Serum 25-hydroxyvitamin D [25(OH)D] is the major circulating form of vitamin D and a standard indicator of vitamin D status 1 2 . Several studies have described an inverse relationship between serum 25(OH)D and cancer risk 3 4 5 . The relationship between regular vitamin D intake and reduced cancer incidence has also been reported 6 . Furthermore, higher plasma 25(OH)D levels are associated with improved survival in prostate 7 , breast 8 , lung 9 , colorectal 10 and ovarian 11 cancers. A better vitamin D status at the time of diagnosis and treatment, adjusted for season of diagnosis, has been shown to improve survival 12 13 .

Several factors are involved in the regulation of 25(OH)D including: age; gender 14 ; race 15 ; dietary intake 2 ; season 16 ; and sunlight exposure 17 . Recently, the relationship between obesity and vitamin D status has been investigated suggesting decreased bioavailability of 25(OH)D from cutaneous and dietary sources in association with obesity 18 . Additional studies have investigated the relationship between obesity and vitamin D levels. The results, however, are conflicting with studies reporting either no relationship 19 , or an inversely proportional relationship 20 21 22 between body mass index (BMI) and serum 25(OH)D.

In studies of obese adolescents in the United States, vitamin D deficiency has been correlated with greater weight and elevated BMI 23 24 . In the healthy adolescent population the distribution of fat was found to be associated with vitamin D status with obese adolescents being found to have 25(OH)D deficiency 25 . Children with a body weight, BMI, bicipital skin fold thickness, waist measurement and waist/height ratio above the 50th percentile for each variable were found to be at a greater risk of having a low serum 25(OH)D concentration 26 . Similarly, body weight, BMI, and waist circumference of healthy women with higher vitamin D levels were smaller than those recorded for women with low vitamin D levels 27 . A statistically significant negative correlation between BMI and serum 25(OH)D in Caucasian and African Americans healthy adults has also been described 28 .

An inverse relationship between obesity and serum levels of 25(OH)D has also been demonstrated in different disease states. In children with epilepsy, female sex and increased BMI were significant risk factors for low vitamin D levels 29 . In patients with Systemic Lupus Erythematosus, being overweight was found to be associated with vitamin D deficiency 30 . In another study, vitamin D deficiency was found to be more prevalent in morbidly obese patients presenting with the metabolic syndrome 31 . Finally, in women with polycystic ovarian disease low serum 25(OH)D concentrations were found as a result of obesity and insulin resistance 32 .

The association between vitamin D and obesity assumes even greater importance in cancer, given the alleged role of both obesity and vitamin D in cancer risk and survival. Although it has been recommended that adiposity should be considered when assessing vitamin D requirements in obese patients 33 , current dietary recommendations do not take into account a person's BMI and it remains unclear whether the dose of vitamin D required for repletion is related to the degree of obesity. And there are to date, no studies which indicate whether the presence of malignant disease compounds these issues. In the current study, we have addressed the first aspect of this question by investigating the relationship between serum 25(OH)D and BMI in a large and diverse population of cancer patients at a comprehensive cancer center.

Characterization of serum vitamin D levels in cancer patients is of considerable importance given the role of vitamin D in influencing cancer risk and survival. An important question that arises when recommending vitamin D supplementation in deficient cancer patients is whether the dose should be adjusted according to a patient's BMI. While there is some evidence in the literature documenting an inverse relationship between BMI and serum 25(OH)D in healthy and diseased populations, this relationship in cancer has never been reported. Thus, the current study was undertaken to investigate this relationship. The results demonstrate that serum 25(OH)D levels are significantly lower in obese cancer patients as compared to normal and overweight patients, and that every unit increase in BMI is associated with a corresponding decrease in serum 25(OH)D that is statistically significant.

Multiple mechanisms have been proposed to explain the association of obesity with hypovitaminosis D, including lack of sunlight exposure from physical inactivity 36 and sequestration of vitamin D in subcutaneous fat depots 33 . Wortsman et al. reported that the capacity of the skin to produce vitamin D is not altered in obesity. However, the increase in serum vitamin D after sun exposure was 57% less in obese compared with non-obese subjects suggesting a decreased bioavailability of vitamin D because of its deposition in body fat compartments, given that vitamin D is fat soluble 18 . Young KA et al. observed that higher BMI and subcutaneous adipose tissue were associated with lower 1,25-dihydroxyvitamin D [1,25[OH]2D], after controlling for 25[OH]D levels, suggesting a more complex relationship between vitamin D and adiposity than simply attributing this association to vitamin D bioavailability 37 . Another hypothesis suggests a negative feedback inhibition of 25(OH)D synthesis in liver by the increased level of 1,25(OH)2D 32 38 . Bell NH et al. reported that alteration of the vitamin D endocrine system in obese subjects is characterized by secondary hyperparathyroidism which is associated with enhanced renal tubular reabsorption of calcium and increased circulating 1,25(OH)2D which causes a feedback inhibition of 25(OH)D synthesis 39 . However, some recent studies have reported an inverse correlation between BMI and serum 1,25(OH)2D, casting a doubt on the hypothesis of negative feedback inhibition 21 28 .

There are obvious clinical implications of this work such as the need to monitor the vitamin D intake and serum 25(OH)D levels in patients with cancer and supplementation of vitamin D in those who are found to have suboptimal levels. In our recently published study in a sample of 799 cancer patients, we found that patients with suboptimal vitamin D levels at baseline, when supplemented with 8000 IU of Vitamin D3 (four 2000 IU D3 capsules) daily as part of their nutritional care plan, showed significant improvement in their serum vitamin D levels after a mean follow-up of 14.7 weeks 40 . A study conducted by Lee P et al. in 95 out-patients found that increments of vitamin D level were less in obese individuals, implying that a larger dose of vitamin D supplementation is required for repletion compared with normal-weight individuals 33 . Similarly, Jorde et al. investigated the serum 25(OH)D response to vitamin D supplementation in relation to BMI and concluded that when giving vitamin D supplements to the very obese, the dose has to be higher than in the lean subjects if the same serum 25(OH)D levels are to be achieved 41 . A study conducted in postmenopausal women by Moschonis G et al. suggested a need for higher daily vitamin D intake in obese than in thinner individuals to compensate for the lower bioavailability of endogenously produced cholecalciferol 42 . Blum M et al. found that change in 25(OH)D levels in response to vitamin D supplementation was inversely associated with BMI in healthy men and women 65 years of age and older. As a result, they recommend that that body size should be taken into account when estimating the amount of vitamin D intake needed to raise 25(OH)D to the desired level 43 . The most recent report by the Institute of Medicine recommends a dietary reference intake of 600 IU for vitamin D 44 . The results of our study, coupled with the findings reported by other researchers as described above, provide preliminary evidence to suggest that obese people might require a higher dose of vitamin D to achieve optimal serum levels.

Interestingly, we found a weak but significantly positive association between age and 25(OH)D levels. This is unexpected since the efficiency of the photosynthesis of vitamin D in human skin decreases with age 45 . In addition, older people may receive less sunlight exposure because of frailty and reduced exercise levels or for cultural and behavioral reasons 46 . The literature in this regard is inconsistent with reports being presented purporting to demonstrate a positive relationship 45 47 , no relationship 48 , and an inverse relationship 49 50 between age and 25(OH)D level. Although it is reasonable to postulate that differences in life style and dietary habits will explain these inconsistencies, the reason for these divergent results remains unclear and warrants rigorously controlled studies.

Our study has some limitations. This study, because of its retrospective nature, relies on data not primarily meant for research. As a result, we could not adjust for several potential confounding factors that could have influenced serum 25(OH)D levels. For example, we did not adjust for season of blood draw in our analyses. However, our analysis was limited to patients tested in late winter, spring and early summer, so a major difference in sun exposure seems unlikely to account for the differences in the serum vitamin D levels of our patient population. We included only one serum sample from each subject. Intervention and interpretation of serum 25(OH)D levels might require multiple measurements over a period of time. Moreover, we did not have information on intake of vitamin D or data regarding their typical sun exposure which could have shed further light on the subjects' vitamin D status.

Other variables such as race, physical activity and cancer treatment history are all thought to affect 25(OH)D status but were not controlled for in the analyses. Because anthropometric indicators of adiposity such as BMI are traditionally weaker than direct measures of adiposity, it is likely that we are underestimating the association between vitamin D and overall adiposity by using BMI as a measure of obesity 37 . However, BMI is non-invasive, low cost and east to perform. Despite these limitations, our study provides evidence of an inverse relationship between serum vitamin D and BMI in cancer patients - a novel finding in the oncology patient population. Strengths of the present investigation are its relatively large sample size and the fact that the vitamin D analyses were all performed using the same assay.

The results of this study suggest several areas for future research. Paramount among these is the immediate need to determine the response to vitamin D supplementation in cohorts of patients segregated according to BMI or other measures of obesity. Such studies are well within the capacity of clinical investigators and are critical to establishing optimal vitamin D dose and schedules for adequate repletion. The results of such studies should support further investigation of the consequences of vitamin D repletion on clinical outcomes in cancer patients pertinent to either specific functions (e.g. treatment response, wound healing) or more general outcomes such as prognosis and QoL. Ultimately, such studies should determine whether restoration and maintenance of adequate vitamin D levels can influence tumor control and survival. Although the current study was conducted in a large heterogeneous cancer population, the same approaches would be appropriate for elucidating the importance of vitamin D levels in homogeneous patient populations segregated according to tumor type and treatment selection.

We found that obese cancer patients (BMI >= 30 kg/m²) had significantly lower levels of serum 25(OH)D as compared to non-obese patients (BMI <30 kg/m²). BMI should be taken into account when assessing a patient's vitamin D status and more aggressive vitamin D supplementation should be considered in obese cancer patients.

The authors declare that they have no competing interests.

PGV participated in concept, design, data collection, data analysis, data interpretation and writing. CAL participated in data collection, data interpretation and writing. DPB participated in writing, data interpretation and general oversight of the study. DG participated in data collection, data analysis, data interpretation and writing. All authors read and approved the final manuscript.