Osteoarthritis – epidemiology, pathophysiology, diagnosis, and treatment

Osteoarthritis – epidemiology, pathophysiology, diagnosis, and treatment

Jay A. Swedberg

Osteoarthritis is responsible for more impairment in the elderly than any other single diagnosis. [1] This extremely common disease affects function, independence and quality of life. [2] The following definition of osteoarthritis was developed at a recent National Institutes of Health workshop [3]:

“Osteoarthritis (osteoarthritis, degenerative joint disease) is a degenerative disease of the cartilage of joints. It is of diverse etiology and obscure pathogenesis. Clinically, the disease is characterized by joint pain, tenderness, limitation of movement, crepitus, occasional effusion, and variable degrees of local inflammation, but without systemic effects. Pathologically, the disease is characterized by irregularly distributed loss of cartilage (more frequent in areas of increased load), sclerosis of subchondral bone, subchondral cysts, marginal osteophytes, increased metaphyseal blood flow, and variable synovial inflammation. Histologically, the disease is characterized early by fragmentation of the cartilage surface, cloning of chondrocytes, vertical clefts in the cartilage, variable crystal deposition, remodeling, and eventual violation of the tidemark by blood vessels. It is also characterized by evidence of repair, particularly in osteophytes, and later by total loss of cartilage, sclerosis, and focal osteonecrosis of the subchondral bone. Biomechanically, the disease is characterized by alteration of the tensile, compressive, and shear properties and hydraulic permeability of the cartilage; increased water; and excessive swelling. These cartilage changes are accompanied by increased stiffness of the subchondral bone. Biochemically, the disease is characterized by reduction in the proteoglycan concentration, possible alterations in the size and aggregation of proteoglycans, alteration in collagen fibril size and weave, and increased synthesis and degradation of matrix macromolecules. Therapeutically, the disease is characterized by a lack of a specific healing agent.”


It is estimated that 63 to 85 percent of Americans over age 65 have radiographic signs of osteoarthritis and that 35 to 50 percent have symptoms of pain, stiffness or limitation of motion. Between 9 and 12 percent of elederly Americans (approximately 3 million people) have enough impairment from osteoarthritis that they cannot perform their major activities, and half of these individuals are totally disabled (confined to bed or a wheelchair). [1]

Most individuals who are totally diabled have other diseases in addition to osteoarthritis. In fact, the best predictors of subsequent diability from osteoarthritis are (1) the extent of other chronic diseases, such as coronary artery disease, congestive heart failure, chronic obstructive pulmonary disease, visual or hearing impairment, or renal impairment, (2) current functional capacity and (3) factors such as education, income, social support from family, friends and neighbors, and the availability of social and home care services. [1]

Although age is the major risk factor for osteoarthritis, the disease is not caused by wear and tear of the joints, and it is not simply a feature of normal aging. [2,4-7] Osteoarthritis is said to be age-related, but not necessarily age-dependent. [8] The disease occurs in all animals with a bony skeleton, including birds, amphibians, reptiles and mammals, even swimming mammals (such as whales and porpoises) that spend their lives supported in water and have totally nonweight-bearing joints. [9]

Other factors associated with the development of osteoarthritis include joint trauma, calcium pyrophosphate or uric acid crystal deposition in the joints, metabolic disorders such as Wilson’s disease or hemochromatosis, and endocrine diseases such as diabetes mellitus, acromegaly or hyperparathyroidism.

Osteoarthritis is a heterogeneous disorder that may be classified as primary or secondary. If progressive deterioration of articular cartilage can be related to preceding trauma, inflammation or infection, the disease is considered to be secondary. In most cases, however, osteoarthritis is primary (idiopathic), since no significant preceding event or conditon can be identified. Recently one precocious form of primary osteoarthritis has been shown to be inherited as a mendelian dominant disorder through one allele of the gene for type II procollagen. [10]

In osteoarthritis, the age of onset and the rate of progression vary widely, and the symptoms of pain and stiffness tend to wax and wane, especially early in the disease process. The condition occurs at an earlier age in some joints than in others. For example, osteoarthritis appears in the first metatarsophalangeal joint after 25 years of age, in the wrist and the facet joints of the spine after 35 years of age, in the distal interphalangeal joints after 45 years of age, and in the knee and hip joints after 55 years of age. [6] There appears to be no consistent relationship between weight bearing and osteoarthritis, since the ankle joint is rarely involved. [5]

The prevalence of osteoarthritis is approximately 2 percent in persons younger than 45 years of age, 30 percent in persons 45 to 64 years of age and 63 to 85 percent in those over 65 years of age. [6]


Radiographically, the earliest signs of osteoarthritis are localized loss of joint space and subchondral sclerosis. As the condition progresses, ostephytes, subchondral cysts with sclerotic margins, and intra-articular osseous bodies may become evident. Finally, subchondral bony collapse may result from the compression of weakened and deformed trabeculae. Various radiographic signs of osteoarthritis are shown in Figures 1 through 9.

Histologically, the disease progression seen in radiographs corresponds to fibrillation, softening and erosion of cartilage, followed by bony proliferation at joint margins and at the base of fissures in the


cartilage. Osteophyte formation is probably a sign of repair, which creates more subchondral bone to support the load on the joint. However, this new bone is brittle and prone to microfractures.

In addition to the radiographic and histopathologic changes, osteoarthritis is also characterized by biochemical changes in the cartilage. These changes suggest an acceleration in the remodeling process, which involves both repair and breakdown. [7,11,12]

The reparative process is stimulated by various growth factors released from osteophytes in cartilage, platelets and lymphocytes and by growth factors found in serum [7,13] (Table 1). These growth factors act by inducing the proliferation of chondrocytes and the synthesis of proteoglycans and collagen. [13,14] Some growth factors, such as transforming growth factor-beta, may also increase the relapse of protease inhibitors that limit the breakdown of proteoglycans and suppress the inflammatory processes driven by cytokines such as interleukin-1. [7,14,16]

The breakdown or catabolic processes are mediated by cytokines such as interleukin-1 (derived from macrophage/monocytes and synovial cells) and tumor necrosis factor. Cytokines can stimulate cultured chondrocytes to release proteases and can stimulates both chondrocytes and synovial cells to release collagenases and prostaglandin [E.sub.2]. [6-8,12,13,17 The increased levels of proteases cleave protein from proteoglycan molecules, resulting in products that no longer bind to hyaluronic acid to form normal proteoglycan aggregates (Figure 10).

Collagenases break down collagen, which acts as a structural framework to contain the proteoglycan. Disrupted collagen allows proteoglycan, which is very hydrophilic, to expand as it soaks up more water, further impairing the

structure and function of the cartilage. The amount of water in cartilage is dependent on the integrity of the collagen meshwork structure. As the cartilage deteriorates, components of the cartilage matrix (proteoglycan


Changes in Cartilage Associated with Aging

and Osteoarthritis

Cartilaginous factors Aging Osteoarthritis

Proteoglycan concentration Normal or Decreased

low normal

Water content Decreased Increased

Synthesis of collagen and Decreased Increased


Degradation enzymes such as Normal or Increased

proteoglycanases and low normal


Degradation enzyme inhibitors Normal Decreased

Growth factors Normal Increased

low normal

Proteoglycan aggregation Normal Decreased

(proteoglycan interaction

with hyaluronic acid)

and collagen subunits) enter the synovial fluid, which further stimulates the synovium to synthesize and release interleukin-1. (7,12,13,17) The net interaction of all these processes results in an imbalance between repair and breakdown. As the osteoarthritic process continues, the breakdown side of the equation tends to dominate, possibly because of a deficit in protease and collagenase inhibitors (11,18,19) (Figure 11).

Biologically and structurally, cartilage from patients with osteoarthritis differs from aged cartilage (Table 2). Although it is clear that osteoarthritis is not simply a function of aging, the etiology of the disease remains unknown. However, several theories have been proposed. (9) One theory is that repetitive, subtle mechanical trauma over a period of time initiates the process of repair and breakdown that eventually becomes unbalanced and results in osteoarthritis. (7) Another theory postulates that the initial osteoarthritic process begins in the synovium, which is stimulated to synthesize proteolytic enzymes, and that degradation is inadequately controlled because of a lack of inhibitors. (11,18)

According to yet another theory, osteoarthritis


begins with changes in the subchondral bone. In the presence of abnormal biomechanical stresses, the subchondral bone undergoes remodeling that causes stiffening of the bone. This process ultimately affects the overlying cartilage.

The most widely held theory about the etiology of osteoarthritis is that the disease process begins in the cartilage and is associated with changes in the microenvironment of cartilage. (13) An exaggerated breakdown and repair process is initiated and becomes dominated by the breakdown side of the equation. What initiates the process and why it escapes homeostatic controls is unknown. What is becoming increasingly clear is that the cartilage, synovium and subchondral bone are interdependent, with each one influencing the microenvironment of the other.


The osteoarthritic process leads to a slowly accelerating spiral of events, ultimately ending in joint failure and disability. Pain discourages use of the joint, which leads to loss of strength (deconditioning), which may progress to loss of range of motion (contractures), which limits function (disability) and results in loss of independence.

Disability is more likely when osteoarthritis occurs with other chronic diseases that further limit activity. Depression, anxiety, poor coping skills and insufficient social support can contribute to impairment and increase disability. (2,20,21)


Osteoarthritis remains a clinical diagnosis based on the occurrence of joint pain, joint stiffness (usually lasting less than 30 minutes) and lack of systemic symptoms. The pain is poorly localized, usually asymmetric and initially episodic. At first, pain occurs with activity, but as the disease progresses, it also occurs with rest. (4)

Signs of osteoarthritis include joint enlargement and crepitus with movement of the affected joint. At times, joint line tenderness, synovial thickening of joint effusion may be present. later in the disease process, decreased muscle strength, reduced range of motion and contractures may become evident.

Radiographic findings indicate the severity of joint pathology, but these findings do not necessarily correlate with the degree of pain or disability. Laboratory findings in osteoarthritis are usually within normal limits. The sedimentation rate (Westergren) would be expected to be less than 4 mm per hour and the rheumatoid antibody titer less than 1:80. Examination of joint fluid reveals clear to slightly yellow, viscous synovial fluid with fewer than 1,000 while blood cells per [mm.sup.3] (1.0 X [10.sup.9] per L) and a predominance of mononuclear cells. Culture of synovial fluid should have no growth, and crystals (uric acid or calcium pyrophosphate) are not present on birefringent microscopy. (5) Laboratory findings are not diagnostic but are helpful in excluding other disease processes (4,5) (Table 3).

Differential Diagnosis


The incidence of calcium pyrophosphate disease increases with age. It affects 10 to 15 percent of persons 65 to 75 years


of age and 30 to 60 percent of persons over age 85. The disease often occurs in areas affected by osteoarthritis or at the sites of previous joint trauma, and it may be responsible for the synovitis seen in osteoarthritis. (22)

The usual representation of this disease is as an acute monoarticular synovitis (pseudogout) involving the knee, wrist or shoulder. The disease may also present as a chronic pyrophosphate arthropathy associated with chondrocalcinosis in the cartilage around the shoulder, the meniscus of the knee or the triangular ligament of the wrist. The structural changes in pyrophosphate arthropathy are the same as those in osteoarthritis (i.e., joint space narrowing, bony sclerosis, subchondral cysts and osteophyte formation), and treatment is the same even though an underlying condition may be identified. (22)

Chondrocalcinosis is increased in hyperparathyroidism, hemochromatosis, hypothyroidism, gout, hypophosphatemia and hypomagnesemia. A serum calcium level and thyroid function tests may be warranted to screen for these associated metabolic conditions. Treatment of the primary cause usually does not significantly affect chronic pyrophosphate arthropathy. (22)


A number of other conditions may lead to secondary osteoarthritis. These include inflammatory processes such as rheumatoid arthritis or gout and infections such as septic arthritis or Lyme disease. Traumatic injury resulting in intra-articular fractures or ligamentous instability also must be considered. If recognized early, osteoarthritis secondary to these conditions may be amenable to treatment.


Treatment of osteoarthritis is directed at controlling pain, maintaining function, achieving or maintaining independence and minimizing complications. Successful treatment often requires stabilization of co-existing diseases and the provision of adequate social and psychologic support, as well as specific interventions. The advantages and disadvantages of various medications and treatments must be considered and discussed thoroughly with the patient, and treatment must be individualized (Table 4).

Physiotherapy, occupational therapy and analgesia are important aspects of management. Appropriate treatment can effectively reduce pain, provide joint protection and maximize function through improved strength, range of motion and use of adaptive equipment. (3,5) Since osteoarthritis of large joints is usually associated with muscular deconditioning, exercise is an important aspect of management. When possible, active exercise is preferred over passive exercise. Isometric exercises, which do not put undue stress on the joint, may initially be better tolerated than isotonic exercises. Reducing body weight, improving strength and maintaining range of motion not only improve the patient’s functional capacity buy may also improve joint stability and slow the processes leading to further disability. (23)

It is important to encourage continued activity and weight bearing, since immobilization by itself can result in rapid progression of osteoarthritis. (9) Cartilage does not have a blood supply and is dependent on the movement of synovial fluid for chondrocyte nutrition, joint lubrication and the removal of toxins. Cyclic motion and load bearing are essential for chondrocyte survival and normal proteoglycan and collagen synthesis. Just as weight bearing is necessary for proper cartilage function, adequate rest beween activities is also necessary to allow nutritional diffusion and minimize inflammation. (9,12)

Exercise should be titrated so that symptoms associated with pain or activity, such as stiffness, do not last more than two hours. In many cases, shorter, more frequent exercise is better tolerated than longer, less frequent activity. Joint protection during activity can be added by using devices such as canes, walkers, elevated toilet seats and orthotics. (5)

Pain control is crucial. The application of heat or cold may provide temporary pain relief. Heat is often applied before activity, while cold is usually applied after activity.

Many patients with osteoarthritis require medication for pain control. When pain is controlled, it is easier for a patient to perform conditioning exercises to achieve maximal functional capacity. However, the side effects of various pain medications need to be minimized in patients who may be taking these agents frequently or chronically.

In most cases, pain can be controlled as well with analgesics that do not have anti-inflammatory activity (e.g., acetaminophen or propoxyphene with acetaminophen) as it can with nonsteroidal anti-inflammatory drugs (NSAIDs). (24) Furthermore, the analgesic dose of NSAIDs is lower than the anti-inflammatory dose, making lower doses as effective in pain management. (24-26) When arthritis flares and is associated with signs of inflammation, short courses (seven to 10 days) of anti-inflammatory doses of NSAIDs may be beneficial.

Adverse effects of NSAIDs, such as upper gastrointestinal bleeding (gastric ulcers occur in 10 to 15 percent of chronic users, one-third of whom are asymptomatic), peripheral edema, hyponatremia (especially if NSAIDs are used with diuretics), hyperkalemia, and renal (10 to 15 percent of elderly patients treated with NSAIDs) or hepatic toxicity, tend to increase with increasing doses and duration of therapy, especially in the elderly. (27-29) Because of the potential adverse effects of chronic NSAID use, it is prudent to use shorter course at the lowest effective dose for exacerbations of arthritic symptoms associated with signs of inflammation.

Some studies have reported that NSAIDs adversely affect normal cartilage metabolism and potentially accelerate break-down of articular cartilage, [26,30-32] but other studies have suggested that some of these agents exert a protective effect against cartilage degeneration. [33-35] Although NSAIDs provide relief of symptoms, they probably have no effect on the underlying disease process in osteoarthritis. [19,24,25,36] There is very little evidence that NSAIDs are any more effective in osteoarthritis than are analgesics with anti-inflammatory activity. [24]

If a single joint is involved, an intra-articular steroid injection may be given. Steroids, however, can cause degeneration of cartilage and should be avoided if possible. Intra-articular steroid injections should be used infrequently, probably no more than two or three times per year. There is no legitimate place for systemic steroids or narcotics in the long-term treatment of osteoarthritis. [7]

Surgery may be considered in some patients with severe debilitating osteoarthritis. Joint replacement has been used in osteoarthritis of the hip and knee. However, artificial joints have a limited functional life (about 10 to 15 years), and they may need to be replaced if used in younger individuals.

Other procedures that may be considered in the treatment of osteoarthritis are arthroscopy with debridement of cartilage and washout of the joint space. [4] Occasionally (especially in younger patients), lower-extremity osteotomy or wedging of shoes is helpful to shift the stress off weight-bearing joint onto other parts of the cartilage. [3,9] Joint fusion (arthrodesis) is effective in removing pain, but it eliminates movement of the joint, and it may impair function.


[1] Yelin E. Impact of musculoskeletal conditions on the elderly. Geriatr Med Today 1989;8(3):103-18.

[2] Kelley WN, Arnold WJ, Avant RF, Chaney EJ, Ham RJ, Hazzard WR, et al., eds. Arthritis and aging. Health Learning Systems, Inc., Grant from Syntex Laboratories, Inc., Palo Alto, Calif., 1988.

[3] Mankin HJ, Brandt KD, Shulman LE. Work-shop on etiopathogenesis of osteoarthritis. J Rheumatol 1986;13:1130-60.

[4] Moskowitz RW. Primary osteoarthritis: epidemiology, clinical aspects,and general management. Am J Med 1987;83(5A):5-10.

[5] Quinet RJ. Osteoarthritis: increasing mobility and reducing disability. Geriatrics 1986;41(2):36-50.

[6] Tsang IK. Update on osteoarthritis. Can Fam Physician 1990;36:539-41,614.

[7] Mankin HJ, Treadwell BV. Osteoarthritis: a 1987 update. Bull Rheum Dis 1986;36(5):1-10.

[8] Hamerman D. Current leads in research on the osteoarthritic joint. J Am Geriatr Soc 1983;31:299-304.

[9] Bland JH. The reversibility of osteoarthritis: a review. Am J Med 1983;74(6A);16-26.

[10] Knowlton RG, Katzenstein PL, Moskowitz RW, et al. Genetic linkage of a polymorphism in the type II procollagen gene (COL2A1) to primary osteoarthritis associated with mild chondrodysplasia. N Engl J Med 1990;322:526-30.

[11] Ehrlich MG. Degradative enzyme systems in osteoarthritic cartilage. J Orthop Res 1985;3(2):170-84.

[12] Treadwell BV, Mankin HJ. The synthetic processes of articular cartilage. Clin Orthop Rel Res 1986;(213):50-61.

[13] Hamerman D. The biology of osteoarthritis. N Engl J Med 1989;320:1322-30.

[14] Sporn MB, Roberts AB. Transforming growth factor-beta. Multiple actions and potential clinical applications. JAMA 1989;262:938-41.

[15] Murphy G, Reynolds JJ. Current reviews of collagen degradation. Progress toward understanding the resorption of connective tissue. Bioessays 1985;2:55-60.

[16] Morales TI, Hascall VC. Factors involved in the regulation of proteoglycan metabolism in articular cartilage. Arth Rheum 1989;32:1197-201.

[17] Shinmei M, Kikuchi T, Masuda K, Shimomura Y. Effects of interleukin-1 and anti-inflammatory drugs on the degradation of human articular cartilage. Drugs 1988;35(Suppl 1):33-41.

[18] Glynn LE. Primary lesion in osteoarthrosis. Lancet 1977;1(8011):574-5.

[19] Brandt KD. Pain, synovitis, and articular cartilage changes in osteoarthritis. Semin Arth Rheum 1989;18(4 Suppl 2):77-80.

[20] Stewart AL, Greenfield S, Hays RD, et al. Functional status and well-being of patients with chronic conditions. Results from the Medical Outcomes Study. JAMA 1989;262:907-13 [Published erratum appears in JAMA 1989;262:2542].

[21] Summers MN, Haley WE, Reveille JD, Alarcon GS. Radiographic assessment and psychologic variables as predictors of pain and functional impairment in osteoarthritis of the knee or hip. Arth Rheum 1988;31:204-9.

[22] Doherty M, Dieppe P. Crystal deposition disease in the elderly. Clin Rheum Dis 1986;12:97-116.

[23] Semble EL, Loeser RF, Wise CM. Therapeutic exercise for rheumatoid arthritis and osteoarthritis. Semin Arth Rheum 1990;20:32-40.

[24] Bradley JD, Brandt KD, Katz BP, Kalasinski LA, Ryan SI. Comparison of an antiinflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee. N Engl J Med 1991;325:87-91.

[25] Liang MH, Fortin P. Management of osteoarthritis of the hip and knee [Editorial]. N Engl J Med 1991;325:125-7.

[26] Brandt KD. Effects of nonsteroidal anti-inflammatory drugs on chondrocyte metabolism in vitro and in vivo. Am J Med 1987;83(5A):29-34.

[27] Fries JF. NSAID gastropathy: epidemiology. J Musculoskel Med 1991;Feb:21-8.

[28] Stillman MT, Schlesinger PA. Nonsteroidal anti-inflammatory drug nephrotoxicity. Should we be concerned? Arch Intern Med 1990;150:268-70.

[29] Bush TM, Shlotzhauer TL, Imai K. Nonsteroidal anti-flammatory drugs. Proposed guidelines for monitoring toxicity. West J Med 1991;155(1):39-42.

[30] Palmoski MJ, Brandt KD. In vivo effect of aspirin on canine osteoarthritis cartilage. Arth Rheum 1983;26:994-1001.

[31] Fujii K. Tajiri K, Sai S, Tanaka T, Murota K. Effects of nonsteroidal antiinflammatory drugs on collagen biosynthesis of cultured chondrocytes. Semin Arth Rheum 1989;18(3 Suppl 1):16-8.

[32] Pettipher ER, Henderson B, Edwards JC, Higgs GA. Effect of indomethacin on swelling, lymphocyte influx, and cartilage proteoglycan depletion in experimental arthritis. Ann Rheum Dis 1989;48:623-7.

[33] Hess EV, Herman JH. Cartilage metabolism and anti-inflammatory drugs in osteoarthritis. Am J Med 1986;81(5B):36-43.

[34] Kalbhen DA. The influence of NSAIDs on morphology of articular cartilage. Scand J Rheumatol 1988;77(Suppl):13-22.

[35]Chondroprotection [Editorial]. Lancet 1991;337(8744):769-70.

[36] Muir H. Current and future trends in articular cartilage research and osteoarthritis. In: Kuettner K, Schleyerbach R, Hascall VC, eds. Articular cartilage biochemistry. New York: Raven Press, 1986:423-40.

JAY A. SWEDBERG, M.D. is an associate professor of family practice and a faculty member at the University of Wyoming Family Practice Residency Program-Casper. A graduate of the University of Colorado School of Medicine, Denver, Dr. Swedberg completed a family practice residency at Madigan Army Medical Center, Tacoma, Wash.

JEFFREY R. STEINBAUER, M.D. is an associate professor of family medicine and the director of the family practice residency program at the University of Oklahoma Health Sciences Center, Oklahoma City.

COPYRIGHT 1992 American Academy of Family Physicians

COPYRIGHT 2004 Gale Group