Reply #94: Above = 400IU VitD3 & serum not "biologically meaningful", but @ 1100 IU, serum 25(OH)D>80nm/L =Yep!

[tiptoe]

(See also #92 for link to video commentary by Dr. Cedric Garland)

Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial
Joan M Lappe, Dianne Travers-Gustafson, K Michael Davies, Robert R Recker and Robert P Heaney
American Journal of Clinical Nutrition, Vol. 85, No. 6, 1586-1591, June 2007
Discussion

...
The current study is, to our knowledge, the first randomized controlled trial that involved a vitamin D intervention sufficient to raise serum 25(OH)D >80 nmol/L and reported a cancer outcome. Our findings of decreased all-cancer risk with improved vitamin D status are consistent with a large and still growing body of epidemiologic and observational data showing that cancer risk, cancer mortality, or both are inversely associated with solar exposure, vitamin D status, or both (1–10, 12–18, 26). Our conclusion that the observed effect was not simply a chance association is strengthened both by the observed, substantial improvement in RR when cancers occurring early in the trial were excluded and by the highly significant predictive effect of both the baseline and the 1-y serum 25(OH)D values in addition to the intervention itself.

The only other randomized trial of vitamin D and cancer of which we are aware was the Women’s Health Initiative (WHI), which used a much lower dose of vitamin D (400 IU) and a sample of women with substantially lower baseline vitamin D status (median serum 25(OH)D: 42 nmol/L) and with much poorer treatment adherence (27). The WHI reported no significant effect of the vitamin D intervention on colorectal cancer incidence but did note a highly significant inverse relation between baseline 25(OH)D and incident cancer risk (27, 28), just as we report here for all cancers.

Although the raw data suggested a marginal protective effect for the Ca-only intervention, per-protocol analysis based on compliance did not improve the RR for the Ca-only group, nor did removal of first year cancers. Thus, we are uncertain whether the marginal calcium effect represents a chance occurrence. The results of many calcium trials have been reported, but few have had cancer endpoints or reported cancer outcomes. Exceptions include a trial that used calcium carbonate in persons at risk of colon polyps (29). Not only was polyp recurrence reduced significantly, but, in a secondary analysis, prostate cancer risk was also found to be reduced by approximately half (30). High calcium intakes are generally considered to be protective for colon cancer (19, 20), at least in part by virtue of their intraluminal binding of cancer promoters in the digestive residue (19). Only 3 of our 50 cancers were colorectal; 2 of those were in the placebo group. How calcium might have been operating in our study is unclear, but its effect, if real, can be plausibly connected to vitamin D status. High calcium intakes reduce circulating concentrations of calcitriol, which, in turn, is known to shorten the half-time for serum 25(OH)D (31)—ie, higher calcitriol concentrations result in greater metabolic consumption and degradation of 25(OH)D, effectively lowering vitamin D status. Such a mechanism, effectively equivalent to a lower vitamin D dose, could explain the weaker effect found for the Ca-only group. It has also been proposed that calcium intake may alter cell-to-cell adhesion, because calcium is an integral component of the structures responsible for intercellular adhesion (18). It is uncertain, however, whether this mechanism would be applicable within the physiologic range of serum calcium concentrations.

Strengths of the present study include that it was population based, that it had a low drop-out rate (<3.5%/y) and a high level of treatment adherence, and that it used a vitamin D dose sufficient to raise serum 25(OH)D by a biologically meaningful amount. This latter feature may be a principal point of difference from most other investigations, both randomized trials and observational studies. In the WHI, the achieved vitamin D dose, taking compliance into consideration, would have been ~200 IU/d (27), sufficient to elevate serum 25(OH)D from a median of 42 nmol/L to only 47 nmol/L (32). This is in striking contrast to the much higher 25(OH)D values in our treated women at both baseline and 1 y (Table 2). The principal weakness of our study was that, at the time the study was designed (1996), cancer was not a primary outcome variable. However, given the large body of observational data suggesting a causal linkage for vitamin D with a variety of cancers, it is logical to look for a cancer outcome in a study such as this. Further, the randomization, the blinding, and the high treatment adherence and completion rate in the present study make it hard to imagine how extraneous factors could have “pushed” cancers into the placebo group.
...

Figure 1
Kaplan-Meier survival curves (ie, free of cancer) for the 3 treatment groups randomly assigned in the entire cohort of 1179 women. Sample sizes are 288 for the placebo group, 445 for the calcium-only (Ca-only) group, and 446 for the calcium plus vitamin D (Ca + D) group. The survival at the end of study for the Ca + D group is significantly higher than that for placebo, by logistic regression.

Figure 2
Kaplan-Meier survival curves (ie, free of cancer) for the 3 treatment groups randomly assigned in the cohort of women who were free of cancer at 1 y of intervention (n = 1085). Sample sizes are 266 for the placebo group, 416 for the calcium-only (Ca-only) group, and 403 for the calcium plus vitamin D (Ca + D) group. The survival at the end of study for the Ca + D group is significantly higher than that for the placebo group, by logistic regression.