Osteoarthritis (OA) is characterized by loss of cartilage and concurrent changes in subchondral bone, and there is evidence that subchondral bone has a major influence on the development of OA and its worsening (1). The OA process includes rapid remodeling of subchondral bone (2, 3), and the capacity of bone to respond to various stresses including loading may alter the trajectory of OA. Further, high or low levels of bone density may influence the expression of disease and affect the likelihood of incident or progressive disease (4–6). Healthy remodeling of bone depends on adequate availability of vitamin D (7).
Vitamin D sufficiency may also influence cartilage metabolism. Hypertrophic chondrocytes in OA cartilage redevelop vitamin D receptors like cells in growth plate cartilage (8). Vitamin D may influence these chondrocytes and somehow alter their metabolic processes and products. Thus, vitamin D may have effects on bone, and possibly also cartilage, with implications regarding disease.
Two longitudinal epidemiologic studies have shown that low vitamin D levels worsen the course of OA. In one, using data from the original Framingham Study cohort, McAlindon and colleagues (9) showed that subjects who had vitamin D levels in the lowest and middle tertiles had a 3-fold increased risk of radiographic worsening of preexisting knee OA. In a subsequent article, Lane et al (10) reported that levels of vitamin D in the lowest and middle tertiles were associated with incident hip OA, defined as development of joint space loss. Risk was similar to that described in the Framingham Study subjects. As a result of these reports, investigators have begun clinical trials to test the therapeutic efficacy of vitamin D in OA. While the results of these studies seem to replicate each other, in each of them, effects of vitamin D on disease were inconsistent. In one (9), vitamin D insufficiency increased the risk of disease incidence but did not influence progression in those with preexisting OA, and in the other (10), only effects on incidence were reported.
Vitamin D deficiency is extremely common, especially in northern latitudes (7). Any effect of vitamin D deficiency on OA or its worsening would have public health implications and would warrant testing of vitamin D levels in all patients with OA or at risk of developing OA. Thus, a careful characterization of the association of vitamin D deficiency with the course of OA is needed. The inconsistent findings within prior studies suggest the need for further evidence of the association of low vitamin D levels with disease. Using 2 different longitudinal studies of knee OA, we reevaluated 25-hydroxyvitamin D (25[OH]D) levels and their association with knee OA worsening (consisting of disease incidence and progression). In one study, of a community-based cohort selected without regard to the presence of knee OA, we evaluated the association of 25(OH)D levels with joint space loss over time. In the second cohort of patients who had symptomatic knee OA, we evaluated the association of 25(OH)D levels with loss of joint space seen on radiographs and with cartilage loss seen on magnetic resonance imaging (MRI).
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- SUBJECTS AND METHODS
- AUTHOR CONTRIBUTIONS
In the Framingham Study, 715 subjects underwent both vitamin D measurement and a longitudinal radiographic followup. These subjects had a mean age of 53.1 years at baseline, and more than half were women (Table 1). Most knees at baseline were graded as not showing evidence of OA (87% had a K/L score <2). Over the 9.5 average years of followup, 20.3% of these knees showed tibiofemoral joint space loss on radiography.
Table 1. Characteristics of the subjects in the Framingham Offspring Study and the BOKS*
|Characteristic||Framingham Offspring Study subjects (n = 715)||BOKS subjects|
|Radiographic followup subjects (n = 277)||MRI followup subjects (n = 211)|
|Age at baseline, mean ± SD years||53.1 ± 8.7||66.2 ± 9.3||66.5 ± 9.6|
|Sex, % female||53.1||41.4||38.4|
|BMI at baseline, mean ± SD kg/m2||27.4 ± 4.8||31.2 ± 5.5||31.3 ± 5.6|
|Weight change from baseline, mean ± SD kg||+3.1 ± 8.0||+0.1 ± 5.3||+0.1 ± 5.4|
|% of knees in each K/L grade at baseline|| || || |
|% of knees showing progression at radiographic followup||20.3||23.6||27.4|
|% of knees with ≥1 cartilage plate showing progressive cartilage loss on MRI followup||–||–||57.4|
|25(OH)D level, mean ± SD ng/ml||19.7 ± 7.4||20.2 ± 8.3||20.3 ± 8.3|
In the BOKS, subjects were older (mean age 66.2 years) and heavier (mean BMI 31.2) (Table 1) and, based on enrollment criteria, were much more likely to have radiographic OA at baseline than subjects in the Framingham Study. Of those with radiographic followup, only 21% had K/L grades <2 at baseline, and most of these had grade 1 disease. (Those with a K/L grade of 0 had isolated patellofemoral OA, which would make a subject eligible for the BOKS.) Over the 30-month followup period in the BOKS, 23.6% of the knees with radiographic followup and 27.4% of the knees with MRI followup showed radiographic joint space loss in the tibiofemoral joint.
We found that in Framingham Study subjects, high levels of vitamin D (high tertile) were associated with slightly greater rates of worsening than were low levels (Table 2). After adjustment for other risk factors, there was no significant association of vitamin D level with disease worsening. Similarly in the BOKS (Table 2), those with high levels of vitamin D had a higher risk of worsening than those with lower levels, and the adjusted risk of worsening showed a modest but not significant protective effect of low and medium levels of vitamin D on worsening, the opposite direction of findings of prior studies.
Table 2. Risk of joint space loss by 25(OH)D tertile in the Framingham Study and the BOKS
|25(OH)D tertile*||Framingham Study||BOKS|
|Proportion of knees with joint space loss, no. (%)||Adjusted OR (95% CI)†||Proportion of knees with joint space loss, no. (%)||Adjusted OR (95% CI)†|
|High tertile (>23 ng/ml)||65/468 (13.9)||1 (reference)||39/140 (27.9)||1 (reference)|
|Middle tertile (17–22 ng/ml)||63/471 (13.4)||0.98 (0.57–1.68)||26/110 (23.6)||0.85 (0.44–1.66)|
|Low tertile (≤16 ng/ml)||75/474 (15.8)||0.87 (0.51–1.47)||26/135 (19.3)||0.56 (0.28–1.12)|
We then examined whether levels of vitamin D thought to represent deficiency increased the risk of worsening of radiographic OA (Table 3). In the Framingham Study, knees of subjects with vitamin D deficiency (<20 ng/ml) showed a slightly higher risk of joint space loss than those without deficiency, but the adjusted risk was not elevated. In the BOKS, the risk of worsening was actually slightly higher in persons without vitamin D deficiency, and the adjusted risk showed a modest but not significant protective effect of low levels of vitamin D, once again the opposite effect of the one anticipated.
Table 3. Risk of joint space loss seen on radiograph, by 25(OH)D level*
| ||Framingham Study||BOKS|
|Proportion of knees with joint space loss, no. (%)||Adjusted OR (95% CI)||Proportion of knees with joint space loss, no. (%)||Adjusted OR (95% CI)|
|25(OH)D ≥20 ng/ml||87/647 (13.4)||1 (reference)||54/205 (26.3)||1 (reference)|
|25(OH)D <20 ng/ml||116/766 (15.1)||0.83 (0.54–1.27)||37/180 (20.6)||0.63 (0.35–1.14)|
With regard to osteophyte growth, in the Framingham Study, those with low vitamin D levels had a modestly decreased risk (odds ratio [OR] 0.71, 95% confidence interval [95% CI] 0.50–1.00) compared with those with sufficient levels. In the BOKS, we found no association of low vitamin D levels with osteophyte growth (among subjects with low levels, the OR for osteophyte growth was 0.99 [95% CI 0.37–2.66]).
When we examined cartilage loss on MRI in the BOKS, our results were similar (Table 4). Those with vitamin D deficiency actually experienced a slightly lower risk of cartilage loss than those with sufficient levels of vitamin D (9.9% of those with 25[OH]D levels <20 ng/ml showed worsening of cartilage score versus 13.1% of those with 25[OH]D levels ≥20 ng/ml), and this translated into a modest protective effect of vitamin D deficiency on cartilage loss. We also explored whether vitamin D levels evaluated as a continuous measure affected the risk of loss, and we found no significant association (Table 4).
Table 4. Risk of cartilage loss by 25(OH)D level in the BOKS*
| ||Adjusted OR (95% CI)|
|25(OH)D ≥20 ng/ml||1 (reference)|
|25(OH)D <20 ng/ml||0.74 (0.50–1.09)|
|25(OH)D (continuous) per ng/ml||1.01 (0.99–1.03)|
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- SUBJECTS AND METHODS
- AUTHOR CONTRIBUTIONS
Contrary to expectations, in 2 longitudinal studies examining knee OA we found no association of vitamin D levels with structural disease worsening, defined as joint space loss on radiography or as worsening cartilage score on MRI. Findings are occasionally null when real associations are missed as a consequence of an excessively small sample size (Type II error). To determine whether our null results were a consequence of inadequate power, we looked at vitamin D deficiency using an accepted threshold. We found that the confidence limits were narrow, with the upper limit being 1.27 in the Framingham Study and 1.14 in the BOKS. This suggests that vitamin D deficiency could not increase the odds of joint space loss by more than 27% and 14%, respectively. Such an increased risk, even though small, could have public health implications given the safety and low cost of vitamin D. Our data suggest that vitamin D has no effect on the structural worsening of OA, at least with regard to cartilage loss. Furthermore, our point estimates of most likely risk tended to suggest, if anything, a protective effect of low vitamin D levels. Although this finding did not reach statistical significance, it suggests that, in contrast to previously reported findings (9, 10), vitamin D is not likely to increase risk.
Within each of the earlier studies (9, 10), there were actually inconsistencies in findings. In the study by McAlindon et al (9), which used another study group at Framingham, the strongest effect on OA risk was vitamin D intake, and intake had a weak association with blood levels of 25(OH)D (r = 0.24). The radiographic data used consisted of full-extension AP radiographs only. This would probably now be unacceptable as a method for defining progression because such radiographs without fluoroscopic positioning cannot be used to accurately assess joint space loss over time (20), leading to concerns over whether OA progression in fact occurred in knees labeled as showing progression. It is nonetheless possible that the association of vitamin D with OA in the original cohort differed from that in the offspring cohort because of the younger age (mean age 53.1 years versus 70.3 years) and commensurate healthier status of the subjects in the Offspring cohort. In the former study, low levels of vitamin D were not related at all to OA incidence (OR 0.92, 95% CI 0.45–1.87).
Lane and colleagues (10) did not examine the effects on disease progression (when disease is present at baseline), and, contrary to the results of the Framingham Study, they found that low vitamin D levels increased the risk of disease incidence. In both studies, therefore, vitamin D levels were not consistently related to change, and many analyses testing their association with disease change yielded null results. We suggest that these null findings were likely correct.
Our longitudinal cohorts included persons with incident disease (most subjects in the Framingham Offspring cohort started with no disease) and those with extant disease at baseline (all subjects in the BOKS), thereby allowing us to test effects of vitamin D at different disease stages. Vitamin D levels are known to vary by season (19). In additional analyses, we created, for each subject, a level of vitamin D adjusted for season (a residual of vitamin D level regressed on season). Testing this residual value produced the same findings as the analyses presented here, showing no increase in risk of OA worsening by seasonally adjusted vitamin D level. We also carried out analyses of physical activity and found it to be unrelated to disease incidence or progression in Framingham Study subjects (21). Thus, physical activity did not confound the associations described here. We also investigated whether one measure of vitamin D captures a person's long-term vitamin D status, by testing average vitamin D levels over all visits in the BOKS. Results did not differ in this analysis. It should be noted that the measure of 25(OH)D used in the present study was the same as that used in prior studies that showed an association with disease.
We read radiographs paired and without blinding for sequence (although in a subsample in the BOKS we read radiographs with blinding for sequence and obtained the same results). In a longitudinal radiographic study of vertebral fractures, Ross et al (22) found that, compared with reading with blinding for sequence, reading without blinding for sequence led to better detection of known risk factors for fracture and fewer errors in characterizing fractures. We contend that reading all radiographs without blinding for sequence is a more accurate way of assessing progression and is valid, especially if the reader does not know the risk factor status of the subject.
There were a few limitations to our study. First, the number of subjects was not huge, and a small increased risk of vitamin D deficiency could have been missed. However, the effects we found were in the opposite direction of those previously reported. Also, MRIs were not acquired in a way that permits evaluation of change in cartilage volume, so we might have missed such an effect. In addition, there was loss to followup and selective participation in the vitamin D substudy in the Framingham Study. The total number of subjects followed up was ∼1,200, but vitamin D levels were measured in only a few more than 700 subjects. There was little loss to followup (13%) in the BOKS.
While vitamin D may have little effect on cartilage loss, as identified on MRI or radiograph, it is quite possible that vitamin D deficiency could importantly affect other elements of disease, including pain and weakness, which are critical to a patient's experience with OA. Low vitamin D levels have been shown to be associated with muscle weakness (23) and with an increased risk of generalized pain in persons with painful disorders. It is also possible that effects of vitamin D on bone ultimately influence the structural progression of disease, although there was an interval of 9 years between baseline and followup in our studies, suggesting that any effect of vitamin D on structure, at least as visible radiographically, would likely have been detected.
In conclusion, findings from 2 longitudinal studies have not confirmed that low vitamin D levels predispose to worsening of knee OA. However, other effects of vitamin D that are not visible as cartilage loss or as radiographic progression may be important to our understanding of disease pathogenesis and may be associated with a possible therapeutic or preventive role of vitamin D in OA.
- Top of page
- SUBJECTS AND METHODS
- AUTHOR CONTRIBUTIONS
Dr. Felson had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study design. Dr. Felson.
Acquisition of data. Dr. Felson, Ms Clancy, and Drs. Sack, Guermazi, Rogers, and Booth.
Analysis and interpretation of data. Drs. Felson, Niu, Guermazi, Amin, and Booth.
Manuscript preparation. Drs. Felson, Hunter, Amin, and Booth.
Statistical analysis. Dr. Niu.
Image interpretation. Drs. Aliabadi, Guermazi, and Sack.
Manuscript review. Dr. Guermazi.