1 Boston University Clinical Epidemiology Research and Training Unit, 2 VA Boston Health Care System and 3 The Arthritis Center at Boston University School of Medicine, Boston, MA, USA.
Correspondence to: D. T. Felson, 715 Albany Street, A207, Boston University School of Medicine, Boston, MA 02118, USA. E-mail: dfelson{at}bu.edu
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Abstract |
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Methods. Using data from a natural history study of persons with symptomatic knee OA, we obtained fluoroscopically positioned postero-anterior (PA) radiographs at baseline, 15 and 30 months. Using an atlas, osteophyte size was scored on a scale of 03 at each of four sites on the PA film and, for each knee, both compartment-specific (i.e. medial; lateral) and overall osteophyte scores were computed. Progression was defined as an increase over follow-up in medial or lateral joint space narrowing, based on a semiquantitative grading. Mechanical alignment was assessed using long limb films at the 15 month examination. Logistic regression was used to evaluate the relation of osteophyte size with progression, adjusting for age, gender and body mass index, and with and without adjustment for alignment.
Results. Of 270 subjects who had 470 eligible knees with follow-up, 104 (22%) knees showed progression. Overall, osteophyte score modestly increased the risk of progression [odds ratio (OR) per S.D. increase of osteophyte score = 1.4 (95% CI 1.1, 1.8, P = 0.02)], but this effect weakened and became non-significant after adjustment for limb alignment (OR = 1.3). Compartment osteophyte score was strongly associated with malalignment to the side of the osteophyte (e.g. medial osteophyte and varus). Compartment-specific osteophyte score markedly increased the risk of ipsilateral progression (e.g. medial osteophytes medial progression) [OR per S.D. = 1.9 (95% CI 1.5, 2.5, P<0.001)] and decreased the risk of contralateral progression [OR per S.D. = 0.6 (95% CI 0.5, 0.8, P = 0.002)], but these associations diminished when we adjusted for limb alignment (OR = 1.5 and 0.7 respectively).
Conclusions. Large osteophytes do not affect the risk of structural progression. They are strongly associated with malalignment to the side of the osteophyte, and any relation they have with progression is partly explained by the association of malalignment with progression.
KEY WORDS: Knee osteoarthritis, Osteophyte, Natural history, Biomechanics, Alignment
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Introduction |
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The teleological purpose of osteophytes is unclear. In hip osteoarthritis, reconstitution or recovery of the joint space has been linked to the development of large osteophytes [4, 5], which presumably stabilize the hip joint.
In the knee, after a tear of the anterior cruciate ligament, osteophytes develop anteriorly and posteriorly and limit translocation of the femur on the tibia, stabilizing the joint in the sagittal plane. Pottenger et al. [6] reported, in knee osteoarthritis specimens, that removal of medial and lateral osteophytes increases varusvalgus motion. If, in knee OA, an increase in stability prevents structural progression, then knees with large osteophytes should experience less progression over time than those with smaller osteophytes.
While this may be the theoretical effect of osteophytes, two longitudinal studies of knee OA using non-fluoroscopic conventional radiography [7, 8] have reported that knees with large osteophytes, have, if anything, an increased risk of subsequent joint space loss, which suggests cartilage loss. No studies using fluoroscopic positioning techniques have examined this question, nor have studies examined whether the effect of osteophytes is specific to the side of the osteophyte or whether osteophytes are related to limb malalignment, which has been recently shown to be a potent risk factor for progression [9, 10].
If osteophyte size has little relation to disease progression, or even increases it, that might suggest that either osteophytes do not increase stability or that joint stability does not influence disease progression.
We evaluated the effect of osteophytes on disease progression in knee OA, recognizing that this might not be relevant to their effect in other joints. In a longitudinal study of patients with knee OA in which serial fluoroscopically positioned radiographs were obtained, we determined whether osteophytes affect the risk of disease progression, defined on radiographs as joint space loss. In addition, we evaluated the relation of osteophyte size to limb alignment and tested whether osteophytes on one side of the joint might be related to progression on the same or the other side of the joint, and whether any relation of osteophytes to progression might, in part, be explained by malalignment.
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Materials and methods |
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The study included a baseline examination and follow-ups at 15 and 30 months. At all examinations, subjects obtained knee radiographs. They also were weighed using a balance beam scale with their shoes off, and height was assessed. The baseline and follow-up examinations were approved by the Boston University Medical Center and the Veterans Administration Boston Healthcare System IRBs. Each subject's written consent was obtained according to the Declaration of Helsinki.
Radiographs
Subjects underwent weight-bearing postero-anterior (PA) radiography using the protocol of Buckland-Wright [11]. Using fluoroscopic positioning, we aligned the beam relative to the centre of the knee, and the knee was flexed so that the anterior and posterior lips of the medial tibial plateau were superimposed. Feet were rotated until the tibial spines were centred in the notch and outlines of foot rotation were then made on foot maps, so, for subsequent films, the foot rotation was the same. Fluoroscopic positioning has been shown to produce more accurate assessments of the joint space relative to non-fluoroscopic acquisition and to improve reproducibility of joint space assessment.
For evaluation of progression, we focused on the joint space width of the medial and lateral compartments, as that has been found to correlate with cartilage thickness [12]. For reading of joint space we used the Osteoarthritis Research Society International Atlas [13] in which each of the medial and lateral tibiofemoral joint spaces is graded from 0 (normal) to 3 (bone on bone). We defined progression of joint space narrowing in a knee compartment as progression by 1 grade. No knees showed progression in both medial and lateral compartments. One reader (DTF) read all films. While all subjects were read unblinded to sequence, a subsample of subjects also had films read blinded to sequence so as (i) to test the reproducibility of progression measurement and (ii) to evaluate possible bias in characterizing progression based on the fact that films were not read blinded to sequence. Intra-observer agreement for reading progression blinded vs unblinded to sequence was
= 0.81 (P<0.001), and disagreements between blinded and unblinded readings were in no particular directionthere was no greater tendency for unblinded readings to be read as showing progression.
For Kellgren and Lawrence grade, we used the Atlas of Standard Radiographs [14].
For osteophyte score, we used the baseline PA radiograph and scored each marginal osteophyte on a scale of 03 according to the OARSI atlas [13]. For each knee, we scored four sites: medial tibia, medial femur, lateral tibia and lateral femur. The reliability for reading each osteophyte's score was = 0.78 (P<0.001).
The overall osteophyte score for a knee consisted of the sum of the scores of the individual osteophytes (no more than one osteophyte at each site) and could range from 0 to 12 (03 at four sites). In addition to an overall osteophyte score, we evaluated medial and lateral osteophyte scores (hereafter called compartment-specific osteophyte scores) for each knee consisting of the sum of tibia and femur osteophytes on the medial and lateral sides, respectively (both ranged from 06).
Measure of alignment
Mechanical alignment was measured on a long limb film which was acquired at the second visit using methods previously described [10]. We measured alignment as the angle in degrees subtended by one line connecting the middle of the femoral head with the middle of the knee and the other line connecting the middle of the ankle with the middle of the knee. Inter-observer agreement for reading alignment was high [intra-class correlation coefficient = 0.97 (P<0.001)]. Unless otherwise specified, alignment was evaluated as a continuous measure.
Data analysis
We initially examined whether overall osteophyte score was related to the risk of subsequent radiographic progression. Because osteophytes are so closely tied to disease severity and to narrowing, we felt that adjusting for baseline narrowing in regression analyses would not be an adequate adjustment for this relation. We therefore used an analytical approach we have previously used to separate effects of two related predictors [15]. To separate the effect of osteophytes from baseline narrowing, we stratified knees by the worse joint space narrowing grade in the knee (03) at baseline and, within each grade of narrowing, calculated a z score using the knee's overall osteophyte score. These z scores were then used as the measure of osteophyte size in the analysis. We used the same z score approach to compute a compartment-specific osteophyte score.
We examined mean compartment-specific osteophyte score by quartile of alignment and the correlation of osteophyte score by alignment.
To evaluate the relation of osteophyte score to progression, we used logistical regression with progression as the dependent variable. Generalized estimating equations were used to adjust for the correlation between knees. We performed these analyses before and after adjustment for limb alignment, which was defined continuously. To evaluate compartment-specific osteophytes and their effects, we started by examining each possible association (medial osteophytes medial progression; lateral osteophytes
medial progression; medial osteophytes
lateral progression; lateral osteophytes
lateral progression) and, when we determined that medial and lateral osteophytes had similar effects on ipsilateral progression and also had similar effects on contralateral progression (e.g. effects of medial osteophytes
medial progression similar to lateral osteophytes
lateral progression), we combined all ipsilateral and contralateral analyses (e.g. combining medial
medial progression and lateral
lateral progression). We defined a weakening of an odds ratio (OR) linking osteophytes to progression as a 10% change in the OR toward the null [16].
We examined all knees eligible for progression, but our study also included knees with only patellofemoral disease. Therefore, we conducted secondary analyses in which knees without any tibiofemoral findings and only disease in the patellofemoral compartment were excluded.
All P values reported are two-tailed.
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Results |
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Discussion |
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How can our findings be explained? We suggest that osteophytes may not have any primary effect themselves but rather they serve as markers for two factors that strongly affect the risk of progression. First, they are highly correlated with limb malalignment. We found this especially for medial osteophytes and believe that our failure to find a similar strong linear association with lateral osteophytes is due to the predominant medial osteoarthritis in this sample of subjects (there were small medial osteophytes in many knees with lateral compartment osteoarthritis). We regard the more salient association of lateral osteophytes with valgus malalignment as being represented by the most valgus versus neutral quartiles of alignment, not the varus alignment seen in Fig. 2b.
A second factor probably affecting progression is the existence of disease in the compartment. In animal models, osteophytes develop at sites of adjacent cartilage loss [17]. Thus, the association of osteophyte size with an increased risk of ipsilateral progression may not reflect an effect of osteophytes, per se, but rather that large osteophytes serves as a marker for nearby cartilage loss. This may explain the findings of one previous longitudinal radiographic study of OA [8], which reported an association of osteophytes with progression only in knees in which the joint space was minimally narrowed or normal. In these knees, osteophytes may have served as the evidence for nearby cartilage loss not yet detectable as joint space narrowing on the radiograph.
Given the strong association of osteophytes with two risk factors for disease progression, malalignment and pre-existing cartilage loss, we speculate that any effect of osteophytes on progression independent of these factors would be hard to detect. Even so, our data suggest that osteophytes do not have any direct role in disease progression but may serve as markers of the location and severity of the pathologic process.
Our findings are relevant to osteophytes in the knee and not necessarily to osteophytes in other joints nor osteophytes in specific locations where shape and size may result in genuine joint stabilization. Nagaosa et al. [18] have noted that osteophyte shapes may differ and the curvature of an osteophyte or its placement near the joint capsule may stabilize the joint.
Since osteophytes may stabilize joints, our failure to find an effect of osteophytes on progression might suggest that joint instability and laxity may be less important as factors affecting progression than have been suspected.
There are a number of important limitations to our study. First, most of the study participants were men. Obviously, most patients with OA are women. Although it may be suspected that osteophyte size was greater in men, if anything, women tended to have slightly larger osteophytes. The relation of osteophytes to progression did not differ by gender. Our assessment of limb alignment occurred in the middle of the follow-up, not at baseline, and if osteophytes could affect limb alignment it is conceivable that osteophytes at baseline could have affected subsequent alignment. Additional analyses using the middle examination as baseline showed similar findings to the ones presented here.
Also, we employed a crude osteophyte scale. Two-dimensional radiographs may miss the three-dimensional extent and size of osteophytes, and their particular location may be important in terms of effects on joint stabilization.
In summary, osteophytes are strongly associated with malalignment to the side of the osteophyte, and malalignment is a potent risk factor for progression of OA. In analyses unadjusted for alignment, osteophytes on the side of the narrowing appeared to increase the risk of subsequent narrowing, but this effect did not persist when malalignment is adjusted for. Thus, we found no clear-cut independent relation of osteophyte size to the risk of progression of knee OA.
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Acknowledgments |
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The authors have declared no conflicts of interest.
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References |
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