Manal Hasan, MBBS, MD, Rhonda Shuckett, MD, FRCPC, Diplomate ABIM

Clinical features and patho- genetic mechanisms of osteo- arthritis of the hip and knee

Understanding how osteoarthritis develops is critical to treating this disabling disease.

ABSTRACT: Osteoarthritis is a non- steoarthritis (OA) is a non- tween X-ray findings and symptoms inflammatory form of arthritis that inflammatory form of arth- of OA.1 accounts for 25% of visits to primary ritis. A common miscon- OA accounts for 25% of visits to care physicians. When osteoarthritis Oception is that OA is due primary care physicians, and 50% of affects the hip and knee, it can lead solely to wear and tear, since OA is NSAID prescriptions.2 It is estimated to major disability and compromised typically a disease of persons in the that up to 80% of the population will quality of life. Diagnosis relies on sixth decade and beyond. “Degenera- have radiographic evidence of OA by clinical symptoms, physical find- tive arthritis” is often used as a syno - age 65, with 60% of those showing ings, and radiographic findings. The nym for OA, but OA is not the result of symptoms and thereby having clinical interplay between mechanical and a bland degenerative process; rather, OA.3 Another study found that by age systemic factors such as congenital OA involves both degenerative and 70 to 74 years, about 33% of men and abnormalities, obesity, and malalign- regenerative processes. 40% of women will have OA with ment may predispose individuals to OA is common and serves as the clinical and X-ray features.4 The life- osteoarthritis of the hip and knee. main source of chronic joint com- time risk of developing symptomatic We must identify these factors and plaints in adults. The morbidity con- knee OA is about 45%, rising to 66% the underlying causes of osteoarth- ferred by OA of the knee and hip in an in obese persons. While there is vari- ritis if we are to develop more pro- ever-aging population is major. Its ation in these numbers, it is clear that gressive early interventions for this high prevalence and huge impact on the morbidity and disability conferred common affliction. quality of life demand that we engage by OA of the hip and knee is enormous in better understanding of OA by con- and demands our attention.5 sidering diagnostic, epidemiological, clinical, and radiographic features. An Symptoms and understanding of how OA is classified physical findings and OA risk factors is also critical. The main symptoms of OA of the knee or hip are pain, stiffness, and altered Diagnosis and function. Initially this tends to be epidemiology worse with weight bearing and ambu- The diagnosis of OA relies on clinical lation. Eventually this can progress to symptoms, physical findings, and radiographic findings. Not all persons Dr Hasan is a rheumatology fellow in the who have radiographic OA have clin- Division of Rheumatology at the University ical disease. Conversely, not all per- of British Columbia, sponsored by the King- sons who have joint pain demonstrate dom of Saudia Arabia. Dr Shuckett is a clin- plain radiographic findings of OA. ical associate professor in the Division of Thus, there is often discordance be - Rheumatology at UBC.

www.bcmj.org VOL. 52 NO. 8, OCTOBER 2010 BC MEDICAL JOURNAL 393 Clinical features and pathogenetic mechanisms of osteo arthritis of the hips and knees

pain day and night once cartilage loss al compartment OA of the knees. Less leads to bone-on-bone contact. True commonly, patients may present with hip pain is felt in the groin most com- a valgus or knock-knee deformity, monly, but can also present in the but- indicative of more advanced disease tock and often down the anteromedial in the lateral compartment of the knee. thigh to the knee. Not uncommonly, On occasion, and much less common- patients may present solely with knee ly, patients may present with isolated pain when the problem is in the hip. OA in the patellofemoral joint, which Pain arising from osteoarthritis of the can of itself be very symptomatic. knee is felt right around the knee joint, In the case of the hip, a true cap- and unlike pain caused by hip OA, this sular pattern of limitation is found pain does not typically radiate. with groin or buttock pain (or both) In contrast to inflammatory arthri- and particular pain with internal rota- tides such as rheumatoid arthritis, with tion of the hip. Flexion deformity of their prolonged morning stiffness and the involved hip can be present with worsened pain in the morning, OA advanced OA. Patients will often walk Figure 1. Radiograph of osteoarthritis of tends to worsen as the day progresses. with a limp, and a waddling Trende- the hip showing predominant superolateral The stiffness in OA is termed “inac- lenburg gait may be evident in late joint space narrowing, subchondral sclerosis of whitening of the bone adjacent tivity stiffness” and contrasts with stages. to the joint space, and some marginal the prolonged “morning stiffness” of osteophytes. rheumatoid arthritis. Inactivity stiff- X-ray findings ness in osteoarthritic lower limb joints Standard knee X-rays should include lasts about 5 to 10 minutes and occurs a standing anteroposterior (AP) view when the patient gets up and bears of both knees, plus lateral views. In weight after prolonged immobility. patients with suspected posterolateral On physical examination, a small OA with a mild valgus de formity, a effusion with a fluid bulge sign can be 30 degree flexed standing posteroan- present in OA of the knee. Larger effu- terior (PA) view with the beam sions can occur but are less frequent directed 15 degrees from cephalad to than in the inflammatory arthropathies. caudad may be valuable in showing Synovial fluid analysis after aspira- the disease in the posterior aspect of tion of an OA knee effusion reveals the lateral compartment of the knee.6,7 that the fluid is thick and viscous with In early cases, a standard standing AP a low synovial white blood cell count, view may appear normal or indicate most of which are mononuclear cells. very mild OA, whereas the standing On examination, there may be carti- flexed PA view may show bone- laginous crepitus or a crackling feel- on-bone contact. Patellofemoral OA ing on palpation of the knee with mo - of the knee cap is also a common tion. Eventually there may be coarse finding, best diagnosed on a skyline bone-on-bone crepitus whereby the X-ray view. opposing bone ends, denuded of carti- X-rays of the hips to evaluate for lage, seem to grate against one anoth- OA should include a standing AP er. There is often a loss of range of pelvis view and frog-leg views of the motion of the involved knee or hip, suspected hip joint. It is important to Figure 2. Medial compartment particularly with progression of OA. always order standing X-rays of both osteoarthritis of the knee with medial Loss of cartilage of the knee can knees in the case of suspected knee compartment joint space loss.This marked lead to malalignment of the leg with a OA and an X-ray of the pelvis and not narrowing is between the medial tibial plateau and the medial femoral condyle. varus deformity or bow-legged posi- just the affected hip in the case of sus- The fibula can be seen in its lateral tioning of the leg being evident. This pected hip OA. This will allow for location. angulation of the knee applies to medi- comparison between sides and im-

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proves the ability to diagnose mild to application. MRI has emerged as an Table 1. Traditional classification of OA moderate disease. excellent modality for detection of OA On plain X-ray evaluation, loss of when the plain radiographs indicate Primary osteoarthritis the radiolucent cartilage, termed joint no disease or mild disease, and the • Idiopathic space narrowing, is seen in OA. In the patient’s symptoms are out of keeping • Generalized hip joint the joint space narrowing with the apparent severity of disease. • Erosive tends to be more in the weight-bearing MRI can detect large focal articular superolateral aspect of the joint, again cartilage lesions that cannot be detect- Secondary osteoarthritis 6-8 • Due to mechanical incongruity of joint, highlighting the role of mechanics in ed on plain films. congenital or acquired (e.g., acetabular OA (Figure 1 ). However, there are dysplasia of hip or internal knee different patterns of OA of the hip, and Classification of OA derangement) it is possible to get more central wear, Traditionally OA has been classified • Due to prior inflammatory disease (e.g., rheumatoid arthritis) particularly in patients with deep sock- as primary or secondary (Table 1 ).9 • Due to endocrine disorders (e.g., ets or protrusio acetabuli. In the knee, Primary OA denotes generalized or diabetes, acromegaly) main involvement is often in the medi- erosive OA with no identifiable cause. • Due to metabolic disorders (e.g., calcium al joint compartment (Figure 2 ), but Secondary OA denotes OA caused by pyrrophosphate dihydrate crystals, involvement of other compartments an underlying condition, including hemochromatosis) or of the entire joint is also common. those caused by inflammatory dis- • Miscellaneous (e.g., avascular necrosis) On plain X-ray of an osteoarthrit- eases, trauma, and mechanical factors. Source: Adapted from Brandt KD.9 ic joint, in addition to joint space nar- In a large series of cases of so- rowing, there tends to be subchondral called primary osteoarthritis of the sclerosis or an appearance of whiten- hip, some underlying mechanical Table 2. Classification of OA by cause ing of the subchondral bone. Osteo- developmental variation could be found A. Abnormal concentrations of force on phytes, which reflect a regenerative in most cases to account for the onset normal cartilage 10 process with formation of fibrocarti- of the disease. For instance, the sub- • Cartilage surface irregularities (e.g., laginous extensions or hooks at the tle presence of a shallow cup of the intra-articular fractures, meniscal tear) joint margins, are common. Interest- hip, called acetabular dysplasia, is a • Malalignment of the joint (e.g., leg length ingly, the presence of osteophytes in common precursor to OA of the hip. disparity, acetabular dysplasia, one compartment, such as the lateral In middle-aged men, femoroacetabu- congenital hip dislocation) • Loss of ligamentous stability (e.g., compartment in a patient with medial lar impingement (FAI) is thought to anterior cruciate ligament tear) compartment OA, is not indicative of be the most common cause of OA of • Loss of protective sensory feedback (e.g., disease in that compartment. It is sim- the hip. FAI of the pincer type occurs diabetic neuropathy) ply indicative of the body’s reparative most often in middle-aged women. On • Other causes (e.g., obesity, occupational) response to the abnormal stresses and occasion, patients may present with B. Normal concentrations of force on presence of disease in the medial com- symptoms of impingement prior to abnormal cartilage partment. the development of advanced OA. It • Pre-existing arthritis (e.g., rheumatoid The identification of OA on plain thus appears that the term “primary or arthritis) X-rays means there is already full idiopathic OA” is probably a mis- • Metabolic abnormalities (e.g., crystal thickness cartilage loss and even nomer as it applies to the hip or knee, arthropathy) bone-on-bone contact. These radi- and that if we look hard enough an • Genetic (e.g., generalized osteoarthritis ographic findings occur relatively late underlying structural cause will often of hands) in the course of OA. It would be ideal be apparent. C. Normal concentrations of force on to be able to identify OA before gross In the 1970s Mitchell and Cruess normal cartilage supported by stiffened changes are apparent on radiographs. proposed a more pathogenetic classi- subchondral bone • Paget disease Earlier OA detection is important in fication of OA (Table 2 ). This classi- identifying disease before the pro- fication system assumes that osteo - D. Normal concentrations of force on gressive bone-on-bone stage. Joint arthritis can arise from an intrinsic normal cartilage supported by weakened ultrasound has been applied in studies problem of the cartilage as encoun- subchondral bone to identify OA earlier, but this is more tered after years of chronic inflamma- • Avascular necrosis a research tool than a routine clinical tory arthritis.11 Thus, OA can occur Source: Adapted from Mitchell NS, Cruess RL.11

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is gaining increasing recognition as a major structural precursor to hip OA. These are usually asymptomatic before possible progression to OA and can be seen on a screening AP pelvis radi- ograph. Such pre-symptomatic X- rays, however, are not ordered rou- Subtle and asymptomatic anatomic tinely. variations have been associated Genetic factors with hip osteoarthritis. The strongest association between genetic factors and OA applies to gen- eralized osteoarthritis of the hands. Evidence for a correlation between genetics and knee or hip OA is less conclusive.15,16

Physical activity Although the health of cartilage and with (A) normal force on abnormal Gender and the other joint tissues requires regular cartilage. Alternatively, it can occur estrogen connection joint loading, excessive loading may with (B) abnormal concentrations of Women are more likely than men to contribute to OA. While some studies force on normal cartilage. This would have OA, be it generalized OA of the suggest a strong positive relationship implicate mechanical aberrations such hands or OA of the hips and knees.12 between work-related knee bending as malalignment, the post-meniscecto- The increase in OA in menopausal exposure and knee OA, others have my knee, or a cruciate deficient knee. women has led to numerous investi- failed to find a direct relationship The abnormally formed hip mention - gations into the relationship between between the presence of knee OA ed above would fall into this category hormonal factors and OA. The results and habitual physical activity or rec- as well. have been conflicting and inconclu- reational running.17 A relationship Mitchell and Cruess’s classifica- sive.13,14 Clearly, other health issues between heavy manual work, farming tion system also includes situations are of concern when determining in particular, and hip OA was found in where there is (C) stiffened subchon- whether hormone replacement thera- different studies, but the association is dral bone, as in the case of the rare py is to be considered in the post- still considered a weak one.18 Paget disease, which does indeed pre- menopausal patient. Although it makes sense that high dispose to OA of an involved joint. levels of impact and repeated torsion- Alternatively, they describe situations Congenital/developmental al loading could increase the risk of where (D) weakened subchondreal abnormalities articular cartilage degeneration, this bone, as in avascular necrosis, predis- Local factors that affect the shape of is not borne out consistently in stud- poses to OA. the joint may increase local stress on ies. Still, it would appear prudent to cartilage and contribute to the devel- suggest that anyone with a known Risk factors for OA opment of osteoarthritis, especially in underlying predisposition to OA, such OA is best viewed as the end result of the hip joint. As already mentioned, as abnormal hip or joint anatomy or an interplay between local and sys- subtle and asymptomatic anatomic excessive body weight, avoid repeti- temic factors. Such factors are well variations have been associated with tive impact-loading activities such as outlined in the classification schema hip osteoarthritis. These include ace - jogging. of mechanical factors proposed by tabular dysplasia or epiphysiolysis, Mitchell and Cruess. Several local which are common milder variants of Obesity systemic factors may be operative in congenital hip dislocation and slipped Every step taken in a normal gait places predisposing patients to OA of the hip capital femoral epiphysis, respective- about three times an individual’s body or knee. ly.10 Femoralacetabular impingement weight on lower limb joints. Thus it

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should not be surprising that obesity tis. An exception to this is the pres- deformity that will challenge accurate and high body mass index have long ence of intra-articular fractures, that leg length measurement. It is key to been recognized as potent risk factors is, fractures that extend though the place the patient’s legs in proper align- for OA, especially medial compart- joint line. The disruption of the carti- ment. There should be an equal dis- ment OA of the knee in females. lage and subchondral bone with an tance between the medial malleoli The Framingham Study found that intra-articular fracture does portend a of the ankles, and the feet should be women who lost about 5 kg had a 50% heightened risk of OA of the involved centred in a neutral position under the reduction in the risk of developing joint in future decades. Trauma of corresponding hips. The apparent leg new symptomatic knee OA.19 Weight- the knees leading to internal knee length is measured from the umbilicus loss interventions have been shown to derangement such as a mensical or to the medial malleolus on each side. decrease pain and disability in estab- major ligamentous tear will predis- A discrepancy usually signals a scol- lished knee OA. The Arthritis, Diet, pose to osteoarthritis. In the case of iosis. The true leg length is measured and Activity Promotion Trial showed the hip, acetabular labral tears, which from the anterior superior iliac spine that weight loss combined with exer- can only be seen on MRI combined to the medial malleolus, and a discrep- cise, but not either weight loss or exer- with an arthrogram, will increase the ancy suggests a true variation between cise alone, was effective in decreasing risk of future OA of the involved hip the two legs. For a true leg length dis- pain and improving function in obese joint. An acetabular labral tear is often crepancy of more than 1 cm, a shoe lift elders who already had symptomatic an indication for hip arthroscopy to or built-up orthotic that adjusts for half knee OA.20 trim the torn fragment. Hip arthros - of the leg length difference is typical- When patients ask their physicians copy is not often done for diagnostic ly recommended. For a large discrep- how they can prevent OA of the knees, purposes because MRI is so effective ancy this may not be readily attainable. weight control is paramount. Unfortu- at picking up lesions. Varus deformities, valgus deform- nately weight loss is challenging in It is thought that blunt trauma such i ties, and cruciate ligament tears are established OA of the knee due to the as contact with a dashboard in a motor other factors that can predispose to the limited physical activity possible. vehicle accident can lead to patello - development and progression of knee The relationship between excess femoral syndrome and chondromala- OA. Detailed discussion of such fac- weight and hip OA is less clear. The cia patella. However, whether these tors is beyond the scope of this article. evidence in hip OA is not as compel - pre-OA lesions will progress in future Like the medial compartment and ling as with knee OA.21,22 decades to full thickness confluent the lateral compartment, the patello - In addition, there is evidence that cartilage loss signifying OA has not femoral compartment of the knee is obesity predisposes to osteoarthritis been determined. often afflicted with OA. While injury in non-weight-bearing joints such as is a common factor in medial and lat- the joints of the hand. Clearly excess Alignment, including leg length eral compartment OA, malalignment weight in a biomechanical sense alone Strong evidence suggests that altered is a more common factor in patel- does not explain this finding. Recent mechanics play a role in OA incidence lafemoral OA. Most cases of chon- studies have shown that body fat, par- and progression, and recent studies dromalacia patella that result from ticularly central fat deposits, are bio- are beginning to isolate specific malalignment are nonprogressive, but chemically active and produce sub- mechanical factors that may be of par- some can progress to OA.24 stances such as leptin and adiponectin.23 ticular importance. Such alignment It has also been shown that leptin can problems include a leg length discrep- Conclusions induce the formation of cytokines, ancy of more than 1 cm, which con- OA of the hip and knee is a major such as interleukin-6, which can have fers an increased risk of OA of the hip health care issue in an ever-aging pop- a deleterious effect on chondrocytes on the long leg side. All patients ulation. OA of weight-bearing joints of the cartilage. should be assessed for this. confers major disability and compro- Leg length measurements include mised quality of life. At this time, Trauma the apparent and the true leg length. medical treatment of OA is not as In general, there is a paucity of good To measure leg length, you should sophisticated as the treatment of documentation to support the con- have the patient lie flat on his or her rheumatoid arthritis. All too often we tention that blunt trauma to a joint back on the examining table and en- fail with conservative treatment, and increases the risk of future osteoarthri- sure that there is no hip or knee flexion patients with hip and knee OA progress

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to total joint arthroplasty. Advances in al. Correlation between radiographically The risk of osteoarthritis with running and joint replacement seem to overshad- diagnosed osteophytes and magnetic aging: A 5-year longitudinal study. J ow advances in more conservative resonance detected cartilage defects in Rheumatol 1993;20:461-468. medical treatment of OA. The better the patellofemoral joint. Ann Rheum Dis 18. Maetzel A, Makela M, Hawker G, et al. we understand the underlying causes 1998;57:395-400. Osteoarthritis of the hip and knee and and mechanisms of OA, the better we 9. Brandt KD. Osteoarthritis: Clinical pat- mechanical occupational exposure—A will be equipped to develop more pro- terns and pathology. In: Kelly W, Harris E, systematic overview of the evidence. J gressive early interventions for this Ruddy S, et al. (eds). Textbook of rheuma- Rheumatol 1997;24:1599-1607. common affliction. As Ilardi and tology. 2nd ed. Philadelphia: Sauders; 19. Felson DT, Zhang Y, Anthony JM, et al. Sokoloff, two pioneers in the study of 1985:1432. Weight loss reduces the risk for sympto- OA, said several decades ago, “Our 10. Stulberg SD, Harris WH. Acetabular dys- matic knee osteoarthritis in women. The treatment of osteoarthritis can be no plasia and development of osteoarthritis Framingham Study. Ann Intern Med more rational than our understanding of the hip. In: Harris WH (ed). The hip. 1992;116:535-539. of its pathogenesis.”25 Proceedings of the Second Open Scien- 20. Messier SP, Loeser RF, Miller GD, et al. tific Meeting of the Hip Society. St Louis: Exercise and dietary weight loss in over- Competing interests CV Mosby; 1974:82. weight and obese older adults with knee None declared. 11. Mitchell NS, Cruess RL. Classification of osteoarthritis: The Arthritis, Diet, and degenrative arthritis. Can Med Assoc J Activity Promotion Trial. Arthritis Rheum References 1977;117:763. 2004;50:1501-1510. 1. Hannan MT, Felson DT, Pincus T. Analy- 12. Srikanth VK, Fryer JL, Zhai G, et al. A 21. Heliovaara M, Makela M, Impivaara O, et sis of the discordance between radi- meta-analysis of sex differences in preva- al. Association of overweight, trauma and ographic changes and knee pain in osteo- lence, incidence and severity of osteo - workload with coxarthrosis. A health sur- arthritis of the knee. J Rheumatol 2000; arthritis. Osteoarthritis Cartilage 2005; vey of 7,217 persons. Acta Orthop Scand 27:1513-1517. 13:769-781. 1993;64:413-518. 2. Lawrence RC, Felson DT, Helmick CG, et 13. Nevitt MC, Felson DT, Williams EN, et al. 22. Karlson EW, Mandl LA, Aweh GN, et al. al. Estimates of the prevalence of arthri- The effect of estrogen plus progestin on Total hip replacement due to osteoarthri- tis and other rheumatic conditions in the knee symptoms and related disability in tis: The importance of age, obesity, and United States. Part II. Arthritis Rheum postmenopausal women: The Heart and other modifiable risk factors. Am J Med 2008;58:26-35. Estrogen/Progestin Replacement Study, 2003;114:93-98. 3. Agency for Healthcare Research and a randomized, double-blind, placebo-con- 23. Simopoulou T, Malizos KN, Iliopoulos D, Quality. Hospitalizations for osteoarthri- trolled trial. Arthritis Rheum 2001;44: et al. Differential expression of leptin and tis rising sharply. Newswise. www.news 811-818. leptin’s receptor isoform (Ob-Rb) mRNA wise.com/articles/hospitalizations-for- 14. Hannan MT, Felson DT, Anderson JJ, et between advanced and minimally affect- osteoarthritis-rising-sharply (accessed al. Estrogen use and radiographic osteo - ed osteoarthritis cartilage; effect on car- 27 July 2010). arthritis of the knee in women. The Fram- tilage metabolism. Osteoarthritis Carti- 4. Kopec JA , Rahman MM, Berthelot ingham Osteoarthritis Study. Arthritis lage 2007;15:872-883. J-M, et al. Descriptive epidemiology of Rheum 1990;33:525-532. 24. Hunter DJ, Zhang YQ, Niu JB, et al. Patel- osteoarthritis in British Columbia, Cana- 15.Zhai G, Ding C, Stankovich J, et al. la malalignment, pain and patellofemoral da. J Rheumatol 2007;34:386-393. The genetic contribution to longitudinal progression: The Health ABC Study. 5. Murphy L, Schwartz T, Helmick CG, et al. changes in knee structure and muscle Osteoarthritis Cartilage 2007;15:1120- Lifetime risk of symptomatic knee osteo- strength: A sibpair study. Arthritis Rheum 1127. arthritis. Arthritis Rheum 2008;59:1207- 2005;52:2830-2834. 25. Ilardi CF, Sokoloff L. The pathology of 1213. 16. Lian K, Zmuda JM, Nevitt MC, et al. Type osteoarthritis: Ten strategic questions 6. Leach RE, Gregg T, Siber FJ. Weight- I collagen alpha1 Sp1 transcription factor for pharmacologic management. Semin bearing radiography in osteoarthritis of binding site polymorphism is associated Arth ritis Rheum 1981;11:3-7. the knee. Radiology 1970;97:265-268. with reduced risk of hip osteoarthritis 7. Cibere J. Do we need radiographs to defined by severe joint space narrowing diagnose osteoarthritis? Best Pract Res in elderly women. Arthritis Rheum 2005; Clin Rheumatol 2006;20:27-30. 52:1431-1436. 8. Boegard TL, Rudling O, Petersson IF, et 17. Lane NE, Michel B, Bjorkengren A, et al.

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