In the first post in this series, I critiqued the “naked ape hypothesis of optimal serum 25(OH)D,” which I believe influences many researchers to interpret uncertainties in the scientific literature in a way that is biased towards recommendations for high intakes of vitamin D that could be harmful to some people, especially without appropriate attention to the nutrient density and balance of the diet, and to the overall context of a healthy diet and lifestyle.
Now I would like to begin critiquing the use of low 25(OH)D on its own to determine vitamin D status. As the series progresses, I will discuss numerous explanations for low 25(OH)D besides vitamin D deficiency. In this post, I will discuss why a deficient intake of calcium can probably cause low 25(OH)D.
I’ve explained the gist of this post and its bottom line over at the Daily Lipid Video Blog. The details follow.
25(OH)D Is Not a Specific Marker of Vitamin D Status
Although commonly used as one, 25(OH)D is not a specific marker of vitamin D status. 25(OH)D is a compound that we make from vitamin D in our liver. Vitamin D will indeed dose-dependently increase 25(OH)D, but many other factors affect the rate at which 25(OH)D is synthesized, used, or degraded. These include variations in the genetics of vitamin D metabolism, intakes of other nutrients, crisis states such as inflammation, and disease states such as cancer.
Some of the factors that cause low 25(OH)D are bad and some of them are good. While there is likely some critical threshold below which low 25(OH)D almost certainly indicates a major problem, this is not necessarily the case with moderately low 25(OH)D. In order to determine whether moderately low 25(OH)D is a good thing or a bad thing, and in order to understand what, if anything, to do about it, we need to understand why it’s low.
Let’s begin by considering one of the “bad” things that can cause low 25(OH)D besides a deficiency of vitamin D itself: a deficiency of calcium.
Vitamin D Regulates Serum Calcium
In order to understand why a deficiency of calcium can cause low 25(OH)D, we need only consider the most well established and best understood role of vitamin D: to regulate the level of calcium in our blood.
If our blood level of calcium drops for any reason — for example, if we aren’t consuming or absorbing enough calcium from our food — our endocrine system quickly launches a systematic program to bring that level back to normal (1). Our parathyroid glands ramp up their production of parathyroid hormone, which sends a signal to our kidneys to ramp up their conversion of 25(OH)D to calcitriol, the most active form of vitamin D. Calcitriol then increases serum calcium in two ways: preventing loss of calcium in the urine and feces, and extracting calcium from bone.
Or one could splice it three ways: we absorb more calcium from our food, and we lose more from our bones into our blood, but we lose less from our blood into our urine.
Even a slight increase in calcitriol can lead to a big drop in 25(OH)D. This may seem counter-intuitive at first, but it makes more sense if we realize that when we look at the concentration of a compound in the blood, we are taking a static snapshot of a dynamic process. Molecules are always coming and going. As a result, maintaining a constant blood level of a given compound requires a continuous supply of that compound itself. Since calcitriol is made from 25(OH)D, maintaining a given concentration of calcitriol also requires a continuous supply of 25(OH)D.
Calcitriol disappears far more rapidly than 25(OH)D (2). The amount of 25(OH)D that would sustain a certain concentration of itself in the blood for a day would only maintain the same concentration of calcitriol for an hour. So if the body decides to maintain a slightly higher concentration of calcitriol, it would have to levy a much heavier tax on the supply of 25(OH)D.
We should expect, then, that a deficient intake of calcium will lead to increased production of calcitriol, and thereby to depletion of 25(OH)D.
Would an excess of calcium, conversely, cause higher than normal 25(OH)D? Maybe, but not necessarily. While excess calcium would be expected to suppress the production of parathyroid hormone and calcitriol, thereby sparing 25(OH)D, it also elicits additional responses to suppress serum calcium: in response to high levels of calcium, our thyroid glands produce calcitonin, which not only blocks the loss of calcium from bone (1), but appears to stimulate the production of an enzyme that degrades both 25(OH)D and calcitriol to other products generally thought to be inactive (3). Excess calcium could, therefore, have conflicting effects on 25(OH)D, preventing its conversion to calcitriol but increasing its degradation through an alternative pathway, perhaps leading to no net change in 25(OH)D at all.
Overall, then, we would expect that a deficiency in calcium would cause low 25(OH)D, and that correcting the deficiency would normalize the 25(OH)D, but that beyond a certain threshold, increasing calcium intake might not increase 25(OH)D any further.
Let’s take a look at some of the evidence suggesting this is indeed the case.
Calcium Deficiency Depletes 25(OH)D in Rats
In rats, experimental calcium deficiency in the presence of adequate vitamin D caused a more than four-fold elevation of calcitriol and a more than 60 percent drop in 25(OH)D from just under 40 ng/mL to about 15 ng/mL (4) (click to enlarge):
Consistent with the physiology I described above, calcium deficiency also caused a large increase in parathyroid hormone. These findings indicate that, as expected, dietary calcium deficiency causes our parathyroid glands to make more parathyroid hormone, thus increasing the conversion of 25(OH)D to the more active calcitriol. As a result, 25(OH)D tanks.
A similar study came to similar conclusions, but also looked at a number of additional enzymes involved in vitamin D metabolism (5). This study found that calcium deficiency stimulates the production of calcitriol regardless of vitamin D intake, while vitamin D deficiency has no effect on calcitriol levels. When both calcium and vitamin D were adequate, the rats produced more of an enzyme that degrades 25(OH)D. Despite the increase in this enzyme, 25(OH)D was nevertheless highest in that group. This suggests that at least up through the recommended intakes, the predominant effect of calcium is to spare 25(OH)D.
Perhaps with excessive calcium intake, the sparing and degrading effects would balance out differently. If that is the case, it could explain why some human studies described below have had trouble demonstrating an effect of calcium intake on 25(OH)D.
Ambiguous But Supportive Evidence in Humans
To my knowledge, no studies have definitively demonstrated an effect of calcium intake on 25(OH)D in humans. This is most likely because it has hardly been studied rather than because the effect does not exist. Indeed, the basic physiology works the same in humans and rats, and the likelihood that calcium deficiency doesn’t deplete 25(OH)D in humans strikes me as extremely small.
Should we have expected them to? Not really. There are some important obstacles to showing this effect in humans, particularly in Americans, who tend to have high calcium intakes, especially the older Americans targeted for calcium supplementation studies who are usually already keeping an eye on their calcium intake.
First, none of these studies were dealing with true calcium deficiency. Before supplementation, mean calcium intakes were roughly 700 mg/day (8), 800 mg/day (7), and 1000 mg/day (6). It may be that calcium intakes lower than these cause drops in 25(OH)D, but that calcium intakes higher than these have little effect on 25(OH)D.
Second, as I am in the process of explaining through this series, many different factors affect 25(OH)D. 25(OH)D levels in these studies were roughly 26 ng/mL (8), 30 ng/mL (7), or unreported (6). Since the individuals in these studies by definition fall both above and below the mean, these studies likely had some individuals who had pretty low 25(OH)D and others who did not. Similarly, while the mean calcium intakes were reasonably adequate there may have been individuals with calcium intakes much lower than the mean. Of those with low 25(OH)D, then, there may have been some individuals whose low 25(OH)D was a result of calcium deficiency, but these individuals could have been few and far between.
The ideal way to test this principle in humans would be to specifically target individuals with low calcium intakes and low 25(OH)D and randomize them to supplementation with calcium or a placebo, but I am not aware of such studies.
Reference 8 nevertheless seems to provide some slightly supportive evidence, statistically underpowered thought it may be (click to enlarge):
As can be seen when comparing the data in the red square to that in the green square, the placebo group had zero people with “sufficient” 25(OH)D, while the calcium supplementation group had five fewer people in the “deficient” and “insufficient” ranges, with those five missing folks being found — score! — in the “sufficient” range.
The evidence is not all that convincing because the difference is not statistically significant and calcium supplementation didn’t seem to help the people who were also getting vitamin D at all, but it is possible that if this study had been much larger or had specifically targeted people with low calcium intake and low 25(OH)D, it would have demonstrated the effect more convincingly.
There is some observational evidence suggesting that one of the reasons rural Indians with abundant sun exposure have such low 25(OH)D is because of low intakes of bioavailable calcium (9). These particular Indians consume diets dominated by cereal grains, with relatively few animal products and vegetables providing only five percent of calories. Cereal grains provide very little calcium but large amounts of phytate, which inhibits the absorption of calcium. As calcium intake increases among these subjects and phytate intake declines, 25(OH)D status improves:
Perhaps one of the reasons that the Maasai and Hadza have considerably higher 25(OH)D status than rural Indians (as discussed in the previous post in this series) despite all three groups being exposed to abundant sunshine is because calcium deficiency is prevalent among neither the Maasai nor the Hadza. The Maasai herd cattle and consume large amounts of dairy products. In addition to animal products, the Hadza consume some 14 percent of their diet as baobab, which some investigators have said is one of the Hadza’s five food groups (10), and which is very rich in calcium (11).
Low 25(OH)D? Check Your Calcium Intake!
Although randomized controlled trials have thus far not provided the definitive evidence that low calcium intake is a cause of low 25(OH)D in humans, this is far more likely to be because no trials have adequately addressed the question than because the interaction does not exist. Experimental evidence in rats has demonstrated the interaction beyond doubt, and the physiology — which very clearly implies the interaction — appears to be, for all relevant intents and purposes, identical between humans and rats. It is thus extremely unlikely in my opinion that low calcium intake is not a cause of low 25(OH)D in humans.
The practical implications are two-fold. First, we are in desperate need of clinical trials to address this question adequately. In the mean time, if someone has low 25(OH)D, they should assess their calcium intake.
Obtaining a bird’s-eye view of one’s calcium intake is relatively easy to do without the help of a professional, any fancy software, or even an internet database. Most Americans and others in modern, industrial society have easy access to just three sets of foods that are rich in highly absorbable and utilizable calcium: dairy products, edible bones, and cruciferous vegetables.
Most people are well aware that dairy products are rich in calcium.
Bone broth is delicious and provides important bone-building trace minerals and amino acids, but it contains relatively little calcium relative to our overall requirement. The soft edible bones in canned fish, however, or, for adventurous eaters, the soft edible knobs on the ends of small chicken bones, are all very rich in calcium.
Calcium is widely distributed in plant foods, but the amounts are often small and in some calcium-rich leafy greens like spinach, the availability is terrible. Calcium absorption from kale, however, is better than that from conventional, commercial milk (12). Numerous cruciferous vegetables provide anywhere from half as much to twice as much absorbable calcium, cup for cup, as commercial milk (13).
As a rule of thumb, then, I would say that if someone has low 25(OH)D and she is eating two to three servings of dairy products or soft, edible bones, or two to three cups of cruciferous vegetables per day (which have their downsides), then calcium deficiency is unlikely to be the explanation. If one is not eating these foods, however, it could very easily be the explanation. In such a case, the person has little to lose and much to gain by including more calcium-rich foods.
Because the calcium content and availability is quite variable even between different cruciferous vegetables, and because many other plant foods contain smaller amounts of calcium that could contribute to the overall intake or, on the other hand, anti-nutrients that could detract from the overall intake, greater attention should be paid to this possibility if someone is attempting to meet their calcium requirement with plant foods alone. If such a person has low 25(OH)D and thinks she is getting enough calcium, she would do well to record her dietary habits, research the relative amounts of calcium and anti-nutrients in the foods she is eating, and consider consulting a registered dietician or another type of professional nutritional consultant.
If poor calcium intake is depleting vitamin D stores and thereby causing low 25(OH)D, throwing extra vitamin D at the problem is not the optimal solution. It will not be the most effective way of normalizing the hormonal milieu or preventing bone loss. Only calcium can correct a calcium deficiency. Throwing a calcium supplement at the problem is not the ideal solution either. Both vitamin D and calcium supplements leave the diet lacking in a broad spectrum of other important nutrients found in dairy products, bones, and leafy greens.
In future posts in this series, I will discuss other potential causes of low 25(OH)D besides poor vitamin D exposure. By the end of the series, I’ll provide a systematic approach for interpreting the likely cause of low 25(OH)D. In the mean time, I’d love to hear your thoughts in the comments!
1. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Ross AC, Taylor CL, Yaktine AL, et al., editors. Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): National Academies Press (US); 2011. p. 40. [NCBI Bookshelf]
2. Jones G. Pharmacokinetics of vitamin D toxicity. Am J Clin Nutr. 2008;88(2):582S-6S. [Pubmed]
3. Gao XH, Dwivedi PP, Omdahl JL, Morris HA, May BK. Calcitonin stimulates expression of the rat 25-hydroxyvitamin D3-24-hydroxylase (CYP24) promoter in HEK-293 cells expressing calcitonin receptor: identification of signaling pathways. J Mol Endocrinol. 2004;32(1):87-98. [PubMed]
4. D’Amour P, Rousseau L, Hornyak S, Yang Z, Cantor T. Influence of Secondary Hyperparathyroidism Induced by Low Dietary Calcium, Vitamin D Deficiency, and Renal Failure on Circulating Rat PTH Molecular Forms. Int J Endocrinol. 2011;2011:469783. [PubMed]
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6. Elders PJ, Lips P, Netelenbos JC, van Ginkel FC, Khoe E, van der Vijgh WJ, van der Stelt PF. Long-term effect of calcium supplementation on bone loss in perimenopausal women. J Bone Miner Res. 1994;9(7):963-70. [PubMed]
7. McKane WR, Khosla S, Egan KS, Robins SP, Burritt MF, Riggs BL. Role of calcium intake in modulating age-related increases in parathyroid function and bone resorption. J Clin Endocrinol. Metab. 1996;81(5):1699-703. [PubMed]
8. McCullough ML, Bostick RM, Daniel CR, Flanders WD, Shaukat A, Davison J, Rangaswamy U, Hollis BW. Vitamin D status and impact of vitamin D3 and/or calcium supplementation in a randomized pilot study in the Southeastern United States. J Am Coll Nutr. 2009;28(6):678-86. [PubMed]
9. Harinarayan CV, Ramalakshmi, Prasad UV, Sudhakar D, Srinivasarao PV, Sarma KV, Kumar EG. High prevalence of low dietary calcium, high phytate consumption, and vitamin D deficiency in healthy south Indians. Am J Clin Nutr. 2007;85(4):1062-7. [PubMed]
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11. Prentice A, Laskey MA, Shaw J, Hudson GJ, Day KC, Jarjou LM, Dibba B, Paul AA. The calcium and phosphorus intakes of rural Gambian women during pregnancy and lactation. Br J Nutr. 1993;69(3):885-96. [PubMed]
12. Heaney RP, Weaver CM. Calcium absorption from kale. Am J Clin Nutr. 1990;51(4):656-7. [PubMed]
13. Weaver CM, Heaney RP. 2006. Food sources, supplements, and bioavailability. In: WeaverCM, HeaneyRP, editors. Calcium & human health. Totowa , N.J. : Humana Press. 137 p. [Springer]🖨️ Print post