates the presence of radiographic OA in combination with knee symptoms attributable to OA. Not all individuals with radiographic OA have concomitant symptoms. OA may be described in a joint-specific manner (eg, knee OA, hip OA), or, when several joint areas are involved, it may be considered as being generalized (eg, involvement with OA of at least 1 of each joint area: knee, hip, and hand), although a standard definition for generalized OA does not yet exist.
Incidence and prevalence of OA
One estimate of the lifetime risk of developing symptomatic knee OA was approximately 40% in men and 47% in women, with higher risks among those who are obese.
Age- and sex-standardized incident rates for symptomatic hand, hip, and knee OA have been estimated to be 100, 88, and 240 cases per 100,000 person-years, respectively, with incidence rates rising sharply after age 50 and leveling off after age 70 years (Fig. 1).
However, the interpretation of the leveling off or decline in OA incidence at older ages should be made with caution, given the potential biases related to competing risks and depletion of susceptibles (see later discussion on methodologic challenges).
Recent estimates of incidence of hand OA derived from the Framingham Osteoarthritis Study were approximately 34% to 35% for OA incidence in any hand joint for both sexes, with incidence of symptomatic hand OA being 4% for men and 9.7% for women over a 9-year period.
Fig. 1Incidence of osteoarthritis of hand, hip, and knee in a community health plan, 1991 to 1992, by age and sex.
(Data from Oliveria SA, Felson DT, Reed JI, et al. Incidence of symptomatic hand, hip, and knee osteoarthritis among patients in a health maintenance organization. Arthritis Rheum 1995;38:1134–41.)
There has been an increase in OA prevalence, with an estimated 27 million United States adults in 2005 having clinical OA of their hand, knee, or hip joint, an increase from 21 million in 1995.
Such increases are likely due to aging of the population and the rising prevalence of obesity. In Framingham, the age-standardized prevalence of radiographic hand OA was 44.2% in women and 37.7% in men,
From the Johnston County Osteoarthritis Project, approximately 28% of African Americans and Caucasians aged 45 or older had knee OA and 28% had hip OA.
Prevalence of knee symptoms and radiographic and symptomatic knee osteoarthritis in African Americans and Caucasians: the Johnston County Osteoarthritis Project.
Prevalence of hip symptoms and radiographic and symptomatic hip osteoarthritis in African Americans and Caucasians: the Johnston County Osteoarthritis Project.
Symptomatic prevalence estimates for OA are lower because it requires the presence of radiographic OA with pain, aching, or stiffness in the joint. The age-standardized prevalence of symptomatic hand OA was 14.4% and 6.9% in women and men, respectively, in younger Framingham cohorts,
Prevalence of knee symptoms and radiographic and symptomatic knee osteoarthritis in African Americans and Caucasians: the Johnston County Osteoarthritis Project.
Prevalence of hip symptoms and radiographic and symptomatic hip osteoarthritis in African Americans and Caucasians: the Johnston County Osteoarthritis Project.
There has also been an increase in prevalence of symptomatic knee OA over the past 20 years by 4.1% and 6% among women and men, respectively, in the Framingham cohort.
Racial/ethnic differences in the prevalence of OA and specific patterns of joint involvement have been noted. In the Johnston County OA Project, African American men had a higher prevalence of radiographic hip OA than Caucasian men (32.2% vs 23.8%), whereas there was no difference between African American and Caucasian women (40.3% vs 39.4%).
Prevalence of hip symptoms and radiographic and symptomatic hip osteoarthritis in African Americans and Caucasians: the Johnston County Osteoarthritis Project.
Characterization of individual radiographic features of hip osteoarthritis in African American and White women and men: the Johnston County Osteoarthritis Project.
In the Beijing Osteoarthritis Study, hand and hip OA were less prevalent among Chinese than Caucasians (age-standardized prevalences 44.5%–47% vs 75.2%–85% and 0.8% vs 3.8–4.5%, respectively), but knee OA was more prevalent among Chinese women than among Caucasian women (46.6% vs 34.8%).
Very low prevalence of hip osteoarthritis among Chinese elderly in Beijing, China, compared with whites in the United States: the Beijing osteoarthritis study.
Comparison of the prevalence of knee osteoarthritis between the elderly Chinese population in Beijing and whites in the United States: the Beijing Osteoarthritis Study.
Lower prevalence of hand osteoarthritis among Chinese subjects in Beijing compared with white subjects in the United States: the Beijing Osteoarthritis Study.
OA can be thought of as the phenotypic manifestation of a series of different pathways leading to a common end-stage pathology (Fig. 2). As such, the disease has a multifactorial etiology, with different sets of risk factors (at a person and/or joint level) acting together to cause onset of OA in any given individual. Person-level factors are generally those that are thought to act at a systemic level on all relevant joints or are a characteristic of the individual, whereas joint-level factors generally refer to those that are joint specific and may be unique to a particular joint.
Fig. 2Potential risk factors for susceptibility to incidence and progression of osteoarthritis (OA), each with varying degrees of evidence to support their association (see text for details). LLI, leg-length inequality.
The exact mechanism is not known, but is likely related to a combination of changes in the capacity for joint tissues to adapt to biomechanical insults, and age being a proxy for the accumulation of a sufficient set of risk factors over the years.
Female sex is associated with higher prevalence and greater severity of OA.
The increase in prevalence and incidence of OA at the time of the menopause has led to hypotheses regarding the role of estrogen in OA, such as the loss of estrogen potentially unmasking the symptoms of OA by enhancing pain sensitivity. However, results from observational studies and clinical trials have been conflicting regarding estrogen effects on OA.
The effect of estrogen plus progestin on knee symptoms and related disability in postmenopausal women: the Heart and Estrogen/Progestin Replacement Study, a randomized, double-blind, placebo-controlled trial.
In the Heart and Estrogen/Progestin Replacement Study, there was no difference in knee pain in those randomized to receive estrogen replacement therapy compared with those receiving placebo.
The effect of estrogen plus progestin on knee symptoms and related disability in postmenopausal women: the Heart and Estrogen/Progestin Replacement Study, a randomized, double-blind, placebo-controlled trial.
On the other hand, in the Women’s Health Initiative, unopposed estrogen therapy was associated with a borderline significant lower rate of joint arthroplasty, but no such association was noted for estrogen plus progestin in comparison with placebo.
Women may have thinner and more reduced volume of knee cartilage than men (even after taking into account differences in height, weight, and bone size); whether women have a more accelerated rate of loss of cartilage volume than men is not clear.
Obesity
Obesity has long been identified as a risk factor for knee OA.
In a meta-analysis, those who were obese or overweight had 2.96-times higher risk of incident knee OA compared with those of normal weight (95% confidence interval [CI] 2.56–3.43).
Assuming the prevalence of obesity in a hypothetical population to be 25%, the population-attributable risk percentage due to obesity would therefore be 29% (95% CI 24%–34%); this would be higher where obesity prevalence is higher.
Furthermore, those who were only overweight (not obese) had more than twice the chance of developing knee OA compared with their normal-weight counterparts.
Risk of incident knee OA increases with increasing body mass index (BMI; weight in kilograms divided by height in meters squared, ie, kg/m2), regardless of knee alignment.
Duration of exposure to high BMI during adulthood confers risk of incident knee OA, suggesting the importance of weight control throughout life as a means of primary prevention of knee OA.
Obesity also contributes to symptoms in knee OA, with the Arthritis, Diet, and Activity Promotion Trial (ADAPT) and Intensive Diet and Exercise for Arthritis (IDEA) trial both demonstrating improvements in pain accompanying weight loss related to dietary and exercise interventions.
In contrast to data supporting the role of obesity in the development of knee OA, high BMI was not associated with progressive radiographic knee OA in one study.
demonstrated that high BMI increased the risk of both mild radiographic OA (KL = 2) and moderate to severe radiographic OA (KL = 3 or 4) among knees that were KL = 0 at baseline, respectively. Because knees that develop KL = 3 or 4 over time must have gone through the KL = 2 stage, this provides indirect evidence that obesity increases the risk of incident knee OA and also accelerates the progression of knee OA.
The effects of obesity on OA may be through both mechanical and systemic effects (eg, metabolic or inflammatory). There is no doubt about an effect of increased load related to overall body weight, but there may be differential systemic effects that depend on the degree of fat versus lean mass; unfortunately, BMI does not differentiate between the two. Recently, total body fat measured by dual-energy x-ray absorptiometry was associated with decreased cartilage thickness while lean mass was associated with increased cartilage thickness.
Adipose tissue is known to be metabolically active, secreting adipokines such as adiponectin, leptin, and resistin, but the role of these adipokines in OA is not yet clear.
further supporting potential metabolic or inflammatory effects of obesity. By contrast, the association between obesity and hip OA has been variable and, where noted, less strong than for the knee or hand.
To date 3 loci, GDF5, which encodes the growth differentiation factor 5 (a bone morphogenetic protein expressed in skeletal and articular structures), chromosome 7q22, and MCF2L have been associated with OA at genome-wide significance levels.
Two single-nucleotide polymorphisms (SNPs) were on chromosome 3, in linkage disequilibrium with each other within an exon of nucleostemin-encoding GNL3; one on chromosome 9 close to ASTN2; one on chromosome 6 between FILIP1 and SENP6; one on chromosome 12 close to KLHDC5 and PTHLH; and another on chromosome 12 close to CHST11.
Of note, the previously identified loci did not achieve genome-wide significance in this arcOGEN sample.
Pain severity related to OA may also have genetic contributions. A functional polymorphism (Val158Met) in the COMT gene, which has been associated with pain sensitivity in other clinical conditions, was associated with hip OA–related pain in one cohort study, but has not yet been replicated in other cohorts.
Other genes associated with pain sensitivity have also been studied in relation to OA pain. TRPV1 and the PACE4 gene Pcsk6 were associated with pain in knee OA in two separate meta-analyses,
High systemic bone mineral density increases the risk of incident knee OA and joint space narrowing, but not radiographic progression of existing knee OA: the MOST study.
recently confirmed the previous observation that higher systemic bone mineral density (BMD) was associated with an increased risk of incident OA. Whether this finding is related to factors contributing to bone remodeling or peak bone mass that may be genetically determined,
or whether the higher systemic BMD represents higher BMI load over the years before onset of OA (itself a strong risk factor for OA), is not clear. Paradoxically, BMD was not associated with progressive OA in the same study.
High systemic bone mineral density increases the risk of incident knee OA and joint space narrowing, but not radiographic progression of existing knee OA: the MOST study.
That is, once symptomatic OA has developed an individual may decrease his or her physical activity and therefore loading of the joint, which in turn can contribute to low BMD. Furthermore, there is evidence to suggest that although the apparent density of bone in OA may be increased, the bone itself is less mineralized, resulting in lower material density.
The effects of readily modifiable dietary factors in humans have been inconclusive. Studies of the relationship between vitamin D and OA have been conflicting.
Effect of vitamin D supplementation on progression of knee pain and cartilage volume loss in patients with symptomatic osteoarthritis: a randomized controlled trial.
One difficulty in the conduct of such a study is that it is unethical to conduct a fully placebo-controlled trial; whether the 400 IU/d given to the control arm was sufficient to account for the negative results is not clear. Antioxidant vitamins such as vitamins C and E have also been studied in relation to OA, with conflicting results.
A case-control study of serum tocopherol levels and the alpha- to gamma-tocopherol ratio in radiographic knee osteoarthritis: the Johnston County Osteoarthritis Project.
Supplementary vitamin E does not affect the loss of cartilage volume in knee osteoarthritis: a 2 year double blind randomized placebo controlled study.
Vitamin K, which has potential bone and cartilage effects, has been associated cross-sectionally with hand and knee OA, incident radiographic knee OA, and MRI-based cartilage lesions, and with potentially less hand OA progression among those who were deficient at baseline in a randomized trial, although the overall trial results were null.
Association of low dietary vitamin K intake with radiographic knee osteoarthritis in the Japanese elderly population: dietary survey in a population-based cohort of the ROAD study.
Selenium and iodine deficiency has been associated with Kashin-Beck osteoarthropathy. In 2 observational cohort studies, both low and high levels of selenium have been associated with OA.
Incidence of severe knee and hip osteoarthritis in relation to dietary intake of antioxidants beta-carotene, vitamin C, vitamin E and Selenium: a population-based prospective cohort study.
and jobs requiring kneeling or squatting were associated with an increased risk of knee OA, particularly among those who were overweight or whose jobs required carrying or lifting, as well as worse cartilage morphology scores on MRI at the patellofemoral joint.
A recent meta-analysis noted a 1.6-fold increased risk of knee OA related to occupational activities, with most activities conferring increased risk other than standing.
These data are also supported by an increase in OA found in the interphalangeal joint of the thumb and in the second and third proximal interphalangeal and metacarpophalangeal joints of the hand used to eat with chopsticks, compared with other joints of that same hand or any joint in the opposite hand among Beijing Chinese.
Physical activity may have benefits for the joint by strengthening periarticular muscles to help stabilize the joint, but may potentially be detrimental if it places undue load on the joint, particularly one that is already vulnerable because of other risks. General population studies have shown that habitual levels of activity are not associated with incident radiographic/symptomatic OA or new knee replacement, whereas more vigorous levels of activity appeared to increase the risk of OA.
A recent study reported that daily walking of more than 10,000 steps per day may be associated with worsening of certain MRI features; however, certain biases could not be ruled out.
Risk of osteoarthritis associated with long-term weight-bearing sports: a radiologic survey of the hips and knees in female ex-athletes and population controls.
the mechanism by which vigorous or elite-level (or equivalent) physical activity/sports may be associated with increased risk of OA may be related to factors other than simple load bearing. In one study of athletes, the increased risk of OA appeared to be related to knee injury among soccer players, and increased BMI as well as squatting among weightlifters.
Several studies have demonstrated the importance of knee injury, such as injury related to meniscal tears requiring meniscectomy or anterior cruciate ligament injury, as a risk factor for onset of OA.
High prevalence of knee osteoarthritis, pain, and functional limitations in female soccer players twelve years after anterior cruciate ligament injury.
Long-term outcome of meniscectomy: symptoms, function, and performance tests in patients with or without radiographic osteoarthritis compared to matched controls.
Meniscal tear in knees without surgery and the development of radiographic osteoarthritis among middle-aged and elderly persons: The Multicenter Osteoarthritis Study.
For example, floor layers, who spend much time kneeling, were more likely to have degenerative meniscal tears than were graphic designers with no knee demands.
These studies support the importance of maintaining an intact meniscus to protect against development of OA.
Muscle strength
The effect of knee injury on the risk of OA may be partially related to muscle strength. Muscle weakness and atrophy can occur as a consequence of OA related to disuse resulting from pain avoidance, but whether it is a risk factor for the development of OA is not clear. In some studies, quadriceps muscle weakness was associated with increased risk of structural knee OA.
In another study, discrepant findings were noted for low knee extensor strength being associated with incident symptomatic knee OA, but not with incident radiographic OA.
In this study, the patellofemoral joint was included in the evaluation of incident symptomatic whole knee OA, but was not included in the definition of incident radiographic tibiofemoral OA. On the other hand, greater quadriceps strength in the setting of malalignment and laxity was associated with increased risk of progression of tibiofemoral OA in one study,
but no association with tibiofemoral progression was noted in another study, where it was also associated with less cartilage loss in the lateral patellofemoral joint,
Muscle strength could also potentially play a role in hand OA. For example, greater grip strength was associated with increased risk of developing radiographic hand OA.
However, potentially as a consequence of existing hand OA, a cross-sectional study found an inverse association between grip strength and prevalent OA of the first carpometacarpal joint, and between pinch strength and prevalent OA of the metacarpophalangeal joint.
Dynamic alignment (ie, the alterations in the knee that occur during gait) may be pertinent for understanding the specific load effects the joint is experiencing. In epidemiologic studies, however, static alignment from full-limb radiographs (mechanical axis) or from posteroanterior knee radiographs (ie, anatomic axis) is typically assessed according to feasibility. Prior studies have had conflicting findings regarding the effects of alignment on incident OA,
although more recent studies have reported that varus malalignment assessed by full-limb radiographs increased the incidence of both radiographic knee OA and cartilage damage.
These findings may imply that the association between alignment and development of OA is a vicious cycle: joint-space narrowing (eg, due to cartilage and meniscal abnormalities) and alterations of bony contour occurring in OA may themselves lead to joint malalignment, and malalignment itself can further alter joint loading and accelerate disease progression. However, no study to date has documented slowing of disease progression if alignment is corrected. Of interest, in post hoc analysis of data from a randomized placebo-controlled trial of doxycycline in obese middle-aged women with unilateral knee OA, varus malalignment was found to negate the potential chondroprotective effects of doxycycline.
Using a computational modeling approach with finite or discrete element analysis, knees that developed incident symptomatic OA demonstrated higher maximal contact stress and larger area of engagement with higher contact stresses at baseline than control knees that did not develop symptomatic OA, suggesting a local biomechanical role in the development of symptomatic knee OA.
Leg-length inequality (LLI) is an easily modifiable abnormality. Persons with LLI of at least 2 cm in the Johnston County OA Project were almost twice as likely to have prevalent radiographic knee OA, but no association was noted for incident knee OA.
Hazard of incident and progressive knee and hip radiographic osteoarthritis and chronic joint symptoms in individuals with and without limb length inequality.
Similar findings were noted using data from The MOST Study, in which persons with LLI of 1 cm or more were almost twice as likely to have prevalent radiographic knee OA in the shorter limb.
An association with incident radiographic knee OA was not found in that study, although LLI was associated with incident symptomatic knee OA. This discordance, as discussed earlier, may be related to the inclusion of the patellofemoral joint in the definition of symptomatic whole knee OA, whereas it is excluded from incident radiographic tibiofemoral OA.
Bone and joint morphology
The anatomy or the shape of a joint may contribute to the risk of OA, given that biomechanical load distribution through the joint is partially dependent on the geometric shape over which that load is distributed in addition to the material properties of the joint tissues receiving that load. This aspect has perhaps been best studied and described in the hip in relation to OA where, using active shape modeling, the 2-dimensional shape of the hip has been associated with OA.
Early identification of radiographic osteoarthritis of the hip using an active shape model to quantify changes in bone morphometric features: can hip shape tell us anything about the progression of osteoarthritis?.
Association of mild acetabular dysplasia with an increased risk of incident hip osteoarthritis in elderly white women: the study of osteoporotic fractures.
Pistol-grip deformity, or cam-type femoral acetabular impingement (FAI) syndrome, as well as the pincer-type FAI, have been associated with hip OA and hip pain.
Statistical shape modeling describes variation in tibia and femur surface geometry between Control and Incidence groups from the osteoarthritis initiative database.
Clinical symptoms related to knee OA are known to be activity related in the early stages, progressing to more persistent symptoms in late stages of disease that are punctuated with intermittent increased pain.
In The MOST Study, approximately 40% of persons with or at high risk of knee OA had fluctuating knee pain; these individuals had less severe KL grades on radiography, fewer depressive symptoms, and less widespread pain.
In the Longitudinal Examination of Arthritis Pain, an observational cohort study of 287 adults with hip or knee OA in which pain assessments were conducted weekly over 12 weeks, psychological factors fluctuated with pain severity,
supporting an important link between the pain experience and psychological state. Indeed, because numerous factors (many of which may not be assessed in a particular study) can contribute to the pain experience, such as genetics, sociocultural environment, and medications, among others, in addition to psychological factors, a so-called structure-symptom discordance is often described in OA.
However, when such between-person variability and confounding factors are accounted for by using a within-person knee-matched study design (in which one knee has pain while the other does not), a strong association between radiographic severity and knee pain can be discerned, even at the earliest stages of radiographic knee OA (Fig. 3).
Such findings indicate that certain structural lesions within the knee may be a cause of knee pain. Furthermore, specific MRI features of OA that can change over time, including bone marrow lesions, synovitis, and effusions, have been associated with fluctuation of knee pain.
As structural lesions worsened, the likelihood that the knee would be painful increased. Similarly, a decrease in the structural abnormalities of a knee was associated with the pain in that knee having subsided. A recent systematic review supports an association of MRI-detected bone marrow lesions and synovitis with the pain experience of OA.
Fig. 3Associations of frequent knee pain with Kellgren and Lawrence (KL) grade among people with two knees discordant for frequent knee pain status. Number of case knees (ie, with knee pain) and control knees (ie, without knee pain) are shown beneath the graph for each KL grade. Note that the y-axis is logarithmically scaled. CI, confidence interval.
(Data from Neogi T, Felson D, Niu J, et al. Association between radiographic features of knee osteoarthritis and pain: results from two cohort studies. BMJ 2009;339:b2844. http://dx.doi.org/10.1136/bmj.b2844.)
Most risk factors for OA, such as obesity or BMD, are chronic in nature. These chronic factors are likely to be present long before subjects are enrolled in a study. If those chronic risk factors have already caused a substantial proportion of subjects to develop knee OA, it is quite possible that participants who are still exposed to such a risk factor without yet having developed OA are less susceptible to knee OA than are individuals who have never been exposed to such a risk factor. For example, long-standing exposures such as obesity may have caused OA at an earlier age than in those being studied, but such a true effect cannot be discerned because those individuals who already have knee OA are excluded from studies of incident disease. Individuals who have been obese for a long time and who are free of OA at study onset may in fact be less susceptible to developing OA. Thus observational studies evaluating the association between a chronic exposure and incident knee OA may not be able to detect the true magnitude of effect. Such a phenomenon has been observed in other fields. For example, studies that have assessed BMI in midlife (in one’s 40s, 50s, and 60s) find that higher BMI is associated with an increased risk of death over the subsequent decades (in one’s 60s, 70s, and 80s). However, many investigations of BMI at age 70 or older find associations with mortality that are less clear.
One potential explanation for such findings is depletion of susceptibles among the elderly. Because the risk of knee OA increases rapidly around the middle 50s to 60s, one would ideally study subjects younger than this age to identify risk factors for incident knee OA. If OA studies consist of a large proportion of subjects who are older than the typical age of onset, the overall effect of a specific chronic risk factor is likely to be underestimated, owing to depletion of those who were susceptible to OA.
Loss to Follow-up and Competing Risks
The risk of developing new-onset OA is difficult to determine because of several challenges. OA is a chronic disease whose onset is typically unknown. In most OA cohort studies, repeated study visits with imaging may occur with a substantial interval between each study visit. As a result, there is a potential for loss to follow-up. For example, in 2 large cohort studies where knee radiographs were repeated after 4 and 9 years, respectively, both studies reported that approximately 40% did not undergo radiography at the follow-up visit.
Given that OA is a disease with onset in middle or older ages, death attributable to other causes than OA (competing risks) makes risk estimation difficult and prone to bias. In most cases, estimates of the risk of OA can only be obtained among subjects who provide both baseline and follow-up data. If loss to follow-up is associated with the occurrence of OA (as might be expected when older adults or obese participants are lost to follow-up, for example), the estimate of risk of OA based on those who are followed with complete data could be an underestimate.
Potential Discordant Findings for Risk Factors for Incident and Progressive Knee OA
Some risk factors associated with incident disease are not associated with or are even paradoxically protective against progressive OA. In observational studies of progression of OA, eligible knees consist of those that already have knee OA, that is, KL = 2 or KL = 3, representing a mixture of differing degrees of severity that may vary among exposed and nonexposed groups. The outcome is also heterogeneous: knees that progress from KL = 3 to KL = 4 are considered the same as those that progress from KL = 2 to KL = 3 or to KL = 4 over the same period of time. Finally, studies of OA progression are, in essence, conducted to assess an association between a risk factor that causes initiation of OA to progress to more severe OA. This approach results in conditioning on an intermediate stage of OA when assembling the study sample, that is, by limiting the study sample to those who already had mild to moderate knee OA at baseline. This limitation blocks the potential effect of a risk factor on the risk of OA progression if the risk factor of interest was present before any OA abnormality occurred.
Conditioning on an intermediate stage of OA can also result in collider bias. For example, in a hypothetical study of obesity as a risk factor for progressive radiographic OA, the assembled knees with KL = 2 or KL = 3 would be divided into those knees that belong to obese persons and those that belong to nonobese persons. Those knees with OA among the nonobese participants must have developed OA that was due to some other risk factors. Without accounting for those risk factors that led to the development of OA in those knees, the results of the study will be confounded, and will tend to be negatively biased (toward the null).
Discerning Independent Effects
Over the past several years, MRI has enabled identification of various pathologic changes in the joint. However, little is known about the true natural history of the occurrence of these structural lesions detected on MRI, particularly in relation to one another. There is often an attempt to include all structural lesions in a statistical regression model to compare the effect of each structural lesion on the outcome of interest. Without knowing the causal pathway and chronology of occurrence of these lesions, standard approaches of automatically mutually adjusting for all factors can lead to biased effect estimates and, moreover, the effect estimates for each structural lesion are not directly comparable with one another, resulting in incorrect interpretations of study findings.
OA poses a substantial public health burden, given its prevalence that continues to increase. Several risk factors have been recognized, including some modifiable ones such as obesity and avoiding joint injury. There are numerous methodologic challenges to studying risk factors for OA, therefore prevention of OA and its progression also remain challenging. There is a need for ongoing epidemiologic and intervention studies on the prevention of incident and progressive OA, as well as pain related to OA, with adoption of novel approaches to avoid some of the methodologic challenges identified.
References
Lawrence R.C.
Felson D.T.
Helmick C.G.
et al.
Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II.
Joint space width measures cartilage thickness in osteoarthritis of the knee: high resolution plain film and double contrast macroradiographic investigation.
Prevalence of abnormalities in knees detected by MRI in adults without knee osteoarthritis: population based observational study (Framingham Osteoarthritis Study).
Prevalence of knee symptoms and radiographic and symptomatic knee osteoarthritis in African Americans and Caucasians: the Johnston County Osteoarthritis Project.
Prevalence of hip symptoms and radiographic and symptomatic hip osteoarthritis in African Americans and Caucasians: the Johnston County Osteoarthritis Project.
Characterization of individual radiographic features of hip osteoarthritis in African American and White women and men: the Johnston County Osteoarthritis Project.
Very low prevalence of hip osteoarthritis among Chinese elderly in Beijing, China, compared with whites in the United States: the Beijing osteoarthritis study.
Comparison of the prevalence of knee osteoarthritis between the elderly Chinese population in Beijing and whites in the United States: the Beijing Osteoarthritis Study.
Lower prevalence of hand osteoarthritis among Chinese subjects in Beijing compared with white subjects in the United States: the Beijing Osteoarthritis Study.
The effect of estrogen plus progestin on knee symptoms and related disability in postmenopausal women: the Heart and Estrogen/Progestin Replacement Study, a randomized, double-blind, placebo-controlled trial.
High systemic bone mineral density increases the risk of incident knee OA and joint space narrowing, but not radiographic progression of existing knee OA: the MOST study.
Effect of vitamin D supplementation on progression of knee pain and cartilage volume loss in patients with symptomatic osteoarthritis: a randomized controlled trial.
A case-control study of serum tocopherol levels and the alpha- to gamma-tocopherol ratio in radiographic knee osteoarthritis: the Johnston County Osteoarthritis Project.
Supplementary vitamin E does not affect the loss of cartilage volume in knee osteoarthritis: a 2 year double blind randomized placebo controlled study.
Association of low dietary vitamin K intake with radiographic knee osteoarthritis in the Japanese elderly population: dietary survey in a population-based cohort of the ROAD study.
Incidence of severe knee and hip osteoarthritis in relation to dietary intake of antioxidants beta-carotene, vitamin C, vitamin E and Selenium: a population-based prospective cohort study.
Risk of osteoarthritis associated with long-term weight-bearing sports: a radiologic survey of the hips and knees in female ex-athletes and population controls.
High prevalence of knee osteoarthritis, pain, and functional limitations in female soccer players twelve years after anterior cruciate ligament injury.
Long-term outcome of meniscectomy: symptoms, function, and performance tests in patients with or without radiographic osteoarthritis compared to matched controls.
Meniscal tear in knees without surgery and the development of radiographic osteoarthritis among middle-aged and elderly persons: The Multicenter Osteoarthritis Study.
Hazard of incident and progressive knee and hip radiographic osteoarthritis and chronic joint symptoms in individuals with and without limb length inequality.
Early identification of radiographic osteoarthritis of the hip using an active shape model to quantify changes in bone morphometric features: can hip shape tell us anything about the progression of osteoarthritis?.
Association of mild acetabular dysplasia with an increased risk of incident hip osteoarthritis in elderly white women: the study of osteoporotic fractures.
Statistical shape modeling describes variation in tibia and femur surface geometry between Control and Incidence groups from the osteoarthritis initiative database.
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