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Epidemiology of Osteoarthritis

Published:November 12, 2012DOI:https://doi.org/10.1016/j.rdc.2012.10.004

      Keywords

      Key points

      • Osteoarthritis (OA) is the most common form of arthritis, with OA of the knee, hand, or hip having a similar prevalence of approximately 20% to 30% of adults in various populations.
      • Person-level factors associated with OA include increasing age, female sex, overweight/obesity, and race/ethnicity, which may represent genetic or sociocultural influences.
      • Joint-level factors associated with OA are reflective of mechanisms related to abnormal loading of the joints.
      • Several methodologic challenges to the study of OA exist, which have affected our ability to identify important relationships.
      • There is a need for ongoing epidemiologic and intervention studies regarding the prevention of incident and progressive OA and related pain.

      Introduction

      Osteoarthritis (OA) is the most common form of arthritis,
      • Lawrence R.C.
      • Felson D.T.
      • Helmick C.G.
      • et al.
      Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II.
      and one of the most common diagnoses in general practice.
      • Hsiao C.J.
      • Cherry D.K.
      • Beatty P.C.
      • et al.
      National ambulatory medical care survey: 2007 summary.
      Given its predilection for lower extremity joints such as the knee and hip, OA is the leading cause of lower extremity disability among older adults.
      • Guccione A.A.
      • Felson D.T.
      • Anderson J.J.
      • et al.
      The effects of specific medical conditions on the functional limitations of elders in the Framingham Study.

      Defining osteoarthritis

      OA is frequently defined by radiography, with the most commonly used radiographic grading system being the Kellgren and Lawrence (KL) grade, which scores OA severity on a scale of 0 to 4; definite radiographic OA is KL grade 2 or greater.
      • Kellgren J.H.
      • Lawrence J.S.
      Atlas of standard radiographs.
      The KL grading system has been used for the hand, hip, and knee; however, at the knee it is only used to define tibiofemoral OA. Patellofemoral radiographic OA can also be assessed if appropriate radiographic views are obtained. The Osteoarthritis Research Society International Atlas provides a means to score individual radiographic features, such as osteophytes and joint-space narrowing, in a semi-quantitative manner,
      • Altman R.D.
      • Hochberg M.
      • Murphy Jr., W.A.
      • et al.
      Atlas of individual radiographic features in osteoarthritis.
      and other methods are available to quantify joint-space width on radiographs.
      • Buckland-Wright J.C.
      • Macfarlane D.G.
      • Lynch J.A.
      • et al.
      Joint space width measures cartilage thickness in osteoarthritis of the knee: high resolution plain film and double contrast macroradiographic investigation.
      Numerous joint structures that are not otherwise visualized on radiographs can be examined by magnetic resonance imaging (MRI). An MRI definition of OA has been proposed, but requires validation.
      • Hunter D.J.
      • Arden N.
      • Conaghan P.G.
      • et al.
      Definition of osteoarthritis on MRI: results of a Delphi exercise.
      However, individual structural lesions on MRI are well described, including cartilage lesions, osteophytes, bone marrow lesions, synovitis, effusion, and subchondral bone attrition.
      • Hunter D.J.
      • Guermazi A.
      • Lo G.H.
      • et al.
      Evolution of semi-quantitative whole joint assessment of knee OA: MOAKS (MRI Osteoarthritis Knee Score).
      • Peterfy C.G.
      • Guermazi A.
      • Zaim S.
      • et al.
      Whole-Organ Magnetic Resonance Imaging Score (WORMS) of the knee in osteoarthritis.
      Of knees without radiographic evidence of tibiofemoral OA (KL 0) in adults 50 years or older, the enhanced sensitivity of MRI revealed that 89% had at least 1 such abnormality in the tibiofemoral joint, with similar prevalences in painful and painless knees.
      • Guermazi A.
      • Niu J.
      • Hayashi D.
      • et al.
      Prevalence of abnormalities in knees detected by MRI in adults without knee osteoarthritis: population based observational study (Framingham Osteoarthritis Study).
      Symptomatic OA indicates the presence of radiographic OA in combination with knee symptoms attributable to OA. Not all individuals with radiographic OA have concomitant symptoms. OA may be described in a joint-specific manner (eg, knee OA, hip OA), or, when several joint areas are involved, it may be considered as being generalized (eg, involvement with OA of at least 1 of each joint area: knee, hip, and hand), although a standard definition for generalized OA does not yet exist.

      Incidence and prevalence of OA

      One estimate of the lifetime risk of developing symptomatic knee OA was approximately 40% in men and 47% in women, with higher risks among those who are obese.
      • Murphy L.
      • Schwartz T.A.
      • Helmick C.G.
      • et al.
      Lifetime risk of symptomatic knee osteoarthritis.
      Age- and sex-standardized incident rates for symptomatic hand, hip, and knee OA have been estimated to be 100, 88, and 240 cases per 100,000 person-years, respectively, with incidence rates rising sharply after age 50 and leveling off after age 70 years (Fig. 1).
      • Oliveria S.A.
      • Felson D.T.
      • Reed J.I.
      • et al.
      Incidence of symptomatic hand, hip, and knee osteoarthritis among patients in a health maintenance organization.
      However, the interpretation of the leveling off or decline in OA incidence at older ages should be made with caution, given the potential biases related to competing risks and depletion of susceptibles (see later discussion on methodologic challenges).
      • Neogi T.
      • Zhang Y.
      Osteoarthritis prevention.
      Recent estimates of incidence of hand OA derived from the Framingham Osteoarthritis Study were approximately 34% to 35% for OA incidence in any hand joint for both sexes, with incidence of symptomatic hand OA being 4% for men and 9.7% for women over a 9-year period.
      • Haugen I.K.
      • Englund M.
      • Aliabadi P.
      • et al.
      Prevalence, incidence and progression of hand osteoarthritis in the general population: the Framingham Osteoarthritis Study.
      Figure thumbnail gr1
      Fig. 1Incidence of osteoarthritis of hand, hip, and knee in a community health plan, 1991 to 1992, by age and sex.
      (Data from Oliveria SA, Felson DT, Reed JI, et al. Incidence of symptomatic hand, hip, and knee osteoarthritis among patients in a health maintenance organization. Arthritis Rheum 1995;38:1134–41.)
      There has been an increase in OA prevalence, with an estimated 27 million United States adults in 2005 having clinical OA of their hand, knee, or hip joint, an increase from 21 million in 1995.
      • Lawrence R.C.
      • Felson D.T.
      • Helmick C.G.
      • et al.
      Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II.
      Such increases are likely due to aging of the population and the rising prevalence of obesity. In Framingham, the age-standardized prevalence of radiographic hand OA was 44.2% in women and 37.7% in men,
      • Haugen I.K.
      • Englund M.
      • Aliabadi P.
      • et al.
      Prevalence, incidence and progression of hand osteoarthritis in the general population: the Framingham Osteoarthritis Study.
      and 19% had knee OA among adults aged 45 years and older.
      • Felson D.T.
      • Naimark A.
      • Anderson J.
      • et al.
      The prevalence of knee osteoarthritis in the elderly. The Framingham Osteoarthritis Study.
      From the Johnston County Osteoarthritis Project, approximately 28% of African Americans and Caucasians aged 45 or older had knee OA and 28% had hip OA.
      • Jordan J.M.
      • Helmick C.G.
      • Renner J.B.
      • et al.
      Prevalence of knee symptoms and radiographic and symptomatic knee osteoarthritis in African Americans and Caucasians: the Johnston County Osteoarthritis Project.
      • Jordan J.M.
      • Helmick C.G.
      • Renner J.B.
      • et al.
      Prevalence of hip symptoms and radiographic and symptomatic hip osteoarthritis in African Americans and Caucasians: the Johnston County Osteoarthritis Project.
      This latter estimate is higher than the 7% prevalence noted in the Study of Osteoporotic Fractures among Caucasian women older than 65 years.
      • Nevitt M.C.
      • Lane N.E.
      • Scott J.C.
      • et al.
      Radiographic osteoarthritis of the hip and bone mineral density. The Study of Osteoporotic Fractures Research Group.
      Symptomatic prevalence estimates for OA are lower because it requires the presence of radiographic OA with pain, aching, or stiffness in the joint. The age-standardized prevalence of symptomatic hand OA was 14.4% and 6.9% in women and men, respectively, in younger Framingham cohorts,
      • Haugen I.K.
      • Englund M.
      • Aliabadi P.
      • et al.
      Prevalence, incidence and progression of hand osteoarthritis in the general population: the Framingham Osteoarthritis Study.
      which increased to 26.2% and 13.4%, respectively, among those aged 71 and older in an older Framingham cohort.
      • Zhang Y.
      • Niu J.
      • Kelly-Hayes M.
      • et al.
      Prevalence of symptomatic hand osteoarthritis and its impact on functional status among the elderly: the Framingham Study.
      The prevalence of symptomatic knee OA among adults 45 years and older was approximately 7% in Framingham,
      • Felson D.T.
      • Naimark A.
      • Anderson J.
      • et al.
      The prevalence of knee osteoarthritis in the elderly. The Framingham Osteoarthritis Study.
      whereas in the Johnston County OA Project it was approximately 17%.
      • Jordan J.M.
      • Helmick C.G.
      • Renner J.B.
      • et al.
      Prevalence of knee symptoms and radiographic and symptomatic knee osteoarthritis in African Americans and Caucasians: the Johnston County Osteoarthritis Project.
      Symptomatic hip OA was present in approximately 10% of the Johnston County cohort.
      • Jordan J.M.
      • Helmick C.G.
      • Renner J.B.
      • et al.
      Prevalence of hip symptoms and radiographic and symptomatic hip osteoarthritis in African Americans and Caucasians: the Johnston County Osteoarthritis Project.
      There has also been an increase in prevalence of symptomatic knee OA over the past 20 years by 4.1% and 6% among women and men, respectively, in the Framingham cohort.
      • Nguyen U.S.
      • Zhang Y.
      • Zhu Y.
      • et al.
      Increasing prevalence of knee pain and symptomatic knee osteoarthritis: survey and cohort data.
      Racial/ethnic differences in the prevalence of OA and specific patterns of joint involvement have been noted. In the Johnston County OA Project, African American men had a higher prevalence of radiographic hip OA than Caucasian men (32.2% vs 23.8%), whereas there was no difference between African American and Caucasian women (40.3% vs 39.4%).
      • Jordan J.M.
      • Helmick C.G.
      • Renner J.B.
      • et al.
      Prevalence of hip symptoms and radiographic and symptomatic hip osteoarthritis in African Americans and Caucasians: the Johnston County Osteoarthritis Project.
      Individual radiographic features at the hip and knee were also noted to differ between the two groups.
      • Braga L.
      • Renner J.B.
      • Schwartz T.A.
      • et al.
      Differences in radiographic features of knee osteoarthritis in African-Americans and Caucasians: the Johnston county osteoarthritis project.
      • Nelson A.E.
      • Braga L.
      • Renner J.B.
      • et al.
      Characterization of individual radiographic features of hip osteoarthritis in African American and White women and men: the Johnston County Osteoarthritis Project.
      In the Beijing Osteoarthritis Study, hand and hip OA were less prevalent among Chinese than Caucasians (age-standardized prevalences 44.5%–47% vs 75.2%–85% and 0.8% vs 3.8–4.5%, respectively), but knee OA was more prevalent among Chinese women than among Caucasian women (46.6% vs 34.8%).
      • Nevitt M.C.
      • Xu L.
      • Zhang Y.
      • et al.
      Very low prevalence of hip osteoarthritis among Chinese elderly in Beijing, China, compared with whites in the United States: the Beijing osteoarthritis study.
      • Zhang Y.
      • Xu L.
      • Nevitt M.C.
      • et al.
      Comparison of the prevalence of knee osteoarthritis between the elderly Chinese population in Beijing and whites in the United States: the Beijing Osteoarthritis Study.
      • Zhang Y.
      • Xu L.
      • Nevitt M.C.
      • et al.
      Lower prevalence of hand osteoarthritis among Chinese subjects in Beijing compared with white subjects in the United States: the Beijing Osteoarthritis Study.
      A higher prevalence of lateral tibiofemoral knee OA was also noted in Beijing Chinese in comparison with Framingham Caucasian subjects.
      • Felson D.T.
      • Nevitt M.C.
      • Zhang Y.
      • et al.
      High prevalence of lateral knee osteoarthritis in Beijing Chinese compared with Framingham Caucasian subjects.

      Risk factors for radiographic OA

      OA can be thought of as the phenotypic manifestation of a series of different pathways leading to a common end-stage pathology (Fig. 2). As such, the disease has a multifactorial etiology, with different sets of risk factors (at a person and/or joint level) acting together to cause onset of OA in any given individual. Person-level factors are generally those that are thought to act at a systemic level on all relevant joints or are a characteristic of the individual, whereas joint-level factors generally refer to those that are joint specific and may be unique to a particular joint.
      Figure thumbnail gr2
      Fig. 2Potential risk factors for susceptibility to incidence and progression of osteoarthritis (OA), each with varying degrees of evidence to support their association (see text for details). LLI, leg-length inequality.

      Person-Level Risk Factors

      Age and sex

      Age is one of the strongest risk factors for OA.
      • Lawrence R.C.
      • Felson D.T.
      • Helmick C.G.
      • et al.
      Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II.
      The exact mechanism is not known, but is likely related to a combination of changes in the capacity for joint tissues to adapt to biomechanical insults, and age being a proxy for the accumulation of a sufficient set of risk factors over the years.
      Female sex is associated with higher prevalence and greater severity of OA.
      • Srikanth V.K.
      • Fryer J.L.
      • Zhai G.
      • et al.
      A meta-analysis of sex differences prevalence, incidence and severity of osteoarthritis.
      The increase in prevalence and incidence of OA at the time of the menopause has led to hypotheses regarding the role of estrogen in OA, such as the loss of estrogen potentially unmasking the symptoms of OA by enhancing pain sensitivity. However, results from observational studies and clinical trials have been conflicting regarding estrogen effects on OA.
      • Hanna F.S.
      • Wluka A.E.
      • Bell R.J.
      • et al.
      Osteoarthritis and the postmenopausal woman: epidemiological, magnetic resonance imaging, and radiological findings.
      • Nevitt M.C.
      • Felson D.T.
      • Williams E.N.
      • et al.
      The effect of estrogen plus progestin on knee symptoms and related disability in postmenopausal women: the Heart and Estrogen/Progestin Replacement Study, a randomized, double-blind, placebo-controlled trial.
      • Cirillo D.J.
      • Wallace R.B.
      • Wu L.
      • et al.
      Effect of hormone therapy on risk of hip and knee joint replacement in the Women's Health Initiative.
      In the Heart and Estrogen/Progestin Replacement Study, there was no difference in knee pain in those randomized to receive estrogen replacement therapy compared with those receiving placebo.
      • Nevitt M.C.
      • Felson D.T.
      • Williams E.N.
      • et al.
      The effect of estrogen plus progestin on knee symptoms and related disability in postmenopausal women: the Heart and Estrogen/Progestin Replacement Study, a randomized, double-blind, placebo-controlled trial.
      On the other hand, in the Women’s Health Initiative, unopposed estrogen therapy was associated with a borderline significant lower rate of joint arthroplasty, but no such association was noted for estrogen plus progestin in comparison with placebo.
      • Cirillo D.J.
      • Wallace R.B.
      • Wu L.
      • et al.
      Effect of hormone therapy on risk of hip and knee joint replacement in the Women's Health Initiative.
      A review of sex differences in MRI features of OA and biomarkers of joint metabolism noted variable findings.
      • Maleki-Fischbach M.
      • Jordan J.M.
      New developments in osteoarthritis. Sex differences in magnetic resonance imaging-based biomarkers and in those of joint metabolism.
      Women may have thinner and more reduced volume of knee cartilage than men (even after taking into account differences in height, weight, and bone size); whether women have a more accelerated rate of loss of cartilage volume than men is not clear.

      Obesity

      Obesity has long been identified as a risk factor for knee OA.
      • Felson D.T.
      • Anderson J.J.
      • Naimark A.
      • et al.
      Obesity and knee osteoarthritis. The Framingham Study.
      In a meta-analysis, those who were obese or overweight had 2.96-times higher risk of incident knee OA compared with those of normal weight (95% confidence interval [CI] 2.56–3.43).
      • Blagojevic M.
      • Jinks C.
      • Jeffery A.
      • et al.
      Risk factors for onset of osteoarthritis of the knee in older adults: a systematic review and meta-analysis.
      Assuming the prevalence of obesity in a hypothetical population to be 25%, the population-attributable risk percentage due to obesity would therefore be 29% (95% CI 24%–34%); this would be higher where obesity prevalence is higher.
      • Zhang W.
      Risk factors of knee osteoarthritis—excellent evidence but little has been done.
      Furthermore, those who were only overweight (not obese) had more than twice the chance of developing knee OA compared with their normal-weight counterparts.
      • Blagojevic M.
      • Jinks C.
      • Jeffery A.
      • et al.
      Risk factors for onset of osteoarthritis of the knee in older adults: a systematic review and meta-analysis.
      Risk of incident knee OA increases with increasing body mass index (BMI; weight in kilograms divided by height in meters squared, ie, kg/m2), regardless of knee alignment.
      • Niu J.
      • Zhang Y.Q.
      • Torner J.
      • et al.
      Is obesity a risk factor for progressive radiographic knee osteoarthritis?.
      Decreasing BMI by 2 units or more over 10 years (∼5 kg) was associated with a 50% lower risk of developing symptomatic knee OA among women,
      • Felson D.T.
      • Zhang Y.
      • Anthony J.M.
      • et al.
      Weight loss reduces the risk for symptomatic knee osteoarthritis in women. The Framingham Study.
      findings supported by a recent meta-analysis.
      • Christensen R.
      • Bartels E.M.
      • Astrup A.
      • et al.
      Effect of weight reduction in obese patients diagnosed with knee osteoarthritis: a systematic review and meta-analysis.
      Duration of exposure to high BMI during adulthood confers risk of incident knee OA, suggesting the importance of weight control throughout life as a means of primary prevention of knee OA.
      • Wills A.K.
      • Black S.
      • Cooper R.
      • et al.
      Life course body mass index and risk of knee osteoarthritis at the age of 53 years: evidence from the 1946 British birth cohort study.
      Obesity also contributes to symptoms in knee OA, with the Arthritis, Diet, and Activity Promotion Trial (ADAPT) and Intensive Diet and Exercise for Arthritis (IDEA) trial both demonstrating improvements in pain accompanying weight loss related to dietary and exercise interventions.
      • Messier S.P.
      • Loeser R.F.
      • Miller G.D.
      • et al.
      Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis: the Arthritis, Diet, and Activity Promotion Trial.
      • Messier S.P.
      • Nicklas B.J.
      • Legault C.
      • et al.
      The Intensive Diet and Exercise for Arthritis Trial: 18-month clinical outcomes.
      In contrast to data supporting the role of obesity in the development of knee OA, high BMI was not associated with progressive radiographic knee OA in one study.
      • Niu J.
      • Zhang Y.Q.
      • Torner J.
      • et al.
      Is obesity a risk factor for progressive radiographic knee osteoarthritis?.
      However, using the same data, Zhang and colleagues
      • Zhang Y.
      • Niu J.
      • Felson D.T.
      • et al.
      Methodologic challenges in studying risk factors for progression of knee osteoarthritis.
      demonstrated that high BMI increased the risk of both mild radiographic OA (KL = 2) and moderate to severe radiographic OA (KL = 3 or 4) among knees that were KL = 0 at baseline, respectively. Because knees that develop KL = 3 or 4 over time must have gone through the KL = 2 stage, this provides indirect evidence that obesity increases the risk of incident knee OA and also accelerates the progression of knee OA.
      The effects of obesity on OA may be through both mechanical and systemic effects (eg, metabolic or inflammatory). There is no doubt about an effect of increased load related to overall body weight, but there may be differential systemic effects that depend on the degree of fat versus lean mass; unfortunately, BMI does not differentiate between the two. Recently, total body fat measured by dual-energy x-ray absorptiometry was associated with decreased cartilage thickness while lean mass was associated with increased cartilage thickness.
      • Ding C.
      • Stannus O.
      • Cicuttini F.
      • et al.
      Body fat is associated with increased and lean mass with decreased knee cartilage loss in older adults: a prospective cohort study.
      Adipose tissue is known to be metabolically active, secreting adipokines such as adiponectin, leptin, and resistin, but the role of these adipokines in OA is not yet clear.
      • Sandell L.J.
      Obesity and osteoarthritis: is leptin the link?.
      • Sowers M.R.
      • Karvonen-Gutierrez C.A.
      The evolving role of obesity in knee osteoarthritis.
      Obesity is also associated with both incident radiographic and symptomatic hand OA,
      • Carman W.J.
      • Sowers M.
      • Hawthorne V.M.
      • et al.
      Obesity as a risk factor for osteoarthritis of the hand and wrist: a prospective study.
      • Oliveria S.A.
      • Felson D.T.
      • Cirillo P.A.
      • et al.
      Body weight, body mass index, and incident symptomatic osteoarthritis of the hand, hip, and knee.
      further supporting potential metabolic or inflammatory effects of obesity. By contrast, the association between obesity and hip OA has been variable and, where noted, less strong than for the knee or hand.
      • Grotle M.
      • Hagen K.B.
      • Natvig B.
      • et al.
      Obesity and osteoarthritis in knee, hip and/or hand: an epidemiological study in the general population with 10 years follow-up.
      • Heliovaara M.
      • Makela M.
      • Impivaara O.
      • et al.
      Association of overweight, trauma and workload with coxarthrosis. A health survey of 7,217 persons.
      • Karlson E.W.
      • Mandl L.A.
      • Aweh G.N.
      • et al.
      Total hip replacement due to osteoarthritis: the importance of age, obesity, and other modifiable risk factors.
      • Tepper S.
      • Hochberg M.C.
      Factors associated with hip osteoarthritis: data from the First National Health and Nutrition Examination Survey (NHANES-I).
      • van Saase J.L.
      • Vandenbroucke J.P.
      • van Romunde L.K.
      • et al.
      Osteoarthritis and obesity in the general population. A relationship calling for an explanation.

      Genetics

      The heritable component of OA has been estimated to be 40% to 65%, and stronger for hand and hip OA than for knee OA.
      • Felson D.T.
      • Couropmitree N.N.
      • Chaisson C.E.
      • et al.
      Evidence for a Mendelian gene in a segregation analysis of generalized radiographic osteoarthritis: the Framingham Study.
      • Palotie A.
      • Vaisanen P.
      • Ott J.
      • et al.
      Predisposition to familial osteoarthrosis linked to type II collagen gene.
      • Spector T.D.
      • Cicuttini F.
      • Baker J.
      • et al.
      Genetic influences on osteoarthritis in women: a twin study.
      To date 3 loci, GDF5, which encodes the growth differentiation factor 5 (a bone morphogenetic protein expressed in skeletal and articular structures), chromosome 7q22, and MCF2L have been associated with OA at genome-wide significance levels.
      • Evangelou E.
      • Valdes A.M.
      • Kerkhof H.J.
      • et al.
      Meta-analysis of genome-wide association studies confirms a susceptibility locus for knee osteoarthritis on chromosome 7q22.
      • Valdes A.M.
      • Evangelou E.
      • Kerkhof H.J.
      • et al.
      The GDF5 rs143383 polymorphism is associated with osteoarthritis of the knee with genome-wide statistical significance.
      • Day-Williams A.G.
      • Southam L.
      • Panoutsopoulou K.
      • et al.
      A variant in MCF2L is associated with osteoarthritis.
      A recent large, well-powered study from the arcOGEN Consortium identified 5 new susceptibility loci for OA with genome-wide significance.
      arcOGEN ConsortiumarcOGEN Collaborators
      Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study.
      Two single-nucleotide polymorphisms (SNPs) were on chromosome 3, in linkage disequilibrium with each other within an exon of nucleostemin-encoding GNL3; one on chromosome 9 close to ASTN2; one on chromosome 6 between FILIP1 and SENP6; one on chromosome 12 close to KLHDC5 and PTHLH; and another on chromosome 12 close to CHST11.
      arcOGEN ConsortiumarcOGEN Collaborators
      Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study.
      Of note, the previously identified loci did not achieve genome-wide significance in this arcOGEN sample.
      Pain severity related to OA may also have genetic contributions. A functional polymorphism (Val158Met) in the COMT gene, which has been associated with pain sensitivity in other clinical conditions, was associated with hip OA–related pain in one cohort study, but has not yet been replicated in other cohorts.
      • van Meurs J.B.
      • Uitterlinden A.G.
      • Stolk L.
      • et al.
      A functional polymorphism in the catechol-O-methyltransferase gene is associated with osteoarthritis-related pain.
      Other genes associated with pain sensitivity have also been studied in relation to OA pain. TRPV1 and the PACE4 gene Pcsk6 were associated with pain in knee OA in two separate meta-analyses,
      • Valdes A.M.
      • De Wilde G.
      • Doherty S.A.
      • et al.
      The Ile585Val TRPV1 variant is involved in risk of painful knee osteoarthritis.
      • Malfait A.M.
      • Seymour A.B.
      • Gao F.
      • et al.
      A role for PACE4 in osteoarthritis pain: evidence from human genetic association and null mutant phenotype.
      while an association with a SCN9 SNP could not be replicated.
      • Valdes A.M.
      • Arden N.K.
      • Vaughn F.L.
      • et al.
      Role of the Nav1.7 R1150W amino acid change in susceptibility to symptomatic knee osteoarthritis and multiple regional pain.

      Bone mineral density

      The material properties of bone may influence susceptibility to OA. Nevitt and colleagues
      • Nevitt M.C.
      • Zhang Y.
      • Javaid M.K.
      • et al.
      High systemic bone mineral density increases the risk of incident knee OA and joint space narrowing, but not radiographic progression of existing knee OA: the MOST study.
      recently confirmed the previous observation that higher systemic bone mineral density (BMD) was associated with an increased risk of incident OA. Whether this finding is related to factors contributing to bone remodeling or peak bone mass that may be genetically determined,
      • Naganathan V.
      • Zochling J.
      • March L.
      • et al.
      Peak bone mass is increased in the hip in daughters of women with osteoarthritis.
      or whether the higher systemic BMD represents higher BMI load over the years before onset of OA (itself a strong risk factor for OA), is not clear. Paradoxically, BMD was not associated with progressive OA in the same study.
      • Nevitt M.C.
      • Zhang Y.
      • Javaid M.K.
      • et al.
      High systemic bone mineral density increases the risk of incident knee OA and joint space narrowing, but not radiographic progression of existing knee OA: the MOST study.
      Low BMD has been associated cross-sectionally with reduced joint-space width at the hip, which could be a reflection of effects of existing OA.
      • Jacobsen S.
      • Jensen T.W.
      • Bach-Mortensen P.
      • et al.
      Low bone mineral density is associated with reduced hip joint space width in women: results from the Copenhagen Osteoarthritis Study.
      That is, once symptomatic OA has developed an individual may decrease his or her physical activity and therefore loading of the joint, which in turn can contribute to low BMD. Furthermore, there is evidence to suggest that although the apparent density of bone in OA may be increased, the bone itself is less mineralized, resulting in lower material density.
      • Li B.
      • Aspden R.M.
      Composition and mechanical properties of cancellous bone from the femoral head of patients with osteoporosis or osteoarthritis.

      Nutritional factors

      The effects of readily modifiable dietary factors in humans have been inconclusive. Studies of the relationship between vitamin D and OA have been conflicting.
      • Felson D.T.
      • Niu J.
      • Clancy M.
      • et al.
      Low levels of vitamin D and worsening of knee osteoarthritis: results of two longitudinal studies.
      • Chaganti R.K.
      • Parimi N.
      • Cawthon P.
      • et al.
      Association of 25-hydroxyvitamin D with prevalent osteoarthritis of the hip in elderly men: the osteoporotic fractures in men study.
      • McAlindon T.
      • Felson D.T.
      Nutrition: risk factors for osteoarthritis.
      A recent randomized controlled trial of the effects of vitamin D on knee OA did not demonstrate a beneficial effect on cartilage loss on MRI.
      • McAlindon T.
      • LaValley M.
      • Schneider E.
      • et al.
      Effect of vitamin D supplementation on progression of knee pain and cartilage volume loss in patients with symptomatic osteoarthritis: a randomized controlled trial.
      One difficulty in the conduct of such a study is that it is unethical to conduct a fully placebo-controlled trial; whether the 400 IU/d given to the control arm was sufficient to account for the negative results is not clear. Antioxidant vitamins such as vitamins C and E have also been studied in relation to OA, with conflicting results.
      • McAlindon T.E.
      • Jacques P.
      • Zhang Y.
      • et al.
      Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis?.
      • Chaganti R.
      • Tolstykh I.
      • Javaid K.
      • et al.
      Association of baseline vitamin C with incident and progressive radiographic knee OA: the MOST Study.
      • Peregoy J.
      • Wilder F.V.
      The effects of vitamin C supplementation on incident and progressive knee osteoarthritis: a longitudinal study.
      • De Roos A.J.
      • Arab L.
      • Renner J.B.
      • et al.
      Serum carotenoids and radiographic knee osteoarthritis: the Johnston County Osteoarthritis Project.
      • Jordan J.M.
      • De Roos A.J.
      • Renner J.B.
      • et al.
      A case-control study of serum tocopherol levels and the alpha- to gamma-tocopherol ratio in radiographic knee osteoarthritis: the Johnston County Osteoarthritis Project.
      • Wluka A.E.
      • Stuckey S.
      • Brand C.
      • et al.
      Supplementary vitamin E does not affect the loss of cartilage volume in knee osteoarthritis: a 2 year double blind randomized placebo controlled study.
      Vitamin K, which has potential bone and cartilage effects, has been associated cross-sectionally with hand and knee OA, incident radiographic knee OA, and MRI-based cartilage lesions, and with potentially less hand OA progression among those who were deficient at baseline in a randomized trial, although the overall trial results were null.
      • Neogi T.
      • Booth S.L.
      • Zhang Y.Q.
      • et al.
      Low vitamin K status is associated with osteoarthritis in the hand and knee.
      • Neogi T.
      • Felson D.T.
      • Sarno R.
      • et al.
      Vitamin K in hand osteoarthritis: results from a randomised clinical trial.

      Misra D, Booth SL, Tolstykh I, et al. Vitamin K deficiency is associated with incident knee osteoarthritis. Am J Med, in press.

      • Oka H.
      • Akune T.
      • Muraki S.
      • et al.
      Association of low dietary vitamin K intake with radiographic knee osteoarthritis in the Japanese elderly population: dietary survey in a population-based cohort of the ROAD study.
      Selenium and iodine deficiency has been associated with Kashin-Beck osteoarthropathy. In 2 observational cohort studies, both low and high levels of selenium have been associated with OA.
      • Engstrom G.
      • Gerhardsson de Verdier M.
      • Nilsson P.M.
      • et al.
      Incidence of severe knee and hip osteoarthritis in relation to dietary intake of antioxidants beta-carotene, vitamin C, vitamin E and Selenium: a population-based prospective cohort study.
      • Jordan J.M.
      • Fang F.
      • Arab L.
      • et al.
      Low selenium levels are associated with increased risk for osteoarthritis of the knee.

      Joint-Level Risk Factors

      Occupation, physical activity, and injury

      Repetitive joint use may predispose to OA. For example, squatting among Beijing Chinese,
      • Zhang Y.
      • Hunter D.J.
      • Nevitt M.C.
      • et al.
      Association of squatting with increased prevalence of radiographic tibiofemoral knee osteoarthritis: the Beijing Osteoarthritis Study.
      and jobs requiring kneeling or squatting were associated with an increased risk of knee OA, particularly among those who were overweight or whose jobs required carrying or lifting, as well as worse cartilage morphology scores on MRI at the patellofemoral joint.
      • Amin S.
      • Goggins J.
      • Niu J.
      • et al.
      Occupation-related squatting, kneeling, and heavy lifting and the knee joint: a magnetic resonance imaging-based study in men.
      • Coggon D.
      • Croft P.
      • Kellingray S.
      • et al.
      Occupational physical activities and osteoarthritis of the knee.
      • Felson D.T.
      • Hannan M.T.
      • Naimark A.
      • et al.
      Occupational physical demands, knee bending, and knee osteoarthritis: results from the Framingham Study.
      A recent meta-analysis noted a 1.6-fold increased risk of knee OA related to occupational activities, with most activities conferring increased risk other than standing.
      • McWilliams D.F.
      • Leeb B.F.
      • Muthuri S.G.
      • et al.
      Occupational risk factors for osteoarthritis of the knee: a meta-analysis.
      Occupational lifting and prolonged standing have been associated with hip OA.
      • Croft P.
      • Coggon D.
      • Cruddas M.
      • et al.
      Osteoarthritis of the hip: an occupational disease in farmers.
      • Croft P.
      • Cooper C.
      • Wickham C.
      • et al.
      Osteoarthritis of the hip and occupational activity.
      • Yoshimura N.
      • Sasaki S.
      • Iwasaki K.
      • et al.
      Occupational lifting is associated with hip osteoarthritis: a Japanese case-control study.
      Occupations involving manual dexterity, particularly repeated pincer grip, have been associated with features of hand OA.
      • Hadler N.M.
      • Gillings D.B.
      • Imbus H.R.
      • et al.
      Hand structure and function in an industrial setting.
      • Lawrence J.S.
      Rheumatism in cotton operatives.
      These data are also supported by an increase in OA found in the interphalangeal joint of the thumb and in the second and third proximal interphalangeal and metacarpophalangeal joints of the hand used to eat with chopsticks, compared with other joints of that same hand or any joint in the opposite hand among Beijing Chinese.
      • Hunter D.J.
      • Zhang Y.
      • Nevitt M.C.
      • et al.
      Chopstick arthropathy: the Beijing Osteoarthritis Study.
      Physical activity may have benefits for the joint by strengthening periarticular muscles to help stabilize the joint, but may potentially be detrimental if it places undue load on the joint, particularly one that is already vulnerable because of other risks. General population studies have shown that habitual levels of activity are not associated with incident radiographic/symptomatic OA or new knee replacement, whereas more vigorous levels of activity appeared to increase the risk of OA.
      • Hannan M.T.
      • Felson D.T.
      • Anderson J.J.
      • et al.
      Habitual physical activity is not associated with knee osteoarthritis: the Framingham Study.
      • McAlindon T.E.
      • Wilson P.W.
      • Aliabadi P.
      • et al.
      Level of physical activity and the risk of radiographic and symptomatic knee osteoarthritis in the elderly: the Framingham study.
      • Wang Y.
      • Simpson J.A.
      • Wluka A.E.
      • et al.
      Is physical activity a risk factor for primary knee or hip replacement due to osteoarthritis? A prospective cohort study.
      A recent study reported that daily walking of more than 10,000 steps per day may be associated with worsening of certain MRI features; however, certain biases could not be ruled out.
      • Dore D.A.
      • Winzenberg T.M.
      • Ding C.
      • et al.
      The association between objectively measured physical activity and knee structural change using MRI.
      Although studies focused on former athletes have had conflicting results,
      • Lane N.E.
      • Oehlert J.W.
      • Bloch D.A.
      • et al.
      The relationship of running to osteoarthritis of the knee and hip and bone mineral density of the lumbar spine: a 9 year longitudinal study.
      • Panush R.S.
      • Schmidt C.
      • Caldwell J.R.
      • et al.
      Is running associated with degenerative joint disease?.
      • Marti B.
      • Knobloch M.
      • Tschopp A.
      • et al.
      Is excessive running predictive of degenerative hip disease? Controlled study of former elite athletes.
      • Spector T.D.
      • Harris P.A.
      • Hart D.J.
      • et al.
      Risk of osteoarthritis associated with long-term weight-bearing sports: a radiologic survey of the hips and knees in female ex-athletes and population controls.
      the mechanism by which vigorous or elite-level (or equivalent) physical activity/sports may be associated with increased risk of OA may be related to factors other than simple load bearing. In one study of athletes, the increased risk of OA appeared to be related to knee injury among soccer players, and increased BMI as well as squatting among weightlifters.
      • Kujala U.M.
      • Kettunen J.
      • Paananen H.
      • et al.
      Knee osteoarthritis in former runners, soccer players, weight lifters, and shooters.
      Several studies have demonstrated the importance of knee injury, such as injury related to meniscal tears requiring meniscectomy or anterior cruciate ligament injury, as a risk factor for onset of OA.
      • Lohmander L.S.
      • Ostenberg A.
      • Englund M.
      • et al.
      High prevalence of knee osteoarthritis, pain, and functional limitations in female soccer players twelve years after anterior cruciate ligament injury.
      • Roos E.M.
      • Ostenberg A.
      • Roos H.
      • et al.
      Long-term outcome of meniscectomy: symptoms, function, and performance tests in patients with or without radiographic osteoarthritis compared to matched controls.
      Two recent meta-analyses report knee injury to confer a 4-fold increased risk of developing knee OA.
      • Blagojevic M.
      • Jinks C.
      • Jeffery A.
      • et al.
      Risk factors for onset of osteoarthritis of the knee in older adults: a systematic review and meta-analysis.
      • Muthuri S.G.
      • McWilliams D.F.
      • Doherty M.
      • et al.
      History of knee injuries and knee osteoarthritis: a meta-analysis of observational studies.
      Beyond certain sports, some occupational activities may also increase the risk of meniscal tears, which are known to confer high risk of knee OA.
      • Englund M.
      • Guermazi A.
      • Roemer F.W.
      • et al.
      Meniscal tear in knees without surgery and the development of radiographic osteoarthritis among middle-aged and elderly persons: The Multicenter Osteoarthritis Study.
      For example, floor layers, who spend much time kneeling, were more likely to have degenerative meniscal tears than were graphic designers with no knee demands.
      • Rytter S.
      • Egund N.
      • Jensen L.K.
      • et al.
      Occupational kneeling and radiographic tibiofemoral and patellofemoral osteoarthritis.
      Although the prevalence of meniscal abnormalities increases as the radiographic severity of knee OA increases,
      • Englund M.
      • Guermazi A.
      • Gale D.
      • et al.
      Incidental meniscal findings on knee MRI in middle-aged and elderly persons.
      surgical intervention has not been shown to reduce these risks.
      • Lohmander L.S.
      • Englund P.M.
      • Dahl L.L.
      • et al.
      The long-term consequence of anterior cruciate ligament and meniscus injuries: osteoarthritis.
      These studies support the importance of maintaining an intact meniscus to protect against development of OA.

      Muscle strength

      The effect of knee injury on the risk of OA may be partially related to muscle strength. Muscle weakness and atrophy can occur as a consequence of OA related to disuse resulting from pain avoidance, but whether it is a risk factor for the development of OA is not clear. In some studies, quadriceps muscle weakness was associated with increased risk of structural knee OA.
      • Brandt K.D.
      • Heilman D.K.
      • Slemenda C.
      • et al.
      Quadriceps strength in women with radiographically progressive osteoarthritis of the knee and those with stable radiographic changes.
      • Slemenda C.
      • Heilman D.K.
      • Brandt K.D.
      • et al.
      Reduced quadriceps strength relative to body weight: a risk factor for knee osteoarthritis in women?.
      In another study, discrepant findings were noted for low knee extensor strength being associated with incident symptomatic knee OA, but not with incident radiographic OA.
      • Segal N.A.
      • Torner J.C.
      • Felson D.
      • et al.
      Effect of thigh strength on incident radiographic and symptomatic knee osteoarthritis in a longitudinal cohort.
      In this study, the patellofemoral joint was included in the evaluation of incident symptomatic whole knee OA, but was not included in the definition of incident radiographic tibiofemoral OA. On the other hand, greater quadriceps strength in the setting of malalignment and laxity was associated with increased risk of progression of tibiofemoral OA in one study,
      • Sharma L.
      • Dunlop D.D.
      • Cahue S.
      • et al.
      Quadriceps strength and osteoarthritis progression in malaligned and lax knees.
      but no association with tibiofemoral progression was noted in another study, where it was also associated with less cartilage loss in the lateral patellofemoral joint,
      • Amin S.
      • Baker K.
      • Niu J.
      • et al.
      Quadriceps strength and the risk of cartilage loss and symptom progression in knee osteoarthritis.
      suggesting a more complex interrelationship.
      Muscle strength could also potentially play a role in hand OA. For example, greater grip strength was associated with increased risk of developing radiographic hand OA.
      • Chaisson C.E.
      • Zhang Y.
      • Sharma L.
      • et al.
      Higher grip strength increases the risk of incident radiographic osteoarthritis in proximal hand joints.
      However, potentially as a consequence of existing hand OA, a cross-sectional study found an inverse association between grip strength and prevalent OA of the first carpometacarpal joint, and between pinch strength and prevalent OA of the metacarpophalangeal joint.
      • Dominick K.L.
      • Jordan J.M.
      • Renner J.B.
      • et al.
      Relationship of radiographic and clinical variables to pinch and grip strength among individuals with osteoarthritis.

      Alignment

      Dynamic alignment (ie, the alterations in the knee that occur during gait) may be pertinent for understanding the specific load effects the joint is experiencing. In epidemiologic studies, however, static alignment from full-limb radiographs (mechanical axis) or from posteroanterior knee radiographs (ie, anatomic axis) is typically assessed according to feasibility. Prior studies have had conflicting findings regarding the effects of alignment on incident OA,
      • Brouwer G.M.
      • van Tol A.W.
      • Bergink A.P.
      • et al.
      Association between valgus and varus alignment and the development and progression of radiographic osteoarthritis of the knee.
      • Hunter D.J.
      • Niu J.
      • Felson D.T.
      • et al.
      Knee alignment does not predict incident osteoarthritis: the Framingham osteoarthritis study.
      although more recent studies have reported that varus malalignment assessed by full-limb radiographs increased the incidence of both radiographic knee OA and cartilage damage.
      • Sharma L.
      • Chmiel J.S.
      • Almagor O.
      • et al.
      The role of varus and valgus alignment in the initial development of knee cartilage damage by MRI: the MOST study.
      • Sharma L.
      • Song J.
      • Dunlop D.
      • et al.
      Varus and valgus alignment and incident and progressive knee osteoarthritis.
      Nevertheless, a best-evidence synthesis concluded there was a lack of sufficient evidence to draw a conclusion.
      • Tanamas S.
      • Hanna F.S.
      • Cicuttini F.M.
      • et al.
      Does knee malalignment increase the risk of development and progression of knee osteoarthritis? A systematic review.
      Knee malalignment is one of the strongest predictors of progressive knee OA.
      • Sharma L.
      • Song J.
      • Dunlop D.
      • et al.
      Varus and valgus alignment and incident and progressive knee osteoarthritis.
      These findings may imply that the association between alignment and development of OA is a vicious cycle: joint-space narrowing (eg, due to cartilage and meniscal abnormalities) and alterations of bony contour occurring in OA may themselves lead to joint malalignment, and malalignment itself can further alter joint loading and accelerate disease progression. However, no study to date has documented slowing of disease progression if alignment is corrected. Of interest, in post hoc analysis of data from a randomized placebo-controlled trial of doxycycline in obese middle-aged women with unilateral knee OA, varus malalignment was found to negate the potential chondroprotective effects of doxycycline.
      • Mazzuca S.A.
      • Brandt K.D.
      • Chakr R.
      • et al.
      Varus malalignment negates the structure-modifying benefits of doxycycline in obese women with knee osteoarthritis.
      Using a computational modeling approach with finite or discrete element analysis, knees that developed incident symptomatic OA demonstrated higher maximal contact stress and larger area of engagement with higher contact stresses at baseline than control knees that did not develop symptomatic OA, suggesting a local biomechanical role in the development of symptomatic knee OA.
      • Segal N.A.
      • Anderson D.D.
      • Iyer K.S.
      • et al.
      Baseline articular contact stress levels predict incident symptomatic knee osteoarthritis development in the MOST cohort.

      Leg-length inequality

      Leg-length inequality (LLI) is an easily modifiable abnormality. Persons with LLI of at least 2 cm in the Johnston County OA Project were almost twice as likely to have prevalent radiographic knee OA, but no association was noted for incident knee OA.
      • Golightly Y.M.
      • Allen K.D.
      • Helmick C.G.
      • et al.
      Hazard of incident and progressive knee and hip radiographic osteoarthritis and chronic joint symptoms in individuals with and without limb length inequality.
      • Golightly Y.M.
      • Allen K.D.
      • Renner J.B.
      • et al.
      Relationship of limb length inequality with radiographic knee and hip osteoarthritis.
      Similar findings were noted using data from The MOST Study, in which persons with LLI of 1 cm or more were almost twice as likely to have prevalent radiographic knee OA in the shorter limb.
      • Harvey W.F.
      • Yang M.
      • Cooke T.D.
      • et al.
      Association of leg-length inequality with knee osteoarthritis: a cohort study.
      An association with incident radiographic knee OA was not found in that study, although LLI was associated with incident symptomatic knee OA. This discordance, as discussed earlier, may be related to the inclusion of the patellofemoral joint in the definition of symptomatic whole knee OA, whereas it is excluded from incident radiographic tibiofemoral OA.

      Bone and joint morphology

      The anatomy or the shape of a joint may contribute to the risk of OA, given that biomechanical load distribution through the joint is partially dependent on the geometric shape over which that load is distributed in addition to the material properties of the joint tissues receiving that load. This aspect has perhaps been best studied and described in the hip in relation to OA where, using active shape modeling, the 2-dimensional shape of the hip has been associated with OA.
      • Gregory J.S.
      • Waarsing J.H.
      • Day J.
      • et al.
      Early identification of radiographic osteoarthritis of the hip using an active shape model to quantify changes in bone morphometric features: can hip shape tell us anything about the progression of osteoarthritis?.
      • Lynch J.A.
      • Parimi N.
      • Chaganti R.K.
      • et al.
      The association of proximal femoral shape and incident radiographic hip OA in elderly women.
      Even mild acetabular dysplasia has been associated with a risk of incident hip OA.
      • Lane N.E.
      • Lin P.
      • Christiansen L.
      • et al.
      Association of mild acetabular dysplasia with an increased risk of incident hip osteoarthritis in elderly white women: the study of osteoporotic fractures.
      Pistol-grip deformity, or cam-type femoral acetabular impingement (FAI) syndrome, as well as the pincer-type FAI, have been associated with hip OA and hip pain.
      • Doherty M.
      • Courtney P.
      • Doherty S.
      • et al.
      Nonspherical femoral head shape (pistol grip deformity), neck shaft angle, and risk of hip osteoarthritis: a case-control study.
      • Reid G.D.
      • Reid C.G.
      • Widmer N.
      • et al.
      Femoroacetabular impingement syndrome: an underrecognized cause of hip pain and premature osteoarthritis?.
      More recently, using MRI data, 3-dimensional bone shape has been shown to predict the onset of knee OA.
      • Bredbenner T.L.
      • Eliason T.D.
      • Potter R.S.
      • et al.
      Statistical shape modeling describes variation in tibia and femur surface geometry between Control and Incidence groups from the osteoarthritis initiative database.
      • Neogi T.
      • Bowes M.
      • Niu J.
      • et al.
      MRI-based 3D bone shape predicts incident knee OA 12 months prior to its onset.

      Recent insights into risk factors for knee pain

      Clinical symptoms related to knee OA are known to be activity related in the early stages, progressing to more persistent symptoms in late stages of disease that are punctuated with intermittent increased pain.
      • Hawker G.A.
      • Stewart L.
      • French M.R.
      • et al.
      Understanding the pain experience in hip and knee osteoarthritis—an OARSI/OMERACT initiative.
      In The MOST Study, approximately 40% of persons with or at high risk of knee OA had fluctuating knee pain; these individuals had less severe KL grades on radiography, fewer depressive symptoms, and less widespread pain.
      • Neogi T.
      • Nevitt M.C.
      • Yang M.
      • et al.
      Consistency of knee pain: correlates and association with function.
      In the Longitudinal Examination of Arthritis Pain, an observational cohort study of 287 adults with hip or knee OA in which pain assessments were conducted weekly over 12 weeks, psychological factors fluctuated with pain severity,
      • Wise B.L.
      • Niu J.
      • Zhang Y.
      • et al.
      Psychological factors and their relation to osteoarthritis pain.
      supporting an important link between the pain experience and psychological state. Indeed, because numerous factors (many of which may not be assessed in a particular study) can contribute to the pain experience, such as genetics, sociocultural environment, and medications, among others, in addition to psychological factors, a so-called structure-symptom discordance is often described in OA.
      However, when such between-person variability and confounding factors are accounted for by using a within-person knee-matched study design (in which one knee has pain while the other does not), a strong association between radiographic severity and knee pain can be discerned, even at the earliest stages of radiographic knee OA (Fig. 3).
      • Neogi T.
      • Felson D.
      • Niu J.
      • et al.
      Association between radiographic features of knee osteoarthritis and pain: results from two cohort studies.
      Such findings indicate that certain structural lesions within the knee may be a cause of knee pain. Furthermore, specific MRI features of OA that can change over time, including bone marrow lesions, synovitis, and effusions, have been associated with fluctuation of knee pain.
      • Zhang Y.
      • Nevitt M.
      • Niu J.
      • et al.
      Fluctuation of knee pain and changes in bone marrow lesions, effusions and synovitis on MRI: the Most Study.
      As structural lesions worsened, the likelihood that the knee would be painful increased. Similarly, a decrease in the structural abnormalities of a knee was associated with the pain in that knee having subsided. A recent systematic review supports an association of MRI-detected bone marrow lesions and synovitis with the pain experience of OA.
      • Yusuf E.
      • Kortekaas M.C.
      • Watt I.
      • et al.
      Do knee abnormalities visualised on MRI explain knee pain in knee osteoarthritis? A systematic review.
      Figure thumbnail gr3
      Fig. 3Associations of frequent knee pain with Kellgren and Lawrence (KL) grade among people with two knees discordant for frequent knee pain status. Number of case knees (ie, with knee pain) and control knees (ie, without knee pain) are shown beneath the graph for each KL grade. Note that the y-axis is logarithmically scaled. CI, confidence interval.
      (Data from Neogi T, Felson D, Niu J, et al. Association between radiographic features of knee osteoarthritis and pain: results from two cohort studies. BMJ 2009;339:b2844. http://dx.doi.org/10.1136/bmj.b2844.)

      Methodologic challenges in the study of incident and progressive radiographic knee OA

      There are several methodologic challenges to the conduct, analysis, and interpretation of results from studies of OA, as discussed elsewhere
      • Neogi T.
      • Zhang Y.
      Osteoarthritis prevention.
      • Zhang Y.
      • Niu J.
      • Felson D.T.
      • et al.
      Methodologic challenges in studying risk factors for progression of knee osteoarthritis.
      and reviewed briefly here.

      Depletion of Susceptibles

      Most risk factors for OA, such as obesity or BMD, are chronic in nature. These chronic factors are likely to be present long before subjects are enrolled in a study. If those chronic risk factors have already caused a substantial proportion of subjects to develop knee OA, it is quite possible that participants who are still exposed to such a risk factor without yet having developed OA are less susceptible to knee OA than are individuals who have never been exposed to such a risk factor. For example, long-standing exposures such as obesity may have caused OA at an earlier age than in those being studied, but such a true effect cannot be discerned because those individuals who already have knee OA are excluded from studies of incident disease. Individuals who have been obese for a long time and who are free of OA at study onset may in fact be less susceptible to developing OA. Thus observational studies evaluating the association between a chronic exposure and incident knee OA may not be able to detect the true magnitude of effect. Such a phenomenon has been observed in other fields. For example, studies that have assessed BMI in midlife (in one’s 40s, 50s, and 60s) find that higher BMI is associated with an increased risk of death over the subsequent decades (in one’s 60s, 70s, and 80s). However, many investigations of BMI at age 70 or older find associations with mortality that are less clear.
      • Manson J.E.
      • Bassuk S.S.
      • Hu F.B.
      • et al.
      Estimating the number of deaths due to obesity: can the divergent findings be reconciled?.
      One potential explanation for such findings is depletion of susceptibles among the elderly. Because the risk of knee OA increases rapidly around the middle 50s to 60s, one would ideally study subjects younger than this age to identify risk factors for incident knee OA. If OA studies consist of a large proportion of subjects who are older than the typical age of onset, the overall effect of a specific chronic risk factor is likely to be underestimated, owing to depletion of those who were susceptible to OA.

      Loss to Follow-up and Competing Risks

      The risk of developing new-onset OA is difficult to determine because of several challenges. OA is a chronic disease whose onset is typically unknown. In most OA cohort studies, repeated study visits with imaging may occur with a substantial interval between each study visit. As a result, there is a potential for loss to follow-up. For example, in 2 large cohort studies where knee radiographs were repeated after 4 and 9 years, respectively, both studies reported that approximately 40% did not undergo radiography at the follow-up visit.
      • Cooper C.
      • Snow S.
      • McAlindon T.E.
      • et al.
      Risk factors for the incidence and progression of radiographic knee osteoarthritis.
      • Felson D.T.
      • Zhang Y.
      • Hannan M.T.
      • et al.
      Risk factors for incident radiographic knee osteoarthritis in the elderly: the Framingham Study.
      Given that OA is a disease with onset in middle or older ages, death attributable to other causes than OA (competing risks) makes risk estimation difficult and prone to bias. In most cases, estimates of the risk of OA can only be obtained among subjects who provide both baseline and follow-up data. If loss to follow-up is associated with the occurrence of OA (as might be expected when older adults or obese participants are lost to follow-up, for example), the estimate of risk of OA based on those who are followed with complete data could be an underestimate.

      Potential Discordant Findings for Risk Factors for Incident and Progressive Knee OA

      Some risk factors associated with incident disease are not associated with or are even paradoxically protective against progressive OA. In observational studies of progression of OA, eligible knees consist of those that already have knee OA, that is, KL = 2 or KL = 3, representing a mixture of differing degrees of severity that may vary among exposed and nonexposed groups. The outcome is also heterogeneous: knees that progress from KL = 3 to KL = 4 are considered the same as those that progress from KL = 2 to KL = 3 or to KL = 4 over the same period of time. Finally, studies of OA progression are, in essence, conducted to assess an association between a risk factor that causes initiation of OA to progress to more severe OA. This approach results in conditioning on an intermediate stage of OA when assembling the study sample, that is, by limiting the study sample to those who already had mild to moderate knee OA at baseline. This limitation blocks the potential effect of a risk factor on the risk of OA progression if the risk factor of interest was present before any OA abnormality occurred.
      • Zhang Y.
      • Niu J.
      • Felson D.T.
      • et al.
      Methodologic challenges in studying risk factors for progression of knee osteoarthritis.
      Conditioning on an intermediate stage of OA can also result in collider bias. For example, in a hypothetical study of obesity as a risk factor for progressive radiographic OA, the assembled knees with KL = 2 or KL = 3 would be divided into those knees that belong to obese persons and those that belong to nonobese persons. Those knees with OA among the nonobese participants must have developed OA that was due to some other risk factors. Without accounting for those risk factors that led to the development of OA in those knees, the results of the study will be confounded, and will tend to be negatively biased (toward the null).

      Discerning Independent Effects

      Over the past several years, MRI has enabled identification of various pathologic changes in the joint. However, little is known about the true natural history of the occurrence of these structural lesions detected on MRI, particularly in relation to one another. There is often an attempt to include all structural lesions in a statistical regression model to compare the effect of each structural lesion on the outcome of interest. Without knowing the causal pathway and chronology of occurrence of these lesions, standard approaches of automatically mutually adjusting for all factors can lead to biased effect estimates and, moreover, the effect estimates for each structural lesion are not directly comparable with one another, resulting in incorrect interpretations of study findings.
      • Robins J.M.
      • Greenland S.
      Identifiability and exchangeability for direct and indirect effects.

      Summary

      OA poses a substantial public health burden, given its prevalence that continues to increase. Several risk factors have been recognized, including some modifiable ones such as obesity and avoiding joint injury. There are numerous methodologic challenges to studying risk factors for OA, therefore prevention of OA and its progression also remain challenging. There is a need for ongoing epidemiologic and intervention studies on the prevention of incident and progressive OA, as well as pain related to OA, with adoption of novel approaches to avoid some of the methodologic challenges identified.

      References

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