Dietary Supplement Use in Women: Current Status and Future Directions

Transcription

1 Dietary Supplement Use in Women: Current Status and Future Directions Interaction of Science, Consumer Practices and Policy: Calcium and Bone Health as a Case Study 1 Anne C. Looker 2 National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, MD ABSTRACT Data to support a relationship between calcium and bone health are a major part of the body of evidence that underlie calcium-related policy in the United States. Examples of these policies include dietary intake recommendations, health claims for calcium and osteoporosis on food labels and an objective to improve calcium intake of the U.S. population in Healthy People Median calcium intakes among females fall below recommended levels after childhood even when supplemental calcium intakes are included. This is a concern in light of data that support a positive relationship between calcium and bone health. Most of the studies on the calcium bone relationship have focused on older women, and several have used fracture as the endpoint; a meta-analysis of their results suggests that increased calcium intake is associated with 30% decrease in fracture risk. Studies in children, adolescents and premenopausal women have focused on the relationship between calcium and bone mineral density rather than fracture; most of these also support a positive relationship between calcium intake and skeletal health although some data gaps remain. Calcium appears to be a threshold nutrient (e.g., intakes above a certain level do not result in further benefit to bone). The effect of increased calcium intake on bone density does not appear to persist unless the higher intakes are sustained. There are certain conditions, such as lactation, during which calcium intake does not appear to influence bone. Other factors that may influence the effect of calcium on bone include bone-specific genotypes and physical activity. J. Nutr. 133: 1987S 1991S, KEY WORDS: dietary calcium bone osteoporosis 1 From the National Institutes of Health (NIH) conference Dietary Supplement Use in Women: Current Status and Future Directions held on January 28 29, 2002, in Bethesda, MD. The conference was sponsored by the National Institute of Child Health and Human Development and the Office of Dietary Supplements, NIH, U.S. Department of Health and Human Services (DHHS) and was cosponsored by the Centers for Disease Control and Prevention, Food and Drug Administration Office of Women s Health, NIH Office of Research on Women s Health, National Institute of Diabetes and Digestive and Kidney Diseases Division of Nutrition Research Coordination, DHHS; National Center for Complementary Medicine, U.S. Department of Agriculture Agricultural Research Service; International Life Sciences Institute North America; March of Dimes; and Whitehall Robbins Healthcare. Conference proceedings were published in a supplement to The Journal of Nutrition. Guest editors for this workshop were Mary Frances Picciano, Office of Dietary Supplements, NIH, DHHS; Daniel J. Raiten, Office of Prevention Research and International Programs, National Institute of Child Health and Human Development, NIH, DHHS; and Paul M. Coates, Office of Dietary Supplements, NIH, DHHS. 2 To whom correspondence should be addressed. acl1@cdc.gov. Calcium plays an important role in human health as a vital part of bones and teeth. It is also involved in various physiological and biochemical processes that are critical for life, such as muscle contraction, nerve transmission, maintenance of blood vessel tone and activation of enzyme reactions and hormone secretions. The critical role of calcium has been recognized for many years, which is reflected by a long history of calcium intake recommendations dating to the early 1940s, when the first edition of the Recommended Dietary Allowances were published (1). Since that time, calcium intake recommendations and policies have been reviewed and occasionally adjusted. Thus, calcium can serve as a case study to examine the interaction of science, consumer practices and public policy regarding nutrient intakes. Dietary calcium intake has been related to several health conditions, including skeletal status, blood pressure and cancer (2). However, the data linking calcium and bone health are a major part of the scientific rationale for calcium-related policy, given the vast amount of data that has accumulated on this topic. For example, skeletal calcium content has been used as a primary indicator of calcium nutriture when setting recommended dietary intakes (3). Thus, only calcium s relationship with bone health will be used to illustrate the interaction among science, practices and policy in this paper. To illustrate how consumer practices, science and policy interact in regard to calcium, the following questions will be considered: What are calcium intakes in the population? What evidence is there to link calcium to bone health? What are some examples of federal efforts to address calcium needs in the population? In addition, selected examples of emerging issues in the calcium bone relationship will be reviewed because these could potentially lead to revisions in calciumrelated policy in the future. Current intakes Median dietary intakes of calcium from food and supplements among females in the U.S. population are illustrated in /03 $ American Society for Nutritional Sciences. 1987S

2 1988S SUPPLEMENT FIGURE 1 Median calcium intakes of females, Source: CDC/NCHS, Third National Health and Nutrition Examination Survey, (4). *Adequate intake recommendations from Food and Nutrition Board, Institute of Medicine, National Academy of Sciences, 1997 (3). Figure 1. These data are taken from the third National Health and Nutrition Examination Survey (NHANES III, ) (4). The figure illustrates calcium intakes from food alone and also when calcium from supplemental sources (vitamin-mineral supplements and calcium-containing antacids) are added to intakes from food. Methods used to obtain these estimates have been described in detail elsewhere (5 8). Figure 1 also shows the most recent adequate intake (AI) 3 recommendations for calcium from the Food and Nutrition Board (3). In general, younger female children had median intakes of calcium from food that approached or exceeded the AI value at the time of NHANES III, but after early childhood median intakes of calcium from food among females fell below the AI (Fig. 1). Among women 20 years of age, 30% reported consuming some amount of calcium from vitamin-mineral supplements and antacids in NHANES III. However, this figure includes many individuals who were consuming multivitamin mineral supplements with small amounts of calcium, so it is unlikely that they selected those products because they were specifically seeking calcium. Only 15% of women consumed at least 200 mg/d of calcium from these supplemental sources and only 6% consumed at least 500 mg/d of calcium. Thus, the percentage that consumed a significant amount of calcium from these supplemental sources at the time of NHANES III was rather small. In light of this, it is not surprising that addition of calcium from vitamin-mineral supplements and antacids to that from food did not result in major changes in calcium intakes among women in the population (Fig. 1). Median values were somewhat higher in older age groups after the supplemental calcium was added but were still noticeably under AI levels. Among younger females, median intakes did not change much when supplemental calcium intakes were included. So in terms of consumer practices, median intakes of calcium among females in the population fell below recommended levels at the time of NHANES III even when calcium from supplements was added to intakes from food. Data linking calcium to skeletal health A large body of research has examined the relationship between calcium and skeletal health, but the studies vary in 3 Abbreviations used: AI, adequate intake; RCT, randomized-controlled trials; UL, tolerable upper intake level. design. Data from randomized-controlled trials (RCT) provide the most compelling data for two reasons. First, this design is generally regarded as the gold standard for evaluating the efficacy of an intervention (9). Second, RCT offer an additional advantage to studies that focus on dietary intakes because the treatment group receives a known amount of the nutrient of interest in the form of a supplement. Thus, the nutrient intakes of the comparison groups are unlikely to overlap, and the amount by which they differ is usually known with greater accuracy in RCT than in observational studies (10). The greatest amount of RCT data linking calcium and skeletal health is available for postmenopausal and elderly women. Importantly, RCT data relate calcium to fracture in this age group. Studies with fracture endpoints offer the strongest evidence for the role of a risk factor in osteoporosis because fracture is the endpoint of clinical significance in this disease. Furthermore, using an endpoint other than fracture, such as bone density, may underestimate the effect of calcium. This has been observed when antiresorptive agents such as bisphosphonates, estrogen and calcitonin have been studied. These agents appear to reduce fracture risk more than would be predicted based on their effect on bone density (11). Because calcium acts as an antiresorptive agent, it is useful to assess its effect on fracture risk in light of this possibility. In a recent meta-analysis, Cumming and Nevitt (12) reviewed data from four RCT that assessed the relationship between calcium and fracture in older women. All four studies were double-blinded, placebo-controlled trials with adequate sample sizes and study duration. The latter condition is important in studies of bone-related interventions because of a phenomenon known as the bone remodeling transient: a transient increase in bone density caused by a temporary imbalance between bone resorption, which is reduced by antiresorptive agents, and bone formation (13). When results were combined using meta-analysis techniques, Cumming and Nevitt concluded that calcium significantly reduces fracture risk at various skeletal sites by 30%. Fewer RCT have been performed to examine calcium and bone health in premenopausal women. Welten et al. (14) recently performed a meta-analysis of four studies on calcium and bone health in this age group. These studies focused on bone mineral density rather than fracture because fragility fractures are not common in this age range. The meta-analysis results indicated that calcium does have a positive effect on bone mineral density in this group because the supplemented groups lost less bone per year. Unfortunately, only one of the four intervention studies in this meta-analysis used a doubleblinded, placebo-controlled design. In addition, these studies focused on older premenopausal women (e.g., ages y), which leaves a data gap for younger adult women. Several RCT have assessed the effect of calcium on skeletal health in children and adolescents. Data from eight RCT were included in the recent meta-analysis performed by Wosje and Specker (15). As for premenopausal women, these studies also focused on bone mineral density rather than fracture. All but one of these studies used a randomized, double-blinded, placebo-controlled design. They covered a fairly wide range of ages, pubertal stages and skeletal sites; two of the studies used food to augment calcium intake rather than supplements. Results of this meta-analysis indicated that calcium has a positive effect in this age group, as evidenced by an increase in the amount of bone gained ranging from as little as 0.1% to as much as 4%. In general then, RCT data support a positive relationship between calcium and bone health from childhood through old

3 CALCIUM AND BONE HEALTH 1989S age (16). However, some questions remain, particularly regarding the strength of the data in younger individuals (17), as noted above. In addition, it is not clear whether the effect of calcium on bone health persists if the higher intakes are not maintained indefinitely. Only a few studies have been published in full form on this question (18 22). All of these studies reexamined subjects who had participated in an RCT of calcium. Four of these studies focused on children or adolescents and the fifth focused on the elderly. All five studies had found positive effects of calcium at the end of the active intervention period. However, most participants did not continue taking calcium supplements after the active trial ended. Bone status was reexamined a few years (range y) after the increased calcium intake was discontinued. In four of the five studies, no significant differences were found between the treated and untreated groups at the end of the follow-up period. Thus, there is not much evidence that the advantage achieved in the supplemented group at the end of the trial was maintained once supplements were discontinued. The study that reported positive findings (20) is interesting for several reasons. First, more detailed analyses suggested that the permanent effect is primarily related to an effect on bone size rather than bone density, but because bigger bones may structurally be stronger bones, this may still result in a lower fracture risk in the future. Also of interest is the use of calcium-enriched foods (milk-extracted calcium phosphate incorporated into food) rather than a conventional calcium supplement in this study; the authors speculated that the form of calcium might account for their positive findings. Preliminary follow-up data from another RCT that used milk to supplement calcium intakes also suggest that the effects might persist when food is used rather than supplements (23). However, Merrilees et al. (21) did not find persistent effects in their trial with teenage girls and dairy products. Thus, more data are needed to clarify the discrepancies between studies on the persistence of the calcium effect. Although questions remain as to whether a nonsustained increase in calcium intake can result in permanent benefit to bone, it is clearer that sustained increases in calcium intake result in sustained benefits. For example, sustained increases in intakes have been associated with a sustained reduction of fracture risk or rate of bone loss beyond the time when the bone remodeling transient effect could account for these changes (24 28). Other complexities in the calcium bone relationship are also worthy of note. For example, the relationship temporarily may not hold during certain hormonal conditions, such as lactation. Several recent studies documented the occurrence of bone loss during lactation that cannot be prevented by calcium supplementation (29,30). Fortunately, this bone loss appears to be temporary, as bone is regained within a few months after weaning, again with little or no regard to calcium intake (29). Another complex aspect of the calcium bone relationship is its threshold nature; i.e., increasing calcium beyond a certain point may not provide further benefits to bone. Wosje and Specker (15) found that the effect of calcium appears to depend on the baseline intake; for example, the effect of increased calcium intakes was greatest in the children or adolescents with lower intakes at the outset of the study. Heaney and Matkovic (31) published calcium balance data that also support this hypothesis. Finally, it is important to note that chronic consumption of high levels of calcium may carry some risks, such as renal stones, hypercalcemia and renal insufficiency (milk-alkali syndrome), and possible interference with other minerals in the diet such as iron and zinc (3). These conditions are not likely to occur in most healthy individuals, but some vulnerable segments of the population may be at risk, such as those with renal failure, those using thiazide diuretics, and groups with low intakes of minerals that interact with calcium (3). Examples of policy and related efforts that reflect interactions between science and consumer practices The interaction between the evidence supporting the calcium bone relationship and data on calcium consumption in the population that were described above is reflected in various current federal policies and related efforts in regard to calcium. These include calcium intake recommendations, health claims for calcium that are permitted on food and supplement labels, inclusion of an objective related to calcium intake in Healthy People 2010 and several national educational campaigns aimed at increasing calcium intakes of the population. Although the examples discussed here focus on efforts undertaken or supported by the federal government, examples of this interaction also exist at the state and local government and private sector levels. The examples provided below are not intended to be exhaustive but rather to illustrate the scope and nature of these efforts. Dietary recommendations. Dietary recommendations for the U.S. population published by the Food and Nutrition Board of the National Academy of Sciences have included calcium since their inception in 1941 (1). Changes in these recommendations in response to the accumulating evidence linking calcium to bone health provide a particularly relevant example of the interaction among science, practices and policy. An examination of the calcium recommendations for females since 1974 shows a tendency for higher intakes being recommended in recent years, particularly for the adult age groups (Fig. 2). Other changes in the dietary recommendations for the U.S. population from the Food and Nutrition Board also provide relevant examples. For example, the recent findings on the lack of an effect of calcium on bone loss during lactation are reflected in the latest edition of the dietary recommendations, which no longer recommend a higher calcium intake during lactation for most women (3). Another relevant change in the latest recommendations from the Food and Nutrition Board is the inclusion of a tolerable upper intake level (UL) for calcium intakes of 2500 mg/d. This UL was set in light of the potential adverse effects of high calcium intakes (3) but it is also consistent with the threshold nature of the calcium bone FIGURE 2 Recommended calcium intakes for females. Source: Food and Nutrition Board, Institute of Medicine, National Academy of Sciences, (3,32 34).

4 1990S SUPPLEMENT relationship. It is useful to be aware of this UL because even though most females tend to have intakes that fall well below it, some population subgroups do approach it. For example, estimates of the upper percentiles of calcium intake from the 1994 USDA Continuing Survey of Food Intakes of Individuals indicated that 5% of young adolescent boys have intakes that approach the upper limit of 2500 mg/d and 2% exceeded that amount (3). (These data were adjusted for withinperson variability using the method of Nusser et al. (35).) It is important to be aware of high intakes in these adolescent males when considering the best approach for improving intakes in women. Health claims for calcium. Health claims linking calcium and osteoporosis that are now permitted on food and supplements labels provide another example that reflects the interaction among science, consumer practices and policy. In 1993 after an extensive review of the evidence linking calcium to osteoporosis, the FDA began to permit foods and supplements that contain at least 200 mg of calcium per serving to include a calcium osteoporosis health claim on the label (36). The FDA provided examples of the type of statements that could be included (Table 1), although other wording is also permissible. An additional statement is recommended for foods and supplements with higher amounts of calcium (e.g., 400 mg/ serving). This statement, which indicates that intakes above 2000 mg are not likely to be beneficial, is consistent with the threshold nature of calcium. Calcium objective in Healthy People A third example of calcium-related policy is the inclusion of an objective targeting improvements in calcium intake of the population in Healthy People 2010, the current prevention agenda for the nation (7). The purpose of Healthy People 2010 is to identify significant, preventable threats to health and to establish national goals to reduce them. As discussed previously, many groups in the U.S. population have average calcium intakes that fall below recommended levels. This problem was felt to be significant enough to warrant an objective, namely to increase the proportion of persons aged 2 y and older who meet dietary recommendations for calcium from the baseline value of 46% in to 75% by 2010 (Objective 19 11). National education campaigns. Several national education campaigns have also been developed to educate various TABLE 1 Model health claims used in food labeling to describe the relationship between calcium and osteoporosis Calcium source Most conventional foods with mg calcium/serving Foods exceptionally high in calcium and most calcium supplements ( 400 mg calcium/serving) Model health claim Regular exercise and a healthy diet with enough calcium helps teens and young adult white and Asian women maintain good bone health and may reduce their high risk of osteoporosis later in life. Regular exercise and a healthy diet with enough calcium helps teens and young adult white and Asian women maintain good bone health and may reduce their high risk of osteoporosis later in life. Adequate calcium intake is important, but intakes above about 2,000 mg are not likely to provide any additional benefit. Source: U.S. Food and Drug Administration website (36). vulnerable population subgroups about the importance of calcium. Recent efforts have focused on children and adolescents, which reflects the current hypothesis that the age during which peak bone mass is attained represents a unique opportunity to influence skeletal health (37). Three recent examples are the Milk Matters campaign, which was recently launched by National Institute for Child Health and Human Development of the National Institutes of Health and focuses on children and teenagers (38); the National Bone Health Campaign, which is a joint effort of the Centers for Disease Control and Prevention, the Office of Women s Health of the Department of Health and Human Services and the National Osteoporosis Foundation and currently focuses on girls ages 9 12 y (39); and the Calcium! Do You Get It? program developed by the Food and Drug Administration, which focuses on girls ages y (40). Emerging issues Data to refine our understanding of the calcium bone relationship continue to accumulate. These data are periodically reviewed and adjustments are made in policy when warranted. One recent example of a change in policy resulting from the accumulation of new data are the revision of recommendations for dietary calcium intake during lactation. Other emerging data on the calcium bone relationship are not yet sufficiently well defined to be considered in policy decisions, although they may affect efforts in the future. An example of emerging data is evidence suggesting that certain factors may interact with the calcium bone relationship (i.e., the relationship between calcium intake and bone health may depend on the influence of a third factor). One such potential interacting factor physical activity was suggested by a meta-analysis by Specker (41) of 17 randomized and nonrandomized intervention trials in peri- and postmenopausal women. Results indicated that the positive effect of calcium appears more likely in those who exercised than in those who did not. However, results were less consistent in children (42), and longitudinal data are needed to directly test this possibility (3). These data gaps led the most recent Food and Nutrition Board panel to conclude that there was insufficient evidence at that time to justify different calcium recommendations for people with different levels of physical activity (3). Another factor that may interact with the calcium bone relationship is an individual s genotype for the vitamin D receptor. Ferrari et al. (43) found that prepubertal girls with BB or Bb genotypes show an increase in bone mass when given calcium supplements whereas girls with the bb genotype do not. Other studies also found that response to calcium varies depending on vitamin D receptor genotype but they differ in regard to the specific genotype associated with this effect (44 46). Some researchers noted that these discrepant effects may be due to differences in the level of calcium intake being examined or the age of the individuals (43,44). Thus, additional data are needed on this point before its implications for calcium-related policies and efforts can be determined. Summary Data from national surveys indicate that calcium intakes among females are below recommended levels after childhood. This is a concern given the positive relationship between calcium and bone health. Some complexities in this relationship are worth noting; for example, intakes above a threshold level probably offer no benefit and high intakes may be harm-

5 CALCIUM AND BONE HEALTH 1991S ful to some vulnerable subgroups. It is also uncertain whether the effects of a temporary increase in calcium intake persist once intakes return to a lower level. Finally, in some circumstances such as lactation, calcium intake does not influence bone status. Interactions between science and consumer practices are evident in various federal efforts regarding calcium. Examples include dietary recommendations, health claims, inclusion of a calcium objective in Healthy People 2010, and national educational campaigns. These efforts are not static, however, as new data on the calcium bone health relationship are reviewed periodically. Some emerging issues that may affect these efforts in the future include a better understanding of the effect of physical activity and bone-related genotypes on the calcium bone relationship. However, more data are needed to clarify these effects before firm conclusions can be drawn. LITERATURE CITED 1. Mertz, W. (2000) Three decades of dietary recommendations. Nutr. Rev. 58: NIH Consensus Development Panel on Optimal Calcium Intake. (1994) Optimal calcium intake. JAMA 272: Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride. Washington, DC: National Academy Press, National Center for Health Statistics. (1994) Plan and Operation of the Third National Health and Nutrition Examination Survey, Vital Health Stat 1(32). DHHS Publ No. (PHS) NCHS, Hyattsville, MD. 5. Bialostosky, K., Wright, J., Kennedy-Stephens, J., McDowell, M. & Johnson, C. (2002) Dietary intake of macronutrients, micronutrients and other dietary constituents: United States Vital Health Stats 11(245). DHHS Publ No (PHS) , NCHS, Hyattsville, MD Ervin, R. B., Wright, J. D. & Kennedy-Stephenson, J. (1999) Use of dietary supplements in the United States, National Center for Health Statistics. Vital Health Stat. 11(244). 7. U. S. Department of Health and Human Services. Healthy People nd ed. Understanding and Improving Health and Objectives for Improving Health. 2 vols. Washington DC: U. S. Government Printing Office, November 2000 (Also available at Accessed May 1, 2002.) 8. Briefel, R. R., Bialostosky, K., Kennedy-Stephenson, J., McDowell, M. A., Ervin, R. B. & Wright, J. D. (2000) Zinc intake of the U. S. population: findings from the Third National Health and Nutrition Examination Survey, J. Nutr. 130:1367S 1373S. 9. Barton, S. (2000) Which clinical studies provide the best evidence? BMJ 321: Heaney, R. P. (1997) Nutrient effects: discrepancy between data from controlled trials and observational studies. Bone 21: Cummings, S. R., Karpf, D. B., Harris, F., Genant, H. K., Ensrud, K., LaCroix, A. Z. & Black, D. M. (2002) Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs. Am. J. Med. 112: Cumming, R. G. & Nevitt, M. C. (1997) Calcium for prevention of osteoporotic fractures in postmenopausal women. J. Bone Miner. Res. 12: Heaney, R. P. (2001) The bone remodeling transient: interpreting interventions involving bone-related nutrients. Nutrition Rev. 59: Welten, D. C., Kemper, H. C., Post, G. B.& van Staveren, W. A. (1995) A meta-analysis of the effect of calcium intake on bone mass in young and middle aged females and males. J. Nutr. 125: Wosje, K. S. & Specker, B. L. (2000) Role of calcium in bone health during childhood. Nutr. Rev.58: Heaney, R. P. (2000) Calcium, dairy products and osteoporosis. J. Am. Coll. Nutr. 19(2 Suppl):83S 99S. 17. Kanis, J. A. (1999) The use of calcium in the management of osteoporosis. Bone 24: Slemenda, C. W., Peacock, M., Hui, S., Zhou, L. & Johnston, C. C. (1997) Reduced rates of skeletal remodeling are associated with increased bone mineral density during the development of peak skeletal mass. J. Bone Miner. Res. 12: Lee, W.T.K., Leung, S.S.F., Leung, D.M.Y. & Cheng, J.C.Y. (1996) A follow-up study on the effects of calcium-supplement withdrawal and puberty on bone acquisition of children. Am. J. Clin. Nutr. 64: Bonjour, J. P., Chevalley, T., Ammann, P., Slosman, D. & Rizzoli, R. (2001) Gain in bone mineral mass in prepubertal girls 3.5 years after discontinuation of calcium supplementation: a follow-up study. Lancet 358: Merrilees, M. J., Smart, E. J., Gilchrist, N. L., Frampton, C., Turner, J. G., Hooke, E., March, P. L. & Maguire, P. (2000) Effects of dairy food supplements on bone mineral density in teenage girls. Eur. J. Nutr. 39: Dawson-Hughes, B., Harris, S. S., Krall, E. A. & Dallal, G. E. (2000) Effect of withdrawal of calcium and vitamin D supplements on bone mass in elderly men and women. Am. J. Clin. Nutr. 72: Barker, M. E., Lambert, H. L., Cadogan, J., Jones, N., Wallace, F. & Eastell, R. (1998) Milk supplementation and bone growth in adolescent girls: is the effect ephemeral? (Abstract). Bone 23 (Suppl):S Riggs, B. L., O Fallon, W. M., Muhs, J., O Connor, M. K., Kumar, R. & Melton, L. J. (1998) Long-term effects of calcium supplementation on serum parathyroid hormone level, bone turnover, and bone loss in elderly women. J Bone Miner Res 13: Recker, R., Hinders, S., Davies, K. M., Heaney, R. P., Stegman, M. R., Lappe, J. M.& Kimmel, D. B. (1996) Correcting calcium nutritional deficiency prevents spine fractures in elderly women. J. Bone Miner. Res. 11: Reid, I. R., Ames, R. W., Evans, M. C., Gamble, G. D. & Sharpe, S. J. (1995) Long-term effects of calcium supplementation on bone loss and fractures in postmenopausal women: a randomized controlled trial. Am. J. Med. 98: Chapuy, M. C., Arlot, M. E., Delmas, P. D. & Meunier, P. J. (1994) Effect of calcium and cholecalciferol treatment for three years on hip fractures in elderly women. BMJ 308: Elders, P.J.M., Lips, P., Netelenbos, J. C., Van Ginkel, F. C., Khoe, E., Van der Vijgh, W.J.F. & Van der Stelt, P. F. (1994) Long-term effect of calcium supplementation on bone loss in perimenopausal women. J. Bone Miner. Res. 9: Kwalkarf, H. J., Specker, B. L., Bianchi, D. C., Ranz, J. & Ho, M. (1997) The effect of calcium supplementation on bone density during lactation and after weaning. N. Engl. J. Med. 337: Prentice, A. (2000) Maternal calcium metabolism and bone mineral status. Am. J. Clin. Nutr. 71(suppl): 1312S 1316S. 31. Matkovic, V. & Heaney, R. P. (1992) Calcium balance during human growth: evidence for threshold behavior. Am. J. Clin. Nutr. 55: Institute of Medicine. (1974) Recommended Dietary Allowances, 8 th 33. Institute of Medicine. (1980) Recommended Dietary Allowances, 9 th 34. Institute of Medicine. (1989) Recommended Dietary Allowances, 10 th 35. Nusser, S.M., Carriquiry, A. L., Dodd, K. W. & Fuller, W. A. (1996) A semi-parametric transformation approach to estimating usual daily intake distributions. J. Am. Stat. Assoc. 91: Code of Federal Regulations Title 21, Volume 2. Sec Health claims: calcium and osteoporosis. 58 Federal Register 2676, Jan. 6, 1993; 58 Federal Register 17101, Apr. 1, 1993; 62 Federal Register 15342, Mar. 31, (Information available at lrd/cf html. Accessed March 15, 2002.) 37. Heaney, R. P., Abrams, S., Dawson-Hughes, B., Looker, A., Marcus, R., Matkovic, V. & Weaver, C. (2000) Peak bone mass. Osteoporos. Int. 11: National Institute of Child Health and Human Development, National Institutes for Health. (1997) Milk Matters Calcium Education Campaign, Bethesda MD. (Information available at Accessed May 1, 2002.) 39. Centers for Disease Control and Prevention, U. S. Department of Health and Human Services Office on Women s Health, and National Osteoporosis Foundation. (2001) Powerful Bones. Powerful Girls. The National Bone Health Campaign. (Information available at Accessed May 1, 2002.) 40. U. S. Food and Drug Administration, Center for Food Safety and Applied Nutrition. (1996) Calcium! Do you get it? (Information available at dms/ca-toc.html. Accessed May 1, 2002.) 41. Specker, B. L. (1996) Evidence for an interaction between calcium intake and physical activity on changes in bone mineral density. J. Bone Miner. Res. 11: Weaver, C. M. (2000) Calcium requirements of physically active people. Am. J. Clin. Nutr. 72(suppl): 579S 84S. 43. Ferrari, S. L., Rizzoli, R., Slosman, D. O. & Bonjour, J. P. (1998) Do dietary calcium and age explain the controversy surrounding the relationship between bone mineral density and vitamin D receptor gene polymorphisms? J. Bone Miner. Res. 13: Kiel, D. P., Myers, R. H., Cupples, L. A., Kong, X. F., Zhu, X. H., Ordovas, J., Schaefer, E. J., Felson, D. T., Rush, D., Wilson, P.W.F., Eisman, J. A., Holick, M. F. (1997) The BsmI vitamin D receptor restriction fragment length polymorphism (bb) influences the effect of calcium intake on bone mineral density. J. Bone Miner. Res. 12: Krall, E. A., Parry, P., Lichter, J. B. & Dawson-Hughes, B. (1995) Vitamin D receptor alleles and rates of bone loss: influences of years since menopause and calcium intake. J. Bone Miner. Res 10: Ferrari, S., Rizzoli, R., Chevalley, T., Slosman, D.,, Eisman J. A. & Bonjour, J. P. (1995) Vitamin D-receptor-gene polymorphisms and change in lumbarspine bone mineral density. Lancet 345: