Why is osteoarthritis an age-related disease?




Although older age is the greatest risk factor for osteoarthritis (OA), OA is not an inevitable consequence of growing old. Radiographic changes of OA, particularly osteophytes, are common in the aged population, but symptoms of joint pain may be independent of radiographic severity in many older adults. Ageing changes in the musculoskeletal system increase the propensity to OA but the joints affected and the severity of disease are most closely related to other OA risk factors such as joint injury, obesity, genetics and anatomical factors that affect joint mechanics. The ageing changes in joint tissues that contribute to the development of OA include cell senescence that results in development of the senescent secretory phenotype and ageing changes in the matrix including formation of advanced glycation end-products that affect the mechanical properties of joint tissues. An improved mechanistic understanding of joint ageing will likely reveal new therapeutic targets to slow or halt disease progression. The ability to slow progression of OA in older adults will have enormous public health implications given the ageing of our population and the increase in other OA risk factors such as obesity.


Osteoarthritis (OA) is a classic age-related disorder. It is often described as a chronic degenerative disease and thought by many to be an inevitable consequence of growing old. In OA, degradation and loss of the articular cartilage is a central feature that is sometimes attributed to wear and tear. However, unlike an automobile tire that wears thin over time, the tissues affected by OA contain living cells that respond to mechanical stimulation and function to maintain joint homeostasis. Rather than OA being a simple consequence of joint ageing and repeated wear and tear, the current conceptual framework for the relationship between ageing and OA is that ageing of the musculoskeletal system increases the susceptibility to OA but alone does not cause it. Changes outside the joint (including sarcopenia and reduced proprioception) and within the joint (including cell and matrix changes in joint tissues) contribute to the development of OA, when other OA risk factors are also present ( Fig. 1 ). The concept that ageing contributes to, but does not directly cause, OA is consistent with the multifactorial nature of OA and the knowledge that not all older adults develop OA and not all joints in the body are affected to the same degree. In this review, we discuss the relationship between ageing and the development of OA from both an epidemiological perspective and a biological perspective, with the goal of answering the question of why OA is an age-related disease.




Fig. 1


Relationship between musculoskeletal aging and the development of osteoarthritis. Changes that affect joint structure and function with aging increase the susceptibility to developing osteoarthritis but additional factors (OA factors) are usually also present which lead to the development of symptomatic OA. Reproduced with permission from Hazzard’s Geriatric Medicine and Gerontology, Sixth Edition, McGraw Hill Medical, 2009.


Epidemiology of OA relevant to ageing


OA is the most common joint disorder in the world and one of the most common sources of pain and disability in the elderly . While there remains considerable heterogeneity in defining OA among epidemiological studies, the evidence is conclusive that age remains the single greatest risk factor for the development of OA in susceptible joints. Radiographic changes, in particular, osteophytosis, are very common in the ageing population and, when used alone, may provide an overestimation of the true prevalence of symptomatic OA. Defining OA solely as joint pain occurring in an older adult without evidence for another form of arthritis is also inaccurate as there are many causes of non-articular pain, such as bursitis, that are common in older adults. In a study of 480 adults over the age of 65 years, who reported chronic knee pain, only about 50% had radiographic evidence of knee OA . A recent systematic review comparing the prevalence of knee pain and radiographic knee OA found considerable discordance between the two, adding further evidence to that already present that joint pain and severity of radiographic changes of OA do not correlate. However, Duncan et al. have shown through their work with the Knee Clinical Assessment Study cohort that, as the severity and persistence of knee pain increases, the degree of discordance between symptoms and radiography diminishes .


Due to the discrepancies between pain and radiographic evidence of OA, most current epidemiological studies define OA by a combination of clinical and radiographic criteria. The most-often used system for defining symptomatic OA is the American College of Rheumatology (ACR) OA criteria. The ACR OA criteria were developed to standardise the definition of hip, knee and hand OA and are comprised of joint symptoms, exclusion of inflammatory conditions and positive radiography . The Kellgren–Lawrence (K–L) system for radiographic grading of OA has been the standard for several decades and is based upon the presence and severity of certain defined radiographic features including osteophytosis, joint space narrowing, joint line sclerosis and subchondral cysts . These radiographic features are used to grade the severity of OA from 0 (normal joint) to 4 (complete joint space loss).




Joint-specific prevalence and incidence of OA in the elderly


Knee


The knee is commonly affected by OA and is thought to account for most of disability from OA. The Framingham Osteoarthritis Study evaluated the prevalence of knee osteoarthritis in 1420 subjects aged 60 and older . OA was defined as the presence of knee symptoms in a patient with ipsilateral (KL) grade 2 or greater radiographic changes. The prevalence of radiographic OA increased with each decade of life from 33% among those aged 60–70 to 43.7% among those over 80 years of age ( Fig. 2 ). The prevalence of symptomatic knee OA in all subjects was 9.5% and increased with age in women but not in men ( Fig. 3 ). The Johnson County Osteoarthritis Project is a population-based cohort of knee and hip OA based in a rural county in North Carolina . Over 3000 study participants were involved, with almost one-third being African-Americans. Radiographic knee OA (RKOA) was considered a KL score of 2 or greater and symptomatic OA was defined as knee symptoms in at least one knee with corresponding radiographic OA. The prevalence of RKOA rose from 26.2% in the 55- to 64-year range to nearly half of participants in the 75+ age group. The prevalence of symptomatic knee OA similarly increased from 16.3% to 32.8% between these groups .




Fig. 2


Relationship between age in years and the prevalence of radiographic knee OA. Data was extracted from the following studies: Johnston County , Framingham , NHANES (III) , and Zoetermeer .



Fig. 3


Relationship between age in years and the prevalence of symptomatic knee OA. Data was extracted from the following studies: Johnston County , Framingham , and NHANES(III) .


The National Health and Nutrition Examination Survey (NHANES) III reported the prevalence of RKOA in 2415 persons and symptomatic knee OA in 2394 persons over the age of 60 . Only single anterior–posterior (AP) non-weight-bearing images were obtained, therefore, RKOA was defined as osteophytosis and sclerosis. The prevalence of K-L grade II or greater RKOA in at least one knee was 37.4%. The prevalence of symptomatic RKOA was 12.1% . The Zoetermeer survey, a cohort of over 6500 participants, evaluated the prevalence of knee OA from a suburban area near The Hague . All participants over the age of 45 years received standing AP knee films. The prevalence of K-L 2+ knee OA (average of both knees) increased sequentially through each age group . The increase in prevalence was more prominent in women. No symptom survey was included. Prevalence figures from both the Netherlands and the US appear to be higher than that reported from Greece but lower than what was reported from the recent Japanese Research on Osteoarthritis Against Disability (ROAD) study .


The largest study to date on incident knee OA comes from the Fallon Community Health Plan, which is a heath maintenance organisation in the United States that provides services to some 130 000 members. Using the organisation’s database, the authors in this study were able to report a yearly incidence of symptomatic knee OA of >1% and >0.8% in women and men, respectively, over the age of 70 . The Framingham Study detected a comparable yearly incidence of symptomatic knee OA for both women and men .


Hip


Hip OA appears to be somewhat less common in the ageing population than knee OA, but is still quite prevalent. A recent systematic review of the prevalence of primary hip OA detected a clear trend towards increasing prevalence with age . The prevalence of primary radiographic hip OA increased from 0.7% in the 40–44 age group to 14% in the 85+ age group . Analysis of symptomatic hip OA from the Johnston County group published just after the systematic review by Dagenais et al., reported a higher prevalence of symptomatic hip OA in their population of 5.9% in the 45–54 age group increasing to 17% in the 75+ age group . Symptomatic hip OA appeared to be more common in African-Americans and women. The prevalence and incidence of hip OA in women over age 65 has now been well defined with the recent analysis from the Study of Osteoporotic Fractures cohort . Supine AP radiographs of the pelvis were obtained in 5839 women at baseline and (on average) at 8 years of follow-up. Eleven different definitions of hip OA were reported and the prevalence and incidence varied accordingly. Excluding minimum joint space of less than 2.5 mm as a definition, the prevalence ranged from 1.8% to 9.4% and the incidence from 3.6% to 8.9% .


Hand


The hand is the appendicular joint most commonly affected by OA in the ageing population and, although it often not as disabling as OA of the knee or hip, it can interfere with hand function. Estimates from the Zoetermeer survey found that radiographic involvement of the distal interphalangeal joint (DIP) affected more than half of the men over the age of 65 and more than half of the women over the age of 55 . Thirteen percent of the men and 26% of the women over the age of 70 were found to have symptomatic hand OA involving at least one joint in the Framingham study . Yearly incidence rates from the Fallon Community Health Plan for hand OA were 0.35% and 0.21% for men and women over the age of 60, respectively . The incidence rates for those younger than 60 were dramatically lower.


A less common form of hand OA that is found mainly in the older adult population is erosive OA. Erosive OA is characterised by central erosions in distal and/or proximal interphalangeal joints accompanied by other changes typical to OA such as joint space loss, osteophytosis and subchondral sclerosis . It is thought that calcium crystals, such as hydroxyapatite and calcium pyrophosphate, may play a role in erosive OA. Erosive OA is considered to be much more inflammatory than non-erosive OA, a finding confirmed by a recent ultrasound study .




Joint-specific prevalence and incidence of OA in the elderly


Knee


The knee is commonly affected by OA and is thought to account for most of disability from OA. The Framingham Osteoarthritis Study evaluated the prevalence of knee osteoarthritis in 1420 subjects aged 60 and older . OA was defined as the presence of knee symptoms in a patient with ipsilateral (KL) grade 2 or greater radiographic changes. The prevalence of radiographic OA increased with each decade of life from 33% among those aged 60–70 to 43.7% among those over 80 years of age ( Fig. 2 ). The prevalence of symptomatic knee OA in all subjects was 9.5% and increased with age in women but not in men ( Fig. 3 ). The Johnson County Osteoarthritis Project is a population-based cohort of knee and hip OA based in a rural county in North Carolina . Over 3000 study participants were involved, with almost one-third being African-Americans. Radiographic knee OA (RKOA) was considered a KL score of 2 or greater and symptomatic OA was defined as knee symptoms in at least one knee with corresponding radiographic OA. The prevalence of RKOA rose from 26.2% in the 55- to 64-year range to nearly half of participants in the 75+ age group. The prevalence of symptomatic knee OA similarly increased from 16.3% to 32.8% between these groups .




Fig. 2


Relationship between age in years and the prevalence of radiographic knee OA. Data was extracted from the following studies: Johnston County , Framingham , NHANES (III) , and Zoetermeer .



Fig. 3


Relationship between age in years and the prevalence of symptomatic knee OA. Data was extracted from the following studies: Johnston County , Framingham , and NHANES(III) .


The National Health and Nutrition Examination Survey (NHANES) III reported the prevalence of RKOA in 2415 persons and symptomatic knee OA in 2394 persons over the age of 60 . Only single anterior–posterior (AP) non-weight-bearing images were obtained, therefore, RKOA was defined as osteophytosis and sclerosis. The prevalence of K-L grade II or greater RKOA in at least one knee was 37.4%. The prevalence of symptomatic RKOA was 12.1% . The Zoetermeer survey, a cohort of over 6500 participants, evaluated the prevalence of knee OA from a suburban area near The Hague . All participants over the age of 45 years received standing AP knee films. The prevalence of K-L 2+ knee OA (average of both knees) increased sequentially through each age group . The increase in prevalence was more prominent in women. No symptom survey was included. Prevalence figures from both the Netherlands and the US appear to be higher than that reported from Greece but lower than what was reported from the recent Japanese Research on Osteoarthritis Against Disability (ROAD) study .


The largest study to date on incident knee OA comes from the Fallon Community Health Plan, which is a heath maintenance organisation in the United States that provides services to some 130 000 members. Using the organisation’s database, the authors in this study were able to report a yearly incidence of symptomatic knee OA of >1% and >0.8% in women and men, respectively, over the age of 70 . The Framingham Study detected a comparable yearly incidence of symptomatic knee OA for both women and men .


Hip


Hip OA appears to be somewhat less common in the ageing population than knee OA, but is still quite prevalent. A recent systematic review of the prevalence of primary hip OA detected a clear trend towards increasing prevalence with age . The prevalence of primary radiographic hip OA increased from 0.7% in the 40–44 age group to 14% in the 85+ age group . Analysis of symptomatic hip OA from the Johnston County group published just after the systematic review by Dagenais et al., reported a higher prevalence of symptomatic hip OA in their population of 5.9% in the 45–54 age group increasing to 17% in the 75+ age group . Symptomatic hip OA appeared to be more common in African-Americans and women. The prevalence and incidence of hip OA in women over age 65 has now been well defined with the recent analysis from the Study of Osteoporotic Fractures cohort . Supine AP radiographs of the pelvis were obtained in 5839 women at baseline and (on average) at 8 years of follow-up. Eleven different definitions of hip OA were reported and the prevalence and incidence varied accordingly. Excluding minimum joint space of less than 2.5 mm as a definition, the prevalence ranged from 1.8% to 9.4% and the incidence from 3.6% to 8.9% .


Hand


The hand is the appendicular joint most commonly affected by OA in the ageing population and, although it often not as disabling as OA of the knee or hip, it can interfere with hand function. Estimates from the Zoetermeer survey found that radiographic involvement of the distal interphalangeal joint (DIP) affected more than half of the men over the age of 65 and more than half of the women over the age of 55 . Thirteen percent of the men and 26% of the women over the age of 70 were found to have symptomatic hand OA involving at least one joint in the Framingham study . Yearly incidence rates from the Fallon Community Health Plan for hand OA were 0.35% and 0.21% for men and women over the age of 60, respectively . The incidence rates for those younger than 60 were dramatically lower.


A less common form of hand OA that is found mainly in the older adult population is erosive OA. Erosive OA is characterised by central erosions in distal and/or proximal interphalangeal joints accompanied by other changes typical to OA such as joint space loss, osteophytosis and subchondral sclerosis . It is thought that calcium crystals, such as hydroxyapatite and calcium pyrophosphate, may play a role in erosive OA. Erosive OA is considered to be much more inflammatory than non-erosive OA, a finding confirmed by a recent ultrasound study .




Risk factors for development of OA in the elderly


The common risk factors for OA such as obesity, joint injury, genetics and anatomical abnormalities are important in the elderly just as they are in younger adult populations. There is some evidence to suggest that after an acute joint injury, such as an anterior cruciate ligament tear, that older adults will develop OA faster than younger adults . Some factors contributing to the development of OA, including degenerative changes in the meniscus and joint ligaments, increased bone turnover as well as calcification of joint tissues appear to be more common in older adult populations. These contributing factors will be discussed further.


Meniscal damage is increasingly being appreciated as a major risk factor for the development of OA. Results from the Multicenter Osteoarthritis Study (MOST) showed an odds ratio of 7.4 for the development of RKOA, after 30 months, in symptomatic subjects with significant meniscal damage . Englund et al., also recently reported that incidental meniscal damage, seen on magnetic resonance imaging (MRI), is quite common in the elderly . In subjects ranging from 50 to 90 years of age, the prevalence of meniscal tears was lowest (19%) in women aged 50–59 and was highest (56%) in men in the 70–90 age group. The prevalence increased to 63% in symptomatic subjects with KL >2 RKOA . These studies suggest that age-related changes in the meniscus may contribute to meniscal degeneration that in turn may contribute to the development and progression of knee OA.


Anterior cruciate ligament (ACL) injury is also known to be a risk factor for the development of knee OA and is a common cause of post-traumatic OA developing in young adults as a result of sports injuries. The prevalence of acute ACL injury in the elderly is not well known and although the incidence is reported to be low, the latter likely represents a bias towards reporting athletic injuries . A recent magnetic resonance imaging (MRI) study in people without a known history of an acute injury found that ACL disruption associated with OA might be more common than appreciated . The changes that occur in ageing ligaments are not entirely known, though increasing stiffness from collagen cross-linking combined with decreasing fibril diameter may increase the risk for ACL tears . Studies are needed to determine if ageing changes in joint ligaments are important contributors to the development of OA in older adults.


Bone is clearly involved in the development of OA, although the mechanism by which changes in bone influence the development or progression of OA is not clear . An increase in either bone turnover or regional bone remodelling may be a factor in OA progression and these processes are potentially affected by ageing. Bone marrow lesions detected by MRI may represent areas of localised abnormal bone remodeling . These lesions are associated with knee pain, limb malalignment and meniscal derangement, and may predict OA progression . Recently, increasing age has been shown to be a risk factor for the development of bone marrow lesions in asymptomatic individuals . This is another area where future research may help elucidate how ageing changes in a tissue other than cartilage contributes to the risk of OA progression in older adults.


Calcification and crystal formation within joint tissues, most notably the cartilage and menisci, are known to increase with age. Calcium pyrophosphate’s association with the presence of radiographic osteoarthritis has been well established . Although it is known that the prevalence of chondrocalcinosis increases with age as does OA, the role of calcium crystals in the progression of OA is less clear . Some investigators believe that they are common but separate age-related conditions and others believe that the two are closely connected . Since OA and calcium pyrophosphate are equally associated with osteophyte formation, it has been suggested that mechanical stress may induce release of chemokines which encourage both proliferative bone changes and calcium pyrophosphate formation . Further work is ongoing to determine additional mechanisms by which calcium crystals contribute to the development and potential progression of OA. In the next section, we discuss how ageing at the biological level may contribute to the development of OA.




Cell and tissue ageing and the development of OA


Most of the conditions associated with ageing, OA included, result from an age-related loss in the ability of cells and tissues in the body to maintain homeostasis, particularly when placed under stress . In OA, excessive or abnormal mechanical stresses clearly play a key role in the development of the disease . Under conditions where an anatomically normal joint is stressed, the joint tissues appear to be capable of adapting to stress without resulting in OA. As an example of successful adaptation, the chronic repetitive loads endured by long-distance runners do not appear to result in OA later in life . However, joint stress resulting from abnormal load distribution or abnormal joint anatomy clearly contributes to OA. In the knee, a varus alignment is strongly associated with the development of medial compartment disease while valgus alignment predisposes to lateral compartment disease . Malalignment appears to be particularly important in individuals who are also overweight or obese .


Because OA is rare in young adults and even serious joint injuries usually do not manifest as OA until years later , it appears that young joint tissues can compensate, to some degree, to abnormal mechanical stress. However, with ageing, the ability to compensate to stress declines. As noted above, older adults who experience a joint injury develop OA much more rapidly than younger adults with a similar injury . Similarly, older adults, who develop inflammatory arthritis, such as rheumatoid arthritis, exhibit more rapid joint destruction relative to younger adults . If the basic cellular mechanisms that maintain tissue homeostasis decline with ageing, then the response to stress or joint injury will not be adequate and joint tissue destruction and loss will be the result.


There is mounting evidence that the changes that occur in the articular cartilage during the development of OA are the result of a loss in normal homeostasis. The chondrocyte is the one cell type present in articular cartilage and, therefore, is responsible for both the synthesis and the breakdown of the cartilaginous extracellular matrix . Signals generated by cytokines, growth factors and the matrix regulate chondrocyte metabolic activity. In OA cartilage, it appears that the inflammatory and catabolic signals are in excess of the anti-inflammatory and anabolic signals. This signalling imbalance promotes increased production of matrix-degrading enzymes by the chondrocyte, including matrix metalloproteinases (MMPs), aggrecanases and other proteases that degrade the cartilage matrix. Ageing changes that occur in the chondrocyte appear to contribute to the loss in homeostasis, and are discussed next.




Chondrocyte senescence


Chondrocytes are very unique cells that may be particularly prone to the development of ageing-related changes. The chondrocytes present in the cartilage of an 80-year-old are likely to be the very same cells that were present at age 25 years. There is little to no cell division or cell death in normal adult articular cartilage , and there does not appear to be a ready supply of progenitor cells to replace chondrocytes if they do die. Although recent studies have challenged the notion that cartilage does not contain progenitor cells, these studies were performed with either bovine tissue from very young animals or OA tissue that latter of which can include cells from the synovium and bone marrow.


Adult articular chondrocytes are capable of cell division. When chondrocytes are removed from the joint and placed in tissue culture, they do divide, and after multiple passages will exhibit telomere shortening . Proliferation of chondrocytes is a common feature of OA where clusters of chondrocyte clones can be seen in the regions of cartilage where matrix loss has occurred . However, without disease, ageing itself is not associated with chondrocyte proliferation, but rather with a loss in the normal mitogenic response of isolated chondrocytes to growth factor stimulation .


The fact that with normal ageing chondrocytes rarely divide suggests that classic replicative senescence, which requires over 30 to 40 population doublings , would not be the form of senescence affecting chondrocytes. Replicative senescence or intrinsic senescence is thought to be related to shortened telomeres accompanied by telomere dysfunction . Evidence of telomere shortening in chondrocytes from older adults has been reported . However, extrinsic or stress-induced senescence that occurs from diverse stimuli including oxidative damage, activated oncogenes and inflammation can also damage telomeres and is a much more likely mechanism for senescence in cartilage .


Besides limiting cell replication, changes that occur in ageing cells can result in the senescent secretory phenotype . This phenotype is characterised by the increased production of cytokines, including IL-6 and IL-1, MMPs and growth factors such as epidermal growth factor (EGF). The accumulation of cells expressing the senescent secretory phenotype can contribute to tissue ageing . The senescent secretory phenotype has some features in common with the OA chondrocyte phenotype, including increased production of cytokines and MMPs, suggesting an important role for chondrocyte senescence in the development of OA ( Table 1 ).


Nov 11, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Why is osteoarthritis an age-related disease?
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