1 - Epidemiology of Osteoarthritis
Authors: Moskowitz, Roland W.; Altman, Roy D.; Hochberg, Marc C.; Buckwalter, Joseph A.; GoldberG, Victor M.
Title: Osteoarthritis: Diagnosis and Medical/Surgical Management, 4th Edition
Copyright 2007 Lippincott Williams & Wilkins
> Table of Contents > I - Basic Considerations > 1 - Epidemiology of Osteoarthritis
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Epidemiology of Osteoarthritis
Leena Sharma
Dipali Kapoor
Introduction
Osteoarthritis (OA) is the most common form of arthritis and a leading cause of chronic disability, in large part due to knee and/or hip involvement. The societal burden of OA relates to its pervasive presence. For example, in the Rotterdam study, only 135 of 1040 persons 55 to 65 years of age were free of radiographic OA (definite osteophyte presence or more severe) in the hands, knees, hips, or spine.1 Not all OA is symptomatic; still, the World Health Organization estimates that OA is a cause of disability in at least 10% of the population over age 60 years2 and OA affects the lives of more than 20 million Americans.3 Knee OA alone was as often associated with disability as were heart and chronic lung disease.4 Current treatments for OA may improve symptoms but do not delay progression. Progression of OA to advanced and disabling stages is the leading indication for joint replacement.
The increase in the prevalence of symptomatic OA with age, coupled with the inadequacy of symptom-relieving or disease-modifying treatment, contributes to its impact. The number of persons in the U.S. with arthritis is anticipated to rise from 15% of the population (40 million) in 1995 to 18% of the population (59 million) by 2020.3 A better understanding of the factors that contribute to disease and disability in OA is a high priority, especially given the lack of disease-modifying treatment options.
Epidemiologic studies, in addition to incidence and prevalence data, have supplied much of what is known about the natural history of OA and predisposing or protective factors. In addition, epidemiologic investigation has provided information to aid the performance and interpretation of clinical trials; such background information is critical in a disease like OA, which is heterogeneous in its expression and variably progressive.
The following chapter will provide an overview of the areas in which epidemiologic investigation of OA has occurred or has spurred methodologic development: defining OA for study, identifying typical patterns of disease (intra-articular localization, inter-articular joint clustering), developing approaches to assess OA progression, identifying risk factors for OA development and progression, identifying factors that mediate the effect of other factors, and understanding pathogenesis in terms of both anatomic and functional outcomes. This chapter focuses on knee, hip, and hand OA: knee and/or hip OA bear most of the responsibility for the burden of OA; hand OA may also be a source of symptoms, and may be a marker of a systemic predisposition toward OA.
Defining Osteoarthritis
Consensus Definition
Over the twentieth century, the definition of OA has evolved from hypertrophic arthritis to the most recent current consensus definition:5 OA diseases are a result of both mechanical and biologic events that destabilize the normal coupling of degradation and synthesis of articular cartilage chondrocytes and extracellular matrix, and subchondral bone. Although they may be initiated by multiple factors, including genetic, developmental, metabolic, and traumatic, OA diseases involve all of the tissues of the diarthrodial joint. Ultimately, OA diseases are manifested by morphologic, biochemical, molecular, and biomechanical changes of both cells and matrix which lead to a softening, fibrillation, ulceration, loss of articular cartilage, sclerosis and eburnation of subchondral bone, osteophytes, and subchondral cysts. When clinically evident, OA diseases are characterized by joint pain, tenderness, limitation of movement, crepitus, occasional effusion, and variable degrees of inflammation without systemic effects.
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Classification of Osteoarthritis
OA is usually classified as primary (idiopathic) or secondary to metabolic conditions, anatomic abnormalities, trauma, or inflammatory arthritis (Table 1-1).
Diagnostic Criteria
Diagnostic criteria have been developed for knee,6 hip,7 and hand8 OA. Recursive partitioning yielded criteria sets with the best combination of sensitivity and specificity (Table 1-2). In the studies in which these criteria were developed, comparison groups were patients with causes of joint pain other than OA. The American College of Rheumatology (ACR) criteria are intended to distinguish OA from other causes of symptoms and are best suited to recruit participants from clinical settings in which a high prevalence of other arthritides or soft tissue conditions and a higher (than the general population) likelihood of having symptomatic OA is expected. Of note, in community-based studies, the ability to distinguish OA from the absence of joint disease is paramount,9, 10,11 and definitions of OA for epidemiologic study have been developed with this in mind. These definitions are discussed in the following paragraphs.
TABLE 1-1 CLASSIFICATION OF OSTEOARTHRITIS | ||||||||||||||||||||||||||||||||||||
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Patterns of Disease
Specific inter- and intra-articular patterns of OA may represent subsets that have distinctive risk factor profiles and disease course, and, in theory, respond differently to treatment.
Knee Osteoarthritis
Unilateral and bilateral knee OA may represent not different subsets as much as different stages within the same subset. Bilateral knee OA is more common than unilateral disease, affecting 5% versus 2%, respectively, of persons 45 to 74 years of age in NHANES I.12 Having OA in one knee increases the likelihood of having OA in the contralateral knee.13, 14 Among Chingford study participants with unilateral knee OA, 34% developed contralateral OA within 2 years.15 In a clinic-based study of 63 patients with knee OA, 12 of 13 with unilateral OA at baseline developed contralateral OA over 11 years.16
Based on x-ray data, it is believed that tibiofemoral OA is more common than patellofemoral OA. In the Framingham cohort, patellofemoral OA was found in 5%, tibiofemoral OA in 23%, and mixed tibiofemoral and patellofemoral OA in 20%.17 In a community study in the United Kingdom, men with symptomatic OA most often had isolated medial disease (21%, vs. patellofemoral in 11%, mixed in 7%).18 In women, however, patellofemoral OA was most common (24% vs. medial in 12%, mixed in 6%).
Studies which have examined whether OA is more likely on the right or left side revealed no difference in one study19 and, in a recent study, a slightly greater prevalence of tibiofemoral OA on the right side.20
Hip Osteoarthritis
In persons with hip OA, bilateral involvement was reported in 35%21 and 42%.22 Involvement of one hip increased the likelihood of contralateral hip OA in the Chingford study.14 Hip OA appears to be equally common on the right and left sides.19, 20
Superior or lateral involvement is more common than medial involvement. In 6000 patients who had bowel x-rays, 4.7% had hip OA; of these, involvement was lateral in 50% and medial in 24%.23 In a hospital-based study, Ledingham et al. found superior pole migration in 82%, medial/axial migration in 8%, and an indeterminate pattern in 10%.22 Superomedial and medial/axial patterns were more common in women, and superolateral patterns were more common in men.22
Hand Osteoarthritis
There is strong evidence for clustering of hand joint involvement in OA. Having OA in either distal interphalangeal (DIP) or proximal interphalangeal (PIP) joints at baseline increased the risk of incident OA in all other hand joints.24 Having thumb base OA at baseline increased the risk of developing metacarpophalangeal (MCP) OA and, to
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a lesser extent, DIP and PIP OA.24 After adjusting for age, the risk of hand OA was increased by having contralateral hand OA,25 prevalent OA in one or more joints in the same row,24,25 or prevalent OA in the same ray.24,25 DIP OA was more common on the right than on the left side;20 a previous study revealed no differences between dominant and non-dominant hands.26
TABLE 1-2 OSTEOARTHRITIS CLASSIFICATION CRITERIA | ||||||||||||||||||||||||
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A study of 53-year-old men and women from a large general population sample revealed evidence of a polyarticular hand OA subset that involved the DIP, PIP, and thumb base joints.27 Clustering was most apparent by row (rather than by ray) and by symmetric involvement of the same joint in both hands. There was clear evidence of clustering in the men as well, and the patterns were indistinguishable between men and women.27
Clustering of Osteoarthritis Involvement of the Knee, Hip, and Hand
Multiple involvement of five joint groups DIP, PIP, carpometacarpal (CMC), knee, and hip occurred more frequently than could be expected by chance in the Chingford population.14 However, the association between contralateral joints was stronger than the associations between different joint groups. Knee and hip OA are each associated with the presence of hand OA.28,29,30 When examined within the same population, the link between knee and hand OA appeared stronger.14,31 In BLSA participants, an association was found between knee OA and DIP OA, PIP OA, and OA in two or more hand joint groups, adjusting for age and BMI (ORs 1.71 to 2.16).28 Of patients who had undergone
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meniscectomy, those with hand OA had more frequent and more severe knee OA in both operated and unoperated knees than did those without hand OA, adjusting for sex and age.32,33 The presence of hand OA was associated with a threefold increase in the risk of hip OA.29,30
Defining Osteoarthritis for Epidemiologic Study
Much effort has been devoted toward developing a definition of OA for epidemiologic study that encapsulates symptoms, disability, and joint pathology. At the heart of the difficulty is the issue that, while there is some correlation between radiographic disease severity and both symptoms and disability, the relationships are not as strong as one would expect.
As noted above, in epidemiologic studies, a key distinction is between OA and the absence of arthritis. For this reason, and the frequency of mild or intermittent symptoms, epidemiologic studies have tended to rely upon radiographic definitions of OA. Symptomatic, radiographic OA has been defined by a radiographic criterion coupled with a positive response to a question, e.g., pain, in that joint, on most days of a month within the preceding year. The use of a definition combining symptom and x-ray criteria reflects a desire to capture persons with clinically significant OA. A potential limitation of this approach is that a subset of persons with OA may have physically limiting disease but self-reported symptoms that fall below the applied symptomatic cut-off.
The most widely used system to grade radiographic severity continues to be the Kellgren and Lawrence grading system,34 by which 1 of 5 grades is assigned with the aid of atlas reproductions, according to the following definitions: 0 for normal, 1 for possible osteophytic lipping, 2 for definite osteophytes and possible joint space narrowing, 3 for moderate or multiple osteophytes, definite joint space narrowing, some sclerosis, and possible bony attrition, and 4 for large osteophytes, marked joint space narrowing, severe sclerosis, and definite bony attrition. The K/L system is osteophyte driven; it is unclear how to handle knees with joint space narrowing without osteophytes. Also, the K/L system is limited by incorrect assumptions, including the following: that change in any one feature is linear and constant, and that the relationship between features is constant.35 Most investigators assess individual radiographic features in addition to a global score.
Although x-ray continues to be used heavily, MRI is common in epidemiologic studies, and provides rich opportunities to assess articular cartilage, subarticular bone, menisci, ligaments, and, aided by contrast, synovium. An MRI-based definition of OA has not as yet been established.
Knee Osteoarthritis
The presence of definite osteophytes is the recommended definition for radiographic knee OA.36,37 Further validating an osteophyte-based definition, tibiofemoral osteophytes predicted cartilage defects on MRI, whether or not radiographic joint space narrowing (as defined by <3 mm) was present, in individuals 49 to 58 years of age.38,39 In the patellofemoral joint however, osteophytes predicted MRI cartilage defects only in narrowed patellofemoral joints, suggesting that osteophytes alone may not be sufficient to identify cases of patellofemoral OA.39
Hip Osteoarthritis
A definition including joint space width appears to be valid and practical for epidemiologic study of hip OA.9,40 In men, an overall grade, minimal joint space width, and thickness of subchondral sclerosis were most predictive of hip pain.40 Minimal joint space was best associated with other radiographic features, and measures of joint space were more reproducible than other indices.40 However, there are caveats with a joint space width definition: the cut-off for what is a normal joint space width at the hip may differ between ethnic groups and change with age; it is unclear how to handle osteophytes without joint space narrowing; a less stringent cut-off increases sensitivity but sacrifices specificity.9 Specificity may be enhanced by requiring at least one other radiographic feature or by using a global system.9 Of note, minimum joint space width 2 mm or less was more closely associated (than global radiographic scoring approaches) with hip pain.41 The effect of using alternative definitions of disease on estimates of prevalence has been demonstrated.42
Hand Osteoarthritis
Defining hand OA is important to advance the investigation of hand OA itself and to document its presence as a marker of a systemic predisposition towards OA. Most epidemiologic studies have relied on the presence of definite osteophytes, or K/L 2. Alternative global radiographic scoring systems were developed.43,44 While Heberden's node presence and DIP osteophytes had similar sensitivity, the specificity and positive predictive value of radiographic osteophytes was higher for detecting knee, CMC, and PIP OA, and OA in more than two groups of joints.45
At present there is no agreement on the best definition of generalized OA; Cooper et al. demonstrated that thresholds could be defined for the number of involved joint groups that distinguished a polyarticular subset of OA; these thresholds varied with age and other factors.14
Incidence
Knee Osteoarthritis
In the Framingham study (participant mean age 70.8 years), 2% of women per year developed radiographic knee OA, and 1% per year developed symptomatic, radiographic knee OA, versus 1.4% and 0.7% of men, respectively.13 In a Dutch population-based study (participant age 46 to 66 years), about 2% of women and 0.8% of men developed radiographic knee OA per year.46 In the Goteborg study (participant age 75 years), the incidence of knee OA was 0.9% per year.47
Two incidence studies were restricted to patients seeking medical care with symptomatic joint disease. Oliveria et al. evaluated incident symptomatic, radiographic knee OA
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rates in a large HMO in central Massachusetts, mostly involving white, blue-collar workers, and found higher rates in women (female to male ratio for hand, hip, and knee OA 2:1), and an increase in incidence with age until 80 years.48 The age- and sex-standardized incidence rate for knee OA was 240 per 100,000 person-years (95% confidence interval (CI) 218.00 262.00). The incidence of clinical knee OA was over 1% per year in women of age 70 to 89 years. Wilson et al. found equal rates of incident symptomatic OA in men and women of Olmstead County Minnesota (mostly northern European).49 The age- and sex-adjusted rate for knee OA was 163.8 per 100,000 person-years (95% CI 127.1 200.6). The difference in results between these two studies may relate in part to broader exclusions for secondary OA in the latter study.
Hip Osteoarthritis
Over 8 years, 3.5% to 11.9% (depending on the radiographic definition used) of women of age 65 years and older in the study of osteoporotic fractures (SOF) developed hip OA.50 The age- and sex-standardized incidence rate for symptomatic, radiographic hip OA was reported to be 88 per 100,000 person-years (95% CI 75-101) by Oliveria et al.48 and 47.3 per 100,000 person-years (95% CI 27.8 -66.8) by Wilson et al.49
Hand Osteoarthritis
In the Tecumseh Community Health Study, 1.8% of participants (of age 27 to 51 years) developed hand OA per year.51 In the Goteborg study (participant age 75 years), 2.7% of participants developed DIP or PIP OA per year.47 In the Framingham study (mean age 55 years), Chaisson et al. found that 3.6% of women and 3.2% of men developed radiographic OA in at least one hand joint per year.24 Women had more incident disease than men in all hand joints except the MCP group for which rates were comparable between men and women. The most frequently affected joints were, in decreasing order, DIP-2 (57% in women, 36% in men), thumb IP, CMC-1, and DIP-5.24 The higher overall rate in the older Framingham cohort versus the younger Tecumseh cohort (51) most likely reflects an increase in the incidence of hand OA with age, but also may relate to differences in how OA was defined.
TABLE 1-3 PREVALENCE OF KNEE OSTEOARTHRITIS | |||||||||||||||||||||||||||||||||||
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In a cohort of men of age 60 years and above in the Baltimore Longitudinal Study of Aging (BLSA), the incidence was highest at the DIP joints and increased with age in all hand joints.52 Oliveria et al. reported an age- and sex-standardized incidence rate for symptomatic, radiographic hand OA of 100 per 100,000 person-years (95% CI 86-115).48
Prevalence
Studies of the prevalence of knee OA are summarized in Table 1-3.19,53,54,55 The prevalence of radiographic knee OA rises in women from 1% to 4% in those 24 to 45 years of age to 53% to 55% in those of age 80 years and older. In men, the prevalence rises from 1% to 6% in those 45 years and younger to 22% to 33% in those 80 years and
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older. Other studies report a prevalence of 12% (Chingford, women 45 to 64 years),56 3.6% (Michigan Bone Health Study, women 24 to 45 years),57 and 29% (Rotterdam, >55 years).58 In the Beijing Osteoarthritis study, prevalence of radiographic OA in Chinese men rose from 10% at 60 to 64 years to 45.7% at ages over 80 years, similar to findings in Framingham men.59 Rates in Beijing women in these age groups were 39.6% and 59.1% respectively, about 40% higher than what was found in Framingham women, applying the same case definitions and radiographic methods.
TABLE 1-4 PREVALENCE OF HIP OSTEOARTHRITIS | ||||||||||||||||||||||||||||||||||||||||||
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TABLE 1-5 PREVALENCE OF RADIOGRAPHIC HAND OSTEOARTHRITIS | ||||||||||||||||||||||||||||||||||||||||||||
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Studies of the prevalence of hip OA are summarized in Table 1-4. 19,21,53,60 An increase in hip OA with age is seen in both genders, especially in women. Other studies report a prevalence of 3% in women and 3.2% in men (NHANES I, 55 to 74 years),61 and15.9% in women and 14.1% in men (Rotterdam, >55 years). 58 Hoaglund et al. found only five cases of hip OA (graded K/L 3-4) in 500 Hong Kong southern Chinese hospital patients.62 A subsequent study similarly found a lower prevalence of hip OA in Hong Kong Chinese men.63 Prevalence of hip OA in men and women was substantially lower in Beijing men and women than in U.S. cohorts assessed using the same methods.64 For radiographic hip OA, prevalence ratios were 0.07 (Chinese women to white women in the SOF), 0.22 (Chinese women to women in the NHANES I), and 0.19 (Chinese men to white men in the NHANES I).
Though reported differences may relate to study methodology, the prevalence of hip OA may be lower in Jamaicans,65 Asian Indians,66 and Nigerians67 than in European populations.
Two studies of the prevalence of hand OA are summarized in Table 1-5.53,69 The prevalence of radiographic and also of symptomatic, radiographic hand OA at all sites rises with age, and is greater in women. Plato and Norris provide age-specific prevalence rates for individual hand joints for men in the BLSA, and summarize several previous U.S. studies.68 Other studies report a prevalence of 14% in the DIP and 16% in CMC-1 (Chingford, women 45 to 64 years);56 3% in DIP joints, 1.0% in PIP, 0.7% in MCP, 0 in CMC-1, 0.5% in IP-1 (Michigan Bone Health Study, women 24 to 45 years);57 35% in DIP joints in women, and 24% in men (Hong Kong southern Chinese, >54 years);62 and 30%, for symptomatic hand OA in women, and 29% in men (National Household Education Surveys [NHES] 25 to 74 years).69
Risk Factors for Incident Osteoarthritis
Individual studies have traditionally sought to identify risk factors for incident disease or OA progression but not both, in large part due to the cost and logistics of powering both outcomes. The current era is witness to the development and initiation of large-scale studies that will have power to look at incidence, progression, and disability within the same study: the Rotterdam study MOST (Multicenter Osteoarthritis Study), and the OAI (Osteoarthritis Initiative).
A candidate's risk factor's effect on each outcome incidence and progression should be specifically and separately examined. It is widely believed that the risk factor profiles for each of these key outcomes may overlap but are not identical. Also, the magnitude of the effect of a given risk factor may differ according to the stage of OA disease present in a given joint, i.e., prior to definite OA (the stratum for study of incident OA), or after OA is definitely present (the stratum for progression). As is the case in these studies, it is ideal that the examination of effect on incident and progressive OA occurs within the same study. Otherwise, if the effect on incidence differed from that on progression when these outcomes were examined in separate studies, it would remain possible that the difference was linked to methodologic differences between studies.70 An additional key design element of MOST and the OAI reflects evolution in views of the basic OA condition that is of highest priority to study in terms of potential intervention and/or prevention strategy development: the cohorts of each of these studies includes individuals with symptomatic radiographic knee OA or those at higher (than the general population) risk to develop it.70
To identify risk factors for incident OA, longitudinal studies, which allow determination of the relationship of a risk factor at baseline to new disease development over time, are of course optimal, but are more expensive to perform. Cross-sectional studies of the relationship between exposure to a given factor and risk of having disease have been more common. OA development is often attributed to a joint-specific local mechanical environment within a systemic milieu, leading to categorization of risk factors as either systemic or local. However, certain risk factors like age, a systemic factor that may act in part by altering the mechanical environment, illustrate that categorization may oversimplify what are complex risk factor effects. Unless otherwise specified, the following studies have focused on a radiographic definition of OA (i.e., K/L 2).
Body Weight
In Framingham participants of median age 37 years, weight predicted the presence of knee OA 36 years later.71 The age-adjusted relative risk for knee OA in the heaviest quintile of baseline weight versus the lightest three quintiles was 2.07 (95% CI 1.67 2.55) for women and 1.51 for men. Results were unaffected by adjustment for serum uric acid level and physical activity. Weight change in Framingham women affected the risk for developing knee OA.72 A decrease in BMI of 2 units over the previous 10 years decreased the odds of knee OA (OR 0.46, 95% CI 0.24 0.86). Analyses were adjusted for age, baseline BMI, knee injury, smoking, job physical labor, habitual physical activity, and educational level.
A subsequent Framingham study (mean subject age 70.5 years) in subjects free of disease at baseline confirmed that higher BMI increased the risk of OA (OR 1.6/5 unit increase, 95% CI 1.2 2.2) and weight change was directly related to risk of OA (OR 1.4/10 lb change in weight).73 These findings were present in women; per the authors, the absence of relationship in men may reflect a gender difference or the small number of incident cases in men.
In a longitudinal study of the Chingford population (women, mean age 54 years), belonging to the top BMI tertile was associated with an increased risk of knee OA (OR
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2.38, 95% CI 1.29 4.39), adjusting for hysterectomy, estrogen replacement therapy, physical activity, knee pain, and social class.74 In Chingford participants with unilateral knee OA, 46% in the top BMI tertile developed OA in the uninvolved knee over 2 years versus 10% in the lowest tertile.15
Obesity was more strongly associated with bilateral (OR 6.6, 95% CI 4.71 9.18) than unilateral OA (OR 3.4 in right knees), adjusting for injury, age, and gender in 45 to 74 year old NHANES I participants.12 There is little evidence of a metabolic link between body weight and knee OA. With one exception,75 population-based studies have not revealed an independent relationship of a metabolic correlate of obesity (e.g., serum lipids, glucose or glucose tolerance test, body fat distribution, and blood pressure) with knee OA.76,77,78,79
In both the Framingham and Chingford populations, while BMI was linked to all patterns of knee OA (tibiofemoral, patellofemoral, and mixed), odds ratios were highest for mixed involvement.17,80
The possibility remains, albeit small, that knee symptoms preceding OA lead to lower levels of activity which contribute to obesity, and that other factors cause OA. However, analysis of NHANES I data55 revealed no evidence that the association between BMI and knee OA is stronger for those with knee symptoms. In Framingham women, the association between weight and knee OA was stronger in those without symptoms; in men, the association appeared to be stronger in those with symptomatic disease.71
In contrast to the knee, a more modest association between body weight and hip OA has been described. In NHANES I, neither obesity nor fat distribution was associated with hip OA.61 However, being overweight was more closely associated with bilateral (OR 2.0, 95% CI 0.97- 4.15) than unilateral hip OA (OR 0.54, 95% CI 0.26- 1.16), adjusting for gender, age, race, and education. In the Zoetermeer study, obesity was linked to OA in the right but not the left hip in men, and was not associated with hip OA in women81 In another study involving farmers, the risk of hip OA was highest in the tallest and heaviest members of the sample though the association with weight, height, or BMI did not achieve significance.82 In an early report from the Rotterdam study it was stated that being overweight increased the risk of incident knee OA but not incident hip OA.83
Support for a link between obesity and hand OA comes from one longitudinal study51 and some cross-sectional studies76,79,81 but not others.57,84,85 In the Tecumseh study, mean age- and smoking-adjusted baseline weight was higher among those who developed hand OA than among those who remained free of disease.51 Blood pressure, cholesterol, uric acid, and glucose were not linked to the development of hand OA. A cross-sectional relationship was detected in men and women in the Zoetermeer study,81 men and women in NHES and NHANES I for combined hand/foot OA,76 and in men only of the Goteborg population,79 but not in men84 or women85 in the BLSA. In the Michigan Bone Health Study, no association was detected between the presence of hand OA and BMI; relationship between BMI and hand radiographic scores did not persist after adjusting for age and bone mineral density (BMD).57
Cross-sectional studies examining the relationship between specific hand joint groups and weight have had conflicting results. In the Zoetermeer survey, obesity was associated with DIP and PIP OA but not with CMC OA,81 while in the Chingford population, BMI was associated with CMC OA but not with DIP or PIP OA.86
Age
Aged cartilage has altered chondrocyte function and material properties and responds differently to cytokines and growth factors. In addition, joint-protective neural and mechanical factors may become impaired with age, such as proprioception, varus-valgus laxity,87 and muscle strength.88
In a longitudinal study of the Chingford population (women, mean age 54 years), belonging to the highest of three age groups was associated with an increased risk of knee OA (OR 2.41, 95% CI 1.11 5.24), adjusting for hysterectomy, estrogen replacement therapy, smoking, physical activity, pain, social class, height, and weight.74 Knee osteophyte development increased by 20% per 5-year age increase. The magnitude of risk associated with aging appears to decrease as older ages are reached. Age did not affect the risk of knee OA in a longitudinal Framingham study in which the mean subject age at baseline was 70.5 years.73 Several cross-sectional studies have demonstrated a higher prevalence of knee OA with increasing age, including those of Lawrence et al.,53 the Framingham study,54 NHANES I,12,55 and the Zoetermeer survey.19
Hip OA is more prevalent at older ages. A relationship between age and hip OA is supported by two Scandinavian studies,21,23 the Zoetermeer survey,19 and NHANES I.61 In the NHANES I data, age increased the risk of hip OA (OR 2.38 for ages 70 to 74 years versus 55 to 59 years, 95% CI 1.15 4.92), adjusting for gender, race, marital status, education, and family income.61
Age is closely associated with the development of hand OA11 as shown in the reports of Lawrence,53 the BLSA,52,84 the Zoetermeer survey,19 and the Michigan Bone Health Study.57 In a longitudinal BLSA study, Kallman et al. found that age increased the risk of OA for almost every radiographic feature in every hand joint group.52 In pre- and perimenopausal women, age was more strongly linked to hand than knee OA.57
Gender
Gender may influence knee OA via multiple routes including hormonal influences on cartilage metabolism, gender variation in injury risk, and gender differences in the mechanical environment of the knee (e.g., varus-valgus laxity,87 strength relative to body weight88).
Women develop knee OA more frequently than men. In a longitudinal Framingham study, women had a greater risk of developing OA than men (OR 1.8, 95% CI 1.1 3.1), adjusting for age, BMI, smoking, injury, chondrocalcinosis, hand OA, and physical activity.73 Cross-sectional studies have demonstrated that knee OA is more prevalent in women.12,19,55 In NHANES I, bilateral OA was twice as prevalent in women than in men.12 No gender difference
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was seen in the prevalence of unilateral OA. Anderson et al. found that, among NHANES I subjects aged 35 to 74 years, knee OA increased with age in both sexes and, beginning in those 45 to 54 years, was greater in women than in men.55 In the Zoetermeer survey, severe OA was much more prevalent in women.19
In a cross-sectional study involving a convenience sample, in which 15% of men and 19% of women had radiographic OA, men had greater patellar and tibial cartilage volume than women. Differences were reduced (though some difference remained) after adjusting for gender differences in height, weight, and bone size.89 In a small study of young persons with healthy knees, Faber et al. found that a gender difference in cartilage volume was primarily due to difference in joint surface area (epiphyseal bone size) and not to difference in cartilage thickness.90
Hip OA may be more common in women than men at older ages, but the gender difference is less pronounced than at the knee. Danielsson et al. found no difference between men and women in the prevalence of hip OA.21 Jorring reported a female to male ratio of 3:2.23 In those over 60 years, severe hip OA was more common in women. In the Zoetermeer survey, between ages 55 and 64 years, hip OA was more common in men; in those aged 65 and older, hip OA was more common in women.19 Analyses of NHANES I data revealed no association between hip OA and gender.61 Parity, age at menarche, and age at menopause were not linked to the presence of hip OA.
In the Tecumseh study, women had 2.6 (95% CI 1.65- 4.18) times the risk than men of developing hand OA, adjusting for baseline age, weight, and cigarettes per day.51 In the Zoetermeer survey, DIP OA was more common in women than men.19 Cauley et al, examining white women mean age 74 years, found no association between serum sex hormones (estrone, estradiol, testosterone, and androstenedione) and severity of hand OA.91 In the Michigan Bone Health Study, estradiol levels were not associated with hand OA scores.57
Occupational Activity
The health of cartilage and other joint tissues requires regular joint loading. However, if loading is extreme in frequency or intensity, it could exceed the tolerance of a joint and contribute to OA development. The role of occupational activity is better understood in men than in women, in part because previous studies assessed paid labor, did not include homemaking or child-rearing activities, and occurred when most women did not work outside the home. In a longitudinal Framingham study, risk of later radiographic knee OA was highest in men whose jobs, ascertained 20 years earlier, were classified as having at least medium physical demands and as likely to involve knee bending (OR. 2.2, 95% CI 1.4 3.6) versus a job with sedentary demands and no knee bending.92 Analyses were adjusted for age, BMI, history of knee injury, education, and smoking. Analyses of NHANES I data revealed that radiographic knee OA was more common in 55- to 64-year-old men and women whose current job by title included much knee-bending versus some knee bending (OR 2.45 for men and 3.49 for women), adjusting for race, education level, and BMI.55 In women, job title associated with high versus moderate strength demands was associated with knee OA. Kivimaki et al. found an association between duration of knee bending activities and knee OA in male carpenters, floor layers, and painters.93
In a case-control study, an increased risk of knee OA was found in those whose main job entailed more than 30 minutes/day squatting or kneeling, or climbing more than 10 flights of stairs, adjusting for BMI and the presence of Heberden's nodes.94 Regularly lifting >25 kg, as well as kneeling, squatting, or climbing stairs was associated with a fivefold increase in risk of knee OA, versus no exposure to these activities. No association was found between knee OA and prolonged walking, standing, sitting, or driving. Other studies have suggested an increase in knee OA in miners95 and dockworkers.96
As summarized by Maetzel et al.,97 a consistent though weak relationship between work-related exposure (especially farming) and hip OA in men has been reported. Farming for 10 or more years (vs. <1 year) was associated with hip OA in men (OR 2.0, 95% CI 0.9 4.4), adjusting for age, height, and weight.82,98 Analyses of NHANES I data revealed a nonsignificant 40% to 50% increase in the odds of radiographic hip OA among men in rural areas, after adjusting for age, race, and BMI.99 Male veterans administeration clinic patients with hip OA and controls were surveyed about lifetime occupational and recreational activities and grouped based on estimates of joint compression forces produced.100 Participants in the intermediate and heavy work groups had, respectively, 2.0 and 2.4 times the odds of having hip OA.
Certain occupations predispose toward hand OA. Lawrence et al. found that British cotton mill workers had more hand OA than did age matched controls.101 Hadler et al. found in textile workers that burlers and spinners (tasks involving precision grip) had significantly more DIP OA than did winders (task involving a power grip).102 Winders did not have more OA in the CMC joint by radiographic score but did have decreased CMC range of motion as compared to burlers and spinners. The likelihood of more severe OA (grade 3 or more) in the right-hand thumb and the index and middle fingers was elevated in dentists compared to teachers.103
Nonoccupational Physical Activity
The role of nonoccupational physical activity has been evaluated in epidemiologic studies in a variety of ways, e.g., OA prevalence in ex-elite athlete groups (competed at the national or international levels), the relationship between running and OA development, and the relationship between composite physical activity and OA.
In a study of men who were formerly elite athletes, the highest prevalence of tibiofemoral OA was found in soccer players (26%), and the highest prevalence of patellofemoral OA was found in weight-lifters (28%).104 Previous knee injury, higher BMI at age 20, and hours of participation in team sports predicted tibiofemoral OA; previous knee injury, higher BMI at age 20, years spent in heavy work,
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and work involving kneeling or squatting predicted patellofemoral OA. Of note, unlike Framingham participants,72 elevations in BMI within the non-obese range were linked to knee OA in these athletes, introducing the possibility that the pathogenic role of excess weight in knee OA may be modified by the nature and intensity of physical activity. Women who were formerly elite athletes (67 runners and 14 tennis players) had a threefold increase in the risk of tibiofemoral and patellofemoral OA versus age-matched women, adjusting for height and weight differences.105 Results were unaffected by further adjustment for injury, smoking, menopause, hysterectomy, BMI, or age.
Recreational runners do not appear to have an increased risk of knee OA. In a study of runners versus controls matched for age, sex, education, and occupation, Lane et al. found that, of 73 participants, 9 developed knee OA over a 5-year period by ACR criteria: 5 were controls and 4 were runners.106 Panush et al. also found no difference in rate of OA development between 17 male runners (53% marathon runners) and age- and weight-matched controls.107
In the Framingham study, habitual physical activity (a weighted and summed measure of hours/day at various activities), assessed at two previous exams, did not predict the presence of knee OA.108 In a case-control study, there was no association between knee OA and lifetime leisure activities including walking, cycling, gardening, dancing, and outdoor sports in subjects aged 55 years and older.109 In participants with a mean age of 79 years, Bagge et al. found no association between occupational or leisure activity and knee OA.79 In longitudinal studies of the Chingford cohort, physical activity was not linked to incident OA in the uninvolved knee in those with unilateral knee OA12, nor was it linked to incident OA in the full cohort.74 As the authors note,74,79 only a small number of participants were involved in heavy activity.
There are two caveats to note. First, it is believed, although not based upon formal investigation, that an anatomic abnormality in a joint or periarticular structure may increase the physical activity-associated risk of OA.110 Second, one longitudinal study introduces the possibility that the combination of very heavy physical activity and age may be linked to an increased risk of knee OA.73,111 In elderly persons (mean age of 70 years), the odds of developing radiographic knee OA between two exams 8 years apart were increased by heavy physical activity (e.g., OR 7.2, 95% CI 2.5 20.0 for >4 hours per day of heavy activity) assessed by a questionnaire at mid-study, adjusting for age, gender, BMI, weight loss, injury, health status, calorie intake, and smoking.111 Risk was greatest in the top tertile of BMI. No relationship was detected with moderate or light physical activity, number of blocks walked, or number of flights of stairs climbed daily.
Based on a small number of studies, high intensity, nonoccupational activity may be linked to hip OA. A case control study of men up to age 49 with total hip replacements versus men from the general population revealed that high exposure to any sport increased the risk of hip OA (RR 3.5 to 4.5), adjusting for age, BMI, smoking, and occupational physical activity.112 Puranen et al. found that hip OA prevalence was not greater in former champion distance runners than individuals who were not runners.113 However, Marti et al. found that hip OA was more prevalent in former national team long-distance runners than in bobsled competitors or controls.114 Age and mileage run in 1973 predicted radiographic hip OA in 1988.
Bone Mineral Density
The relationship between BMD and knee OA has been examined in longitudinal studies including those of the Framingham, Rotterdam, and Chingford cohorts. As reported by Zhang et al., over 8 years of follow-up of the Framingham cohort, risk of incident OA was lowest in the lowest femoral neck BMD quartile (5.6%) and was higher in the higher 3 BMD quartiles (14.2%, 10.3%, and 11.8%).115 Similarly, in the Rotterdam study, the incidence of radiographic knee OA was higher in those in the highest femoral neck (10.5%) and spine BMD (14.3%) quartiles than in those in the lower quartiles (3.4% and 3.3%).116 Women in the Chingford study with incident knee osteophytes had significantly higher baseline spine and hip BMD than those without incident disease.117
In the Rotterdam population, those with knee and/or hip OA had 3% to 8% higher femoral neck BMD versus those without OA, a difference that was significant in women only.118 Repeat BMD measurements 2 years later revealed that the rate of bone loss was higher in participants with OA. In theory, a decline in BMD might be cytokine mediated or a consequence of reduced physical activity.118
Both the Framingham and Chingford studies revealed that participants with knee OA had a 5% to 10% higher BMD than those without knee OA.56,119 In the Framingham study, women with K/L 1 and 2 knees had a 5% to 9% higher femoral neck BMD than those with K/L 0 knees, adjusting for age, BMI, and smoking, and men with K/L 1 knees had a higher femoral neck BMD than men with K/L 0 knees.119 Women in the Chingford study with knee OA had a 7.6% and 6.2% higher BMD at lumbar spine and femoral neck sites, respectively, versus controls, adjusting for age and BMI.56 Results were unaffected by further adjustment for smoking, alcohol use, exercise, estrogen replacement therapy, social class, and spine osteophytes. In the BLSA, lumbar spine BMD was 4% higher in men and 3.7% higher in women with knee osteophytes, adjusting for age, BMI, and smoking.120 Knee OA was not linked to BMD assessed at upper extremity sites.119,121
Several studies support that those with hip OA have a higher bone mass at both axial and appendicular sites (reviewed in Lane and Nevitt122). In cross-sectional analyses in the SOF, women with K/L grade 3-4 hip OA had higher age-adjusted BMD at the femoral neck and Ward's triangle, trochanter, lumbar spine, distal radius, and calcaneus versus those with K/L grade 0-1 in the worse hip.123 Elevations in BMD were greatest in the femoral neck of hips with OA, in women with bilateral hip OA, and in women with hip osteophytes.
In the longitudinal Tecumseh study, women who developed OA were more likely to have had higher baseline bone mass (metacarpal bone cortical area) than women who did not develop OA; these women also had a greater likelihood
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of bone loss over time.124 In men84 and women125 in the BLSA, upper extremity BMD, adjusted for age and BMI, was not correlated with radiographic grade of hand OA. Women in the Chingford study with OA had higher BMD than controls, adjusting for age and BMI: those with DIP OA had 5.8% greater BMD at the lumbar spine only; those with CMC OA had 2.5% to 3% greater BMD at the femoral neck and lumbar spine.56 Results were not altered by adjustment for smoking, alcohol use, exercise, estrogen replacement therapy, social class, and spine osteophytes.
Postmenopausal Hormone Replacement Therapy
Estrogen may have direct effects on articular cartilage, or may influence OA development via effects on bone or other joint tissues. Postmenopausal estrogen replacement therapy may protect against the development of knee OA. In many studies, the relationship does not achieve significance. However, results are consistent in the direction and magnitude of the relationship, and suggest a gradient of protection (i.e., greater protection conferred with current estrogen replacement therapy vs. past use).126 In a longitudinal Framingham study, the odds ratio for incident OA associated with past estrogen replacement therapy use versus never use was 0.8 (95% CI 0.5 1.4) and associated with current use versus never use was 0.4 (95% CI 0.1 3.0), adjusting for age, BMI, femoral neck BMD, physical activity, weight change, knee injury, smoking, and baseline K/L grade.127 Similarly, a nonsignificant protective effect for incident knee osteophytes was seen with current estrogen replacement therapy in a longitudinal Chingford study (OR 0.41, 95% CI 0.12 1.42), adjusted for hysterectomy, smoking, physical activity, knee pain, and social class.74 In a case control study, Samanta et al. also found a nonsignificant association between estrogen replacement therapy and reduced likelihood of large joint OA (OR 0.31, 95% CI 0.07 1.35).128
An MRI-based study suggests that women using estrogen replacement therapy may have greater articular cartilage volume than non-users.129 Total tibial cartilage volume was 7.7% (0.23 mL) greater in the group of estrogen users than in the non-users. The difference persisted after adjusting for years since menopause, BMI, age at menopause, and smoking (adjusted difference 0.30 mL, 95% CI 0.08 0.52), and findings were very similar after excluding women with established knee OA.
In a cross-sectional study of white women 65 years and older in the SOF, current users of estrogen replacement therapy had a reduced risk of any hip OA (OR 0.62, 95% CI 0.49 0.86), and of moderate-severe hip OA.130 Current users for 10 or more years had a greater reduction in risk of any hip OA versus users of less than 10 years. Current use for 10 or more years was also associated with a nonsignificant trend for a reduced risk of moderate to severe symptomatic hip OA. In the Chingford population, for current users there was a hint of protective effect, though not significant, of hormone replacement therapy for DIP OA (OR 0.48 95% CI 0.17 1.42) and no clear effect for CMC OA, adjusting for age, height and weight, menopausal age, and femoral neck BMD.131
Injury
OA may result after an injury, either as a primary effect (i.e., direct damage to articular cartilage) or secondarily, due to the greater stress to cartilage resulting from damage to load-attenuating knee tissues. Apparent in several cross-sectional studies, the link between knee injury and OA has been more difficult to demonstrate in longitudinal studies,73,74 perhaps due to the possibility that injured individuals developed OA before the baseline evaluation of a given study and would therefore not be included in analyses of incident OA.73 In a study by Gelber and colleagues, over a median follow-up of 36 years, the cumulative incidence of knee OA by age 65 was 13.9% in persons who had a knee injury during adolescence and young adulthood and 6.0% in those who did not.132 Joint injury at cohort entry or during follow-up substantially increased the risk for subsequent osteoarthritis specific to site (RR 5.17, 95% CI 3.07 8.71 and 3.50, 95% CI 0.84 14.69 for knee and hip, respectively).
Cross-sectional studies have shown a link between knee injury and knee OA.12,57,109 Though linked to both unilateral and bilateral knee OA, knee injury was more closely associated with unilateral OA.12 Knee injury (OR 16.3, 95% CI 6.50 40.89) was a stronger predictor than obesity (OR 3.4) of unilateral knee OA. Injury increased OA risk at both tibiofemoral and patellofemoral sites.109
In analyses of NHANES I data, hip trauma was associated with hip OA (OR 7.84, 95% CI 2.11 29.10), adjusting for sex, age, race, and education.61 When men and women were examined separately, the relationship remained significant for men but not for women. Hip trauma was significantly associated with unilateral hip OA; no hip trauma was reported among those with bilateral hip OA. In women in the Michigan Bone Health Study, hand injury was associated with hand OA (OR 2.98, 95% CI 1.05 8.46).57
Genetic Factors
A large literature dealing with genetic factors has been produced since Stecher's observation that Heberden's nodes were three times more common than expected in the sisters of affected individuals,133 and Kellgren observed that the first-degree relatives of patients with generalized OA were more likely to have OA.134 Twin, sibling-risk, and segregation studies make up much of this literature. The original approach, a focus on generalized OA, fed by the belief that this subset had a major genetic component, did not have anticipated yields; it is increasingly believed that a more joint-specific approach will be superior.135 It is only feasible to provide a few examples of studies in the space available here. Outstanding overviews have recently been published.135,136,137
The correlations of specific features of hand and knee OA were higher in monozygotic twins than in dizygotic twins; adjusting for age and weight, 39% to 65% of the variance of hand and knee OA was attributed to genetic factors.138 Further adjustment for estrogen replacement therapy, smoking, exercise, menopause, and height had little effect on the results.
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The heritability of OA involving hand and knee was assessed in a large sample of randomly ascertained families.139 The correlation of OA joint count was higher between siblings (r = 0.12 to r = 0.31) and between mothers and offspring than between fathers and offspring. The models that best fit were those postulating a mixed model, i.e., a mendelian gene in the context of multifactorial transmission. The familial aggregation of hand and knee OA was also evaluated by Hirsch et al. in the BLSA cohort.140 After adjustment for age, sex, and BMI, sib-sib correlations were found for OA of the DIP, PIP, CMC-1 joints, for OA at two or three hand sites, and for polyarticular OA (r = 0.33 to 0.81).
Studies have described a greater frequency in subjects with generalized OA of HLA-A1B8 and MZ alpha-1 antitrypsin phenotypes,141 particular estrogen receptor genotypes,142 and in those with hip, hand, spine, or knee OA, an association of IGF-1 genotype.143 In a study using affected sib pair analysis, an association between nodal OA and two loci on the short arm of chromosome 2 was detected (candidate genes include fibronectin, alpha-2 chain of collagen type V, IL-8 receptor).144 A specific CRTM allele appeared to protect against the presence of hip OA (OR 0.51, 95% CI 0.26 0.99), adjusting for age and BMI.1 The Rotterdam Study revealed a predisposition for radiographic OA of the hip in heterozygous and homozygous carriers of the IL1B-511T and of the IL1RN VNTR allele 2.145 An additive effect was observed with carriers for risk alleles of both polymorphisms.
Two population-based studies have described an association between the VDR locus and knee osteophytes, adjusting for age, BMI, and BMD.146,147 In the Framingham study, no linkage of OA with VDR/COL2A1 locus was found.148 Using affected sib pair analyses, with control allele frequencies calculated from an unrelated group of unknown OA status, no linkage was demonstrated between generalized OA and three cartilage matrix genes, COL2A1, CRTL1 (encodes cartilage link protein), or CRTM.149 In another study, an association between hip OA and polymorphisms of candidate genes, VDR, COL1A1, and COL2A1, were not seen in postmenopausal women.150
Findings from the Framingham study revealed eight chromosome regions 1, 2, 7, 9, 11-13, 19 with suggestive linkages for at least one phenotype for hand OA, none clearly coinciding with areas previously linked with OA.151 A linkage study by Gillaspy et al. using fine mapping did not demonstrate any clear linkage at chromosome 2q for hand or knee OA.152 These studies in aggregate suggest that hand OA, globally considered, have not consistently shown strong linkage to any chromosome sites. The Framingham Study revealed four sites showing evidence of linkage when a more joint-specific approach was undertaken. A linkage region for DIP OA was found on chromosome 7, for first CMC OA on chromosome 15, and, in women only, for DIP OA on chromosome 1 and first CMC OA on chromosome 20.153
As summarized by Loughlin,135 genes that are believed to play some role in susceptibility include the IL-1 cluster,145 the matrilin 3 gene (MATN3), the IL-4 receptor [alpha]-chain gene (IL4R), the secreted frizzled-related protein 3 gene (FRZB),154,155 the metalloproteinase gene ADAM12, and the asporin gene (ASPN).156,157
An area of recent interest has been heritability of cartilage volume and other articular and periarticular features. A twin study revealed heritability estimates of 61%, 76%, 66%, and 73% for femoral, tibial, patellar, and total cartilage volume.158 In a longitudinal study of sibling offspring of patients who had undergone total knee replacement for OA, heritability estimates (for change) were 73% and 40% for medial and lateral cartilage volume, 20% and 62% for medial and lateral tibial bone size, 98% for medial chondral defects, and 64% for muscle strength; adjusting for other change parameters and what was predominantly mild OA had little impact.159
Congenital Abnormalities
Local factors that affect the shape of the joint may increase local stress on cartilage and contribute to the development of OA, especially in the hip joint. Blatant examples of such abnormalities include congenital hip dislocation, Legg-Perthes disease, and slipped capital femoral epiphysis. However, more subtle and asymptomatic anatomic variations have also been associated with hip OA. Lane et al., examining baseline and 8-year follow-up x-rays in the SOF, found that an abnormal center-edge angle and acetabular dysplasia were each associated with increased risk of incident hip OA, adjusting for age, current weight, BMI, affected side, and investigational site (adjusted OR 3.3, 95% CI 1.1 10.1, and 2.8, 95% CI 1.0 7.9, respectively).160 In this study population with a mean +/- SD age of 65.6 +/- 6.5 years, 9.3% developed incident radiographic hip OA. In the Rotterdam study, individuals with acetabular dysplasia (center-edge angle <25 degrees) had a 4.3-fold increased risk for incident radiographic OA of the hip (95% CI 2.2 8.7) compared with individuals without acetabular dysplasia.161
Meniscectomy
Cooper et al. demonstrated that meniscectomy increased the risk of knee OA, controlling for BMI, Heberden's nodes, and a family history of OA.109 The prevalence of knee OA 21 years after open meniscectomy was 48% versus 7% in age and gender matched control.162 A series of studies by Englund et al. have shown that: the risk of tibiofemoral OA was increased more than threefold by a history of total meniscectomy and doubled by partial meniscectomy;163 obesity substantially increased the likelihood of OA in the those with a history of meniscectomy;163 and the likelihood of patellofemoral OA (either isolated or, more often, with tibiofemoral OA) was greater in those who had undergone medial or lateral meniscectomy than controls matched on age, sex, and postal code who had not undergone meniscectomy.164
Other Factors
In a longitudinal Framingham study, smokers had a lower risk of knee OA than nonsmokers, which persisted after adjusting for age, sex, BMI, knee injury, chondrocalcinosis, hand OA, and physical activity.73 However, smoking was
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not linked to incident knee OA in a longitudinal Chingford study.165 Cross-sectional studies have had mixed results.
Analyses of NHANES I data including those aged 35 to 74 revealed that African-American women had an increased risk of knee OA versus white women (OR 2.12, 95% CI 1.39 3.23), adjusting for age, BMI, skinfold thickness, income, education, marital status, uric acid level, and smoking.55 The risk of knee OA was not greater in African-American men than in white men. In women, knee extensor strength was 18% lower at baseline among those who developed incident knee OA than among controls, adjusting for body weight.88 Reduced quadricep strength relative to body weight may be a risk factor for knee OA.
In a longitudinal Framingham study, greater grip strength in men was associated with increased risk of OA at the PIP joints, MCP joints, and thumb base, and in women at the MCP joints (OR 2.7 to 2.9).166 Maximal grip is a global measure of the muscle force that can be generated during a common activity. Forces at the DIP during grip are less than those at the other hand joints. These findings support the concept that OA development relates not only to the frequency of certain tasks, but also to the magnitude of force generated during the task. In cross-sectional analyses of BLSA men, associations between increasing grade of DIP OA and lower grip strength and forearm circumference did not persist after adjusting for age.84
A modest association between the presence of chondrocalcinosis and knee OA, accounting for age, was present in a cross-sectional Framingham study.167 In a longitudinal study, chondrocalcinosis was not a risk factor for incident knee OA; analyses were limited by the small number of participants with chondrocalcinosis.73 Doherty et al. reported that, in 100 patients 25 years after unilateral meniscectomy, chondrocalcinosis was detected in 20% of operated knees versus only 4% of unoperated knees.168 Severe radiographic changes were more common when chondrocalcinosis was present.
The prevalence of hand OA in patients with CVA and hemiparalysis was significantly lower than in elderly persons without stroke.169 The differences between paretic and nonparetic hand radiographs were greater when only those with moderate to severe paralysis were considered, and greatest when severe paralysis of over 3 years was considered.
Progression of Osteoarthritis
Gaps in knowledge of the natural history of human OA are due in part to difficulty dealing with heterogeneous presentations, the inability to pinpoint disease onset, slow course, intra- and intersubject variation in progression rate, and variation in how progression is assessed especially as the technology of image acquisition evolves. Efforts to consolidate the information provided by published studies are frustrated by methodologic variations, especially regarding how images were obtained, how measurements were made off the image, and how progression was defined. Efforts to develop consensus and standardized approaches have clearly improved studies to assess OA progression.37,170,171,172
Knee Osteoarthritis
Most epidemiologic studies are using both x-ray and MRI, with a gradual shift toward MR based outcomes as a primary approach.
Application of X-ray
Historically, most epidemiologic studies relied on conventional, extended knee radiography. Acquisition protocols have been developed over the past several years to enhance the quality of medial tibiofemoral joint space measurement by improving superimposition of the anterior and posterior medial tibial rims. Generally accepted protocols include two with fluoroscopic confirmation, the Buckland-Wright protocol173 and the Lyon-Schuss protocol,174 and two not using fluoroscopy, the MTP protocol175 and the fixed-flexion protocol.176 A discussion of the strengths and weaknesses of these protocols has been published.172,177
It is recommended that individual radiographic features as well as a global score be recorded.37 Recommendations to treat joint space width as the primary outcome in tibiofemoral OA progression studies are supported by joint space width reflects cartilage loss; with adherence to protocol, joint space width can reliably reflect medial compartment cartilage thickness;178 joint space narrowing was the best single variable for assessing progression;179 and sensitivity to change was higher for joint space measurements than for K/L grade.180 Rates of progression vary widely between studies. Different sources of subjects may explain some of this variation; progression may be faster in clinic-based samples.
Application of MRI
The advantages of MRI over plain radiography e.g., direct three-dimensional visualization of cartilage, ability to detect focal and diffuse cartilage changes, less vulnerability to joint positioning and technique, and opportunity to visualize other tissues affected by OA have led to a dramatic increase in its use in epidemiologic studies, especially as longitudinal MRI data have become available. Both the validity and the reliability (in persons with and without knee OA, short- and long-term) of image acquisition and processing for cartilage volume have been demonstrated in several studies, summarized in recent reviews.181,182 MRI allows shorter duration studies with fewer participants than if x-ray is used. Longitudinal data on changes in cartilage volume suggest that 4% to 6% of cartilage volume is lost per year in knees with OA.183,184,185,186 MRI may be able to detect change in knee OA cartilage volume as early as 6 months.181 Cartilage volume loss was modestly associated with worsening of pain (R = 0.21) and function (R = 0.28) in one study.187 As there have been no head-to-head comparisons of cartilage volume assessment and cartilage integrity grading,188 it is unclear which approach is more sensitive to change and which is more closely related to person-relevant outcomes.
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Much effort is being directed toward identifying imaging parameters that could ultimately serve as early indicators of disease progression and outcome measures of treatment response, i.e., even before anatomic damage. One approach, delayed gadolinium enhanced MRI of cartilage, or dGEMRIC, has been used to examine the relative distribution of glycosaminoglycan (GAG) in cartilage.189 Longitudinal studies applying dGEMRIC are underway.
Ultimately, how progression is assessed impacts not only issues of the necessary sample size and study duration, but also potentially the profile of factors linked to progression. Current beliefs about the natural history of knee OA are based on less than optimal radiographic techniques, and may undergo some revision as we evolve in our ability to assess disease progression.
Table 1-6 shows several knee OA progression studies and the risk factors they have identified.15,16,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207
Malalignment
Alignment at the knee (the hip-knee-ankle angle as measured by full-limb radiography) can either be varus (bow-legged), valgus (knock-knee), or neutral. In the MAK study mechanical factors in arthritis of the knee study (MAK), the presence of varus malalignment was associated with a fourfold increase in the risk of medial tibiofemoral OA progression (4.1, 95% CI 2.2 7.6), while valgus malalignment increased the risk of lateral tibiofemoral disease progression (4.9, 95% CI 2.1 11.2).198,199 Varus-valgus alignment also influenced the likelihood of patellofemoral OA progression in a compartment-specific manner at 18 month follow-up.203 Varus alignment increased the odds of patellofemoral OA progression isolated to the medial patellofemoral compartment (adjusted OR 1.85, 95% CI 1.00 3.44). Valgus alignment increased the odds of PF OA progression isolated to the lateral compartment (adjusted OR 1.64, 95% CI 1.01 2.66).
In a longitudinal MRI-based study, Cicuttini et al. found that for every 1 degree increase in baseline varus angulation, there was an average annual loss of medial femoral cartilage of 17.7 l (95% CI 6.5 28.8), with a trend toward a similar relationship with medial tibial cartilage volume loss.204 For every 1 degree increase in valgus angle, there was an average loss of lateral tibial cartilage volume of 8.0 l (95% CI 0.0 16.0).
Alignment and BMI in Osteoarthritis Progression
Recent evidence suggests that alignment, in addition to its effect on load distribution, may also amplify or mediate the effect of other factors associated with knee OA progression. Load distribution between the compartments is more equitable in valgus knees (until severe valgus is reached) than in varus knees. In keeping with this, the relationship between BMI and disease severity in the MAK study had a significantly steeper slope in varus than in valgus knees.208 Also, the BMI/medial OA severity relationship was substantially attenuated after adjusting for varus severity. That alignment modifies the BMI effect is also supported by a recent longitudinal study, in which some effect of BMI on progression was found in knees with moderate malalignment (OR 1.23/2-unit increase in BMI, 95% CI 1.05 1.45) but not in knees with neutral alignment.209 Collectively, these findings are most likely related to the malalignment-associated alteration in distribution of body weight forces between the two tibiofemoral compartments.
Nutritional Factors
As reported by McAlindon et al., in the Framingham cohort, risk for knee OA progression was greater in those with lower vitamin D intake (OR for lower compared with upper tertile 4.0, 95% CI 1.4 11.6) and in those with lower serum levels of vitamin D (OR for the lower compared with the upper tertile 2.9, 95% CI 1.0 8.2).195 Low serum levels of vitamin D specifically predicted loss of joint space as well as osteophyte growth. A randomized clinical trial of vitamin D, including assessment of potential disease-modifying effect, is underway at Tufts University.
A threefold reduction in risk of OA progression was found for both the middle and highest tertiles of vitamin C intake, primarily related to a reduced risk of joint space loss.196 Those with high vitamin C intake also had a reduced risk of developing knee pain (adjusted OR 0.3, 95% CI 0.1 0.8). No significant association of incident OA was found with any nutrient.
Quadriceps Strength
Several cross-sectional studies and short-term trials suggest strength is a correlate of physical function and that increasing quadriceps strength reduces pain and improves function. In women without knee OA, those who went on to develop disease were 18% weaker at baseline than those who did not develop knee OA, suggesting that quadriceps strength may protect against knee OA in women.88 However, the two studies examining the relationship of quadriceps strength and subsequent tibiofemoral OA progression found no evidence of a protective effect.210,211 In a study in which the strength/progression relationship was examined within knee subsets, in malaligned knees and in lax knees, greater strength at baseline was associated with a greater risk of OA.211 This finding suggests that a generic muscle strengthening intervention may not be appropriate for all persons with knee OA and that strength programs tailored to knee subsets need to be developed.
The Role of Bone
Dieppe and others have emphasized the important role of subchondral bone in OA progression.212 Baseline subchondral bone activity as reflected by scintigraphy was strongly related to knee OA progression: 88% of knees with severe scan abnormalities progressed, while none of the knees with normal scans at entry progressed.192
Bone Mineral Density. As reported by Zhang et al., over 8 years of follow-up of the Framingham cohort, risk of incident OA was lowest in the lowest 4-year BMD quartile (5.6%) and was higher in the higher 3 BMD quartiles (14.2%, 10.3%, and 11.8%).115 Among those with OA, however, with greater BMD at baseline, risk of progressive OA decreased from 34.4% in the lowest BMD quartile to 19% in the
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highest quartile. While the Rotterdam study also found a protective effect of high femoral neck BMD (at baseline) on progression of OA, this effect was lost after accounting for mobility.116 Persons with progressive knee OA were more disabled and more often were using a walking aid. This may be the source of an apparent link between low BMD and knee OA progression.
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Hurwitz et al.213 and Wada et al.214 demonstrated a relationship between the adduction moment and medial to lateral ratio of proximal tibial BMD. As noted by Hurwitz, while it is a long held belief that the adduction moment is the chief determinant of medial/lateral tibiofemoral load distribution, these studies represent the first evidence of its relationship to underlying bone,213 recently Lo et al. found that medial bone marrow lesions were associated with a higher medial to lateral BMD ratio, and lateral bone lesions to a lower ratio.215
Bone Marrow Edema. Investigators are increasingly using the phrase bone marrow abnormality to describe the increased focal signal in the subchondral marrow of the knee of fat-suppressed T2-weighted MR images, rather than bone marrow edema, because of the abundance of other histopathologic findings in these lesions (fibrosis, osteonecrosis, bony remodeling216). Presence of these lesions was strongly associated with subsequent knee OA progression.202 There was a greater than sixfold increase in the likelihood of medial tibiofemoral OA progression in knees with medial bone marrow abnormality (OR 6.5, 95% CI 3.0 14.0), and in the odds of lateral progression in knees with lateral bone marrow abnormality, with some attenuation after adjustment for severity of malalignment. Varus-aligned limbs had a higher prevalence of medial lesions than neutral or valgus limbs (74.3% vs. 16.4%). Similarly, the prevalence of lateral bone marrow abnormality was higher in valgus than in neutral or varus knees.
Varus Thrust and Knee Adduction Moment
A varus thrust is the dynamic worsening or abrupt onset of varus alignment while the limb is bearing weight during ambulation, with return to less varus alignment during non-weight-bearing conditions. In an 18-month study, Chang and colleagues found that the presence of a varus thrust visualized during gait was associated with a fourfold increase (95% CI 2.11 7.43) in the likelihood of medial OA progression.205 In varus-aligned knees examined separately, a thrust was associated with a threefold increase in the likelihood of progression, suggesting that a thrust further increases the risk of progression over and above the risk conferred by static varus alignment. In theory, the impact of a varus thrust on progression of knee OA may be mediated through the associated dynamic instability of the knee and/or an acute increase in load across the medial tibiofemoral compartment, the most common site of OA disease at the knee. Having a thrust in both versus neither knee was associated with a twofold increase in the OR for poor physical function outcome (not achieving significance).213
The moment that adducts the knee during the stance phase of gait and assessed during quantitative gait analysis is widely believed to be a correlate of medial tibiofemoral load. Miyazaki et al. found that baseline adduction moment magnitude was strongly associated with risk of medial OA progression (OR 6.46, 95% CI 2.40 17.45), adjusting for age, gender, BMI, pain, mechanical axis, and joint space width.199
Meniscus Tears and Extrusion
In patients with knee osteoarthritis, MR images every 6 months for 2 years revealed that knees with severe medial meniscal tear at baseline lost on average 10% of global cartilage volume and 14% of medial compartment cartilage volume (vs. 5% and 6%, respectively, in knees without a tear).206 Knees with medial meniscal extrusion experienced a 15.4% loss of medial cartilage volume versus 4.5% in knees with no extrusion.
Hip Abduction Moment
Recently, a greater hip internal abduction moment at baseline was identified as a factor protecting against ipsilateral medial OA progression over 18 months.207 The odds of medial OA progression were reduced by 50% with every additional one unit of hip abduction moment. This protective effect persisted after adjustment for potential confounders (OR 0.43, 95% CI 0.22 0.81). The magnitude of hip muscle torque generated during ambulation can be measured in quantitative gait analysis. Weakness of hip abductor muscles in the stance limb may cause excessive pelvic drop in the contralateral swing limb, thereby shifting the body's center of mass toward the swing limb and increasing forces across the medial tibiofemoral compartment of the stance limb. Hip muscle strength is the major source of hip abduction moment magnitude with the hip joint ligaments and capsule also making a small contribution to the moment. These results suggest the need for future studies to examine the effect of interventions targeting hip abductor strengthening.
Hip Osteoarthritis
More information about risk factors for progression of hip OA is emerging. In the Rotterdam study, age, female sex (OR 1.8, 95% CI 1.4 2.4), presence of hip pain (OR 2.4, 95% CI 1.7 3.5), joint space width at baseline 2.5 mm or less (OR 1.9, 95% CI 1.2 2.9), and a K/L score of 2 or more at baseline (OR 5.8, 95% CI 4.0 8.4) independently predicted hip OA progression.217 Similarly, in the SOF, progression was greater by all measures in those with both radiographic OA and hip pain at baseline (OR 1.9, 95% CI 1.4 2.6); femoral osteophytes, superolateral joint space narrowing, and subchondral bone changes independently predicted progression.218 Of note, Seifert et al. had also observed that radiographic cysts at baseline were linked to worse 5-year outcome.219 In another study, rapid structural progression, i.e., loss of more than 50% of hip joint space, was more common in women.220
In hospital patients, Ledingham et al found that hips with rapid radiographic progression more often had superior migration or an atrophic bone response; those with no progression more often had an indeterminate, medial or axial migration, protrusio or mild OA at presentation.221 Higher rates of progression were seen in women, and were linked to older age at symptom onset and higher K/L grade
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at entry. BMI, symptom duration, chondrocalcinosis, hand OA/Heberden's nodes, or Forestiers disease had no effect on progression. Functional status decline was more common in those with radiographic progression.
In the SOF, over 8 years, 64.6% of hips with OA showed radiographic progression or were replaced, 12.9% of women with baseline radiographic OA underwent THR, and 22.8% had substantial worsening of lower extremity disability.218 As reported by Danielsson et al from another study, among 121 osteoarthritic hips (identified in 4000 individuals), 7% had radiographic improvement, 28% had no change, and 65% had deterioration over 10 years.21 In a study of hospital hip OA patients (followed for a median of 27 months), about 15% of hips progressed by one K/L grade, 47% progressed using another global scoring system, and 64% progressed in at least one radiographic feature.221 Ten % experienced functional deterioration by Steinbrocker index.
Based on clinical observation and some data,21 radiographic improvement is believed to be more common at the hip than at other joint sites. Perry et al. described 14 hips in which definite or probable joint space recovery occurred, possibly linked to the formation of upper and lower pole osteophytes that developed after early joint space loss.222
Hand Osteoarthritis
Over half of BLSA men with DIP OA had radiographic progression over 10 years.52 Progression was most rapid in the DIP joints. The median time for 50% of the cohort to progress one K/L grade was 8.9 years for older subjects, 12.4 years for middle-aged subjects, and 15.8 years for young subjects. In a clinic-based study, progression at DIP, PIP, and CMC-1 sites was similar, with 47% to 50% progressing, 45% to 46% unchanged, and 6% to 8% improving over a 10 years, using the highest K/L grade.223 Using the sum of grades for all sites, 96% of subjects deteriorated using K/L, 90% using osteophytes, and 74% using joint space narrowing. Age, gender, and BMI did not differ between severe and minor progressors.
Risk Factors for Pain and Disability In Osteoarthritis
Risk factor profiles for each of the three domains structural disease, pain, and disability overlap but are not identical. For example, analyses of NHANES I and NHES data demonstrated that known or suspected correlates of radiographic OA (age, gender, race, obesity, physical activity, Heberden's nodes) were not associated with knee pain.224 Pain is complex to study longitudinally; it does not inexorably worsen and may not follow a pattern. Current knowledge of determinants of pain and disability in OA is based on a small number of longitudinal studies and several cross-sectional studies, examples of which are provided here.
Correlates of Pain
More severe radiographic disease has been associated with increased reports of knee pain in most but not all studies. In the Framingham cohort, 8% with K/L 0 knees had pain on most days in the previous month, 11% with K/L 1, 19% with K/L 2, and 40% with K/L 3-4.54 Though there was a relationship between pain and K/L, the proportion at K/L 3-4 without pain is noteworthy. Lethbridge-Cejku et al. found in BLSA participants that 56% of those with K/L 3-4 knee OA had current pain.225 The presence of radiographic knee OA was associated with ever pain (OR 4.0, 95% CI 2.3 6.4) and current pain (OR 4.8), adjusting for age, sex, and BMI. Odds ratios increased with increasing radiographic severity.
Recent studies have attempted to identify specific features of OA that are responsible not only for pain presence but also for severity. Bone and synovium 226 are emerging as potential sources of pain. In BOKS, bone marrow lesions were more common in OA knees with symptoms (defined as pain, aching, or stiffness on most days) than in knees without symptoms.227 Also, knees in which bone marrow lesions were present had higher pain scores on average than knees without such lesions, though the difference was not significant.
Sowers et al. found that bone marrow lesions 1 cm or larger in size were more frequent in OA knees with pain than in OA knees without pain.228 In their study, a primary difference between painful and painless OA knees was whether or not bone was intact under full-thickness cartilage defects. They termed this feature bone ulceration, defined as any defect of the subchondral cortex beneath a cartilage defect. Most full-thickness cartilage defects in persons with painful OA were accompanied by bone ulceration. They questioned whether a bone marrow lesion has to be accompanied by other changes in bone to cause pain.
Among subjects with knee and/or hip OA, an association has been reported between joint pain and psychological factors, including poor psychological well being,224 feeling in low spirits, 229 depression, anxiety or coping style,230,231,232 and hypochondriasis.233 Quadriceps weakness and pain have been associated232,234 although the studies of Slemenda et al.235 provide evidence that the relationship between pain and weakness may not be as strong prior to OA or in prodromal stages as in more advanced stages.
Function Limitation
Most studies of OA have emphasized physical function limitation, assessed by self-report and/or specific task performance, and have less often examined disability, i.e., performance within a typical physical, social, and cultural context. Like pain, physical function is predicted by radiographic disease severity in some studies and not others. More recent studies have dealt with specific pathoanatomic/pathophysiologic aspects of disease (i.e., beyond radiographic aspects) and how they contribute to impaired function.
In the longitudinal organization to assess strategies for ischemic syndromes (OASIS) and MAK studies, self-efficacy predicted both self-reported and performance outcomes, after adjusting for pain, strength, and other potential confounders or mediators.237,238 In both studies, greater
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baseline knee pain intensity predicted function decline. In OASIS, the relationship between pain intensity and function decline was reduced after accounting for self-efficacy and the self-efficacy-strength interaction.236 In the MAK study, the strength/function outcome relationship was lost after adjustment for self-efficacy.238 Together, these results suggest a close relationship between strength, knee pain intensity, and self-efficacy in their effect on physical function in knee OA. Pain may acutely reduce the maximal voluntary contraction and lead to chronic activity revision or avoidance. A downward spiral of pain, weakness, and reduced self-efficacy may lead to substantial reduction in activity.
Other factors linked to physical function in knee OA from longitudinal analyses of the MAK study were age, medial-lateral laxity, varus-valgus alignment, social support, and SF36 mental health score.238 A relationship between depressive symptoms and physical function has also been described in longitudinal studies not limited to individuals with arthritis, as summarized by Ormel et al.239
The association between baseline radiographic knee OA and physical functioning 10 years later was evaluated in NHANES I participants.240 For women with knee OA, difficulty was most often identified with heavy chores, and, for men, walking 1/4 mile. In women, moderate to severe arthritis was associated with worse scores than seen with mild disease for 14 activities. The added presence of knee OA substantially increased the likelihood of disability in those with heart disease, pulmonary disease, hypertension, or obesity.241 In the Framingham study, persons with infrequent symptoms but severe radiographic disease were more likely to have lower extremity functional limitations than those with symptoms and less severe disease.241 Radiographic knee OA increased the odds of dependence in stair climbing, walking one mile, light housekeeping, and carrying bundles.4 Radiographic OA of the hand, wrist, foot, or ankle was associated with disability in women.243 In another study, radiographic hand/wrist OA was linked to health assessment questionnare (HAQ) score.244
Pain is a key correlate of physical functioning in OA.58,240,241,242,245,246,247 Ettinger et al. found that of men with symptomatic knee OA, 50% reported difficulty with ambulation and 43.8% with transfer; only 19% of men with OA and without symptoms reported difficulty with each activity.241 In women with symptomatic OA, 70.5% reported difficulty with ambulation and 67.2% with transfer versus 24.8% and 27.5%, respectively, of those without pain. The odds of functional impairment among those with radiographic knee OA were increased by the presence of symptoms, adjusting for age, race, and education.
A number of studies demonstrate a link between impaired physical function and psychological factors including pain coping,247 psychological well-being,247 depression, and anxiety.230,231,232,249 Bivariate correlations between self-efficacy and task performance were similar in magnitude to those seen for aerobic capacity and for strength. Several studies have linked quadriceps strength and function in knee OA.234,245,246,247,250
Conclusion
As the most common arthritis and a leading cause of chronic disability, osteoarthritis (OA) is associated with substantial cost to the individual and to society. Epidemiologic studies have supplied, in addition to incidence, prevalence, and risk factor data, much of what is known about the natural history of OA. Especially given the anticipated increase in OA prevalence, the need to identify risk factors for incident OA, OA progression, OA associated physical function decline, and disability is a high priority. In recent years, emphasis has shifted toward the identification of risk factors for OA progression. Several risk factors for progression are emerging, many of which originate or relate to the local joint organ environment. This shift in focus relates in part to the concept that risk factors for progression might ultimately be targeted to delay OA progression or to enhance the effect of a potentially disease-modifying drug. As additional studies are completed and more is learned about these and other factors, opportunities will very likely arise for intervention and prevention strategy development.
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