Risk factors and causes of osteoarthritis

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

Gender is important in the development of osteoarthritis - women are more likely to develop osteoarthrosis of most localizations. The results of a Finnish study involving 6647 farmers showed that female gender is an independent predisposing factor for the development of gonarthrosis. A review of 29 epidemiological studies of osteoarthritis of the knee and hip joints in 14 countries around the world suggests that osteoarthritis of the hip joints is more common in men than in women; Knee joints are more often affected in women, especially those over the age of 45. However, most other studies show a high incidence of coxarthrosis in women. In osteoarthrosis of the joints of the hands, there is a rapid rise in the incidence in women under 60 years of age, then the frequency of osteoarthritis of this localization does not change significantly; men have a slower increase in incidence, it continues during the 7-8th decade of life. Differences in the prevalence of monoosteoarthrosis, oligososteoarthrosis and generalized (poly-) osteoarthrosis between men and women were found.

Risk factors for osteoarthritis

Genetic	female gender) inherited pathology of type II collagen gene type II collagen gene mutation other hereditary diseases of bones and joints racial / ethnic background
Non-genetic	elderly age overweight decrease in the level of female sex hormones (for example, in the postmenopausal period) malformations of bones and joints history of joint surgery (for example, meniscectomy)
Exogenous	professional activity joint injury playing sports

These features suggest that endocrine factors play a role in osteoarthritis. Indeed, the results of many studies, especially studies on models of osteoarthrosis in animals, indicate that sex hormones can modify metabolism in cartilage tissue. Estrogen receptors are found in the articular cartilage of many animal species. The study JAP Da Silva and co-authors (1994) noted that oophorectomy increases the rate of destructive processes in animal cartilage. On models of osteoarthritis in animals, it has been demonstrated that estradiol can inhibit the synthesis of proteoglycans. Superphysiological doses of estradiol increase the "breakdown" of cartilage, which is blocked by the antiestrogen tamoxifen. In rabbits after oophorectomy, who received high doses of estrogen, thinning and dilation of the articular cartilage developed, i.e. Changes typical of osteoarthritis in humans.

There is also a number of epidemiological evidence of the involvement of sex hormones, primarily estrogen, in the development of osteoarthritis. These include a higher incidence of osteoarthritis in women, which increases by the period of menopause, the connection of common 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 hyperproduction of estrogen are prone to generalized osteoarthritis.

In addition, the possible role of estrogens in the pathogenesis of osteoarthritis is suggested based on the “antagonistic” relationship of osteoporosis with osteoarthrosis and an increased risk of osteoarthrosis in obesity. Estrogens regulate bone metabolism, their deficiency causes bone loss of the mineral component in women during the pre- and postmenopausal period; high bone mineral density (BMD) in the postmenopausal period may indicate prolonged maintenance of excess estrogens. In postmenopausal women with gonarthrosis, coxarthrosis, osteoarthrosis of the joints of the hands and with polyosteoarthrosis, there is an increase in bone density, which is not caused by obesity or slower bone loss in women with osteoarthrosis during menopause. With high bone density, articular cartilage can withstand increased mechanical stress.

Obesity is also associated with a higher level of endogenous estrogen in the postmenopausal period. Obesity increases the risk of osteoarthritis of the knee, hip joints and hand joints in women, but the question of what caused this (the mechanical effect of overweight on cartilage, higher estrogen levels or other systemic effects) has not yet been studied.

Some evidence of the relationship of female sex hormones to osteoarthrosis was obtained in studies of the risk factors for osteoarthritis in women receiving hormone replacement therapy with estrogen (HHTE). HRT has been shown to reduce the risk of gonarthrosis and coxarthrosis. In women who received HST for 8 years, slowed progression of osteoarthritis was observed. Since HRTE reduces bone metabolism, it can be assumed that estrogen contributes to the stabilization of osteoarthritis by slowing the remodeling of the subchondral bone.

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

In general, evidence for the association of osteoarthritis with factors associated with the effects of sex hormones in women is contradictory. It is possible that estrogens have a different effect, which depends on the time of menopause and the stage of osteoarthrosis.

An important among the genetic risk factors for osteoarthritis is an inherited or acquired mutation of the procollagen type II gene (basic hyaline cartilage collagen) COL ₂ A _b located on the 12th chromosome. The earliest descriptions of the genetic relationship between the phenotype of early osteoarthritis and COL ₂ A refer to the end of the 80s and the beginning of the 90s of the last century. In one of them, a COL ₂ A mutation was reported in relatives with early osteoarthrosis, which was manifested by replacing the amino acid arginine with cysteine at position 519 in a type II collagen molecule. To date, another 4 families described a similar mutation. CJ Williams et al. (1995) discovered another COL ₂ A mutation! In the family, in members of which early development of osteoarthrosis was noted, the replacement of arginine with cysteine in position 75. The authors note that the phenotype of osteoarthrosis in this family is different from that in families whose members found the replacement of arginine with cysteine in position 519. JF Bleasel and co-authors (1995) identified the same COL ₂ A mutation in another family. In addition to those described above in families whose members have been diagnosed with early osteoarthrosis, there are other COL ₂ A mutations : replacement of glycine with the series at position 976, at position 493.

Hereditary predisposition is often detected with a generalized form of osteoarthritis (GOA). JH Kellgren and co-authors (1963) found Bouchard and Heberden’s nodules in 36% of the relatives of men and 49% of the relatives of women with a generalized form of osteoarthritis; in the general population, these figures were respectively 17 and 26%. In patients with a generalized form of osteoarthritis, HLA Al B8 haplotype and MZ form a, α-antitrypsin are more often found. TD Spector and co-authors (1996) in studying the influence of heredity on the occurrence of a nodular form of the disease in twins also note a certain role of genetic factors in the development of this form of osteoarthritis.

In large families with a generalized form of osteoarthrosis, a joint inheritance of osteoarthrosis and the allele of the procollagen type II gene (COL ₂ A,) is shown by linkage analysis. This allele was cloned and a single mutation was found in position 519 in the 1st collagen chain, which was present in all sick family members, but was not detected in any healthy one. Primary generalized osteoarthritis appears to be a heterogeneous disease and may be associated with mutations in other genes. Recently conducted studies of polymorphic markers of genes encoding type II collagen, cartilage matrix protein and binding protein in 38 pairs of siblings did not confirm the assumption of their relation to susceptibility to osteoarthrosis loci. Probably only a small proportion of cases can be explained by this genetic disorder.

Population studies indicate the role of race / ethnicity in the development of osteoarthrosis, but the authors often provide conflicting data. So, according to JJ Anderson and DT Felson (1988), African-American women are more likely to have osteoarthritis of the knee joints in women with white skin; for coxarthrosis, the authors did not reveal racial differences. In the aforementioned review of 29 epidemiological studies conducted in 14 countries of the world, it is indicated that representatives of the Caucasians are more likely to have X-ray signs of coxarthrosis; however, the prevalence of gonarthrosis in both populations was the same.

The prevalence of osteoarthritis among members of different ethnic / racial groups

Ethnic / racial group	Age years	The prevalence of OA,%
		Women	Men
The British	>35	70	69
Americans - Caucasians	>40	44	43
Eskimos of Alaska	>40	24	22
Rural Jamaica population	35-64	62	54
North American Pima Indians	>30	74	56
North American Indians of the Blackfoot Tribe	>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 is mainly affected by elderly people and its prevalence is extremely low in the age group younger than 45-50 years old, it cannot be called the inevitable consequence of aging. The prevalence of osteoarthritis of the joints of the hands, hip and knee joints increases sharply in men and women aged 50 to 80 years. However, the reasons for which age is one of the significant risk factors for osteoarthrosis are not clear. 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 that is “lost” as a result of damage or normal (for this age) metabolism, and as a result a deficit of matrix components develops (as in osteoporosis). On the other hand, the cartilage matrix in old age may become more sensitive to normal cumulative microtraumas, and the repair mechanisms of cells are not able 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 the matrix to respond to these influences. And although the time from the onset of initial changes in the joints to the onset of symptoms and radiographic signs of osteoarthrosis is different, it is usually measured in years and decades. However, the rate of progression of osteoarthrosis in individual patients varies even in the same age group and with the same localization of the disease. This implies 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 wrist joints increases with age, but the incidence of osteoarthrosis of the cervical spine is reduced. In addition, an increase in the number of joints affected by osteoarthrosis is observed in individuals of older age groups.

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

Age years	Number of patients,%
	Monoarthrosis	Oligoarthritis	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

Relatively few studies have been conducted in which studies of the effect of aging on the progression of osteoarthritis, although the significance of older age in the development of osteoarthrosis is generally recognized. In one of them, most patients with osteoarthrosis (60% of the examined knee joints) did not show any radiographic changes according to Kellgren and Lawrence during 11 years of observation, and only minor changes in 33%. Thus, the progression of osteoarthritis is not always an inevitable process and probably depends on the different ability to restore and degrade the tissues of the joint after they are damaged.

In population studies, it is unambiguously established that overweight streets register a higher risk of developing gonarthrosis. The greatest risk of osteoarthritis in individuals with a body mass index (BMI)> 25 (Centers for Disease Control). The NHANES-1 study showed that in obese women with a BMI above 30, but below 35, the risk of developing osteoarthritis was 4 times higher than in women who had a BMI of 25. In men with the same overweight, the risk increased in 4, 8 times compared with men with normal body weight. A significant direct association was found between BMI and gonarthrosis in persons of both sexes: for every 5 units of BMI, the relative ratio (95% confidence intervals) of connection with osteoarthritis of the knee joints 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 and co-authors (1996), overweight was associated with osteoarthritis and tibiofemoral and patellofemoral parts of the knee joint. The authors suggested that body weight increased already after the development of osteoarthrosis due to the limitation of motor activity. However, there is evidence that in the presence of overweight in people aged 37 years, when osteoarthritis is extremely rare, the risk of developing osteoarthritis of the knee joints by the age of 70 increases. The results of a prospective population-based study and repeated X-ray observations suggested that overweight in people without osteoarthritis is a potential risk factor for osteoarthritis of the knee joints in the future.

With overweight, not only is the risk of osteoarthritis of the knee joints high, but, as long-term observations have shown, the risk of disease progression is also high, and in women, the development of bilateral osteoarthrosis is high.

M.A. Davis and colleagues (1989) investigated the relationship between overweight and uni / bilateral osteoarthritis of the knee, radiographically diagnosed. In NHAINS-1, 3885 people aged from 45 to 74 years old participated, of which 226 (4.9%) had bilateral and 75 (1.8%) unilateral gonarthrosis; A BMI above 30 is noted in 65% of patients with bilateral gonarthrosis, in 37.4% with osteoarthritis of the right knee joint, in 43.3% with osteoarthrosis of the left knee joint and in 17.7% of healthy individuals. The relative ratio (95% confidence intervals) of overweight associated with bilateral gonarthrosis was 6.58 (4.71; 9.18), whereas with right-side and left-sided osteoarthritis, respectively, 3.26 (1.55; 7.29) and 2.35 (0.96; 5.75).

The relationship between overweight and gonarthrosis in relation to the nature of the distribution of subcutaneous fatty tissue (PZHK) in people aged 45-74 years who participated in NHAINS-I, was studied by MA Davis et al. (1990). The central distribution of subcutaneous adipose tissue was determined by measuring the thickness of the skin fold below the angle of the scapula, the peripheral - folds in the region of the triceps muscle of the shoulder. The authors did not find a connection between the thickness of the corresponding skin folds and the presence of uni / bilateral osteoarthritis of the knee joints, regardless of gender, age, race, BMI. However, the association of BMI with bilateral gonarthrosis was found to be strong in men and women, with unilateral, only in men.

M.S. Hochberg et al. (1995) investigated the relationship between the distribution of Alslavic acid, the percentage of subcutaneous fatty tissue in 465 men and 275 Caucasians who participated in the Baltimore Longitudinal Study for Aging, and also in 169 men and 99 women with X-ray diagnosed osteoarthrosis. The distribution of subcutaneous adipose tissue was determined by the ratio of the circumference of the wrist and hip, while the standard equation was used to calculate the percentage of subcutaneous adipose tissue, which included indicators such as folds below the angle of the scapula, abdomen, and in the region of the triceps of the shoulder. As expected, BMI had a strong connection with the presence of gonarthrosis of the streets of both sexes. However, the authors of the study did not find an association between radiographically diagnosed osteoarthrosis of the knee joints and the nature of the distribution of subcutaneous fatty tissue (central / peripheral), as well as the percentage of subcutaneous fatty tissue.

In studies of K. Martin and co-authors (1997), Davis MA and co-authors (1988), it was shown that in obesity, the occurrence of osteoarthritis of the knee joints is influenced by mechanical rather than metabolic factors.

With overweight, there is an increased risk of 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 persons are predisposed to bilateral, and not to unilateral osteoarthritis of the hip joints.

According to a prospective (for 23 years) observation with overweight, there is also a higher risk of osteoarthritis of the joints of the hands. In studies conducted in London with the participation of twins, an association of overweight with osteoarthrosis of the carpometacarpal joint of the first finger of the hand was also found..

The relationship of overweight and osteoarthritis can be explained by an increase in the load on the joints, which causes a mechanical “breakdown” of cartilage, which then leads to the development of osteoarthritis. However, this explanation is applicable only for osteoarthritis of the knee and hip joints, but not for osteoarthritis of the joints of the hands. It is also possible that in persons with obesity there is still an unknown factor that accelerates the “breakdown” of cartilage and contributes to the development of the disease. In addition, obese people show a higher BMD, which is also considered a risk factor for osteoarthritis.

In the Framingham study, patients were examined once every 2 years for 40 years, while it was established that an increase in body weight is a risk factor for manifest osteoarthritis of the knee joints in women, and a 5 kg weight reduction in women with a BMI of 25 (t. E. Above average), reduced the risk of osteoarthritis by 50%.

For women with a BMI below average, neither an increase nor a decrease in weight significantly influenced the risk of developing the disease. Consequently, obesity is an important risk factor for osteoarthritis of the knee, hip joints and hand joints, in these patients there is also a high risk of a progressive course of the disease. Weight loss can prevent disease, especially knee OA.

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

There is convincing evidence of the connection of occupational factors with the development of osteoarthritis, an excessive load on certain joints is associated with an increased risk of developing osteoarthrosis of these joints. Miners are at risk (osteoarthritis of the knee and lumbar spine), dockers and shipyards (osteoarthritis of the knee and wrist joints), cotton pickers and mill workers (osteoarthritis of individual wrist joints), pneumatic tools operators (osteoarthritis of the elbow and wrist joints), painters and concrete workers (osteoarthritis of the knee joints), farmers (osteoarthritis of the hip joints.

Professional sport (football, athletics, etc.) is associated with a high risk of osteoarthritis. In individuals engaged in physical culture unprofessional, the risk of osteoarthritis of the knee and hip joints does not differ from the total in the population.

A very important risk factor for osteoarthritis is joint injury / damage. Injury of the knee joint (especially the anterior cruciate ligament) is associated with a high risk of osteoarthritis of the knee joint among professional footballers.

MA Davis et al. (1989) in the NHAINS-I described above investigated the relationship between knee joint injury and uni / bilateral radiographically confirmed gonarthrosis. In 5.8% of surveyed individuals with bilateral gonarthrosis, in 15.8% of 37 people with right-sided gonarthrosis and in 1.5% of control subjects in the history there were indications of injury to the right knee joint, while information about the injury of the left knee in the history of the joint, 4.6% of people with bilateral lesions, 27% with left-sided gonarthrosis and 1.8% in the control group. Statistical analysis of the 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.S. Hochberg (1993) studied the relationship between hip injury and radiographically confirmed coxarthrosis in 2,359 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 joint injury and coxarthrosis (relative ratio (95% confidence intervals) —7.84 (2.11; 29.1). Analyzing the relationship between hip injury and uni / bilateral damage, 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 injury Go and knee joints are an important risk factor for coxarthrosis and gonarthrosis, especially unilateral.

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

In patients with osteoarthritis of the knee, weakness of the quadriceps muscle of the thigh is often found, which is usually associated with atrophy due to restriction of movement in the affected limb. However, the weakness of this muscle is also found in patients with non-manifest gonarthrosis, in whom there was no pain in the joint and at the time of examination and in the history, muscle mass not only did not decrease, and even sometimes was increased. Prospective studies suggest that the weakness of the quadriceps femoris is not only a consequence of manifest gonarthrosis, but may also be a risk factor for osteoarthritis. Among women without radiological signs of gonarthrosis at the beginning of observation and with X-ray diagnosed osteoarthrosis, after 30 months, the initial strength of the knee extensor was significantly less (p <0.04) than in those women who did not develop osteoarthritis.

C. Slemenda et al. (1997) determined that an increase in knee extensor strength for every 10 pounds / foot ^{2 is} associated with a decrease in the likelihood of developing osteoarthritis of the knee by 20%, and manifest osteoarthrosis by 29%. A relatively small increase in the extensor strength of the knee (approximately 20% of the average for men and 25% of the average for women) is associated with a decrease in the risk of gonarthrosis by 20 and 30%, respectively.

The role of the quadriceps muscle of the thigh in protecting the knee joint from damage is related to the joint-stabilizing function and also to the fact that it provides resistance to the gravity of the entire lower limb.

[1], [2], [3], [4], [5]