Osteoarthritis

Advanced Drug Delivery Reviews 58 (2006) 150 – 167 www.elsevier.com/locate/addr

OsteoarthritisB Joseph A. Buckwalter *, James A. Martin University of Iowa Department of Orthopaedics and Rehabilitation, Iowa City, IA 52242, USA Received 18 May 2005; accepted 30 January 2006 Available online 13 March 2006

Abstract Osteoarthritis (OA), the syndrome of joint pain and dysfunction caused by joint degeneration, affects more people than any other joint disease. In most instances joint degeneration develops in the absence of an identifiable cause, but increasing age, excessive joint loading, and joint abnormalities and insults increase the risk of OA. Articular surface contact stress that causes tissue damage and compromises that ability of chondrocytes to maintain and restore the tissue has an important role in the development of joint degeneration Current methods of attempting to restore an articular surface in osteoarthritic joints include penetrating subchondral bone, altering joint loading, osteotomies and insertion of soft tissue grafts. Dramatic advances in the prevention and treatment of OA are likely to stem from better understanding of the role of mechanical forces in the initiation and progression of joint degeneration. D 2006 Elsevier B.V. All rights reserved. Keywords: Articular cartilage; Osteoarthritis; Joint loading; Joint degeneration

Contents 1. 2. 3. 4.

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Introduction . . . . . . . . . . . Diagnosis . . . . . . . . . . . . Classification . . . . . . . . . . Prevalence, incidence, and costs. 4.1. Prevalence . . . . . . . . 4.2. Incidence . . . . . . . . . 4.3. Costs . . . . . . . . . . . Distribution among joints . . . .

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This review is part of the Advanced Drug Delivery Reviews theme issue on bDrug Delivery in Degenerative Joint DiseaseQ, Vol. 58/2, 2006. * Corresponding author. 01008 Pappajohn Pavilion, Department of Orthopaedics, University of Iowa College of Medicine, Iowa City, IA 52242, USA. Tel.: +1 319 356 2595; fax: +1 319 356 8999. E-mail address: [email protected] (J.A. Buckwalter). 0169-409X/$ - see front matter D 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2006.01.006

J.A. Buckwalter, J.A. Martin / Advanced Drug Delivery Reviews 58 (2006) 150–167

6.

Risk factors . . . . . . . . . . . . . . . . . . . 6.1. Age . . . . . . . . . . . . . . . . . . . 6.2. Joint injury. . . . . . . . . . . . . . . . 6.3. Age and joint injury . . . . . . . . . . . 6.4. Excessive repetitive joint loading . . . . 6.5. Joint dysplasia . . . . . . . . . . . . . . 7. Natural history . . . . . . . . . . . . . . . . . 8. Restoring degenerated articular surfaces . . . . 8.1. Penetration of subchondral bone. . . . . 8.2. Decreased articular surface contact stress 8.3. Osteotomy . . . . . . . . . . . . . . . . 8.4. Soft tissue grafts . . . . . . . . . . . . . 9. Conclusions . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Osteoarthritis (OA), the most common joint disease, is among the most frequent and symptomatic health problems for middle aged and older people [1– 7]. It is characterized by joint pain and dysfunction; and, in its advanced stages, joint contractures, muscle atrophy and limb deformity [8–10]. OA is caused by joint degeneration, a process that includes progressive loss of articular cartilage accompanied by attempted repair of articular cartilage, remodeling and sclerosis of subchondral bone, and osteophyte formation [9,10]. Although increasing age and excessive articular surface contact stress increase the risk of degeneration in all joints, the pathophysiology of the joint degeneration that leads to the clinical syndrome of OA remains poorly understood. For this reason, efforts to prevent this disease or slow its progression are based more on speculation than science. Current treatments do not prevent or cure OA, and symptomatic treatments often fail to provide satisfactory pain relief. Once patients develop OA, they suffer from the disease for the remainder of their lives and the severity of pain and disability generally increase. The frequency and chronicity of OA and the lack of effective preventive measures or cures make this disease a substantial economic burden for patients, health care systems, businesses, and nations [2,3,5,6,11–14]. Improving the prevention and treatment of OA will require finding methods of preventing and slowing the

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joint degeneration that causes OA and decreasing the joint pain and dysfunction. This manuscript was developed in part from the authors’ previously published works [8,9,15–19]. It examines the clinical classification, incidence, prevalence, costs, distribution among joints, risk factors, and natural history of OA. The final section discusses approaches to restoring degenerated joint surfaces.

2. Diagnosis Osteoarthritis results from degeneration of a synovial joint: a generally progressive loss of articular cartilage accompanied by attempted repair of articular cartilage, remodeling and sclerosis of subchondral bone, and in many instances the formation of subchondral bone cysts and marginal osteophytes [8,9]. In addition to the changes in the synovial joint, usually demonstrated by plain radiographs, diagnosis of the clinical syndrome of osteoarthritis requires the presence of chronic joint pain. Many patients with osteoarthritis also have restriction of motion, crepitus with motion and joint effusions. The most severely affected individuals develop joint deformities and subluxations. Most people with osteoarthritis seek medical attention because of joint pain. They often describe the pain as a deep aching poorly localized discomfort that has been present for years. The pain may increase with changes in the weather, especially storms or a

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drop in temperature, and increased activity. Activity associated pain typically begins immediately or shortly after beginning joint use and may persist for hours after cessation of activity. Some people first notice symptoms of degenerative joint disease following a minor joint injury or strenuous physical activity, even though study of their radiographs shows changes consistent with long standing joint degeneration. In the more advanced stages of the disease the pain becomes constant and may awaken patients from sleep. As joint degeneration progresses patients may notice loss of motion and feel crepitus, or grating, catching and grinding sensations in the joint with motion. Joint enlargement due to osteophyte formation, joint subluxation and deformity occur later in the course of the disease. The first signs of osteoarthritis include a decrease in the freedom of active joint movement. Limitation of movement may be due to incongruity or loss of articular cartilage, ligament and capsular contracture, muscle spasm and contracture, osteophytes or intraarticular fragments of cartilage, bone or menisci. Crepitus, joint effusions and joint tenderness also occur in many patients. Osteophytes can cause palpable and often visible tender bony prominences, and progressive loss of articular cartilage and subchondral bone will lead to joint subluxation and deformity. Muscle atrophy occurs with long standing disease. Physicians frequently diagnose osteoarthritis based on the patient’s history and physical findings. Changes on plain radiographs confirm the diagnosis but the correlation between the clinical presentation of the disease and radiographic changes varies considerably among patients. Some people with radiographic evidence of advanced joint degeneration have minimal symptoms, whereas other people with minimal radiographic changes have severe symptoms. The radiographic changes associated with osteoarthritis include narrowing of the cartilage space, increased density of subchondral bone and the presence of osteophytes. Although these three radiographic markers of joint degeneration often occur together, in some joints only one or two of the three may be visible on standard radiographs. Subchondral cysts, or cavities, also develop in osteoarthritic joints. These cavities vary in size and characteristically have dense bony borders. Osteochondral loose bodies, visible on radiographs as intra-articular bony frag-

ments, occasionally develop from pieces of the joint surface. Joint subluxation, deformity and malalignment develop with advanced disease. Bony anklyosis rarely occurs. Imaging studies other than plain radiographs, including bone scans, CT scans and MRI, and arthroscopic examination of joint surfaces, may be helpful in evaluation of early stages of degenerative joint disease, but they rarely are necessary for establishing the diagnosis.

3. Classification OA develops most commonly in the absence of a known cause of joint degeneration, a condition referred to as primary or idiopathic OA [9,10]. Less frequently, it develops as a result of joint degeneration caused by injuries or a variety of hereditary, inflammatory, or developmental, metabolic, and neurologic disorders, a group of conditions referred to as secondary OA (Table 1) [9,10]. Idiopathic OA rarely occurs in people younger than 40 years. Secondary OA, caused by joint insults or abnormalities including injury, infection, dysplasia, Legg–Perthes Disease, avascular necrosis and hemophilia, may occur in younger adults [8–10,20–24]. It is likely that many, if not most, patients with idiopathic OA have a predisposing cause of joint degeneration such as increased genetically determined risk of joint degeneration, joint injury or excessive mechanical stress. The process of joint degeneration (loss of articular cartilage, attempted repair of articular cartilage, remodeling and sclerosis of subchondral bone, and formation of subchondral bone cysts and marginal osteophytes) in young adults with an identifiable predisposing joint insult or abnormality cannot be distinguished from the process of joint degeneration in older individuals with no known predisposing factors.

4. Prevalence, incidence, and costs To some extent, estimates of the prevalence, incidence and costs of OA depend on the criteria used to diagnose the disorder. Symptoms of persistent joint pain and stiffness and evidence of joint degeneration, typically radiographic evidence of articular cartilage loss, osteophytes, and in some

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Table 1 Causes of secondary OA [9] Cause

Presumed mechanism

Joint injuries

Damage to articular surface and/or residual joint incongruity and instability Abnormal joint shape and/or abnormal articular cartilage

Joint dysplasias (developmental and hereditary joint and cartilage dysplasias) Aseptic necrosis Acromegaly Paget’s disease Ehlers–Danlos syndrome Gaucher’s disease (hereditary deficiency of the enzyme, glucocerebrosidase leading to accumulation of glucocerebroside) Stickler’s syndrome (progressive hereditary arthro-ophthalmopathy) Joint infection (inflammation) Hemophilia Hemochromatosis (excess iron deposition in multiple tissues) Ochronosis (hereditary deficiency of enzyme, homogentisic acid oxidase leading to accumulation of homogentisic acid) Calcium pyrophosphate deposition disease Neuropathic arthropathy (Charcot’s joints: syphilis, diabetes mellitus, syringomyelia, meningomyelocele, leprosy, congenital insensitivity to pain, amyloidosis)

instances increased subchondral bone density and cysts, establish the diagnosis of OA [8]. More severe joint degeneration is associated with increased prevalence of pain, but the prevalence of pain associated with joint degeneration varies among joints and among individuals. For example, some individuals with advanced joint degeneration have minimal pain and disability. In contrast, other individuals have symptoms consistent with the diagnosis of OA, but lack radiographic evidence of joint degeneration. For this reason, studies of the prevalence, incidence and costs of OA based on evidence of joint degeneration or symptoms alone, may yield higher numbers of affected individuals than studies that require evidence of joint degeneration and joint pain for the diagnosis of OA [5,6,25,26]. OA affects people of all ethnic groups in all geographic locations, it develops in both men and women, although it occurs more commonly in women, [7] and it is the most common cause of long-term disability in most populations of people over 65 [6,27]. Lawrence et al [28] estimate that more

Bone necrosis leads to collapse of the articular surface and joint incongruity Overgrowth of articular cartilage produces joint incongruity and/or abnormal cartilage Distortion or incongruity of joints due to bone remodeling Joint instability Bone necrosis or pathologic bone fracture leading to joint incongruity Abnormal joint and/or articular cartilage development Destruction of articular cartilage Multiple joint hemorrhages Mechanism unknown Deposition of homogentisic acid polymers in articular cartilage Accumulation of calcium pyrophosphate crystals in articular cartilage Loss of proprioception and joint sensation results in increased impact loading and torsion, joint instability and intra-articular fractures

than 20 million Americans have OA; the World Health Organization (WHO) estimates that 10% of the world’s people over the age of 60 years suffers from OA, and that 80% of people with OA have limitation of movement and 25% cannot perform major daily activities [29,30]. 4.1. Prevalence The prevalence of OA in all joints increases with age. More than a third of people over 45 years report joint symptoms that vary from a sensation of occasional joint stiffness and intermittent aching associated with activity, to permanent loss of motion and constant deep pain [6,7,9,10,31]. In some populations, more than 75% of the people over age 65 have OA that involves one or more joints [27]. 4.2. Incidence After age 40 the incidence of OA increases rapidly with each passing decade in all joints, and in most

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joints the incidence is greater in women than in men [32,33]. Because of the strong correlation between age and the incidence of OA, the total number of people suffering from this disease is rising rapidly as the proportion of the population over age 40 increases [34]. 4.3. Costs Despite its high and growing prevalence and profound effects on function and mobility, economists, demographers, and health service researchers have paid little attention to the costs of OA [35]. Most investigators have grouped OA with other joint diseases or with all musculoskeletal conditions, making it impossible to accurately define the economic consequences of the disease [35]. Despite these limitations, it is possible to provide some estimates of the costs of OA. These estimates rank OA as a major worldwide cause of economic loss [36]. Reginster [2] reported that the total economic burden of arthritis is 1% to 2.5% of the gross national product of western nations, and that OA accounts for a major share of this burden. Others have calculated that OA costs more than 60 billion dollars per year in United States [5,6,12,35,37]. Osteoarthritis is second to ischemic heart disease as a cause of work disability in men over age 50 years [28]. In managed care plans, patients with OA incur charges for medical care at about twice the rate of enrollees without OA [14]. Estimated costs of job-related OA are $3.4 to $13.2 billion per year, making job-related osteoarthritis at least as costly as job-related renal and neurological disease combined [3]. These estimates of economic impact do not include pain and suffering, adverse psychosocial effects, lost opportunities for increased productivity, decreased ability to participate in regular exercise that could improve general health, and the costs to family members who help provide care for patients with OA [38].

5. Distribution among joints Osteoarthritis can affect any synovial joint. Idiopathic OA rarely occurs in the ankle, wrist, elbow and shoulder, but it is common in the hand, foot, knee, spine and hip joints [5,6,21,22,27,31,39] In a study of

607 consecutive patients referred to the University of Iowa orthopaedic clinic for treatment of severe ankle, hip or knee OA, 7% of the patients with ankle OA, 69% of the patients with hip OA and 85% of the patients with knee OA had primary disease. Seventythree percent of the patients with ankle OA had posttraumatic OA compared with 9% of the patients with hip OA and 13% of the patients with knee OA [15]. Although primary OA rarely occurs in the ankle, wrist, elbow, and shoulder, these joints commonly degenerate and become painful and dysfunctional after injury [26,40–52]. The risk of posttraumatic OA in the ankle, wrist, elbow, and shoulder appears to be at least as great as in the hand, foot, knee, and hip [42,46,48,49,52,53]. Variability in risk of posttraumatic OA among joints has not been studied, but differences among joints in congruity, articular cartilage thickness, force transmission across articular surfaces [54,55], stability, and the presence of menisci could make some joints more vulnerable to articular surface damage and less able to tolerate posttraumatic incongruity, instability or malalignment [56]. For example, the knee has thick menisci but the ankle does not, and the ankle joint has smaller bearing surface and is more constrained. The distal tibial articular surface has much thinner cartilage than the proximal tibial articular surface [26] and loading of the articular surface of the distal tibia after creation of chondral defects causes higher subchondral bone strains than loading of the proximal tibial articular surface [54]. These differences may make the distal tibial articular surface more vulnerable to degeneration following intraarticular fractures.

6. Risk factors In addition to the disorders associated with the multiple forms of secondary OA (Table 1), genetic predisposition, obesity, female gender, greater bone density, and joint laxity have been identified as risk factors [21,57–61]. Although these factors may increase the risk of OA in selected populations, the most important risk factor in all populations is age. Mechanical loading that exceeds the ability of a joint to repair or maintain itself is another universal risk factor. Repetitive joint overuse, joint injury, posttrau-

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matic joint incongruity, instability or malalignment and joint dyplasia all can create mechanical demands that damage articular surfaces. 6.1. Age Age is the overriding risk factor for OA. The percent of people with evidence of OA in one or more joints increases from less than 5% of people between 15 and 44 years, to 25% to 30% percent of the people 45 to 64 years of age, and to more than 60% and as high as 90% in some populations, of the people over 65 years of age [6,12,22,27,35]. Despite this strong association between age and OA, and the widespread view that OA results from b. . .normal wear and tearQ and b. . .eventually stiffens the joints of virtually everybody who lives past 65. . .Q [62], the available evidence shows that lifelong joint use alone does not cause joint degeneration [63–66]. Recent work suggests that age-related deterioration of chondrocyte function decreases the ability of the cells to maintain and restore articular cartilage. [67– 72]. With increasing age, the cells synthesize smaller aggrecans and less functional link proteins, leading to the formation of smaller more irregular proteoglycan aggregates. Their mitotic and synthetic activities decline with age and they become less responsive to anabolic cytokines and mechanical stimuli. Evidence that chondrocytes undergo age-related telomere erosion and increase expression of the senescence marker beta-galactosidase suggest that cell senescence, possibly due to oxidative damage, is responsible for the age-related loss of chondrocyte function [67–71]. 6.2. Joint injury Clinical experience and epidemiologic studies show that direct and indirect joint impact loading; meniscal, ligament, and joint capsule tears; dislocations, and intra-articular fractures increase the risk of the progressive joint degeneration that causes posttraumatic OA [16,18,56,57,73,74]. The causes of this increased risk are poorly understood. The relationships between severity of acute articular surface injury and risk of joint degeneration have not been well defined, and the mechanisms responsible for progressive loss of grossly normal articular surfaces after various types of joint injuries have received little

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attention. Furthermore, the risk of posttraumatic OA varies among joints and among individuals [56]. The available evidence indicates that the acute joint injury kills at least a few chondrocytes [75] and that posttraumatic joint incongruity, instability and malalignment compromise repair of the articular surface and increase the risk of progressive degeneration of residual grossly normal articular cartilage [18,56]. The relative contributions of the severity of the immediate tissue damage and posttraumatic joint incongruity, instability, and malalignment have not been defined. 6.3. Age and joint injury Age may increase the risk of OA after joint injuries. Studies of patients with intra-articular fractures of the knee show that patients older than 50 years of age have a twofold to fourfold greater risk of developing OA than younger patients [16,76–78]. Patients over 40 years who have acetabular fractures [79–81] and patients over 50 years who have displaced ankle fractures may also have a greater risk of OA than younger patients who have similar injuries, [41] and age increases the risk of knee joint degeneration after anterior cruciate ligament injury [82]. 6.4. Excessive repetitive joint loading Maintenance of normal synovial joint structure and function require regular joint use, lifelong normal daily activities and regular recreational running have not been shown to increase the risk of joint degeneration [63–65]. There is evidence, however, that repetitive loading of normal joints can exceed the tolerance of a joint and cause degeneration. Surveys of individuals with physically demanding occupations including farmers, construction workers, metal workers, miners, and pneumatic drill operators suggests that repetitive intense joint loading over a decade or more increases the risk of joint degeneration [63– 65,83–92]. Specific activities that have been associated with joint degeneration include repetitively lifting or carrying heavy objects, awkward work posture, vibration, continuously repeated movements, and working speed determined by a machine; other studies have suggested that participation in sports that repetitively expose joints to high levels of impact or torsional loading also increase the risk of joint

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degeneration [65,84,91,93,94]. The contralateral knees of people with lower limb amputations have more degenerative changes than the knees of people without amputations [95], suggesting that the increased loading of the knees of their normal limbs caused degeneration of the knee. The degeneration of normal joints in people with joint fusions [96,97], for example the degeneration of the ipsilateral knee joint in people with hip fusions, may have a similar explanation, that is, the loss of motion in the fused joint places increased mechanical demands on other joints. Obesity has also increases the risk of knee degeneration, but it is uncertain if this is the result of increased repetitive joint loading, varus malalignment in patients with obesity or metabolic abnormalities [27,98–102]. The biologic mechanisms responsible for the joint degeneration associated with repetitive intense joint loading are not known: but excessive loading may accelerate the age-related loss of chondrocyte function and thus lead to accelerated degeneration of articular cartilage [19].

patients, especially if they have minimal loss of articular cartilage, and a study of experimental hip dysplasia in rabbits showed that osteotomy may prevent loss of articular cartilage [119]. These clinical and experimental observations suggest that relieving excessive levels of articular surface contact stress in dysplastic joints can slow or prevent joint degeneration. Enthusiasm for performing prophylactic osteotomies in patients with joint dysplasia or malalignment should be tempered by the risk of complications of these procedures, the lack of evidence that they relieve excessive contact stress, uncertainty concerning the optimal degree of joint re-alignment and the limited number of prospective clinical studies demonstrating long term benefits. Despite these cautions, the evidence supports further investigation of methods of decreasing excessive articular surface contact stress as a method of preventing OA in people with a high risk of progressive joint degeneration.

7. Natural history 6.5. Joint dysplasia The abnormal shape of a dysplastic joint apparently increases the risk of joint degeneration [103–106]. In some forms of joint dysplasia, abnormalities of the articular cartilage may contribute to the degeneration of the joint, but in others the articular surface structure and composition appear to be normal. In these latter instances, the abnormal shape presumably leads to joint degeneration by causing increased stress on parts of the articular surface and joint instability. Although any joint presumably can develop an abnormal shape, [103,107–111] the most extensively studied form of joint dysplasia occurs in the hip, a condition referred to as developmental dysplasia of the hip [104,112,113]. Evaluation of 83 patients with unilateral hip dysplasia at an average of 29.2 years from the time of diagnosis, showed a strong relationship between the calculated articular surface contact stress and the development of joint degeneration [114,115]. In an effort to decrease pain and slow or prevent progressive joint degeneration, some surgeons recommend osteotomies in young adult patients with hip pain and hip dysplasia [116–118]. Clinical studies suggest that this approach is effective in some

Although physicians and patients commonly regard OA as relentlessly progressive, [62] the disease does not necessarily follow this course (Table 2) [89,120–128]. The symptoms of OA may remain unchanged, slowly progress over many years, improve temporarily, or progress rapidly to the point that the patient is disabled within a few years of the onset of the disease [20,39]. Most patients with OA have intervals of symptomatic improvement [9,20,39,126]. Longitudinal studies of patients with hip and knee OA show that over a decade or more the radiographic signs of joint degeneration do not progress in 1/3 to 2/3s of patients, [20,39] and a longitudinal study of 63 patients showed that over 11 years the radiographic signs of joint degeneration improved in 10% of the patients with knee OA [123]. Spontaneous restoration of radiographic cartilage space and decreased pain have also been described in patients with hip OA [129]. The reasons for the variability in the natural history of OA have not been discovered, although joint injuries, repetitive excessive joint torsion and impact loading, crystal deposition, and neuromuscular dysfunction have been associated with more rapid progression of joint degeneration [20,39,64].

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8. Restoring degenerated articular surfaces For more than 250 years surgeons have been seeking ways to repair or regenerate degenerated articular surfaces. Repair refers to restoring a damaged articular surface with new tissue that resembles but does not duplicate the structure, composition and function of articular cartilage; regeneration refers to forming new tissue indistinguishable from normal articular cartilage [17,130–132]. They made little progress for 200 years, but in the last 50 years use of surgical procedures to repair or regenerate articular surfaces has become common. Surgeons now treat selected patients with by penetrating the subchondral bone, altering joint loading and implanting soft tissue grafts in degenerated joints to stimulate formation of a new articular surface. Experimental studies of cell transplantation, growth factors, artificial matrices suggest that these approaches may help promote formation of a new articular surface. The apparent potential of these multiple methods for stimulating formation of cartilaginous articular surfaces has created interest on the part of patients, surgeons and scientists, however the wide variety of methods and approaches to assessing their results have made it difficult to evaluate their success in restoring joint function and to define their most appropriate current clinical applications. 8.1. Penetration of subchondral bone Penetration of subchondral bone was the first method developed to stimulate formation of a new articular surface and is still the most commonly used [9,17,130,131,133,134]. In regions with full thickness loss or advanced degeneration of articular cartilage,

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penetration of the exposed subchondral bone disrupts subchondral blood vessels leading to formation of a fibrin clot over the bone surface. If the surface is protected from excessive loading, undifferentiated mesenchymal cells migrate into the clot, proliferate and differentiate into cells with the morphologic features of chondrocytes [135]. In some instances they form a fibrocartilagenous articular surface, but in others they fail to restore an articular surface [135]. Surgeons first debrided degenerated articular cartilage and drilled into the subchondral bone through arthrotomies and found that many patients reported a decrease in symptoms following recovery from the procedure [136–139]. One group advocated treating patellar articular surface degeneration by excising damaged cartilage along with underlying subchondral bone, a procedure they referred to as spongialization. They found good or excellent results in a high percentage of their patients [140]. Surgeons have developed a variety of other methods of penetrating subchondral bone to stimulate formation of a new cartilaginous surface including arthroscopic abrasion of the articular surface and making multiple small diameter defects or fractures with an awl or similar instrument [9,17,131]. Prospective randomized controlled trials of arthroscopic abrasion treatment of osteoarthritic joints have not been reported, but several authors have reviewed series of patients and found that these procedures can decrease the symptoms due to isolated articular cartilage defects and osteoarthritis of the knee [141– 147]. One group of investigators reported less successful results in their series of 44 patients (49 knees): they found early treatment failures in 19 knees (39%), and 23 knees (47%) had failed at final follow up examination [148]. In this same series, excellent

Table 2 Natural history of knee OA Authors

Number of patients

Measures

Follow up (years)

Progression (%)

Hernborg and Nilsson [120] Hernborg and coworkers [120,121] Schouten et al. [122] and Schouten [173] Spector et al. [123,124] Massardo et al. [125] Ledingham et al. [126]

84 106 142 63 31 188

Clinical and Radiographic Radiographic Radiographic Radiographic Radiographic Radiographic Clinical

15 15 12 11 8 2

Means

614

55 33 34 33a 62 39 48 39

a

10% improved.

8

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results decreased from 20 knees (41%) at the time of maximum improvement to 12 knees (24%) at the time of final follow up. Examination of joint surfaces following arthroscopic abrasion has shown that in some individuals it results in formation of fibrocartilagenous articular surface that varies in composition from dense fibrous tissue with little or no type II collagen to hyaline cartilage like tissue with predominantly type II collagen [144–147]. Johnson also found that in many patients with radiographic evidence of cartilage joint space narrowing, or no radiographically demonstrable joint space, the joint space increased following abrasion [144–147]. Although an increase in radiographic joint space following subchondral abrasion presumably indicates formation of a new articular surface, the development of this new surface does not necessarily result in symptomatic improvement. Bert and Maschka [149] and Bert [150] found that 30 (51%) of 59 patients treated with abrasion arthroplasty had evidence of increased radiographic joint space two years after treatment, but 18 (31%) of these individuals either had no symptomatic improvement or more severe symptoms. Some of the variability in the clinical results of attempts to restore an articular surface by penetrating subchondral bone may result from differences in the extent and quality of the repair tissue. However, no studies have documented a relationship between the extent and type of repair tissue and symptomatic or functional results, suggesting that formation of a new articular surface following penetration of subchondral bone does not necessarily relieve pain. The lack of predictable clinical benefit from formation of cartilage repair tissue may result from variability among patients in severity of the degenerative changes, joint alignment, patterns of joint use, age, perception of pain, pre-operative expectations or other factors. It may also result from the inability of the newly formed tissue to replicate the properties of articular cartilage. Examination of the tissue that forms over the articular surface following penetration of subchondral bone shows that it lacks the structure, composition, mechanical properties and in most instances the durability of articular cartilage [9,16,17,130–132, 135]. For these reasons, even though it covers the subchondral bone, it may fail to distribute loads across the articular surface in a way that avoids

pain with joint loading and further degeneration of the joint. Currently, it is not clear which method of penetrating subchondral bone produces the best new articular surface, and differences in patient selection and technique among surgeons using the same method may be responsible for variations in results making it difficult to compare techniques. However, comparison of bone abrasion with subchondral drilling for treatment of an experimental chondral defect in rabbits showed that while neither treatment predictably restored the articular surface, drilling appeared to produce better long term results than abrasion [151]. This observation fits well with previous experimental work showing that chondral repair tissue that grows up through multiple drill holes that pass from the articular surface into vascularized bone will spread over exposed subchondral bone between holes and form a fibrocartilagenous articular surface [152]. It also suggests that small diameter holes that leave the bone intact between defects lead to formation of more stable repair tissue than abraded bone surfaces [151]. One recent report suggests that the age of the patient may influence the results of attempts to stimulate articular cartilage repair by penetrating subchondral bone. Kumai et al. [153] described the results of arthroscopic drilling of osteochondral lesions of the talus in 18 ankles (17 patients). They found that all patients had decreased pain at between two and 9.5 years after treatment. Twelve of the thirteen ankles in patients less than 30 years old had a good result, but only one of five ankles in patients over 50 years old had a good result. This data supports the concept that with increasing age the probability of a good result of an attempt to repair or regenerate articular cartilage decreases [68–71,154]. Despite the evidence that penetration of subchondral bone stimulates formation of fibrocartilagenous repair tissue, the clinical value of this approach remains uncertain. In contrast with reports of symptomatic improvement in patients with cartilage degeneration treated with penetration of subchondral bone [141,145–147], one investigator has concluded that while joint debridement can improve symptoms in many patients, abrasion or drilling of subchondral bone does not benefit patients with osteoarthrosis of the knee, and may increase symptoms [150]. In addition, the short

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periods of follow up, lack of well defined evaluations of outcomes, lack of randomized controlled trials and the possibility for a significant placebo effect or an improvement in symptoms due to joint irrigation alone make it difficult to define the indications for penetration of subchondral bone to stimulate formation of a new articular surface. 8.2. Decreased articular surface contact stress Several sets of observations suggest that decreased articular surface contact stress combined with joint movement may stimulate restoration of an articular surface in osteoarthrotic joints. Before the development of artificial joints, surgeons found that resection of an osteoarthritic joint surface followed by decreased loading and joint motion resulted in the formation of fibrocartilagenous tissue over the bony surfaces [9,17,132]. When the surgeon resected the degenerated articular surfaces along with some underlying bone, the space between the bone surfaces filled with a fibrin clot, and then granulation tissue. Decreased loading and motion of resected joint facilitated formation of opposing fibrocartilagenous surfaces, immobilization and compression could lead to bony or fibrous ankylosis. Reports of the effects of releasing the muscles that act across degenerated hip joints in an attempt to decrease joint loading suggest that this procedure improved symptoms and increased the radiographic cartilage space in some patients [155–157]. Recently these observations concerning the effects of decreasing joint contact stress combined with motion have been supported by clinical studies of the effects of joint distraction and motion using external fixators. Aldegheri and colleagues used joint distraction that allowed joint motion to treat 80 patients with a variety of hip disorders [158]. Twenty-four patients who either had inflammatory joint disease or were older than 45 years had poor results, and only four patients over 45 years of age had good results; but, 42 of 59 patients younger than 45 years with osteoarthrits, hip dysplasia, avascular necrosis and chondrolysis had good results. These results suggest that, at least in people less than 45 years of age, decreased contact pressure and motion of damaged hip joint surfaces can decrease symptoms. A retrospective study by van Valburg et al. [159] showed

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that joint distraction and motion treatment for patients with posttraumatic ankle osteoarthrosis produced favorable results. They treated advanced posttraumatic osteoarthrosis of the ankle with joint distraction in 11 patients. After application of an Ilizarov device, the authors distracted the joints 0.5 mm per day for 5 days and then maintained the distraction of the articular surfaces throughout the course of treatment. Patients were allowed to walk a few days after the operation, active joint motion was started between six and 12 weeks after surgery. After 12 to 22 weeks, the distraction device was removed. At an average of 20 months after treatment none of the patients had proceeded with an arthrodesis: all 11 patients had less pain, and five were pain free; six had more motion; and, three of six that had radiographic studies had increased joint space. Subsequently, the same group of investigators treated 17 patients with advanced ankle osteoarthritis with joint distraction for three months. Thirteen of these patients had decreased pain and improved function more than two year after treatment, four patients did not improve. Although these reports have important limitations, the symptomatic improvement and delay, if not avoidance, of arthrodesis in most patients indicates that distraction or other methods of decreasing joint contact forces combined with motion deserve further evaluation. 8.3. Osteotomy Surgeons perform osteotomies to re-align osteoarthritic joints with the intent of relieving joint pain and improving function. In general, they plan osteotomies to decrease loads on the most severely damaged regions of the joint surface, bring regions of the joint surface that have remaining articular cartilage into opposition with regions that lack articular cartilage or correct joint malalignment that may contribute to symptoms and joint dysfunction. Clinical experience has led many surgeons to accept osteotomy as a method of treating hip and knee joints with localized loss or degeneration of the articular surface [130]. Osteotomies have not been commonly used for treatment of osteoarthrosis in joints other than the hip and knee, but in one study tibial osteotomies produced good or excellent results in 15 of 18 patients with primary ankle osteoarthrosis, a rare condition in

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which osteoarthrosis develops in the absence of any history of trauma [160]. Some surgeons have combined joint debridement and penetration of subchondral bone with osteotomy, but this approach is not widely used. Most hip and knee osteotomies performed to treat OA alter joint alignment in the coronal plane (varus and valgus osteotomies), however surgeons design some hip osteotomies to change joint alignment in the sagittal plane (flexion and extension osteotomies) or alter the relationship of the joint surfaces by rotation of the femoral head relative to the acetabulum (rotational osteotomies). The optimal planes and degrees of joint realignment for specific osteoarthrotic joints have not been defined, nonetheless, clinical experience shows that osteotomies of the hip and knee can decrease symptoms and stimulate formation of a new articular surface [130]. The decreased pain could result from decreasing stresses on regions of the articular surface with the most advanced cartilage degeneration, decreasing intraosseous pressure or formation of a new articular surface, but the mechanisms of symptomatic improvement and formation of new articular surfaces remain poorly understood [130]. Most clinical studies have shown that in at least some patients osteotomies lead to improvement in the radiographic signs of joint degeneration including resolution of subchondral cysts or lucencies, decreased subchondral bone density and increased radiographic joint space [130]. This latter change may result either from the altered relationship between the articular surfaces or the formation of a new articular surface. That is, osteotomies may alter joint alignment to separate previously opposed joint surfaces or they may rotate a cartilage covered articular surface into opposition with a surface consisting of exposed bone, thus creating a radiographically visible cartilage space where prior to the osteotomy bone opposed bone. In one series of 757 intertrochanteric osteotomies performed to treat osteoarthrosis of the hip, the radiographic joint space increased immediately following the procedure in approximately one-third of the patients [161]. In these patients the increased joint space presumably resulted from alterations in the relationships between the joint surfaces. In another third of the patients the radiographic joint space increased during the next 18 months, and these individuals had better clinical

results. This result suggests that over 18 months these patients developed a new articular surface in some areas of the joint as a result of the altered loading. Evidence that hip osteotomies stimulate formation of fibrocartilagenous tissue over articular surfaces that previously consisted of exposed bone supports this suggestion [162,163]. Reports of the treatment of degenerative disease of the knee with osteotomies also describe increased radiographic joint space accompanied by decreased subchondral bone density, and in some people formation of a new fibrocartilagenous articular surface [130]. One group of investigators biopsied the articular cartilage of the medial femoral condyle at the time of osteotomy and then again at an average of two years after osteotomy in 19 patients with degenerative disease of the medial side of the knee joint [164]. The biopsies showed formation of a new fibrocartilagenous articular surface in nine patients, no change in eight patients and deterioration of the articular surface in two patients. Radiographic examination showed that six knees had improved, 11 had remained unchanged and two had deteriorated. There was no correlation among the histologic studies, the radiographic appearance, the postoperative varus–valgus angle or the clinical results. A similar study of 14 patients found proliferation of a new fibrocartilagenous surface on the tibial condyle in eight patients and on the medial femoral condyle in nine patients two years following osteotomy [165]. This study also did not find a correlation between restoration of an articular surface and clinical outcome. 8.4. Soft tissue grafts The potential benefits of soft tissue grafts include introduction of a new cell population along with an organic matrix, a decrease in the probability of anklyosis before a new articular surface can form, and some protection of the graft or host cells from excessive loading. Treatment of osteoarthrotic joints by soft tissue grafts involves debriding the joint and interposing soft tissue grafts consisting of fascia, joint capsule, muscle, tendon, periosteum or perichondrium between debrided or resected articular surfaces [130]. The success of soft tissue arthroplasty depends not only on the severity of the joint abnormalities and the

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type of graft, but on postoperative motion to facilitate generation of a new articular surface. Animal experiments and clinical experience show that perichondrial and periosteal grafts placed in articular cartilage defects can produce new cartilage [130]. O’Driscoll has described the use of periosteal grafts for the treatment of isolated chondral and osteochondral defects, and in preliminary evaluation of a small series of patients he has found good or excellent results in more than three quarters of the patients [166–168]. Other investigators have reported encouraging results with perichondrial grafts [169– 171]. One study suggests that increasing patient age adversely affects the results of soft tissue grafts. Seradge et al. studied the results of rib perichondrial arthroplasties in 16 metacarpophalangeal joints and 20 proximal interphalangeal joints at a minimum of three years following the procedure [172]. Despite the small number of patients and joints, the results suggested that increasing age adversely affected the results for both metacarpalphalangeal and interphalangeal joints. Among the patients who had had an arthroplasty of the metacarpalphalageal joint, all three who were less than 20 years old, three of four who were between twenty and thirty and only three of six who were more than thirty had a good result. Of the patients who had an arthroplasty of the interphalangeal joint, four of five who were less than twenty, four of six who were between twenty and thirty and only one of three who was more than 30 years old had a good result. None of the patients older than 40 years had a good result with either type of arthroplasty. The authors concluded that perichondrial arthroplasty could be used for treatment of posttraumatic osteoarthrosis of the metacarpophalangeal joint and proximal interphalangeal joints of the hand in young patients. The clinical observation that perichondrial grafts produced the best results in younger patients [172] agrees with the concept that age may adversely affect the ability of undifferentiated cells or chondrocytes to form an articular surface or that with age the population of cells that can form an articular surface declines [18,19,69] and the evidence that with increasing age chondrocyte synthetic activity and response to anabolic growth factors decline [18,19,69]. The age-related differences in the ability of cells to form a new articular surface may also help explain some of the variability in

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the results of other procedures including osteotomies or procedures that penetrate subchondral bone, that is, younger people may have greater potential to produce a more effective articular surface when all other factors are equal [67,154].

9. Conclusions Despite the great success of joint replacement and the proliferation of medical, nutritional, and physical treatments, the problem of OA has not been solved, and its adverse impacts on individuals, populations and economies will continue to increase. Replacing a severely degenerated joint with an implant is much like replacing a failing heart with a mechanical pump, both operations restore function, but neither treats the disease, the costs are high and the complications severe. None of the medical, nutritional, and physical treatments of osteoarthritis cure OA. For these reasons, the adverse effects of OA on the quality of life for tens of millions of people, the costs of health care, and the costs of lost economic productivity continue to present major challenges. A variety of methods have the potential to stimulate formation of a new articular surface including penetration of subchondral bone, osteotomies, joint distraction, soft tissue grafts, cell transplantation, growth factors and artificial matrices. The available evidence indicates that the results vary considerably among individuals, the potential for articular cartilage repair declines with age and the tissue that forms following these treatments does not duplicate the composition, structure and mechanical properties of normal articular cartilage. However, regeneration of normal articular cartilage may not be necessary for a procedure to be beneficial; in at least some instances stimulating formation of articular cartilage repair tissue may decrease symptoms and improve joint function. To find ways of preventing and slowing the progression of OA, it will be necessary to arouse greater interest and support for OA research and to show that research can lead to strategies that will decrease the burden of OA. In particular, translational research should be directed toward understanding how aging and mechanical loading lead to joint degeneration, how some joints are resistant to primary OA, and how joints can partially reverse the degenerative process.

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Pursuing these directions offers the possibility of find ways to prevent, slow the progression, or even reverse the process of joint degeneration.

Acknowledgement The work reported in this manuscript was supported by award P50 AR48939 National Institutes of Health Specialized Center on Research for OA. http:// poppy.obrl.uiowa.edu/Specialized Center of Research/ SCOR.htm. This grant was awarded to the University of Iowa and the authors receive salary and research support from the grant.

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