Epidemiology of Osteoarthritis

Age

Age is a one of the strongest risk factors for OA of all joints (1, 6, 15). The increase in the prevalence and incidence of OA with age probably is a consequence of cumulative exposure to various risk factors and biologic changes that occur with aging that may make a joint less able to cope with adversity, such as cartilage thinning, weak muscle strength, poor proprioception, and oxidative damage.

Gender and hormones

Women not only are more likely to have OA than men, they also have more severe OA (16). The definite increase in OA in women around the time of menopause has led investigations hypothesize that hormonal factors may play a role in the development of OA. However, results on effect of estrogen, either endogenous or exogenous, on OA from observational studies have been conflicting (17-19). In a randomized clinical trial (the Heart and Estrogen/Progestin Replacement Study) in a group of older postmenopausal women with heart disease, no significant difference was found in the prevalence of knee pain or its associated disability between those taking estrogen plus progestin therapy or those taking placebo (20). Data from the Women's Health Initiative showed that, women on estrogen replacement therapy were 15% less likely to require total knee or hip arthroplasty than those not taking such therapy (hazard ratio 0.86; 95% Confidence Interval, 0.70-1.00), but that estrogen combined with progestin therapy was not associated with the risk of joint replacement (21).

Race/ethnicity

The prevalence of OA and patterns of joints affected by OA vary among racial and ethnic groups. Both hip and hand OA were much less frequent among Chinese in the Beijing Osteoarthritis Study than in whites in the Framingham Study (22, 23), but Chinese women in the Beijing Osteoarthritis Study had significantly higher prevalence of both radiographic and symptomatic knee OA than white women in Framingham Study (24). Results from the Johnston County Osteoarthritis Project have shown that the prevalence of hip OA in African American women (23%) was similar to that in white women (22%), and prevalence was slightly higher in African American men (21%) than that in white men (17%)(25). Interestingly, prevalence of individual radiographic features of hip OA varied between African Americans compared with Whites. For example, superior joint space narrowing and osteophytes at lateral compartment are more common in African Americans than in Whites (25). In addition, African Americans were also more likely to have more severe and tri-compartmental osteophytes than their White counterparts(26). Whether some of these racial/ethnic differences are related to differences in anatomic femoral and acetabular features, shown to be important in radiographic hip OA in whites (27, 28), is worthy of further study.

Genetics

Results from several studies have shown that OA is inherited and may vary by joint site. Twin and family studies have estimated the heritable component of OA to be between 50 and 65% with larger genetic influences for hand and hip OA than for knee OA (29-31). In a genome-wide association study, Kerkhof et al (32) reported that the C allele of rs3815148 on chromosome 7q22 was associated with a 1.14-fold increased prevalence of knee and/or hand OA and also with a 30% increased risk of knee OA progression. Several studies also found that an inverse association between general joint hypermobility, a lone benign trait, with hand and knee OA and serum cartilage oligometric matrix protein levels (33, 34).

Congenital/developmental conditions

A few congenital or developmental abnormalities (i.e., congenital subluxation, Legg-Calvé-Perthes disease, and slipped capital femoral epiphysis) have been associated with occurrence of hip OA in later life (35-37); however, because these developmental deformities are uncommon, they probably only account for a small proportion of the hip OA in the general population. Several studies have examined sub-clinical acetabular dysplasia, a more common, milder developmental abnormality, in relation to hip OA, with conflicting results (27, 38-41). Lane and colleagues (27) reported that abnormal center-edge angle or acetabular dysplasia were each associated with an approximately threefold increased risk of incident hip OA in women (27), suggesting that subclinical acetabular dysplasia may be a significant risk factor for the development of hip OA.

Diet

Dietary factors are the subject of considerable interest in OA, results of studies, however, are conflicting. One of the most promising nutritional factors for OA is vitamin D. Without sufficient vitamin D, bones can become thin, brittle, or misshapen. In the Framingham Study subjects in the lowest (<27 ng/ml) and middle (27.0 – 33.0 ng/ml) tertile of serum 25-hydroxyvitamin D had a 3-fold increased risk for progressive knee OA compared with those in the highest tertile; however, no such effect was observed for risk of incident disease (42). In the Study of Osteoporotic Fractures, women in the middle (23-29 ng/mL) and lowest (8-22 ng/mL) tertiles of serum 25-vitamin D were 3 times as likely to develop incident hip OA, defined by joint space narrowing, as those in the highest tertile (30-72 ng/mL). However, serum vitamin D levels were not associated with the risk of hip OA characterized by osteophytes or with new disease defined according to the summary grade (43). However, results from two cohort studies failed to confirm protective effect of vitamin D on the structural worsening of knee OA (44). A randomized, placebo-controlled clinical trial of vitamin D is currently underway to examine whether this vitamin can affect knee symptoms and cartilage loss measured on MRI in established knee OA.

Low vitamin C dietary intake was associated with an increased risk of progression, but not incidence, of both radiographic and symptomatic knee OA among the participants in the Framingham Study (45). In the Johnston County Osteoarthritis Project subjects with a high ratio of alpha:gamma tocopherol had 50% lower risk in development of radiographic knee OA (46). However, results from a controlled clinical trial of vitamin E failed to ameliorate symptoms in patients who had symptomatic knee OA or to prevent knee OA progression, as measured by cartilage volume by MRI (47).

Animal studies have shown that selenium deficiency is associated with irregular bone formation, decreased bone strength, and abnormalities in type I and II collage in cartilage (48, 49). In areas of China and eastern Asian where selenium levels in the soil is extreme low, the prevalence of Kashin-Beck Disease, an early onset of osteoarthropathy, was also high and food supplement of selenium decreased the incidence of this disease(50, 51). Preliminary results from the Johnston County Osteoarthritis Project have shown that sub-optimal selenium levels, measured in toenails, were associated with worse knee OA (52). However, others have reported that high selenium intake was significantly associated with increased risk of both hip and knee OA (53).

In one study, high levels of serum vitamin K were associated with a low prevalence of radiographic hand OA in one study, particularly for the presence of large osteophytes (54). The relation of serum vitamin K levels to knee radiographic OA is less clear. A recent randomized, placebo-controlled trial of vitamin K supplementation (phylloquinone, 500 μg/day) did not confirm a protective effect of vitamin K on the severity of radiographic hand OA.

Obesity

Obesity and overweight have long been recognized as potent risk factors for OA, especially OA of the knee (1). The results from the Framingham Study demonstrated that women who had lost about 5 kg had a 50% reduction in the risk of development of symptomatic knee OA (55). The same study also found that weight loss was strongly associated with a reduced risk of development of radiographic knee OA. Weight-loss interventions have been shown to decrease pain and disability in established knee OA (56, 57). The Arthritis, Diet, and Activity Promotion Trial showed that weight loss combined with exercise, but neither weight loss nor exercise alone, were effective in decreasing pain and improving function in obese elders who had symptomatic knee OA (56). Results from a meta-analysis concluded that while the effects of weight loss on pain were less consistent weight reduction by about a 5% was associated with an improvement of physical function (57).

The relationship between overweight and hip OA is inconsistent and, if it exists, is weaker than that with knee OA (58, 59). There is, however, more consistent evidence that obesity increases the risk of bilateral radiographic as well as symptomatic hip OA (60). In the Nurses' Health Study, higher BMI, especially BMI at age 18, was strongly associated with an increased risk of total hip replacement therapy(61). Increased loading on the joint is probably the main, but not only, mechanism by which obesity causes knee or hip OA. Overloading the knee and hip joints could lead to synovial joint breakdown and failure of ligamentous and other structural support.

Injury/surgery

Numerous studies have shown that knee injury is one of the strongest risk factors for OA. Severe injury to the structures of a joint, particularly a trans-articular fracture, meniscal tear requiring meniscectomy, or anterior cruciate ligament injury, can result in an increased risk of OA development and musculoskeletal symptomatology (62, 63). In the Framingham Study the prevalence of meniscal damage was much higher among subjects with radiographic knee OA (82%) than those without OA (25%). The prevalence of meniscal damage increased with an increase in K/L grade (P<0.001 for trend); among those with moderate (K/L=3) and severe (K/L=4) radiographic knee OA 95% had evidence of meniscal damage (64).

Occupation

Repetitive use of joints at work is associated with an increased risk of OA. Studies have found that farmers have a high prevalence of hip OA (65). The prevalence of Heberden's nodes was much higher in the cotton mill workers, whereas spinal OA was no more common in these workers than in controls (66). Workers whose jobs required repeated pincer grip had more OA at distal interphalangeal joints than did workers whose job required power grip (67).

The risk of development of knee OA was more than two times greater for men whose jobs required both carrying and kneeling or squatting in mid-life had more than for those whose jobs did not require these physical activities (68). And the risks of knee OA associated with kneeling and squatting were much higher among subjects who were overweight or whose job also involved with lifting (69).

Physical activity/sports

Studies examining the relationship between sports activities and subsequent OA have produced conflicting results. There is some evidence that elite long distance runners are at high risk for the development of knee and hip OA (70-72); and elite soccer players are at higher risk of getting knee OA when compared with non-soccer players (71, 73). Surprisingly, the general level of physical activity itself may also increase the risk of OA. For instance, physical activity among elderly subjects in the Framingham Study was generally characterized by leisure time walking and gardening. However, person who engaged in relatively high levels of such activity had a threefold greater risk of developing radiographic knee OA than sedentary persons over 8 years of follow-up (74). Similar findings also were reported in another study in which women who had a high lifetime level of physical activity had a high prevalence of hip OA (75). In contrast, others have shown that, in the absence of acute injury, recreational (moderate) long distance running and jogging did not appear to increase the risk of OA (76, 77).

Mechanical factors

The relationship between muscle strength and OA is complex, may vary by joint site, and is not entirely understood. Muscle weakness and atrophy commonly associated with knee OA had been thought to be the product of disuse resulting from pain-avoidance. One study reported that women who had asymptomatic radiographic knee OA but had no muscle atrophy showed quadriceps muscle weakness (78), suggesting that this might be a risk factor for the development of symptomatic knee OA (78). Baker and colleagues (79) confirmed that persons who had both asymptomatic patellofemoral and tibiofemoral radiographic knee OA had weaker quadriceps strength than those who did not have OA (79). In a follow-up study quadriceps muscle weakness not only resulted from painful knee OA, but also increased the risk of knee structural damage (80, 81). Other studies (82), however, showed that greater quadriceps muscle strength in the setting of malalignment and laxity may actually be associated with an increased risk of knee OA progression.

Using the data from the Genetics of Generalized Osteoarthritis Study, Dominick and colleagues (83) found an inverse cross-sectional associations between grip strength and OA of the carpometacarpal joint and between pinch strength and OA of the metacarpophalangeal joint. On the other hand, greater grip strength was associated with an increased risk of radiographic hand OA among the participants of the Framingham Study: men whose maximal grip strength was in the highest tertile had a threefold increased risk of OA in the proximal interphalangeal, metacarpophalangeal, or thumb base joints, as compared with those with lowest tertile (84). The authors suggested that the maximal force exerted on specific joints might influence development of OA in those joints.

Alignment

Knee alignment (i.e., the hip-knee-ankle angle) is a key determinant of load distribution. Any shift from a neutral or collinear alignment of the hip, knee and ankle affects load distribution at the knee. Therefore, one would speculate that malaligned knees may have a higher risk of developing OA and a higher subsequent risk of progression than knees with neutral alignment.

In a prospective cohort study, Sharma et al (85) demonstrated that in the presence of existing knee OA, abnormal anatomic alignment was strongly associated with accelerated structural deterioration in the compartment under greatest compressive stress (85). Knees with varus alignment at baseline had a fourfold increase in the risk of medial progression of knee OA, and those with valgus alignment at baseline had a nearly fivefold increase in the risk of lateral progression. The same study also found that the impact of varus or valgus malalignment on the risk of OA progression was greater in knees with more severe baseline radiographic disease than knees with mild or moderate disease (86). Another study found that knee malalignment was associated with the size and progression of bone marrow lesions as well as with rapid cartilage loss on MRI (87).

The association between malalignment and risk of incident knee OA is less clear, however. The results from the Rotterdam study found that among knees with K/L grade 0 and 1, knees with valgus alignment had a 54% increased risk and knees with varus alignment had a twofold increased risk for the development of radiographic knee OA, compared with normal aligned knees (88). In the Framingham Study, however, Hunter and colleagues using four measures of knee joint alignment (i.e., the anatomic axis, the condylar angle, the tibial plateau angle, and the condylar tibial plateau angle) found none of these measures to be associated with an increased risk of incident radiographic knee OA. The authors speculated that malalignment may not be a primary risk factor for the occurrence of radiographic knee OA but rather a marker of disease severity and/or its progression (89).

Laxity

Knee laxity is another potential risk factor for knee OA. Varus-valgus knee laxity is greater in the non-arthritic knees of patients who have idiopathic disease than in the knees of controls, suggesting that a portion of the increased laxity of knee OA precedes disease development and may predispose to disease (90). And sagittal plane or anterior-posterior laxity may be increased in persons who have mild OA, and anterior-posterior laxity seems to decline with increasing severity of knee OA (91, 92). Because knee laxity may be altered by the disease itself, longitudinal data will be helpful to confirm these relationships.

Another factor that can alter biomechanics at the knee and hip is limb length inequality (LLI). In the Johnston County Osteoarthritis Project persons with a LLI of at least 2 cm were almost twice as likely to have radiographic knee OA and 40% more likely to have knee symptoms (93). The results from the Multicenter Osteoarthritis Study also demonstrated that leg length inequality ≥ 1 cm was not only associated with a higher prevalence of prevalent radiographic knee OA, but also increased the risk of incident symptomatic and progressive knee OA(94). These results point to LLI as a potentially modifiable risk factor for knee OA.