Risk factors and causes of osteoarthritis

Osteoarthritis occurs as a result of interaction of multiple genetic and environmental (including traumatic) factors. It was the analysis of risk factors for osteoarthritis in various locations that contributed to the emergence of the concept of disease heterogeneity. Thus, clear differences in risk factors for coxarthrosis and gonarthrosis have been established: there are no gender differences in osteoarthritis of the hip joints, it is rarely diagnosed in representatives of the Mongoloid race, and is often combined with congenital developmental defects; gonarthrosis is more common in women of the Negroid race than in representatives of the Caucasian race, they are characterized by previous traumatic damage to the joints. There is evidence that the group of risk factors for osteoarthritis of the patellofemoral region of the knee joints differs from the risk factors for damage to the medial tibiofemoral region - the first type is associated with a family history of osteoarthritis and the presence of nodular lesions of the hands, the second is partly associated with obesity and previous surgical interventions on the knee joint.

Gender plays an important role in the development of osteoarthritis - women are more likely to develop osteoarthritis of most localizations. The results of a Finnish study involving 6647 farmers showed that female gender is an independent predisposing factor to the development of gonarthrosis. Data from a review of 29 epidemiological studies of osteoarthritis of the knee and hip joints in 14 countries indicate that osteoarthritis of the hip joints is more common in men than in women; knee joints are more often affected in women, especially at the age of over 45. However, most other studies note a high incidence of coxarthrosis in women. With osteoarthritis of the joints of the hands, a rapid increase in incidence is observed in women up to 60 years, after which the incidence of osteoarthritis of this localization does not change significantly; in men, a slower increase in incidence is observed, it continues during the 7th-8th decade of life. Differences in the prevalence of monoosteoarthrosis, oligoosteoarthrosis and generalized (poly-) osteoarthrosis were found between men and women.

Risk factors for osteoarthritis

Genetic	gender (female) inherited pathology of the gene of type II collagen collagen type II gene mutation other hereditary diseases of bones and joints racial/ethnic origin
Non-genetic	old age overweight decreased levels of female sex hormones (for example, during postmenopause) malformations of bones and joints history of joint surgery (eg, meniscectomy)
Exogenous	professional activity joint injury sports activities

These features suggest that endocrine factors play a certain role in osteoarthrosis. Indeed, the results of many studies, especially studies on animal models of osteoarthrosis, indicate that sex hormones are capable of modifying metabolism in cartilage tissue. Estrogen receptors have been found in the articular cartilage of many animal species. In a study by JAP Da Silva et al. (1994), it was noted that ovariectomy increases the rate of destructive processes in animal cartilage. Animal models of osteoarthrosis have demonstrated that estradiol can inhibit proteoglycan synthesis. Supraphysiological doses of estradiol increase cartilage "breakdown", which was blocked by the antiestrogen tamoxifen. In rabbits after ovariectomy, which received high doses of estrogens, thinning and fraying of the articular cartilage developed, i.e. changes typical of human osteoarthrosis.

There is also some epidemiological evidence of the involvement of sex hormones, primarily estrogens, in the development of osteoarthritis. These include a higher incidence of osteoarthritis in women, which increases around menopause, and the association of widespread osteoarthritis with factors such as gynecological surgery, bone mass, and obesity, which may reflect the effects of endogenous sex hormones. According to TD Spector and GC Champion (1989), women with estrogen overproduction are predisposed to generalized osteoarthritis.

In addition, a possible role of estrogens in the pathogenesis of osteoarthritis is suggested based on the "antagonistic" relationship between osteoporosis and osteoarthritis and the increased risk of osteoarthritis in obesity. Estrogens regulate bone metabolism, their deficiency causes loss of bone mineral component in women in the pre- and postmenopausal period; high bone mineral density (BMD) in the postmenopausal period may indicate long-term preservation of estrogen excess. Postmenopausal women with gonarthrosis, coxarthrosis, osteoarthritis of the hand joints and polyosteoarthrosis have an increase in bone density, which is not caused by obesity or a slower loss of bone tissue in women with osteoarthritis during menopause. With high bone density, articular cartilage can withstand increased mechanical load.

Obesity has also been associated with higher levels of endogenous estrogens in the postmenopausal period. Obesity increases the risk of developing osteoarthritis of the knees, hips, and hands in women, but whether this is due to the mechanical effects of excess body weight on cartilage, higher levels of estrogens, or other systemic influences is not yet understood.

Some evidence of the link between female sex hormones and osteoarthritis has been obtained in studies examining risk factors for osteoarthritis in women receiving estrogen replacement therapy (HRT). It has been shown that HRT reduces the risk of developing gonarthrosis and coxarthrosis. In women receiving HRT for 8 years, a slowdown in the progression of osteoarthritis was observed. Since HRT reduces bone metabolism, it can be assumed that estrogens contribute to the stabilization of osteoarthritis by slowing down the remodeling of subchondral bone.

The role of estrogens in the development of osteoarthritis is most likely realized through the influence on inflammatory and anabolic cytokines, which in turn affect cartilage metabolism. The action of estrogens on bone is apparently related in part to interleukin-1 (IL-1), IL-6, tumor necrosis factor α (TNF-α). Estrogen receptors are found in articular cartilage, and IL-1 and IL-6 are likely able to mediate the action of estrogens on its metabolism. Insulin-like growth factor 1 (IGF-1) and transforming growth factor beta (TGF-beta) are involved in the synthesis and repair of cartilage matrix, and estrogens probably have a complex effect on growth factors.

Overall, evidence for an association of osteoarthritis with factors related to sex hormone exposure in women is inconsistent. It is possible that estrogens have different effects depending on the timing of menopause and the stage of osteoarthritis.

An important genetic risk factor for osteoarthritis is an inherited or acquired mutation of the procollagen type II gene (the main collagen of hyaline cartilage) COL ₂ A _b located on chromosome 12. The earliest descriptions of the genetic link between the phenotype of early osteoarthritis and COL ₂ A date back to the late 80s and early 90s of the last century. One of them reported a mutation of COL ₂ A in relatives with early osteoarthritis, which was manifested by the replacement of the amino acid arginine with cysteine at position 519 in the collagen type II molecule. To date, a similar mutation has been described in 4 more families. CJ Williams et al. (1995) discovered another mutation of COL ₂ A! In a family whose members developed early osteoarthritis, there was a substitution of arginine for cysteine at position 75. The authors note that the osteoarthritis phenotype in this family differs from that in families whose members developed a substitution of arginine for cysteine at position 519. JF Bleasel et al. (1995) found the same mutation in COL ₂ A in another family. In addition to those described above, other mutations in COL ₂ A are found in families whose members developed early osteoarthritis: a substitution of glycine for serine at position 976, at position 493.

Hereditary predisposition is more often revealed in the generalized form of osteoarthritis (GOA). JH Kellgren et al. (1963) found Bouchard's and Heberden's nodes in 36% of male relatives and 49% of female relatives with the generalized form of osteoarthritis; in the general population, these figures were 17 and 26%, respectively. In patients with the generalized form of osteoarthritis, the HLA Al B8 haplotype and the MZ form of a,-antitrypsin are more often found. TD Spector et al. (1996), when studying the influence of heredity on the occurrence of the nodular form of the disease in twins, also noted a certain role of genetic factors in the development of this form of osteoarthritis.

In large families with generalized osteoarthritis, linkage analysis has shown co-inheritance of osteoarthritis and an allele of the type II procollagen gene (COL ₂ A,). This allele was cloned and was found to carry a single mutation at position 519 in the first collagen chain, which was present in all affected family members but not in healthy individuals. Primary generalized osteoarthritis appears to be a heterogeneous disorder and may be associated with mutations in other genes. Recent studies of polymorphic markers of genes encoding type II collagen, cartilage matrix protein, and linking protein in 38 sib pairs did not support the hypothesis of their relationship to osteoarthritis susceptibility loci. Probably, only a small proportion of cases can be explained by this genetic abnormality.

Population studies suggest a role for race/ethnicity in the development of osteoarthritis, but often the authors present conflicting data. Thus, according to JJ Anderson and DT Felson (1988), African American women are more likely than white women to have knee osteoarthritis; the authors found no racial differences in coxarthrosis. The above-mentioned review of 29 epidemiological studies conducted in 14 countries indicates that Caucasians are more likely than non-Caucasians to have radiographic signs of coxarthrosis; however, the prevalence of gonarthrosis in both populations was the same.

Prevalence of osteoarthritis among different ethnic/racial groups

Ethnic/racial group	Age, years	Prevalence of OA,%
		Women	Men
The English	>35	70	69
Americans are representatives of the Caucasian race	>40	44	43
Eskimos of Alaska	>40	24	22
Rural population of Jamaica	35-64	62	54
North American Pima Indians	>30	74	56
North American Blackfoot Indians	>30	74	61
South Africans are representatives of the Negroid race	>35	53	60
On average in 17 populations	>35	60	60

Despite the fact that osteoarthrosis predominantly affects elderly people and its prevalence in the age group under 45-50 years is extremely low, it cannot be called an inevitable consequence of aging. The prevalence of osteoarthrosis of the joints of the hands, hips and knees increases sharply in men and women aged 50 to 80 years. However, the reasons why age is one of the significant risk factors for osteoarthrosis are unclear. It is possible that, on the one hand, human chondrocytes in the process of aging lose the ability to replenish or restore the matrix of articular cartilage, “lost” as a result of damage or normal (for this age) metabolism, and as a result, a deficiency of matrix components develops (as in osteoporosis). On the other hand, the cartilage matrix in old age can become more sensitive to normal cumulative microtrauma, and the restorative mechanisms of the cells are unable to compensate for this increased sensitivity. In both cases, there is a discrepancy between the influence of the external environment on the articular cartilage and the ability of chondrocytes or matrix to respond to these influences. Although the time from the appearance of initial changes in the joints to the onset of symptoms and radiographic signs of osteoarthrosis varies, it is usually measured in years and decades. At the same time, the rate of progression of osteoarthrosis in individual patients varies even within the same age group and with the same localization of the disease. This suggests the participation in the development of osteoarthrosis of such factors as genetic predisposition, level of physical activity, differences between joints, etc.

According to L. Buratti et al. (1995), the incidence of osteoarthrosis of the hip, knee, and hand joints increases with age, but the incidence of osteoarthrosis of the cervical spine decreases. In addition, in older age groups, an increase in the number of joints affected by osteoarthrosis is observed.

Number of joints affected by osteoarthrosis in different age groups (according to Ciocci A, 1996, with changes)

Age, years	Number of patients, %
	Monoarthrosis	Oligoarthrosis	Generalized OA
<50	54.8	33.9	11.3
51-60	56.5	34	9.5
61-70	38.2	45.3	16.5
>70	19.4	20	60.6

There are relatively few studies examining the effect of aging on the progression of osteoarthritis, although the importance of old age in the development of osteoarthritis is generally recognized. In one of them, the majority of patients with osteoarthritis (60% of the examined knee joints) did not show any radiographic changes according to Kellgren and Lawrence during 11 years of observation, and 33% had only minor changes. Thus, the progression of osteoarthritis is not always an inevitable process and probably depends on the different ability of joint tissues to restore and degrade after their injury.

Population studies have clearly established that overweight people have a higher risk of developing gonarthrosis. The highest risk of developing osteoarthritis is in people with a body mass index (BMI) > 25 (Centers for Disease Control). The NHANES-1 study showed that obese women with a BMI above 30 but below 35 had a 4-fold higher risk of developing osteoarthritis compared to women with a BMI of 25. In men with the same excess weight, the risk increased by 4.8 times compared to men with normal body weight. A significant direct association was found between BMI and gonarthrosis in individuals of both sexes: for every 5 BMI units, the relative ratio (95% confidence intervals) of the association with knee osteoarthritis was 2.1 (1.7; 2.58) for men and 2.2 (1.95; 2.5) for women. These data are similar to the results of other studies. According to T. MacAlinden et al. (1996), excess body weight was associated with osteoarthritis of both the tibiofemoral and patellofemoral sections of the knee joint. The authors suggested that body weight increased after the development of osteoarthritis due to limited physical activity. However, there is evidence that in the presence of excess body weight in individuals aged 37 years, when osteoarthritis is extremely rare, the risk of developing knee osteoarthritis by the age of 70 increases. Results of a prospective population-based study and repeated radiographic observations provided grounds to assert that excess body weight in individuals without osteoarthritis is a potential risk factor for future knee osteoarthritis.

With excess body weight, not only is the risk of developing osteoarthritis of the knee joints high, but, as long-term observations have shown, there is also a high risk of disease progression, and in women - the development of bilateral osteoarthritis.

M.A. Davis et al. (1989) investigated the relationship between excess body weight and unilateral/bilateral knee osteoarthritis diagnosed radiographically. NHAINS-1 involved 3885 individuals aged 45 to 74 years, of whom 226 (4.9%) had bilateral and 75 (1.8%) unilateral gonarthrosis; BMI over 30 was noted in 65% of patients with bilateral gonarthrosis, 37.4% with osteoarthritis of the right knee joint, 43.3% with osteoarthritis of the left knee joint, and 17.7% of healthy individuals. The relative ratio (95% confidence intervals) of the association of excess body weight with bilateral gonarthrosis was 6.58 (4.71; 9.18), while with right-sided and left-sided osteoarthritis it was 3.26 (1.55; 7.29) and 2.35 (0.96; 5.75), respectively.

The relationship between excess body weight and gonarthrosis in relation to the distribution of subcutaneous fat tissue (SFA) in individuals aged 45-74 years who participated in NHAINS-I was studied by M.A. Davis et al. (1990). The central distribution of subcutaneous fat tissue was determined by measuring the thickness of the skin fold below the angle of the scapula, and the peripheral distribution was determined by measuring the fold in the area of the triceps muscle of the shoulder. The authors did not find a relationship between the thickness of the corresponding skin folds and the presence of uni/bilateral osteoarthrosis of the knee joints regardless of gender, age, race, or BMI. However, the relationship between BMI and bilateral gonarthrosis was strong in men and women, and with unilateral gonarthrosis only in men.

M.S. Hochberg et al. (1995) examined the relationship between subcutaneous fat distribution and percentage subcutaneous fat in 465 Caucasian men and 275 women from the Baltimore Longitudinal Study of Aging and in 169 men and 99 women with radiographically diagnosed osteoarthritis. Subcutaneous fat distribution was determined using the wrist-to-thigh circumference ratio, while percentage subcutaneous fat was calculated using a standard equation that included such parameters as the thickness of the folds in the angle of the scapula, abdomen, and triceps brachii. As expected, BMI was strongly associated with the presence of gonarthrosis in both sexes. However, the study authors did not find an association between radiographically diagnosed knee osteoarthritis and the distribution of subcutaneous fat (central/peripheral) or the percentage of subcutaneous fat.

Studies by K. Martin et al. (1997), Davis MA et al. (1988) showed that in obesity, mechanical rather than metabolic factors influence the occurrence of osteoarthritis of the knee joints.

Overweight individuals are at increased risk of developing osteoarthritis of the hip joints, although this association is not as strong as with gonarthrosis. The results of such studies are contradictory. It is noted that such individuals are predisposed to bilateral, rather than unilateral, osteoarthritis of the hip joints.

According to prospective (23 years) observation, excess body weight is also associated with a higher risk of developing osteoarthritis of the hand joints. Studies conducted in London involving twins also revealed an association between excess body weight and osteoarthritis of the carpometacarpal joint of the first finger.

The relationship between excess body weight and osteoarthritis can be explained by the increased load on the joints, which causes mechanical “breakdown” of the cartilage, which then leads to the development of osteoarthritis. However, this explanation is applicable only to osteoarthritis of the knee and hip joints, but not to osteoarthritis of the hand joints. It is also possible that in obese individuals there is an as yet unknown factor that accelerates the “breakdown” of cartilage and contributes to the development of the disease. In addition, obese people have a higher BMD, which is also considered a risk factor for osteoarthritis.

The Framingham Study examined patients every 2 years for 40 years and found that weight gain was a risk factor for overt knee osteoarthritis in women, and that a 5 kg weight loss in women with a BMI of 25 (i.e. above average) reduced the risk of developing osteoarthritis by 50%.

For women with a BMI below the average, neither weight gain nor weight loss significantly affected the risk of developing the disease. Therefore, obesity is an important risk factor for knee, hip, and hand osteoarthritis, and these patients are also at high risk for progressive disease progression. Weight loss can prevent the disease, especially knee OA.

According to KD Brandt et al. (1986), approximately 80% of all cases of idiopathic hip osteoarthritis are associated with unrecognized developmental defects such as dysplasia and subluxation. At the same time, the frequency of these developmental anomalies does not provide a clear explanation for the high prevalence of hip osteoarthritis in Europe and the USA.

There is strong evidence linking occupational factors with the development of osteoarthritis, with excessive loads on certain joints being associated with an increased risk of developing osteoarthritis of these joints. Those at risk include miners (osteoarthritis of the knees and lumbar spine), dockers and shipyard workers (osteoarthritis of the knees and wrists), cotton pickers and mill workers (osteoarthritis of individual joints of the wrists), pneumatic tool operators (osteoarthritis of the elbow and wrist), painters and concrete workers (osteoarthritis of the knees), and farmers (osteoarthritis of the hips).

Professional sports (football, track and field, etc.) are associated with a high risk of developing osteoarthritis. In individuals who are not professionally involved in physical culture, the risk of developing osteoarthritis of the knee and hip joints does not differ from the general population.

A very important risk factor for osteoarthritis is trauma/damage to the joint. Trauma to the knee joint (especially the anterior cruciate ligament) is associated with a high risk of developing knee osteoarthritis in professional football players.

M. A. Davis et al. (1989) in the above-described NHAINS-I investigated the association between knee trauma and uni/bilateral radiographically confirmed knee osteoarthritis. A history of right knee trauma was reported in 5.8% of subjects with bilateral knee osteoarthritis, 15.8% of 37 subjects with right knee osteoarthritis, and 1.5% of controls, while a history of left knee trauma was reported in 4.6% of subjects with bilateral lesions, 27% of subjects with left knee osteoarthritis, and 1.8% of controls. Statistical analysis of the obtained data showed that the relative ratio (95% confidence intervals) of the association of knee joint injury and bilateral gonarthrosis was 3.51 (1.8; 6.83), right-sided gonarthrosis - 16.3 (6.5; 40.9) and left-sided gonarthrosis - 10.9 (3.72-31.93).

S. Terreg and M.C. Hochberg (1993) studied the relationship between hip trauma and radiographically confirmed coxarthrosis in 2359 individuals aged 55 to 74 years who participated in NHAINS-I; of these, only 73 (3.1%) were diagnosed with osteoarthritis of one or both hip joints. Statistical analysis revealed a significant association between a history of hip trauma and coxarthrosis (relative ratio (95% confidence intervals) - 7.84 (2.11; 29.1). Analyzing the relationship between hip trauma and uni/bilateral damage, the authors determined a more pronounced association with unilateral (relative ratio (95% confidence intervals) - 24.2 (3.84; 153)) than with bilateral coxarthrosis (relative ratio (95% confidence intervals) - 4.17 (0.5; 34.7). Thus, hip and knee trauma is an important risk factor for the development of coxarthrosis and gonarthrosis, especially unilateral.

In addition to the above, KD Brandt (2000) identifies weakness of the periarticular muscles as a risk factor for the development of gonarthrosis.

In patients with osteoarthrosis of the knee joints, weakness of the quadriceps femoris is often found, which is usually associated with atrophy due to limitation of movement in the affected limb. However, weakness of this muscle is also found in patients with latent gonarthrosis, who had no pain in the joint both at the time of examination and in the anamnesis, muscle mass not only did not decrease, but was even sometimes increased. Prospective studies indicate that weakness of the quadriceps femoris is not only a consequence of manifest gonarthrosis, but can also be a risk factor for osteoarthrosis. Among women without radiographic signs of gonarthrosis at the beginning of the observation and with radiographically diagnosed osteoarthrosis after 30 months, the initial strength of the knee extensor was significantly lower (p < 0.04) than in those women who did not develop osteoarthrosis.

S. Slemenda et al. (1997) determined that an increase in knee extensor strength by every 10 lb/ft2 ^is associated with a 20% reduction in the likelihood of developing knee osteoarthritis and a 29% reduction in manifest osteoarthritis. A relatively small increase in knee extensor strength (approximately 20% of the average for men and 25% of the average for women) is associated with a 20% and 30% reduction in the risk of developing gonarthrosis, respectively.

The role of the quadriceps muscle in protecting the knee joint from injury is related to its joint stabilizing function, as well as the fact that it provides resistance to gravity for the entire lower limb.

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