Osteoarthritis

Best Practice & Research Clinical Rheumatology 25 (2011) 801–814

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Osteoarthritis David J. Hunter* Rheumatology Department, Royal North Shore Hospital and Northern Clinical School, University of Sydney, Sydney, NSW, Australia

Keywords: Osteoarthritis Prevention Progression

The pathogenesis of osteoarthritis (OA) appears to be the result of a complex interplay between mechanical, cellular and biochemical forces. Obesity is the strongest risk factor for disease onset in the knee, and mechanical factors dominate the risk for disease progression. OA is a highly prevalent and disabling disease. The current pre-eminent focus in OA research and clinical practice is on persons with established radiographic symptomatic disease. This is the very end-stage of disease genesis, and modern therapies hence are largely palliative. In an effort to mitigate the rising tide of increasing OA prevalence and disease impact, we need to focus more on preventing the onset of disease and modifying the structural progression of OA. Greater therapeutic attention to the important role of mechanical factors, joint injury and obesity in OA etiopathogenesis, is required if we are to find ways of reducing the public health impact of this condition. Ó 2011 Elsevier Ltd. All rights reserved.

Osteoarthritis (OA) is a highly prevalent and disabling disease that consequently has a formidable individual and societal impact. Approximately 10–12% of the adult population has symptomatic OA [1,2]. The risk of mobility disability (defined as needing help walking or climbing stairs) attributable to knee OA alone is greater than that due to any other medical condition in people aged 65 and over [3,4]. OA reduces both quality and quantity of life. In the estimates for the Global Burden of Disease 2000 study [5], OA is the fourth leading cause of total years lost due to disease at the global level. On average, a 50–84-year-old non-obese person with knee OA will lose 1.9 quality-adjusted life years due to OA [6]. If obese with knee OA, this increases loss to 3.5 quality-adjusted life years and the estimated remaining quality-adjusted life expectancy is decreased by 21–25%. This effect of symptomatic knee OA on quality of life is similar to that of metastatic breast cancer. A recent study also found that persons with OA are at

* Tel.: þ61 2 9926 7379; fax: þ61 2 9906 1859. E-mail address: [email protected]. 1521-6942/$ – see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.berh.2011.11.008

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higher risk of death compared with the general population (standardised mortality ratio 1.55, 95% confidence interval 1.41–1.70) [7]. If you consider OA to be a common disease now, by the year 2020, the number of people with OA will have doubled, due in large part to the exploding prevalence of obesity and the greying of the ‘baby boomer’ generation [8]. This will have a tremendous impact on already strained health-care resources with most western countries spending 1–2% of their gross domestic product on care for persons with arthritis [9]. A large component of the direct health-care costs for managing persons with OA is the cost of total joint replacements, for which OA accounts for about 95% of surgical volume. The aetiology of OA OA is a heterogeneous disease characterised by failure of the synovial joint organ [10]. The disease occurs when the dynamic equilibrium between the breakdown and repair of joint tissues becomes unbalanced, often in a situation where the mechanical loads applied exceed those that can be tolerated by the joint tissues [11]. OA is characterised by progressive cartilage loss, subchondral bone remodelling, osteophyte formation and synovial inflammation, with resultant joint pain and increasing disability (see Fig. 1). Whilst the progressive joint failure may cause pain and disability [4], many persons with structural changes consistent with OA are asymptomatic [12]. The aetiology of OA is perhaps best understood as resulting from excessive mechanical stress applied in the context of systemic susceptibility. Susceptibility to OA may be increased in part by

Fig. 1. Schematic of the knee joint depicting the synovial joint tissues affected in OA. Modified from [98]. Consistent with the theory that OA is a disease of the whole synovial joint.

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genetic inheritance (a positive family history increases risk), age, ethnicity, nutritional factors and female gender [13]. In persons vulnerable to the development of knee OA, local mechanical factors such as abnormal joint congruity, joint malalignment, muscle weakness or alterations in the structural integrity of the joint environment such as meniscal damage, bone-marrow lesions or ligament rupture can facilitate susceptibility to, and progression of, OA. Loading can also be affected by obesity and joint injury (either acutely as in a sporting injury or after repetitive overuse such as occupational exposure), both of which can increase the likelihood of development or progression of OA. In epidemiological investigation, OA is typically defined using conventional radiographs, and less frequently self-report. The reported prevalence of OA varies according to the method used to define the disease. The characteristic radiographic features used to define and classify OA severity are osteophytes (osteocartilaginous growths) (Fig. 2), subchondral sclerosis and joint space narrowing. By contrast, symptomatic OA is defined as the concomitant presence of pain (usually defined as pain on most days of the last month) and radiographic features. It is the presence of symptomatic OA that is important clinically, not simply the radiographic identification of an osteophyte or self reported OA (where misclassification is even more problematic than the commonly used radiographic OA definition). Before commenting on the prevalence of different joint involvement in OA, it is important to note that OA is not just a disease of elderly persons, with approximately two-thirds of patients with OA being less than 65 years of age. During a one-year period, 25% of people over 55 years of age have a persistent episode of knee pain, of whom about one in six consult their general practitioner about it

Fig. 2. Knee X-ray shows diffuse marginal osteophytosis of the tibia and femur (arrows).

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[14]. Population-based estimates suggest that about 6% of adults aged >30 years and 13% of persons aged 60 and over have symptomatic knee OA [15]. While OA is common in the knee, it is even more prevalent in the hands, especially the distal and proximal interphalangeal joints and the base of the thumb (carpometacarpal (CMC) joint). When symptomatic, especially so for the base of thumb joint, hand OA is associated with functional impairment, substantial pain, instability, deformity and loss of motion [16]. Over the age of 70 years, approximately 5% of women and 3% of men have symptomatic OA affecting this joint with impairment of hand function [16]. The prevalence of hip OA is about 9% in Caucasian populations [17]. By contrast, studies in Asian, black and East Indian populations indicate a very low prevalence of hip OA [18]. The prevalence of symptomatic hip OA is approximately 4% [15].

Will we cure OA and how? In 1743, William Hunter stated soberly “From Hippocrates to the present age it is universally allowed that ulcerated cartilage is a troublesome thing and that once destroyed, is not repaired” [19]. Whilst modern definitions describe OA as a disease of the whole synovial joint organ (cartilage has lost its centricity), it remains true that once lost, ulcerated cartilage cannot truly be repaired. It will be more straightforward to prevent disease than cure it through reversing (‘curing’) the structural changes that occur with disease. Preventing OA is achievable if appropriate resources and attention are paid towards it. At present most of the health-care resources spent on OA management are directed towards persons whose joints have failed in the latter stages of disease. If we are to truly impact the dramatic prevalence of this disease, prevention has to become part of the equation (see Table 1 for examples of this). Like many diseases in our ‘modern’ evolving society, the true impact of our ageing community and increasing overweight and obesity has not reached its full peak. If we wait for this to occur and do little to address the effect of these risk factors on the oncoming epidemic of OA, our already stretched health-care resources will be overwhelmed [20]. Many of the attendant risk factors for disease development and its progression are modifiable, yet at present we do little to modify them. Take knee OA as the first example. While undoubtedly the aetiology of OA is multifactorial [13], the two major risk factors for knee OA development (obesity and joint injury [21,22]) are modifiable. Obesity is the single most important risk factor for development of severe OA of the knee and more so than other potentially damaging factors including heredity [17,23]. For every 1 kg of weight carried by the body, the contact load across the knee joint experiences 4 times that load [24]. Societal trends in obesity are concerning with some projecting by 2030, 86.3% of adults will be overweight or obese; and Table 1 Currently OA management is largely focused on palliation. More resources and effort should be shifted towards strategies before end-stage disease occurs as outlined in the examples below. Modified from [100]. Primary prevention

Secondary prevention/ impacting disease incidence

Tertiary prevention/ impacting progression

Palliation

Risk/ Phenotype

Predisposition through obesity or risk of joint injury

Malalignment, symptomatic disease

Joint failure

Possible interventions

Weight reduction strategies for the obese or neuromuscular training for sports participation to reduce injury risk Overweight and obesity assessment and identification of high risk sports Population level overweight and obesity prevalence or joint injury incidence

Femoro-acetabular impingement (FAI), familial risk, prior joint injury Surgical correction of FAI, disease modification

Alignment correction through mechanical intervention or diseasemodifying therapy MRI or radiographic assessment

Analgesia or joint replacement

MRI or radiographic assessment

Self reported symptoms

Possible screening Monitoring assessment

Joint shape MR imaging or biochemical markers MRI of shape and joint integrity

Self reported symptoms

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51.1%, obese [25]. Primary prevention of obesity is likely to be challenging and involve complex strategies including tax on processed foods, supporting healthy food alternatives, promoting physical activity, restricting unhealthy food advertising and appropriate labelling of food. Whilst these strategies may be socially challenging, weight reduction at the population level as a public health measure would be very effective in reducing knee and hip OA incidence. We need to carefully model how best to spend our health-care resources balancing out the alternatives competing for health-care resources of reducing overweight and obesity or waiting to intervene on symptomatic radiographic disease. Focussing weight reduction efforts on only women aged 50 and over could itself prevent anywhere from 25.1% to 48.3% of knee OA in women [17]. Despite trial evidence of the efficacy of weight loss interventions, wider dissemination of this to the at-risk community has been limited. In addition, the impacts of weight reduction from a co-morbidity perspective will be profound. If obesity prevalence were reversed to the levels seen 10 years ago, a modest reduction in mean body mass index (BMI) of only 0.6 unit (1.7 kg reduction for a person about 170 cm), it is estimated that this small reduction would avert 0.7% coronary heart disease cases, 2.5% diabetes mellitus cases and 1.9% total knee replacements over the remaining life span of the US population [6]. Anterior cruciate ligament (ACL) injuries have an incidence of at least 81 per 100,000 persons annually aged between 10 and 64 years [26]. ACL ruptures are associated with marked short-term morbidity and long-term consequences. It typically occurs in the younger population and as such leads to prolonged disability and economic cost [27]. largely due to work loss. As many as 77% of formerly young and active individuals who sustain ACL injuries end up with moderate to severe disabilities, like OA, instability, meniscal and chondral surface damage [28]. ACL ruptures have been found to be linked to osteoarthritic (OA) changes in 50–70% of the patients, 10–15 years following the injury [29,30]. Knee injury/trauma has been identified as the most important modifiable risk factor for subsequent knee OA in men and is second only to obesity in women [31]. It is estimated that 25% of incident symptomatic knee OA could be prevented by preventing knee injuries among men (women, 14%) [17]. Numerous trials of neuromuscular conditioning programmes have demonstrated efficacy in reducing the risk of ACL injury by as much as 60% [32]. Despite the impact of joint injury and the efficacy of these prevention trials, dissemination and implementation of neuromuscular conditioning programmes have been limited. Similar to knee OA, the number of persons with hip OA in our community is increasing and there are opportunities for prevention of this disabling disease [17]. There is strong evidence that mechanical and structural changes around the hip are major etiological factors in the development of hip OA [33]. As much as 90% or more of hip OA cases can be attributed to anatomical abnormalities termed ‘femoroacetabular impingement (FAI)’ [34,35]. FAI describes repetitive abutment between the proximal femur and the acetabular rim, due to either abnormal hip morphology or excessive hip motion, in patients with no childhood history of hip pathology. Patients, typically young (20’s and 30’s [36]), active adults, generally present with groin pain [37]. FAI is estimated to affect 10–15% of the general population [38], which suggests that not all cases lead to OA. Two mechanisms by which the cartilage and labrum are affected by FAI have been described [35]. Cam impingement is a result of a non-spherical femoral head abutting against the acetabular rim in flexion and internal rotation (Fig. 3B). The abutment creates shear forces resulting in damage to the anterosuperior acetabular cartilage. Pincer impingement occurs as a result of linear contact between the femoral head–neck junction and the acetabular rim (Fig. 3C). Repeated abutment leads to degeneration of the labrum and circumferential cartilage damage [39]. Recent advances in surgical techniques, such as the arthroscopic debridement and periacetabular osteotomy [40], have provided us with powerful techniques to correct these anatomic abnormalities. Their potential to reduce the incidence of hip OA needs formal evaluation.

Preclinical disease – can this be addressed? Unfortunately, at present there is no OA equivalent to measuring high lipid levels, atherosclerosis, hypertension or high glucose and glucose tolerance, for example, as we have for cardiovascular disease and diabetes, where one can detect and treat the disease precursors pre-emptively before the

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Fig. 3. Femoro-acetabular impingement disease patterns [99]. The reduced clearance during joint motion leads to repetitive abutment between the proximal femur and the anterolateral acetabular rim. (A) Normal clearance of the hip, (B) Reduced femoral head-neck offset (cam impingement). (C) Excessive coverage of the femoral head by the acetabulum (pincer impingement), and (D) Combination of reduced head-neck offset and excessive femoral head coverage (combined impingement).

associated processes lead to end-organ failure (Table 2). Instead, the ‘watchful waiting’ of steady decline to end-stage joint disease is a major cause of disablement and loss of quality of life. Recent advances in other prevalent rheumatic diseases have resulted in diseases that were associated with inexorable decline, be treated proactively with associated preservation of structure and function. The advance of biologic therapy in rheumatoid arthritis has seen dramatic shifts in preservation of structure and discussion of a new classification of disease remission. Recent evolution in medical care for osteoporosis has seen a marked reduction in fracture rates with their associated morbidity, with the appropriate institution of anti-resorptive therapy. Unfortunately, we do not have this proactive stance available in OA, and with current structural definitions and measurement strategies that is unlikely to change. We desperately need to focus on earlier disease where changes may be reversible, if we are not to continue current therapeutic approaches that are largely palliative. Table 2 Osteoarthritis comparisons with other common, chronic diseases with substantive morbidity. Our current management paradigm for OA targets organ failure. (Modified from [100]). Molecular abnormality

Silent/subclinical disease

Symptomatic disease

Organ failure

Abnormal biochemical markers Elevated blood sugar

Asymptomatic structural abnormality e.g. MRI Arteriosclerosis

Symptomatic osteoarthritis

Joint failure Renal failure, blindness

Hyperlipidaemia Elevated anti-CCP and RF Bone turnover favouring resorption

Atherosclerosis

Mild nephropathy, visual impairment Myocardial infarction Symptomatic rheumatoid arthritis

Osteoporosis on DEXA

Heart failure Joint deformity Fracture

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A number of obstacles exist to revising the status of OA care, but foremost amongst these is our penchant to use radiography to diagnose and study OA [41]. This means of defining disease serves to limit itself to a disease window that evaluates only some of the synovial joint features affected by OA, and this evaluation may reflect the latter stages of disease evolution. Other technologies such as magnetic resonance imaging (MRI) may be more sensitive to early pathologic changes [42]. Efforts to modify the course of the disease may not be successful if we focus on late disease when the mechanical derangements overwhelm any reparative potential [43]. If non-surgical interventions as a single therapy are to be trialled effectively, selecting those with earlier disease, prior to the development of marked aberrant mechanics, is a preferable solution. The denudation of cartilage (subchondral bone exposed) is not reversible and by the time persons develop radiographic OA, the overwhelming majority of persons have areas of denuded cartilage [44]. MRI studies provide strong evidence that ascertainment of disease on radiographs only provides insights into late-stage disease [45,46]. Further, we need to identify and target the tissue that leads to the cascade of events we describe as joint failure. Preclinical studies with varying levels of efficacy success suggest that a wide array of agents including glucosamine sulphate, chondroitin sulphate, sodium hyaluronan, doxycycline, MMP inhibitors, bisphosphonates, calcitonin, diacerein and avocado–soybean unsaponifiables can modify disease progression [47]. At this point, however, there is no pharmacologic agent that has been approved by regulatory authorities for disease modification in OA. It may be a while before a disease-modifying drug is available as current trial strategies remain neglectful of some simple fundamentals. Cartilage is not a direct source of symptoms and yet this remains the major focus of drug development opportunities. Our current paradigm of studying persons with end-stage irreversible disease needs to change if we are to identify a stage of the disease where the structural changes may be reversible. There are promising therapies being developed for new OA targets for both symptoms and structure, but we need to pay heed to the lessons we have learnt and consider the obstacles to development if they are to be effective [48]. The role of inflammation This imbalance between the breakdown and repair of joint tissues in OA is the result of the activation of joint cells by inflammatory mediators, matrix components and mechanical stress [49]. A number of putative mediators have been implicated in the catabolic process including proteases, cytokines (e.g., matrix metalloproteases and interleukin-1b, respectively), growth factors and radicals [50]. Counterbalancing this insulin growth factor (IGF)-1, transforming growth factor (TGF)-b and bone morphogenetic proteins (BMPs) are endogenous anabolic factors that stimulate bone and cartilage generation and remodelling [51,52]. At the macroscopic level, inflammation is directly linked to clinical symptoms such as joint swelling, synovitis and inflammatory pain. On biopsy, the synovial reaction in OA includes synovial hyperplasia, fibrosis, thickening of synovial capsule, activated synoviocytes and, in some cases, lymphocytic infiltrate (B- and T-cells as well as plasma cells) [53]. The site of infiltration of the synovium is of relevance as one of the most densely innervated structures of the joint is the white adipose tissue of the fat pad which also shows evidence of inflammation and can act as a rich source of inflammatory adipokines [54]. Synovial causes of pain include irritation of sensory nerve endings within the synovium from osteophytes and synovial inflammation that is due, at least in part, to the release of prostaglandins, leukotrienes, proteinases, neuropeptides and cytokines [55,56]. Non-invasive imaging techniques such as MRI and ultrasonography can visualise this change in vivo. Synovitis and effusion are frequently present in OA and relate to pain and other clinical outcomes [57]. A semi-quantitative measure of synovitis from the infrapatellar fat pad is associated with pain severity, and similarly change in synovitis is associated with change in pain severity [58]. Of the three locations for synovitis in this study, changes in the infrapatellar fat pad were most strongly related to pain change. In an important caveat to this analysis, a recent study compared non-enhanced fat-suppressed proton density-weighted MRI with fat-suppressed contrast-enhanced (CE) T1-weighted MRI for semiquantitative assessment of peripatellar synovitis in OA [59]. This data suggested that signal alterations in Hoffa’s fat pad on non-enhanced MRI do not always represent synovitis as seen on CE T1-weighted MRI but are a rather non-specific albeit sensitive finding.

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As synovitis is associated with clinical symptoms, synovium-targeted therapy could help alleviate the symptoms of the disease. Efficacy of intra-articular corticosteroids is presumably through their action on the synovium, although their widespread use in clinical practice is questionable. Their maximum efficacy usually appears within less than 1 week, however, their benefits typically do not last beyond 2–4 weeks [60]. Furthermore, there are legitamate concerns that steroids may speed up progression of OA particularly when injected repeatedly. The synovium is densely innervated by small-diameter sensory nerve fibres [61]. IL-1 b and TNFa have the capacity to excite and sensitise nociceptors and contribute in vivo to behavioural signs of inflammatory hyperalgesia [62]. Moreover, cytokines enhance the release of PGE2 and histamine from chondrocytes and mast cells, which in turn can (indirectly) increase the sensitisation of nociceptors [63]. Widespread use of TNF inhibitors and other biologics in the treatment of rheumatoid arthritis has led to unprecedented success in disease management. Intra-articular injection of specific IL-I inhibitors or antagonists has been shown to slow disease progression in animal models of OA. By contrast, the first randomised placebo-controlled trial of an IL-1 beta antagonist (a single intra-articular injection of 50 or 150 mg) had no analgesic effect during 3 months of follow-up [64], although 150 mg of IL-1 ra had an early analgesic effect. Anti-TNF alpha therapy has also been tested in isolated cases of digital and knee OA with little success in clinical trials to date. Pain and how it can be addressed The determinants of pain and mechanical dysfunction in OA are not well understood, but are believed to involve multiple interactive pathways that are best framed in a biopsychosocial framework (posits that biological, psychological and social factors all play a significant role in pain in OA) [56,65]. From a biological perspective, neuronal activity in the pain pathway is responsible for the generation and ultimate exacerbation of the feeling of joint pain. During inflammation, chemical mediators are released into the joint which sensitise primary afferent nerves such that normally innocuous joint movements (such as increased physical activity, high heeled shoes and weather changes) now elicit a painful response. This is the neurophysiological basis of allodynia that is, the sensation of pain in response to a normally non-painful stimulus such as walking. Over time, this increased neuronal activity from the periphery can cause plasticity changes in the central nervous system by a process termed ‘wind-up’. In this instance, second-order neurones in the spinal cord increase their firing rate such that the transmission of pain information to the somatosensory cortex is enhanced. This central sensitisation phenomenon intensifies pain sensation and can even lead to pain responses from regions of the body remote from the inflamed joint, that is, referred pain. Constitutional factors that can predispose to symptoms including self-efficacy, pain catastrophising and the social context of arthritis (social support, pain communication) are all important considerations in understanding the pain experience. The symptoms of OA are typically described as mechanical, that is, they occur with physical activity. However, subjects with the same degree of structural damage experience widely different levels of pain, a phenomenon that is poorly understood [56]. In population studies, there is a significant discordance between radiographically diagnosed OA and knee pain [12]. Whilst radiographic evidence of joint damage predisposes to joint pain, it is clear that the relation of the severity of joint damage to the severity of the pain is not strong. However, using other imaging modalities such as MRI, numerous structural alterations evident on MRI such as subchondral bone-marrow lesions [66], subarticular bone attrition [67], synovitis and effusion [57,58] have been related to knee pain. It remains unclear which of these local tissue factors predominate. The recommended hierarchy of pain management for OA should consist of non-pharmacologic modalities first, then drugs and then surgery. Too frequently, the first step is forgotten or not emphasised sufficiently to the patients’ detriment [68]. In the absence of a cure, current therapeutic modalities are primarily aimed at reducing pain and improving joint function by agents targeted towards symptoms that do not facilitate any improvement in joint structure or long-term disease amelioration [69,70]. The standard pattern of management of OA in clinical practice is analgesia followed by surgical intervention. The most widely used analgesic agents, non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors are associated with high rates of adverse events [71,72]. In

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addition, these drugs rarely relieve symptoms completely. In clinical trials of OA, different NSAIDs performed similarly, with persons reporting an approximate 30% reduction in pain and 15% improvement in function [73]. As a clinician managing OA pain, efforts should be made where possible to influence modifiable risk factors. In the first instance, the clinical encounter should target identification of individual risk factors (including altered alignment, obesity and muscle weakness) and the therapeutic intervention should be tailored to target the individual. The majority of persons with OA are overweight or obese, there is good evidence for the efficacy of weight management for OA [74] and this is advocated by most OA guidelines [69,70,75]. In practice, however, weight management is not frequently implemented [76]. If someone is overweight or obese they should be engaged in a combination diet and exercise programme aimed at weight reduction of greater than 5% of body weight [74]. Trial results suggest this leads to an approximately 30% improvement in pain and function [74]. Another pivotal and frequently ignored [76] aspect of conservative treatment of OA is exercise. Exercise increases aerobic capacity, muscle strength and endurance, and also facilitates weight loss [74]. All persons capable of exercise should be encouraged to partake in a low impact aerobic exercise programme (walking, biking, swimming or other aquatic exercise) designed not to aggravate their underlying symptoms. Quadriceps weakness is common among patients with knee OA, in whom it had been believed to be a manifestation of disuse atrophy, which develops because of unloading of the painful extremity [77]. Quadriceps strengthening exercises have been demonstrated to lead to improvements in pain and function [78]. Quadriceps weakness is also a risk factor for the development of knee OA, presumably by decreasing stability of the knee joint and reducing the shock-attenuating capacity of the muscle [77,79]. Recently, a clinical trial evaluated the effects of lower-extremity strength training on knee OA progression [80]. The strength training group experienced less frequent progression than the range of motion comparator. Guidelines routinely advocate exercise [69,70,75], however, clinical practice does not reflect this recommendation [76]. Can mechanical intervention modulate progression of OA? Modern insights no longer see OA as a passive, degenerative (yes that’s right – the use of this term is archaic) disorder but rather as an active disease process with an imbalance between the repair and destruction of joint tissues that is driven primarily by mechanical factors [81,82]. Local mechanical factors such as the adduction moment, malalignment and muscle strength make the knee joint vulnerable to the development and progression of OA [83]. The lower limb synovial joint bears considerable forces on the articular surfaces during weight bearing. In theory, any shift from a neutral or collinear alignment of the hip, knee and ankle affects load distribution at the knee [84]. The medial tibiofemoral compartment bears a resultant 60–70% of the force across the neutrally aligned knee during weight bearing [85] and, because it is subjected to more load than the lateral compartment, this may play a role in the predisposition to medial tibiofemoral compartment progression in OA [86]. In a varus knee, this axis passes medial to the knee and a moment arm is created, which further increases force across the medial compartment. By contrast, in a valgus knee, the load-bearing axis passes lateral to the knee, and the resulting moment arm increases force across the lateral compartment [84]. Varus and valgus malalignment, respectively, have been shown to increase the risk of subsequent medial and lateral knee OA radiographic progression [87]. Malalignment provides only a static impression of the mechanical forces being imparted on the joint in one plane. The dynamic moment that provides a major contribution to the total loading across the knee joint is usually labelled the adduction (or external varus) moment at the knee [85]. Higher maximum adduction moments at the knee are related to OA disease severity and to a higher rate of progression of knee OA [88,89]. Of the risk factors known to be associated with disease progression, the adduction moment is the most potent that has been identified [89]. Understanding the role alignment plays in OA etiopathogenesis is important because it modulates the effect of standard risk factors for knee OA progression including obesity [90] and quadriceps strength [91]. The patellofemoral (PF) joint transmits relatively high forces through relatively small contact areas. The PF joint reaction force (JRF) increases with increasing knee flexion. The JRF during walking (10–15 of flexion) is approximately 50% of body weight. Walking up stairs (60 ), the JRF is 3.3 times body

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weight. During squats (130 ), the JRF is 7.8 times body weight [92]. It is therefore not surprising that the patella is involved in over half of cases of symptomatic knee OA, with combined tibiofemoral and PF OA found in 41% of subjects and isolated PF disease found in 11% of subjects [93]. The pain and disease progression of PF OA occur when abnormal kinematics (lateral patellar tilt) produce excessive pressure on the lateral patellar facet [94]. A number of studies have demonstrated that the relation of the patella with reference to the femur plays a critical role in determining the rate of disease progression and predisposing to symptoms in persons with PF OA [95,96]. There is strong evidence that mechanical and structural changes around the hip are major etiological factors in the development of hip OA [33,34]. Despite their current under-emphasis in clinical trials and practice, therapies targeting the pathomechanics of OA are efficacious [97]. At present, there are a number of therapeutic options that can modify joint forces, including patella taping, braces, orthotics, shoes and osteotomies for the knee and surgical correction of hip deformity associated with FAI syndrome. Observational study data would suggest that through altering joint mechanics we may also alter the rate of disease progression; however, this remains to be demonstrated in a well-designed clinical trial.

Practice points 1. Many of the attendant risk factors for disease development and its progression are modifiable and we need to pay closer attention to mechanical factors, injury and obesity. 2. The clinical encounter should target identification of individual risk factors (including altered alignment, obesity and muscle weakness) and the therapeutic intervention should be tailored to target the individual. 3. Therapies targeting the pathomechanics (including patella taping, braces, orthotics, shoes and osteotomies) of OA are efficacious.

Research agenda 1. Purpose-developed public health interventions focussed on kerbing obesity and joint injury need to be implemented and disseminated. 2. We need to change the disease paradigm to focus on persons at high risk for developing or with early disease where structural changes may be preventable or reversible. This will require imaging biomarker qualification and evaluation in the context of DMOAD trials. Summary The pathogenesis of OA appears to be the result of a complex interplay between mechanical, cellular and biochemical forces. Obesity is the strongest risk factor for disease onset and mechanical factors dominate the risk for disease progression. Analgesic therapy and end-stage joint replacement are the standard modes of medical intervention as it relates to OA management in 2011. A major shift in the focus of OA research and clinical practice is critically needed if an impact is to be made for the millions living with the chronic pain and disability of OA. Greater therapeutic attention to the important role of mechanical factors, injury and obesity in OA etiopathogenesis is required if we are to find ways of reducing the public health impact of this condition. Therapies directed at reducing joint loads such as weight loss and mechanical interventions are not used as frequently as they should. Competing interest None to declare.

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Acknowledgements Dr Hunter is funded by an Australian Research Council Future Fellowship. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. This is a narrative review and the comments and editorial expressed herein represent those of the author and do not reflect those of any official scientific role or institution that the author may hold or be affiliated with. References [1] Prevalence and impact of chronic joint symptoms–seven states, 1996. MMWR – Morbidity & Mortality Weekly Report 1998;47:345–51. [2] Dunlop DD, Manheim LM, Song J, Chang RW. Arthritis prevalence and activity limitations in older adults. Arthritis & Rheumatism 2001;44:212–21. [3] Prevalence of disabilities and associated health conditions among adults–United States, 1999 [erratum appears in MMWR Morb Mortal Wkly Rep 2001 Mar 2;50(8):149.]. MMWR – Morbidity & Mortality Weekly Report 2001;50: 120–5. 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