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Osteoporosis


Figure 1: Osteoid Volume Expressed as a Function of Serum 25(OH)D Concentration


4 5


3 2 1 0 20 25 30 35 Serum 25(OH)D (ng/ml)


25(OH)D = 25-hydroxyvitamin D; BV = bone volume; OV = osteoid volume. Data shown are from those individuals in Priemel et al.’s study25


with serum 25(OH)D values


of 20 ng/ml or higher (i.e. the level proposed by the Institute of Medicine as ‘adequate’). The horizontal dashed line demarcates normal values for osteoid volume, and the vertical dashed line demarcates the 25(OH)D boundary between those individuals with and without abnormal osteoid volume. Source: redrawn from the data from Priemel, et al., 201025 (copyright Robert P Heaney, 2011. All rights reserved. Used with permission).


100 µg/day as the UL, it provides explicit assurance that there would be no harm.)


Completeness requires me to note also that, relative to the 1997 dietary reference intakes (DRIs), the IOM panel did produce quite substantial elevations in its recommendations. For adults up to the age of 50, the daily intake recommendation was tripled from 5 to 15 μg (200 to 600 IU); for adults aged 50–70, it was increased from 10 to 15 μg (400 to 600 IU); and for adults aged over 70, it was increased from 15 to 20 μg (600 to 800 IU). Further, in the 1997 DRIs, the UL was 50 μg/day (2,000 IU/day) and it was doubled to 100 μg/day (4,000 IU/day).


There is general agreement that these moves were in the right direction. Still, most working vitamin D scientists have concluded that the IOM did not go far enough, and many of them have publicly expressed their dissent from the IOM position both on skeletal and non-skeletal endpoints. (See, for example, a series of letters to the ditor in Public Health Nutrition4–12 journals.13,14


as well as further dissents in other


) While nutrient intake recommendations are often a contentious subject, it appears that the reaction to the IOM’s 2011 DRIs for vitamin D is of an order of magnitude more vocal and widely shared than had previously been elicited by any comparable set of IOM recommendations.


Since the focus of this review is explicitly bone health, and since the calcium intake recommendations were little changed from the 1997 values, I shall confine my analysis and comment to the IOM recommendations for vitamin D and specifically to those that relate to calcium homeostasis and skeletal endpoints.


Are Serum 25-hydroxyvitamin D Values Above 20 ng/ml Adequate for Skeletal Health? Three lines of evidence converge on the conclusion that 20 ng/ml is not adequate to achieve the skeletal and calcium metabolic benefits of vitamin D. These are:


58 40 45 50


• randomised controlled trials (RCTs) with fracture endpoints and meta-analyses of such trials;


• •


physiological studies of calcium absorption; and


studies of bone histology with emphasis on osteoid volume. Anti-fracture Trials


Serum 25(OH)D was raised from 21 ng/ml to 30 ng/ml, and osteoporotic fractures combined were reduced by 33 % in the vitamin D-treated group, relative to placebo. Not all trials, to be sure, have shown such a positive result,16–18


One of the earliest of the reported trials involved 2,686 older British individuals in a five-year, double-blind, placebo controlled study and used a dose of 100,000 IU of vitamin D every four months (averaging 820 IU/day).15


but, in most of the null studies,


compliance was so poor or the dose so low (often both) that the achieved dose of vitamin D was too low to test a hypothesis of benefit.16–18


That was certainly the case in the Women’s Health Initiative, where, taking compliance into consideration, the actual dose was only about 200 IU/day.18


In a series of meta-analyses of


published trial results, with particular emphasis on achieved 25(OH)D levels, Bischoff-Ferrari et al. showed that fracture reduction is either small or barely detectable at achieved serum 25(OH)D levels <32 to perhaps 40 ng/ml.19–22


Thus, there is strong positive evidence that


raising achieved serum 25(OH)D values above 20 ng/ml produces substantial reduction in osteoporotic fracture risk, and that trials failing to raise serum 25(OH)D appreciably will not alter fracture risk.


Studies of Calcium Absorption


Facilitation of calcium absorption is the canonical effect of vitamin D. Strangely, only two studies testing the response of calcium absorption as a primary outcome to additional vitamin D have been performed to date in humans.23,24


Both showed an increase in calcium absorption


when baseline 25(OH)D values averaging 20 ng/ml were elevated, in one case to 35 ng/ml and in the other to 29 ng/ml. Furthermore, the slope of that rise on the change in 25(OH)D was virtually identical in the two studies. These data show that, just as with anti-fracture trials, serum 25(OH)D values of 20 ng/ml are not adequate to insure a physiologically appropriate response of calcium absorption to vitamin D. Higher values are simply better, at least up to 30 or 32 ng/ml. (Since vitamin D itself does not cause calcium absorption, but only enables the body to regulate it, the fact that extra vitamin D allowed calcium absorption to rise in both studies strongly suggests that baseline values for 25(OH)D had limited the participants’ ability to respond adequately to their own calcium need.)


Studies of Bone Histology


Osteomalacia is the adult bone disease classically related to vitamin D deficiency. Its histological hallmark is widened osteoid seams and increased coverage of trabecular surfaces with unmineralised osteoid on bone biopsy. The quantitative relationship of these bone changes to vitamin D status had essentially not been studied until recently when, in a report of 675 autopsies, osteoid volume was measured as a function of serum 25(OH)D concentration.25 from this study are presented in Figure 1.


A portion of the results


The figure shows the osteoid volume values for individuals with 25(OH)D values of 20 ng/ml or higher – i.e., the level judged ‘adequate’ by the IOM. There is a visually evident (and highly significant) trend toward lower osteoid volume as serum 25(OH)D rises above 20 ng/ml. It is also clear that no individual with a 25(OH)D value above 32 ng/ml had an osteoid value greater than 1 %


EUROPEAN ENDOCRINOLOGY


OV/BV (%)


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