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Editorials |
Creighton University, Omaha, Nebraska 68178
Calcium nutrition not only is widely recognized as important for bone health, but also has been implicated in such disorders as hypertension, preeclampsia, premenstrual syndrome, and colon cancer. In all but the last of these, the amount of calcium actually absorbed across the intestinal mucosal barrier is what counts. Largely because calcium was a surfeit nutrient in the environment in which hominids evolved, our physiologies are optimized to prevent toxicity, rather than to deal with what would have been only intermittent scarcity. As a consequence, gross calcium absorption efficiency is low—averaging ~30% at 300-mg loads for foods with good bioavailability. Because of the high calcium content of digestive secretions, net absorption is substantially lower still—generally between 10% and 20%.
These summary figures hide a great deal of variability. In healthy women, gross absorption efficiency spans at least a threefold range, from 15% to 45%, even after adjustment for differences in intake (1); patients with various metabolic or digestive disorders may absorb at values outside these limits. What such a range means can be illustrated as follows. A woman absorbing at 45% efficiency extracts 135 mg of the calcium in an 8-ounce serving of milk and, after subtracting digestive juice calcium, nets ~100 mg. A woman with gross absorption of 15%, however, extracts only 45 mg and, after allowing for digestive juice calcium, nets 10 mg or less, barely one-tenth as much.
The reasons for much of this interindividual variability are still unclear; nevertheless, it is known that there is a high degree of within-individual consistency in absorptive performance over time, i.e., some individuals are efficient absorbers and others are poor absorbers (2). Thus, whether a person's calcium intake is adequate or not may depend on where he or she falls within this range of absorptive efficiencies. Clearly it would be clinically useful to be able to assess calcium absorptive performance.
Blood calcium concentrations are tightly regulated and, during absorption, the increment attributable to intestinal input is damped by compensatory down-regulation of the input from bone. As a result, even large ingested loads increase serum calcium very little. Nevertheless, under very carefully controlled conditions, the small absorptive increases that do occur can be used to compare absorbability of different sources. This approach, however, does not yield absolute absorbed quantities, nor is it useful for comparing individuals or for screening or diagnosis. For such purposes, investigators have generally had recourse to a tracer method, typically using a stable or radioactive calcium isotope and, increasingly in recent years, stable strontium (which looks chemically to the body much like calcium, and which goes into the bone mineral crystal lattice very nearly as well as calcium).
Wasserman (3) succinctly reviewed strontium/calcium relationships in these pages recently, noting that all cellular transport processes discriminate to some extent against strontium. The relationship is nonlinear, and hence not quite so straightforward as would be the case if one could say simply that strontium was transported at, for example, two-thirds the efficiency of calcium. What Wasserman did not stress is that the relationship is even more complex for composite processes such as intestinal absorption, in which some portion is by active cellular transport and some by passive diffusion around the mucosal cells. The former involves binding of ions to a carrier protein that discriminates against strontium, whereas little if any strontium/calcium discrimination occurs with the latter. As a consequence, when a strontium tracer is used to measure calcium absorption in individuals with low absorption efficiencies (mostly diffusional), it gives quantitatively very nearly the same answer as does a calcium tracer; whereas at high absorption efficiencies, the strontium-derived value will be substantially lower than the calcium-derived value. For this reason, strontium is inherently ill-suited for nutritional physiological and metabolic studies in which the absolute quantity of calcium absorbed is the desired datum. For such studies, a true calcium tracer, a load size approximating that of a calcium-containing meal, presence of co-ingested foods, and an anion similar to those in foods have all been shown to be important.
Nevertheless, methods that fail several of these criteria may still work perfectly well for diagnostic purposes. Need et al. (4), for example, use a 45Ca method that involves a low carrier dose, the chloride anion, and fasting conditions; predictably, the results do not correlate well with food calcium absorption. Nevertheless, the test does allow clinicians to reliably detect calcium malabsorbers, who can then be treated with low doses of calcitriol, a stratagem that produces demonstrably better results than simply giving everyone a calcium supplement (4). Indeed, such screening of individuals before calcium supplementation is an illustration of precisely why and how one uses a clinical chemical test. The same pragmatic approach can be taken to the strontium-based tests.
In this issue of the Journal, Vezzoli et al. (5) present results attained with their strontium method, using the chloride salt ingested fasting, in a group of hyperabsorptive, hypercalciuric stone formers. They report that the method yielded high estimates of absorption, as should be expected, and that strontium absorption correlated with concurrently measured values for the calciotropic hormones, just as calcium absorption would. In other words, the method worked. Sips et al. (6) have reported the same congruence with physiological expectations for their strontium absorption test. Nevertheless, despite the encouraging behavior of strontium in these largely grouped data, there is not sufficient experience to allow secure estimates of the sensitivity and specificity of the strontium-based methods in individuals.
Still, a few tentative observations can be offered at this stage of our experience. To begin with, strontium is a surrogate for calcium; any substitution inevitably introduces some error, compounded in this case by the nonlinear differences in body handling of the two alkaline earth elements. Although a high degree of correlation with a calcium method is to be expected before a strontium test is even considered, correlation alone is not enough. The crucial issue is the error of the estimate, as reflected both by regression against simultaneous calcium-based measurements, and by short-term within-individual reproducibility. Both Sips and co-workers (6)(7) and Milsom et al. (8) have looked at these issues and have reported data that indicate a 95% probability interval about a strontium-based estimate of fractional calcium absorption amounting to approximately ± 30%. In other words, a strontium-based value of 0.30 might have been as little as 0.21 or as much as 0.39, had it been measured with a true calcium tracer instead. Is this good enough? Possibly. Only time will tell. Most tests lack perfect sensitivity and specificity, and we learn to live with the resulting ambiguity.
However, given these inevitable substitution errors, it may be useful to revisit the issue of using a calcium isotope. 45Ca is, one should have thought, about as close to the ideal diagnostic radionuclide as one could imagine. Its 165-day half-life gives it a highly acceptable shelf-life for the laboratory offering the procedure. 45Ca has no gamma emission, and its weak beta particle dissipates most of its energy in the inert matter of bone, with a corresponding 50-fold reduction in the possibility of biological damage (relative to a comparable radionuclide distributed in soft tissue). Currently used 45Ca-based methods deliver a radiation dose that is a small fraction of the annual natural background and far less than that delivered by virtually any radiologic diagnostic procedure. Although there is appropriate reluctance to cause even small radiation exposures for investigational purposes in healthy children or pregnant women, even in those vulnerable groups that objection disappears when we move to diagnose disease or monitor treatment.
Nor are the 45Ca methods difficult or expensive. The tracer cost per dose is negligible, and the methods used both by Need et al. (4) and our own group (9)(10)(11) require only a single blood sample. As for practicability, our laboratory at Creighton University recently performed nearly 8000 45Ca-based absorption tests for the multicenter Study Of Fractures project (11) over a period of a few months, at a direct laboratory cost of less than $32 per test, including preparation and shipping of the labeled test doses.
The principal barrier to adoption of 45Ca outside of an investigative context may well be a chicken-egg situation. Regulation of 45Ca was transferred some years ago from the Department of Energy to the Food and Drug Administration, which placed it in the category of "investigational new drugs" (IND). It would appear that, uncertain of demand, the radionuclide supplier has not considered it worthwhile to regularize the tracer, and so it languishes in its IND status. Accordingly, laboratories wishing to use it must obtain FDA clearance (easy enough to get, but one more hurdle to jump), and without clinical availability there is, of course, little clinical demand. Furthermore, the "investigational" label may be a barrier to third-party reimbursement.
Nevertheless, awareness of the need to assess calcium absorption continues to grow. Favus (12) argued a decade ago that the time had come, even then, to make measurement of calcium absorption available to clinicians. The recent emergence of strontium is clear witness to this interest in measuring calcium absorption. It may be that the principal impact of the strontium-based tests will be to increase the demand for the measurement.
References
The following articles in journals at HighWire Press have cited this article:
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  J. E. Kerstetter, K. O. O'Brien, and K. L. Insogna Low Protein Intake: The Impact on Calcium and Bone Homeostasis in Humans J. Nutr., March 1, 2003; 133(3): 855S - 861. [Abstract] [Full Text] [PDF]
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 S. DeSantiago, L. Alonso, A. Halhali, F. Larrea, F. Isoard, and H. Bourges Negative calcium balance during lactation in rural Mexican women Am. J. Clinical Nutrition, October 1, 2002; 76(4): 845 - 851. [Abstract] [Full Text] [PDF]
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 R. P. Heaney, M. S. Dowell, and R. L. Wolf Estimation of True Calcium Absorption in Men Clin. Chem., May 1, 2002; 48(5): 786 - 788. [Full Text] [PDF]
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M. Dijkgraaf-ten Bolscher, J. C. Netelenbos, R. Barto, and W. J.F. van der Vijgh Strontium as a Marker for Intestinal Calcium Absorption: The Stimulatory Effect of Calcitriol Clin. Chem., February 1, 2000; 46(2): 248 - 251. [Abstract] [Full Text] [PDF]
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