Peak adductor moment
The peak adductor moment reflects the magnitude of the intrinsic compressive load on the medial compartment of the knee in stance (). Varus–valgus alignment is a major determinant of peak adductor moment. Varus further increases the medial compartment load during gait; valgus acts similarly to increase stress in the lateral compartment (). The peak adductor moment predicts radiographic progression in patients with medial compartment OA () and development of knee pain in asymptomatic elderly subjects (). A greater degree of toe-out walking, which reduces the peak adductor moment, diminished the risk of radiographic progression of OA (). Interventions that reduce the peak adductor moment improve both symptoms and structural abnormalities of OA, providing a proof-of-concept of their etiopathogenetic importance.
Repetitive impulsive loading
Physiologically, the viscoelasticity of articular cartilage and subchondral bone serves to maximize the contact area in a loaded joint, minimizing the stress (force per unit area) within the articular cartilage and transmitting load to the underlying bone, sparing the cartilage from damage (). If, however, the ability of the articular cartilage to deform with loading is restricted so that it cannot conform completely to the load, the size of the contact area will be reduced and high stress will be generated within the articular cartilage. It is relevant, therefore, that the congruity of joints increases with age (as does the prevalence of OA), so that they become less flexible under load (). The subchondral bone deforms less, or becomes stiffer, when load is applied rapidly than when loading is more gradual, limiting the chondroprotective effect of the shock-absorbing capacity of the bone. Joint damage caused by excessive loading may be related, therefore, not only to the magnitude of the load, but also to the rate of loading. Rapid repetitive impulsive loading does not permit sufficient time for the flow of interstitial fluid needed to absorb the energy that is transmitted, thereby protecting the articular cartilage matrix and cells (). The data on the magnitude of the peak adductor moment in knee OA and the data on the rates of loading require reconciliation, but in any case, they strongly suggest that mechanical abnormalities play a principal role in the etiopathogenesis of structural damage and the symptoms experienced by patients with knee OA.
The structural and clinical improvement that may be seen after distraction of OA hips, knees, and ankles with external fixation ([19, 20, 55]), and after hip and knee osteotomy ([58, 59]), further support this view. In this country, however, osteotomy has, to a large extent, been superceded by arthroplasty as a surgical treatment for symptomatic OA. In the hands of most orthopedic surgeons it is a more reliable procedure and, for the patient, is associated with a much more rapid return to load-bearing activities than osteotomy. Parenthetically, with respect to the adequacy of radiography as an outcome measure for RCTs of putative DMOADs, plain radiography has clearly demonstrated structural improvement after both osteotomy and joint distraction ([19-22, 55]).
Several presumptive DMOADs studied in placebo-controlled RCTs have been aimed at blocking the effect(s) on articular cartilage of, e.g., a matrix-degrading protease or cytokine or toxic oxygen radical, or increasing the concentration of cartilage matrix macromolecules (). In none of them, however, were attempts made to correct existing local biomechanical abnormalities. It is important to differentiate the pathogenesis of joint breakdown, due to, e.g., proteases, matrix-degrading cytokines, or toxic oxygen radicals, from the etiopathogenesis of OA, which, in most cases, is mechanically induced and mechanically driven.
Although no DMOAD has received approval for use in humans with OA, not all RCTs of putative DMOADs have yielded negative results. Examination of studies in which positive results were obtained can be informative, and examples are presented below.
In a placebo-controlled trial (), doxycycline significantly slowed the rate of JSN in the index knee, but not the contralateral knee, of patients in whom unilateral radiographic OA was seen on standing anteroposterior radiography, whereas the mean rates of medial tibiofemoral JSN in the contralateral and index knees of the placebo-treated patients were comparable. Lateral and/or sunrise views, however, commonly indicated the presence of patellofemoral or posterior tibial OA in the contralateral knee (), leading to speculation that the target(s) for doxycycline in knees with early structural damage may differ from that in knees with more severe OA.
Although the efficacy of glucosamine hydrochloride, alone or in combination with chondroitin sulfate, was not significantly different from that of placebo with regard to effects on the rate of JSN in the Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) (), the efficacy of chondroitin sulfate as a DMOAD remains debated by some. Significant limitations in the experimental design and power of the GAIT study, however, severely limit the conclusions that may be drawn with respect to the reported results ().
Licofelone, a dual inhibitor of cyclooxygenase and lipoxygenase, exhibited DMOAD activity, based on JSW measurements from Lyon schuss radiographs obtained at baseline and at 6, 12, and 24 months (). Quantitative change in articular cartilage volume was assessed by MRI at the same intervals. The authors compared the results with those in a group of OA patients who received naproxen 500 mg twice daily. The mean loss of articular cartilage volume with licofelone was greater than that with naproxen at both 12 months and 24 months. The reduction in radiographic JSW in patients who received licofelone was less than that in the naproxen arm, but the difference between treatment groups in this respect was not significant. The relative insensitivity of Lyon schuss radiography in comparison with qMRI in assessing articular cartilage thickness in that study contrasts with recent findings reported by Le Graverand et al ().
In a recent phase III RCT using radiography with a fixed flexion view, strontium ranelate, an osteoporosis treatment that dissociates bone remodeling processes, inhibits resorption of subchondral bone, and stimulates chondrogenesis in vitro, exhibited DMOAD activity ([66, 67]). In the strontium ranelate treatment group the rate of JSN was slower, and the proportion of patients with radiographic progression smaller, than in the placebo group. As noted above, however, the fixed flexion view does not assure a high degree of alignment of the medial tibial plateau with the central x-ray beam, which has been shown to significantly affect the appearance of JSW (and, hence, the rate of JSN in serial images) ([7, 8, 43]). Also, given the important contribution of subchondral bone to the structural changes and symptoms of OA () and the hypothetical worsening of OA by dissociation of bone formation and bone resorption, the results of the strontium ranelate RCT require confirmation.
In conclusion, the genes whose identification may be required for prevention and treatment of common, garden-variety OA may not be those that regulate metabolism of the chondrocyte. Rather, they may be genes that control congenital and developmental deformities of the joint (thereby reducing the habitually loaded area of the joint surface) or that underlie micro-incoordination of the patient (resulting in concentration of the peak dynamic load on the joint, with ensuing microdamage and remodeling of joint tissues that are detrimental to joint function). Possibly, had the treatments that failed to exhibit DMOAD activity been studied under conditions in which the effects of measures to alleviate the elevated levels of intraarticular stress were also evaluated, e.g., in a factorial design, some may have demonstrated efficacy or been shown to be unnecessary.