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ARTICLE

Relation of Dietary Intake and Serum Levels of Vitamin D to Progression of Osteoarthritis of the Knee among Participants in the Framingham Study

right arrow Timothy E. McAlindon, DM; David T. Felson, MD; Yuqing Zhang, DSc; Marian T. Hannan, DSc; Piran Aliabadi, MD; Barbara Weissman, MD; David Rush, MD; Peter W.F. Wilson, MD; and Paul Jacques, ScD

1 September 1996 | Volume 125 Issue 5 | Pages 353-359

Background: Evidence suggests that pathophysiologic processes in bone are important determinants of outcome in osteoarthritis of the knee. Low intake and low serum levels of vitamin D may compromise favorable responses of bone to osteoarthritis, predisposing patients to progression.

Objective: To determine whether dietary intake and serum levels of vitamin D would predict the incidence and progression of osteoarthritis of the knee in participants of the Framingham Study.

Design: Prospective observational study.

Setting: The Framingham Study.

Participants: Participants in the Framingham Heart Study who had knee radiography at examinations 18 (done between 1983 and 1985) and 22 (done between 1992 and 1993) and received interim assessments of vitamin D intake and serum levels.

Measurements: Intake of vitamin D and serum levels of 25-hydroxyvitamin D, calculated on the basis of dietary habits and supplement use as reported on a questionnaire, were evaluated at examination 20 (1988 to 1989). Knee radiographs were given scores for global severity of osteoarthritis, using a modification of the scale of Kellgren and Lawrence (range, 0 to 4), and for the presence of osteophytes and joint-space narrowing (range, 0 to 3). Covariates measured at examinations 18 and 20 were age, sex, body mass index, weight change, injury, physical activity, health status, bone mineral density, and energy intake.

Results: 556 participants (mean age at baseline ±SD, 70.3 ± 4.5 years) had complete assessments. Incident osteoarthritis occurred in 75 knees; progressive osteoarthritis occurred in 62 knees. Serum levels of vitamin D were modestly correlated with vitamin D intake (r = 0.24). Risk for progression increased threefold in participants in the middle and lower tertiles for both vitamin D intake (odds ratio for the lower compared with the upper tertile, 4.0 [95% CI, 1.4 to 11.6]) and serum levels of vitamin D (odds ratio for the lower compared with the upper tertile, 2.9 [CI, 1.0 to 8.2]). Low serum levels of vitamin D also predicted loss of cartilage, as assessed by loss of joint space (odds ratio, 2.3 [CI, 0.9 to 5.5]) and osteophyte growth (odds ratio, 3.1 [CI, 1.3 to 7.5]). Incident osteoarthritis of the knee occurring after baseline was not consistently related to either intake or serum levels of vitamin D.

Conclusions: Low intake and low serum levels of vitamin D each appear to be associated with an increased risk for progression of osteoarthritis of the knee.


Osteoarthritis is a common age-related disorder that is present in more than 10% of persons older than 65 years of age; it results in substantial disability and economic cost in elderly persons [1]. Despite its frequency, osteoarthritis remains poorly understood, and few therapeutic options for it are available [2].

Osteoarthritis has traditionally been regarded primarily as a disorder of articular cartilage, but many of its recognized features, such as osteophytosis, subchondral sclerosis, and cyst formation, indicate that bone plays a prominent role in the pathophysiology of this condition [3-5]. Early cartilage abnormalities in patients with osteoarthritis are followed by changes in the periarticular trabecular bone and thickening of the subchondral plate [6-8]. More severe manifestations include stress fractures, necrosis in bone denuded of cartilage or undermined by cysts, and bony infarction [9].

These changes in subchondral bone may have adverse effects resulting from decreased mechanical compliance of periarticular bone to physical stresses and from shock-absorbing capacity [10] or impaired reparative response [11], or they may help stabilize an osteoarthritic joint [12] or contain the disease process [13]. It has also been suggested that bone mineral density, which is inversely related to osteoarthritis at certain sites [5, 14], may influence the skeletal expression of the disease: A more "deforming, erosive, inflammatory" form of osteoarthritis may predominate in persons with "softer" bone [15]. Osteoarthritis shows considerable heterogeneity in terms of the presence of many of these features [11, 16]. The idea that the nature of bone response in osteoarthritis may determine outcome [10] has been advanced by the recent demonstration that patients who have abnormalities seen on bone scanning that are adjacent to an osteoarthritic knee have a higher rate of progression of osteoarthritis than do patients without such abnormalities [17]. Thus, the quality of periarticular bone and its capacity to respond to various stresses, including changes in loading force caused by altered biomechanics, may influence whether osteoarthritis stabilizes or progresses.

Normal bone metabolism depends on the presence of vitamin D, a compound derived largely from the diet or from cutaneous exposure to ultraviolet light. Suboptimal levels of vitamin D may have adverse effects on calcium metabolism, osteoblastic activity, matrix ossification, and bone density [18, 19]. Low levels of vitamin D in tissue may impair the ability of bone to respond optimally to pathophysiologic processes in osteoarthritis and may predispose patients to disease progression. Furthermore, both osteoarthritis and hypovitaminosis D occur with increased frequency in elderly populations. We therefore investigated the hypothesis that the relative deficiency of vitamin D, as determined by dietary intake and serum levels, predisposes patients to progression of osteoarthritis of the knee.


Methods
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The persons we studied were participants in the population-based Framingham Study who had been followed for more than 40 years. As part of a study of osteoarthritis, radiography of the knee was done in these participants at biennial examinations 18 (between 1983 and 1985) and 22 (between 1992 and 1993). Methods with which to assess the incidence and progression of osteoarthritis of the knee were previously reported in detail [20]. In brief, participants in the Framingham Study received anteroposterior weight-bearing radiography of the knee at baseline (biennial examination 18) and received follow-up radiography at examination 22. Follow-up radiography was occasionally done in participants' homes when participants were too frail to come to the examination site. Paired baseline and follow-up radiographs were simultaneously graded for global severity of osteoarthritis and for individual radiographic features of osteoarthritis. Each pair of radiographs was read by one of two academic bone and joint radiologists and then by a rheumatologist. All readings were done independently, and all readers were blinded to the exposures of interest. Scores for individual radiographic features of osteoarthritis were determined on the basis of the radiologist's reading. If readers disagreed about a patient's osteoarthritic status, the radiographs in question were read by an additional academic bone and joint radiologist. If this radiologist's reading disagreed with the initial radiologist's reading, the grades for overall severity and individual features were reevaluated by an adjudication panel that consisted of two radiologists and the rheumatologist.

Outcome Variables

Scores for Global Severity

Radiographs were given scores according to a modification of the Kellgren and Lawrence scale (range, 0 to 4), in which 0 = no osteophytes or joint-space narrowing; 1 = questionable presence of osteophytes, questionable presence of joint-space narrowing, or both; 2 = either definite presence of osteophytes with possible joint-space narrowing or definite mild joint-space narrowing with or without osteophytes; 3 = definite moderate joint-space narrowing (at least 50%) (cysts or sclerosis may be present, and osteophytes are usually present); and 4 = severe joint-space narrowing [3]. This system is widely used to classify osteoarthritis of the knee and to describe radiographic progression in natural history studies [21, 22]. Joint-space narrowing, osteophytosis, and sclerosis, which are the key elements of this system, have been shown to be relatively reliable indicators of progression in osteoarthritis of the knee, both independently and in combination [23]. Osteoarthritis was classified as present if a grade of 2 or more was given. Knees that received arthroplasty during the study period were assigned a grade of 4 after chart review confirmed that the knees had had clinical and pathologic features of osteoarthritis at the time of surgery. Knees without osteoarthritis at baseline (grade ≤ 1) that had developed osteoarthritis by the time of follow-up were classified as having incident osteoarthritis. Knees with prevalent disease at baseline that progressed by at least one grade were classified as having progressive osteoarthritis. Controls for each of these groups were knees that were eligible for the given outcome at baseline but that did not develop incident or progressive osteoarthritis.

Scores for Specific Radiographic Features

The presence and severity of osteophytes and joint-space narrowing in the two compartments of each knee (the medial and lateral tibiofemoral compartments) were graded on a scale of 0 to 3 in relation to an atlas of standard radiographic features of osteoarthritis compiled from the Framingham osteoarthritis study. A score of 2 or more for joint-space narrowing was intended to designate a reduction in joint space of more than 50%. We defined "cartilage loss" as an increase of 1 or more in the maximal score for joint-space narrowing within a knee between baseline and follow-up. Similarly, "osteophyte growth" was defined as an increase of 1 or more in the maximal score for osteophytes between baseline and follow-up.

The inter- and intra-rater reproducibilities of these systems were measured in a sample of 100 anteroposterior radiographs of the knee that were stratified by disease severity and scored independently by two radiologists and twice by one observer. The {kappa} values for intra-rater reproducibility were 0.91 for the modified Kellgren and Lawrence grade (scores of 0 or 1 compared with scores of 2, 3, or 4); 0.72 for the joint-space narrowing score; and 0.79 for the osteophyte score (0 compared with 1, 2, or 3) (P < 0.001 for all comparisons). The interrater {kappa} values were 0.50 for the modified Kellgren and Lawrence grade (P = 0.025), 0.50 for the joint-space narrowing score, and 0.64 for the osteophyte score (P < 0.001 for the latter two comparisons).

Exposure Variables

Nutrition

Typical dietary intake was estimated at examination 20 (1988 to 1989) using a self-administered food frequency questionnaire developed by Willett and colleagues [24, 25]. This questionnaire lists approximately 130 individual food items with specified portion sizes; study participants were asked how often, on average, they had consumed these food items during the previous year. Nine responses were possible, ranging from "never or less than once per month" to "more than six times per day." The questionnaire also requested information about the use of specified vitamin and mineral supplements and included open-ended sections for information on foods and supplements not specified on the questionnaire. We calculated the average daily intake of nutrients for each participant by multiplying the nutrient content of each food item and supplement by the reported frequency of consumption and summing the results. This questionnaire provides information on more than 90% of total intake relevant to more than 70 nutritional variables. It has been validated using both long-term dietary records and biochemical markers of nutrient status [3, 26-28]. We excluded persons whose reported intakes were judged to be unreliable because their forms were incomplete (>12 items left blank) or because their reported intakes were deemed unrealistic (<600 or >4000 kcal/d). We also adjusted the nutrient variables for energy intake as suggested by Willett [29].

Serum Levels of Vitamin D

Blood samples were collected from study participants during examinations 19 or 20 (1987 to 1989). We measured circulating levels of 25-hydroxyvitamin D [25(OH)D] by using a competitive protein-binding assay after extracting 25(OH)D from plasma into ethanol as previously described [30].

Confounders

Information about potential confounding variables was available from the Framingham Study database. Body mass index was calculated using the mean height and weight measured at examinations 18 and 20. Weight change was defined as the difference in weight between examination 18 and examination 20. Levels of habitual physical activity were estimated at examination 20 from responses to validated standard questions about the number of hours spent in a typical day at different levels of activity. The number of hours reported at each activity level was weighted and summed according to the method described by Kannel and Sorlie [31], generating a theoretical range of 24 to 120. Use of this physical activity index previously showed an association between high levels of activity and the development of osteophytes in men [32]. An estimate of total daily energy intake was derived from the food frequency questionnaire. Information about knee injury was derived from the response to a standard question posed at baseline, "Have you ever had a fracture or injury to a knee requiring the use of crutches or a cane?" The overall health status of participants was determined from responses to the question, "In general, how is your health now—excellent, good, fair, or poor?" This question has been widely used in other studies and is predictive of death in both women and men [33]. Bone mineral density at the femoral neck was measured at examination 20 by using dual-photon absorptiometry [34]. Estimates of vitamin C intake and total daily energy intake were derived from responses to the food frequency questionnaire. Level of exposure to sunlight was determined on the basis of a standard question that asked about the number of months spent in a Sunbelt state each year. This variable has previously been shown to correlate with serum levels of vitamin D (Jacques P. Personal communication).

Statistical Analysis

Our strategy for analysis was to stratify our sample into sex-specific tertiles of intake for each nutrient in question and then to compare risk for incidence or progression of osteoarthritis of the knee among the tertiles. We did the analysis at the level of the knees and computed unadjusted and adjusted odds ratios for incidence and progression of osteoarthritis by using logistic regression with adjustment for correlation between fellow knees by using the generalized estimating equation approach of Liang and Zeger [35]. Only knees eligible for the outcome of interest were included in each analysis (for example, risks for incident disease were evaluated only in knees that did not have osteoarthritis at baseline). In addition, because of the potential for correlation between the two outcomes (for example, incident disease in one knee may have been related to prevalent osteoarthritis in the other), the normal knees of participants with unilateral osteoarthritis of the knee were censored from the analyses of incident osteoarthritis.

We tested the relations among serum levels of vitamin D, vitamin D intake, body mass index, bone mineral density, physical activity index, and knee injury to evaluate collinearity and potential confounding using correlation and chi-square tests. In the multivariate models, we entered the nutrients in tertiles, using the upper tertile as the referent category and using age, sex, body mass index, weight change, physical activity index, knee injury, total energy intake, and health status as independent variables. We further adjusted for vitamin C intake and exposure to sunlight and did subgroup analyses to investigate the influence of vitamin supplement use. We tested the influence of bone mineral density as an intervening variable by entering it as an independent variable into the model. We then repeated the analyses using feature-specific outcomes (cartilage loss and osteophyte growth) to look for consistent effects.


Results
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Dietary information and estimations of serum levels of vitamin D were available for 928 cohort participants. Of these, 556 had complete radiographic data from examinations 18 and 22. Three hundred seventy-two did not participate in our study because of death (n = 166), loss to follow-up (n = 78), and incomplete overlap between the groups that had different assessments (n = 128). The participants who did not have complete radiographic data were older (72.4 compared with 70.3 years of age; P < 0.001), more likely to be men (43.6% compared with 37.0%; P < 0.05), and somewhat less active (physical activity score, 26.5 compared with 32.9; P < 0.05). They were similar in body mass index (26.5 compared with 26.1 kg/m2), bone mineral density (0.78 compared with 0.77 g/cm), serum levels of vitamin D (30.0 compared with 29.6 ng/mL), vitamin D intake (322 compared with 321 IU/d), and total energy intake (1728 compared with 1764 kcal/d) (P > 0.05 for all comparisons). Of the 556 participants who had complete assessments, 394 had no osteoarthritis at baseline and 162 had prevalent disease (80 had bilateral osteoarthritis of the knee). Thus, 788 normal and 126 osteoarthritic knees were available for analysis (82 normal knees from participants with unilateral osteoarthritis of the knee and 16 knees with end-stage disease were censored).

Serum levels of vitamin D were positively correlated with vitamin D intake (r = 0.24; P < 0.001), bone mineral density (r = 0.15; P < 0.001), and physical activity index (r = 0.09; P = 0.005) and were inversely correlated with body mass index (r = –0.1;P = 0.0004). Vitamin D intake also correlated with total energy intake (r = 0.26; P < 0.001) but not with bone mineral density, physical activity index, or body mass index. No relation was found between the tertile of intake of vitamin D and the tertile of either bone mineral density or knee injury (P > 0.2 for both comparisons).

In unadjusted analyses, an increased incidence of osteoarthritis of the knee after baseline was found for the middle compared with the upper tertile of vitamin D intake only (odds ratio, 2.6 [95% CI, 1.3 to 5.2]). The risk for progression was also elevated for persons in the lower tertiles of vitamin D intake (odds ratio, 1.8 [CI, 0.8 to 4.2]) and serum level of vitamin D (odds ratio, 2.8 [CI, 1.1 to 6.9]).

In adjusted analyses, an apparent increase in the risk for incident osteoarthritis of the knee after baseline was found for persons in the middle compared with those in the upper tertile of vitamin D intake. However, this association was not seen for persons in the lower tertile of vitamin D intake, and no association with serum levels of vitamin D was observed (Table 1).


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(Table 1). Incidence and Progression of Osteoarthritis of the Knee: Independent Associations with Dietary Intake and Serum Levels of Vitamin D*

 

Risk for progression of osteoarthritis of the knee in persons with prevalent disease at baseline was markedly increased for those in the middle and lower tertiles compared with those in the upper tertile for both intake and serum levels of vitamin D (Table 1). These effects were preserved after exclusion of 140 persons who reported regularly consuming vitamin D supplements, multivitamin supplements, or cod liver oil (odds ratio for the lower compared with the upper tertile of vitamin D intake, 3.7 [CI, 1.3 to 10.3]). Adjustment for exposure to sunlight did not change these results (for example, the odds ratio for the lower compared with the upper tertile of vitamin D intake was 3.9 [CI, 1.3 to 11.7]). Further adjustment for vitamin C intake did not substantially alter the effect size (odds ratio for the lower compared with the upper tertile of vitamin D intake, 4.0 [CI, 1.2 to 13.5]).

We examined whether bone mineral density had any influence on progression of osteoarthritis of the knee. Including bone mineral density in the multivariate models did not influence the association between vitamin D (either intake or serum level) and progression.

Among participants who had prevalent disease at baseline, serum levels of vitamin D appeared to predict osteophyte growth (odds ratio for the lower compared with the upper tertile, 3.1 [CI, 1.3 to 7.5]) and, to a lesser extent, cartilage loss (odds ratio, 2.3 [CI, 0.9 to 5.5]). Associations with vitamin D intake were less convincing for osteophyte growth (odds ratio, 1.1 [CI, 0.4 to 2.7]) and cartilage loss (odds ratio, 2.1 [CI, 0.8 to 5.4]).

Finally, for progression of osteoarthritis of the knee, we repeated the analyses but confined them to the subset of patients who did not have knee replacement surgery during the follow-up period. This did not change our estimates of the association between progression and intake or serum levels of vitamin D.


Discussion
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Our study suggests that persons with low intake and low serum levels of vitamin D are approximately three times more likely to have progression of established osteoarthritis of the knee than are persons with high intake and high serum levels. On the other hand, we found no evidence that low intake and low serum levels of vitamin D influence the risk for developing osteoarthritis in a previously normal knee. Our results, which need confirmation, suggest that persons with osteoarthritis of the knee who have modest intake of vitamin D or serum levels of 25(OH)D less than 30 ng/mL may benefit from increased vitamin D intake or exposure to sunlight.

We had originally hypothesized that suboptimal levels of vitamin D might blunt any favorable response of bone to cartilage damage resulting from osteoarthritis. This hypothesis was based on the proposition that the nature of bone response in this disorder is a determinant of progression of osteoarthritis, a suggestion supported by increasing evidence [3-17]. According to this construct, suboptimal levels of vitamin D should have a greater effect on progression than on incidence, because bony changes are secondary to cartilage damage [6]. The association of intake and serum levels of vitamin D with progression (but not incidence) of osteoarthritis of the knee is in keeping with this theory, and the fact that the relation is consistent for two partly independent measures of vitamin D status (intake level and serum level) adds weight to these findings.

Although our results are compatible with the hypothesis that suboptimal intake and serum levels of vitamin D compromise protective responses to bone in patients with osteoarthritis, vitamin D may directly affect articular cartilage. For example, vitamin D has been shown to stimulate synthesis of proteoglycan by mature articular chondrocytes in tissue culture [36]. However, the influence of this nutrient on adult joint cartilage has been the subject of relatively little research and requires further study.

We considered the possibility that confounding by participants taking regular vitamin supplements may have biased our results. However, exclusion of persons who took vitamin D supplements, multivitamin supplements, or cod liver oil did not substantially change this apparent protective association of high intake or high serum levels of vitamin D with progression of osteoarthritis. In the event that vitamin D status was acting as a proxy for general debility, we controlled for health status using the response to a well-validated question about the patient's perception of his or her health. Because we had previously found that vitamin C has an apparent protective influence in relation to progression of osteoarthritis of the knee [37], we also adjusted for intake of this nutrient. Neither maneuver substantially altered our results. Similarly, inclusion of bone mineral density as an independent variable did not affect the relation between intake or serum levels of vitamin D and osteoarthritis.

Several things must be considered when results derived from complex nutritional analyses such as ours are interpreted. Sequential radiographs of the knee were unavailable for 372 members of the cohort; this could have biased our results if low intake or serum levels of vitamin D had coincided with the low rate of osteoarthritis in those persons. In fact, the two groups had similar intake and serum levels of vitamin D. Furthermore, because the nonresponders were older, the prevalence of osteoarthritis among them was probably at least as great as it was among the participants. Therefore, any bias resulting from the use of the selected subset of persons with radiographs of the knee and data on nutrient intake would tend to reduce the observed relative risk toward the null.

The food frequency questionnaire is a widely used and well-validated nutritional assessment instrument, but it is semi-quantitative and is better for ranking individual persons than for providing an absolute estimate of nutrient intake. Because it is best suited to categorical analysis, estimates of absolute intakes (such as the tertile cut-off for vitamin D intake) should be treated with caution. Another problem with the food frequency questionnaire is that it makes inflexible assumptions about portion sizes and makes demands on the judgment and memory of responders. On the other hand, we found a correlation between dietary intake of vitamin D and serum 25(OH)D levels (r = 0.24) that was equal to or higher than that seen in previous studies [38]. Given that serum levels of vitamin D are also influenced by factors other than dietary intake and that the relation between intake and serum levels may be nonlinear, this degree of correlation is of an appropriate magnitude and could be regarded as strengthening the validity of the dietary assessment [24].

Another potential limitation of our data relates to the single assessments of intake and serum levels of vitamin D during an 8-year follow-up period. The estimate of vitamin D intake was predominantly derived from reported (on the food frequency questionnaire) intake of dairy products, especially milk, which have been shown to be reasonably stable (r {cong} 0.5) over periods as long as 10 years [24]. Serum 25(OH)D levels may also vary substantially, and some misclassification will probably have occurred with respect to both dietary and serum measures of vitamin D. These factors, along with other confounders not assessed in this study (such as the presence of renal impairment), might be expected to bias our results toward the null. Therefore, our results may have underestimated the true magnitude of the association between intake and serum levels of vitamin D and osteoarthritis.

One strength of our study lies in the sampling design of the Framingham Study. Thus, the range of intake of vitamin D and serum 25(OH)D levels, comorbid conditions, and osteoarthritic outcomes seen in our participants is likely to be representative of and generalizable to other elderly population samples.

In conclusion, we have shown that persons with either relatively low dietary intake of vitamin D or serum 25(OH)D levels less than approximately 74.88 nmol/L (30 ng/mL) have a substantially increased risk for progression of osteoarthritis of the knee. These findings have important implications for the secondary prevention of osteoarthritis of the knee. Confirmation and further study in other population samples are needed.

Drs. Aliabadi and Weissman: Department of Radiology, Brigham and Women's Hospital, Boston, MA 02115.

Drs. Rush and Jacques: USDA Human Nutrition Center, Tufts University, Boston, MA 02111.

Dr. Wilson: The Framingham Study, 5 Thurber Street, Framingham, MA 01701.


Author and Article Information
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From Boston University Medical Center, Tufts University, and Brigham and Women's Hospital, Boston, Massachusetts; and the Framingham Study, Framingham, Massachusetts.
Acknowledgments: The authors thank the staff and participants of the Framingham Study.
Grant Support: In part by grants AR20613 and RO-1 AG09300 from the Boston University Arthritis Center and a Traveling Research Fellowship from the Arthritis and Rheumatism Council of the United Kingdom (Dr. McAlindon).
Requests for Reprints: Timothy McAlindon, MD, MPH, The Arthritis Center, Boston University Medical Center, Room A203, 80 East Concord Street, Boston, MA 02118.
Current Author Addresses: Drs. McAlindon, Felson, Zhang, and Hannan: The Arthritis Center, Boston University Medical Center, Room A203, 80 East Concord Street, Boston, MA 02118.


References
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