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concentrations due to intake and those due to sun exposure is not possible for most studies.

The utility of serum 25OHD level as a biomarker of effect is less certain. Prentice et al. (2008) pointed out that the adequacy of the vitamin D supply in meeting functional requirements depends upon many factors, including the uptake of 25OHD by target cells, the rate of conversion of calcitriol and its delivery to target tissues, the expression and affinity of the VDR in target tissues, the responsiveness of cells to the activated VDR, and the efficiency of induced metabolic pathways.

Nonetheless, despite these uncertainties, serum 25OHD levels can be regarded as a useful tool in considering vitamin D requirements; in fact, such measures are virtually the only tool available at this time. As pointed out by AHRQ-Tufts, when a non-validated intermediate outcome must be considered, the implicit assumption is that it would have the properties of a validated surrogate outcome, and this assumption should be made explicit and the uncertainties identified. This is a reasonable approach and allows the appropriate inclusion of consideration of serum 25OHD concentrations for the purposes of specifying the potential indicator of bone health.

Relationship between calcium absorption and serum 25OHD level Ensuring desirable rates of calcium uptake from the intestinal lumen into the body—calcium absorption—is an important aspect of bone health. Because vitamin D is instrumental in calcium absorption, the relationship between vitamin D and calcium absorption is relevant to an indicator for bone health. The literature in this area focuses on fractional calcium absorption (i.e., fraction of a given dose of calcium that is absorbed) and its association with serum 25OHD level.

Although calcitriol has been shown to stimulate intestinal calcium absorption directly and calcitriol levels correlate with absorption, the understanding of the current relationship between 25OHD level and calcium absorption requires examination. Widely quoted as evidence of the threshold for maximal calcium absorption at serum 25OHD levels above 75 nmol/L is an analysis of results from three separate studies (Barger-Lux and Heaney, 2002; Bischoff et al., 2003; Heaney et al., 2003) as put forward by Heaney (2005). Less widely understood is the nature of the evidence from each of these studies and, thus, the limitations of this graphic analysis. In only one of these studies (Barger-Lux and Heaney, 2002) was calcium absorption directly measured using a single calcium isotope method; the difference between the lower (approximately 75 nmol/L) and higher (approximately 125 nmol/L) serum 25OHD levels was non-significant. Although the single-isotope method is considered less accurate than the dual-isotope method for measuring calcium absorption, this method is viewed as appropriate. The two values from the Barger-Lux and Heaney

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