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Creighton University, Omaha, Nebraska
2To whom correspondence should be addressed. E-mail: rheaney{at}creighton.edu.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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15%. The combined effect of improved intakes of dietary calcium and the small amount of calcium added by the multivitamin tablets resulted in a mean calcium intake for the control group > 800 mg (20 mmol)/d, possibly at or near the threshold beyond which additional calcium has no further effect on bone accrual.
KEY WORDS: • calcium nutrition • calcium supplementation • young adults • bone mass • peak bone mass
An adequate intake of calcium (Ca) is generally recognized as essential for acquisition and maintenance of the skeletal mass called for in the genetic program as modified by mechanical loading activity (1–7). However, Ca is also recognized as a threshold nutrient (2,6), i.e., the effect of variations in intake are evident only up to some threshold intake level, above which further increases in intake produce no further change in skeletal mass. Precisely what those threshold values may be at various life stages remains uncertain. This study was designed to examine a life stage (skeletal consolidation in the 3rd decade) for which, to our knowledge, no controlled trials have been performed or published.
In an earlier observational study from our research unit, physical activity, nutrient intakes, and bone mass were observed longitudinally for up to 5 y in 156 healthy, college-aged women (8). In this group, bone mass was increasing at a yearly rate of 1.25% for the total body and 0.59% at the lumbar spine. Overall, bone gain was directly related to the calcium content, specifically to the Ca:protein ratio, of the subjects’ usual, self-selected diets, suggesting that calcium intake could be a limiting factor in postadolescent skeletal consolidation. We undertook the present study formally to test this possibility, specifically in young women whose self-selected diets exhibited low Ca:protein ratios.
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SUBJECTS AND METHODS |
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Subjects.
We recruited healthy, nonsmoking, nonpregnant young women, aged 19–27 y at last birthday. We excluded candidates who reported height and weight that yielded a BMI 
30 kg/m2, binge drinking (9), significant risk of pregnancy, or more than occasional use of Ca supplements or Ca-containing antacids. Qualified candidates who agreed to continue kept 7-d food diaries; we accepted candidates whose reported mean daily dietary Ca:protein ratio did not exceed 13 mg/g. At mean reported protein intakes, a calcium:protein ratio of 13:1 translates into a calcium intake of 780 mg/d. We screened 982 young women; 465 failed to meet entry criteria, 365 declined to participate, and 152 were randomly assigned to groups and entered the study (Ca group, n = 81, placebo group, n = 71). The median value for oral contraceptive use was 82.0% of time in the study (interquartile range, 3.5–100%). Oral contraceptive use did not differ by treatment group.
Intervention. Subjects were assigned to take 3 tablets/d (500 mg Ca as the carbonate per tablet or placebo capsules identical in appearance); the tablets were to be consumed with food. Tablets were packaged in bottles of 90 by the manufacturer; a research pharmacist selected and labeled the bottles. A system was devised to ensure, without disclosing to the investigators the actual treatment assignment, that tablet selection consistently followed the randomization scheme. The tablets used in our study were specially formulated for the Calcium for Preeclampsia Prevention (CPEP) trial (10).
All participants were also supplied with fully-labeled Geritol® multivitamin tablets, to be taken once daily to ensure at least minimal status for vitamin D and other trace nutrients. Ca, placebo, and multivitamin tablets were supplied without charge by the manufacturer (SmithKlineBeecham). Tablet bottles were dispensed at each visit, and each bottle was weighed at issue and at return. Each subject’s overall compliance fraction was calculated as observed/expected tablet consumption, expressed as a percentage.
Data gathering. A range of data was gathered at each visit (Table 1). To detect changes in serum and urine calcium, and to detect hypercalcemia or hypercalciuria in response to treatment, we measured serum Ca and urine Ca:creatinine ratio at Visits 1 and 2 (entry and 2 mo, respectively). After a 12-h overnight fast and without water restriction, a 2-h urine sample was collected after an early morning void. Urine and serum calcium were measured by atomic absorption spectrophotometry (AAnalyst 100, Perkin-Elmer) and urine creatinine by Chiron Express Plus (Bayer Healthcare). The calcium content of the active-agent tablets was verified by atomic absorption spectrophotometry of ashed specimens, and absorbability of the calcium in the supplement tablets by an established pharmacokinetic method (11–13). Nutrient intakes were assessed at baseline and midstudy using a 7-d food diary; the data were analyzed using ESHA Food Processor Plus, Version 7.4.
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Data analysis and statistical methods.
Data were collected between May 1995 and April 2000. We carried out 2 sets of calculations for use in examining the results for evidence of within-group changes and between-group differences in rate of change. We adjusted each subject’s scan results to her entry values to create relative values that would better allow pooling of change data across subjects of different skeletal sizes. We also calculated individual rates of change (as %/y) that could be used for tests of within-group change (difference from zero) and between-group difference. Analyses were carried out using standard statistical methods and SPSS 12.0 for Windows (SPSS). All statistical tests of DXA data were carried out with weighting for years in the study (i.e., the interval between each subject’s first and last DXA scans), as described elsewhere (14). Differences were tested against a null hypothesis of zero change, and regression slopes against a zero value. All tests were 2-sided, with 
= 0.05.
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RESULTS |
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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0.6 that rate. In addition, total hip BMC also increased at >1%/y, yet total hip BMD, although it decreased slightly, was essentially unchanged (P = 0.85). Thus, clearly, there was appreciable skeletal consolidation, easily detectable by BMC (if not BMD), occurring in these women in their 3rd decade. In the present trial, however, calcium supplementation did not exert a measurable effect on this bone mass accrual. There are several possible explanations. Although the available data do not allow us to make a definitive choice among them, they are worth a brief exploration.
First, the diets of the untreated individuals may have provided sufficient calcium to meet the small demands for growth at this life stage, i.e., their diets were already at (or close to) the calcium intake threshold. Hence, following the usual pattern for threshold nutrients, further calcium intake would be without effect. The observed rate of whole-body BMC augmentation (0.28%/y), applied to the mean baseline value of total body BMC, translates to a calcium retention of 6 mg (0.15 mmol)/d. More than half of the placebo-treated subjects had final calcium intakes > 800 mg (20 mmol)/d. Given the variability in individual requirements, the intakes of many of these women would likely have been located on the plateau region for calcium retention (2,6,16), and hence they would have been nonresponders. However, we cannot conclude that calcium intake has no effect under any circumstances. Rather, calcium’s effect on bone mass accrual, like iron’s effect on hemoglobin mass, depends upon the starting value. If this explanation for our finding of no difference is the correct one, then many subjects in our contrast group already had an intake high enough to cause them to express most or all of the effect of a high calcium intake.
Second, after attrition in this study, we likely had insufficient power to find a difference that might be clinically important. Post hoc calculation of power revealed that our final sample sizes would have yielded a power of 0.37 for a difference in augmentation rate of as little as 0.3%/y for total BMC and a power of 0.36 for a difference of 0.5%/y for hip and spine.
Third, the degree of actual calcium intake augmentation could, in theory, have been insufficient to produce a detectable effect. This possibility breaks down as follows: 1) too small a dose, 2) poor compliance, or 3) low supplement potency (or some combination of all 3). There was a difference of >1200 mg (30 mmol)/d in Ca intake between the groups (Table 5), a difference for which other studies had shown a Ca effect [e.g., (5,7,17,18)]. Thus, too low a dose seems unlikely. Estimating compliance is always an uncertain issue. Nevertheless, the relation between project staff and participants was generally good; hence we are inclined to believe that the compliance reported was accurate. Alternatively, the Ca supplement we used could have possessed reduced absorbability. We examined this possibility and found that our tablets produced less than half the rise in serum Ca, post-dosing, than expected for their Ca content (13). Although this meant that we were actually giving less Ca than we had planned, the differences in intake between groups would still have been > 500 mg/d, probably large enough to produce a difference if Ca intake were a limiting variable at prevailing intakes. Nevertheless, the fact that there was no significant rise in urine Ca in the supplemented group, which was not known until the study blind was broken, suggests that there was little actual difference between the placebo and active treatments in the quantity of Ca consumed and/or absorbed. Although urine Ca is a crude reflection of Ca absorption, it has been used by several investigators as a test of Ca absorbability (19), and one might have expected a detectable increase.
In conclusion, the null hypothesis cannot be rejected by these data. We judge that a combination of insufficient final power, a relatively ample calcium intake in the placebo group, and a less than fully potent supplement combined to impair a definitive test of the role of augmented Ca intake in the skeletal consolidation naturally occurring in women in their 3rd decade.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: BMC, bone mineral content; BMD, bone mineral density; DXA, dual energy X-ray absorptiometry.
Manuscript received 20 May 2005. Initial review completed 14 June 2005. Revision accepted 19 July 2005.
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LITERATURE CITED |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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1. Heaney R. P., Abrams S., Dawson-Hughes B., Looker A., Marcus R., Matkovic V., Weaver C. M. Peak bone mass. Osteoporos. Int. 2000;11:985-1009.[Medline]
2. Food and Nutrition Board, Institute of Medicine. Peak bone mass. Dietary Reference Intakes for Calcium, Magnesium, Phosphorus, Vitamin D, and Fluoride. National Academy Press Washington, DC.
3. NIH Consensus Conference. Optimal calcium intake. J. Am. Med. Assoc. 1994;272:1942-1948.[Medline]
4. U.S. Department of Health and Human Services. Optimal calcium intake. Bone Health and Osteoporosis. A Report of the Surgeon General. U.S. DHHS, Office of the Surgeon General Rockville, MD.
5. Heaney R. P. Calcium, dairy products and osteoporosis. J. Am. Coll. Nutr. 2000;19:83S-99S.
6. Heaney R. P. Ethnicity, bone status, and the calcium requirement. Nutr. Res. 2002;22:153-178.
7. Johnston C. C., Jr, Miller J. Z., Slemenda C. W., Reister T. K., Hui S., Christian J. C., Peacock M. Calcium supplementation and increases in bone mineral density in children. N. Engl. J. Med. 1992;327:82-87.[Abstract]
8. Recker R. R., Davies K. M., Hinders S. M., Heaney R. P., Stegman M. R., Kimmel D. B. Bone gain in young adult women. J. Am. Med. Assoc. 1992;268:2403-2408.[Abstract]
9. Wechsler H., Dowdall G. W., Davenport A., Rimm E. B. A gender-specific measure of binge drinking among college students. Am. J. Public Health. 1995;85:982-985.
10. Sibai B. M., Ewell M., Levine R. J., Klebanoff M. A., Esterlitz J., Catalano P. M., Goldenberg R. L., Joffe G., for the Calcium for Preeclampsia Prevention (CPEP) Study Group. Risk factors associated with preeclampsia in healthy nulliparous women. Am. J. Obstet. Gynecol. 1997;177:1224-1226.
11. Heaney R. P., Dowell M. S., Bierman J., Hale C. A., Bendich A. Absorbability and cost effectiveness in calcium supplementation. J. Am. Coll. Nutr. 2001;20:239-246.
12. Heaney R. P. Quantifying human calcium absorption using pharmacokinetic methods. J. Nutr. 2003;133:1224-1226.
13. Heaney R. P. Quantifying human calcium absorption using pharmacokinetic methods. The challenges of calcium. Functional Foods & Nutraceuticals May 2005.
14. Heaney R. P. Design considerations for clinical investigations of osteoporosis. Marcus R. Kelsey J. Feldman D. eds. Design considerations for clinical investigations of osteoporosis. 2nd ed. Osteoporosis. 2001;2:513-532 Academic Press San Diego, CA.
15. Heaney R. P. BMD: the problem. Osteoporos. Int. 2005; (Epub ahead of print), March.
16. Matkovic V., Heaney R. P. Calcium balance during human growth. Evidence for threshold behavior. Am. J. Clin. Nutr. 1992;55:992-996.
17. Cadogan J., Eastell R., Jones N., Barker M. E. Milk intake and bone mineral acquisition in adolescent girls: randomised, controlled intervention trial. Br. Med. J. 1997;315:1255-1260.
18. Jackman L. A., Millane S. S., Martin B. R., Wood O. B., McCabe P., Peacock M., Weaver C. M. Calcium retention in relation to calcium intake and postmenarcheal age in adolescent females. Am. J. Clin. Nutr. 1997;66:327-333.
19. Broadus A. E., Domintuez M., Bartter F. C. Pathophysiological studies in idiopathic hyperalciuria: use of an oral calcium tolerance test to characterize distinctive hypercalciuric subgroups. J. Clin. Endocrinol. Metab. 1978;47:751-760.[Abstract]
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