Lessons from Epidemiology/Role of Joint Stress

Osteoarthritis is conceived of as a process that is initiated and perpetuated by mechanical stress. Normal healthy joints are defined by their nearly frictionless excursion and physiologic loading, as maintained and limited by constraints on joint range of motion. Increased mechanical stress resulting from traumatic ligamentous and cartilage injuries and from increased mechanical forces associated with obesity is a prominent risk factor for the development of knee OA. Interest in the role of gait variance as an OA risk factor is evolving. Yet OA is a tissue-based process. The mechanical forces that result in OA are translated into biochemical and cellular perturbation that manifests as and is a consequence of focal loading defects.

As with all disease, OA is a consequence of the interplay between host and environmental factors. Lifestyle and life cycle events influence the natural history of OA. Osteoarthritis is described as primary (idiopathic) or secondary, localized or generalized. Osteoarthritis that is associated with trauma, congenital defects, inflammatory arthritis, or neuropathic or metabolic disease is conceived of as secondary.³² Knee OA can present in isolation or in association with polyarticular OA, especially OA of the hands.¹⁷

Aging and female gender are invariant risk factors associated with increased incidence of knee OA. By contrast, obesity and trauma are life experience variables that correlate with knee OA incidence and progression. In all cases, knee OA can be conceived of as resulting from excessive joint loading caused by perturbations of joint biomechanics.

Explanations for the increased incidence and prevalence of OA with aging include factors attributable to events earlier in life and special circumstances of aging. For example, radiographic knee OA may present in old age, but events that initiated the OA may have occurred years earlier. The natural history of OA is such that it likely takes years to manifest as radiographic damage. The initial radiographic marker of OA is uncertain; once established radiographically, detectable cartilage volume loss seen on x-ray may be as little as less than 2% per year.¹⁹ Muscle strength, reaction time, and proprioception are factors implicated in joint stability and health; all are impaired with aging. As a consequence, aging is characterized by an increased inclination to injury. The risk of OA in aging is magnified by a decreased capacity for cellular repair. These two characteristics of the aging process alone may contribute to increased risk of knee OA incidence and progression,³² although microscopic and subcellular changes of aging are also likely to play a role.

The predilection of women’s joints to OA is not well understood. In the Framingham cohort, women developed symptomatic radiographic OA at a rate of 1% per year as compared with 0.7% per year for men. At baseline, the women in this cohort had a mean age of 71 years. Estrogens are presumed to be protective, and in the postmenopausal state their relative deficiency may correlate with accelerated cartilage loss. However, no clear consensus has been reached with respect to the role of estrogen biology as it pertains to the risk of incidence or progression of OA. Instead, the reported increased risk may correlate with other genetic and phenotypic variables. A Dutch study reported the protective effects of an allelic variation of one of the bone morphogenetic proteins—growth differentiation factor 5 (GDF5)—on the incidence of hand and knee OA in women, but not in men, suggesting that as yet unidentified biochemical variables may influence the observed OA gender dimorphism.^40,43 Equally straightforward and well-documented differences in life expectancy, adiposity, muscle mass, ligamentous laxity, joint stability, and propensity to obesity may influence OA risk.

The obesity epidemic has wide-ranging implications for public health. A recent analysis demonstrated that if current obesity trends continue, the deleterious effects of weight gain on life expectancy will shortly outweigh the positive impact on life expectancy of decreased rates of smoking. Estimates suggest that in the United States, obesity currently accounts for 5% to 15% of deaths each year. It is projected that nearly half the population (45%) will be obese (body mass index [BMI] > 30) by the year 2020.³⁸

Obesity has a profound impact on joint health. The incidence of knee OA across all population studies is highly correlated with BMI. Initial observations in the Framingham study correlating knee OA with obesity continue to be substantiated.⁸ The Johnston County, North Carolina, cohort study concluded that lifetime risk of knee OA for obese (BMI ≥30) persons is 60.5% versus 46.9% for the overweight (BMI, 25 to <30) and 30.2% for those with BMI <25.²⁶ An influence of childhood obesity on lifetime OA risk is likely. Several studies have demonstrated a correlation between increased BMI early in life and the development of subsequent knee OA.¹¹ However, the Johnston County cohort showed that obesity at baseline and follow-up visits more strongly correlates with lifetime OA risk than BMI at 18 years of age. Equally, although obesity is clearly and strongly correlated with risk for OA, several studies have suggested that obesity does not necessarily correlate with OA progression. In a study of 60 obese and 81 nonobese women followed by x-ray over 12 months, although the obese women demonstrated greater initial radiographic OA severity, their joint space widths did not diminish.²² Another study showed a correlation between radiographic progression and obesity among patients with a neutral or valgus alignment, but not a varus alignment, lending further insight into the complexity of the relationship between obesity and knee OA progression.⁶

Obesity in combination with cardiovascular risk factors may enrich a patient’s risk for knee OA. In an intriguing analysis, Sowers and associates evaluated 482 women (mean age, 47 years) using knee films for evidence of diabetes mellitus and/or dyslipidemia and hypertension, with the result that obese patients with cardiometabolic clustering had a knee OA prevalence of 23.2% versus 12.8% among obese women without cardiometabolic clustering. In addition, women with the cardiometabolic syndrome reported more knee pain than those without the cardiometabolic syndrome. These data point to the influence of metabolic factors on joint health.³⁷

The medial and lateral compartments of the tibial-femoral knee joint do not bear load equally. In neutrally aligned knees, the medial compartment bears 60% to 70% of the force across the knee in weight-bearing activities. Therefore, it is not surprising that the medial compartment of the knee is disproportionately afflicted with OA, with medial OA representing up to 75% of the disease burden. Equally patellar-femoral osteoarthritis is also disproportionately medial.²⁰

By extension, knee malalignment is the single biggest risk factor in OA disease progression. Varus-valgus malalignment correlates with OA progression in isolation and/or in synergy with other risk factors. Varus malalignment increases the predisposition to OA disease progression by upward of fourfold, and valgus malalignment by as much as fivefold in some studies.³³ Data on the role of malalignment as a risk factor for initiation of disease are not as consistent as for progression. Traditionally, mechanical knee malalignment is assessed with static limb x-rays. Mechanical axis and dynamic adduction moments are highly correlated. Yet forces across the joint during the dynamic phase of gait may have an even more powerful effect on disease progression than malalignment measured during a static stance. During normal gait, the adduction moment is approximately 3.3% of body weight × height, compared with 4.2% body weight × height in patients with medial knee OA.³¹ The degree of joint space loss has been shown to correlate with the degree of adduction moment. Persons with greater adduction moment lost joint space more quickly.²⁵

Static knee alignment is determined by a variety of biomechanical factors. Tibiofemoral congruence, integrity of the anterior cruciate ligament (ACL) and the meniscus, and supporting muscular strength all influence joint alignment.²⁰ Torn ACLs and damaged and extruding menisci have long been known to be associated with progression of knee OA. The standard of care for debilitating knee pain used to include total meniscectomy, until it was learned that surgical meniscal resection correlates with accelerated OA. Menisci tear both as a consequence of trauma, a very common athletic injury, and secondary to degenerative change. The advent of magnetic resonance imaging (MRI) as an OA investigational tool allowed for the prospective examination of 121 cases and 294 control knees over a 30-month period as part of the Observational Multicenter Osteoarthritis Study. Patient age ranged from 50 to 79 years, and all were determined to be at high risk for OA because they were overweight, had persistent knee pain, or had a history of knee trauma. Patients were followed in two cohorts: one with incident OA, and the other studied as controls. Meniscal damage at baseline was more frequent in knees with progressive joint space loss/cartilage degeneration than in radiographically stable knees (54% vs. 18%; P < .001). A dose effect of meniscal damage with more severe baseline meniscal disease was noted to correlate with increased progressive radiologic OA. It was no surprise that 30-month MRIs captured new meniscal tears in both cohorts, although more frequently in the OA than in the non-OA group. Taken together, these data show the pivotal role that meniscal integrity plays in knee health; they also raise compelling questions about the pathoetiologic role of meniscal deformities. Do they initiate or propagate OA? No doubt their role is complex, with meniscal injuries at once resulting in and signifying the biomechanical derangement and modification of associated joint structures.⁶

Lessons from Radiology

Adapting to changing load is a requirement of a healthy joint. Each tissue and cell type contributes. Osteoarthritis results when the capacity to adapt is exceeded, resulting in structure modifications that cause characteristic tissue changes. In recent years, insights provided by MRI study of knee OA have expanded our understanding of the pathophysiology. Historically, OA was thought of as a primary condition of articular hyaline cartilage. Now it is appreciated that all joint tissues are concurrently involved—cartilage, synovium, and bone together—and that tissue inflammation and inflammatory pathways play a prominent role in the pathophysiology of OA. Enthesitis, synovitis, bone marrow lesions, and cartilage loss are all lesions of evolving interest in OA. In particular, evolving evidence suggests that synovitis and bone marrow lesions may correlate with joint pain and progression of OA.³⁰

Bone is the defining characteristic of skeletal anatomy. Bone is at once brittle and resilient. It is characterized by its ability to respond to mechanical stress with upregulation of bone formation with osteoblast activation, and resorption with osteoclast activation, allowing for the dynamic response of the skeleton to environmental forces. This homeostatic remodeling process is perturbed in OA, resulting in characteristic subchondral sclerosis and subchondral plate thickening. In several studies, these changes have preceded cartilage volume loss.⁴

Subchondral bone is the interface between overlying articular cartilage and underlying cortical and trabecular bone. Although the volume of trabecular bone may increase in OA, paradoxically, perhaps in response to altered mineralization kinetics, the stiffness of this new bone may actually decrease.¹³

Bone marrow lesions first came to the attention of investigators more than 20 years ago and were originally described as bone marrow edema.⁴⁶ Nearly a decade ago, the correlation between bone marrow lesions and OA progression and pain was first identified.¹⁰ More recently, 70% of patients with bone marrow lesions were found to have pseudocysts on histopathologic examination of surgical specimens.³⁹ These lesions corresponded to the areas of most severe damage in the overlying cartilage and likely correlated with areas of focal bone necrosis.

Bone marrow lesions are of interest not only because of their pathophysiologic significance, but also because they correlate with knee pain. In a 2001 study, Felson and colleagues showed that 37% of patients with documented x-ray OA with knee pain had bone marrow lesions versus only 2% of patients with x-ray OA but without knee pain (P < .001).⁹

Osteophytes are a pathopneumonic radiologic finding of OA. They are known to precede joint space narrowing and cartilage degradation. It has been suggested that they may represent a compensatory response to ligamentous injury or laxity. Anterior and posterior osteophytes form in response to ACL tear and limit tibial-femoral excursion.⁴² Thus although conceived of as pathogenic, they may contribute to joint stability. Osteophytes form in areas of active joint loading as a result of endochondral ossification. Periosteal cells first proliferate then differentiate into chondrocytes, which, in turn, hypertrophy and ossify.¹³

Synovial hypertrophy is a hallmark of advanced OA; on MRI, it strongly correlates with knee pain. Synovial lining hypertrophy correlates topographically with areas of underlying cartilage denudation and bone damage. Several prospective MRI studies of OA cohorts have concluded that a decrease in synovitis on MRI correlates with a decrease in pain score. Synovitis is often correlated with joint effusions and joint capsular swelling. The size of a joint effusion itself correlates with the degree of knee pain. The synovium is an extremely bioactive tissue. In addition to playing the role of synovial-like fibroblasts in the production of synovial fluid, it is home to various monocytes and macrophages, which, when activated, assume an inflammatory phenotype. The relevance of inflammation to osteoarthritis has taken on new importance as the role of synovium in OA has become better appreciated with the advent of newer radiologic techniques.³⁰