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
]. 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
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
], no relationship [48
], and an inverse relationship [49
] 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.