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Vitamin D and Bone Health – Discussion Points Following the Recent IOM Recommendations

of bone volume, which we can thus take as the upper limit of normal for this measure. It is clear also that, in the 25(OH)D range between 20 and 32 ng/ml, fully half of the individuals included had elevated osteoid volume, some more than four times the upper limit of normal – i.e., they exhibited histological evidence of osteomalacia. The IOM panel was aware of this study and nevertheless judged this prevalence of osteomalacia to be ‘acceptable’ at a population level.

Concordant findings had earlier been published showing greater osteoid volume in winter than in summer in the biopsies of the studied women.26

In this study, winter 25(OH)D values averaged 20.4 ng/ml,

and summer values 24.4 ng/ml. Thus, in both studies, which involved very different populations, patients with 25(OH)D values of 20–32 ng/ml still exhibit histological evidence of osteomalacia, which does not disappear until 25(OH)D values rise appreciably.

Convergent Evidence

Thus all three lines of evidence converge on the conclusion that a 25(OH)D value of 20 ng/ml is not ‘healthy’, and that preventable disease or dysfunction (fracture, calcium malabsorption, and histological osteomalacia) persists until serum 25(OH)D is at least 30 or perhaps even 40 ng/ml.

Daily Requirement

Thousands of clinicians worldwide using vitamin D in their deficient patients know from personal experience that the IOM’s recommended dietary allowance (600 IU/day for individuals up to the age of 70) is not close to sufficient to produce the stated ‘normal’ 25(OH)D value of 20 ng/ml or higher. Even if patients start with values above 10 ng/ml, 600 IU would still not be enough for most of them. Figure 2 sets out the best available estimates of the expected rise in serum 25(OH)D for each 100 IU daily dose, plotted as a function of the starting 25(OH)D value. (The data in Figure 2 were derived from a study of over 3,500 adults ingesting daily vitamin D doses ranging from zero to 50,000 IU.)27

discovered, and as the figure demonstrates, the absolute value of the rise in 25(OH)D in response to a given dose declines as baseline status rises. What Figure 2 does is to put numbers to this experience.

To apply the information in Figure 2, note that, for a starting 25(OH)D value close to zero (i.e., ‘unmeasurable’ in many assays), each 100 IU predicts a rise of about 1.1 ng/ml or, for 600 IU, an aggregate rise of about 7 ng/ml – certainly not 20 ng/ml or higher. In fact, to reach 20 ng/ml requires an all-source, daily input (cutaneous plus oral) averaging about 1,800 IU/day and, to reach 32 ng/ml, the required input averages close to 4,000 IU/day – a figure confirmed in a previously reported, long-duration dose-ranging study.28

Prudential Caution

One possible reason for the surprisingly low recommendations from the IOM is a concern not to do more harm than good. If, for example, the lower end of the normal range had been set at 30, or even 40 ng/ml, and the RDA set at 2,000 IU/day (figures many experts would consider fully justifiable), given the inevitable Gaussian distribution of values, some individuals might conceivably be pushed into a potentially toxic range. That would not be formal vitamin D intoxication to be sure – as the raised UL (4,000 IU/day) assures us – but possibly some of the other ostensible benefits would disappear or unanticipated negative effects would develop. Concern for such unintended outcomes is entirely appropriate and would be


In a similar vein, the IOM panel undoubtedly noted that, for certain endpoints (mostly non-skeletal), apparent benefit waned at the highest percentiles of a particular population’s distribution of 25(OH)D values – and, in some reports, even reversed.30,31

Vieth has insightfully

explained that this is due to wide annual variations in serum 25(OH)D concentrations, and has shown why this oscillation nullifies any apparent benefit.32

been the case in the study using 500,000 IU once yearly.29

Exactly such wide annual oscillation also would have Vieth noted

that annual oscillations of more than a few ng/ml are unphysiological and described its effect well in advance of the IOM panel’s deliberations, but whether the panel was aware of his work is not clear.

59 0.8 0.6 0.4 0.2 0.0 0 20 40 60 80 100 Starting serum 25(OH)D (ng/ml)

25(OH)D = 25-hydroxyvitamin D; IU = international unit. Source: redrawn from the data from Garland, et al., 201127 Used with permission).

(copyright Robert P Heaney, 2011. All rights reserved.

expected of such a policy-making body. However, action taken on such concern must depend heavily on the quality of the evidence suggesting untoward effects – in this case, at 25(OH)D concentrations above 40 or 50 ng/ml (specifically cited in the IOM report).

Once again, as most clinicians have

A single study suggesting such harm used 500,000 IU once yearly, and showed an actual increase in falls and fractures,29

certainly a concern if

applicable. However, it is questionable whether any weight at all should be given to this particular study in view of the fact that, with once yearly dosing, it employed an extremely unphysiological approach to replacement therapy. A comparable approach in the field of clinical endocrinology would be to treat hypothyroid patients with a single dose of 12,000 µg l-thyroxine once every three months. Such a regimen would be both ineffective and dangerous. As the half-life of 25(OH)D is approximately four times that of thyroxine, the two regimens just described (yearly for vitamin D and quarterly for thyroxine) are exactly equivalent. It is not surprising, therefore, that the outcomes of such a vitamin D study are not representative of the outcomes that would have been produced by the same dose had it been given on a daily basis (which would have averaged about 1,370 IU/day).

120 140 Figure 2: Expected Rise in Serum 25(OH)D for Each

100 IU of Additional Vitamin D3, Expressed as a Function of the Basal Value

1.4 1.2 1.0

Rise in serum 25(OH)D (ng/ml) per 100 IU/day

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