Arthritis & Allied Conditions
15th Edition

New bone formation occurs in two separate locations in relation to the joint surface: in exophytic growths at the margins of the articular cartilage and in the immediately subjacent bone marrow (Fig. 108.4). Marginal osteophytes have two patterns of growth. One consists of a protuberance into the joint space, whereas the other develops within capsular and ligamentous attachments to the joint margins. In
each circumstance, the direction of the osteophyte is governed by the lines of mechanical force exerted on the area of growth, generally corresponding to the contour of the joint surface from which the osteophyte protrudes. The osteophyte consists in large part of bone that merges imperceptibly with the other cortical and cancellous tissue of the subchondral bone. The osteophyte is capped by a layer of hyaline and fibrocartilage continuous with the adjacent synovial lining. In advanced lesions, the landmarks are obliterated because the osteophytic surface itself undergoes degeneration, and fibrous tissue may cover the marginal portions of the osteophyte.

On the femoral head, proliferative tissue frequently occupies the fovea of the ligamentum teres and extends down along the femoral neck to form buttress osteophytes. These buttress osteophytes may obscure the normal boundary between the femoral head and the femoral neck. In most surgical specimens of the femoral head removed for OA, the combination of degenerative and proliferative activity has destroyed virtually all of the native articular cartilage.

The proliferation of bone in the subchondral tissue is most marked in areas denuded of their cartilaginous covering (5). In these regions, the articulating surface consists of bone that has been rubbed smooth. The glistening appearance of this polished sclerotic surface suggests ivory, hence the name eburnation. Nubbins of newly proliferated cartilage usually protrude through minute gaps in the eburnated bone. Proliferation of new bone at these sites is an integral part of eburnation (16, 86). Dense bone at the articular surface is accompanied by marked sclerosis of the underlying subchondral bone (87). Morphometric studies have confirmed the histologic impression of thickened trabeculae in the subchondral bone (25), and dual x-ray absorptiometry has established increased bone mineral content (24). These changes are more marked with increasing severity of OA.

“Cystic” areas of rarefaction of bone are commonly seen immediately beneath eburnated surfaces in the hip (Fig. 108.5D). Such structures are much less frequent in other joints. The cystic areas occur on both femoral and acetabular sides of the joint. The lesions are most frequently present on the superolateral weight-bearing surface. In severe instances, they may involve other regions of the hip as well (5). In a few cases, these lesions appear roentgenographically before narrowing of the joint space has given evidence of cartilage destruction. The lesions only infrequently contain pockets of mucoid fluid and thus are not truly cystic. The trabeculae in the affected areas disappear, and the bone marrow undergoes fibromyxoid degeneration. Fragments of dead bone, cartilage, and amorphous debris are often interspersed within them. Macrophages found in these cysts can differentiate into osteoclasts promoting enlargement (88). In time, the entire area is encircled by a rim of reactive new bone and compact fibrous tissue (Fig. 108.3B). Minute gaps in the overlying articular cortex, resulting from microfractures, are commonly seen at the apex of the pseudocysts (Fig. 108.3). These findings are consistent with an intrusion of pressure, if not of synovial fluid, from the joint cavity through a defect in the articular cortex into the subchondral bone marrow. Intraarticular pressures exceeding 1,000 mm Hg occur in hip joints with effusions (5). The increased pressure is dissipated radially into the adjacent bone marrow, compressing the medullary blood vessels and thereby leading to the retrogressive changes. This mechanism is not contradicted by observations that the intraosseous pressure is normal in osteoarthritic femoral heads at the time of arthroplasty. In these specimens, bulk pressures, rather than localized gradients, are measured. Furthermore, remodeling has compensated so that cysts are much less prominent in advanced lesions subjected to total hip arthroplasty. The “punched out” lesions observed radiographically in gout and the bone “cysts” in hemophilic arthropathy correspond pathologically to the pseudocysts in OA, except that they have specific exudates within the pseudocysts that are absent in OA.

New bone formation also occurs in the form of focal enchondral ossification at the base of the articular cartilage (82). Such metaplasia is a component of the remodeling process by which bone is added to a portion of the articular cortex while other areas of the joint undergo resorption of bone. During the period of active skeletal growth, this osteochondral junction underlying the calcified cartilage zone has an epiphysis-like function that permits actual enlargement of the bone through sequential ossification of the calcified cartilage. In adults, the interface between calcified and noncalcified hyaline articular cartilage is demarcated by a thin, undulating, hematoxyphilic line (the tidemark; Fig. 108.5A). In older persons, this line is usually transformed into several parallel discontinuous ones whose presence is clear evidence of the progression of the calcification front into the articular cartilage (14). The possibility that the progression of the basilar calcification might lead to thinning of the articular cartilage (senile atrophy) in the absence of pathologic new bone formation in OA has not been substantiated (5).

The role of osteonecrosis in the generation of OA has been the subject of considerable discussion. Much of the deformity in symptomatic OA results from collapse of the joint surface. Localized areas of necrosis are seen frequently in this location (Fig. 108.4), and occlusion of minute intramedullary arteries has been demonstrated in the past by angiography (5). However, distinctive histologic differences have been noted between subchondral vessels of resected femoral heads in osteonecrosis and OA (89).

Not infrequently, small secondary infarcts of eburnated bone are seen in surgically resected OA femoral heads (5,9,90). These changes are more frequent in severe OA (91), in which, in a recent study, 38.2% of 1,007 OA femoral heads demonstrated secondary osteonecrosis. A small percentage demonstrated deep, wedge-shaped infarcts, similar to those of primary osteonecrosis (9). In the past, extensive morphologic studies have led some to suggest that osteonecrosis might be involved in all cases of OA
of the hip, but this clearly exceeds the evidence (91). Hypercoagulability demonstrated in some patients with primary OA might also be operative in this complication (92). Nevertheless, rapidly destructive variants of OA are frequently accompanied by subchondral bone necrosis (93). Some patients with progressive OA have demonstrated sterile subchondral inflammatory foci histologically distinct from both pseudocysts and secondary osteonecrosis (94). These may also contribute to collapse of the articular surface. Primary and secondary osteonecrosis of the femoral head appear pathologically distinct from collapse of the articular surface owing to subchondral insufficiency fracture, another recently described entity (95, 96).

The frequency of chondrocalcinosis, especially in the older age group, has generated divergent opinions regarding the relationship of this condition to OA (see Chapter 116). Confusion over the exact role of chondrocalcinosis in OA is enhanced by the fact that calcium pyrophosphate dihydrate (CPPD) deposition disease, the most common form of chondrocalcinosis, occurs in both primary and secondary variants. The latter form of the disorder is associated with a wide range of conditions, including hemochromatosis, ochronosis, hepatolenticular degeneration, hyperparathyroidism, acromegaly, and hemophilic arthropathy. The primary form of CPPD is frequently found in association with OA, especially in older patients (97). However, chondrocalcinosis is also exceptionally common as an asymptomatic phenomenon in the knee joints of elderly persons (98). The experience of Sokoloff and Varma (99) indicates that meniscal chondrocalcinosis is present in roughly half of knees treated surgically for OA after 68 years of age. The risk for meniscal calcinosis in surgically removed knees was sixfold that of an age- and sex-adjusted postmortem population. A study of synovial fluid from patients undergoing total knee arthroplasty for OA demonstrated CPPD or basic calcium phosphate (BCP) crystals (or both) in 60% (100). In another study using atomic emission spectroscopy, calcium content of menisci correlated strongly with degeneration in OA (101). By contrast, CPPD crystals are rarely found in femoral heads removed for OA. Chondrocalcinosis also is relatively infrequent in fractured hips before the age of 85 years (5). Why the meniscus is the predominant site of involvement in OA of the knee, while the hyaline articular cartilages are largely spared, remains a matter of conjecture (102). Ordinarily, the deposition of CPPD in the osteoarthritic knee engenders no inflammatory reaction. Deposits of lipid are associated with CPPD deposits and are also present in the adjacent chondrocytes (5). The role of this lipid material in the deposition of crystals is unclear. In contrast to the articular chondrocytes that degenerate at sites of CPPD crystal deposition (103), meniscal fibrochondrocytes apparently remain metabolically active in the presence of these crystals (5). Several observers have noted that “joint mice” are more frequent in OA specimens with chondrocalcinosis than in those without crystal deposition.

In a recent study, serum nucleotide pyrophosphohydrolase activity was increased in patients with OA whether or not CPPD crystals were present in joints (104). To complicate the situation further, some cases of OA harbor CPPD crystals that are too small to be resolved by conventional polarizing microscopy (105). This leads to the possibility that the role of CPPD crystals in the pathogenesis of OA might be underestimated despite preoperative synovial fluid examination in patients undergoing total knee arthroplasty revealing a 60% prevalence of calcium crystals (100). Because apoptotic chondrocytes produced pyrophosphate in one study (60), a common basic mechanism of chondrocyte injury may be operative whether or not microscopically verifiable CPPD crystals are produced as the end result.

Another form of radiologic chondrocalcinosis is associated with deposition of BCP (apatite) crystals (see Chapter 118). The observation that BCP crystals are quantitatively associated with more severe cases of OA of the knee has promoted the theory that BCP crystals might be released from abraded eburnated surfaces (5), but this has not been established. However, BCP crystal deposition is characteristically associated with more severe arthropathy and occasional Charcot-like breakdown of joints. Unlike CPPD crystals, most of which can be seen with conventional polarizing microscopy, BCP crystals are too small (105) and require specialized techniques such as alizarin red staining of centrifuged synovial fluid for detection. Thus, it is difficult to establish the presence of BCP crystals in severe OA unless a specific search is employed.

During recent years, the inflammatory manifestations of OA have stimulated considerable discussion. By definition, OA is inherently a noninflammatory condition, but some degree of synovial villous hypertrophy and fibrosis is seen in most symptomatic cases (Fig. 108.6). A moderate focal chronic synovitis has been described in about one-fifth of surgically resected specimens (5). This synovitis is characterized by hyperplasia and enlargement of synovial lining cells and by the presence of lymphocytes and mononuclear cells (106). The infiltrate is generally mild and heterogeneous with respect to immunopathology (5). Polyclonal B lymphocytes compose part of the infiltrate, and extracellular deposits of complement component C3 also have been described (5). Fibronectin is deposited in exudative foci (5). Other tissue changes, such as hemosiderin deposition, foreign body reaction to joint detritus, and xanthoma-like changes around fat necrosis, may be seen. The stage of any particular case may be important because the synovial response has varied from an early inflammatory pattern in mild cases to a late fibrotic stage in advanced disease (107).
In a few cases, the synovial inflammation may be so pronounced as to resemble RA. Immunopathologic studies, however, show significant qualitative differences in the infiltrates characterizing the two diseases (108). Synovial macrophages are more frequent in RA (5). The mean nuclear density of cellularity is higher in RA, and immunoglobulin-producing plasma cells, common in RA, are rare in osteoarthritic synovia (5). Immunoblasts are not seen in the synovial fluid in OA (5). Helper-to-suppressor (CD4/ CD8) ratios vary between upper and lower synovial regions in RA but are uniform throughout the synovium in OA (5). Although CD4⁺ T cells are more numerous in RA synovium (109), those in OA also expressed an activated phenotype (110), indicating possible immune mechanisms. Natural killer cells with CD16/56⁺ phenotype are more frequent in OA than RA (111). In line with this latter observation, natural killer (NK) cell-associated granzyme expression is also increased in osteoarthritic synovial specimens (112). Mast cells occur in increased numbers in the synovium of patients (113) with OA and in one report were actually more numerous than in synovium from RA patients (114). Mast cells in OA are also of a tryptase-positive, chymase-negative phenotype associated with inflammation in other conditions (115).

Taken as a whole, these findings clearly differentiate the cellular inflammatory responses in OA from those in RA. However, the presence of inflammation in many cases of OA is undeniable. Epidemiologic studies have linked progression of early radiologic OA of the knee to higher serum levels of the inflammatory marker C-reactive protein
(116). Similar low-grade inflammatory responses occur in other joint diseases of nonphlogistic origin such as those accompanying acromegalic, ochronotic, and neuropathic arthropathies.

Autosensitization to joint detritus is an attractive consideration in the genesis of the inflammatory reaction. A so-called detritic synovitis is observed in many cases of severe OA requiring joint replacement, but is much less common in early cases treated with arthroscopic surgery (117). The synovial reaction to osteocartilaginous fragments not only causes inflammation but also may result in generation of cytokines and release of degradative enzymes such as cathepsin K by synovial macrophages (118). Such cytokines are associated with synovial inflammation in OA (119). Detritic synovitis also provides a possible mechanism for autosensitization to cartilage structural proteins. In fact, cartilage-derived molecules are present in sera of patients with OA (39,42,43,120).

Additional supportive evidence for autosensitization is the finding of autoantibodies directed against both native and denatured type II collagen in 50% of OA cartilage extracts (5). Analysis of DNA restriction enzyme patterns of T lymphocytes from osteoarthritic synovia shows an oligoclonal pattern of T cell receptor b-chain gene rearrangements, suggesting a response by a limited number of T cell clones (121), as might occur in a response to released indigenous articular cartilage molecules. Peripheral blood lymphocytes from OA patients are highly reactive in proliferation assays against human cartilage link protein (122). Evidence for an immune response in certain types of OA also includes the finding of immunoglobulin-complement complexes deposited in the superficial zones of osteoarthritic articular cartilage (123). Whether the deposits in OA are a primary phenomenon or merely a response to matrix damage is not known, but autoantibodies associated with deposition in articular cartilage are a recognized finding in generalized, nodal OA (124).

As previously discussed, another possible mechanism for the inflammatory changes in the synovium involves responses to CPPD or BCP crystals. Both species occur in the synovium, cartilage, and synovial fluid. Crystals have been proposed as one mechanism for induction of cytokine release. IL-1 stimulates synovial cells and articular chondrocytes to release neutral proteases capable of destroying cartilage matrix (52). Studies have also implicated tumor necrosis factor (TNF) in the process (125).

Other soft tissues also participate in OA. Minute tears in capsular tissue appear as slender, fibrovascular seams disrupting the principal axes of the collagen bundles. Secondary osteochondromatosis occurs at times but is much more characteristic of neuropathic arthropathy than of OA. In the hip joints, the ligamentum teres commonly disintegrates. In the knee joint, the cruciate ligaments and menisci also become frayed. Substantial clinical (126,127) and experimental (5) evidence suggests that meniscectomy leads to OA, especially when the meniscus is removed because of a degenerative (102), rather than a traumatic, (128) tear. Furthermore, postmeniscectomy OA of the knee shows a strong association with OA of the hands and opposite knee (129). Degeneration is more severe, however, on the operated side and is independent of age and sex. This study suggests that a predisposition to primary OA influences the development of secondary degeneration and makes a clear distinction between these two subsets of the disease more difficult. Others have found evidence of increased prevalence of generalized OA in individuals with severe knee (5) or hip (130) OA. Although meniscectomy can precipitate OA, underlying or systemic factors may contribute to its severity.

Among other soft tissue changes, fibrillation and fibrosis of the synovial surface and even mild cartilaginous metaplasia of the patellar tendon have been described. Lipochondral degeneration is seen in hip capsular tissues that have previously undergone nodular chondroid metaplasia (62). Amyloid deposits have been reported in the joint capsule in OA (131), but they also occur in joint capsules and articular cartilage of normal joints and in the intraarticular discs of older individuals (5). Serum amyloid A–activating factor increases expression of matrix metalloproteinases in OA cartilage (132). Amyloid or amyloid-like materials, however, have been described in several different tissues of aged individuals (5). Any claim for specificity for amyloid in cartilage requires a considerably more discriminatory technique than screening by green birefringence after Congo red staining, the usual histochemical method. Destructive amyloid arthropathy is characteristic, not of OA, but of dialysis-associated osteoarthropathy due to β₂-microglobulin retention (133).

A progressive increase in the amount of fibrous tissue separating the synovial capillaries from the joint space has been described as an age-related finding. It is unlikely that this condition interferes with the nourishment of the cartilage, but distinction from amyloid must be made on histologic grounds. Focal hyaline sclerosis of minute vessels is a common finding even in joint tissues of young individuals (5). It is unlikely that this finding is directly related to OA. Periarticular muscle undergoes atrophy, with type 2 myofibers being affected primarily (5).

Of the vertebral ankylosing disorders, the best known entity goes by several names: hyperostotic spondylosis, senile ankylosing hyperostosis of Forestier and Rotes-Querol, and spondylorheostosis. Hyperostotic spondylosis nominally is distinguished from ordinary spondylosis by the absence of disc degeneration (5,172). The distal thoracic spine is the site of predilection (173). The ankylotic bridges are located on the anterolateral portions of the vertebral bodies and extend into the anterior longitudinal ligaments (Fig. 108.7). This appearance has often led to confusion with ankylosing spondylitis. However, ankylosing hyperostosis is not an inflammatory disorder, unlike the spondyloarthropathies. Ossification of the posterior longitudinal ligament is also frequently associated with vertebral hyperostosis (174), as is ossification of the stylohyoid ligament (175). In some instances, the vertebral lesion is accompanied by excessive osteophyte formation in peripheral joints, especially the pelvis, heel, elbow, and knee joints (173). From this feature comes still another term for this condition, diffuse idiopathic skeletal hyperostosis (DISH) (176,177,178). Currently, diagnosis is made on purely radiologic grounds because no tissue or serum markers exist. However, hyperglycemia is a common clinical finding in these patients (179). A possible relationship to relative excess of growth hormone has been postulated (180). Other studies have linked an increased likelihood of clinically palpable finger nodules (Heberden and Bouchard nodes) to DISH (181). Animal models of this disease exist in the Mediterranean sand rat (147) and the hyperostotic (twy/twy) mouse (182).

Ankylosis, distinct from that of hyperostotic spondylosis, may accompany severe spondylosis in humans and other species. The disc space is narrowed. Destructive changes are present in the cortex of the anterior portion of the vertebral bodies (182). Dense new bone formation is seen in the anterior longitudinal ligament. The appearance suggests that the ligament is first avulsed from the osteophyte and then repaired.

Several patterns of dorsal protrusion and bridging of cervical vertebrae (posterior spondylotic osteophytes) may cause life-threatening cervical myelopathy (183). The relation of physiologic vertebral ligamentous ossification to the preceding disorder and to hyperostotic spondylosis is uncertain (174). It occurs in 7% of Japanese (184) and 0.3% of American adults (5). These lesions are asymptomatic in individuals with large spinal canals, but they require surgical decompression when spinal canals are small and myelopathy has developed (5). In women, ossification of the posterior longitudinal ligament of the spine has been associated with estrogen receptor and IL-1β gene polymorphisms (185).

Baastrup’s syndrome, an OA-like change that is due to bursitis between the distal portions of “kissing” lumbar dorsal spinous processes (5), is usually associated with severe spondylosis.

Despite the relative antiquity of the description of Heberden’s nodes (2) and their frequency, comparatively little information is available on their histopathology, possibly because early lesions are seldom available (186). They usually manifest
as marginal osteophytes of the distal interphalangeal joints. In more advanced cases, these lesions are indistinguishable from those arising in osteoarthritic remodeling in other sites (Fig. 108.8). Ossific transformation of the tendinous insertion into the joint capsule creates the osteophytosis. In other instances, mucoid transformation of the periarticular fibroadipose tissue is associated with proliferation of myxoid fibroblasts and cyst formation. These types of Heberden’s nodes are usually associated with radiographically demonstrable distal interphalangeal osteophytes but not invariably so (187). These cysts, like the osteophytes, are not unique anatomic features of Heberden’s nodes. Indistinguishable changes may be present in other osteoarthritic joints and in other species. The process has certain morphologic similarities to ganglion formation or to cystic degeneration of the semilunar cartilages and to the subchondral pseudocysts of OA. Unilateral sparing from Heberden’s nodes after hemiplegia has been reported (188). This observation suggests the possibility of neurovascular contributions to the development of the lesion but does not exclude a biomechanical explanation. One study comparing groups of women with qualitatively similar manual tasks definitely related Heberden’s node formation to the quantitative use of the hands (189). The association of the paraarticular mucinous cysts of the distal interphalangeal joints with osteophytes has been emphasized because they are likely to recur after excision unless the osteophytes are also removed.

The term erosive osteoarthritis has been applied to a disorder resembling OA in its predilection for the distal and proximal interphalangeal joints, but in which a distinct inflammatory component exists (190). A nonspecific, chronic synovial lymphocytic and mononuclear cell infiltrate is present. The nosologic status of the disorder is uncertain, and most reports deal with radiographic classification of the condition rather than pathology (191). One possibility is that this entity simply represents OA with a prominent, detritic synovitis. In a few cases, the lesion disseminates (5) to other joints and has been reported to evolve into RA. Such RA patients, however, are generally seronegative and show a much greater tendency toward osteophyte formation than patients with seropositive RA. Variants of nodal OA associated with chronic sialadenitis have also been described (192) whose relationships to erosive arthritis and seronegative RA are unclear. Bony ankylosis may occasionally occur in the finger joints in association with Heberden nodes, especially of the inflammatory type. Because of the difficulty in obtaining pathologic material from these sites, histologic studies are rare (186).

Primary generalized OA was first defined as an entity by Kellgren and associates (5). Conspicuous features of the
disorder included a preponderance in middle-aged women, Heberden node formation, and involvement of the first carpometacarpal and knee joints. Hip joints were affected less commonly. Key features of the syndrome as described included signs of articular inflammation and radiologic evidence that proliferation of adjacent bone, rather than erosion of articular cartilage, was the primary event in the genesis of the lesions. The description of the syndrome was based on limited anatomic material, a situation not entirely corrected by succeeding studies (186,187,188,189,190,190,193).

The status of generalized OA remains controversial. Most patients with this pattern of disease do not present for surgical intervention. Thus, the condition is far more common in rheumatologic than in orthopedic practice. Some studies have confirmed an association of generalized OA with OA of the hips (194), whereas others have denied this relationship. The association of OA of the hands and knees has been established by radiologic studies (195). From the obverse viewpoint (5), patients requiring hip and knee surgery for localized OA are significantly more likely to have generalized disease as well. When hip disease is associated with Heberden nodes, particularly in patients with inflammatory features, it is of the concentric type (5) rather than the more common deforming type. Some authors maintain that this pattern of hip involvement is only a part of the generalized OA syndrome (5). The genetic predisposition to the development of generalized OA has been related to several types of markers. These include increased frequency of human leukocyte antigen (HLA)-DR2 (196,197), certain polymorphisms of the estrogen receptor gene (198), and abnormalities on chromosome 2q (199). Using radiographic hand and knee OA as the index condition, segregation analyses suggest a significant contribution from a major recessive gene together with possible environmental factors (200). This supports the observations made a generation previously by Kellgren (5) and recently confirmed elsewhere (201).

Other forms of polyarticular OA associated with mutant type II collagens have been described in several unrelated families (202,203,204,205). These disorders produce precocious generalized OA with accentuated involvement of weight-bearing joints. In one family, a mild spondylodysplasia with truncal shortening was present (202), and in others, more severe manifestations of spondyloepiphyseal dysplasia were noted (203). In the mildly spondylodysplastic family, a single point mutation at residue 519 in the triple helical domain substituted cysteine for arginine, producing abnormal posttranslational overmodification (204). The abnormal collagen has been isolated from cartilage remaining on a surgically excised femoral head from an affected family member (206) in which about one-fourth of the a1(II) chains contained the substitution. This was associated with severe precocious ulceration of articular cartilage. More recently, type II collagen with this particular point substitution has shown decreased affinity for binding type IX collagen (207). Electron microscopy of articular cartilage in one kindred demonstrated parallel lamellar arrays of collagen fibrils rather than the normal structure (205). Affected families showed definite or probable autosomal-dominant inheritance (202,203,204,205), with an age-dependent penetrance approaching 100%. Some other family studies have suggested an inherited defect in one of the introns or promoters for the procollagen II gene (208). Transgenic mice harboring copies of a transgene with mutations engineered into the mouse type II collagen gene develop early-onset knee joint degeneration along with other skeletal abnormalities (140,209).

Conversely, evidence to link defects in the type II procollagen gene to the common type of generalized nodal OA has not as yet been readily forthcoming (210). Molecular analysis of DNA from cases of generalized erosive nodal OA failed to disclose evidence of a single point mutation in collagen II a1(II) chain residue 519 (204). Sibling pair analysis in generalized nodal OA also fails to suggest linkage to loci encoding type II collagen (211). Some studies have suggested differential allelic expression from sequence dimorphisms of the type II collagen gene in osteoarthritic cartilage, but this could be a manifestation of somatic mutation (212), as has been described with abnormalities of chromosome 7 in synovia, osteophytes, and cartilage from patients with OA (213). Furthermore, the usual pattern in generalized OA does not include a clinically detectable spondyloarthropathy (see Chapter 110).

Alkaptonuria is caused by a deficiency in homogentisic acid oxidase caused by a mutation on chromosome 3q (214) that eventually results in a generalized degeneration of joints similar to OA (see Chapter 120). Several differences are notable, however. External remodeling is less prominent than in idiopathic OA (5), and destructive spinal changes are more marked (215). This includes a calcification or ossification of the nucleus pulposus of the intervertebral discs and breakdown of the vertebral end plates. Osteophyte production is not a conspicuous feature of the spondylopathy either. In many cases, the spinal disease is so severe as to imitate that of a mucopolysaccharidosis or ankylosing spondylitis (216). Some investigators have postulated an increased prevalence of HLA-DR7 antigen in patients with clinical ochronosis (217). Moreover, the pigmented cartilage is extremely brittle, so that comminution with a resultant detritic synovitis is prominent. Pigmented cartilage fragments are found in the synovial fluid (218). Reactive polyps of the synovium containing these fragments are common and may be mistaken for loose bodies on radiographs. Fibrosis near ulcerated zones of the articular surface along with wavy alterations of the cartilage collagenous fibrillar ultrastructure has been noted (219). A
complicating feature is that both calcium pyrophosphate and BCP crystals have been identified in ochronotic cartilage (5). Homogentisic acid, the substance that accumulates in cartilage in ochronosis, has been shown to cause chondrocyte toxicity in vitro (220), possibly by producing oxidative DNA damage (221) because this effect can be delayed by ascorbic acid, glutathione, and D-penicillamine (220).

Kashin-Beck disease, formerly known as endemic osteoarthrosis deformans, affects at least 2 million individuals in northern China, North Korea, Siberia (224), and Tibet (225). The changes first appear during childhood and develop with variable severity in different affected individuals. The early changes consist of a zonal necrosis of the articular and epiphyseal chondrocytes (5). Profound deformity is the result in many affected individuals (226,227). Several theories as to the cause of the disorder have emerged. The most evidence favors the soil and water in the region being deficient in selenium and iodine (228), and the combination of these two factors results in the disorder. Although earlier studies failed to demonstrate inhibitory effects of selenium deficiency on short-term chondrocyte monolayer cultures (5), intact selenium-deficient mice develop a Kashin-Beck-type osteoarthropathy when supplemented with dietary fulvic acid, a product of mold growth (229). Interestingly, mycotoxins, particularly those of Fusarium species, have long been suspected as having some role in the disorder (230). Fulvic acid, a complex contaminant of water derived from decay of moldy soil, inhibits processing of type II procollagen in chicken articular cartilage (231). Related mold-derived compounds known as the humic acid solvent extraction fraction induce oxidative stress in cultured rabbit articular chondrocytes (232). Thus, a synergism between selenium deficiency and mold toxins may be the basis of the disorder. However, the exact pathogenesis of this regionally devastating disorder remains obscure (233).

Mseleni disease, common in northern Zululand, has been described more recently than Kashin-Beck disease. The disorder is polyarticular and noninflammatory, and the hip is particularly susceptible. In surgically resected femoral heads, eburnation was absent. The joint surface was instead covered by a combination of regenerated and degenerated cartilage (5). Some investigators have proposed that the disorder is heterogeneous, in part being hereditary spondyloepiphyseal dysplasia (5). With regard to spondyloepiphyseal dysplasia, localized occurrences of a dwarfing variant have been described (234), and some studies have suggested mutation in the type II collagen gene (235). Patients with Mseleni joint disease are also more likely to show histologic evidence of osteopenia, osteomalacia, and osteoclast failure, but abnormalities in calcium metabolism have not been identified (5). Generalized OA of the usual sort seen in predominantly European populations occurs less frequently in black Africans (236). As with Kashin-Beck disease, the definitive pathogenesis is as of yet unclear.

Handigodu disease is another form of proliferative OA seen in a geographically confined region of South India. The disorder is polyarticular, affects both genders, and can lead to severe deformity. Many similarities to Mseleni osteoarthropathy exist. However, at least some cases of Handigodu disease demonstrate an autosomal-dominant pattern of inheritance (237). Some cases may be related to borreliosis (238).

Several childhood hip abnormalities lead to premature osteoarthritic degeneration in adult life. Such disorders include developmental dysplasia of the hip (congenital hip dysplasia) (246), Legg-Calvé-Perthes disease (254), slipped capital femoral epiphysis (255), and congenital coxa vara (256). At times, there is such a clear history that a pathogenetic sequence seems certain. In other patients, however, no precursor state is evident. These patients are sometimes considered to have a forme fruste of congenital hip dysplasia (5). This retrospective view may be questioned because subluxation has been documented only as a late manifestation of the joint deformity. Earlier views that subclinical hip dysplasia is frequently responsible for isolated OA of the hip have not been substantiated (257,258).

Legg-Calvé-Perthes disease results from necrosis of the growth center of the femoral head in childhood. The disorder may be primary or a complication of surgical intervention in congenital hip dysplasia (259,260). A severe secondary OA characterized by a flattened femoral head with bilateral beaklike osteophytes results. Because synovitis is a feature of early stages in the disorder (261), increased intraarticular pressure has been implicated. Hypercoagulability due to inherited factor V (Leiden) mutations is also associated with the disorder (262) and may influence severity (263). Slipped capital femoral epiphysis occurs in older boys of endomorphic habitus and results from a fracture through the physeal growth plate. Complete or total detachment is characterized by secondary osteonecrosis
and severe precocious OA (255). Between 25% and 40% of cases are bilateral (264). The disorder is also associated with acromegaly and conditions treated with synthetic growth hormone (265), such as renal failure. Studies of archived human skeletons suggested that 8% were involved by slipped capital femoral epiphyses and that the condition was associated with severe OA (266). Thus, the condition is not uncommon as a cause of adult OA.

The term chondromalacia patellae is used loosely to describe a clinically distinctive, posttraumatic softening of the articular cartilage of the patella in young persons. The anatomic lesions resemble those of early OA, although subtle differences have been described by some authors (33, 34). Changes involve the cartilage and the subchondral bone (5). Softening, swelling, and increased water content of cartilage have all been reported in the early stages of chondromalacia. In a minority of patients, a significant inflammatory component may be present secondary to irritation of synovium from detachment of cartilage fragments (detritic synovitis). Some studies have suggested that many cases of chondromalacia patellae do not progress to OA of the type seen in older individuals (35). Some evidence favors hypermobility of the knee joint as an evocative factor (267).

Neuropathic arthropathies comprise articular degenerations with varying morphologies according to the duration and type of the underlying sensory defects (268) (see Chapter 93). Collectively, these are called Charcot joints owing to their description by J. M. Charcot in 1868. The changes resemble those of severe OA but are more profoundly destructive. Extensive detritic synovitis is characteristic and is frequently accompanied by secondary osteochondromatosis. The pathogenesis of these lesions is complex, with damaged neurovascular reflexes, sensory denervation, and metabolic factors all having advocates. In the diabetic foot, the most frequent site of Charcot joints in the United States (269), the landmarks of the tarsal bones are often obliterated by fusion (5), indicating extensive remodeling. Some authors have proposed that subtle sensory deprivation contributes to the acceleration of some cases of idiopathic OA (270). The clinical and pathologic similarity between Charcot joints and severe examples of CPPD crystal arthropathy has also been noted.

OA as a late sequela of previous bone infarction (osteonecrosis) has been the subject of a large body of literature. The epiphyseal ends of the bones are involved primarily in osteonecrosis because they receive a discrete arterial supply distinct from that to the remainder of the bone (5). The femoral and humeral heads are the most frequent sites of osteonecrosis (5). Articular cartilage derives nutrition from synovial fluid, so that infarction is limited to the subchondral bone and marrow, which fracture and collapse, leading to loss of the normal congruency of the joint surface. Proliferative remodeling leads to osteophyte formation, although the osteophytes are often not as pronounced as in primary OA. As the disorder progresses, the articular cartilage may slough, leading to exposure of bone and further remodeling. Osteonecrosis principally begins in only one articular member of a joint, but in later stages, secondary degeneration involves the mating articular surfaces (271). Although overt OA may ensue, eburnation is usually not a conspicuous feature. Ordinary OA of the hip may be associated with areas in which the osteocytes of underlying subchondral bone (Fig. 108.4) are necrotic (9, 90). The preponderance of evidence, however, suggests that such necrosis is a secondary event (9) that may contribute to rapid progression of deformity (8, 93). Primary osteonecrosis is associated with a number of conditions that enhance thrombosis of the osseous microcirculation (263,272). The possible role, if any, of hypercoagulability and venous occlusive disease observed in some cases of OA (92) secondary to osteonecrosis has not been established.

A special form of osteonecrosis of the medial femoral condyle develops in elderly persons (5) and leads to gonarthrosis. The sudden onset of symptoms (pain) may have been precipitated by a segmental fracture with depression of the articular cortex. Others have associated the disorder with medial meniscus tears (5) and with meniscectomy (273). OA has been described as a late consequence of meniscal disease as well. Thus, when segmental infarction occurs in OA of the knee (5), it probably is a secondary phenomenon, as in the hip.

OA frequently develops in joints with clearcut preexisting structural abnormalities. These cases are classified as secondary OA. In primary OA, no trauma or other predisposition can be identified, and intrinsic alterations of the articular tissues, or response to normal cumulative stresses, are presumed to be responsible. Differences in the conformation of OA joints in ochronotic or postinflammatory arthropathies suggest that intrinsic cartilage damage is also responsible for concentric (nonhypertrophic) OA, whereas mechanical overloading is responsible for the much more common varieties in which overt joint remodeling is conspicuous. In the hip joint, the patterns of cartilage loss and osteophyte development have been proposed as representative of the original causal abnormalities (5). Use of surgically resected femoral heads to support such causal explanations is quite difficult, owing to the advanced nature of the changes in such specimens. One school of thought proposes that a preexisting structural basis for OA of the hip can be identified in most cases (5). The entire issue is controversial because others report a much lower percentage of preexisting conditions (257,258,266,274) and recognize primary OA of the hip as the dominant entity (275). There is also evidence that generalized OA is common in individuals requiring hip surgery for localized disease (276). Similar frequency of polyarticular disease is found in patients who present with OA of the knee (195). Because the possibility exists that a genetic predisposition to generalized OA (197,198) might predispose to secondary OA (129), the entire issue is far from resolved.

If the earliest events in the progression to OA occur in articular cartilage (6,7,17,18,36,37,55,56,57,58,59,60,61), then the bone remodeling results from the loss of energy-absorbing function of the cartilage. The osteophytes in primary OA can thus be viewed as an attempt to redistribute the increased transmitted forces over a greater surface area. If the primary alteration is in the subchondral bone (16,19,20,21,22,23,24,25,26,27,28) or in the basal layer of calcified cartilage (14,15,18), then the cartilage changes represent a failure of cartilage repair to compensate for the remodeling, including that of calcified cartilage (14, 15). Evidence that bony changes underlie the deterioration of cartilage includes the following: (a) articular cartilage has little measurable impact-absorbing function; (b) microfractures and subchondral trabecular sclerosis precede measurable changes in the cartilage; and (c) cartilage is mechanically more susceptible to impact loading that produces deformation of subchondral bone than to shearing stresses. Osteophytes, the most conspicuous features of established OA of the hip, develop very early, concomitant with the first radiologic evidence of joint space narrowing (5). Similar early remodeling changes are present in experimental OA in rabbits (11) and dogs (12, 151). The pathogenesis of OA likely involves an interaction between intrinsic deranged cartilage metabolism and extrinsic potentiating mechanical factors. Their relative contribution may vary in different joints and in different forms of OA.

Several systemic factors have been previously considered in relation to OA, including age, metabolic and genetic influences, obesity, and exercise. A salient feature of OA is a strong association with advancing age (5). This may suggest either that a series of cumulative insults is required to produce disease or that time-dependent molecular alterations engendered by genetic defects occur independently of environmental insults. Some degree of deterioration of the articular surface occurs linearly with increasing age, but the rate is greater in some joints than others (275). The changes in surgically resected osteoarthritic hip and knee specimens are far outside the normal distribution of changes seen in natural aging, suggesting that other local or systemic factors are necessary for progressive OA to occur (274,275).

Mechanical factors have been proposed to evoke OA in specific joints. Elbow OA of foundry workers using long tongs to lift hot metals and “coal miner’s back” are two such examples. Vibratory trauma has been implicated in the cause of OA of the hands and feet in some studies, but not others (283). OA of the knee was more common in a study in individuals whose occupations involved heavy labor (283). OA of the hip has been correlated with heavy physical workload in women (274) and men (296). Heavy use of the hands is linked with interphalangeal OA (189) as well.

In numerous studies, the occurrence of OA in runners was not increased over control populations (283). Other types of athletic activity may be more influential. Retired soccer players, for example, had more OA of the hips than age- and weight-matched control group athletes in one study, but not in another (5). However, competitive sports have been considered a significant risk factor for OA of the knee (283). The possibility that repetitive trauma induces OA more commonly in genetically predisposed susceptible individuals cannot be excluded (130). Single injuries probably do not cause OA unless they are severe enough to disorganize the joint surface or its major stabilizing structures (Fig. 108.6).

Direct evidence for the mechanical abrasion of cartilage from the joint surface is provided by the shards of cartilage found in the synovial fluid and synovium in OA (117). In ochronosis, such joint detritus is a dominant feature of the disease and incites significant immune and inflammatory response in the synovium (218). The actual mechanical basis of the abrasion injuries in common OA is less obvious, but their presence is undeniable for direct morphologic (117) and indirect biochemical (118) evidence.

One cause of increased cartilage abrasion could be decreased or disordered joint lubrication (5). The articular cartilage of animal joints oscillated in vitro in the absence of synovial fluid undergoes rapid frictional destruction. Instillation of testicular hyaluronidase also leads to in vitro scoring of joint surfaces. Although the depolymerization of synovial mucin could account for the friction, it is possible that the hyaluronidase may also have acted directly on the cartilage matrix. The subject of joint lubrication has attracted much interest in recent years. Hyaluronidase abolishes the viscosity of synovial fluid but not its lubricating ability (5). Under conditions reproducing the joint loading occurring during walking, the friction on human femoral heads increased after hyaluronidase digestion of synovial fluid (5). These studies reflect the different characteristics of boundary and fluid film lubrication processes operating in joint function (297).

The volume, hyaluronate content, and relative viscosity of synovial fluid are usually normal in OA, although other studies have shown diminished polymerization of synovial mucin and a reduction of the hyaluronate content (5). The contradictory data arise in part because truly normal synovial fluids are not readily obtained for comparison. In the absence of joint disease, the amount of synovial fluid within joints is small, and many joints aspirated have low-grade synovitis (5). The synovial fluid also contains a lubricating glycoprotein called lubricin (297,298) and a surface-active phospholipid produced by synovial cells (299). The latter is bound to the surface of cartilage, probably transported to that site by the former. Some studies have indicated that lubricin may function in lubrication as a carrier for the phospholipid (300). In other studies, phospholipase digestion failed to abolish the lubricating ability of synovial fluid (301). Studies of femoral heads and knees removed for severe OA showed decreased surface-active phospholipid recoverable from the surface of worn as opposed to unworn areas (302). Whether this is a primary or secondary phenomenon is unclear. In a synthetic bearing test system, no deficiency in the boundary-lubricating ability of synovial fluid was found in OA in previous studies (5).

The forces applied over the hip, knee, and ankle joints are characterized by being intermittent and are often several multiples of the body weight (303), even in simple, apparently nonstressful movements such as walking on level ground. The resistance to wear under such conditions is a complex function involving lubrication, the elastic properties of the articular cartilage, and the deformation of the underlying bone (discussed in detail in Chapters 7 and 8). The elastic properties of cartilage, as measured by either stiffness or recovery from deformation, are not altered by aging unless fibrillation is also present (5).

The stiffness of the underlying bone has been increasingly considered as a factor in the development of OA (19,20,21), and the decreased stiffness of osteoporotic bone may explain why OA is less common in osteoporotic patients (28,284,285). However, some evidence from studies of comparative pathology of OA suggests that deficiency of mineralized bone may adversely affect cartilage (5). Such deficiency of mechanical support may contribute to the arthropathy seen in hyperparathyroidism (97). Conversely, osteopetrosis, a rare condition characterized by markedly increased stiffness of bone, favors the development of premature OA (5). The cause-and-effect relationship, however, is still unclear because fractures with deformity also characterize this disorder.

Paget disease (osteitis deformans) produces significant bone abnormalities that may extend into the subchondral osteoarticular junction and produce irregularities at the
joint surface (see Chapter 123). The hip is frequently the site of mixed patterns of Paget disease and OA (304), and protrusio acetabuli develops in approximately 25% of such patients, a far higher frequency than in OA without Paget disease (5).