Pathogenesis

Despite the continuing difficulty in defining, measuring and assessing osteoarthritis, it is a long-standing disease in humans and non-humans.^13,14 Absent from the skeletal remains of hominids, the first widespread evidence of the disease in Homo sapiens was provided by Neanderthal remains.^1,15-17

The specific pathogenesis of osteoarthritis, however, remains undetermined. In Cushnaghan and Dieppe's study 10 of 500 individuals with limb joint osteoarthritis, an obvious predisposing cause of osteoarthritis was apparent in only 46 (9.2%). These causes included severe trauma, meniscectomy, epiphysial dysplasia and joint instability. Although data from this and other studies ^3,5,18 indicate that osteoarthritis of different joints may involve different risk factors, clearly, there is a link between some osteoarthritis sites.³

In studying the incidence of arthritic disorders in animals, Fox ¹⁹ determined body size to be the pertinent discriminatory variable separating those species more susceptible to osteoarthritis from those largely unaffected by the disorder, concluding that weight-bearing plays a significant role in the development of osteoarthritis. Hutton's theory of the pathogenesis of osteoarthritis addresses both the localization of osteoarthritis within joints as well as between them. Hutton hypothesized that osteoarthritis is more likely to develop in "underdesigned" joints because of insufficient evolutionary pressure to allow them to accommodate to the demands of the bipedalism of humans.²⁰ Upright posture, for example, leads to a relative uncovering of the femoral head at the superior margin of the joint-the area most susceptible to osteoarthritis.³

The exact sequence of events involving the generation of osteoarthritis remains controversial, but evidence is accumulating that primary osteoarthritis is a disorder of the bone in its initial stages rather than of the cartilage.²¹ Radin et al.^22,23 hypothesized that one of the mechanisms of initiation of osteoarthritis may be a steep stiffness gradient in the underlying subchondral bone; the failure of subchondral bone to deform with an impact load leads to damage of the overlying articular cartilage, causing osteoarthritis.²⁴

Information regarding the natural history of osteoarthritis in individuals and its reparative processes is limited.^{5,11,12,25-27} Although cartilage damage is an extremely common, age-related phenomenon,^28,29 progression of osteoarthritis is considered generally to be slow, with rates varying among joint sites.^30,31 It has been proposed ³² that only a proportion of the cartilage changes seen will progress. In the study by Spector et al.³³ of osteoarthritic individuals with a mean interval of 11 years between radiologic examinations, approximately one third got worse, a few improved and most did not change markedly, indicating that the condition can be stable for extended periods. However, a Swedish study of patients with knee osteoarthritis evaluated in the early 1950s and again in 1968 ^34,35 revealed that most had marked radiologic deterioration at follow-up and no osteoarthritic knees showed improvement.⁵

Data from the Baltimore Longitudinal Study on Aging suggested that, in subjects with hand osteoarthritis, progression of osteoarthritis in a given joint was slow. It took 10-20 years to progress one grade, and once the higher grades of osteoarthritis were reached, a stable "burnout" stage seemed to persist.^26,31 In contrast, a study of the natural history of hip osteoarthritis over a 10-year period showed clinical and radiologic improvement in 14 of 31 hips (45%).³⁶ These studies and others suggest that cessation and at least partial reversal of osteoarthritis may be possible; however, more research in this area is certainly needed.

Symptoms

It is unknown what differentiates symptomatic osteoarthritis from asymptomatic radiologic disease, or whether these are two distinct subsets of disease.^12,37,38 What is known is that those with severe radiographic evidence of osteoarthritis more often have symptoms than those with less radiographic abnormality ³⁹ and that the association between symptoms and radiographic features is stronger for weight-bearing joints than non-weight-bearing joints.⁴⁰ While there is poor correlation between radiographic change and symptoms in the lumbar spine, hips and knees, generally, the more severe the radiographic disease, the more likely it is that the individuals will have symptoms.^5,12,39

The proportion of individuals who have symptoms varies by joint, age and sex.⁴¹ Despite the knowledge that the main symptoms of the disease are use-related pain and difficulty initiating movement (Table 2), there is still little understanding of the causes of pain.¹¹ Although, radiologically, the disease is most common in the hands and feet, hand osteoarthritis is less frequently and severely symptomatic than is radiologic disease in other joints.¹² Lawrence et al.,⁴² for example, found that only 9% of men and 25% of women with radiographic evidence of moderate or severe osteoarthritis in the DIP joints reported symptoms.

Women are reported to have symptoms more often and to have severe radiographic changes more often.⁴⁰ Other studies have found that symptomatic osteoarthritis of the knee is more common in females, but there is disagreement as to whether this is due to a higher prevalence of the disease in women or to a greater willingness to report symptoms.³⁹ In contrast to these findings, data from the US National Health and Nutrition Examination Survey I (NHANES I) indicated that men with radiographic osteoarthritis of the knee were slightly more likely than women to report symptoms.^41,43

Lawrence et al.⁴² found that obese subjects with osteoarthritis of the knee were more likely to have symptoms than non-obese subjects. No association, however, was found between obesity and symptoms in subjects with knee osteoarthritis in the NHANES I and the NHANES I Epidemiologic Followup Survey (NHEFS).^44,45 In the Tecumseh Community Health Study (TCHS),⁴⁶ obesity (measured by body mass index) was associated with pain in hand osteoarthritis but not in knee osteoarthritis.

Diagnosis

Lacking commonly accepted criteria for the diagnosis of osteoarthritis, diagnosis is often based on the presence of symptoms and a suggestive radiographic appearance in the absence of other arthritic disease. Clinical findings are non-specific, differing from one joint to the other, with the exception of minimal morning stiffness and age over 40 years.² Although different studies have used different definitions of osteoarthritis, often creating confusion and limiting comparability between studies,² epidemiologically, the most widely used criteria for osteoarthritis are the radiologically based criteria developed by Kellgren and Lawrence.⁴⁷

Mortality

Relatively little data exist on whether osteoarthritis is associated with decreased survival. Many studies have not taken into account co-morbid conditions or other mortality risk factors potentially related to osteoarthritis such as obesity,^48,49 diabetes,⁵⁰ high blood pressure ⁵¹ or tobacco use.^52,53

Monson and Hall ⁵⁴ found an 11% excess of deaths from respiratory and gastrointestinal causes in osteoarthritis patients, compared to the general population. Lawrence et al.⁵⁵ studied mortality in persons aged 55-74 with radiographic knee osteoarthritis, using data from the NHEFS. Age-adjusted cumulative mortality rates, analyzed without controlling for potentially confounding co-morbid conditions or medication use,⁵⁶ were significantly higher in women with knee osteoarthritis than in those without the condition. Survival analysis revealed decreased survival over the 8-10-year period of follow-up among women with knee osteoarthritis, but not among men.⁴⁶ The analysis done by Cerhan et al.⁵⁶ of the relation between full-body radiographically defined osteoarthritis and survival showed a decreased survival for women and an increasing number of joint groups affected with osteoarthritis, independent of age and other co-morbid conditions tested.

Morbidity

Geographic Variation

Osteoarthritis has a world-wide distribution ^57-59 (Table 3), and although some studies suggest that the disorder may be less prevalent in cold climates, such as Alaska and Finland, studies by latitude show no gradient in prevalence.⁷⁴

While European and American national data show similar trends in age and sex for osteoarthritis of the DIP joints, there is a marked difference in the frequency of knee osteoarthritis.⁵

van Sasse et al.⁵⁹ compared radiological osteoarthritis in a Dutch population with 10 other populations in the countries of Japan, the United States, Bulgaria, England and South Africa. They concluded that age-specific patterns of osteoarthritis by site were similar across studies and that the differences existing between populations are differences in level for most joints; joints with a low prevalence of osteoarthritis in one population are relatively osteoarthritis-free in all populations. However, it has yet to be established whether these differences are real, or due to inter-observer variation, or to differences in genetics or the distribution of risk factors.

Morbidity in Canada

The extent to which reported arthritis in population surveys can be interpreted as synonymous with osteoarthritis is a critical factor. The best comparison is in the NHANES I, where overall agreement was good between reported musculoskeletal symptoms and those confirmed by a physician.⁷⁵ Clinical examination confirmed the diagnosis of arthritis or rheumatism for 16.3% of this population aged 24-74, and for 75% of these individuals (12.3% of the population), the confirmed diagnosis was osteoarthritis.⁷⁵

In Canada, Badley reports that results from the 1990 Ontario Health Survey (OHS) and the 1987 Canadian Health and Activity Limitation Survey (HALS)⁷⁶ are essentially compatible with those of earlier Canadian surveys and of population surveys in other countries.⁷⁵ The findings from both the OHS and HALS have been weighted to be representative of the entire population of Canada.⁷⁵ Badley and Tennant stated that, in HALS, 20.6% of the population aged 16 and older reported arthritis, rheumatism, or back or limb and joint disorders.⁷⁷ In the OHS, 18.5% of the population aged 16 and older reported arthritis in any context,⁷⁵ and 15.2% reported this as a long-term chronic health problem.⁷⁸ The prevalence of any arthritis increased with age, from 6.3% in the 16-74 age group to 51.2% in those aged 75 and over, and the overall prevalence was 21.1% for women and 15.7% for men.⁷⁸

Canadian hospitalization rates (Table 4) for osteoarthritis include rates for spondylosis and "allied" disorders. In general, the average annual male hospitalization rates increased with increasing age. For women, however, the rates increased with increasing age only up to the 80-84 age group.

Although hospitalization rates provide information primarily about the severity of the problem in the population, hospitalization rates for joint replacement (Table 5) also offer information about the severity of the problem for individuals. In general, the average annual hospitalization rates for joint replacement increased with age for all three time periods, with the exception of the 80+ age groups in 1989-1992.

Age

Age has been the factor most strongly and consistently associated with osteoarthritis. This is true of the prevalence of osteoarthritis in all joints,¹² although the age pattern differs between males and females.⁷⁴ It is estimated by the National Arthritis Data Workgroup that approximately one third of the US population aged 25-74 have radiographic osteoarthritis involving at least one of either the hand, foot, knee or hip joints.⁷⁹ The greatest increase in the occurrence of osteoarthritis, however, is between the ages of 40 and 50. ² Osteoarthritis is relatively uncommon in those under the age of 40 ¹² and is very common in those aged 75 and over; in fact, more than 80% of the population aged 75+^80,81 are affected by osteoarthritis.

Original autopsy studies by Heine ²⁹ revealed almost universal evidence of cartilage damage in those 65 and over. The US Health Examination Survey for osteoarthritis of hands and feet found that radiographic hand osteoarthritis was present in less than 5% of individuals under age 35 and in more than 70% of those aged 65 or over.¹⁴

Epidemiologically, it is suggested that osteoarthritis initially appears in the metatarsalphalangeal joint from age 25 on and in the wrist and interfacetal joints of the spine from age 35 on. The greatest incidence of osteoarthritis, however, occurs at age 45 in the interphalangeals and the first CMC, later in the knee and latest in the hip.⁷ The US National Health Interview Survey Supplement on Aging (NHIS-SOA) study, consistent with Framingham and Scandinavian data,⁸² indicates that prevalence rates of osteoarthritis plateau at ages 75-80. ⁸³

Sex

Sex differences in prevalence, site and severity of osteoarthritis have been identified in a number of population surveys.^{41,42,48,84-86} These surveys suggest that women have more multiple joint involvement than men ⁴² and a greater prevalence and severity of osteoarthritis of the hands, knees, ankles and feet. Men have greater prevalence and severity of osteoarthritis of the hips, wrist and spine.^87-89

Males and females appear to be affected equally when all ages are considered,⁹⁰ although under age 45, osteoarthritis appears slightly more often in men and usually involves one or two joints. This is also supported by the NHANES study, which found an excess of radiographic osteoarthritis among men versus women under age 50.⁹¹.

Over 44 years of age, osteoarthritis prevalence rates increase more rapidly for women than for men ⁶⁰ and after age 55, osteoarthritis appears more frequently in women and usually involves multiple joints.^7,90,92 Results from the Women's Health and Aging Study,⁹³ for example, which studied disabled community-dwelling women, reveal that arthritis is the most commonly reported chronic medical condition in the 65 and over population.⁹³

Data from the UK show that radiographic osteoarthritis is found slightly more often in women than in men and that the sex difference is more marked in severe grades of osteoarthritis, older age groups and osteoarthritis of the knee and hand.⁵⁹

Prevalence rates for the sexes vary somewhat when considered on a site-specific basis. According to the National Arthritis Data Workgroup, prevalence of knee osteoarthritis is greater in males aged 44 and younger but greater in women aged 55 and older.⁷⁹ The prevalence of hip osteoarthritis appears to be greater in males than females below the age of 65 and similar between the sexes at age 65 and over.⁹⁴ Data from the Tecumseh study revealed that prevalence rates for osteoarthritis of the hands and wrists were greater among females than males for almost all joints in each age category.⁶¹ Hand and wrist osteoarthritis affected 78% of men and 90% of women aged 65 and over.⁹⁵

Disability

Although there are limited data about the risk factors for pain and disability, it is known that those with osteoarthritis, particularly of the knee or hip, are much more likely to develop disability than those who are osteoarthritis-free.⁹⁶ Osteoarthritis is second only to ischemic heart disease as a cause of work-related disability in men over age 50,⁸⁰ and it is the most common rheumatic disease resulting in the greatest loss of time from work.²

Studies such as the NHIS-SOA,^83,97-100 the Longitudinal Supplement on Aging,^101,102 the Framingham Study ^103,104 and the OHS ¹⁰⁵ reveal the relationship between osteoarthritis and disability-characterized by either functional limitations or difficulty in performing activities of daily living (ADL) and instrumental ADL.⁹³ Data from the NHIS-SOA indicate that those with osteoarthritis, when compared to those without it, were 2.7 times more likely to have difficulty walking, twice as likely to have functional limitation and three times more likely to have five or more functional limitations.⁹⁶ This study also showed that most risk factors for disability were shared by both those with and those without osteoarthritis, except for obesity, which was a risk factor for disability only among those with osteoarthritis.⁹⁶

In HALS, the prevalence of arthritis-associated disability was 2.7%,⁷⁸ similar to that found for the OHS.¹⁰⁵ The prevalence of reported osteoarthritis disability was higher in women (3.8%) than in men (1.6%), and it increased markedly with age to 20.6% for those aged 85 and over. Overall, 53% of respondents with arthritis reported pain that limited activities.⁷⁵

The economic ramifications of osteoarthritis are significant. A national US study of the use of ambulatory health services by elderly women determined that for every 1 000 women over 65 living in the community, arthritis accounted for 270 visits to physician offices each year.⁷⁴ In the OHS, arthritis was the primary cause of long-term disability, ranking second (after respiratory disorders) for restricted activity days and non-prescription drug use and ranking third for both prescription drug use and consulting a health professional.⁷⁵ In the 16-64 age group in the OHS, over half were not in the workforce specifically because of disability. Furthermore, more than twice as many disabled people as compared to non-disabled people had an income below $20,000 (1986).⁷⁵

Risk Factors

It is still unclear why some individuals remain free of osteoarthritis throughout life while others are affected. There are a number of risk factors (Table 6) for osteoarthritis, however, and these can be classified as generalized "systemic" associations and local "biomechanical" factors ⁵ or as "intrinsic" and "extrinsic" factors. In some cases, specific local influences are dominant, while in others, systemic factors are more important. This suggests that osteoarthritis is a disease spectrum with no case attributable to a single risk factor and risk factors differing by site.^21,106,107 It is important to note that a number of risk factors for osteoarthritis have been elucidated through epidemiologic cross-sectional studies, and it is thus unclear whether they have etiologic significance or simply occur as epiphenomena.

Age

Age is one of the most important risk factors for osteoarthritis,^{2,4,7,9,26,40,63,107-109} although the mechanisms by which it is associated are unclear. Joint cartilage changes that occur with age differ from those that characterize osteoarthritis cartilage, yet age-related changes in the biomechanics of some joints may be important in the pathogenesis of osteoarthritis.¹¹⁰ The question is whether or not age-related biomechanical and structural alterations to cartilage change the biomechanical properties of articular cartilage and increase its susceptibility to wear and tear, predisposing to osteoarthritis.²⁵

Sex

Sex differences in the prevalence, location and severity of osteoarthritis have been found in a number of studies.^{41,42,48,84-88} Kellgren and Lawrence ⁴⁸ concluded that the higher prevalence of osteoarthritis in women was unrelated to occupation, history of injury or evidence of rheumatoid arthritis and that although obesity was associated with increased prevalence of osteoarthritis of the weight-bearing joints, it was not associated with the high prevalence of multiple joint arthritis.

Data from the NHANES I revealed that sex was one of the four factors strongly related to knee osteoarthritis.¹⁰⁸ Compared to such changes among men, osteoarthritis knee changes among women are more clearly linked with weight (odds ratio:4.5 for men, 9.0 for women; associated with being 50% above ideal body weight).^5,111 Controlling for obesity, in the NHANES I data, reduced the sex difference in knee osteoarthritis but did not eliminate it, suggesting that factors other than obesity are also important for the sex difference.⁶⁰

Race and Ethnicity

The numerous differences in osteoarthritis found in racial and ethnic populations may be real or may be due to differences in risk factors or to inter-observer variation. It is the examination of these differences, however, that can provide important clues to the etiologies of osteoarthritis. Although the prevalence of osteoarthritis of many sites varies considerably, in all races studied, the prevalence of finger joint osteoarthritis appears to be comparable.^59,91,112

Fewer Heberden's nodes have been found in populations of Nigeria and Liberia than of England.^67,113,114 Black South Africans have a higher prevalence of knee osteoarthritis compared with white South Africans,⁸ and analysis of the NHANES I data reveals that the prevalence of knee osteoarthritis in the US, especially in women, is higher among blacks than among whites.^5,108 South African studies ^8,67 have reported a lower prevalence of multiple joint involvement and of osteoarthritis of the hands, feet and hips in black women compared with white women and a higher prevalence of hand osteoarthritis in black men than in white men.

From their comparison of Japanese Oriental with American white subjects, as well as from other population studies, Hoaglund et al. concluded that primary hip osteoarthritis is a disorder of European-American whites.¹¹⁵ This is supported by the low rates of hip osteoarthritis among black populations from Jamaica, South Africa, Nigeria and Liberia in contrast to the higher rates of hip osteoarthritis among populations from North England, West Germany, Czechoslovakia and Switzerland.⁵⁷ Although studies of Blackfeet and Pima Indians in the US indicate a higher prevalence of osteoarthritis than in the general US population,¹¹² rates of hip osteoarthritis among American Indians seem to be intermediate between high European rates and low rates in other parts of the world.⁵

In some populations studied, the differences in osteoarthritis prevalence and joint distribution appear to be associated with differences in congenital deformities and patterns of joint use.^5,6,58 Hip osteoarthritis, for example, is rare in Hong Kong Chinese and other populations in which congenital hip dysplasia and chair-sitting is uncommon.^6,66,116 Northern Italy, on the other hand, has the highest known rates of both congenital hip dysplasia, including dislocation, and hip osteoarthritis.¹¹⁷ It has been suggested that the higher-than-expected prevalence of knee osteoarthritis in Jamaicans is related to walking on rough foot paths and the low prevalence of metatarsalphalangeal joint osteoarthritis, to walking barefoot.^8,114 Also, the lower prevalence of hip osteoarthritis in the black population is found in parallel with an absence of acetabular or femoral dysplasia or juvenile hip disorder,⁵⁸ while recent studies have found a high prevalence of hip osteoarthritis in two geographically isolated black African communities where there is also a high prevalence of acquired hip dysplasia.^5,58

Genetics

A hereditary factor is clearly noticeable in several distinct forms of osteoarthritis. For example, a genetic predisposition plays a significant role in the development and progression of primary generalized osteoarthritis, the most common form of inherited osteoarthritis.¹¹⁸ Recent studies have identified that several types of osteoarthritis are inherited in an autosomal mendelian pattern. These include a variety of mutations on the type II collagen gene, which encodes the main collagenous component of articular cartilage in some types of familial osteoarthritis and other heritable disorders of cartilage, including Stickler syndrome and the chondrodysplasias.¹¹⁹

Other forms of inherited osteoarthritis are familial chondrocalcinosis, pseudogout (familial calcium pyrophosphate dihydrate deposition disease), hydroxyapatite crystal deposition disease, Stickler syndrome, hereditary arthro-ophthalmopathy and the epiphyseal dysplasias.^{12,94,119-121}

Diseases Predisposing to Osteoarthritis

Inconsistent associations between hypertension and osteoarthritis,^49,51,122 diabetes and osteoarthritis,^{63,111,122,123} and hyperuricemia and osteoarthritis ^{9,49,63,122,123} have been reported; the latter association is found more commonly in persons with generalized osteoarthritis ^86,124 and in younger men with knee osteoarthritis than in osteoarthritis-free persons.¹⁰⁸ A study of several population samples in Great Britain and Jamaica found generalized osteoarthritis to be significantly more common in older males with high, versus low, diastolic blood pressure. Independent of obesity, the osteoarthritis involved primarily the hips, knees, CMC and metacarpophalangeal (MCP) joints.⁷⁴

Chondrocalcinosis, or linear cartilage calcification, is associated with about a 50% greater prevalence of knee osteoarthritis.⁶³ In the Framingham Study the prevalence of chondrocalcinosis increased noticeably with age, and there was some suggestion that chondrocalcinosis and osteoarthritis increase independently with age.⁶³

There are conflicting reports about whether or not developmental defects contribute significantly to the majority of hip osteoarthritis.^117,125-134 Felson ⁵ concludes that certain congenital and developmental diseases of the hip invariably lead to osteoarthritis in later life; the three major developmental abnormalities are congenital dislocation of the hip, Perthes disease and slipped capital femoral epiphysis.

Other disorders (Table 1) that have been associated with osteoarthritis include prior inflammatory joint disease ⁷⁹ and some of the less common endocrine and metabolic diseases, such as hemoglobinopathies and thyroid disorders.²

Estrogen

It has been hypothesized that the sex differences in the rates of osteoarthritis may involve a protective role of estrogens up to the time of menopause. The metabolic changes, such as the changes of sex hormone levels and the increased ratio of free estrogen and progesterone, that occur peri- and postmenopausally may be involved in the development of polyarticular joint degeneration in females.¹³⁵ It has also been suggested that the elevated, sustained levels of free estradiol due to obesity or other known sources over a prolonged period in young or perimenopausal females may be one of the causes of osteoarthritis frequently occurring in postmenopausal women.⁹²

The inverse relationship seen between osteoarthritis and osteoporosis ^136,137 prompted the hypothesis that since estrogen replacement therapy protects against bone loss after menopause,^5,138-144 then estrogen therapy may result in relatively higher bone mass and relatively stiffer subchondral bone.¹⁴⁵ Results of studies, however, conflict as to the role of exogenous and endogenous estrogens.^146,147

Recent findings of elevated levels of synovial estradiol and higher estrogen receptor bindings in human osteoarthritis cartilage suggest the importance of local uptake of estradiol and the possible up-regulation of estrogen receptors.⁹² However, in the NHANES I, there seemed to be no association between knee osteoarthritis and either parity or early menopause.¹⁰⁸ Also, in the Framingham Study, there was no definite association found between the duration of estrogen use and prevalence of osteoarthritis.¹⁴⁵ Rather, there was a modest and generally non-significant protective effect upon osteoarthritis of the knee.¹⁴⁵

Obesity

Some researchers postulate that since obesity is associated with metabolic abnormalities (diabetes mellitus, hyperuricemia, hyperlipidemia), it may act indirectly as opposed to mechanically, resulting in osteoarthritis if these associated disorders alter synovial, cartilage or bone metabolism.^60,122

The implication of these findings is that obesity may have a mechanical effect on some joints, such as in knee osteoarthritis, and a metabolic effect on other joints.³⁰ Studies have inconsistently found an association of obesity with osteoarthritis of the hands and the feet, and more consistently, no association of obesity with hip osteoarthritis or ankle osteoarthritis.^{48,86,87,107,111,147-152}

The relationship of knee osteoarthritis with obesity has been studied in many cross-sectional and longitudinal cohort studies,^{42,48,49,60,63,108,111,122,123,151,153-156} with several showing significant association between obesity and knee osteoarthritis.^{49,108,111,157} In most studies, this association has been stronger in women than in men.¹²

The longitudinal Framingham Study,⁴⁹ which looked at obesity preceding the development of osteoarthritis, revealed that body mass index (weight corrected for height) is strongly associated with knee osteoarthritis and that obesity at the beginning of the study predicted the development of osteoarthritis 36 years later.^12,63 Results from this study also suggest that the long-term effect of obesity on cartilage or subchondral bone may be less important than these same effects on middle-aged and elderly persons.¹⁵⁸

In the NHANES I,¹²² obesity was more strongly associated with bilateral knee osteoarthritis than with knee injury, and knee injury was more strongly associated with unilateral knee osteoarthritis than with obesity. These associations indicate that there may be a cause and effect relationship between obesity and bilateral knee osteoarthritis. In the case of unilateral knee osteoarthritis, there appears to be a stronger association with knee trauma than with obesity.

Using NHANES I data, Davis et al.¹²² looked at obesity-related factors, such as serum cholesterol, serum uric acid, diabetes, fat distribution and blood pressure, and found that these factors did not significantly reduce the association between obesity and knee osteoarthritis. The implications of the above results suggest that obesity acts, for knee osteoarthritis, through a mechanical process (stress on the joint from increased load or the altered mechanics of ambulation)² versus a metabolic one.^60,122,157 While these studies have indicated an impressive association, results have not been as consistent in clinical studies.⁵

Osteoporosis and Bone Mass

Persons with postmenopausal osteoporosis and those with osteoarthritis seem to be anthropometrically different populations.¹³ It has been observed that not everyone will develop osteoarthritis or osteoporotic fracture with aging ¹⁵⁹ and that, epidemiologically, osteoporosis and osteoarthritis seem to uncommonly co-exist.^159,160 Verstraeten et al.¹⁵⁹ concluded that osteoarthritis and osteoporosis are unlikely to develop in the same individuals early in the course of disease, but may be found together more commonly with increasing age.

Evidence exists that osteoporosis may protect against osteoarthritis.^161,162 By contrast, osteopetrosis, a rare inherited disorder in which bones are markedly sclerotic and presumably stiff, is associated with a high risk of generalized osteoarthritis,¹⁶³ and osteoarthritis begins at an early age in persons with this disease.

Healy et al.¹⁶⁴ found a normal prevalence of osteoarthritis of the hip in their osteoporotic subjects and concluded from their study that osteoporosis does not protect against hip osteoarthritis, but that hip osteoarthritis is a negative risk factor for osteoporotic compression fractures.^48,137,165

A number of studies looking at the association of bone density with osteoarthritis have resulted in conflicting reports.^136,166-168 The TCHS concluded that larger mean bone mass was associated with osteoarthritis of the hand.¹³⁵ The NHANES I and the Framingham Study were unable to demonstrate associations between bone density and knee osteoarthritis,⁹⁶ and there is evidence that bone density was not elevated in subjects with generalized osteoarthritis.¹⁶⁹ Dequeker et al.¹³ report that osteoarthritis subjects lose bone more slowly over time than subjects with osteoporosis and that bone mass may be an intervening variable. Additionally, obesity may cause osteoarthritis in postmenopausal women by maintaining high bone mass and preventing osteoporosis.⁵

Exercise and Sports

The question of whether or not exercise is a risk factor for osteoarthritis is a complex one to address. Osteoarthritis has a long asymptomatic phase. Individuals vary in their predisposition to develop joint disease, in exercise patterns and in history of joint injury. Different sports place different demands on specific joints, and response to exercise may differ among joints.¹⁷⁰ Sports also combine the risks of major joint injury, repetitive use and even repetitive use after major injury.⁵ In addition, osteoarthritis definitions and scoring of radiographic osteoarthritis may be different, data on joint injuries and exercise histories are collected retrospectively and most studies are cross-sectional. All these factors make studies of the relationship between exercise and osteoarthritis difficult to evaluate.¹⁷⁰ Thus, the association between sporting activity and subsequent osteoarthritis is unresolved.

Some evidence suggests that high-intensity, high-impact professional athletics in young adults may be a risk factor for osteoarthritis in the joints that have been put under stress.¹⁷⁰ Several studies of such sports have found associations with increased rates of osteoarthritis:⁵ hand osteoarthritis in boxers; elbow ^171,172 and shoulder osteoarthritis ¹⁷³ in baseball pitchers; knee, ankle and foot osteoarthritis in soccer players;^174,175 and knee osteoarthritis in weight lifters.¹⁷⁶ Studies examining hip osteoarthritis and sports have been less conclusive.^166,177-182

The studies of football players ^183,184 raise a key question about the relation between athletic activity and osteoarthritis in that they strongly suggest an association primarily due to significant joint trauma.⁵ It is unclear whether those who do not suffer major joint injury are at increased risk of osteoarthritis. On the other hand, runners (studied in a number of cross-sectional as well as longitudinal studies), with the exception of those with prior joint injury or anatomical joint abnormalities,¹⁸⁵ do not appear to be at increased risk of osteoarthritis.^{96,166,170,179-181,186-188}

One potential risk factor that may predispose even the non-injured athlete to osteoarthritis is the increased bone mass ¹⁶⁶ that accompanies athletic activity.⁵ Also, although the results of studies assessing sports enthusiasts have been conflicting,¹² there is evidence to suggest that certain types of repetitive use are associated with an increased prevalence of osteoarthritis in overused joints.¹⁸⁹

In summary, normal joints appear to better tolerate prolonged, vigorous, low-impact exercise without premature development of osteoarthritis. Individuals with abnormal joint anatomy or injured supporting structures who participate in weight-bearing exercise seem to be at increased risk for premature osteoarthritis.^170,190 People who have experienced injuries of supporting structures (such as ligaments, tendons or menisci) may have premature osteoarthritis in weight-bearing joints, even without added stress to the joint from exercise.^{12,170,190,191}

Occupation

Occupational physical activity exemplifies stereotypic repetitive use of particular joints over prolonged periods of time and may be the purest example of repetitive overuse.⁵ Studies evaluating the relationship of occupation and osteoarthritis have generally focused on industrial workers, and, although suggestive of an association between physical activity and osteoarthritis, the findings are not clearly consistent.⁶

Davis ⁶ cites numerous occupational studies in which no associations were found: coal miners and elbow osteoarthritis,¹⁹² pneumatic drill operators and elbow osteoarthritis,¹⁹³ shipyard workers compared with white-collar workers for hip osteoarthritis,¹⁹⁴ and physical education teachers and knee osteoarthritis.¹⁹⁵

The most consistent finding from occupational studies ^{27,73,196-203} has been an increased prevalence of osteoarthritis, particularly hip osteoarthritis, among agricultural workers. One case-control study ²⁰⁴ found the risk of hip osteoarthritis to be related to occupations that entailed regular heavy lifting, prolonged standing and walking over rough ground. Also, there is some evidence that, in general, body position is a more important risk factor for osteoarthritis than lifting of weight,²⁰⁵ and it is hypothesized that the increased risk of hip osteoarthritis noted in farmers may be related to unfavourable angles of the joint experienced during tractor driving.²⁰¹

Vingard et al.^203,206 suggest that men with long-time exposure to physical work loads and adults in certain occupations and occupational groups classified as highly exposed to forces acting on the lower limbs have an increased risk of hip osteoarthritis and knee osteoarthritis. In one study,²⁰³ male farmers, construction workers and firefighters, and female cleaners had increased risk of knee osteoarthritis. Male farmers, construction workers, firefighters and some food-processing workers had an excess risk of hospitalization due to hip osteoarthritis, and female mail carriers had an excess risk of hip osteoarthritis.²⁰³ Although some studies using broader classifications of occupational activity have found inconsistent associations of osteoarthritis with heavy physical work,^{52,194,197,204} the findings of Vingard et al.²⁰³ are consistent with three case-control studies of knee osteoarthritis conducted in the Netherlands,²⁰⁷ in Sweden ¹²³ and in the US.²⁰⁸

Felson et al.¹⁸⁹ report that, while a strong association of occupational labour and osteoarthritis was found in men in the Framingham Study, they found no significant relationship in women despite finding such an association in NHANES I data.¹⁰⁸ Overall, however, Felson et al. conclude that the findings of several studies evaluating occupational activity and osteoarthritis (including the Framingham Study and NHANES I) suggest that it should be considered as a potential occupational disease.¹⁸⁹

Smoking

Smoking has been found to be negatively correlated with osteoarthritis. Two studies prior to the NHANES I found a negative association between radiographic osteoarthritis and smoking,⁶³ and one British study ²⁰⁹ found no significant association. Analysis of the NHANES I data revealed a modest, statistically significant protective association in a dose-response relationship between smoking and osteoarthritis that persisted after statistical adjustments for age, sex and weight.⁵³

The Framingham knee osteoarthritis study found a negative association for osteoarthritis with smoking after adjusting for age, sex, weight, previous knee injury, physical activity level and other factors.^12,63 These results were not supported by analysis of symptomatic disease, however; the risk of symptomatic osteoarthritis was unaffected by smoking.⁶³ If smoking is protective against osteoarthritis, a biological explanation of how smoking may protect has not been elucidated.

Conclusion

Osteoarthritis is one of the most common of all chronic diseases,⁷⁴ with major accepted risk factors including age, sex, genetic predisposition, mechanical stress, repetitive joint usage, joint trauma, obesity, congenital and developmental disorders and prior inflammatory joint disease. Related to age, osteoarthritis is certain to become an even more prominent health problem in the future with the increasing longevity of individuals, decreasing tolerance for personal immobility and a generally aging society.

Despite the limited understanding of the specific pathogenesis of osteoarthritis, there is sufficient evidence of many of the risk factors to guide prevention strategies and reduce the human and economic costs of osteoarthritis in society. Greater prevention and reduction of occupational and athletic exposure to joint trauma will decrease the osteoarthritis due to injury. Ergonomic approaches and modification of job stress is needed to address the contribution of certain occupational physical demands with osteoarthritis. Appropriate screening will identify high-risk individuals for whom effective treatment of congenital and developmental hip diseases is available. Both general and high-risk primary prevention efforts directed at obesity and physical inactivity ² are germane.

Continued research on osteoarthritis, especially longitudinal studies with comprehensive follow-up, is needed to more clearly identify the etiopathogenesis of osteoarthritis, protective and risk factors for the disease and more effective prevention modalities.

Author References

Kirsten Rottensten, c/o Division of Aging and Seniors, Population Health Directorate, Health Promotion and Programs Branch, Health Canada Mailing address: Julie Stokes, Cancer Bureau, Laboratory Centre for Disease Control, Health Canada, Tunney's Pasture, Address Locator: 0602E2, Ottawa, Ontario K1A 0L2

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References

1. Minugh NS. A brief survey of osteoarthritis outside of modern human populations. J Am Podiatry Assoc 1982;72:217-21.

2. Altman RD. Overview of osteoarthritis. Am J Med 1987;83 Suppl 4B:65-9.

3. Dieppe P, Kirwan J. The localization of osteoarthritis [editorial]. Br J Rheumatol 1994;33:201-4.

4. Dieppe P. Osteoarthritis. A review [see comments]. J Royal Coll Phys London 1990;24:262-7.

5. Felson DT. Epidemiology of hip and knee osteoarthritis. Epidemiol Rev 1988;10:1-28.

6. Davis MA. Epidemiology of osteoarthritis. Clin Ger Med 1988;4:241-55.

7. Peyron JG. Osteoarthritis. The epidemiologic viewpoint. Clin Orthop Rel Res 1986:13-9.

8. Solomon L, Beighton P, Lawrence JS. Rheumatic disorders of the South African Negro: Part II. Osteoarthritis. S Afr Med J 1975;49:1737-40.

9. Lawrence JS. Osteoarthrosis. In: Rheumatism in populations. Bristol (England): J.W. Arrowsmith Ltd, 1977:98.

10. Cushnaghan J, Dieppe P. Study of 500 patients with limb joint osteoarthritis. I. Analysis by age, sex, and distribution of symptomatic joint sites. Ann Rheum Dis 1991;50:8-13.

11. Dieppe P. Osteoarthritis: clinical and research perspective. Br J Rheumatol 1991;30 Suppl 1:1-4.

12. Felson DT. Osteoarthritis. Rheum Dis Clin North Am 1990;16:499-512.

13. Dequeker J, Goris P, Utterhoeven R. Osteoporosis and osteoarthritis (osteoarthrosis): anthropometric distinctions. JAMA 1983;249:1448-51.

14. Engel A. Osteoarthritis and body measurements [abstract]. 1968.

15. Smith FH. The Neanderthal remains from Krapine: a descriptive and comparative study [abstract]. Reports of Investigations 1976;15.

16. Alexandersen V. The pathology of the jaws and the temporomandibular joint. In: Brithwell D, Sandison A, eds. Diseases in antiquity. Springfield (IL): Charles C. Thomas, 1967.

17. Vogel JC, Waterbolk HT. Groningen radiocarbon dates IV. Radiocarbon 1963;5:173.

18. Hannan MT, Anderson JT, Pincus T, Felson DT. Educational attainment and osteoarthritis: differential associations with radiographic changes and symptom reporting. J Clin Epidemiol 1992;45:139-47.

19. Fox H. Chronic arthritis in wild animals. Trans Am Philos Soc 1939;31.

20. Hutton CW. Generalized ostoearthritis: an evolutionary problem? Lancet 1987;i:1463-5.

21. Dequeker J, Mokassa L, Aerssens J. Bone density and osteoarthritis. J Rheumatol 1995;22 Suppl 43:98-100.

22. Radin EL, Paul IL, Tolkoff MJ. Subchondral changes in patients with early degenerative joint disease. Arthr Rheum 1970;13:400-5.

23. Radin EL, Rose RM. Role of subchondral bone in the initiation and progression of cartilage damage. Clin Orthop 1986;213:34-40.

24. Radin EL. Mechanical aspects of osteoarthritis. Bull Rheum Dis 1976;26:862-5.

25. Mankin HJ, Brandt KD, Shulman LE. Workshop on etiopathogenesis of osteoarthritis: proceedings and recommendations. J Rheumatol 1986;13:1130-60.

26. Kallman DA, Wigley FM, Scott WW Jr, Hochberg MC, Tobin JD. The longitudinal course of hand osteoarthritis in a male population. Arthr Rheum 1990;33:1323-32.

27. Dieppe P. Ostearthritis (concurrent session F). Br J Rheumatol 1992;31:132-3.

28. Bennett GA, Waine H, Bauer W. Changes in the knee joint at various ages, with particular reference to the nature and development of degenerative joint disease. New York: Commonwealth Fund, 1942.

29. Heine J. Uber die Arthritis deformans. Virchows Arch 1926;260:521-663.

30. Dieppe PA. Osteoarthritis: are we asking the wrong questions? [editorial]. Br J Rheumatol 1984;23:161-3.

31. Plato CC, Norris AH. Osteoarthritis of the hand: longitudinal studies. Am J Epidemiol 1979;110:740-6.

32. Byers PD, Contepomi CA, Farkas TA. A post-mortem study of the hip joint. Ann Rheum Dis 1970;29:15-31.

33. Spector TD, Dacre JE, Harris PA, Huskisson EC. Radiological progression of osteoarthritis: an 11 year follow up study of the knee. Ann Rheum Dis 1992;51:1107-10.

34. Hernborg JS, Nilsson BE. The natural course of untreated osteoarthritis of the knee. Clin Orthop 1977;123:130-7.

35. Danielsson L, Hernborg J. Clinical and roentgenologic study of knee joints with osteophytes. Clin Orthop 1970;69:302-12.

36. Perry GH, Smith MJF, Whiteside CG. Spontaneous recovery of the joint space in degenerative hip disease. Ann Rheum Dis 1972;31:441-8.

37. Kelsey JL. Prevalence studies of the epidemiology of osteoarthritis. In: Lawrence RC, Shulman LE, eds. Current topics in rheumatology: epidemiology of the rheumatic diseases. Proceedings of the Fourth International Conference, National Institutes of Health. New York: Gower, 1984:302-11.

38. Kuller LH. The epidemiology of osteoarthritis. In: Lawrence RC, Shulman LE, eds. Current topics in rheumatology: epidemiology of the rheumatic diseases, Proceedings of the Fourth International Conference, National Institutes of Health. New York: Gower, 1984:277-81.

39. Felson DT, Naimark A, Anderson J, Kazis L, Castelli W, Meenan RF. The prevalence of knee osteoarthritis in the elderly. The Framingham Osteoarthritis Study. Arthr Rheum 1987;30:914-8.

40. Croft P. Review of UK data on the rheumatic diseases - 3. Osteoarthritis. Br J Rheumatol 1990;29:391-5.

41. Maurer K. Basic data on arthritis knee, hip and sacrolilac joints in adults ages 25-74 years, United States, 1971-1975. Vital and health statistics. Series 11: data from the National Health Survey, no. 213. Hyattsville (MD): National Center for Health Statistics, 1979.

42. Lawrence JS, Bremmer JM, Bier F. Osteo-arthrosis prevalence in the population and relationship between symptoms and x-ray changes. Ann Rheum Dis 1966;25:1-24.

43. Acheson RM, Ginsburg GN. New Haven survey of joint diseases. XVI. Impairment, disability, and arthritis. Br J Prev Soc Med 1973;17:387-403.

44. Hochberg MC, Lawrence RC, Everett DF, Cornoni-Huntley J. Epidemiologic associations of pain in osteoarthritis of the knee: data from the National Health and Nutrition Examination Survey and the National Health and Nutrition Examination-I Epidemiologic Follow-up Survey. Sem Arthr Rheum 1989;18 Suppl 2:4-9.

45. Bagge E, Bjelle A, Eden S, Svanborg A. A longitudinal study of the occurrence of joint complaints in elderly people. Age Ageing 1992;21:160-7.

46. Carman WJ. Factors associated with pain and osteoarthritis in the Tecumseh Community Health Study. Sem Arthr Rheum 1989;18 Suppl 2:10-3.

47. Kellgren JH, Lawrence JS. Atlas of standard radiographs: the epidemiology of chronic rheumatism. Oxford: Blackwell Scientific Publications, 1963.

48. Kellgren JH, Lawrence JS. Osteoarthrosis and disk degeneration in an urban population. Ann Rheum Dis 1958;17:388-97.

49. Felson DT, Anderson JJ, Naimark A, Walker AM, Meenan RF. Obesity and knee osteoarthritis. The Framingham Study. Ann Intern Med 1988;109:18-24.

50. Waine H, Nevinny D, Rosenthal J, et al. Association of osteoarthritis and diabetes mellitus. Tufts Folia Med 1961;7:13-9.

51. Lawrence JS. Hypertension in relation to musculoskeletal disorders. Ann Rheum Dis 1975;34:451-6.

52. Kraus JF, D'Ambrosia RD, Smith EG, et al. An epidemiological study of severe osteoarthritis. Orthopedics 1978;1:37-42.

53. Felson DT, Anderson JJ, Naimark A, Hannan MT, Kannel WB, Meenan RF. Does smoking protect against osteoarthritis? Arthr Rheum 1989;32:166-72.

54. Monson RR, Hall AP. Mortality among arthritics. J Chron Dis 1976;29:459-67.

55. Lawrence RC, Everett DF, Hochberg MC. Arthritis. In: Cornoni-Huntley RR, Feldmen JJ, eds. Health status and well-being of the elderly. National Health and Nutrition Survey-I. Epidemiologic Follow-up Study. New York: Oxford University Press, 1990:136-51.

56. Cerhan J, Wallace R, El-Khoury G, Moore T, Long C. Decreased survival with increasing prevalence of full-body, radiographically defined osteoarthritis in women. Am J Epidemiol 1995;141:225-34.

57. Lawrence JS, Sebo M. The geography of osteoarthritis. In: Nuki G, ed. The aetiopathogenesis of osteoarthrosis. Baltimore: University Park Press, 1988:155-83.

58. Solomon L. Geographical and anatomical patterns of osteoarthritis. Br J Rheumatol 1984;23:177-80.

59. van Saase JL, van Romunde LK, Cats A, Vandenbroucke JP, Valkenburg HA. Epidemiology of osteoarthritis: Zoetermeer survey. Comparison of radiological osteoarthritis in a Dutch population with that in 10 other populations. Ann Rheum Dis 1989;48:271-80.

60. Davis MA, Ettinger WH, Neuhaus JM, Hauck WW. Sex differences in osteoarthritis of the knee. The role of obesity. Am J Epidemiol 1988;127:1019-30.

61. Butler WJ, Hawthorne VM, Mikkelsen WM, et al. Prevalence of radiologically defined osteoarthritis in the finger and wrist joints of adult residents of Tecumseh, Michigan 1962-65. J Clin Epidemiol 1988;41:467-73.

62. Lawrence RC, Hochberg MC, Kelsey JL, et al. Estimates of the prevalence of selected arthritic and musculoskeletal disease in the United States. J Rheumatol 1989;16:427-41.

63. Felson DT. The epidemiology of knee osteoarthritis: results from the Framingham Osteoarthritis Study. Sem Arthr Rheum 1990;20:42-50.

64. Lemont H, Gibley CW, Jr. Prevalence of osteoarthritis of the foot. J Am Podiatry Assoc 1982;72:214-6.

65. Bagge E, Bjelle A, Valkenburg HA, Svanborg A. Prevalence of radiographic osteoarthritis in two elderly European populations. Rheumatol Int 1992;12:33-8.

66. Hoaglund FT, Yau ACMC, Wong WL. Osteoarthritis of the hip and other joints in southern Chinese in Hong Kong. J Bone Joint Surg-Am 1973;55:545-57.

67. Solomon L, Beighton P, Lawrence JS. Osteoarthrosis in a rural South African Negro population. Ann Rheum Dis 1976;35:274-8.

68. Brighton SW, de la Harpe AL, van Staden DA. The prevalence of osteoarthrosis in a rural African community. Br J Rheumatol 1985;24:321-5.

69. Jorring K. Osteoarthritis of the hip. Epidemiology and clinical role. Acta Orthop Scand 1980;51:523.

70. Pogrund H, Rutenberg M, Makin M, Robin GC, Steinberg R, Bloom R. Osteoarthritis of the hand and osteoporosis. Clin Orthop Rel Res 1986:239-43.

71. Pogrund H, Ruttenberg M, Makin M, Robin G, Menczel J, Steinberg R. Osteoarthritis of the hip joint and osteoporosis: a radiological study in a random population sample in Jerusalem. Clin Orthop Rel Res 1982;164:130-5.

72. Ahlberg A, Linder B, Binhemd TA. Osteoarthritis of the hip and knee in Saudi Arabia. Int Orthop 1990;14:29-30.

73. Bjelle A. Epidemiological aspects of osteo-arthritis. An interview survey of the Swedish population and a review of previous studies. Scand J Rheumatol 1982;43 Suppl:35-48.

74. Scott JC, Hochberg MC. Osteoarthritis I: epidemiology. Maryland State Med J 1984;33:712-6.

75. Badley EM. The effect of osteoarthritis on disability and health care use in Canada. J Rheumatol 1995;22 Suppl 43:19-22.

76. Statistics Canada. Health and Activity Limitation Survey microdata user's guide: adults in households. Ottawa: Statistics Canada, 1989.

77. Badley EM, Tennant A. Changing profile of joint disorders with age: findings from a postal survey of the population of Calderdale, West Yorkshire, United Kingdom. Ann Rheum Dis 1992;51:366-71.

78. Reynolds DL, Chambers LW, Badley EM, et al. Physical disability among Canadians reporting musculoskeletal diseases. J Rheumatol 1992;19:1020-30.

79. Hochberg MC. Epidemiology of osteoarthritis: current concepts and new insights. J Rheumatol 1991;18 Suppl 27:4-6.

80. Cooper C. Occupational activity and the risk of osteoarthritis. J Rheumatol 1995;22 Suppl 43:10-2.

81. McKeag DB. The relationship of osteoarthritis and exercise. Clin Sports Med 1992;11:471-87.

82. Bagge E, Bjelle A, Eden S, Svanborg A. Osteoarthritis in the elderly: clinical and radiological findings in 79 and 85 year olds. Ann Rheum Dis 1991;50:535-9.

83. Verbrugge LM, Gates DM, Ike RW. Risk factors for disability among US adults with arthritis. J Clin Epidemiol 1991;44:167-82.

84. Roberts J, Burch TA. Prevalence of osteoarthritis in adults by age, sex, race, and geographic area, United States, 1960-1962 [abstract]. 1966.

85. Mikkelsen WM, Dodge HJ, Duff IF, et al. Estimates of the prevalence of rheumatic diseases in the population of Tecumseh, Michigan, 1959-1960. J Chron Dis 1967;20:351-69.

86. Acheson RM, Collart AB. New Haven survey of joint diseases. XVII. Relationship between some systematic characteristics and osteoarthrosis in a general population. Ann Rheum Dis 1975;34:379-87.

87. Acheson RM. Epidemiology and the arthridities. Ann Rheum Dis 1982;41:325-34.

88. Peyron JG. The epidemiology of osteoarthritis. In: Moskowitz RW, Howell DS, Goldberg VM, et al, eds. Osteoarthritis: diagnosis and management. Philadelphia: WB Saunders, 1984:9-27.

89. Kellgren JH. Osteoarthritis in patients and populations. BMJ 1961;2:1-6.

90. Moskowitz RW. Primary osteoarthritis: epidemiology, clinical aspects, and general management. Am J Med 1987;83:5-10.

91. Gorden T. Osteoarthrosis in US adults. In: Bennett PH, Wood PHN, eds. Population studies of the rheumatic diseases. New York: Excerpta Medica, 1968:391-7.

92. Tsai CL, Liu TK. Osteoarthritis in women: its relationship to estrogen and current trends. Life Sci 1992;50:1737-44.

93. Hochberg MC, Kasper J, Williamson J, Skinner A, Fried LP. The contribution of osteoarthritis to disability: preliminary data from the Women's Health and Aging Study. J Rheumatol 1995;22 Suppl 43:16-8.

94. Hochberg MC. Epidemiology and genetics of osteoarthritis. Curr Op Rheumatol 1991;3:662-8.

95. Mikkelson WM, Duff IF, Dodge HJ. Age-sex specific prevalence of radiographic abnormalities of the joints of the hands, wrists and cervical spine of adult residents of the Tecumseh, Michigan Community Health Study area, 1962-1965. J Chron Dis 1970;23:151-9.

96. Slemenda CW. The epidemiology of osteoarthritis of the knee. Curr Op Rheumatol 1992;4:546-51.

97. Hochberg MC, Ardey SL, Diamond EL. The association of self-reported arthritis with disability: data from the 1984 National Health Interview Survey Supplement on Aging (SOA) [abstract]. Arthr Rheum 1989;32:S101.

98. Verbrugge LM, Lepowski JM, Konkol LL. Levels of disability among US adults with arthritis. J Gerontol 1991;46:S71-S83.

99. Verbrugge LM, Lepowski JM, Imanaka Y. Comorbidity and its impact on disability. Milbank Q 1989;67:450-84.

100. Guralnik JM, LaCroix AZ, Everett DF, Kovar MG. Aging in the eighties: the prevalence of comorbidity and its association with disability. Adv Data Vital Health Stat 1989:1-8.

101. Verbrugge LM. Disability transitions for older persons with arthritis. J Aging Health 1992;67:450-1250.

102. Mor V, Murphy J, Masterson-Allen S, et al. Risk of functional decline among well elders. J Clin Epidemiol 1989;42:895-904.

103. Guccione AA, Felson DT, Anderson JJ, et al. The effects of specific medical conditions on the functional limitations of elders in the Framingham Study. Am J Public Health 1994;84:351-8.

104. Guccione AA, Felson DT, Anderson JJ. Defining arthritis and measuring functional status in elders: methodological issues in the study of disease and physical disability. Am J Public Health 1990;80:945-9.

105. Badley EM, Rasooly I, Webster GK. Relative importance of musculoskeletal disorders as a cause of chronic health problems, disability, and health care utilization: findings from the 1990 Ontario Health Survey. J Rheumatol 1994;21:505-14.

106. Johnson RJ, Kellelkamp DB, Clark W, Leaverton P. Factors affecting late results after menisectomy. J Bone Joint Surg-Am 1974;56:719-29.

107. Hochberg MC, Lethbridge-Cejku M, Plato CC, Wigley FM, Tobin JD. Factors associated with osteoarthritis of the hand in males: data from the Baltimore Longitudinal Study of Aging. Am J Epidemiol 1991;134:1121-7.

108. Anderson JJ, Felson DT. Factors associated with osteoarthritis of the knee in the First National Health and Nutrition Examination Survey (HANES I). Evidence for an association with overweight, race and physical demands of work. Am J Med 1988;128:179-89.

109. Busby J, Tobin J, Ettinger W, Roadarmel K, Plato CC. A longitudinal study of osteoarthritis of the hand: the effect of age. Ann Hum Biol 1991;18:417-24.

110. Brandt KD, Fife RS. Aging in relation to pathogenesis of osteoarthritis. Clin Rheum Dis 1986;12:117-30.

111. Hartz AJ, Fischer ME, Brill G, et al. The association of obesity with joint pain and osteoarthritis in the HANES data. J Chron Dis 1986;39:311-9.

112. Bennett PH, Burch TA. Osteoarthrosis in the Blackfeet and Pima Indians. In: Bennett PH, Wood PHN, eds. Population studies of the rheumatic diseases. New York: Excerpta Medica, 1966:407-12.

113. Muller AS. Population studies on the prevalence of rheumatic diseases in Liberia and Nigeria. The Hague (The Netherlands): Plasmans, 1970:105.

114. Bremmer JM, Lawrence JS, Miall WE. Degenerative joint disease in a Jamaican rural population. Ann Rheum Dis 1968;27:326-32.

115. Hoaglund FT, Shiba R, Newberg AH, Leung KY. Diseases of the hip. A comparative study of Japanese Oriental and American white patients. J Bone Joint Surg-Am 1985;67:1376-83.

116. Alexander C. Flexion angles of the knee in different resting positions and their relation to the prevalence of osteoarthritis. J Rheumatol 1991;18:1223-6.

117. Calandriello B. Degenerative joint diseases secondary to joint deformities, with special reference to congenital dislocation of the hip in Italy. In: Kellgren JH, ed. The epidemiology of chronic rheumatism. Philadelphia: FA Davis Co, 1963:122-7.

118. Harper P, Nuki G. Genetic factors in osteoarthritis. In: Nuki G, ed. The aetiopathogenesis of ostearthritis. Tunbridge Wells (England): Pitman, 1980:184-201.

119. Williams CJ, Jimenez SA. Heritable diseases of cartilage caused by mutagens in collagen genes. J Rheumatol 1995;22 Suppl 43:28-33.

120. Baldwin C, Farrer L, Adaair R, Dharmavaram R, Jimenez S, Anderson L. Linkage of early-onset osteoarthritis and chondrocalcinosis to human chromosome 8q. Am J Hum Genet 1995;56:692-7.

121. Peyron JG. Clinical features of osteoarthritis, diffuse idiopathic skeletal hyperostosis, and hypermobility syndromes. Curr Op Rheumatol 1991;3:653-61.

122. Davis MA, Ettinger WM, Neuhaus JM. The role of metabolic factors and blood pressure in the association of obesity with osteoarthritis of the knee. J Rheumatol 1988;15:1827-32.

123. Bagge E, Bjelle A, Eden S, Svanborg A. Factors associated with radiographic osteoarthritis: results from the population study of 70-year-old people in Goteborg. J Rheumatol 1991;18:1218-22.

124. Lawrence JS. Generalized osteoarthritis in a population sample. Am J Epidemiol 1969;90:381-9.

125. Harris W. Etiology of osteoarthritis of the hip. Clin Orthop 1986;213:20-33.

126. Murray RO. The aetiology of primary osteoarthritis of the hip. Br J Radiol 1965;36:810-24.

127. Solomon L. Patterns of osteoarthritis of the hip. J Bone Joint Surg-Br 1976;58:176-83.

128. Wiberg G. Studies on dysplastic acetabula and congenital subluxation of the hip. Acta Chir Scand 1980;58 Suppl:7.

129. Cooperman DR, Wallensten R, Stulberg S. Acetabular dysplasia in the adult. Clin Orthop 1981;175:79-85.

130. Gofton JP. Studies in osteoarthritis of the hip. III. Congenital subluxation and osteoarthritis of the hip. Can Med Assoc J 1971;104:911-5.

131. Murray RO, Duncan C. Athletic activity in adolescence as an etiologic factor in degenerative hip disease. J Bone Joint Surg-Br 1971;53:406-19.

132. Harris W, Bourne RB, Oh I. Intra-articular acetabular labrum: a possible etiological factor in certain cases of osteoarthritis of the hip. J Bone Joint Surg-Am 1979;61:510-4.

133. Meachim G, Whitehouse GH, Pedley RB, et al. An investigation of radiological, clinical and pathological correlations in osteoarthritis of the hip. Clin Radiol 1980;31:565-74.

134. Lloyd-Roberts GC. Osteoarthritis of the hip: a study of the clinical pathology. J Bone Joint Surg-Br 1955;37:8-47.

135. Sowers M, Zobel D, Weissfeld L, Hawthorne VM, Carman W. Progression of osteoarthritis of the hand and metacarpal bone loss. Arthr Rheum 1991;34:36-42.

136. Foss MVL, Byers PD. Bone density, osteoarthritis of the hip, and fracture of the upper end of the femur. Ann Rheum Dis 1972;31:259-64.

137. Pogrund H, Rutenburg M, Makin M, Robin G, Menczel J, Steinberg R. A radiological study in a random population sample in Jerusalem. Clin Orthop 1982;164:130-5.

138. Lindsay R, Hart DM, Aitken JM, Macdonald EB, Anderson J, Clark AC. Long term prevention of postmenopausal osteoporosis by estrogen: evidence for an increased bone mass after delayed onset of estrogen treatment. Lancet 1976;1:1038-41.

139. Horsman A, Jones M, Francis R, Nordin B. The effect of estrogen dose on postmenopausal bone loss. N Eng J M 1983;309:1405-7.

140. Natchigall LE, Natchigall RH, Natchigall RD, Beckman EM. Estrogen replacement therapy. I. A 10-year prospective study of the relationship to osteoporosis. Obstet Gynecol 1979;53:277-81.

141. Horsman A, Gallagher JC, Simpson M, Nordin BEC. Prospective trial of estrogen and calcium in postmenopausal women. BMJ 1977;2:789-92.

142. Recker RR, Saville PD, Heany RP. Effect of estrogens and calcium carbonate bone loss in postmenopausal women. Ann Intern Med 1977;87:649-55.

143. Grodin JM, Siiteri PK, MacDonald PC. Source of estrogen production in postmenopausal women. J Clin Endocrinol Metab 1973;36:207-14.

144. Ettinger B, Genant HK, Cann CE. Postmenopausal bone loss is prevented by treatment with low dosage estrogen with calcium. Ann Intern Med 1987;106:40-5.

145. Hannan MT, Felson DT, Anderson JJ, Naimark A, Kannel WB. Estrogen use and radiographic osteoarthritis of the knee in women. Arthr Rheum 1990;33:525-32.

146. Johanson NA. Endocrine arthropathies. Clin Rheum Dis 1985;11:297-323.

147. Peyron JG. Epidemiologic and etiologic approach of osteoarthritis. Sem Arthr Rheum 1979;8:288-306.

148. Saville PD, Dicksen J. Age and weight in osteoarthritis of the hip. Arthr Rheum 1968;11:635-44.

149. Tepper S, Hochberg MC. Factors associated with hip osteoarthritis: data from the First National Health and Nutrition Examination Survey (NHANES I). Am J Epidemiol 1993;137:1081-8.

150. Hochberg MC, Lethbridge-Cejku M, Plato CC, Scott WW Jr, Tobin JD. Obesity and osteoarthritis of the hands in women. Osteoarthritis Cartilage 1993;1:129-35.

151. van Saase JLCM, Vandenbroucke JP, van Romunde LKJ, Valkenburg HA. Osteoarthritis and obesity in the general population. A relationship calling for an explanation. J Rheumatol 1988;15:1152-8.

152. Carman WJ, Sowers M, Hawthorne VM, Weissfeld LA. Obesity as a risk factor for osteoarthritis of the hand and wrist: a prospective study. Am J Epidemiol 1994;139:119-29.

153. Davis MA, Ettinger WM, Neuhaus JM, Cho SA, Hauck WW. The association of knee injury and obesity with unilateral and bilateral osteoarthritis of the knee. Am J Epidemiol 1989;130:278-88.

154. Davis MA, Ettinger WM, Neuhaus JM, Mueller WH. Body fat distribution and osteoarthritis. Am J Epidemiol 1990;132:701-7.

155. Davis MA, Ettinger WM, Neuhaus JM. Obesity and osteoarthritis of the knee: evidence from the National Health and Nutrition Examination Survey (NHANES I). Sem Arthr Rheum 1990;20 Suppl 1:34-41.

156. Hart DJ, Spector TD. The relationship of obesity, fat distribution and osteoarthritis in women in the general population: the Chingford Study. J Rheumatol 1993;20:331-5.

157. Felson DT. Weight and osteoarthritis. J Rheumatol 1995;22 Suppl 43:7-9.

158. Felson DT, Zhang Y, Anthony JM, Naimark A, Anderson JJ. Weight loss reduces the risk for symptomatic knee osteoarthritis in women. The Framingham Study [see comments]. Ann Intern Med 1992;116:535-9.

159. Verstraeten A, Van Ermen H, Haghebaert G, Nijs J, Geusens P, Dequeker J. Osteoarthrosis retards the development of osteoporosis. Observation of the coexistence of osteoarthrosis and osteoporosis. Clin Orthop Rel Res 1991:169-77.

160. Peyron JG. Epidemiological aspects of osteoarthritis. Scand J Rheumatol 1988;77 Suppl:29-33.

161. Urist MR. Observations bearing on the problem of osteoporosis. In: Bodahl K, ed. Bone as a tissue. New York: McGraw-Hill, 1960:18-23.

162. Smith RW, Rizek J. Epidemiologic studies of osteoporosis in women of Puerto Rico and Southeastern Michigan with special reference to age, race, national origin and to other related or associated findings. Clin Orthop 1966;45:31-48.

163. Milgram JW. Osteopetrosis: a morphological study of twenty-one cases. J Bone Joint Surg-Am 1982;64:912-29.

164. Healey JH, Vigorita VJ, Lane JM. The coexistence and characteristics of osteoarthritis and osteoporosis. J Bone Joint Surg-Am 1985;67:586-92.

165. Urist MR, Vincent PJ. The excretion of various fractions of the 17-ketosteroids in the urine of women with postmenopausal or senile osteoporosis. Clin Orthop 1960;18:199-208.

166. Lane NE, Bloch DA, Jones HH, Marshall WH Jr, Wood PD, Fries JF. Long-distance running, bone density, and osteoarthritis. JAMA 1986;255:1147-51.

167. Carlsson A, Nilsson BE, Westlin NE. Bone mass in primary coxarthrosis. Acta Orthop Scand 1979;50:187-9.

168. Roh YS, Dequeker J, Mulier JC. Bone mass in osteoarthrosis, measured in vivo by photon absorption. J Bone Joint Surg 1974;56A:587-91.

169. Reid DM, Kennedy NSJ, Smith MA, et al. Bone mass in nodal primary generalized osteoarthritis. Ann Rheum Dis 1983;43:240-2.

170. Lane NE. Exercise: a cause of osteoarthritis. J Rheumatol 1995;22 Suppl 43:3-6.

171. Adams JE. Injury to the throwing arm: a study of traumatic changes in the elbow joints of boy baseball players. California Med 1965;102:127-9.

172. Bennett GE. Shoulder and elbow lesions of the professional baseball pitcher. JAMA 1941;117:510-4.

173. Adams ID. Osteoarthritis and sport. Clin Rheum Dis 1976;2:523-41.

174. Vincelette P. The footballer's ankle and foot. Can Med Assoc J 1972;107:872-7.

175. Brodelius A. Osteoarthrosis of the talar joints in footballers and ballet dancers. Acta Orthop Scand 1961;30:309-14.

176. Kujala U, Kettunen J, Paananen H, et al. Knee osteoarthritis in former runners, soccer players, weight lifters, and shooters. Arthr Rheum 1995;28:539-46.

177. Klunder KB, Rud B, Hansen J. Osteoarthritis of the hip and knee joint in retired football players. Acta Orthop Scand 1980;51:925-7.

178. Marti B, Knobloch M, Tschopp A, Jucker A, Howald H. Is excessive running predictive of degenerative hip disease? Controlled study of former elite athletes. BMJ 1989;299:91-3.

179. Puranen J, Ala Ketola L, Peltokallio B, Saarela J. Running and primary osteoarthritis of the hip. BMJ 1975;2:424-5.

180. Sohn RS, Micheli LJ. The effect of running on the pathogenesis of osteoarthritis of the hips and knees. Clin Orthop 1985;198:106-7.

181. Panush RS, Schmidt C, Caldwell JR, et al. Is running associated with degenerative joint disease? JAMA 1986;255:1152-4.

182. Kujala UM, Kaprio J, Sarna S. Osteoarthritis of weight bearing joints of lower limbs in former elite male athletes. BMJ 1994;308:231-4.

183. Solonen KA. The joints of the lower extremities of football players. Ann Chir Gynaecol 1966;55:176-80.

184. Rall K, McElroy G, Keats TE. A study of long term effects of football injury to the knee. Mo Med 1984;61:435-8.

185. McDermott M, Freyne P. Osteoarthritis in runners with knee pain. Br J Sports Med 1983;17:84-7.

186. Lane NE, Bloch DA, Hubert HB, Jones H, Simpson U, Fries JF. Running, osteoarthritis, and bone density: initial 2-year longitudinal study. Am J Med 1990;88:452-9.

187. Konradsen L, Hansen EM, Sondergaard L. Long distance running and osteoarthrosis. Am J Sports Med 1990;18:379-81.

188. Lane NE, Michel B, Bjorkengren A, et al. The risk of osteoarthritis with running and aging: a 5-year longitudinal study. J Rheumatol 1993;20:461-8.

189. Felson DT, Hannan MT, Naimark A, et al. Occupational physical demands, knee bending, and knee osteoarthritis: results from the Framingham Study. J Rheumatol 1991;18:1587-92.

190. Lane N. Exercise and osteoarthritis. Bull Rheum Dis 1992;41:5-7.

191. Neyret P, Donell ST, DeJour P, et al. Partial meniscectomy and anterior cruciate ligament rupture in soccer players. A study with minimum 20-year follow-up. Am J Sports Med 1993;21:455-60.

192. Lawrence JS. Rheumatism in coal miners. III: occupational factors. Br J Industrial Med 1955;12:249-61.

193. Burke MJ, Fear EC, Wright V. Bone and joint changes in pneumatic drillers. Ann Rheum Dis 1977;36:276-9.

194. Lindberg H, Danielsson LG. The relation between labour and coxarthrosis. Clin Orthop 1984;191:159-61.

195. Eastmond CJ, Hudson A, Wright V. A radiological survey of the hips and knees in female specialist teachers of physical education. Scand J Rheumatol 1979;8:264-8.

196. Louyot P, Savin R. La coxarthrose chez l'agriculteur. Rev Rhum Mal Osteoartic 1966;33:625-32.

197. Typpo T. Osteoarthritis of the hip: radiologic findings and etiology. Ann Chir Gynaecol 1985;74 Suppl 201:1-37.

198. Jacobsson B, Dalen N, Tjornstrand B. Coxarthrosis and labour. Int Orthop 1987;11:311-3.

199. Axmacher B, Lindberg H. Coxarthrosis in farmers as appearing on colon radiograms and urograms. In: Hogstedt C, Reuterwall C, eds. Progress in occupational epidemiology: proceedings of the Sixth International Symposium on Epidemiology in Occupational Health. Amsterdam: Excerpta Medica, 1988:203-6.

200. Forsberg K, Nilsson BE. Coxarthrosis on the island of Gotland. Increased prevalence in a rural population. Acta Orthop Scand 1992;63:1-3.

201. Thelin A. Hip joint arthrosis: an occupational disorder among farmers. Am J Industrial Med 1990;18:339-43.

202. Croft P, Coggon D, Cruddas M, Cooper C. Osteoarthritis of the hip: an occupational disease in farmers [see comments]. BMJ 1992;304:1269-72.

203. Vingard E, Alfredsson L, Goldie I, Hogstedt C. Occupation and osteoarthrosis of the hip and knee: a register-based cohort study. Int J Epid 1991;20:1025-31.

204. Croft P, Cooper C, Wickham C, Coggon D. Osteoarthritis of the hip and occupational activity. Scand J Work Environ Hlth 1992;18:59-63.

205. Anderson JA. Arthrosis and its relation to work. Scand J Work Environ Hlth 1984;10:429-33.

206. Vingard E, Hogstedt C, Alfredsson L, Fellenius E, Goldie I, Koster M. Coxarthrosis and physical work load. Scand J Work Environ Hlth 1991;17:104-9.

207. Schouten JSAG, van den Ouweland FA, Valkenburg HA. A 12 year follow-up study in the general population on prognostic factors of cartilage loss in osteoarthritis of the knee. Ann Rheum Dis 1992;51:932-7.

208. Kohatsu ND, Schurman DJ. Risk factors for the development of osteoarthrosis of the knee. Clin Orthop Rel Res 1990:242-6.

209. Spector TD, Hart DJ, Doyle DV. Are cigarette smoking and HRT protective for osteoarthritis? Br J Rheumatol 1989;28 Suppl 2:11.