More Evidence and Still No Action

Robert P. Heaney

Creighton University Omaha, Nebraska

Address correspondence and requests for reprints to: Robert P. Heaney, M.D., Creighton University, 601 North 30th Street, Suite 4841, Omaha, Nebraska 68131.


    Introduction
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 Introduction
 References
 
Calcium is a nutrient, and vitamin D is a prohormone which, because it requires oral ingestion at mid to upper latitudes, functions effectively as if it were a nutrient. For both, recommended intakes in older adults have recently been increased (relative to the 1989 recommended daily allowances), for calcium by 1.6–1.9 times and for vitamin D by 2–3 times (1, 2). These changes reflect new recognition of age-related decreases in utilization efficiency for dietary calcium and in dermal synthesis of vitamin D.

As nutrients, both must be ingested in sufficient quantities to prevent or reverse manifestations of deficiency, but above some intake threshold, higher intakes produce no further benefit. With the new, higher intake recommendations, it turns out that the intakes of many elderly individuals in Europe and North America are below these thresholds; they, therefore, suffer from insufficiency of one or both nutrients. Accordingly, in clinical trials, it has made sense to supply both. Thus, Chapuy et al. (3), in a double-blind, placebo-controlled trial in 1765 elderly French women, gave 20 µg vitamin D and 1200 mg calcium. Bone loss at the hip was more than 3%/yr in the placebo-treated subjects, ingesting an average of 514 mg calcium/day. The treatment completely arrested this bone loss and by 18 months had reduced hip and other extremity fractures by 30–40%. Similarly, Dawson-Hughes et al. (4), in a 3-yr trial also using a combination of calcium and vitamin D, stopped bone loss and reduced nonvertebral fracture rates in healthy adult men and women by more than 50%.

Despite the formal consensus on new higher intake requirements for both nutrients, some doubt remains as to which of the two might have been responsible for the dramatic changes seen in these two trials. The calcium skeptics allege it was the vitamin D that produced the benefit, perhaps by acting on muscle tone, and the vitamin D skeptics allege it was the calcium. (Perhaps the majority judged that the combination was greater than the sum of its parts.)

In this issue of the journal, Peacock et al. (5) present results of a 4-yr trial that help to resolve this question in 75-yr-old men and women, at least for individuals living in central Indiana. In a three-way study, the authors compared the effects of either 750 mg supplemental calcium or 15 µg 25(OH)D (equivalent to ~20 µg vitamin D3) with placebo. In brief, the placebo-treated subjects, with a mean calcium intake of ~600 mg/day and mean serum 25(OH)D values of ~61 nmol/L, were losing bone at the hip at a rate of ~0.5%/yr. Calcium alone completely arrested that loss, whereas vitamin D alone was intermediate between placebo and calcium at the spine and essentially no different from placebo at the hip and total body. The study was not powered for a fracture end point; and although vertebral fractures were reduced by 50% or more in the calcium group, relative to the other two treatments, the difference was not statistically significant.

In a novel twist, the authors measured femoral medullary cavity expansion in their subjects. Such expansion is a structural expression of the consumption of bone capital to offset insufficient calcium intake and has an immediate and intuitively obvious consequence in terms of bone strength. In the placebo group the femoral medullary cavity was expanding at a rate of ~0.7%/yr, whereas in the calcium group the rate of expansion was only one third as large.

It is clear from these results that calcium alone had a major bone-sparing effect in these subjects. By repairing any vitamin D insufficiency, the administered 25(OH)D would have been expected to augment absorption of calcium from the participants’ self-selected diets, thereby effectively duplicating the effect of simply giving more calcium. Why it did not produce the same bone-sparing effect in this trial is indicated by the change in urinary calcium excretion, which was substantially greater for the calcium supplement than for the 25(OH)D. Urine calcium spillage is a measure, albeit weak, of intestinal absorption, and from the urine calcium data one can infer that substantially more calcium was absorbed from the supplement than from the dietary calcium of those given enough vitamin D to bring them to repletion. This is an indication, if one were needed, that the new dietary calcium recommendations presume normal vitamin D status and that vitamin D, by itself, cannot make up for an inadequate calcium intake. (After all, even efficient absorption of not very much calcium still yields not very much calcium.) Whether a combination of calcium plus extra vitamin D would have produced a greater effect in these subjects cannot be determined from the published data.

Whereas the skeletal benefit was qualitatively similar to that of the French trial (3), there is an important difference between the two subject groups. The subjects in the Indiana trial had a mean serum 25(OH)D concentration of 61 nmol/L, whereas in the older French women mean 25(OH)D was 29 nmol/L, vastly more deficient. Hence, virtually all of the French subjects would have been expected to benefit from both nutrients, whereas in the Indiana trial many of the subjects would have been close enough to vitamin D sufficiency at baseline as to derive relatively little measurable benefit from adding only more vitamin D. This conclusion is supported in the study by Peacock et al. (5) by the finding, in a post hoc analysis of the data, that hip bone mineral density loss was greatest in those who had the combination of the lowest calcium intakes and the lowest serum 25(OH)D values.

I (6), in a summary review of papers on calcium and bone, was able to find, through mid 1999, 39 randomized controlled trials of calcium supplementation with a skeletal end point. All but two reported a benefit of extra calcium (i.e. increased bone gain during growth, decreased bone loss with age, and/or fewer osteoporotic fractures). (The sole exceptions were a trial in men in which the control group intake was greater than 1100 mg/day and a trial in early postmenopausal women, in whom estrogen withdrawal is known to be the principal causal factor for bone loss.) Peacock et al. (5) add another strong piece of evidence to the positive side of the ledger.

Given the accumulated weight of all the evidence, it might seem that more would be overkill. Nevertheless, this study is useful in that it helps sort out the interactions of vitamin D and calcium. Moreover, it emphasizes that, despite regional variations in vitamin D status, insufficient calcium intake tends to be a constant across different populations. Thus, normalizing vitamin D status will not suffice by itself. The NIH Consensus Development Conference on Optimal Calcium Intake (1) emphasized the need for higher calcium intake 6 yr ago. Their conclusions effectively underscored the finding in "Healthy People 2000," published by the Federal government 10 yr ago (7), to the effect that low calcium intake was one of only two nutrient deficiencies in the United States of sufficient prevalence to warrant a national effort.

It is necessary to stress that, although low calcium intake is by no means the only factor contributing to osteoporosis, it clearly is one such and one that is under our control. To what extent are we exercising that control—with regard either to public awareness or to public policy?

There is, in fact, a fairly general awareness of the importance of calcium throughout life in both the public and the professional practice sectors of North America. Nevertheless, there is just enough dissent to keep the media pot boiling and correspondingly a significant risk that the public may fail to grasp the true consensus. It is important, therefore, to emphasize in communications with the general public that there are effectively no true experimental data in humans that have failed to find a skeletal benefit of added calcium above prevailing intakes; that all of the failed studies were observational in character [and they are in a small minority in even that category (6)]; and, perhaps most important, that vocal opposition typically has an ideological origin, rather than a scientific one. [Commonly, critics of the calcium consensus start from a base of strong opposition to dairy products. Logically, therefore, they cannot be pro-calcium and anti-dairy at the same time. If dairy foods are bad for us—so the reasoning must go—we cannot have any fundamental biological need for a constituent (i.e. calcium) for which dairy products are the major dietary source.]

Despite the increased public awareness of the importance of calcium, actual intake has increased only modestly over the past 20 yr. This is partly because of a decrease in total food intake and partly because of a continuing decline in milk consumption. Supplement use is up, and in the past 18 months there has been an explosion of voluntarily fortified foods available on grocery shelves. However, voluntary compliance (supplement taking, choosing fortified foods over unfortified) is an inefficient means of meeting such a pervasive, population-wide nutrient need. When we became sufficiently convinced of the importance of folic acid in the prevention of neural tube defects, we moved to fortify wheat products with folic acid. Fortification would seem to be an appropriate solution for the calcium crisis as well.

The FDA has a long and puzzling history of reluctance to require fortification of items in the food chain. The first folic acid petition was filed 20 yr before mandatory fortification. Just this summer the agency denied a citizen petition for low-level calcium fortification of grain products (e.g. bread, pasta), after sitting on the petition for 8 yr (!). Its grounds were that it did not have the staff to do the necessary analyses and that the petitioners had failed to do them for the agency (8).

Thus, lacking regulatory guidelines, we are left with manufacturer fortification as the principal national mechanism for defusing the calcium crisis. Such voluntary fortification, driven mainly by market forces, is arguably not the best way to meet this, or indeed most, nutritional objective.

Received July 17, 2000.

Accepted July 17, 2000.


    References
 Top
 Introduction
 References
 

  1. NIH Consensus Conference. 1994 Optimal calcium intake. J Am Med Assoc. 272:1942–1948.[CrossRef][Medline]
  2. Food and Nutrition Board, Institute of Medicine. 1997 Dietary reference intakes for calcium, magnesium, phosphorus, vitamin D, and fluoride. Washington, DC: National Academy Press.
  3. Chapuy MC, Arlot ME, Duboeuf F, et al. 1992 Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med. 327:1637–1642.[Abstract]
  4. Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. 1997 Effect of calcium and vitamin D supplementation on bone density in men and women 65 years or older. N Engl J Med. 337:670–676.[Abstract/Free Full Text]
  5. Peacock M, Liu G, Carey M, et al. 2000 Effect of calcium or 25OH vitamin D3 dietary supplementation on bone loss at the hip in men and women over the age of 60. J Clin Endocrinol Metab. 85:3011–3019.[Abstract/Free Full Text]
  6. Heaney RP. 2000 Calcium, dairy products, and osteoporosis. J Am Coll Nutr. 19:83S–99S.
  7. Healthy People. 2000 U.S. Department of Health and Human Services, Public Health Service, 1990.
  8. Docket No. 92P-0064. 2000 Department of Health and Human Services, Public Health Service, Food and Drug Administration; letter to Paul A. Lachance and Harold L. Newmark, dated June 19, 2000.