A Closer look at calcium absorption and the benefits and risks of dietary versus supplemental calcium.

C L I N I C A L F E AT U R E S

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A Closer Look at Calcium Absorption and the Benefits and Risks of Dietary Versus Supplemental Calcium Anna Booth, MD 1 Pauline Camacho, MD, FACE 2

Resident Physician, Loyola University Medical Center, Maywood, IL; 2 Professor and Endocrinology Fellowship Program Director, Loyola University Medical Center, Maywood, IL 1

DOI: 10.3810/pgm.2013.11.2714

Abstract

Objective: To perform a thorough search of the literature on calcium research and specifically address the topic of calcium absorption. Methods: PubMed and Ovid were the main engines used for primary literature searches; textbooks, review articles, and book chapters are examples of the other sources used for supplemental information. Results: Regarding calcium absorption, it seems apparent that the absorption efficiency of all calcium salts, regardless of solubility, is fairly equivalent and not significantly less than the absorption efficiency of dietary calcium. However, dietary calcium has been shown to have greater impact in bone building than supplemental calcium. This is likely due to improved absorption with meals and the tendency of people to intake smaller amounts more frequently, which is more ideal for the body’s method of absorption. In addition, the cardiovascular risks of excessive calcium intake appear to be more closely related to calcium supplements than dietary calcium; this relationship continues to be controversial in the literature. Conclusions: We conclude that further studies are needed for direct comparison of supplemental and dietary calcium to fully establish if one is superior to the other with regard to improving bone density. We also propose further studies on the cardiovascular risk of long-term increased calcium intake and on physician estimates of patients’ daily calcium intake to better pinpoint those patients who require calcium supplementation. Keywords: calcium; absorption; bioavailability; cardiovascular risk

Introduction

Correspondence: Anna Booth, MD, Loyola University Medical Center, LUHS North Entrance, Room 7611A, 2160 S First Avenue, Maywood, IL 60153. Tel: 708-216-5838 Fax: 708-216-6890 E-mail: [email protected]

The benefits of adequate calcium in the diet have long been recognized, notably increased bone density and decreased fracture rate. Of particular interest has been the population of older women (aged . 50 years), given their higher risk for osteopenia and osteoporosis in the postmenopausal period. As important as it is to encourage older patients to meet the recommended daily allowance of calcium intake, we must be aware of multiple issues surrounding calcium, including absorption; bioavailability (how well the body uses it once absorbed); excretion; variation between sources, particularly supplemental compared with dietary calcium; and risks of excessive calcium intake. Our review addresses and summarizes all of these issues. We also discuss our conclusions on what data are needed in the field of calcium intake and supplementation and on what we believe the next steps should be to further tackle this important topic.

Calcium—General Information

Calcium is the most abundant mineral in the human body. The average adult store of calcium is approximately 1 to 2 kilograms, and 99% of this is in the skeleton and

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Anna Booth and Pauline Camacho

teeth.1 A small fraction of the body’s total calcium is in the form of ionized calcium in the blood. This form of calcium carries a positive charge and is essential to the function of many physiologic processes, including the electrical conduction of the heart.2 Ionized calcium is tightly regulated by parathyroid hormone (PTH), vitamin D (mainly calcitriol), calcitonin, and phosphate. Standard calcium concentration in the blood ranges from 8.5 to 10.5 mg/dL, most of it bound to a major protein, albumin. Calcium balance is tightly controlled: it enters the blood via gut absorption and bone breakdown; it is removed from the blood via secretion into the gastrointestinal (GI) system; excretion in the urine; small losses in sweat, skin, hair, and nails; and deposition into bone. Humans cannot, of course, make calcium and thus it must be obtained through the diet.

Calcium Absorption

Calcium was a surplus nutrient in early hominids, so the human body adapted mainly to prevent toxicity of the element; thus, gross calcium absorption efficiency is relatively low (in a single 300-mg dietary intake of calcium, only about 30% of the calcium is digested and absorbed). However, there is great variability among people in terms of calcium absorption efficiency. Studies have shown that individual variation can range from 15% to 58% in healthy women,3,4 and the reasons for this remain uncertain. Recommended daily calcium intakes range, depending on the population.5 Per the most recent Institute of Medicine (IOM) recommendations,6 released in 2010, adolescents require 1100 to 1300 mg/day; adults and elderly persons, 800 to 1200 mg/day (with a daily maximum recommendation of 2000 mg/day for nonpregnant individuals). Women aged 19 to 50 years should intake 1000 mg/day, and those aged $ 51 years need 1200 mg/day. Men aged 19 to 70 years should intake 1000 mg/day, and those aged $ 71 years need 1200 mg/day.6 A substantial majority of the total US population gets inadequate calcium via food intake, thus, the issue of supplementation often arises in clinical practice. Calcium is absorbed via two methods in the intestines. One method is active absorption, which occurs mainly in the proximal small intestine (duodenum and proximal jejunum).7 Active transport is regulated by dietary intake and bodily needs. The process is fairly complex and beyond the scope of our article, but it is important to note that active transport is saturable due to the requirement of calcium-binding proteins for the transport of calcium across the intestinal cells into the blood. This means that with the intake of a large amount of calcium at once, only a certain amount will be absorbed via active absorption. 74

The second method of calcium absorption by the body is passive. Passive absorption accounts for only about 5% of the daily absorption of calcium (at normal dietary levels of calcium).1 Passive absorption takes place throughout the entire intestine and is the predominate form of calcium absorption in more distal regions.8 It occurs not through cells but around them (via intercellular junctions) and involves mass movement of water and other major solutes, such as sodium and glucose. Importantly, passive absorption of calcium is nonsaturable, and it increases with increased dietary intake of calcium. In addition, other components of the diet that make calcium more soluble within the distal small intestine (such as milk proteins and lactose) help stimulate passive absorption of calcium. In fact, if calcium intake is . 4 g per day, passive intestinal absorption continues to deliver calcium into the blood and can cause excess urinary excretion of calcium, calcification in the kidneys, and progressive renal failure; when renal failure in this setting is accompanied by high intake of antacids for acid reflux, the condition is known as milk-alkali syndrome. The efficiency of calcium absorption, as mentioned, has been found to be highly variable between individuals. Factors that contribute to the variability have been rigorously studied, as discovering what allows some people to absorb calcium more efficiently could lead to a better understanding of how to help those who are less efficient absorbers. As it turns out, no single factor causes the majority of variability. An investigation by Barger-Lux et al9 found that calcium absorption among a group of 41 premenopausal females varied from 27% to 55%. Wolf et al4 found variability ranging from 17% to 58% in a group of 142 pre- and perimenopausal females. Both groups of investigators, as well as many others,4,9–11 looked at what measurable factors contributed to the variability in calcium absorption, and several factors are generally agreed on. Estrogen deficiency causes decreased calcium absorption, but administration of estrogen supplements can correct this. Postmenopausal females require a higher intake of calcium to maintain a positive calcium balance. The reason for this issue is not well described. Aloia et al10 proposed that estrogen deficiency may cause intestinal resistance to the active form of vitamin D, known as calcitriol, which allows the body to absorb calcium. Some studies have found an association between calcium absorption efficiency and levels of vitamin D.9 A detailed description of the relationship between calcium and vitamin D is not the goal of our article, but suffice to say that there is much evidence that adequate vitamin D levels are essential for calcium absorption.1



Benefits and Risks of Dietary Versus Supplemental Calcium

The time it takes for food to pass through the intestines has also been correlated with calcium absorption.4 Increased time in the intestinal lumen allows calcium to have greater contact with the absorptive intestinal surfaces and thus causes more efficient absorption. A study by Wolf et al4 noted a positive association of absorption with dietary fat intake (slower transit time) and a negative association with fiber intake (increased bulk of intestinal contents and decreased transit time). Additionally, calcium intake itself is, paradoxically, negatively associated with calcium absorption efficiency. Multiple studies have noted decreased absorption efficiency with higher loads of calcium, as well as decreased absorption efficiency over time in individuals with higher calcium in their regular diets.4,9–11 Although net calcium absorption increases with increased intake, the fractional absorption of calcium actually decreases. This is likely related to the body’s fine-tuned evolutionary protective mechanism against calcium toxicity. These factors can be somewhat modifiable by modern medicine (estrogen replacement therapy, vitamin D supplements, fiber), however, even more easily modifiable is the type of calcium patients are advised to use. The absorption efficiency of both dietary calcium and supplemental calcium has been fairly well studied, although few studies directly compare the two. Nickel et al12 found no significant difference among the calcium absorption efficiency of 5 different dairy products; mean absorption of all the products in the study was 31.2%, and the individual variation among the subjects was found to be larger than that among the products. Sheikh et al13 compared absorption efficiency between 5 different calcium salts of various solubilities compared with that of milk. Absorption fractions ranged from 27% to 33%; the differences were not statistically significant, and absorption was not related to solubility of the salt. One major proven difference affecting patient calcium absorption efficiency is that of calcium derived from animal products compared with calcium from plant products. A study by Heaney et al14 comparing calcium absorption from spinach with that from milk showed a clear and significantly higher absorption from milk, 27.6%, compared with 5.1% from spinach. The theory behind the absorption differences is that there is a high oxalate concentration in spinach, causing binding of the calcium and thus rendering it nonabsorbable. Many plant products contain oxalate (rhubarb, walnuts, sorrel) or other calcium-binding substances, such as phytates (bran, cereals, seeds), which make them fairly poor calcium sources.15

Calcium from dairy products, on the other hand, although not shown to be more efficiently absorbed than calcium from supplements, does provide other added benefits. The calcium in milk is mostly bound to peptides and proteins, which allows it to remain in solution even when the pH is unfavorable (such as in people with low gastric acid production), and therefore, this milk calcium is more easily absorbed upon reaching the small intestine. Milk calcium can be absorbed without vitamin D due to the presence of lactose, which ensures absorption via the passive absorption route. Milk also does not contain any of the products mentioned that can inhibit intestinal absorption of calcium (oxalates, phytates, etc). In addition, milk and other dairy products provide what is termed a meal effect in that they contribute many other nutrients important both for calcium use in the body (ie, phosphate for bone mineralization), as well as proteins and other vital nutrients. Notably, intake of dairy products has been found to suppress bone remodeling less than use of calcium supplements.11 The difference is likely due to slower gastric emptying, method of ingestion (small doses more frequently, as opposed to large doses given all at once as with supplements), and prolonged passive absorption of dietary calcium.7

Calcium Excretion

As previously stated, the body is adapted to deal with a surplus rather than an insufficiency of calcium in the diet. Multiple characteristics of calcium excretion display this trend towards purging excess calcium. First, approximately half the calcium absorbed by the body is spilled into the urine. This urine calcium is weakly regulated and more sensitive to the effects of other nutrients than to calcium levels; thus the calcium in urine is not modulated by other body calcium levels as is the calcium in bones and blood, allowing calcium to be excreted renally, even in calcium-deplete people. Second, dermal calcium loss through sweat, skin, hair, and nails is completely unregulated.5 Finally, GI secretions account for about 100 to 200 mg/day of calcium lost in the feces (affected by dietary factors).16 Urinary calcium loss averages 100 to 250 mg/day in adults but can vary widely depending on many factors, including intake of dietary calcium (a calcium-free diet can result in as little as 5 mg excreted in the urine in 24 hours), sodium excretion (low sodium in the diet causes a decrease in calcium excretion), urine creatinine, increased calcium in the diet,7 and, of course, patient medications, most often thiazides. Even caffeinated beverages were shown to mildly increase urinary calcium in a small population of healthy


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individuals.17 Healthy kidneys do preserve most of the calcium they receive, however; approximately 8 to 10 g of calcium are filtered daily by the kidneys—only 2% to 3% of the filtered calcium is passed in the urine. Heaney et al18 showed that estrogen-deprived women have higher urinary calcium loss than estrogen-replete females, indicating a link between estrogen status and ability to reabsorb calcium. This link is likely one more factor contributing to the trend towards osteoporosis in postmenopausal females.


Methods for Measuring Calcium Absorption

Before discussing how calcium absorption is measured, we will clarify some definitions. Absorbability refers to how well a substance is absorbed. Quality of absorbability depends on the source of calcium and how it is given, through food or via supplementation. Absorption depends on the absorptive capacity of the intestines, which varies among individuals and also varies, in the case of calcium, upon the body’s calcium reserves, hormonal regulation, and existent dietary calcium supply. Bioavailability is the quantity of the administered amount of a substance that enters patient blood circulation and is then available to exert its intended effect; for calcium, this means the amount that can be used for bone building.15 Bioavailability is the value of most interest to us in determining the usefulness of supplements compared with calciumcontaining foods. Many methods have been proposed and used to measure both the absorption and bioavailability of calcium in persons, and countless studies have been undertaken on this topic.19–21 The most common methods are briefly described.

Balance Method

The balance method was the previous gold standard in the field of calcium absorption measurability, used as early as the beginning of the 20th century to measure calcium absorption.15,22 It is the only method that gives true and absolute data on an individual’s calcium absorbability and bioavailability. The method measures the intestinal balance of calcium loads—the difference between intake at mouth and output in feces. To achieve a net retention value, urinary excretion must also be subtracted. Isotopes can be used in this method to label the calcium. An isotope is injected at the start of the evaluation, which allows measurement of loss of fecal calcium. This method, however, is slow, labor intensive, and time consuming. It is also fairly unreliable in humans as it is affected by intestinal bacteria, can measure only absorption of calcium in a 76

discrete time period, and it cannot be used to compare 2 different sources of calcium.7

Urinary Excretion

The urinary excretion method uses the principle that humans excrete fairly large amounts of calcium in their urine compared with other animals and that human urinary calcium increases as calcium intake increases. Although this principle could theoretically be used to measure efficiency of calcium absorption, urinary calcium is also affected by many other dietary factors, as discussed under the section, Calcium Excretion. Although the method is simple and fast, it is considered fairly imprecise. The urinary excretion method can be used to compare 2 sources of calcium in a very controlled setting but otherwise is not particularly useful for determining bioavailability of calcium.

Isotope Tracer Method

The isotope tracer method is essentially the new gold standard in the field of measuring calcium absorption. It was validated against the balance method in a study by Heaney and Recker21 and is now used frequently in most clinical studies involving calcium. The initial form of this test is known as the doubleisotope method and the process involves having the patient ingest a test meal labeled with 1 calcium isotope; a second, different calcium isotope is then injected into the blood and the behavior of the second isotope reflects 100% absorption. Isotope concentrations are measured 2 to 4 hours later in the blood and 24 to 36 hours later in the urine. The ratio of the 2 isotopes (oral tracer/intravenous tracer) is the fractional absorption (between 0–1) of the test calcium substance (ingested calcium). The isotope tracer method is highly sensitive and easily reproducible. It is also relatively inexpensive and fairly fast in comparison to the balance method (which can take days). The method also allows for several sources of calcium to be rapidly compared. The isotope tracer method is considered a good measure for the inherent absorbability of the calcium from a particular source. Of note, a simpler version of the isotope tracer method, using only a single oral tracer, has been validated in studies as accurately reflective of calcium absorption.19

Target System Effects

The target system effects method refers to the effect of calcium supplementation or dietary changes in calcium intake on eventual body processes, including bone building and fracture rate via measurements of bone density and propensity to fractures as measured in test populations (those with high




calcium intake vs low calcium intake) over a long period of time. This method is, in fact, the most reliable way to measure the long-term effects of different sources of calcium as it targets exactly the issues we are attempting to address with use of calcium supplementation. The method, however, must take into account many variables that may occur in test patients, such as changes in diet over time, changes in activity, chronic illnesses, use of medications, etc. However, all humans, participating in a clinical study or not, encounter variables in their lifetime that affect their calcium status in some way. Evaluating the effects of interventions on patients is truly the best way to determine how we are affecting their future health. The target systems effects method is the best way to measure the long-term bioavailability of ingested calcium.

Other

Several other, less validated methods exist for evaluating calcium absorption and are sometimes used concurrently with one of the described methods. Certain hormone levels in the blood can both affect and be affected by calcium intake, including vitamin D, parathyroid hormone (PTH), and bone-specific markers. In addition, in vitro methods for evaluating calcium absorption have been tested but do not tend to be very accurate due to the difficulty in mimicking the intestinal lumen.

Calcium Benefits for Bone

It has been well proven in many studies that adequate calcium intake is good for bone strength. From adolescents,23 to older men,24 to postmenopausal women11,25 adding calcium to the diet, either in supplement form or by increased dairy products, has proven to increase bone mineral density and decrease fracture events. Many studies23–26 have noted the benefits of dairy products over supplementation as a calcium source. Cheng et al23 found that intake of added cheese into the diet as calcium supplementation in adolescent girls resulted in increased bone thickness compared with use of calcium supplements, calcium plus vitamin D, and placebo. Weaver et al26 compared dry milk solids with calcium carbonate as calcium sources for young rats and discovered increased weight and density, higher breaking force, increased calcium content, and increased thickness in the bones of the rats fed dry milk solids. In addition, the rats fed the dry milk solids had improved bone measurements, even after a period of inadequate dietary calcium intake. Though the best-known function for calcium in bones involves its role in structural integrity, it also plays an

important role as a regulator of skeletal remodeling.27 Bone remodeling serves 2 vital purposes: (1) it repairs fatigue damage and reshapes bones to accommodate growth and injury; and (2) it is the source of calcium ions for the blood. Calcium helps regulate bone remodeling through its effect on PTH. A deficit in calcium stimulates PTH secretion, which in turn stimulates bone breakdown, and thus, bone remodeling. It has been estimated that the optimal remodeling rate to sufficiently repair fatigue damage in the average human skeleton is approximately 2% per year. However, remodeling rates in premenopausal women have been found to be closer to 6% to 7% per year and likely double after menopause. Elevated remodeling rates have been shown to increase bone fragility and fracture risk.27–28 Chapuy et al28 found that fracture risk decreases immediately after beginning calcium therapy in patients with bone deficiency, indicating the likelihood that adequate calcium decreases the remodeling rates much more quickly than it increases bone mass, and decreased remodeling, in turn, decreases bone fragility and fracture risk. A study by Recker and Heaney11 examining the effects of milk supplementation in a group of postmenopausal women during a 2-year period of follow-up, measured bone breakdown and concluded that both milk and calcium carbonate supplementation suppress bone breakdown (milk slightly more so).

Calcium Supplementation

We have discussed not only the importance of calcium to the human body but also the inadequacy of this vital nutrient in our modern diets. Lack of calcium in patients has been addressed clinically by way of calcium supplements that are available in a variety of forms, namely calcium salts, which range in solubilities. Several trials29–31 have compared the absorbability of calcium salts via various means, including urine calcium excretion,29 fecal recovery,30 and long-term measurement of changes in bone mineral density.31 As mentioned, the solubility of these salts has not been shown to affect bioavailability.13 The 2 most often prescribed calcium supplements are calcium carbonate and calcium citrate. Calcium carbonate is inexpensive, readily available (eg, Tums), and contains antacid properties. In addition, calcium carbonate contains a high percentage of calcium. However, it must be taken with food and is poorly absorbed in people who are also taking proton pump inhibitors or histamine-2 blockers. Calcium citrate, though more expensive, tends to be better absorbed. It should be taken on an empty stomach and is the supplement of choice in patients with low gastric acid production (achlohydria). Calcium citrate tends to be the supplement used by


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osteoporosis specialists. Other available natural forms of calcium include oyster shell and bone meal (these are derivatives of calcium carbonate). These derivatives can contain some lead (though this is not thought to be absorbable given that calcium can block lead absorption). In general, these natural forms of calcium are not prescribed by physicians.32 We have also hinted at the perplexing question of whether calcium is better absorbed via a supplement or food. Preliminary studies have shown moderately improved bioavailability when calcium is obtained from a food source. This may be due to the favorable effects of concurrent digestion of a meal on calcium absorption, to additional substances in food that may help aid absorption (lactose, etc), and to the saturation of active intestinal transport of calcium observed when calcium is taken in large doses given all at once (as in supplementation). However, few studies have been performed directly comparing bioavailability of a calcium supplement to calcium found in the diet. In a fascinating meta-analysis, Rafferty et al33 proposed that the best way to increase calcium in the general population might be to begin more seriously fortifying foods with calcium (a range of foods has already been introduced with calcium fortification, mainly snacks and beverages, but with the wide range of options in fortification levels in various food sources, it is difficult to guide both manufacturers and consumers on the best products to make and buy). Several examples of successful fortification campaigns include niacin fortification of white flour, folate fortification of cereals and grains (both now federally mandatory), and the iodination of salt (not mandatory but has virtually eradicated goiter in the United States). Results from the meta-analysis by Rafferty et al found that most calcium salts have similar bioavailability and that the absorption fractions of these salts usually fall within approximately 10% of the absorption fraction of milk calcium. However, the bioavailability of various salts (as well as the calcium in dairy products) can vary widely depending on the specific product that is being fortified and how it is consumed; this is one of the main barriers to fortification noted by the researchers, given that each product created by fortification must be tested individually for bioavailability. Other barriers include concern about over-supplementation of calcium and the issue of individual vitamin D status, which ties so closely into the ability to absorb calcium. In summary, the best way to provide calcium supplements to populations at need remains somewhat in question. Compliance and cost are always issues when prescribing pills, especially to the elderly,34 but supplementation may be unavoidable given the generally poor diets in this population. 78

Fortified foods may be a good option in the future but have yet to be perfected or standardized. Finally, recommending an increase in dietary calcium may be preferable for a certain subgroup of compliant patients, but it is difficult and time-consuming using existing methods for physicians to accurately estimate a patient’s baseline daily dietary calcium intake.35 This issue, too, needs to be further evaluated, given the importance of knowing a patient’s calcium intake before prescribing them more.

Risks of Excessive Calcium

With more and more patients on calcium supplementation, the concern surrounding excessive calcium has become increasingly prominent in the last decade or so. Two recent major bodies of publication have touched on the current pertinent issue of excessive calcium (as well as vitamin D). The IOM (recent daily intake recommendations mentioned earlier) states clearly in their revised 2011 report that although calcium and vitamin D play a key role in bone health, there is no substantial current evidence to support any other health benefits. In addition, higher levels than recommended have not been shown to provide greater benefits in patients and have, in fact, been linked to other health problems.6 Even more recently, the US Preventative Services Task Force (USPSTF) released a review regarding the effects of vitamin D and calcium supplementation in community-dwelling adults. The Task Force concluded that current evidence is insufficient to recommend for or against combined calcium and vitamin D supplementation for primary fracture prevention in premenopausal women and men. Perhaps most pertinent among their conclusions was the recommendation against daily supplementation with # 1000 mg/day of calcium for the primary prevention of fractures in postmenopausal females, given a lack of demonstrated benefit in fracture reduction as well as associated harms (D recommendation). The USPSTF also indicated the need for further research in this area, including studies on potential benefits of greater than recommended intake of calcium and vitamin D in postmenopausal women and older men as well as the effects of calcium and vitamin D supplementation in early adulthood on subsequent fracture risk later in life.36 We touch on 2 major issues of importance regarding calcium excess. First, kidney stones have long been believed to be closely linked to overconsumption of calcium. However, recent research has indicated that high dietary calcium has in fact led to a decrease in calcium oxalate kidney stones. The increased calcium availability helps to bind oxalate, which reduces the oxalate absorption and allows it to be excreted




both via the gastrointestinal system as well as through the urine.37 Curhan et al37 used a large research population of women studied over many years to look at the incidence of kidney stones as it related to both dietary and supplemental calcium intake. They found that intake of dietary calcium was negatively associated with a risk for kidney stones, but supplemental calcium was positively associated with a risk for kidney stones; the hypothesis for this was that supplemental calcium, as it is taken more in bolus form than dietary calcium (meaning it is given in a large dose all at once), causes an increase in urinary calcium and thus has more propensity to cause stones. In addition, if supplemental calcium is not consumed together with oxalate (eg, taken with a meal), it does not provide protection against oxalate absorption. Additionally, the USPSTF review found a statistically increased incidence of kidney stones in women taking combined supplemental vitamin D and calcium in the Women’s Health Initiative study.36 Second, the issue of excessive calcium causing cardiovascular (CV) problems has been fairly pervasive in recent literature. Though the Women’s Health Initiative reported that calcium and vitamin D had no effect on stroke or heart attack risk,38 it is noted that the study population was younger and had a higher percentage of patients on hormone therapy than women in the general population, and both factors may skew the data. Wang et al’s2 extensive review of data on calcium and its effects on CV health did not strongly suggest a statistically significant effect of dietary calcium intake on risk of coronary artery disease or stroke. The review also noted that the studies are fairly mixed on whether calcium is good or bad for CV health. Bolland et al39 studied 1500 postmenopausal females for 5 years, 1 group on a daily calcium supplement (1 g of calcium citrate) and 1 group on placebo. They found that the incidence of heart attack was greater in the calcium-treated group. Li et al40 published a study in Heart in 2012 using data from a larger study regarding incidence of heart attack risk in patients and found an increased risk in patients on a calcium supplement. Proposed mechanisms for this phenomenon hypothesized by these researchers included calcification of the blood vessels; influence on calcium-sensing receptors on smooth muscle, which may cause higher blood pressure; and, interestingly, an association of higher risk with higher blood levels of calcium, an issue that occurs to a much greater degree with calcium supplementation than with dietary calcium and indicates an acute response that may be a contributor to CV risk (of uncertain etiology). Li et al’s

study also found an inverse risk of heart attack in patients who consumed more calcium in their diets. Finally, Bolland et al38 headed another study, a large analysis of 15 studies that included adults receiving calcium supplements for $ 1 year. They found a significant risk of heart attack in the patients receiving calcium without coadministration of vitamin D. They also found an increased risk of heart attack in patients consuming . 850 mg of dietary calcium daily. They, too, proposed that increased calcium intake may increase calcification of the blood vessels. Bolland et al also hypothesized that an increase in blood calcium levels may increase blood thickness or alter blood flow in some way that has not yet been fully discovered.38 What does this all mean for calcium supplementation? It is hard to say at this point as the data remain so mixed. Further research in large populations of patients over a significant time period is needed to obtain concrete information on this issue.

Discussion

We have reviewed basic information about calcium and its role in the body. We have discussed the issues surrounding calcium balance including absorption and excretion and the best methods for measuring these; we have talked about the benefits and risks of calcium intake. Overall, it seems safe to conclude several points: (1) optimal levels of calcium in the body are vital for many aspects of one’s health, most notably bone health and fracture prevention; (2) based on a multitude of studies, it appears as though the bioavailability of most marketable calcium supplements as well as the calcium in dairy products is essentially, for all intents and purposes, equivalent; and (3) though the evidence is mixed, there are data indicating that too much calcium is harmful to one’s health, particularly CV health. Thus, several questions still remain and several new ones have arisen. Given our knowledge that individual variation in calcium absorption appears to be the largest source of variation in studies, it would seem appropriate to suggest testing each individual for his or her unique calcium absorption value and supplementing as appropriate from those results. However, this is neither practical nor feasible until we have an easier and cheaper way to undertake such testing. Therefore, we can only conclude that for now, we must set aside the issue of interindividual variation in calcium absorption and treat as indicated by other clinical criteria and clinical judgment, taking into account several additional issues. The obvious and age-old question that continues to plague clinicians is whether or not to supplement those


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patients who fall into the category of at-risk of calcium deficiency (namely, postmenopausal females), and if so, how much to supplement them. We know that supplements work, but only if patients are compliant. Supplements work more so if patients have a diet low in calcium but only if they are taken with meals (or perhaps only without, as is the case with calcium citrate), and supplements work better if they are taken in smaller doses throughout the day. The list of only ifs goes on and on, proving the point that prescribing supplements is not as simple an issue as we once may have thought. In addition, we cannot ignore some of the gathering evidence on the possibility of increased patient risk of heart attack and stroke with excess calcium. Finally, some evidence does point to improved benefits of calcium when it comes from meals rather than from pills. In essence, what is needed is a study truly dedicated to supplemental versus dietary calcium (large-scale, randomized, long-term, and in the population of patients most at-risk for calcium deficiency). The primary endpoints should be 2-fold: (1) the effects on bone health, reduction in fractures, etc; and (2) the incidence of CV events. Patient compliance and dietary intake of calcium should be carefully recorded. The topic of dietary calcium intake is, in our belief, somewhat overlooked. Many physicians and patients have come to expect that taking medication in pill form is the easiest and best way to treat a condition, thus it would seem fairly straightforward to simply prescribe a calcium pill for persons who are calcium deficient. However, as discussed, it is not quite that simple. Although supplemental calcium has essentially equivalent bioavailability to dietary calcium, taking supplements requires patient compliance at least once or twice daily. In addition, supplementation does not include the additional beneficial nutrients found in dairy products. Finally, supplements are taken in bolus form rather than in smaller and more frequent amounts, as is dietary calcium; this method of calcium boluses has been more strongly associated with greater CV risk. Additionally, preliminary studies show that physicians are fairly poor at quickly and accurately estimating via simple questioning during routine clinic visits whether a patient’s daily calcium intake is adequate.35 This is a vital and necessary step towards deciding whether or not one is, indeed, calcium deficient at all. Thus, an additional essential need is to create a fast, accurate, and easily understood dietary calcium questionnaire that can be administered in the clinic. The decision to treat or not to treat is one that clinicians must make every day; it is, in fact, at the very core of the job. It is important to realize that it is quite impossible to create 80

a generalizable form of medicine. In the area of calcium supplementation, as with so many other issues, each patient is different and must be treated as such. Some patients will prefer to be prescribed a pill rather than change their diets, but many patients will be willing and able to alter their diets to add more calcium rather than trying to remember to take a pill each day. Some patients may have difficulty affording or swallowing a pill. Other patients may not have access to readily available and healthy dairy products. We conclude that calcium supplementation is a complicated and multifaceted issue, and the decision to supplement or not must be carefully considered in each individual patient.

Conflict of Interest Statement

Anna Booth, MD, and Pauline Camacho, MD, FACE, disclose no conflicts of interest.

References

1. Bringhurst FR, Demay MB, Krane SM, Kronenberg HM. Bone and mineral metabolism in health and disease. In: Longo DL, Fauci A, Kasper DL, Hauser S, Jameson J, Loscalzo J, eds. Harrison’s Online, Harrison’s Principles of Internal Medicine. 18th ed. McGraw Hill; Ch 32. http:// www.accessmedicine.com.archer.luhs.org/content.aspx?aID=9142758. Accessed November 2012. 2. Wang L, Manson JE, Sesso HD. Calcium intake and risk of cardiovascular disease: a review of prospective studies and randomized clinical trials. Am J Cardiovasc Drugs. 2012;12(2):105–116. 3. Heaney RP. Absorbing calcium. Clin Chem. 1999;45(2):161–162. 4. Wolf RL, Cauley JA, Baker CE, Ferrell RE, Charron M, Caggiula AW, et al. Factors associated with calcium absorption efficiency in pre- and perimenopausal women. Am J Clin Nutr. 2000;72(2):466–471. 5. Heaney RP. The importance of calcium intake for lifelong skeletal health. Calcif Tissue Int. 2002;70(2):70–73. 6. Institute of Medicine. Dietary reference intakes for calcium and vitamin D. In: Report Brief from National Academy of Sciences. http://www.iom. edu/Reports/2010/Dietary-Reference-Intakes-for-calcium-and-vitaminD.aspx. 2010; revised 2011; updated 2013. Accessed June 2013. 7. Guéguen L, Pointillart A. The bioavailability of dietary calcium. J Am Coll Nutr. 2000;19(suppl 2):119S–136S. 8. Christakos S, Dhawan P, Porta A, Mady LJ, Seth T. Vitamin D and intestinal calcium absorption. Mol Cell Endocrinol. 2011;347(1-2):25–29. 9. Barger-Lux MJ, Heaney RP, Lanspa SJ, Healy JC, DeLuca HF. An investigation of sources of variation in calcium absorption efficiency. J Clin Endocrinol Metab. 1995;80(2):406–411. 10. Aloia JF, Chen DG, Yeh JK, Chen H. Serum vitamin D metabolites and intestinal calcium absorption efficiency in women. Am J Clin Nutr. 2010;92(4):835–840. 11. Recker RR, Heaney RP. The effect of milk supplements on calcium metabolism, bone metabolism and calcium balance. Am J Clin Nutr. 1985;41(2):254–263. 12. Nickel KP, Martin BR, Smith DL, Smith JB, Miller GD, Weaver CM. Calcium bioavailability from bovine milk and dairy products in premenopausal women using intrinsic and extrinsic labeling techniques. J Nutr. 1996;126(5):1406–1411. 13. Sheikh MS, Santa Ana CA, Nicar MJ, Schiller LR, Fordtran JS. Gastrointestinal absorption of calcium from milk and calcium salts. N Engl J Med. 1987;317(9):532–536.



Benefits and Risks of Dietary Versus Supplemental Calcium 14. Heaney RP, Weaver CM, Recker RR. Calcium absorbability from spinach. Am J Clin Nutr. 1988;47(4):707–709. 15. Heaney RP. Factors influencing the measurement of bioavailability, taking calcium as a model. J Nutr. 2001;131(suppl 4):1344S–1348S. 16. Davies KM, Rafferty K, Heaney RP. Determinants of endogenous calcium entry into the gut. Am J Clin Nutr. 2004;80(4):919–923. 17. Heaney RP, Rafferty K. Carbonated beverages and urinary calcium excretion. Am J Clin Nutr. 2001;74(3):343–347. 18. Heaney RP, Recker RR, Ryan RA. Urinary calcium in perimenopausal women: normative values. Osteoporos Int. 1999;9(1):13–18. 19. Lee WH, McCabe GP, Martin BR, Weaver CM. Simple isotopic method using oral stable or radioactive tracers for estimating fractional calcium absorption in adult women. Osteoporos Int. 2010;22(6):1829–1834. 20. Uenishi K, Fujita T, Ishida H, Fujii Y, Ohue M, Kaji H, et al. Fractional absorption of active absorbable algal calcium (AAACa) and calcium carbonate measured by a dual stable-isotope method. Nutrients. 2010;2(7):752–761. 21. Heaney RP, Recker RR. Estimation of true calcium absorption. Ann Intern Med. 1985;103(4):516–521. 22. Nordin BE. Calcium absorption revisited. Am J Clin Nutr. 2010;92(4):673–674. 23. Cheng S, Lyytikäinen A, Kröger H, Lamberg-Allardt C, Alén M, Koistinen A, et al. Effects of calcium, dairy product, and vitamin D supplementation on bone mass accrual and body composition in 10-12-y-old girls: a 2-y randomized trial. Am J Clin Nutr. 2005;82(5):1115–1126. 24. Daly RM, Brown M, Bass S, Kukulian S, Nowson C. Calcium- and vitamin D3-fortified milk reduces bone loss at clinically relevant skeletal sites in older men: a 2-year randomized controlled trial. J Bone Miner Res. 2006;21(3):397–405. 25. Dawson-Hughes B, Dallal GE, Krall EA, Sadowski L, Sahyoun N, Tannenbaum S. A controlled trial of the effect of calcium supplementation on bone density in postmenopausal women. N Engl J Med. 1990;323(13):878–883. 26. Weaver CM, Janle E, Martin B, Browne S, Guiden H, Lachcik P, et al. Dairy versus calcium carbonate in promoting peak bone mass and bone maintenance during subsequent calcium deficiency. J Bone Miner Res. 2009;24(8):1411–1419. 27. Heaney RP, Weaver CM. Newer perspectives on calcium nutrition and bone quality. J Am Coll Nutr. 2005;24(suppl 6):574S–581S. 28. Chapuy MC, Arlot ME, Duboeuf F, Brun J, Crouzet B, Arnaud S, et al. Vitamin D3 and calcium to prevent hip fractures in the elderly women. N Engl J Med. 1992;327(23):1637–1642.

29. Heaney RP, Dowell MS, Bierman J, Hale CA, Bendich A. Absorbability and cost effectiveness in calcium supplementation. J Am Coll Nutr. 2001;20(3):239–246. 30. Martin BR, Weaver CM, Heaney RP, Packard PT, Smith DL. Calcium absorption from three salts and CaSO(4)-fortified bread in premenopausal women. J Agric Food Chem. 2002;50(13):3874–3876. 31. Heaney RP, Recker RR, Watson P, Lappe JM. Phosphate and carbonate salts of calcium support robust bone building in osteoporosis. Am J Clin Nutr. 2010;92(1):101–105. 32. Bikle D. Agents that affect bone mineral homeostasis. In: Katzung B, Masters S, Trevor A, eds. Basic and Clinical Pharmacology. 12th ed. New York, NY: McGraw Hill; Ch 42. http://www.accessmedicine.com. archer.luhs.org/content.aspx?aID=55828986. Accessed November 2012. 33. Rafferty K, Walters G, Heaney RP. Calcium fortificants: overview and strategies for improving calcium nutriture of the U.S. population. J Food Sci. 2007;72(9):R152–R158. 34. Prince RL, Devine A, Dhaliwal SS, Dick MM. Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women. Arch Intern Med. 2006;166(8):869–875. 35. Snyder SM, Tyler CV Jr, Panaite V, Smolak MJ, Powell BL, Young CW, et al. Physicians underestimate calcium intake in women. Fam Med. 2010;42(6):428–432. 36. Moyer VA; U.S. Preventive Services Task Force. Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventative Services Task Force recommendation statement. Ann Intern Med. 2013;158(9):691–696. 37. Curhan GC, Willett WC, Speizer FE, Spiegelman D, Stampfer MJ. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Ann Intern Med. 1997;126(7):497–504. 38. Bolland MJ, Avenell A, Baron JA, Grey A, MacLennan GS, Gamble GD, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010;341:c3691. 39. Bolland MJ, Barber PA, Doughty RN, Mason B, Horne A, Ames R, et al. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ. 2008;336(7638):262–266. 40. Li K, Kaaks R, Linseisen J, Rohrmann S. Associations of dietary calcium intake and calcium supplementation with myocardial infarction and stroke risk and overall cardiovascular mortality in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition study (EPIC-Heidelberg). Heart. 2012;98(12):920–925.


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The risks and benefits of calcium supplementation.

Dietary and supplemental calcium intake and mortality.

Dietary and supplemental calcium intake and mortality.

Dietary and supplemental calcium intake and mortality.

Effects of supplemental dietary calcium on the intestinal association of calcium, phosphate, and bile acids.

Dietary and supplemental calcium intake and mortality--reply.

Calcium absorption and calcium bioavailability.

Effect of dietary calcium and phosphorus on intestinal calcium absorption and vitamin D metabolism.

A closer look at 'Cheap White' cigarettes.

Effect of dietary calcium and lead status on intestinal calcium absorption.

A closer look at papillary thyroid carcinoma.

A closer look at chromosomal inversions.

Taking a closer look at needle sticks.

Taking a closer look at pediculosis capitis.

Taking a closer look at IBD.

Transcriptional regulation. A closer look at E2F.

A closer look at depictions of Cosmas and Damian.

Intestinal calcium absorption: calcium entry.

A closer look at the Iranian model of kidney transplantation.

Embryoscopy: a closer look at first-trimester diagnosis and treatment.

A close look at the contraction and relaxation of the myometrium; the role of calcium.

Vasectomy: benefits versus risks.

Effect of dietary lactose on the absorption of protein, fat and calcium in the postweaning rat.

Calcium metabolism in postmenopausal osteoporosis: the influence of dietary calcium and net absorbed calcium.