The findings of our study indicated a high prevalence rate of serum 25-OHD deficiency and a significant positive association between serum 25-OHD deficiency and knee OA in a subgroup of patients with knee OA aged less than 60 years with greater association in younger patients.
Up to now most studies addressed the association between OA and serum 25-OHD in longitudinal studies [
5,
6,
14–
17]. No study has yet compared serum 25-OHD levels between OA patients and controls. The results of this study are consistent with previous reports [
5–
7,
11,
14,
16] and add new information to current knowledge in relation to the association between serum 25-OHD deficiency and knee OA.
In the "Osteoporotic Fractures in Men Study", similar to our study, the mean serum vitamin D in patients with OA was significantly lower and the proportion of vitamin D insufficiency and deficiency was significantly higher than in controls. Vitamin D deficient men were twice as likely to have prevalent radiographic hip OA compared with controls [
7].
In the "Rotterdam Study", low dietary vitamin D intake was associated with increased risk of knee OA progression over a mean follow-up time of 6.5 years [
5]. In another longitudinal study of elderly women the risk of incidental hip OA increased by odds of 3.34 (95%CI 1.13–9.86) in subjects with low serum 25-OHD levels over an average follow-up period of eight years [
14]. In participants of the "Framingham Study", low serum 25-OHD predicted the development of cartilage loss and knee OA progression [
14]. However, the association of vitamin D deficiency and OA was not confirmed by another longitudinal study by Felson et al. [
16].
Based on current knowledge, knee OA should be considered a bone disease rather than a synovial disease [
4,
8]. Early joint structural changes such as cartilage defects, loss of cartilage volume, subchondral bone expansion and bone marrow lesions are present prior to the onset of joint symptoms and clinical OA [
18]. Bone expansion in the tibial subchondral area play an initial role in the aetiology of knee cartilage defects and cartilage loss. These defects tend to progress in symptomatic knee OA. Prevention of cartilage damage or reducing their severity by intervention may retard OA progression [
18].
Inadequate levels of serum 25-OHD in patients with knee OA is of major concern. Since at low tissue concentrations of serum vitamin D bone response to pathophysiological processes is not optimal, vitamin D deficiency provides a susceptible background for OA progression [
5–
7,
14].
Several mechanisms such as alterations in mechanical properties of bones, increasing bone resorption by raising PTH level, increasing bone turn over, or direct effect of vitamin D metabolites on articular chondrocytes were postulated to explain the contribution of vitamin D deficiency in the progression of OA [
4].
These observations provide a rationale for the measurement of serum 25-OHD in patients with OA and encourage supplementation to raise the serum concentration to adequate levels. Hence, serum 25-OHD measurement should be considered in any patients with symptoms suggestive of knee OA even before the appearance of radiographic changes. By the time radiographic OA is detected 10% of knee joint cartilage has already been lost [
17]. Improvement of serum 25-OHD to a sufficient level augments skeletal health and alters joint response to risk factors and retards progression of OA.
A correlation of vitamin D with structural damage of subchondral bone has been shown [
19]. There are similarities between OA and vitamin D deficiency with regard to increased levels of bone turnover markers [
1,
7]. The potential of vitamin D treatment in suppression of turnover markers supports these observations and suggests that raising serum 25-OHD to sufficient levels may exert beneficial effects in patients with knee OA [
9].
Our study has limitations which should be taken into account. Since performance of radiographic examination in asymptomatic controls was not clinically indicated, inclusion of asymptomatic OA to the control group cannot be ignored. This issue may lower the mean serum 25-OHD level from the actual value in the control group and reduce the mean difference between patient and control groups. Otherwise the real mean difference value between patients and controls, particularly in age groups of 60 years and over, would be greater than that observed in this study. This problem may partly explain the lack of association between vitamin D deficiency and knee OA in the age group of 60 years and older.
Patients with knee OA are expected to have higher body mass index (BMI) than controls. Obese patients may have low serum 25-OHD levels due to decreased passage of vitamin D from skin to the general circulation. However, higher BMI values greater than 30 kg/m
2 were shown to be associated with low vitamin D [
20]. We did not provide data regarding BMI in this study; however, in a previous study of patients with knee OA derived from the general population of this study the mean BMI in patients with knee OA with mean age of 60±11 years was 27.8±8.1 kg/m
2 [
21].
We have shown an age-related modifying role for vitamin D deficiency which has not yet been reported. The association of serum 25-OHD deficiency with knee OA in lower age groups may be explained by greater bone health and higher activity of bone remodelling in younger than in older persons. Healthy remodelling requires the availability of adequate vitamin D [
2]. Therefore, younger individuals are more dependent on vitamin D and are thus expected to be more sensitive to serum 25-OHD deficiency. It is unclear whether age by itself or the degree of OA which presumably is less severe in younger patients, or other factors, can explain the observed association. Comparing serum 25-OH D in patients with different stages of knee OA after allowing for age provide further information in relation to OA stage and serum 25-OHD deficiency.
The results of our study are less affected by seasonal variations, diet, and sunlight exposure or limitation of physical activities due to pain and other confounders because patients and controls of this study were drawn from the general population with unique racial and cultural backgrounds, with similar diet and sunlight exposure. Sampling in both groups was performed over the same seasonal periods and patients with disability and limitation of physical activities were excluded from the study.
In conclusion, this study has demonstrated a significant association between knee OA and vitamin D deficiency in age groups most consistent with initiation of early OA symptoms corresponding with the development of knee cartilage damage. Loss of knee joint cartilage, which starts at about the age of 40 years [
18], progresses incrementally with age as in the normal population, and at a mean age of 57 years approximately two thirds of the joint cartilage is damaged. Identification of high risk subjects and modification of risk factors of subchondral bone such as correction of serum 25-OHD deficiency at this stage is expected to exert beneficial effects. However, the causal relationship of vitamin D deficiency in the development of cartilage defects and the potential of vitamin D treatment in the resolution of these structural lesions requires further prospective studies.
1 Parham Heidari,2 and Karaim Hajian-Tilaki3
This article has been 
<20 ng/ml were considered as deficient levels. Mann-Whitney U test was used for comparisons of means and logistic regression analysis with calculation of odds ratio (OR) was applied to determine association.