The etiology of OA is multifactorial and involves the complex interplay of both systemic and local factors (Fig. 18.1) [36].
Furthermore, these risk factors may present in varying
Table 18.4 ACR criteria for OA of the hand [11]
Clinical
1. Hand pain, aching, or stiffness for most days of prior month 2. Hard tissue enlargement of ³2 of 10 selected hand jointsa 3. MCP swelling in £2 joints
4. Hard tissue enlargement of ³2 DIP joints 5. Deformity of ³1 of 10 selected hand jointsa 1, 2, 3, 4 or 1, 2, 3, 5 required
a10 selected hand joints include bilateral second and third proximal interphalangeal (PIP), second and third distal interphalangeal (DIP), and first carpometacarpal (MCP) joints
Fig. 18.1 Risk factors for development of osteoarthritis (OA). Systemic factors, intrinsic and extrinsic factors acting on the joint contributing to osteoarthritis (OA) susceptibility and progression
177 18 Epidemiology, Risk Factors, and Aging of Osteoarthritis
degrees as they apply to different joints, at different stages of the disease, and more importantly affect the radiographic versus symptomatic features of the disease differently [37].
Non-modifiable Systemic Risk Factors
Age
Most epidemiologic studies agree that age is the strongest risk factor for the development of osteoarthritis [38]. Aside from the biomechanical and biochemical changes that occur in age-related OA, an attempt to explain objectively the mor- phologic alterations of the articular cartilage and subchon- dral bone using MRI of the knee joint showed that there was an increase in cartilage defect severity and prevalence, carti- lage thinning, and bone size with increasing age [29].
Gender and Hormones
Most population-based studies have demonstrated that women have a higher frequency of knee complaints along with higher prevalence of radiographic and symptomatic OA compared to males. This has been usually observed at around menopause where hormones begin to fluctuate and their protective effects on OA are assumed to cease. At a molecular level, several studies have demonstrated the pres- ence of estrogen receptors in bone [39], cartilage [40], liga- ments [41], synovium [42], and muscles [43] in humans.
The interrelationship between OA and estrogen has come from indirect evidence demonstrating that hormone replace- ment therapy lowered the frequency of radiographic OA of both the hip and the knee [44, 45]. Two cross-sectional studies utilizing MRI showed that estrogen replacement therapy was associated with significant reduction in subchondral bone lesions and increase in knee articular car- tilage volume compared to subjects who are not on replace- ment therapy during a 5-year period [46, 47]. Furthermore, animal studies using surgically induced ovarian insuffi- ciency have confirmed the negative effects of estrogen deficiency on cartilage homeostasis and subchondral bone turnover, leading to the development and progression of OA [48].
Geography/Race/Ethnicity
Three population-based studies done in USA have addressed prevalence patterns of OA among Caucasians, African- Americans, and MexicanAmericans. Earlier studies have
suggested that African-Americans have the same or even a lower prevalence of OA [49, 50]. However, recent large population-based studies have shown that African- Americans were more likely than Caucasians and Mexican- Americans to develop radiographic evidence of knee OA [26]. In the developing countries, OA still remains the most common arthritic disease compared to the Western societies [51]. For example, a study in Beijing, China, showed that older Chinese women have a higher prevalence of knee OA compared to women from the Framingham Osteoarthritis Study [52].
Genetic Factors
Hereditary influence in OA has been noted for more than three decades [53]. In an early twin study on women with OA, a genetic risk accounted for at least 50% of OA cases of the hands and hips, and only a modest proportion of that of the knees [54]. Genetic analysis of mutations in the ECM proteins and use of wide genome association studies (GWAS) of large OA populations have identified several genes that contribute to OA. These studies have yielded common synonymous mutations that confer risk factor for primary OA, genetic susceptibility to OA at different sites (Table 18.5) [55, 56]. For example, a variable tandem repeats polymor- phism in the aggrecan gene has been implicated in cartilage disorders, such that an allele with 27 such repeat confers pro- tection from OA, whereas larger or smaller numbers of allele repeats predispose to the disease [57]. Systematic, gene- wide linkage and gene-expression studies have highlighted several ECM proteins (collagen II, COMP, matrillin3, and asporin); cytokines involved in inflammation [COX-2, inter- leukin-1 (IL-1) gene cluster, interleukin-6 (IL-6), interleu- kin-10 (IL-10), and interleukin-4 receptor (IL-4R); protease and its inhibitors (ADAM12, TNA, and AACT); and growth factors (bone morphogenic factors and growth/differentia- tion factor-5 (GDF5))], and other pathways involved in chondrocyte and/or osteoblast differentiation or proteolytic activity [LRP5, secreted frizzled-related protein 3 (FRZB) involved in Wnt signaling; estrogen receptors1 (ESR1) and 2 (ESR2), iodothyroninedeiodinase enzyme type2 (DIO2), and other genes that are associated with OA prevalence (BMP2, antigen CD36, prostaglandin-endoperoxidase syn- thetase-2 (COX2), and NCOR2) or OA progression [carti- lage intermediate layer protein (CILP), osteoprotegerin (OPG), CLEC3B, ESR1, a disintegrin, and metalloprotei- nase domain-12 (ADAM12)], or both [55, 56]. Most of these encode proteins involved in signal transduction pathways that may provide new information on the pathogenesis of OA and its relationship to aging and response to tissue injury at each joint.
Table 18.5Genetic factors in osteoarthritis (OA) PathwaySymbolGene nameTraitPutative function Extracellular matrixCOL2A1Type II collagenKnee OAECM ProteinsCOMPCartilage oligomeric matrix proteinKnee OAECM MATN3Matrilin-3Hand OA, Spine OAECM MetalloproteaseADAM12A disintegrin and metalloproteinase domain-12Knee OAMetalloprotease involved in osteoclast formation and cell–cell fusion TNATetranectinKnee OAPlasminogenbinding protein mediates degradation of ECM ACCTAlpha-1 antiproteinase antitrypsinKnee OANatural inhibitor of serine in the degradation of cartilage proteoglycan BMPCILPCartilage intermediate layer proteinKnee OA, LDDInhibits TGF-b(beta)-mediated induction of cartilage matrix gene ASPAsporinHip/knee OAECM regulates TGFb(beta) BMP2Bone morphogenic protein-2Knee OAGrowth factor involved in chondrogenesis and osteogenesis BMP5Bone morphogenic protein-5Hip OAGrowth factor involved in chondrogenesis and osteogenesis GDF5Growth/differentiation factor-5Hip OAMember of BMP family, regulator of growth and differentiation BMP/WntOPGOsteoprogerinKnee OARegulation of osteoclastogenesis LRP5Low-density lipoprotein receptor-related protein-5Knee OAReceptor involved in Wnt signaling via the canonical beta-catenin pathways FRZBSecreted frizzled-related protein-3Hip/knee OA, GOAWnt antagonist and modulator of chondrocyte maturation Wnt; otherANP32AAcidic leucine-rich nuclear phosphoprotein-32 (pp32 or PHAPI)Knee OARegulator of apoptosis of Wnt signaling InflammationHLAHuman leukocyte antigensHand/hip/knee, GOAAntigen presentation and binding of HLA/antigen complex to the Tcell receptor determining specificity of immune response COX2 (PTGS2)ProstaglandinKnee/spine OACOX2 produced PGE2 modulates cartilage proteoglycan degradation in OA IL-1 geneInterleukin (IL-)1 alpha, IL-beta, and IL-1 receptor antagonistHip/knee OA, knee OARegulation of metalloproteinase gene expression in synovial cells and chondrocyte IL-4RInterleukin-4 receptorHip OAPutative role in chondrocyte response to mechanical signals IL-6Interleukin-6Hip/knee OAPro-inflammatory cytokine, involved in cartilage degradation and induction of ILRa IL-10Interleukin-10Hip/hand OAAnti-inflammatory cytokine inhibits the synthesis of IL-1 OthersOPGOsteoprotegerinKnee OARegulator of osteoclastogenesis VDR1Vitamin D receptorKnee OANuclear receptor, mediates effects of vitamin D whose serum levels affect incidence severity and progression of OA ESR1Estrogen receptorKnee OA, GOAIn chondrocytes, modulator of proteoglycan degradation and matrix metalloproteinase mRNA expression DIO2Iodothyronine-deiodinase enzyme type-2Hip OA, GOAThyroxin signaling: regulates intracellular levels of active thyroid hormones in target tissues CALM1Calmodulin-1Hip OAIntracellular protein, interacts with proteins involved in signal transduction TXCDC3Thioredoxin domain containing 3Knee OAProtein disulfide reductase participating in several cellular processes by way of redox-mediated reactions RHOBRas homolog gene family, member BHip/knee OAGTPase with tumor suppressor (antagonist of the PI3K/Akt pathway) LRCH1Leucine-rich repeats and calponin homolog (CH) domain containing 1Hip/knee OAUnknown ECM extracellular matrix, OA osteoarthritis, GOA generalized osteoarthritis, ILRa interleukin receptor antagonist, LDD lumbar disc disease, PGE2 prostaglandin-2
179 18 Epidemiology, Risk Factors, and Aging of Osteoarthritis
Congenital/Developmental Conditions
Developmental deformities such as Legg–Calve–Perthes disease and slipped capital femoral epiphysis, acetabular hip dysplasia, and the less common chondrodysplasias have been shown to contribute to early onset OA [58]. Legg–Calve–
Perthes disease and slipped capital femoral epiphysis have been associated with the development of hip OA later in life [59, 60]. Acetabular hip dysplasia, which is a more common but milder form of hip developmental abnormality, was associated with a threefold increased risk of incident hip OA in women [61], suggesting its importance as a risk factor in patients with early onset OA.
Modifiable Risk Factors
Obesity
As the prevalence of obesity worldwide rises, so does OA.
Studies have proven that being overweight antedates the development of the disease. In those diagnosed with OA, high Body Mass Index (BMI) increased the radiographic progression of OA [62, 63]. Obesity has been linked strongly to tibiofemoral OA of the knee, but not as strongly associated with either hip or patellofemoral joint OA [64]. Much debate has been presented as to whether the effects of obesity are due to its biomechanical effects as opposed to being part of a metabolic syndrome exerting its effects systemically [65].
Early studies have noted the role of adipose tissue as a poten- tial source of IL-6, a cytokine that can induce the production of C-reactive protein. Increase in serum C-reactive protein levels in turn is found to be a significant predictor of progres- sion of knee OA [66]. Most recent studies have indirectly correlated the effects of weight on OA by concluding that weight loss was strongly associated with a reduction in risk of development of radiographic knee OA, pain, and disabil- ity in patients with already-established knee OA [67, 68].
Bone Mineral Density
Evidence from more than a decade ago showed that there was a negative association between osteoporosis and OA.
Women with evidence of radiographic hip OA had an 8–12%
increase in BMD compared to women without OA [69]. This is also supported by another earlier study demonstrating that higher BMD was associated with women who have OA of the knee [70]. Interestingly, using the same population of the Framingham study, it was found that high BMD increases the risk for knee OA; it actually may have a protective effect against progression once the disease has already been
established. On the contrary, a decrease in the BMD on the same population of subjects with established OA of the knee was associated with an accelerated rate of disease progres- sion of OA [71]. However, an indirect measure of the above observations was not consistently observed by a recent study on the effects of risedronate therapy that showed a decrease in bone and cartilage biomarkers but with no improvement of knee OA symptoms and radiographic progression [72].
Nutrition
Metabolic effects of vitamin D on bone formation have been well established. Earlier studies have suggested that vitamin D receptors can be found in chondrocytes in OA cartilage and may possibly play a direct effect on vitamin D supple- mentation [73]. The Framingham study reported that the risk of progression increased threefold for persons in the middle and lower tertiles of both vitamin D intake and serum levels.
However, this study failed to show that radiographic incidence of OA was prevented by intake of supplemental vitamin D [74]. In a later longitudinal study on hip OA, low vitamin D levels were associated with new onset incident hip OA, as measured by joint space narrowing [75].
Crystal Arthropathies
In most patients with OA, calcium crystals are relatively common but often under-recognized risk factors in the development and progression of the disease [76]. These crystals are often found in advanced OA; however, calcium pyrophosphate dihydrate (CPPD) and apatite crystals (HA) can also be found in early OA stages. They can be mitogenic, stimulate the release of cytokines and chemokines, and activate metalloproteinases, contributing to the pathogenesis of OA [77]. Recent studies have implicated the role of innate immunity through the activation of inflammasome by these crystals, which leads to increase in the production of IL-1b(beta), a pivotal cytokine involved in the OA pathogen- esis and disease progression [78].
Local Extrinsic Risk Factors
Trauma and Physical Activity
Early studies have shown that moderate longdistance running and jogging did not seem to increase the risk of OA [79]. However, there is emerging evidence that elite athletes may be predisposed to OA in the later years [80]. Moreover, injuries such as transarticular fractures, meniscal tear requiring
miniscectomy, or an anterior cruciate ligament (ACL) tear are considered high risks for the eventual development of OA and chronic symptoms of musculoskeletal pain [81, 82].
In the Framingham study, where physical activities in the elderly population were characterized by leisure-time walking and gardening, subjects who engaged in relatively high levels of activity had a threefold increased risk of developing radiographic knee OA compared to sedentary subjects within 8 years of follow-up [83].
Occupational Demands
Repetitive use of a particular joint in specific work environ- ments is associated with an increased risk of OA with the involved joint. In the Framingham study, men whose job required carrying and kneeling or squatting in mid-life were twice at risk for developing knee OA in contrast to those whose jobs did not require this kind of physical work [84]. In specific work environments, there was a high prev- alence of hip OA among farmers [85] and a high prevalence of Heberden’s nodes in cotton mill workers [86], while building and construction work was associated with knee OA in men [87].
Local Intrinsic Risk Factors
Muscle Strength
It has always been long assumed that muscle atrophy or weakness of the quadriceps muscles is a result of disuse and avoidance of the muscles due to knee pain. However, this concept was recently challenged by Slemenda et al. [88];
their study showed that women who had asymptomatic radiographic knee OA had no muscle atrophy but instead had quadriceps muscle weakness, suggesting that weakness rather than atrophy is a risk factor for the development of symptomatic knee OA. Another longitudinal study confirmed that quadriceps muscle weakness was not only associated with painful knee OA but was also itself a risk factor for structural damage to the joint [89]. Muscle strength and its relationship with OA of the hand was addressed in the Framingham study where after adjusting for age, physical activity, and occupation, greater grip strength was associated with an increased risk of radiographic hand OA. Men whose maximal grip strength fell in the highest tertile had a three- fold increased risk of OA in the proximal interphalangeal, metacarpophalangeal, or thumb-base joints [90]. The authors suggest that maximal force exerted on specific joints might influence the development of OA on those joints.
Alignment
Alignment of the lower extremity joints is a major determi- nant of load distribution. Anything that alters the alignment of the leg affects the load distribution at the knee, leading to the development of OA and a higher subsequent risk of pro- gression [37, 91]. A prospective cohort showed that knees with varus alignment at baseline had a fourfold increase in the odds of medial progression of knee OA, while those with valgus alignment at baseline had a nearly fivefold increase in the odds of lateral progression. Progression of the disease was also found to be greater in knees with severe baseline radiographic findings using KL grading compared to those who had mild to moderate disease [91, 92].
However, incident knee OA is not well established in the presence of malalignment. The Rotterdam study found that among subjects whose knees were graded KL 0 and 1, those with valgus alignment had a 54% increased risk and those with varus alignment had a twofold increased risk for the development of radiographic knee OA compared to normal controls [93, 94]. On the contrary, a more comprehensive approach in the Framingham study using four measures of knee joint alignment, namely anatomic axis, condylar angle, tibial plateau, and condylar tibial plateau ankle, found no association with an increased risk of incident radiographic knee OA, suggesting that malalignment might not be a primary risk factor for the occurrence of radio- graphic knee OA but rather a marker of disease severity and/or its progression [94].
Other Biomechanical Factors: Knee Laxity, Leg Length Discrepancy, and Proprioception
Laxity or looseness of the knee, without any associated injury or disease, is considered a potential risk factor of knee OA.
One cross-sectional study suggested that increased laxity of the knee may precede development of the disease and may predispose the patient to developing the disease. They found that varus–valgus knee laxity was greater in nonarthritic knees of patients who have idiopathic disease compared to that in knees of control subjects [95].
Limb length inequality (LLI) and its association with OA development was addressed in subjects from the Johnston County Osteoarthritis Project. They found that those who had an LLI of at least 2 cm were almost twice as likely to develop radiographic knee OA, 40% of whom were more likely to develop knee symptoms, compared to persons with equal leg lengths [96]. The authors of the above study also evaluated symptoms of knee and hip pain in the same population of interest. Participants with LLI were more likely to develop knee and hip symptoms.
181 18 Epidemiology, Risk Factors, and Aging of Osteoarthritis
However, after adjusting for other factors, the LLI was moderately associated with knee symptoms and less strongly with hip symptoms. This study, however, implied that LLI might be a modifiable risk factor for therapy of people with knee and hip symptoms [97].
Proprioception is the conscious perception of body position, loading, and movement [98]. Proprioceptive deficits were found to be greater in people with knee OA compared with that in people of similar age without the deficit [99, 100]. A recent 30-month longitudinal follow-up study failed to demonstrate any associations between proprioceptive acuity and development or progression of symptomatic and radiographic OA [101].